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Sloan Kettering Cancer Center | Date: 2015-04-27

The present disclosure describes a compositions and methods for treatment of Hras-driven cancers. Administration of a farnesyltransferase inhibitor, for example, tipifarnib, alone or in combination with a MEK inhibitor can reduce tumor size and tumor growth in cancers such as poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC).

In certain embodiments the present invention involves methods of killing tumor cells that comprise an oncogenic PDGFR mutation, and methods of treating subjects having tumors that comprise such tumor cells. In some embodiments such methods involve using PI3K inhibitors, or a combination of a PI3K inhibitor and an mTOR inhibitor, or a dual PI3K/mTOR inhibitor. The present invention also provides methods for determining whether a subject is a candidate for treatment, methods for evaluating the efficacy of treatment, and other methods, compositions, model systems, and assays.

Sloan Kettering Cancer Center | Date: 2015-05-19

The present invention relates to methods and compositions for reducing the risk and severity of C. difficile infection. It is based, at least in part, on the discovery that a restricted fraction of the gut microbiota, including the bacterium Clostridium scindens, contributes substantially to resistance against C. difficile infection. Without being bound by any particular theory, it is believed that this is achieved through the biosynthesis of secondary bile acids.

Sloan Kettering Cancer Center | Date: 2016-02-19

The inventive subject matter relates to methods for treating a T-cell deficiency in a subject in need thereof, comprising administering to said subject a T-cell precursor isolated from an allogeneic donor, provided that said allogeneic donor is not MHC-matched to said subject. The inventive methods can be further enhanced by genetic engineering for targeted immunotherapy.

Sloan Kettering Cancer Center and The United States As Represented By The Secretary | Date: 2016-12-02

The presently disclosed subject matter provides for methods and compositions for enhancing the immune response toward cancers and pathogens. It relates to chimeric antigen receptors (CARs) that specifically target human mesothelin, and immunoresponsive cells comprising such CARs. The presently disclosed mesothelin-targeted CARs have enhanced immune-activating properties, including anti-tumor activity.

Sloan Kettering Cancer Center and Eureka Therapeutics | Date: 2016-11-30

The present invention provides antigen binding proteins that specifically bind to Wilms tumor protein (WT1), including humanized, chimeric and fully human antibodies against WT1, antibody fragments, chimeric antigen receptors (CARs), fusion proteins, and conjugates thereof. The antigen binding proteins and antibodies bind to HLA-A0201-restricted WT1 peptide. Such antibodies, fragments, fusion proteins and conjugates thereof are useful for the treatment of WT1 associated cancers, including for example, breast cancer, ovarian cancer, prostate cancer, chronic myelocytic leukemia, multiple myeloma, acute lymphoblastic leukemia (ALL), acute myeloid/myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). In more particular embodiments, the anti-WT1/A antibodies may comprise one or more framework region amino acid substitutions designed to improve protein stability, antibody binding and/or expression levels.

Sloan Kettering Cancer Center | Date: 2014-12-23

The present invention provides methods for radiolabeling compounds useful as Hsp90 inhibitors. The present invention also provides intermediates useful in such methods, and compositions of radiolabeled compounds. The present invention provides, among other things, novel methods for the synthesis of radiolabeled compounds. In certain embodiments, the present invention provides compounds of formula I.

Sloan Kettering Cancer Center | Date: 2016-11-08

The presently disclosed subject matter relates to the use of one or more biomarkers to evaluate whether a PI3K inhibitor would produce an anti-cancer effect in a subject during the course of treatment with a PI3K inhibitor. It is based, at least in part, on the discovery that certain nucleotides can be isolated from the serum of patients undergoing cancer treatment and can be used as a biomarker to indicate the effectiveness of PI3K treatment on cancer growth. Accordingly, in a non-limiting embodiment, a method for determining whether an anti-cancer effect is likely being produced in a cancer by a PI3K inhibitor, comprises determining the presence and/or level of one or more PIK3CA biomarkers in one or more samples serially obtained during PI3K inhibitor treatment, where if the presence and/or level of a PIK3CA biomarker is increased, it is less likely that the PI3K inhibitor is having an anti-cancer effect on the cancer.

Dana-Farber Cancer Institute and Sloan Kettering Cancer Center | Date: 2015-03-17

A method of increasing the efficacy of treatment for a patient suffering from urothelial carcinoma. The method comprises the steps of determining the presence or absence in a biological sample from the patient of somatic ERCC2 mutation followed by performing appropriate treatment. The absence of somatic ERCC2 mutation indicates that the urothelial carcinoma is likely to be unresponsive to cisplatin chemotherapy, and the patient then undergoes surgery to remove the carcinoma without accompanying cisplatin chemotherapy. The presence of somatic ERCC2 mutation indicates that the uroethelial carcinoma is likely to be responsive to cisplatin chemotherapy and the patient then undergoes surgery to remove the carcinoma accompanied by cisplatin chemotherapy.

Agenus, Ludwig Institute for Cancer Research and Sloan Kettering Cancer Center | Date: 2016-09-01

The instant disclosure provides antibodies that specifically bind to human PD-1 and antagonize PD-1 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

Venneti S.,University of Michigan | Thompson C.B.,Sloan Kettering Cancer Center
Annual Review of Pathology: Mechanisms of Disease | Year: 2017

Next-generation sequencing has substantially enhanced our understanding of the genetics of primary brain tumors by uncovering several novel driver genetic alterations. How many of these genetic modifications contribute to the pathogenesis of brain tumors is not well understood. An exciting paradigm emerging in cancer biology is that oncogenes actively reprogram cellular metabolism to enable tumors to survive and proliferate. We discuss how some of these genetic alterations in brain tumors rewire metabolism. Furthermore, metabolic alterations directly impact epigenetics well beyond classical mechanisms of tumor pathogenesis. Metabolic reprogramming in brain tumors is also influenced by the tumor microenvironment contributing to drug resistance and tumor recurrence. Altered cancer metabolism can be leveraged to noninvasively image brain tumors, which facilitates improved diagnosis and the evaluation of treatment effectiveness. Many of these aspects of altered metabolism provide novel therapeutic opportunities to effectively treat primary brain tumors. © 2017 by Annual Reviews. All rights reserved.

Dogan A.,Sloan Kettering Cancer Center
Annual Review of Pathology: Mechanisms of Disease | Year: 2017

Amyloidoses are a spectrum of disorders caused by abnormal folding and extracellular deposition of proteins. The deposits lead to tissue damage and organ dysfunction, particularly in the heart, kidneys, and nerves. There are at least 30 different proteins that can cause amyloidosis. The clinical management depends entirely on the type of protein deposited, and thus on the underlying pathogenesis, and often requires high-risk therapeutic intervention. Application of mass spectrometrydased proteomic technologies for analysis of amyloid plaques has transformed the way amyloidosis is diagnosed and classified. Proteomic assays have been extensively used for clinical management of patients with amyloidosis, providing unprecedented diagnostic and biological information. They have shed light on the pathogenesis of different amyloid types and have led to identification of numerous new amyloid types, including ALECT2 amyloidosis, which is now recognized as one of the most common causes of systemic amyloidosis in North America. © 2017 by Annual Reviews. All rights reserved.

Drilon A.,Sloan Kettering Cancer Center | Cappuzzo F.,Azienda Unita Sanitaria Locale della Romagna | Ou S.-H.I.,University of California at Irvine | Camidge D.R.,Aurora University
Journal of Thoracic Oncology | Year: 2017

The hepatocyte growth factor receptor (MET) is a potential therapeutic target in a number of cancers, including NSCLC. In NSCLC, MET pathway activation is thought to occur through a diverse set of mechanisms that influence properties affecting cancer cell survival, growth, and invasiveness. Preclinical and clinical evidence suggests a role for MET activation as both a primary oncogenic driver in subsets of lung cancer and as a secondary driver of acquired resistance to targeted therapy in other genomic subsets. In this review, we explore the biology and clinical significance behind MET proto-oncogene receptor tyrosine kinase (MET) exon 14 alterations and MET amplification in NSCLC, the role of MET amplification in the setting of acquired resistance to EGFR tyrosine kinase inhibitor therapy in EGFR-mutant NSCLC, and the history of MET pathway inhibitor drug development in NSCLC, highlighting current strategies that enrich for biomarkers likely to be predictive of response. Whereas previous trials that focused on MET pathway–directed targeted therapy in unselected or MET-overexpressing NSCLC yielded largely negative results, more recent investigations focusing on MET exon 14 alterations and MET amplification have been notable for meaningful clinical responses to MET inhibitor therapy in a substantial proportion of patients. © 2016 International Association for the Study of Lung Cancer

Shahrokni A.,Sloan Kettering Cancer Center | Kim S.J.,Sloan Kettering Cancer Center | Bosl G.J.,Sloan Kettering Cancer Center | Korc-Grodzicki B.,Sloan Kettering Cancer Center
Journal of Oncology Practice | Year: 2017

As the number of older patients with cancer is increasing, oncology disciplines are faced with the challenge of managing patients with multiple chronic conditions who have difficulty maintaining independence, who may have cognitive impairment, and who also may be more vulnerable to adverse outcomes. National and international societies have recommended that all older patients with cancer undergo geriatric assessment (GA) to detect unaddressed problems and introduce interventions to augment functional status to possibly improve patient survival. Several predictive models have been developed, and evidence has shown correlation between information obtained through GA and treatment-related complications. Comprehensive geriatric evaluations and effective interventions on the basis ofGAmay prove to be challenging for the oncologist because of the lack of the necessary skills, time constraints, and/or limited available resources. In this article,wedescribehowthe Geriatrics Service at Memorial Sloan Kettering Cancer Center approaches an older patient with colon cancer from presentation to the end of life, show the importance of GA at the various stages of cancer treatment, and how predictive models are used to tailor the treatment.Thepatient's needs andpreferences are at the core of the decision-making process. Development of a plan of care should always include the patient's preferences, but it is particularly important in the older patient with cancer because a disease-centered approach may neglect noncancer considerations. We will elaborate on the added value of co-management between the oncologist and a geriatric nurse practitioner and on the feasibility of adapting elements of this model into busy oncology practices. Copyright © 2017 American Society of Clinical Oncology. All rights reserved.

Ku G.Y.,Sloan Kettering Cancer Center
Surgical Oncology Clinics of North America | Year: 2017

This review summarizes completed and ongoing studies evaluating the activity of immune checkpoint inhibitors in esophagogastric cancer. © 2016 Elsevier Inc.

Friedman C.F.,Sloan Kettering Cancer Center | Proverbs-Singh T.A.,Sloan Kettering Cancer Center | Postow M.A.,Sloan Kettering Cancer Center
JAMA oncology | Year: 2016

Importance: The development of immune checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) has significantly improved the treatment of a variety of cancers and led to US Food and Drug Administration approvals for patients with a variety of malignant neoplasms. Immune checkpoint inhibitors enhance antitumor immunity by blocking negative regulators of T-cell function that exist both on immune cells and on tumor cells. Although these agents can lead to remarkable responses, their use can also be associated with unique immune-related adverse effects (irAEs).Observations: In general, use of PD-1 inhibitors such as nivolumab and pembrolizumab has a lower incidence of irAEs compared with those that block CTLA-4 such as ipilimumab. The combination of nivolumab and ipilimumab has a higher rate of irAEs than either approach as monotherapy. Consensus guidelines regarding the treatment of the most common irAEs including rash, colitis, hepatitis, endocrinopathies, and pneumonitis have been established. The mainstay of irAE treatment consists of immunosuppression with corticosteroids or other immunosuppressant agents such as infliximab; most irAEs will resolve with appropriate management.Conclusions and Relevance: The clinical use of immune checkpoint inhibitors is expanding rapidly. Oncology practitioners will therefore be required to recognize and manage irAEs in a growing patient population. Early recognition and treatment are essential to prevent patient morbidity and mortality, and adherence to established algorithms is recommended.

Antonescu C.R.,Sloan Kettering Cancer Center
American Journal of Surgical Pathology | Year: 2017

CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information, which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared with a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86%), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12%) and rarely in the bone (3%). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84% cases, with a diffuse pattern only in 23% of cases, whereas nuclear WT1 was seen in 92%. A CIC-DUX4 fusion was detected in 57% of cases, with either DUX4 on 4q35 (35%) or on 10q26 in 25 (22%) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43%, which was significantly lower than the 77% 5-year survival in the control Ewing sarcoma group (P=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared with Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors distinct from Ewing sarcoma. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Krebs S.,Sloan Kettering Cancer Center
Clinical Nuclear Medicine | Year: 2017

ABSTRACT: An otherwise healthy 33-year-old man presents with new pain involving the right leg. Radiographs of the femur showed scattered lucent lesions. An MRI of the knee demonstrated nonspecific cortical-based lesions. Biopsy confirmed pseudomyogenic hemangioendothelioma. MDP bone scan and F-FDG PET/CT were obtained to evaluate for extent of disease demonstrating disease limited to the bone of the right leg. Interestingly, the FDG and MDP uptake and CT appearance of the disease were not entirely concordant, with some lesions being lytic on CT and associated with FDG and MDP uptake, other lesions being CT silent and either MDP or FDG avid. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Baldwin M.R.,Sloan Kettering Cancer Center
Critical Care Medicine | Year: 2017

OBJECTIVES:: To determine whether minority race or ethnicity is associated with mortality and mediated by health insurance coverage among older (≥ 65 yr old) survivors of critical illness. DESIGN:: A retrospective cohort study. SETTING:: Two New York City academic medical centers. PATIENTS:: A total of 1,947 consecutive white (1,107), black (361), and Hispanic (479) older adults who had their first medical-ICU admission from 2006 through 2009 and survived to hospital discharge. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: We obtained demographic, insurance, and clinical data from electronic health records, determined each patient’s neighborhood-level socioeconomic data from 2010 U.S. Census tract data, and determined death dates using the Social Security Death Index. Subjects had a mean (SD) age of 79 years (8.6 yr) and median (interquartile range) follow-up time of 1.6 years (0.4–3.0 yr). Blacks and Hispanics had similar mortality rates compared with whites (adjusted hazard ratio, 0.92; 95% CI, 0.76–1.11 and adjusted hazard ratio, 0.92; 95% CI, 0.76–1.12, respectively). Compared to those with commercial insurance and Medicare, higher mortality rates were observed for those with Medicare only (adjusted hazard ratio, 1.43; 95% CI, 1.03–1.98) and Medicaid (adjusted hazard ratio, 1.30; 95% CI, 1.10–1.52). Medicaid recipients who were the oldest ICU survivors (> 82 yr), survivors of mechanical ventilation, and discharged to skilled-care facilities had the highest mortality rates (p-for-interaction: 0.08, 0.03, and 0.17, respectively). CONCLUSIONS:: Mortality after critical illness among older adults varies by insurance coverage but not by race or ethnicity. Those with federal or state insurance coverage only had higher mortality rates than those with additional commercial insurance. Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Ulaner G.A.,Sloan Kettering Cancer Center
Clinical Nuclear Medicine | Year: 2017

ABSTRACT: Transient osteoporosis of the hip (TOH) is characterized by bone pain, osteopenia, and bone marrow edema in the absence of trauma. We present a 59-year-old man with chronic lymphocytic leukemia who underwent F-FDG PET/CT. F-FDG PET/CT demonstrated mildly FDG-avid lymph nodes consistent for chronic lymphocytic leukemia, as well as FDG-avidity in the right femoral head with corresponding osteopenia, rather than a focal lytic lesion. MR demonstrated bone marrow edema consistent with TOH. TOH is benign and self-limiting. Corresponding imaging may prevent misdiagnosis of benign FDG-avid TOH as other more severe hip processes such as tumors or infection. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Xp11 translocation renal cell carcinoma (RCC) are defined by chromosome translocations involving the Xp11 breakpoint which results in one of a variety of TFE3 gene fusions. TFE3 break-apart florescence in situ hybridization (FISH) assays are generally preferred to TFE3 immunohistochemistry (IHC) as a means of confirming the diagnosis in archival material, as FISH is less sensitive to the variable fixation which can result in false positive or false negative IHC. Prompted by a case report in the cytogenetics literature, we identify 3 cases of Xp11 translocation RCC characterized by a subtle chromosomal inversion involving the short arm of the X chromosome, resulting in an RBM10-TFE3 gene fusion. TFE3 rearrangement was not detected by conventional TFE3 break-apart FISH, but was suggested by strong diffuse TFE3 immunoreactivity in a clean background. We then developed novel fosmid probes to detect the RBM10-TFE3 gene fusion in archival material. These cases validate RBM10-TFE3 as a recurrent gene fusion in Xp11 translocation RCC, illustrate a source of false-negative TFE3 break-apart FISH, and highlight the complementary role of TFE3 IHC and TFE3 FISH. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Chiang S.,Sloan Kettering Cancer Center
American Journal of Surgical Pathology | Year: 2017

Primary primitive neuroectodermal tumor (PNET) of the female genital tract is rare, and its proper classification remains unclear. The clinical, histologic, and immunophenotypic features as well as EWSR1 rearrangement status of 19 gynecologic PNETs, including 10 ovarian, 8 uterine, and 1 vulvar tumors, are herein reported. Patient age ranged from 12 to 68 years, with a median age of 20 and 51 years among those with ovarian and uterine PNETs, respectively. Morphologic features of central nervous system (CNS) tumors were seen in 15 PNETs, including 9 medulloblastomas, 3 ependymomas, 2 medulloepitheliomas, and 1 glioblastoma, consistent with central PNET. The remaining 4 PNETs were composed entirely of undifferentiated small round blue cells and were classified as Ewing sarcoma/peripheral PNET. Eight PNETs were associated with another tumor type, including 5 ovarian mature cystic teratomas, 2 endometrial low-grade endometrioid carcinomas, and a uterine carcinosarcoma. By immunohistochemistry, 17 PNETs expressed at least 1 marker of neuronal differentiation, including synaptophysin, NSE, CD56, S100, and chromogranin in 10, 8, 14, 8, and 1 tumors, respectively. GFAP was positive in 4 PNETs, all of which were of central type. Membranous CD99 and nuclear Fli-1 staining was seen in 10 and 16 tumors, respectively, and concurrent expression of both markers was seen in both central and Ewing sarcoma/peripheral PNETs. All tumors expressed vimentin, whereas keratin cocktail (CAM5.2, AE1/AE3) staining was only focally present in 4 PNETs. Fluorescence in situ hybridization was successful in all cases and confirmed EWSR1 rearrangement in 2 of 4 tumors demonstrating morphologic features of Ewing sarcoma/peripheral PNET and concurrent CD99 and Fli-1 expression. In conclusion, central and Ewing sarcoma/peripheral PNETs may be encountered in the female genital tract with central PNETs being more common. Central PNETs show a spectrum of morphologic features that overlaps with CNS tumors but lack EWSR1 rearrangements. GFAP expression supports a morphologic impression of central PNET and is absent in Ewing sarcoma/peripheral PNET. Ewing sarcoma/peripheral PNETs lack morphologic features of CNS tumors. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Peng M.,Sloan Kettering Cancer Center | Yin N.,Sloan Kettering Cancer Center | Li M.O.,Sloan Kettering Cancer Center
Nature | Year: 2017

Mechanistic target of rapamycin complex 1 (TORC1) integrates nutrient signals to control cell growth and organismal homeostasis across eukaryotes1-4. The evolutionarily conserved GATOR complex regulates mTORC1 signalling through Rag GTPases, and GATOR1 displays GTPase activating protein (GAP) activity for RAGA and RAGB (RAGA/B) and GATOR2 has been proposed to be an inhibitor of GATOR15,6. Furthermore, the metazoan-specific SESN proteins function as guanine nucleotide dissociation inhibitors (GDIs) for RAGA/B, and interact with GATOR2 with unknown effects7-9. Here we show that SZT2 (seizure threshold 2), a metazoan-specific protein mutated in epilepsy10-13, recruits a fraction of mammalian GATOR1 and GATOR2 to form a SZT2-orchestrated GATOR (SOG) complex with an essential role in GATOR- and SESN-dependent nutrient sensing and mTORC1 regulation. The interaction of SZT2 with GATOR1 and GATOR2 was synergistic, and an intact SOG complex was required for its localization at the lysosome. SZT2 deficiency resulted in constitutive mTORC1 signalling in cells under nutrient-deprived conditions and neonatal lethality in mice, which was associated with failure to inactivate mTORC1 during fasting. Hyperactivation of mTORC1 in SZT2-deficient cells could be partially corrected by overexpression of the GATOR1 component DEPDC5, and by the lysosome-targeted GATOR2 component WDR59 or lysosome-targeted SESN2. These findings demonstrate that SZT2 has a central role in dictating GATOR-dependent nutrient sensing by promoting lysosomal localization of SOG, and reveal an unexpected function of lysosome-located GATOR2 in suppressing mTORC1 signalling through SESN recruitment. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Eyquem J.,Sloan Kettering Institute | Mansilla-Soto J.,Sloan Kettering Institute | Giavridis T.,Sloan Kettering Institute | Van Der Stegen S.J.C.,Sloan Kettering Institute | And 5 more authors.
Nature | Year: 2017

Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19 (ref. 2), which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific interventions in human cells, including targeted gene delivery to the CCR5 and AAVS1 loci. Here we show that directing a CD19-specific CAR to the T-cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia. We further demonstrate that targeting the CAR to the TRAC locus averts tonic CAR signalling and establishes effective internalization and re-expression of the CAR following single or repeated exposure to antigen, delaying effector T-cell differentiation and exhaustion. These findings uncover facets of CAR immunobiology and underscore the potential of CRISPR/Cas9 genome editing to advance immunotherapies. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Inoue D.,Sloan Kettering Cancer Center | Bradley R.K.,Fred Hutchinson Cancer Research Center | Abdel-Wahab O.,Sloan Kettering Cancer Center
Genes & development | Year: 2016

Genomic analyses of the myeloid malignancies and clonal disorders of hematopoiesis that may give rise to these disorders have identified that mutations in genes encoding core spliceosomal proteins and accessory regulatory splicing factors are among the most common targets of somatic mutations. These spliceosomal mutations often occur in a mutually exclusive manner with one another and, in aggregate, account for the most frequent class of mutations in patients with myelodysplastic syndromes (MDSs) in particular. Although substantial progress has been made in understanding the effects of several of these mutations on splicing and splice site recognition, functional connections linking the mechanistic changes in splicing induced by these mutations to the phenotypic consequences of clonal and aberrant hematopoiesis are not yet well defined. This review describes our current understanding of the mechanistic and biological effects of spliceosomal gene mutations in MDSs as well as the regulation of splicing throughout normal hematopoiesis. © 2016 Inoue et al.; Published by Cold Spring Harbor Laboratory Press.

Wang B.,Sloan Kettering Cancer Center
Nature Chemical Biology | Year: 2017

The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D-R- or L-S- enantiomer, each of which inhibits α-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase (IDH) produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via 'promiscuous' reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Pamer E.G.,Sloan Kettering Cancer Center
Trends in Molecular Medicine | Year: 2017

Bacterial species constituting the intestinal microbiota are implicated in maintenance of health but also pathogenesis of inflammatory disease. The compositional complexity of the microbiota and metabolic interdependencies of microbial species challenge our ability to attribute host responses to specific bacterial strains. Studies using gnotobiotic mice, however, are providing important insights. © 2017 Elsevier Ltd.

Liu B.O.,Sloan Kettering Cancer Center | Abdel-Wahab O.,Sloan Kettering Cancer Center
eLife | Year: 2017

The loss of genes that encode RNA splicing factors weakens cancer cells in a way that could be exploited by new approaches to treatment. © Liu and Abdel-Wahab.

Shaha A.R.,Sloan Kettering Cancer Center
Oral Oncology | Year: 2017

Prognostic factors and risk group analysis are very well known in well differentiated thyroid cancer. One of the major prognostic factors is presence of extrathyroidal extension and residual gross tumor. It is not uncommon to find the final pathology report showing minimal extrathyroidal extension. The debate continues as to the implication of this microscopic or minimal extrathyroidal extension. The previous staging system had upstaged such tumors. However, several reports in the literature suggest no prognostic implication of microscopic or minimal extrathyroidal extension. © 2017 Elsevier Ltd

Ponomarev V.,Sloan Kettering Cancer Center
Molecular Imaging and Biology | Year: 2017

Immunotherapies include various approaches, ranging from stimulating effector mechanisms to counteracting inhibitory and suppressive mechanisms, and creating a forum for discussing the most effective means of advancing these therapies through imaging is the focus of the newly formed Imaging in Cellular and Immune Therapies (ICIT) interest group within the World Molecular Imaging Society. Efforts are being made in the identification and validation of predictive biomarkers for a number of immunotherapies. Without predictive biomarkers, a considerable number of patients may receive treatments that have no chance of offering a benefit. This will reflect poorly on the field of immunotherapy and will yield false hopes in patients while at the same time contributing to significant cost to the healthcare system. This review summarizes the main strategies in cancer immune and cell-based therapies and discusses recent advances in imaging strategies aimed to improve cancer immunotherapy outcomes. © 2017 The Author(s)

Wasmuth E.V.,Sloan Kettering Cancer Center | Lima C.D.,Sloan Kettering Cancer Center
Nucleic Acids Research | Year: 2017

The eukaryotic RNA exosome is an essential, multi-subunit complex that catalyzes RNA turnover, maturation, and quality control processes. Its non-catalytic donut-shaped core includes 9 subunits that associate with the 3′ to 5′ exoribonucleases Rrp6, and Rrp44/Dis3, a subunit that also catalyzes endoribonuclease activity. Although recent structures and biochemical studies of RNA bound exosomes from S. cerevisiae revealed that the Exo9 central channel guides RNA to either Rrp6 or Rrp44 using partially overlapping and mutually exclusive paths, several issues related to RNA recruitment remain. Here, we identify activities for the highly basic Rrp6 C-terminal tail that we term the 'lasso' because it binds RNA and stimulates ribonuclease activities associated with Rrp44 and Rrp6 within the 11-subunit nuclear exosome. Stimulation is dependent on the Exo9 central channel, and the lasso contributes to degradation and processing activities of exosome substrates in vitro and in vivo. Finally, we present evidence that the Rrp6 lasso may be a conserved feature of the eukaryotic RNA exosome. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Yoshimi A.,Sloan Kettering Cancer Center | Abdel-Wahab O.,Sloan Kettering Cancer Center
Clinical Cancer Research | Year: 2017

Splicing of precursor messenger RNA is a critical step in regulating gene expression, and major advances are being made in understanding the composition and structure of the enzymatic complex that performs splicing, which is termed the "spliceosome." In parallel, there has been increased appreciation for diverse mechanisms by which alterations in splicing contribute to cancer pathogenesis. Key among these include change-offunction mutations in genes encoding spliceosomal proteins. Such mutations are among the most common genetic alterations in myeloid and lymphoid leukemias, making efforts to therapeutically target cells bearing these mutations critical. To this end, recent studies have clarified that pharmacologic modulation of splicing may be preferentially lethal for cells bearing spliceosomal mutations and may also have a role in the therapy of MYC-driven cancers. This has culminated in the initiation of a clinical trial of a novel oral spliceosome modulatory compound targeting the SF3B complex, and several novel alternative approaches to target splicing are in development as reviewed here. There is now, therefore, a great need to understand the mechanistic basis of altered spliceosomal function in cancers and to study the effects of spliceosomal modulatory compounds in preclinical settings and in well-designed clinical trials. © 2016 American Association for Cancer Research.

Busam K.J.,Sloan Kettering Cancer Center
Modern Pathology | Year: 2017

Merkel cell carcinoma is a primary cutaneous neuroendocrine carcinoma, which once metastatic is difficult to treat. Recent mutation analyses of Merkel cell carcinoma revealed a low number of mutations in Merkel cell polyomavirus-associated tumors, and a high number of mutations in virus-negative combined squamous cell and neuroendocrine carcinomas of chronically sun-damaged skin. We speculated that the paucity of mutations in virus-positive Merkel cell carcinoma may reflect a pathomechanism that depends on derangements of chromatin without alterations in the DNA sequence (epigenetic dysregulation). One central epigenetic regulator is the Polycomb repressive complex 2 (PRC2), which silences genomic regions by trimethylating (me3) lysine (K) 27 of histone H3, and thereby establishes the histone mark H3K27me3. Recent experimental research data demonstrated that PRC2 loss in mice skin results in the formation of Merkel cells. Prompted by these findings, we explored a possible contribution of PRC2 loss in human Merkel cell carcinoma. We examined the immunohistochemical expression of H3K27me3 in 35 Merkel cell carcinomas with pure histological features (22 primary and 13 metastatic lesions) and in 5 combined squamous and neuroendocrine carcinomas of the skin. We found a strong reduction of H3K27me3 staining in tumors with pure histologic features and virus-positive Merkel cell carcinomas. Combined neuroendocrine carcinomas had no or only minimal loss of H3K27me3 labeling. Our findings suggest that a PRC2-mediated epigenetic deregulation may play a role in the pathogenesis of virus-positive Merkel cell carcinomas and in tumors with pure histologic features.Modern Pathology advance online publication, 10 March 2017; doi:10.1038/modpathol.2017.8. © 2017 USCAP, Inc All rights reserved

Martelotto L.G.,Sloan Kettering Cancer Center
Nature Medicine | Year: 2017

A substantial proportion of tumors consist of genotypically distinct subpopulations of cancer cells. This intratumor genetic heterogeneity poses a substantial challenge for the implementation of precision medicine. Single-cell genomics constitutes a powerful approach to resolve complex mixtures of cancer cells by tracing cell lineages and discovering cryptic genetic variations that would otherwise be obscured in tumor bulk analyses. Because of the chemical alterations that result from formalin fixation, single-cell genomic approaches have largely remained limited to fresh or rapidly frozen specimens. Here we describe the development and validation of a robust and accurate methodology to perform whole-genome copy-number profiling of single nuclei obtained from formalin-fixed paraffin-embedded clinical tumor samples. We applied the single-cell sequencing approach described here to study the progression from in situ to invasive breast cancer, which revealed that ductal carcinomas in situ show intratumor genetic heterogeneity at diagnosis and that these lesions may progress to invasive breast cancer through a variety of evolutionary processes. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Jaspers J.E.,Sloan Kettering Cancer Center | Brentjens R.J.,Sloan Kettering Cancer Center
Pharmacology and Therapeutics | Year: 2017

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy against hematologic malignancies. Antitumor activity of CAR T cells, however, needs to be improved to increase therapeutic efficacy in both hematologic and solid cancers. Limitations to overcome are 'on-target, off-tumor' toxicity, antigen escape, short CAR T cell persistence, little expansion, trafficking to the tumor and inhibition of T cell activity by an inhibitory tumor microenvironment. Here we will discuss how optimizing the design of CAR T cells through genetic engineering addresses these limitations and improves the antitumor efficacy of CAR T cell therapy in pre-clinical models. © 2017.

Landgren O.,Sloan Kettering Cancer Center | Owen R.G.,St James's Hospital
Cytometry Part B - Clinical Cytometry | Year: 2016

In 2015, there is a large body of evidence demonstrating that minimal residual disease (MRD) negativity after therapy is a powerful predictor of progression-free survival and overall survival in multiple myeloma. On the basis of available data, we believe MRD provides a meaningful endpoint for regulatory purposes, academic studies, and a valuable prognostic evaluation of individual patients in the clinical setting. Similar to what has been shown in acute and chronic lymphocytic leukemia, based on emerging data, the prognostic impact of MRD in multiple myeloma appears to be independent of induction therapy received. This fact raises fundamental questions regarding best possible treatment strategies (e.g., fixed number of cycles versus response adapted number of cycles) as well as optimal treatment modalities (e.g., newer effective but less intense combination therapies versus high dose melphalan followed by autologous stem cell transplantation), in particular for patients newly diagnosed with multiple myeloma. © 2015 International Clinical Cytometry Society. © 2015 International Clinical Cytometry Society

Background:The current analysis was performed to evaluate the impact of PIK3CA hotspot mutations on everolimus efficacy in BOLERO-2 participants, using cell-free DNA (cfDNA) from plasma samples collected at the time of patient randomisation.Methods:PIK3CA H1047R, E545K, and E542K mutations in plasma-derived cfDNA were analysed by droplet digital PCR (ddPCR). Median PFS was estimated for patient subgroups defined by PIK3CA mutations in each treatment arm.Results:Among 550 patients included in cfDNA analysis, median PFS in everolimus vs placebo arms was similar in patients with tumours that had wild-type or mutant PIK3CA (hazard ratio (HR), 0.43 and 0.37, respectively). Everolimus also prolonged median PFS in patients with PIK3CA H1047R (HR, 0.37) and E545K/E542K mutations (HR=0.30) with a similar magnitude.Conclusions:Mutation analysis of plasma-derived cfDNA by ddPCR suggests that PFS benefit of everolimus was maintained irrespective of PIK3CA genotypes, consistent with the previous analysis of archival tumour DNA by next-generation sequencing.British Journal of Cancer advance online publication 9 February 2017; doi:10.1038/bjc.2017.25 © 2017 Cancer Research UK

Begg C.B.,Sloan Kettering Cancer Center
British Journal of Cancer | Year: 2017

Background:The somatic molecular profiles of basal-like breast cancers and high-grade serous ovarian cancers share many similarities, leading to the hypothesis that they have similar aetiologies, in which case they should occur together in the same patient more often than expected.Methods:We identified 545 women with double independent primary cancers of the breast and ovary reported to the California Cancer Registry from 1999 to 2013 and examined the coincidence of subtype combinations.Results:For most subtype combinations the observed frequencies were similar to their expected frequencies, but in 103 observed cases vs 43.8 expected (O/E=2.35; 95% CI 1.90–2.81) a triple-negative breast tumour (typically basal-like) was matched with a serous ovarian tumour (typically high-grade).Conclusions:The results provide compelling evidence that basal-like breast cancer and high-grade serous ovarian cancer share a much more similar aetiology than breast and ovarian cancers more broadly. Further research is needed to clarify the influence of germ-line BRCA1 mutations and other risk factors on these results.British Journal of Cancer advance online publication, 23 March 2017; doi:10.1038/bjc.2017.73 © 2017 Cancer Research UK

Zeltner N.,Sloan Kettering Cancer Center
Molecular Psychiatry | Year: 2017

Neuropsychiatric disorders place an enormous medical burden on patients across all social and economic ranks. The current understanding of the molecular and cellular causes of neuropsychiatric disease remains limited, which leads to a lack of targeted therapies. Human-induced pluripotent stem cell (iPSC) technology offers a novel platform for modeling the genetic contribution to mental disorders and yields access to patient-specific cells for drug discovery and personalized medicine. Here, we review recent progress in using iPSC technology to model and potentially treat neuropsychiatric disorders by focusing on the most prevalent conditions in psychiatry, including depression, anxiety disorders, bipolar disorder and schizophrenia.Molecular Psychiatry advance online publication, 21 March 2017; doi:10.1038/mp.2017.40. © 2017 The Author(s)

Shaha A.R.,Sloan Kettering Cancer Center
JAMA Otolaryngology - Head and Neck Surgery | Year: 2016

With the rapid rise in the incidence of thyroid cancer, the number of thyroidectomies has increased remarkably in the last 10 years. Thyroidectomy accounts for approximately 40% of the workload in head and neck fellowship. The decision making in thyroid surgery is quite complex, especially when patients present with recurrent or advanced thyroid cancer. The complications of thyroid surgery can be very serious in relation to quality of life. Some of these complications can be avoided with meticulous surgical technique. Thyroid surgery continues to span various specialties, and surgical volume continues to be an important parameter in outcomes. Technological advances have made a significant impact in thyroid surgery; however, these need to be carefully evaluated before their routine implementation and for extracervical approaches to thyroidectomy. The use of external radiation therapy and targeted therapies has expanded in recent years for patients with recurrent thyroid cancer. In a specialized and tertiary care center, the thyroid expert should be well-trained to make appropriate complex decisions. Thyroid experts should be part of the multidisciplinary team managing thyroid cancer from A to Z. Copyright 2016 American Medical Association. All rights reserved.

Paik P.K.,Sloan Kettering Cancer Center | Paik P.K.,New York Medical College
Cancer Discovery | Year: 2016

Mutations in EGFR stand as the archetype for somatic alterations that lead to oncogene addiction and that predict for response to targeted therapies. In this issue of Cancer Discovery, Konduri and colleagues report on a pair of novel oncogenic and actionable EGFR fusion events in a series of patients with lung adenocarcinomas, casting new light on this model gene. © 2016 American Association for Cancer Research.

Sloan Kettering Cancer Center | Date: 2017-02-01

The present disclosure provides, among other things, methods and compositions for diagnosing and treating stress-induced injuries, hypoxia in particular. The present invention is based, in part, on the novel discovery that a metabolite, L-2-hydroxyglutarate, and certain enzymes and substrates regulating its metabolism, mediate stress-induced cellular mechanisms. In some embodiments, provided methods and compositions are used to diagnose and treat diseases with hypoxia-induced injuries. In some embodiments, provided methods and compositions are used to modulate cell pluripotency or differentiation in vivo or in vitro.

Sloan Kettering Cancer Center | Date: 2017-03-22

Provided herein is a one-step method for chelating actinium-225 to a construct comprising a chelator linked to a biomolecule, such as, an antibody or monoclonal antibody, via a bifunctional ligand in, for example, a 3-arm configuration. Also provided are methods for increasing the radiochemical yield of an actinium-225-chelant-biomolecule complex and for producing a high specific activity actinium-225 complex. The chelation is performed at a physiological temperature, about 37 C. Also provided are high specific activity actinium-225 complexes, that is, actinium-225 chelated to the chelator-biomolecule construct and pharmaceutical compositions thereof. Further provided are methods of treating a neoplastic disease or disorder with the actinium-225 complexes.

Sloan Kettering Cancer Center | Date: 2017-03-01

The present disclosure describes a compositions and methods for treatment of Hras-driven cancers. Administration of a farnesyltransferase inhibitor, for example, tipifarnib, alone or in combination with a MEK inhibitor can reduce tumor size and tumor growth in cancers such as poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC)

Agenus, Sloan Kettering Cancer Center and Ludwig Institute for Cancer Research | Date: 2017-04-05

The present disclosure provides antibodies that specifically bind to human glucocorticoid-induced TNFR family related receptor (GITR) and compositions comprising such antibodies. In a specific aspect, the antibodies specifically bind to human GITR and modulate GITR activity, e.g., enhance, activate or induce GITR activity, utilizing such antibodies. The present disclosure also provides methods for treating disorders, such as cancer and infectious diseases, by administering an antibody that specifically binds to human GITR and modulates GITR activity e.g., enhances, activates or induces GITR activity.

Three leaders in preventing healthcare-associated infections discuss how patients can stay safer in hospital. There’s one place you never want to “go viral”: in the hospital (or in the clinic, nursing home, rehab facility, or even the dentist’s office.) HAIs — hospital-acquired or healthcare-associated infections — claim the lives of tens of thousands of patients in the US every year, and harm countless more. (And it’s not just viruses: bacteria can be just as dangerous.) At a symposium held in Plainview, NY on May 1, an audience heard three leading infection-prevention specialists discuss the ways good patient safety protocols can reduce that toll. The event, one of an annual series hosted by Pulse Center for Patient Safety Education and Advocacy (CPSEA), brought together members of the public and healthcare professionals to hear Janet Eagan, RN (Manager, Infection Control at Sloan Kettering Cancer Center), Dr. Bruce E. Hirsch (Attending Physician, Div. of Infectious Diseases, North Shore University Hospital) and Lisa Wandowski DNP, PNP, CIC (Infection Control Specialist, Standards Interpretation Group, The Joint Commission Enterprise) analyze this serious and growing problem. After the Symposium participants were asked to complete evaluations of what they had learned. Some of the comments were: -       Patients and their advocates need to make sure all medical staff wash hands before approaching the bedside. (Sterile gloves are not a substitute!) -       Having a colonoscopy? Ask about the facility’s equipment sanitation routine: scopes used in colonoscopies are often not sterilized, just sanitized. -       Overuse of powerful antibiotics is a serious issue, encouraging the rise of resistant “superbugs,” compromising patients’ healthy microbiomes, and polluting the environment. -       Dangerous intestinal infections such as “C-Diff” can be successfully treated with “fecal transplants” containing healthy bacteria. In addition to its annual symposia, Pulse — the only grassroots patient safety organization on Long Island — provides a wide range of education, training, and direct work with vulnerable segments of the population. Visit to learn more. To discuss this or other patient safety issues with Pulse President Ilene Corina, call (516) 579-4711.

Leder K.,University of Minnesota | Pitter K.,Sloan Kettering Cancer Center | Laplant Q.,Sloan Kettering Cancer Center | Ross B.D.,University of Michigan | And 4 more authors.
Cell | Year: 2014

Glioblastomas (GBMs) are the most common and malignant primary brain tumors and are aggressively treated with surgery, chemotherapy, and radiotherapy. Despite this treatment, recurrence is inevitable and survival has improved minimally over the last 50 years. Recent studies have suggested that GBMs exhibit both heterogeneity and instability of differentiation states and varying sensitivities of these states to radiation. Here, we employed an iterative combined theoretical and experimental strategy that takes into account tumor cellular heterogeneity and dynamically acquired radioresistance to predict the effectiveness of different radiation schedules. Using this model, we identified two delivery schedules predicted to significantly improve efficacy by taking advantage of the dynamic instability of radioresistance. These schedules led to superior survival in mice. Our interdisciplinary approach may also be applicable to other human cancer types treated with radiotherapy and, hence, may lay the foundation for significantly increasing the effectiveness of a mainstay of oncologic therapy. PaperClip © 2014 Elsevier Inc.

Salz T.,Sloan Kettering Cancer Center | Oeffinger K.C.,Sloan Kettering Cancer Center | McCabe M.S.,Sloan Kettering Cancer Center | Bach P.B.,Sloan Kettering Cancer Center
CA Cancer Journal for Clinicians | Year: 2012

The Institute of Medicine (IOM) recommends the use of survivorship care plans (SCPs) for all cancer survivors. Developing useful SCPs requires understanding what survivors and their providers need and how SCPs can be implemented in practice. Published studies investigating the perspectives of stakeholders (survivors, primary care providers, and oncology providers) were reviewed regarding the content and use of SCPs. All National Cancer Institute (NCI)-designated cancer centers were surveyed concerning the extent to which SCPs for survivors of breast and colorectal cancers are in use, their concordance with the IOM's recommendation, and details about SCP delivery. Survivors and primary care providers typically lack the information the IOM suggested should be included in SCPs. Oncology providers view SCPs favorably but express concerns about the feasibility of their implementation. Fewer than one-half (43%) of NCI-designated cancer centers deliver SCPs to their breast or colorectal cancer survivors. Of those that do, none deliver SCPs that include all components recommended by the IOM. Survivors' and providers' opinions about the use of SCPs are favorable, but there are barriers to implementation. SCPs are not widely used in NCI-designated cancer centers. Variation in practice is substantial, and many components recommended by the IOM framework are rarely included. Copyright © 2012 American Cancer Society, Inc.

Brogi E.,Sloan Kettering Cancer Center
Genes and Development | Year: 2011

The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protected against Taxol-induced tumor cell death in coculture, an effect fully reversed by cathepsin inhibition and mediated partially by cathepsins B and S. Macrophages were also found to protect against tumor cell death induced by additional chemotherapeutics, specifically etoposide and doxorubicin. Combining Taxol with cathepsin inhibition in vivo significantly enhanced efficacy against primary and metastatic tumors, supporting the therapeutic relevance of this effect. Additionally incorporating continuous low-dose cyclophosphamide dramatically impaired tumor growth and metastasis and improved survival. This study highlights the importance of integrated targeting of the tumor and its microenvironment and implicates macrophages and cathepsins in blunting chemotherapeutic response. © 2011 by Cold Spring Harbor Laboratory Press.

Schuhmacher A.J.,Sloan Kettering Cancer Center | Sibilia M.,Medical University of Vienna
Cancer Cell | Year: 2012

Clinical evidence indicates that mutation/activation of EGF receptors (EGFRs) is mutually exclusive with the presence of K-RAS oncogenes in lung and colon tumors. We have validated these observations using genetically engineered mouse models. However, development of pancreatic ductal adenocarcinomas driven by K-Ras oncogenes are totally dependent on EGFR signaling. Similar results were obtained using human pancreatic tumor cell lines. EGFRs were also essential even in the context of pancreatic injury and absence of p16Ink4a/p19Arf. Only loss of p53 made pancreatic tumors independent of EGFR signaling. Additional inhibition of PI3K and STAT3 effectively prevented proliferation of explants derived from these p53-defective pancreatic tumors. These findings may provide the bases for more rational approaches to treat pancreatic tumors in the clinic. © 2012 Elsevier Inc.

Patel D.J.,Sloan Kettering Cancer Center | Wang Z.,Sloan Kettering Cancer Center | Wang Z.,Beijing Normal University
Annual Review of Biochemistry | Year: 2013

This review focuses on a structure-based analysis of histone posttranslational modification (PTM) readout, where the PTMs serve as docking sites for reader modules as part of larger complexes displaying chromatin modifier and remodeling activities, with the capacity to alter chromatin architecture and templated processes. Individual topics addressed include the diversity of reader-binding pocket architectures and common principles underlying readout of methyl-lysine and methyl-arginine marks, their unmodified counterparts, as well as acetyl-lysine and phosphoserine marks. The review also discusses the impact of multivalent readout of combinations of PTMs localized at specific genomic sites by linked binding modules on processes ranging from gene transcription to repair. Additional topics include cross talk between histone PTMs, histone mimics, epigenetic-based diseases, and drug-based therapeutic intervention. The review ends by highlighting new initiatives and advances, as well as future challenges, toward the promise of enhancing our structural and mechanistic understanding of the readout of histone PTMs at the nucleosomal level. © 2013 by Annual Reviews. All rights reserved.

Gasteiger G.,Sloan Kettering Cancer Center | Gasteiger G.,University of Mainz Medical Center | Rudensky A.Y.,Sloan Kettering Cancer Center
Nature Reviews Immunology | Year: 2014

Innate lymphocytes-including natural killer cells and the recently discovered innate lymphoid cells-have crucial roles during infection, tissue injury and inflammation. Innate signals regulate the activation and homeostasis of innate lymphocytes. The contribution of the adaptive immune system to the coordination of innate lymphocyte responses is less well understood. In this Opinion article, we review our current understanding of the interactions between adaptive and innate lymphocytes, and propose a model in which T cells of the adaptive immune system function as antigen-specific sensors for the activation of innate lymphocytes to amplify and instruct local immune responses. We highlight the potential roles of regulatory and helper T cells in these processes, and discuss major questions in the emerging area of crosstalk between adaptive and innate lymphocytes. © 2014 Macmillan Publishers Limited.

Weitzel J.N.,Cancer Genetics Education Program | Blazer K.R.,Cancer Genetics Education Program | MacDonald D.J.,Cancer Genetics Education Program | Culver J.O.,Cancer Screening and Prevention Program | Offit K.,Sloan Kettering Cancer Center
CA Cancer Journal for Clinicians | Year: 2011

Scientific and technologic advances are revolutionizing our approach to genetic cancer risk assessment, cancer screening and prevention, and targeted therapy, fulfilling the promise of personalized medicine. In this monograph, we review the evolution of scientific discovery in cancer genetics and genomics, and describe current approaches, benefits, and barriers to the translation of this information to the practice of preventive medicine. Summaries of known hereditary cancer syndromes and highly penetrant genes are provided and contrasted with recently discovered genomic variants associated with modest increases in cancer risk. We describe the scope of knowledge, tools, and expertise required for the translation of complex genetic and genomic test information into clinical practice. The challenges of genomic counseling include the need for genetics and genomics professional education and multidisciplinary team training, the need for evidence-based information regarding the clinical utility of testing for genomic variants, the potential dangers posed by premature marketing of first-generation genomic profiles, and the need for new clinical models to improve access to and responsible communication of complex disease risk information. We conclude that given the experiences and lessons learned in the genetics era, the multidisciplinary model of genetic cancer risk assessment and management will serve as a solid foundation to support the integration of personalized genomic information into the practice of cancer medicine. © 2011 American Cancer Society.

Wang Z.,Beijing Normal University | Wang Z.,Sloan Kettering Cancer Center | Patel D.J.,Sloan Kettering Cancer Center
Quarterly Reviews of Biophysics | Year: 2014

Altered chromatin structures and dynamics are responsible for a range of human malignancies, among which the status of histone lysine methylation remains of paramount importance. Histone lysine methylation is maintained by the relative activities of sequence-specific methyltransferase (KMT) writers and demethylase (KDM) erasers, with aberrant enzymatic activities or expression profiles closely correlated with multiple human diseases. Hence, targeting these epigenetic enzymes should provide a promising avenue for pharmacological intervention of aberrantly marked sites within the epigenome. Here we present an up-to-date critical evaluation on the development and optimization of potent small molecule inhibitors targeted to histone KMTs and KDMs, with the emphasis on contributions of structural biology to development of epigenetic drugs for therapeutic intervention. We anticipate that ongoing advances in the development of epigenetic inhibitors should lead to novel drugs that site-specifically target KMTs and KDMs, key enzymes responsible for maintenance of the lysine methylation landscape in the epigenome. Copyright © 2013 Cambridge University Press.

Hardwick J.M.,Johns Hopkins University | Chen Y.-B.,Johns Hopkins University | Chen Y.-B.,Sloan Kettering Cancer Center | Jonas E.A.,Yale University
Trends in Cell Biology | Year: 2012

Classical apoptotic cell death is now sufficiently well understood to be interrogated with mathematical modeling and manipulated with targeted drugs for clinical benefit. However, a biological black hole has emerged with the realization that apoptosis regulators are functionally multipolar. BCL-2 family proteins appear to have much greater effects on cells than can be explained by their known roles in apoptosis. Although these effects may be observable simply because the cell is not dead, the general assumption is that BCL-2 proteins have undiscovered biochemical activities. Conversely, these as yet uncharacterized day-jobs also may underlie their profound effects on cell survival, challenging current assumptions about classical apoptosis. Even their sub-mitochondrial localizations remain controversial. Here we attempt to integrate seemingly conflicting information with the prospect that BCL-2 proteins themselves may be the critical crosstalk between life and death. © 2012 Elsevier Ltd.

News Article | July 13, 2016

Zika Virus - What You Should Know Ticked Off! Here's What You Need To Know About Lyme Disease Last week, federal health regulators in the United States suspended the clinical trial of an anticancer treatment developed by Juno Therapeutics following the deaths of three participants this year. Now, after a modification to the leukemia treatment, the U.S. Food and Drug Administration (FDA) has allowed Juno to resume its study, but only without a specific chemotherapy drug. The company's experimental treatment known as JCAR015 is designed to treat adult patients with B cell acute lymphoblastic leukemia. However, in May, one study participant passed away, while two more participants died in late June from swelling of the brain. According to Seattle-based Juno Therapeutics, the problem did not stem from JCAR015, but from a chemotherapy drug called fludarabine, which is used during the pretreatment. The company said last week that it will submit documents to the FDA including revisions in the trial protocol and patient consent forms. Juno will resume its trials but without fludarabine and will instead use the chemotherapy drug cyclophosphamide, which was already part of JCAR015. Juno's JCAR015 treatment, which uses a new approach called chimeric antigen receptor (CAR-T), is "promising, but still unproven," according to The New York Times. The treatment modifies a patient's immune system to target and attack cancer cells. More specifically, the person's white blood cells are taken away from the body and changed to identify and kill cancer cells when returned. Initial studies have shown that striking results in the treatment of lymphoma and leukemia, offering hope to patients, oncologists and investors. However, JCAR015 has been found to induce severe side effects. This includes overreactions in the immune system and neurological toxicity such as intense swelling in the brain known as cerebral edema. Other pharmaceutical companies such as Kite Pharma Inc. and Pfizer Inc. are also pursuing the CAR-T treatment approach. CAR-T is part of a wider scientific trend in which the immune systems of patients are harnessed to fight cancer. Meanwhile, in after-hours trading, the shares of Juno Pharmaceuticals increased 25.3 percent to $34.83. The company's stocks dropped Friday, July 8, after the FDA announced the suspension. Juno was launched in 2013 in collaboration with scientists from the Fred Hutchinson Cancer Research, the Seattle Children's Research Institute and the Sloan Kettering Cancer Center. In December 2014, Juno went public at $24 a share. In 2015, the biotech company announced that it was partnering up with Celgene Corp. for a 10-year project focused on treatments for autoimmune diseases and cancer. According to the Wall Street Journal, Celgene initially invested $1 billion in Juno, including a $150 million payment and an $849.8 million stock purchase. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.

Keshari K.R.,Sloan Kettering Cancer Center | Wilson D.M.,University of California at San Francisco
Chemical Society Reviews | Year: 2014

The study of transient chemical phenomena by conventional NMR has proved elusive, particularly for non-1H nuclei. For 13C, hyperpolarization using the dynamic nuclear polarization (DNP) technique has emerged as a powerful means to improve SNR. The recent development of rapid dissolution DNP methods has facilitated previously impossible in vitro and in vivo study of small molecules. This review presents the basics of the DNP technique, identification of appropriate DNP substrates, and approaches to increase hyperpolarized signal lifetimes. Also addressed are the biochemical events to which DNP-NMR has been applied, with descriptions of several probes that have met with in vivo success. © 2014 The Royal Society of Chemistry.

Garg K.,University of California at San Francisco | Soslow R.A.,Sloan Kettering Cancer Center
Archives of Pathology and Laboratory Medicine | Year: 2014

Context. - Endometrial carcinoma is a disease of older postmenopausal women, and is relatively uncommon in patients younger than 40 years. Endometrial carcinomas in this age group may be familial, associated with Lynch syndrome, or sporadic. Objectives. - To present our current knowledge of endometrial carcinomas in women younger than 40 years. Data Sources. - The review is based on previously published articles on this topic. Conclusions. - Most endometrial carcinomas that occur in this age group are associated with estrogen excess. They are usually low-grade endometrioid carcinomas that present at low stages and are associated with favorable clinical outcomes. Tumors associated with mismatch repair abnormalities and Lynch syndrome appear to be distinct, with worse prognostic factors and, possibly, clinical behavior. Conservative hormonal therapy and ovarian conservation are reasonable considerations in the management of these young patients, but carry the risk of tumor progression, recurrence, and an occult synchronous or metachronous ovarian carcinoma.

O'Sullivan T.E.,Sloan Kettering Cancer Center | Sun J.C.,Sloan Kettering Cancer Center | Sun J.C.,New York Medical College | Lanier L.L.,University of California at San Francisco
Immunity | Year: 2015

Natural killer (NK) cells have historically been considered short-lived cytolytic cells that can rapidly respond against pathogens and tumors in an antigen-independent manner and then undergo cell death. Recently, however, NK cells have been shown to possess traits of adaptive immunity and can acquire immunological memory in a manner similar to that of T and B cells. In this review, we discuss evidence of NK cell memory and the mechanisms involved in the generation and survival of these innate lymphocytes. © 2015 Elsevier Inc.

Abdel-Wahab O.,Sloan Kettering Cancer Center | Dey A.,Genentech
Leukemia | Year: 2013

The recent identification of germline and somatic mutations in BAP1 as well as in multiple members of the ASXL (additional sex combs-like) family of genes has highlighted the role of these proteins in a diverse array of biological functions. A diverse number of possible functions have previously been ascribed to ASXL1 in non-hematopoietic contexts, including physical co-operativity with HP1a and LSD1. Here we discuss new evidence for a BAP1-independent function of ASXL1 in regulating histone H3 lysine 27 methylation through interactions with the Polycomb-repressive complex 2 (PRC2). BAP1, a nuclear-localized deubiquitinase, has been shown to interact with a number of proteins, including ASXL1 and/or ASXL2, but the functional importance of this interaction has remained elusive. Here, we highlight recent work revealing the critical function of BAP1 in restricting myelopoiesis and in regulating hematopoietic stem cell function. These data provide evidence that BAP1 and ASXL1 function as a novel class of tumor suppressors in myeloid malignancies. BAP1 functions through effects on stability of host cell factor-1, and O-GlcNAcylation, and ASXL1 impacts histone post-translational modifications through interaction with PRC2. Future studies investigating the mechanism of transformation by loss of BAP1 and ASXL1 may result in new therapeutic approaches to treat hematological malignancies. © 2013 Macmillan Publishers Limited All rights reserved.

Sloan Kettering Cancer Center and President And Fellows Of Harvard College | Date: 2015-08-20

The present invention relates to a method for predicting three-dimensional structure of a protein from its sequence. Three-dimensional structure may be determined by: (a) generating a multiple sequence alignment for a candidate protein having a known sequence; (b) identifying a covariance matrix between all pairs of sequence positions in the multiple sequence alignment; (c) inverting the covariance matrix and identifying predicted evolutionary constraints using a statistical model of the candidate protein; and (d) simulating folding of an extended chain structure of the candidate protein using the predicted constraints.

Haynes C.M.,Sloan Kettering Cancer Center | Haynes C.M.,New York Medical College | Fiorese C.J.,Sloan Kettering Cancer Center | Fiorese C.J.,New York Medical College | Lin Y.-F.,Sloan Kettering Cancer Center
Trends in Cell Biology | Year: 2013

During development and cellular differentiation, tissue- and cell-specific programs mediate mitochondrial biogenesis to meet physiological needs. However, environmental and disease-associated factors can perturb mitochondrial activities, requiring cells to adapt to protect mitochondria and maintain cellular homeostasis. Several mitochondrion-to-nucleus signaling pathways, or retrograde responses, have been described, but the mechanisms by which mitochondrial stress or dysfunction is sensed to coordinate precisely the appropriate response has only recently begun to be understood. Recent studies of the mitochondrial unfolded-protein response (UPRmt) indicate that the cell monitors mitochondrial protein import efficiency as an indicator of mitochondrial function. Here, we review how the cell evaluates mitochondrial function and regulates transcriptional induction of the UPRmt, adapts protein-synthesis rates and activates mitochondrial autophagy to promote mitochondrial function and cell survival during stress. © 2013 Elsevier Ltd.

White R.,Sloan Kettering Cancer Center | White R.,New York Medical College | Rose K.,Childrens Hospital Boston | Rose K.,Howard Hughes Medical Institute | And 4 more authors.
Nature Reviews Cancer | Year: 2013

The zebrafish is a recent addition to animal models of human cancer, and studies using this model are rapidly contributing major insights. Zebrafish develop cancer spontaneously, after mutagen exposure and through transgenesis. The tumours resemble human cancers at the histological, gene expression and genomic levels. The ability to carry out in vivo imaging, chemical and genetic screens, and high-throughput transgenesis offers a unique opportunity to functionally characterize the cancer genome. Moreover, increasingly sophisticated modelling of combinations of genetic and epigenetic alterations will allow the zebrafish to complement what can be achieved in other models, such as mouse and human cell culture systems. © 2013 Macmillan Publishers Limited. All rights reserved.

Iaea D.B.,New York Medical College | Maxfield F.R.,Sloan Kettering Cancer Center
Essays in Biochemistry | Year: 2015

Sterols are a critical component of cell membranes of eukaryotes. In mammalian cells there is approximately a six-fold range in the cholesterol content in various organelles. The cholesterol content of membranes plays an important role in organizing membranes for signal transduction and protein trafficking as well as in modulating the physiochemical properties of membranes. Cholesterol trafficking among organelles is highly dynamic and is mediated by both vesicular and non-vesicular processes. Several proteins have been proposed to mediate inter-organelle trafficking of cholesterol. However, several aspects of the mechanisms involved in regulating trafficking and distribution of cholesterol remain to be elucidated. In the present chapter, we discuss the cellular mechanisms involved in cholesterol distribution and the trafficking processes involved in maintaining sterol homoeostasis. © The Authors Journal compilation © 2015 Biochemical Society.

Scott A.M.,University of Melbourne | Wolchok J.D.,Sloan Kettering Cancer Center | Wolchok J.D.,New York Medical College | Old L.J.,Sloan Kettering Cancer Center | Old L.J.,New York Medical College
Nature Reviews Cancer | Year: 2012

The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Antibody-drug conjugates are powerful new treatment options for lymphomas and solid tumours, and immunomodulatory antibodies have also recently achieved remarkable clinical success. The development of therapeutic antibodies requires a deep understanding of cancer serology, protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system and cancer cells. This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials. © 2012 Macmillan Publishers Limited. All rights reserved.

Lipchina I.,Sloan Kettering Cancer Center | Studer L.,Sloan Kettering Cancer Center | Betel D.,New York Medical College
Cell Cycle | Year: 2012

MicroRNA (miRNA) has been shown to be essential for regulating cell fate and pluripotency; however, our knowledge of miRNA function in stem cells is incomplete due to experimental limitations and difficulties in identifying their physiological targets. Recent studies implicated hESC-expressed miRNAs (miR-302-367 and miR-371-373 clusters) in regulating BMP signaling and promoting pluripotency, suggesting that low levels of BMP signaling may promote pluripotency by preventing neural induction. A comprehensive list of miR-302-367 targets recently identified by genome-wide approaches suggests a number of additional cellular processes and signaling pathways whose regulation by miR-302-367 may promote pluripotency and reprogramming, such as cell cycle, epigenetic changes, metabolism and vesicular transfer. © 2012 Landes Bioscience.

Yen J.,Wellcome Trust Sanger Institute | White R.M.,Sloan Kettering Cancer Center | Stemple D.L.,Wellcome Trust Sanger Institute
Current Opinion in Genetics and Development | Year: 2014

The need for scalable strategies to probe the biological consequences of candidate cancer genes has never been more pressing. The zebrafish, with its capacity for high-throughput transgenesis, in vivo imaging and chemical/genetic screening, has ideal features for undertaking this task. Unique biological insights from zebrafish have already led to the identification of novel oncogenic drivers and small molecules being used to treat the human cancer. This review summarizes the recent main findings and describes pertinent areas where the zebrafish can greatly contribute to our understanding of cancer biology and treatment. © 2013 The Authors.

Cheong H.,Sloan Kettering Cancer Center | Lu C.,Sloan Kettering Cancer Center | Lu C.,University of Pennsylvania | Lindsten T.,Sloan Kettering Cancer Center | Thompson C.B.,Sloan Kettering Cancer Center
Nature Biotechnology | Year: 2012

The metabolism of cancer cells is reprogrammed both by oncogene signaling and by dysregulation of metabolic enzymes. The resulting altered metabolism supports cellular proliferation and survival but leaves cancer cells dependent on a continuous supply of nutrients. Thus, many metabolic enzymes have become targets for new cancer therapies. Recently, two processes-expression of specific isoforms of metabolic enzymes and autophagy-have been shown to be crucial for the adaptation of tumor cells to changes in nutrient availability. An increasing number of approved and experimental therapeutics target these two processes. A better understanding of the molecular basis of cancer-associated metabolic changes may lead to improved cancer therapies. © 2012 Nature America, Inc. All rights reserved.

Turner N.C.,Institute of Cancer Research | Turner N.C.,Royal Marsden Hospital | Reis-Filho J.S.,Sloan Kettering Cancer Center
Clinical Cancer Research | Year: 2013

Triple-negative breast cancer (TNBC) comprises a highly diverse collection of cancers. Here, we review this diversity both in terms of gene expression subtypes and the repertoire of genetic events. Transcriptomic analyses of TNBC have revealed at least six subtypes, with the luminal androgen receptor (luminal AR) or molecular apocrine cancers forming a distinct group within triple-negative disease. Distinct from the gene expression subtypes, a diverse set of genetic events have been described in TNBC, with a number of potentially targetable genetic events found although all at relatively low frequency. Clinical trials to define the clinical utility of therapies targeting these low-frequency events will require substantial screening efforts to identify sufficient patients. Set against the diversity of TNBC, clinical studies of patients with triplenegative disease will need to be either focused on molecularly defined subsets with upfront molecular stratification, or powered for a secondary endpoint analysis of a molecularly defined subset. Such approaches will be crucial to realize the potential of precision medicine for patients with TNBCs. © 2013 American Association for Cancer Research.

Ward P.S.,Sloan Kettering Cancer Center | Ward P.S.,University of Pennsylvania | Thompson C.B.,Sloan Kettering Cancer Center
Cancer Cell | Year: 2012

Cancer metabolism has long been equated with aerobic glycolysis, seen by early biochemists as primitive and inefficient. Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria but result from oncogene-directed metabolic reprogramming required to support anabolic growth. Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation. No longer can cancer-associated alterations in metabolism be viewed as an indirect response to cell proliferation and survival signals. We contend that altered metabolism has attained the status of a core hallmark of cancer. © 2012 Elsevier Inc.

Howe L.R.,New York Medical College | Subbaramaiah K.,New York Medical College | Hudis C.A.,New York Medical College | Hudis C.A.,Sloan Kettering Cancer Center | Dannenberg A.J.,New York Medical College
Clinical Cancer Research | Year: 2013

The increasing rate of obesity worldwide is predicted to be associated with a surge in diseases. Notably, obesity has been linked to approximately 20% of cancer cases in the United States; obesity is associated with both increased risk and worse outcomes after diagnosis. Altered levels of circulating factors are strongly implicated, including insulin, insulin-like growth factor 1, leptin, adiponectin, and interleukin-6 (IL-6). In addition, increasing attention has focused on the consequences of local adipose inflammation. Inflammatory foci characterized by crown-like structures consisting of dead adipocytes encircled by macrophages occur in white adipose depots, including the breast tissue, of most overweight and obese women. Saturated fatty acids, released as a consequence of obesity-associated lipolysis, induce macrophage activation via Toll-like receptor 4, thereby stimulating NF-κB signaling. This, in turn, activates transcription of proinflammatory genes including COX-2, IL-6, IL-1β, and TNFα. Elevated levels of proinflammatory mediators cause both local and systemic effects. Of particular relevance with regard to breast cancer is increased transcription of the CYP19 gene encoding aromatase, the ratelimiting enzyme for estrogen synthesis. Notably, this obesity-inflammation- aromatase axis provides a plausible explanation for increased rates of postmenopausal, hormone receptor-positive breast cancer associated with obesity and hence may offer targets for interventions to attenuate risk or improve prognosis. Potential approaches include weight reduction, exercise, and suppression of obesity-driven signaling pathways using pharmaceutical or dietary agents. A key future goal is to identify biomarkers that accurately report adipose inflammation, both for identification of at-risk individuals and to assess the efficacy of interventions. © 2013 American Association for Cancer Research.

Chang Q.,Sloan Kettering Cancer Center | Daly L.,Sloan Kettering Cancer Center | Bromberg J.,Sloan Kettering Cancer Center | Bromberg J.,New York Medical College
Seminars in Immunology | Year: 2014

IL-6 signaling plays a prominent role in tumorigenesis and metastasis. In this review we discuss the recent evidence describing the tumor intrinsic and extrinsic functions of this signaling pathway. Although blockade of this pathway in pre-clinical models leads to a reduction in tumor growth and metastasis, its clinical success is less evident. Thus, identifying the features of tumors/patients that predict response to anti-IL6 therapy are needed. © 2014.

Dudakov J.A.,Sloan Kettering Cancer Center | Dudakov J.A.,Monash University | Hanash A.M.,Sloan Kettering Cancer Center | Van Den Brink M.R.M.,Sloan Kettering Cancer Center
Annual Review of Immunology | Year: 2015

Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, γδ T cells, NKT cells, and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has evolved rapidly since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues, including the intestines, lung, liver, kidney, thymus, pancreas, and skin. IL-22 primarily targets nonhematopoietic epithelial and stromal cells, where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function. © 2015 by Annual Reviews. All rights reserved.

Zakrzewski J.L.,Sloan Kettering Cancer Center | Van Den Brink M.R.M.,Sloan Kettering Cancer Center | Hubbell J.A.,Institute of Bioengineering | Hubbell J.A.,University of Chicago
Nature Biotechnology | Year: 2014

Regenerative therapies that use allogeneic cells are likely to encounter immunological barriers similar to those that occur with transplantation of solid organs and allogeneic hematopoietic stem cells (HSCs). Decades of experience in clinical transplantation hold valuable lessons for regenerative medicine, offering approaches for developing tolerance-induction treatments relevant to cell therapies. Outside the field of solid-organ and allogeneic HSC transplantation, new strategies are emerging for controlling the immune response, such as methods based on biomaterials or mimicry of antigen-specific peripheral tolerance. Novel biomaterials can alter the behavior of cells in tissue-engineered constructs and can blunt host immune responses to cells and biomaterial scaffolds. Approaches to suppress autoreactive immune cells may also be useful in regenerative medicine. The most innovative solutions will be developed through closer collaboration among stem cell biologists, transplantation immunologists and materials scientists. © 2014 Nature America, Inc.

Veselis R.A.,Sloan Kettering Cancer Center | Veselis R.A.,New York Medical College
British Journal of Anaesthesia | Year: 2015

As opposed to conscious, personally relevant (explicit) memories that we can recall at will, implicit (unconscious) memories are prototypical of 'hidden' memory; memories that exist, but that we do not know we possess. Nevertheless, our behaviour can be affected by thesememories; in fact, thesememories allowus to function inan ever-changing world. It is still unclear frombehavioural studies whether similar memories can be formed during anaesthesia. Thus, a relevant question is whether implicit memory formation is a realistic possibility during anaesthesia, considering the underlying neurophysiology. A different conceptualization of memory taxonomy is presented, the serial parallel independentmodel of Tulving,which focuses on dynamic information processing with interactions among different memory systems rather than static classification of different types of memories. The neurophysiological basis for subliminal information processing is considered in the context of brain function as embodied in network interactions. Function of sensory cortices and thalamic activity during anaesthesia are reviewed. The role of sensory and perisensory cortices, in particular the auditory cortex, in support of memory function is discussed. Although improbable, with the current knowledge of neurophysiology one cannot rule out the possibility of memory formation during anaesthesia. © 2015 The Author Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.

Lu C.,Sloan Kettering Cancer Center | Lu C.,University of Pennsylvania | Thompson C.B.,Sloan Kettering Cancer Center
Cell Metabolism | Year: 2012

How cells sense and respond to environmental cues remains a central question of biological research. Recent evidence suggests that DNA transcription is regulated by chromatin organization. However, the mechanism for relaying the cytoplasmic signaling to chromatin remodeling remains incompletely understood. Although much emphasis has been put on delineating transcriptional output of growth factor/hormonal signaling pathways, accumulated evidence from yeast and mammalian systems suggest that metabolic signals also play critical roles in determining chromatin structure. Here we summarize recent progress in understanding the molecular connection between metabolism and epigenetic modifications of chromatin implicated in a variety of diseases including cancer. © 2012 Elsevier Inc.

Wellen K.E.,University of Pennsylvania | Thompson C.B.,Sloan Kettering Cancer Center
Nature Reviews Molecular Cell Biology | Year: 2012

It is becoming increasingly clear that cellular signalling and metabolism are not just separate entities but rather are tightly linked. Although nutrient metabolism is known to be regulated by signal transduction, an emerging paradigm is that signalling and transcriptional networks can be modulated by nutrient-sensitive protein modifications, such as acetylation and glycosylation, which depend on the availability of acetyl-CoA and sugar donors such as UDP-N-acetylglucosamine (UDP-GlcNAc), respectively. The integration of metabolic and signalling cues allows cells to modulate activities such as metabolism, cell survival and proliferation according to their intracellular metabolic resources. © 2012 Macmillan Publishers Limited. All rights reserved.

Murali R.,Sloan Kettering Cancer Center | Soslow R.A.,Sloan Kettering Cancer Center | Soslow R.A.,New York Medical College | Weigelt B.,Sloan Kettering Cancer Center
The Lancet Oncology | Year: 2014

Endometrial cancer is the most common gynaecological malignancy in Europe and North America. Traditional classification of endometrial carcinoma is based either on clinical and endocrine features (eg, types I and II) or on histopathological characteristics (eg, endometrioid, serous, or clear-cell adenocarcinoma). Subtypes defined by the different classification systems correlate to some extent, but there is substantial heterogeneity in biological, pathological, and molecular features within tumour types from both classification systems. In this Review we provide an overview of traditional and newer genomic classifications of endometrial cancer. We discuss how a classification system that incorporates genomic and histopathological features to define biologically and clinically relevant subsets of the disease would be useful. Such integrated classification might facilitate development of treatments tailored to specific disease subgroups and could potentially enable delivery of precision medicine to patients with endometrial cancer. © 2014 Elsevier Ltd.

Couch F.J.,Mayo Medical School | Nathanson K.L.,University of Pennsylvania | Offit K.,Sloan Kettering Cancer Center | Offit K.,New York Medical College
Science | Year: 2014

The cloning of the breast cancer susceptibility genes BRCA1 and BRCA2 nearly two decades ago helped set in motion an avalanche of research exploring how genomic information can be optimally applied to identify and clinically care for individuals with a high risk of developing cancer. Genetic testing for mutations in BRCA1, BRCA2, and other breast cancer susceptibility genes has since proved to be a valuable tool for determining eligibility for enhanced screening and prevention strategies, as well as for identifying patients most likely to benefit from a targeted therapy. Here, we discuss the landscape of inherited mutations and sequence variants in BRCA1 and BRCA2, the complexities of determining disease risk when the pathogenicity of sequence variants is uncertain, and current strategies for clinical management of women who carry BRCA1/2 mutations.

Pellegrino M.W.,Sloan Kettering Cancer Center | Nargund A.M.,Sloan Kettering Cancer Center | Kirienko N.V.,Massachusetts General Hospital | Kirienko N.V.,Harvard University | And 4 more authors.
Nature | Year: 2014

Metazoans identify and eliminate bacterial pathogens in microbe-rich environments such as the intestinal lumen; however, themechanisms are unclear.Host cells could potentially use intracellular surveillance or stress response programs to detect pathogens that targetmonitored cellular activities andthen initiate innate immune responses1-3.Mitochondrial function is evaluated bymonitoringmitochondrial protein import efficiency of the transcription factorATFS-1,whichmediates the mitochondrial unfolded protein response (UPRmt). Duringmitochondrial stress, mitochondrial import is impaired4, allowing ATFS-1 to traffic to the nucleus where it mediates a transcriptional response to re-establish mitochondrial homeostasis5. Here we examined the role of ATFS-1 inCaenorhabditis elegans during pathogen exposure, because during mitochondrial stressATFS-1 induced not onlymitochondrial protective genes but also innate immunegenes that included a secreted lysozyme and anti-microbial peptides. Exposure to the pathogen Pseudomonas aeruginosa caused mitochondrial dysfunction and activation of the UPRmt. C. elegans lacking atfs-1 were susceptible to P. aeruginosa, whereas hyper-activation of ATFS-1 and the UPRmt improved clearance of P. aeruginosa from the intestine and prolonged C. elegans survival in a manner mainly independent of knowninnate immune pathways6,7.Wepropose thatATFS-1 import efficiency and the UPRmt is a means to detect pathogens that target mitochondria and initiate a protective innate immune response. © 2014 Macmillan Publishers Limited. All rights reserved.

Magge R.S.,Sloan Kettering Cancer Center | DeAngelis L.M.,Sloan Kettering Cancer Center | DeAngelis L.M.,New York Medical College
Blood Reviews | Year: 2015

The number of available therapies for hematologic malignancies continues to grow at a rapid pace. Unfortunately, many of these treatments carry both central and peripheral nervous system toxicities, potentially limiting a patient's ability to tolerate a full course of treatment. Neurotoxicity with chemotherapy is common and second only to myelosuppression as a reason to limit dosing. This review addresses the neurotoxicity of newly available therapeutic agents including brentuximab vedotin and blinatumomab as well as classic ones such as methotrexate, vinca alkaloids and platinums. Although peripheral neuropathy is common with many drugs, other complications such as seizures and encephalopathy may require more immediate attention. Rapid recognition of adverse neurologic effects may lead to earlier treatment and appropriate adjustment of dosing regimens. In addition, knowledge of common toxicities may help differentiate chemotherapy-related symptoms from actual progression of cancer into the CNS. © 2014 Elsevier Ltd.

Sadelain M.,Sloan Kettering Cancer Center | Papapetrou E.P.,Sloan Kettering Cancer Center | Bushman F.D.,University of Pennsylvania
Nature Reviews Cancer | Year: 2012

DNA and the host genome limit the reliability and safety of transgene integration for therapeutic cell engineering and other applications. Although targeted gene delivery has made considerable progress, the question of where to insert foreign sequences in the human genome to maximize safety and efficacy has received little attention. In this Opinion article, we discuss 'genomic safe harbours'-chromosomal locations where therapeutic transgenes can integrate and function in a predictable manner without perturbing endogenous gene activity and promoting cancer. © 2012 Macmillan Publishers Limited. All rights reserved.

Naredi P.,Sahlgrenska University Hospital | La Quaglia M.P.,Sloan Kettering Cancer Center
Nature Reviews Clinical Oncology | Year: 2015

Patients with cancer generally have better outcomes when treated as part of a clinical trial compared with patients not enrolled in a clinical trial. Unfortunately, surgical participation in, and leadership of such studies, is limited. This lack of clinical investigation is adversely affecting progress in cancer surgery research and, ultimately, hinders the treatment of patients. Some of the reasons for poor surgical participation in clinical research include: limitations on funding provision; inadequate training of junior surgeons in clinical trials methodology; and inadequate support of surgical faculty members as clinical investigators. Despite these shortcomings, numerous successful surgical studies have helped to change concepts, and improve patient care in certain clinical areas. Finally, a number of possible solutions are proposed, which might improve surgical involvement in clinical trials and result in more, and better-designed and executed clinical trials in this important area of research. © 2015 Macmillan Publishers Limited.

Krajcovic M.,Sloan Kettering Cancer Center | Krajcovic M.,New York Medical College | Overholtzer M.,Sloan Kettering Cancer Center | Overholtzer M.,New York Medical College
Cancer Research | Year: 2012

Aneuploidy is a hallmark of human cancers originating from abnormal mitoses. Many aneuploid cancer cells also have greater-than-diploid DNA content, suggesting that polyploidy is a common precursor to aneuploidy during tumor progression. Polyploid cells can originate from cell fusion, endoreplication, and cytokinesis failure. Recently we found that cell cannibalism by entosis, a form of cell engulfment involving live cells, also leads to polyploidy, as internalized cells disrupt cytokinesis of their engulfing cell hosts. By this mechanism, cannibalistic cell behavior could promote tumor progression by leading to aneuploidy. Here, we discuss cell cannibalism in cancer and other mechanisms that result in the formation of polyploid cancer cells. ©2012 AACR.

Roper N.,New York Medical College | Korenstein D.,Sloan Kettering Cancer Center
Journal of General Internal Medicine | Year: 2015

BACKGROUND: Journals have increased disclosure requirements in recent years, in part to deter guest authorship. The prevalence of guest authorship among primary authors (first and last) in the current era of increased disclosure requirements is unknown. OBJECTIVES: Our aim was to examine the self-reported prevalence of guest authorship among primary authors from a sample of randomized clinical trials with and without industry funding and industry collaboration in the design, analysis or reporting of trials. DESIGN: Cross-sectional analysis of randomized, drug/device clinical trials with published details on the “Role of the Funding Source/Sponsor” published in high-impact biomedical journals between 1 December 2011 and 31 November 2012. Phase 1 or 2 trials, secondary trial analyses, and trials that were not listed on were excluded. Primary guest authorship was defined, based on International Committee of Medical Journal Editors (ICMJE) criteria, when neither the first nor last author contributed to either of the following: 1) the design of the trial or the analysis/interpretation of data; or 2) drafting part or all of the manuscript. PARTICIPANTS: One hundred and sixty-eight randomized clinical trials that met inclusion criteria were included. MAIN OUTCOME MEASURES: We measured differences in the prevalence of guest authorship between trials with neither industry funding nor collaboration and 1) trials with industry funding without collaboration, and 2) trials with industry funding with collaboration. RESULTS: The overall prevalence of primary guest authorship was 6 % (10/168). Primary guest authorship was significantly more common in trials with industry funding with collaboration than in those with neither industry funding nor collaboration [13.2 % (10/76) vs. 0 % (0/39); p < 0.02]. Primary guest authorship did not differ between trials with industry funding without collaboration and trials with neither industry funding nor collaboration. CONCLUSIONS: Among a sample of randomized, drug/device clinical trials in high-impact biomedical journals, primary guest authorship was overall uncommon and occurred exclusively among trials with industry funding with collaboration. © 2015, Society of General Internal Medicine.

Rathkopf D.,New York Medical College | Scher H.I.,Sloan Kettering Cancer Center
Cancer Journal (United States) | Year: 2013

Persistent androgen receptor (AR) signaling despite low levels of serum androgens has been identified as a critical target for drug discovery in castration-resistant prostate cancer (CRPC). As proof of principle that the AR remains relevant in CRPC, 2 AR-targeted agents recently approved by the Food and Drug Administration-abiraterone and enzalutamide-have increased overall survival for patients with CRPC in the setting of prior chemotherapy. This review focuses on the AR and 2 direct antagonists, enzalutamide and ARN-509. These next-generation AR antagonists offer great promise for patients with advanced disease. Relative to conventional antiandrogens such as bicalutamide, they bind to the receptor with higher affinity, prevent nuclear translocation and DNA binding, and induce apoptosis without agonist activity in preclinical models. The success of these AR-targeted agents in the clinic has changed the landscape of therapy for patients with CRPC, and further therapeutic options building on this platform are currently in development. Copyright © 2013 Lippincott Williams &Wilkins.

Baker B.M.,Sloan Kettering Cancer Center | Nargund A.M.,Sloan Kettering Cancer Center | Sun T.,Sloan Kettering Cancer Center | Haynes C.M.,Sloan Kettering Cancer Center | Haynes C.M.,New York Medical College
PLoS Genetics | Year: 2012

Cells respond to defects in mitochondrial function by activating signaling pathways that restore homeostasis. The mitochondrial peptide exporter HAF-1 and the bZip transcription factor ATFS-1 represent one stress response pathway that regulates the transcription of mitochondrial chaperone genes during mitochondrial dysfunction. Here, we report that GCN-2, an eIF2α kinase that modulates cytosolic protein synthesis, functions in a complementary pathway to that of HAF-1 and ATFS-1. During mitochondrial dysfunction, GCN-2-dependent eIF2α phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans. Reactive oxygen species (ROS) generated from dysfunctional mitochondria are required for GCN-2-dependent eIF2α phosphorylation but not ATFS-1 activation. Simultaneous deletion of ATFS-1 and GCN-2 compounds the developmental defects associated with mitochondrial stress, while stressed animals lacking GCN-2 display a greater dependence on ATFS-1 and stronger induction of mitochondrial chaperone genes. These findings are consistent with translational control and stress-dependent chaperone induction acting in complementary arms of the UPRmt. © 2012 Baker et al.

Lianoglou S.,Sloan Kettering Cancer Center | Lianoglou S.,New York Medical College | Garg V.,Sloan Kettering Cancer Center | Yang J.L.,Sloan Kettering Cancer Center | And 2 more authors.
Genes and Development | Year: 2013

More than half of human genes use alternative cleavage and polyadenylation (ApA) to generate mRNA transcripts that differ in the lengths of their 3' untranslated regions (UTRs), thus altering the post-transcriptional fate of the message and likely the protein output. The extent of 3' UTR variation across tissues and the functional role of ApA remain poorly understood.We developed a sequencing method called 3'-seq to quantitatively map the 3' ends of the transcriptome of diverse human tissues and isogenic transformation systems. We found that cell typespecific gene expression is accomplished by two complementary programs. Tissue-restricted genes tend to have single 3' UTRs, whereas a majority of ubiquitously transcribed genes generate multiple 3' UTRs. During transformation and differentiation, single-UTR genes change their mRNA abundance levels, while multi-UTR genes mostly change 3' UTR isoform ratios to achieve tissue specificity. However, both regulation programs target genes that function in the same pathways and processes that characterize the new cell type. Instead of finding global shifts in 3' UTR length during transformation and differentiation, we identify tissue-specific groups of multi-UTR genes that change their 3' UTR ratios; these changes in 3' UTR length are largely independent from changes in mRNA abundance. Finally, tissue-specific usage of ApA sites appears to be a mechanism for changing the landscape targetable by ubiquitously expressed microRNAs. © 2013 Lianoglou et al.

Scher H.I.,New York Medical College | Morris M.J.,New York Medical College | Larson S.,New York Medical College | Heller G.,Sloan Kettering Cancer Center
Nature Reviews Clinical Oncology | Year: 2013

To improve future drug development and patient management for patients with castration-resistant prostate cancer (CRPC), surrogate biomarkers that are linked to relevant outcomes are urgently needed. A biomarker must be measurable, reproducible, linked to relevant clinical outcomes, and demonstrate clinical utility. This area is rapidly evolving, with recent trials in patients with CRPC incorporating the detection of circulating tumour cells (CTCs), imaging, and patient-reported outcome biomarkers. We discuss the framework for the development of biomarkers for CRPC, including different categories and contexts of use. We also highlight the requirements of analytical validation, the sequence of trials needed for clinical validation and regulatory approval, and the future outlook for imaging and CTC biomarkers. ©2013 Macmillan Publishers Limited. All rights reserved.

O'Sullivan T.E.,Sloan Kettering Cancer Center | Johnson L.R.,Sloan Kettering Cancer Center | Kang H.H.,New York Medical College | Sun J.C.,Sloan Kettering Cancer Center | Sun J.C.,New York Medical College
Immunity | Year: 2015

Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as clonal expansion, contraction, and generation of long-lived "memory" cells, processes poorly understood at the molecular level. Here, we found that as proliferating NK cells accumulated dysfunctional mitochondria during viral infection, a protective mitophagy pathway was induced during the contraction phase to promote their survival in a reactive oxygen species (ROS)-dependent manner. Inhibition of mechanistic target of rapamycin (mTOR) or activation of AMP-activated protein kinase (AMPK) during the contraction-to-memory phase transition of the antiviral response increased autophagic activity and enhanced memory NK cell numbers through an Atg3-dependent mechanism. Furthermore, we demonstrated a temporally regulated role for mitophagy-inducing proteins BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L) in the generation of robust NK cell memory. Thus, our study reveals the functional importance of mitophagy during the dynamic response of these cytolytic innate lymphocytes. After viral infection, the majority of effector lymphocytes undergo rapid apoptosis. However, it is unclear how a subset of these cells persist to form immunological memory. Sun and colleagues demonstrate that mitophagy promotes the survival of virus-specific NK cells during the contraction phase to promote memory. © 2015 Elsevier Inc.

Shvartsbart A.,University of Pennsylvania | Shvartsbart A.,Sloan Kettering Cancer Center | Smith A.B.,University of Pennsylvania
Journal of the American Chemical Society | Year: 2015

Presented here is a full account on the development of a strategy culminating in the first total synthesis of the architecturally complex daphniphyllum alkaloid, (-)-calyciphylline N. Highlights of the approach include a highly diastereoselective, intramolecular Diels-Alder reaction of a silicon-tethered acrylate; an efficient Stille carbonylation of a sterically encumbered vinyl triflate; a one-pot Nazarov cyclization/proto-desilylation sequence; and the chemoselective hydrogenation of a fully substituted diene ester. © 2015 American Chemical Society.

Levine A.G.,Sloan Kettering Cancer Center | Arvey A.,Sloan Kettering Cancer Center | Arvey A.,Gilead Sciences | Jin W.,Sloan Kettering Cancer Center | And 3 more authors.
Nature Immunology | Year: 2014

Foxp3+ regulatory T cells (Treg cells) maintain immunological tolerance, and their deficiency results in fatal multiorgan autoimmunity. Although heightened signaling via the T cell antigen receptor (TCR) is critical for the differentiation of Treg cells, the role of TCR signaling in Treg cell function remains largely unknown. Here we demonstrated that inducible ablation of the TCR resulted in Treg cell dysfunction that could not be attributed to impaired expression of the transcription factor Foxp3, decreased expression of Treg cell signature genes or altered ability to sense and consume interleukin 2 (IL-2). Instead, TCR signaling was required for maintaining the expression of a limited subset of genes comprising 25% of the activated Treg cell transcriptional signature. Our results reveal a critical role for the TCR in the suppressor capacity of Treg cells. © 2014 Nature America, Inc. All rights reserved.

Budhu S.,Sloan Kettering Cancer Center | Wolchok J.,Sloan Kettering Cancer Center | Wolchok J.,New York Medical College | Merghoub T.,Sloan Kettering Cancer Center
Current Opinion in Genetics and Development | Year: 2014

The clinical success and US FDA approval of two immunotherapies (sipuleucel-T and ipilimumab) have brought tumor immunology to the forefront of cancer research. It has been long recognized that the immune system can infiltrate and survey the tumor microenvironment. The field of tumor immunology has been actively examining this phenomenon since the 1890s when William Coley first treated patients with live pathogenic bacteria and observed occasional regressions leading to long term survival. Recent progress in understanding mechanisms of immune activation and tolerance has led to the development of novel therapies that aim to either overcome inhibitory pathways (i.e. checkpoint blockade such as anti-CTLA-4 and anti-PD-1) or stimulate immune cell activation (i.e. co-stimulation such as anti-GITR and anti-OX40). A major part of the success of immunotherapy has been the development of appropriate mouse models. This review will outline the history and the major findings leading to the accomplishments of modern day immunology with specific attention to the usefulness of animal models. © 2013 Elsevier Ltd.

Monash University, Sloan Kettering Cancer Center and Ludwig Institute for Cancer Research | Date: 2015-02-04

Expression of proteolytically active, high molecular weight ADAM protease is relatively increased in tumour cells that also express the putative tumour stem cell marker CD133. An antibody or antibody fragment such as 8C7 monoclonal antibody may be used to selectively bind to proteolytically active, high molecular weight ADAM10 protease to thereby detect tumour cells and also as a therapeutic agent for treating cancers, tumours and other malignancies inclusive of leukemia, lymphoma, lung cancer, colon cancer, adenoma, neuroblastoma, brain tumour, renal tumour, prostate cancer, sarcoma and/or melanoma.

News Article | November 6, 2016

The NCAB is a private research organization dedicated to providing consumers information about the finest professionals across the nation. Oceanside, NY, November 06, 2016 --( "Dr. Datta is the epitome of a compassionate, expert, skilled physician," said Richard J. Murphy, president and CEO of South Nassau. "His passion for his work and his commitment to providing standard-setting patient-centered care is emblematic of South Nassau's ongoing mission to provide the South Shore communities of Nassau County with the quality healthcare services that they deserve. This honor only confirms what his patients and the South Nassau staff have known for years." The NCAB is a private research organization dedicated to providing consumers information about the finest professionals across the nation. It accepts no fees, sponsorships, donations or advertising to be selected as one of "America's Best Physicians." Selections are based on a proprietary assessment of a doctor's experience, training, continuing education and commitment to excellence to ensure the most impartial unbiased review of all applicants. Dr. Datta is chair of the department of surgery and medical director of the Gertrude & Louis Feil Cancer Center at South Nassau Communities Hospital. His exceptional skills are evidenced by his education and recognition in the field of surgery: he has the unusual distinction of holding three fellowships, as a fellow of the prestigious International College of Surgeons, the American College of Surgeons and the Royal College of Surgeons. Dr. Datta is also a member of the editorial board of International Surgery, the official journal of the International College of Surgeons (ICS), and served as the president of the Nassau County Surgical Society in 2009. Dr. Datta's areas of expertise include cancers of the colon/rectum, endocrine system, breast and head and neck; soft tissue sarcoma and melanoma; upper gastrointestinal and colorectal procedures; tracheal and esophageal surgeries and radio frequency ablation for liver tumors. Not only does he hold the aforementioned South Nassau titles, he is also director of its division of surgical oncology and head and neck surgery. A Castle-Connolly New York Metro Area Top Doctor for 10 consecutive years, Dr. Datta is actively involved in numerous clinical trials that are both federally and privately funded. A graduate of Grant Medical College in Bombay, India, Dr. Datta has trained at some of the most prestigious surgical oncology and head and neck surgery programs in the world, including Tata Memorial Hospital, the largest cancer center in Asia; and England's Royal College of Surgeons, where he achieved Fellowship. Following his stay at the Royal College of Surgeons, Dr. Datta continued his training with a Research Fellowship at Memorial-Sloan Kettering Cancer Center. This was followed by a rare opportunity for a dual Fellowship in head and neck oncology and surgical oncology at Roswell Park Cancer Institute in Buffalo, NY. Dr. Datta is a resident of Muttontown, NY. Under Dr. Datta's leadership, the Gertrude & Louis Feil Cancer Center has evolved into one of the Northeast corridor's premiere providers of compassionate advanced cancer care. Treating approximately 1,500 patients annually, the center is equipped with three of the most effective technologies used to treat and eradicate cancer: the Varian Novalis Tx™, da Vinci® Surgical System and Gamma Knife® Perfexion. The Gertrude & Louis Feil Cancer Center incorporates the following specialty cancer care services: · Center for Breast Health (Valley Stream) · Center for Lung Health (Oceanside/Valley Stream) · Center for Prostate Health Program (Oceanside) · Center for Women's Imaging (Oceanside) • GYN Oncology Department (Valley Stream) • Long Island Gamma Knife® Center (Oceanside) • Radiation Oncology Department (Oceanside and Valley Stream) · RALI PET Imaging (Rockville Centre) • Surgical Oncology Department (Oceanside and Valley Stream) Oceanside, NY, November 06, 2016 --( )-- Prominent surgical oncologist Rajiv Datta, MD, has been named a 2016 "America's Best Physician" by the National Consumer Advisory Board (NCAB). Physicians who earn the honor are recommended by peer physicians, patients, healthcare professionals or by the NCAB's selection committee."Dr. Datta is the epitome of a compassionate, expert, skilled physician," said Richard J. Murphy, president and CEO of South Nassau. "His passion for his work and his commitment to providing standard-setting patient-centered care is emblematic of South Nassau's ongoing mission to provide the South Shore communities of Nassau County with the quality healthcare services that they deserve. This honor only confirms what his patients and the South Nassau staff have known for years."The NCAB is a private research organization dedicated to providing consumers information about the finest professionals across the nation. It accepts no fees, sponsorships, donations or advertising to be selected as one of "America's Best Physicians." Selections are based on a proprietary assessment of a doctor's experience, training, continuing education and commitment to excellence to ensure the most impartial unbiased review of all applicants.Dr. Datta is chair of the department of surgery and medical director of the Gertrude & Louis Feil Cancer Center at South Nassau Communities Hospital. His exceptional skills are evidenced by his education and recognition in the field of surgery: he has the unusual distinction of holding three fellowships, as a fellow of the prestigious International College of Surgeons, the American College of Surgeons and the Royal College of Surgeons. Dr. Datta is also a member of the editorial board of International Surgery, the official journal of the International College of Surgeons (ICS), and served as the president of the Nassau County Surgical Society in 2009.Dr. Datta's areas of expertise include cancers of the colon/rectum, endocrine system, breast and head and neck; soft tissue sarcoma and melanoma; upper gastrointestinal and colorectal procedures; tracheal and esophageal surgeries and radio frequency ablation for liver tumors. Not only does he hold the aforementioned South Nassau titles, he is also director of its division of surgical oncology and head and neck surgery. A Castle-Connolly New York Metro Area Top Doctor for 10 consecutive years, Dr. Datta is actively involved in numerous clinical trials that are both federally and privately funded.A graduate of Grant Medical College in Bombay, India, Dr. Datta has trained at some of the most prestigious surgical oncology and head and neck surgery programs in the world, including Tata Memorial Hospital, the largest cancer center in Asia; and England's Royal College of Surgeons, where he achieved Fellowship. Following his stay at the Royal College of Surgeons, Dr. Datta continued his training with a Research Fellowship at Memorial-Sloan Kettering Cancer Center. This was followed by a rare opportunity for a dual Fellowship in head and neck oncology and surgical oncology at Roswell Park Cancer Institute in Buffalo, NY. Dr. Datta is a resident of Muttontown, NY.Under Dr. Datta's leadership, the Gertrude & Louis Feil Cancer Center has evolved into one of the Northeast corridor's premiere providers of compassionate advanced cancer care. Treating approximately 1,500 patients annually, the center is equipped with three of the most effective technologies used to treat and eradicate cancer: the Varian Novalis Tx™, da Vinci® Surgical System and Gamma Knife® Perfexion.The Gertrude & Louis Feil Cancer Center incorporates the following specialty cancer care services:· Center for Breast Health (Valley Stream)· Center for Lung Health (Oceanside/Valley Stream)· Center for Prostate Health Program (Oceanside)· Center for Women's Imaging (Oceanside)• GYN Oncology Department (Valley Stream)• Long Island Gamma Knife® Center (Oceanside)• Radiation Oncology Department (Oceanside and Valley Stream)· RALI PET Imaging (Rockville Centre)• Surgical Oncology Department (Oceanside and Valley Stream) Click here to view the list of recent Press Releases from South Nassau Communities Hospital

Zamarin D.,Sloan Kettering Cancer Center | Zamarin D.,Sloan Kettering Institute for Cancer Research | Zamarin D.,Cornell University | Postow M.A.,Sloan Kettering Cancer Center | Postow M.A.,Cornell University
Pharmacology and Therapeutics | Year: 2015

Immune recognition and elimination of malignant cells require a series of steps orchestrated by the innate and the adaptive arms of the immune system. The majority of tumors have evolved mechanisms that allow for successful evasion of these immune responses. Recognition of these evasive processes led to the development of immunotherapeutic antibodies targeting the co-stimulatory and co-inhibitory receptors on T cells, with the goal of enhancement of T cell activation or reversal of tumor-induced T cell inhibition. Several of these agents, such as antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) have already demonstrated significant promise in clinical trials. Clinical benefit of these antibodies as single agents, however, has been limited to a subset of patients and has not been observed in all tumor types. These limitations call for the development of rational combination strategies aiming to extend therapeutic benefit to a broader range of patients. These include: 1) modalities that enhance antigen presentation, such as radiation, cryotherapy, chemotherapy, targeted agents, vaccines, toll-like receptor (TLR) agonists, type I interferon, and oncolytic viruses; 2) additional agents aiming to reverse T cell dysfunction, such as other immune checkpoint inhibitors; and 3) agents targeting other immune inhibitory mechanisms, such as inhibitors of indoleamine dioxygenase (IDO), regulatory T cells, and myeloid-derived suppressor cells (MDSCs). It is becoming increasingly evident that the efficacy of specific combinations will likely not be universal and that the choice of a treatment modality may need to be tailored to fit the needs of each individual patient. © 2015 Elsevier Inc. All rights reserved.

Fan J.,Cornell University | Pavletich N.P.,Sloan Kettering Cancer Center
Genes and Development | Year: 2012

Replication protein A (RPA) is the main eukaryotic ssDNA-binding protein with essential roles in DNA replication, recombination, and repair. RPA maintains the DNA as single-stranded and also interacts with other DNA-processing proteins, coordinating their assembly and disassembly on DNA. RPA binds to ssDNA in two conformational states with opposing affinities for DNA and proteins. The RPA-protein interactions are compatible with a low DNA affinity state that involves DNA-binding domain A (DBD-A) and DBD-B but not with the high DNA affinity state that additionally engages DBD-C and DBD-D. The structure of the high-affinity RPA-ssDNA complex reported here shows a compact quaternary structure held together by a four-way interface between DBD-B, DBD-C, the intervening linker (BC linker), and ssDNA. The BC linker binds into the DNAbinding groove of DBD-B, mimicking DNA. The associated conformational change and partial occlusion of the DBD-A-DBA-B protein-protein interaction site establish a mechanism for the allosteric coupling of RPA-DNA and RPA-protein interactions. © 2012 by Cold Spring Harbor Laboratory Press.

Laursen K.B.,Cornell University | Wong P.-M.,Sloan Kettering Cancer Center | Gudas L.J.,Cornell University
Nucleic Acids Research | Year: 2012

Retinoic acid receptors (RARs) α, β and γ are key regulators of embryonic development. Hematopoietic differentiation is regulated by RARα, and several types of leukemia show aberrant RARα activity. Through microarray expression analysis, we identified transcripts differentially expressed between F9 wild-type (Wt) and RARα knockout cells cultured in the absence or presence of the RAR-specific ligand all trans retinoic acid (RA). We validated the decreased Mest, Tex13, Gab1, Bcl11a, Tcfap2a and HMGcs1 transcript levels, and increased Slc38a4, Stmn2, RpL39l, Ref2L, Mobp and Rlf1 transcript levels in the RARa knockout cells. The decreased Mest and Tex13 transcript levels were associated with increased promoter CpG-island methylation and increased repressive histone modifications (H3K9me3) in RARα knockout cells. Increased Slc38a4 and Stmn2 transcript levels were associated with decreased promoter CpG-island methylation and increased permissive histone modifications (H3K9/K14ac, H3K4me3) in RARα knockout cells. We demonstrated specific association of RARα and RXRα with the Mest promoter. Importantly, stable expression of a dominant negative, oncogenic PML-RARα fusion protein in F9 Wt cells recapitulated the decreased Mest transcript levels observed in RARα knockout cells. We propose that RARα plays an important role in cellular memory and imprinting by regulating the CpG methylation status of specific promoter regions. © 2011 The Author(s).

Sasaki M.,Sloan Kettering Cancer Center | Sasaki M.,Cornell University | Lange J.,Sloan Kettering Cancer Center | Keeney S.,Sloan Kettering Cancer Center | And 2 more authors.
Nature Reviews Molecular Cell Biology | Year: 2010

Meiotic recombination, which promotes proper homologous chromosome segregation at the first meiotic division, normally occurs between allelic sequences on homologues. However, recombination can also take place between non-allelic DNA segments that share high sequence identity. Such non-allelic homologous recombination (NAHR) can markedly alter genome architecture during gametogenesis by generating chromosomal rearrangements. Indeed, NAHR-mediated deletions, duplications, inversions and other alterations have been implicated in numerous human genetic disorders. Studies in yeast have provided insights into the molecular mechanisms of meiotic NAHR as well as the cellular strategies that limit it. © 2010 Macmillan Publishers Limited. All rights reserved.

Poulikakos P.I.,Sloan Kettering Cancer Center | Zhang C.,Howard Hughes Medical Institute | Bollag G.,Plexxikon | Shokat K.M.,Howard Hughes Medical Institute | Rosen N.,Sloan Kettering Cancer Center
Nature | Year: 2010

Tumours with mutant BRAF are dependent on the RAFĝ€" MEKĝ€"ERK signalling pathway for their growth. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here we demonstrate the mechanistic basis for these findings. We used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for paradoxical activation of the enzyme by inhibitors. Induction of ERK signalling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAFĝ€"CRAF) or heterodimers (CRAFĝ€"BRAF) inhibits one protomer, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumours, RAS is not activated, thus transactivation is minimal and ERK signalling is inhibited in cells exposed to RAF inhibitors. These results indicate that RAF inhibitors will be effective in tumours in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signalling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumour activity than mitogen-activated protein kinase (MEK) inhibitors, but could also cause toxicity due to MEK/ERK activation. These predictions have been borne out in a recent clinical trial of the RAF inhibitor PLX4032 (refs 4, 5). The model indicates that promotion of RAF dimerization by elevation of wild-type RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumours. In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS. © 2010 Macmillan Publishers Limited. All rights reserved.

Callahan M.K.,Sloan Kettering Cancer Center | Callahan M.K.,Cornell University | Postow M.A.,Sloan Kettering Cancer Center | Postow M.A.,Cornell University | And 2 more authors.
Immunity | Year: 2016

Checkpoint-blocking antibodies can generate potent anti-tumor responses by encouraging the immune system to seek and destroy cancer cells. At this time, the United States Food and Drug Administration has approved three checkpoint-blocking antibodies in three disease indications, and additional approvals are expected to broaden the clinical scope of immunotherapy. Herein, we review the clinical development of CTLA-4-, PD-1-, and PD-L1-blocking antibodies across tumor types and briefly discuss areas of active investigation of potential biomarkers. Targeting molecules that regulate T cell activity is an approach that has been translated into potent cancer therapies. Callahan, Postow, and Wolchok review the clinical development of PD-1-, PD-L1-, and CTLA-4-blocking antibodies. They review the clinical activity of agents in development and toxicities associated with this novel approach and summarize recent developments in the search for biomarkers to guide the clinical use of these drugs. © 2016 Elsevier Inc.

Schlacher K.,Sloan Kettering Cancer Center | Schlacher K.,University of California at Los Angeles | Wu H.,University of California at Los Angeles | Jasin M.,Sloan Kettering Cancer Center
Cancer Cell | Year: 2012

Genes mutated in patients with Fanconi anemia (FA) interact with the DNA repair genes BRCA1 and BRCA2/FANCD1 to suppress tumorigenesis, but the molecular functions ascribed to them cannot fully explain all of their cellular roles. Here, we show a repair-independent requirement for FA genes, including FANCD2, and BRCA1 in protecting stalled replication forks from degradation. Fork protection is surprisingly rescued in FANCD2-deficient cells by elevated RAD51 levels or stabilized RAD51 filaments. Moreover, FANCD2-mediated fork protection is epistatic with RAD51 functions, revealing an unanticipated fork protection pathway that connects FA genes to RAD51 and the BRCA1/2 breast cancer suppressors. Collective results imply a unified molecular mechanism for repair-independent functions of FA, RAD51, and BRCA1/2 proteins in preventing genomic instability and suppressing tumorigenesis. © 2012 Elsevier Inc..

Zelenetz A.D.,Cornell University | Zelenetz A.D.,Sloan Kettering Cancer Center
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2014

During his presentation at the NCCN 19th Annual Conference, Dr. Andrew D. Zelenetz reviewed the updates to the 2014 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas. Dr. Zelenetz first discussed the updates for diffuse large B-cell lymphoma (DLBCL), focusing primarily on the emergence of MYC-positive DLBCL; the limited role of imaging in early-stage disease; new treatment options; the challenge of tumor heterogeneity; and the impact of cell of origin in the selection of future therapies. Then, on behalf of Dr. Steven Horwitz, Dr. Zelenetz presented the new guidelines for primary cutaneous CD30+ T-cell lymphoproliferative disorders and T-cell large granular lymphocytic leukemia. © JNCCN-Journal of the National Comprehensive Cancer Network.

Joyce J.A.,Sloan Kettering Cancer Center | Fearon D.T.,Cold Spring Harbor Laboratory | Fearon D.T.,Cornell University
Science | Year: 2015

Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. This requires not only that cancer-specific Tcells be generated, but also that these Tcells physically contact cancer cells. The coexistence in some patients of cancer cells and T cells that recognize them indicates that tumors may exhibit the phenomenon of immune privilege, in which immunogenic tissue is protected from immune attack. Here, we review the evidence that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells. Overcoming this T cell checkpoint may thus enable optimal immunotherapy.

O'Reilly E.M.,Sloan Kettering Cancer Center | O'Reilly E.M.,Cornell University | Lowery M.A.,Sloan Kettering Cancer Center
Cancer Journal (United States) | Year: 2012

Approximately 15% of patients with a diagnosis of pancreatic adenocarcinoma are candidates for potentially curative surgery. However, most patients who undergo such surgery will die from recurrent disease, most within the first few years, whereas nearly all succumb by 5 to 7 years from diagnosis. Currently, there is a lack of high-level evidence to guide consensus recommendations as to the optimal surveillance strategy after resection. There is considerable variability in clinical practice, ranging from frequent clinical follow-up, with serial Ca 19-9 measurement and routine computed tomographic imaging on a 3-to 6-monthly basis, to a practice of no routine serum or imaging follow-up after surgery. In most part, this divergence in practice reflects a lack of data to define optimal practice. The argument in favor of limited surveillance presumably stems from the relatively uniform poor outcomes after recurrence and the absence of evidence indicating that early detection of local, regional, or metastatic recurrence improves outcomes. However, recent advancements in the treatment of metastatic disease offer hope that earlier detection and initiation of treatment for recurrent disease may positively impact clinical outcomes and at least urges review of the topic. One advantage to the development of defined guidelines would be greater consistency in the setting of both routine clinical follow-up and follow-up after adjuvant therapy on trial. Copyright © 2012 by Lippincott Williams &Wilkins.

Alpdogan O.,Thomas Jefferson University | Van Den Brink M.R.M.,Sloan Kettering Cancer Center
Seminars in Oncology | Year: 2012

Successful allogeneic hematopoietic stem cell transplantation (HSCT) and solid organ transplantation require development of a degree of immune tolerance against allogeneic antigens. T lymphocytes play a critical role in allograft rejection, graft failure, and graft-versus-host disease (GVHD). T-cell tolerance occurs by two different mechanisms: (1) depletion of self-reactive T cells during their maturation in the thymus (central tolerance), and (2) suppression/elimination of self-reactive mature T cells in the periphery (peripheral tolerance). Induction of transplant tolerance improves transplantation outcomes. Adoptive immunotherapy with immune suppressor cells including regulatory T cells, natural killer (NK)-T cells, veto cells, and facilitating cells are promising therapies for modulation of immune tolerance. Achieving mixed chimerism with the combination of thymic irradiation and T-cell-depleting antibodies, costimulatory molecule blockade with/without inhibitory signal activation, and elimination of alloreactive T cells with varying methods including pre- or post-transplant cyclophosphamide administration appear to be effective in inducing transplant tolerance. © 2012 Elsevier Inc. All rights reserved.

Takai H.,Rockefeller University | Xie Y.,Sloan Kettering Cancer Center | Xie Y.,Cornell University | De Lange T.,Rockefeller University | Pavletich N.P.,Sloan Kettering Cancer Center
Genes and Development | Year: 2010

We reported previously that the stability of all mammalian phosphatidylinositol 3-kinase-related protein kinases (PIKKs) depends on their interaction with Tel2, the ortholog of yeast Tel2 and Caenorhabditis elegans Clk-2. Here we provide evidence that Tel2 acts with Hsp90 in the maturation of PIKK complexes. Quantitative immunoblotting showed that the abundance of Tel2 is low compared with the PIKKs, and Tel2 preferentially bound newly synthesized ATM, ATR, mTOR, and DNA-PKcs. Tel2 complexes contained, in addition to Tti1-Tti2, the Hsp90 chaperone, and inhibition of Hsp90 interfered with the interaction of Tel2 with the PIKKs. Analysis of in vivo labeled nascent protein complexes showed that Tel2 and Hsp90 mediate the formation of the mTOR TORC1 and TORC2 complexes and the association of ATR with ATRIP. The structure of yeast Tel2, reported here, shows that Tel2 consists of HEAT-like helical repeats that assemble into two separate a-solenoids. Through mutagenesis, we identify a surface patch of conserved residues involved in binding to the Tti1-Tti2 complex in vitro. In vivo, mutation of this conserved patch affects cell growth, levels of PIKKs, and ATM/ATR-mediated checkpoint signaling, highlighting the importance of Tti1-Tti2 binding to the function of Tel2. Taken together, our data suggest that the Tel2-Tti1-Tti2 complex is a PIKK-specific cochaperone for Hsp90. © 2010 by Cold Spring Harbor Laboratory Press.

Jaulin F.,Cornell University | Jaulin F.,Sloan Kettering Cancer Center | Kreitzer G.,Cornell University
Journal of Cell Biology | Year: 2010

Epithelial polarization is associated with selective stabilization and reorganization of microtubule (MT) arrays. However, upstream events and downstream consequences of MT stabilization during epithelial morphogenesis are still unclear. We show that the anterograde kinesin KIF17 localizes to MT plus ends, stabilizes MTs, and affects epithelial architecture. Targeting of KIF17 to plus ends of growing MTs requires kinesin motor activity and interaction with EB1. In turn, KIF17 participates in localizing adenomatous polyposis coli (APC) to the plus ends of a subset of MTs. We found that KIF17 affects MT dynamics, polymerization rates, and MT plus end stabilization to generate posttranslationally acetylated MTs. Depletion of KIF17 from cells growing in three-dimensional matrices results in aberrant epithelial cysts that fail to generate a single central lumen and to polarize apical markers. These findings implicate KIF17 in MT stabilization events that contribute to epithelial polarization and morphogenesis. © 2010 Jaulin and Kreitzer.

Du J.,Sloan Kettering Cancer Center | Du J.,CAS Shanghai Institutes for Biological Sciences | Patel D.J.,Sloan Kettering Cancer Center
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2014

Epigenetic mechanisms control gene regulation by writing, reading and erasing specific epigenetic marks. Within the context of multi-disciplinary approaches applied to investigate epigenetic regulation in diverse systems, structural biology techniques have provided insights at the molecular level of key interactions between upstream regulators and downstream effectors. The early structural efforts focused on studies at the single domain-single mark level have been rapidly extended to research at the multiple domain-multiple mark level, thereby providing additional insights into connections within the complicated epigenetic regulatory network. This review focuses on recent results from structural studies on combinatorial readout and crosstalk among epigenetic marks. It starts with an overview of multiple readout of histone marks associated with both single and dual histone tails, as well as the potential crosstalk between them. Next, this review further expands on the simultaneous readout by epigenetic modules of histone and DNA marks, thereby establishing connections between histone lysine methylation and DNA methylation at the nucleosomal level. Finally, the review discusses the role of pre-existing epigenetic marks in directing the writing/erasing of certain epigenetic marks. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function. © 2014 Elsevier B.V.

Alonzo E.S.,Sloan Kettering Cancer Center | Sant'Angelo D.B.,Sloan Kettering Cancer Center | Sant'Angelo D.B.,Cornell University
Current Opinion in Immunology | Year: 2011

Recent studies have shown that the transcriptional regulator promyelocytic leukemia zinc finger (PLZF) controls the development of essentially all of the innate-like features of invariant Natural Killer T (NKT) cells. For example, PLZF-deficient NKT cells do not acquire an 'activated' phenotype nor do they acquire the capacity to secrete multiple cytokines upon primary stimulation. The function of a subset of γδ T cells has now also been shown to be dependent upon expression of PLZF. Furthermore, IL-4 produced by PLZF-expressing cells causes some CD8 T cells to acquire innate-like features. Therefore, it is becoming clear that PLZF has a broad impact on the immune response. Here we discuss the current understanding of how expression of PLZF, the innate T cell determinant, is initiated during T cell development. © 2011 Elsevier Ltd.

Gyurkocza B.,Sloan Kettering Cancer Center | Gyurkocza B.,Cornell University | Sandmaier B.M.,Fred Hutchinson Cancer Research Center | Sandmaier B.M.,University of Washington
Blood | Year: 2014

An essential component of allogeneic and autologous hematopoietic cell transplantation (HCT) is the conditioning regimen administered before the hematopoietic cell infusion. Early regimens reliedondose intensity, assuming that high-dose chemoradiotherapy would eliminate malignant disease and reinfusion of the graft would then restore hematopoiesis. However, as the contribution of graft-versus-tumor effects to the success of allogeneic HCT was recognized over time, in an effort to exploit these, many investigators lowered the dose of radiation and chemotherapeutic agents in the preparative regimen. This resulted in a major paradigm shift, and consequently, the pool of eligible patients underwent a remarkable expansion. In this article, we provide a review of the definition of high-dose, reduced-intensity, and nonmyeloablative conditioning regimens, the most commonly used agents and combinations, and the evolution of some early regimens. We also provide a brief review of the toxicities associated with these regimens. © 2014 by The American Society of Hematology.

Sarangi P.,Sloan Kettering Cancer Center | Sarangi P.,Cornell University | Zhao X.,Sloan Kettering Cancer Center
Trends in Biochemical Sciences | Year: 2015

Sumoylation has important roles during DNA damage repair and responses. Recent broad-scope and substrate-based studies have shed light on the regulation and significance of sumoylation during these processes. An emerging paradigm is that sumoylation of many DNA metabolism proteins is controlled by DNA engagement. Such 'on-site modification' can explain low substrate modification levels and has important implications in sumoylation mechanisms and effects. New studies also suggest that sumoylation can regulate a process through an ensemble effect or via major substrates. Additionally, we describe new trends in the functional effects of sumoylation, such as bi-directional changes in biomolecule binding and multilevel coordination with other modifications. These emerging themes and models will stimulate our thinking and research in sumoylation and genome maintenance. © 2015 Elsevier Ltd.

Du J.,CAS Shanghai Institutes for Biological Sciences | Johnson L.M.,Howard Hughes Medical Institute | Jacobsen S.E.,Howard Hughes Medical Institute | Patel D.J.,Sloan Kettering Cancer Center
Nature Reviews Molecular Cell Biology | Year: 2015

Methylation of DNA and of histone 3 at Lys 9 (H3K9) are highly correlated with gene silencing in eukaryotes from fungi to humans. Both of these epigenetic marks need to be established at specific regions of the genome and then maintained at these sites through cell division. Protein structural domains that specifically recognize methylated DNA and methylated histones are key for targeting enzymes that catalyse these marks to appropriate genome sites. Genetic, genomic, structural and biochemical data reveal connections between these two epigenetic marks, and these domains mediate much of the crosstalk. © 2015 Macmillan Publishers Limited. All rights reserved.

Hla T.,Cornell University | Kolesnick R.,Sloan Kettering Cancer Center
Cell Metabolism | Year: 2014

A substantive literature has accumulated implicating sphingolipids, in particular ceramides, as mediators of insulin resistance in metabolic syndrome. Thanks to recent technical advances in mouse genetics and lipidomics, two independent laboratories identify the same sphingolipid, C16:0-ceramide, as principal mediator of obesity-related insulin resistance (Turpin et al.; 2014; Raichur et al.; 2014). © 2014 Elsevier Inc.

Ribas A.,University of California at Los Angeles | Wolchok J.D.,Sloan Kettering Cancer Center | Wolchok J.D.,Ludwig Institute for Cancer Research
Current Opinion in Immunology | Year: 2013

The ability to pharmacologically modulate key signaling pathways that drive tumor growth and progression, but do not negatively impact the function of lymphocytes, provides avenues for rational combinatorial approaches to improve the antitumor activity of tumor immunotherapies. Novel targeted agents can very specifically block oncogenic events in cancer cells, leading to a pro-apoptotic milieu and a potential increase in sensitivity to recognition and attack by cytotoxic T lymphocytes (CTLs). Furthermore, targeted pathway modulation in lymphocytes may change their function and have activating effects in some instances. When tested together with recently developed powerful tumor immunotherapies, such combinations may exploit the highly specific targeting of oncogenes with small molecule inhibitors to lead to high frequency of tumor regressions, and merge this benefit with the durable responses achievable with effective tumor immunotherapies. © 2013 Elsevier Ltd.

Kloss C.C.,Sloan Kettering Cancer Center | Kloss C.C.,Cornell University | Condomines M.,Sloan Kettering Cancer Center | Cartellieri M.,TU Dresden | And 2 more authors.
Nature Biotechnology | Year: 2013

Current T-cell engineering approaches redirect patient T cells to tumors by transducing them with antigen-specific T-cell receptors (TCRs) or chimeric antigen receptors (CARs) that target a single antigen. However, few truly tumor-specific antigens have been identified, and healthy tissues that express the targeted antigen may undergo T cell-mediated damage. Here we present a strategy to render T cells specific for a tumor in the absence of a truly tumor-restricted antigen. T cells are transduced with both a CAR that provides suboptimal activation upon binding of one antigen and a chimeric costimulatory receptor (CCR) that recognizes a second antigen. Using the prostate tumor antigens PSMA and PSCA, we show that co-transduced T cells destroy tumors that express both antigens but do not affect tumors expressing either antigen alone. This 'tumor-sensing' strategy may help broaden the applicability and avoid some of the side effects of targeted T-cell therapies.

Sloan Kettering Cancer Center, Cornell University and Quest Photonic Devices B.V. | Date: 2014-12-31

Presented herein is a multichannel imaging system capable of detecting and distinguishing multiple fluorescent light sources simultaneously. Also described herein are methods of using the system to image disease or cellular abnormalities, e.g., for diagnostic and/or intraoperative purposes.

Sloan Kettering Cancer Center and Cornell University | Date: 2012-02-11

Chronic inflammation increases the risk of several epithelial malignancies. The present invention provides methods for determining cancer risk in a patient which comprises detecting the presence of crown-like structures (CLS), methods for treating cancer associated with CLS presence, methods for determining cancer risk in a patient by quantifying the number of CLS in a sample of adipose tissue of the patient, methods of determining prognosis of a patient with breast cancer or other cancers by detecting CLS, and screening methods for anti-cancer agents or agents that inhibit or reduce CLS formation or consequences thereof.

Provided are cortical interneurons and other neuronal cells and in vitro methods for producing such cortical interneurons and other neuronal cells by the directed differentiation of stem cells and neuronal progenitor cells. The present disclosure relates to novel methods of in vitro differentiation of stem cells and neural progenitor cells to produce several type neuronal cells and their precursor cells, including cortical interneurons, hypothalamic neurons and pre-optic cholinergic neurons. The present disclose describes the derivation of these cells via inhibiting SMAD and Wnt signaling pathways and activating SHH signaling pathway. The present disclosure relates to the novel discovery that the timing and duration of SHH activation can be harnessed to direct controlled differentiation of neural progenitor cells into either cortical interneurons, hypothalamic neurons or pre-optic cholinergic neurons. The present disclosure also relates to compositions of cortical interneurons, hypothalamic neurons or pre-optic cholinergic neurons, and their precursors, that are highly enriched and can be used in variety of application. These cells can be used therapeutically to treat neurodegenerative and neuropsychiatric disorders, and can be used for disease modeling and drug screening.

Sloan Kettering Cancer Center and Cornell University | Date: 2015-05-27

Described herein are nanoparticle drug conjugates (NDCs), which, in certain embodiments, comprise a non-toxic, multi-modality, clinically proven silica-based nanoparticle platform with covalently attached drug molecules/moieties. The nanoparticle drug conjugates (NDCs) demonstrate imaging capability and targeting ligands which efficiently clear through the kidneys. Furthermore, the conjugates incorporate therapeutic agents for cancer detection, prevention, and/or treatment.

Described herein are cyclic peptides, nanoparticles bound with cyclic peptides, and methods for using said cyclic peptides and/or said nanoparticles bound with cyclic peptides for intraoperative nerve tissue imaging.

Griewank K.G.,University of Duisburg - Essen | Murali R.,Sloan Kettering Cancer Center
Pathology | Year: 2013

Uveal melanoma is the most common malignant tumour of the adult eye. Around half of all uveal melanoma patients will eventually die of their disease. There are a number of effective options to treat the primary tumour locally, but once the tumour has metastasised, there are no curative therapies. Traditionally, the diagnosis of uveal melanoma and prognostic prediction was based solely on the clinical presentation and detailed histopathological evaluation. Recent genetic findings have shed light on the biology of these tumours, and led to the development of genetic tests that can help assess their malignant potential and prognosis. The genes, proteins and pathways that have been (and continue to be) discovered will likely result in novel targeted therapeutic approaches with high efficacy and low toxicity. In this review, we summarise the clinical, pathological and genetic features of uveal melanoma, with emphasis on recent discoveries. © 2012 Royal College of Pathologists of Australasia.

Ghosh A.,Sloan Kettering Cancer Center | Ghosh A.,Mount Sinai School of Medicine | Holland A.M.,University of Birmingham | Van den Brink M.R.M.,Sloan Kettering Cancer Center
Immunological Reviews | Year: 2014

Hematopoietic stem cell transplantation has been used for more than 50 years to combat hematologic malignancies. In addition to being the first stem cell therapy, transplantation has provided evidence for the potent anti-tumor effects of T cells. Facilitating T-cell-based immunity against malignancies requires a careful balancing act between generating a robust response and avoiding off-target killing of healthy tissues, which is difficult to accomplish using bulk donor T cells. To address these issues, several approaches have been developed, drawing on basic T-cell biology, to potentiate graft-versus-tumor activity while avoiding graft-versus-host disease. Current strategies for anti-tumor cell therapies include: (i) selecting optimal T cells for transfer; (ii) engineering T cells to possess enhanced effector functions; and (iii) generating T-cell precursors that complete development after adoptive transfer. In this review, we assess the current state of the art in T-lineage cell therapy to treat malignancies in the context of allogeneic hematopoietic stem cell transplantation. © 2013 John Wiley & Sons A/S.

Zheng S.,Sloan Kettering Cancer Center | Vuong B.Q.,Sloan Kettering Cancer Center | Vuong B.Q.,City College of New York | Vaidyanathan B.,Sloan Kettering Cancer Center | And 3 more authors.
Cell | Year: 2015

Transcription through immunoglobulin switch (S) regions is essential for class switch recombination (CSR), but no molecular function of the transcripts has been described. Likewise, recruitment of activation-induced cytidine deaminase (AID) to S regions is critical for CSR; however, the underlying mechanism has not been fully elucidated. Here, we demonstrate that intronic switch RNA acts in trans to target AID to S region DNA. AID binds directly to switch RNA through G-quadruplexes formed by the RNA molecules. Disruption of this interaction by mutation of a key residue in the putative RNA-binding domain of AID impairs recruitment of AID to S region DNA, thereby abolishing CSR. Additionally, inhibition of RNA lariat processing leads to loss of AID localization to S regions and compromises CSR; both defects can be rescued by exogenous expression of switch transcripts in a sequence-specific manner. These studies uncover an RNA-mediated mechanism of targeting AID to DNA. © 2015 Elsevier Inc.

Krejci L.,Masaryk University | Krejci L.,St Annes University Hospital In Brno | Altmannova V.,Masaryk University | Altmannova V.,St Annes University Hospital In Brno | And 2 more authors.
Nucleic Acids Research | Year: 2012

Homologous recombination (HR) is critical both for repairing DNA lesions in mitosis and for chromosomal pairing and exchange during meiosis. However, some forms of HR can also lead to undesirable DNA rearrangements. Multiple regulatory mechanisms have evolved to ensure that HR takes place at the right time, place and manner. Several of these impinge on the control of Rad51 nucleofilaments that play a central role in HR. Some factors promote the formation of these structures while others lead to their disassembly or the use of alternative repair pathways. In this article, we review these mechanisms in both mitotic and meiotic environments and in different eukaryotic taxa, with an emphasis on yeast and mammal systems. Since mutations in several proteins that regulate Rad51 nucleofilaments are associated with cancer and cancer-prone syndromes, we discuss how understanding their functions can lead to the development of better tools for cancer diagnosis and therapy. © 2012 The Author(s).

Moynahan M.E.,Developmental Biology Program | Moynahan M.E.,Sloan Kettering Cancer Center | Jasin M.,Developmental Biology Program
Nature Reviews Molecular Cell Biology | Year: 2010

Mitotic homologous recombination promotes genome stability through the precise repair of DNA double-strand breaks and other lesions that are encountered during normal cellular metabolism and from exogenous insults. As a result, homologous recombination repair is essential during proliferative stages in development and during somatic cell renewal in adults to protect against cell death and mutagenic outcomes from DNA damage. Mutations in mammalian genes encoding homologous recombination proteins, including BRCA1, BRCA2 and PALB2, are associated with developmental abnormalities and tumorigenesis. Recent advances have provided a clearer understanding of the connections between these proteins and of the key steps of homologous recombination and DNA strand exchange. © 2010 Macmillan Publishers Limited. All rights reserved.

O'Neill J.P.,Royal College of Surgeons in Ireland | Shaha A.R.,Sloan Kettering Cancer Center
Oral Oncology | Year: 2013

Purpose Anaplastic thyroid cancer (ATC) is a lethal disease causing a global disproportionate number of thyroid cancer-related deaths. The American Thyroid Association (ATA) has recently produced clear and comprehensive guidelines to assist physicians treating ATC. Methods The recent ATA guideline publication was reviewed. A systematic review of studies indexed in Medline and Pubmed was also undertaken using search terms relevant to ATC. Results Patients with ATC have a median survival of 5 months and less than 20% survive 1 year. Early tumor dissemination results in 20-50% percent of patients having distant metastases and 90% having adjacent tissue invasion on presentation. This highlights the necessity for effective combined therapy. Stage IVA/ IVB, resectable disease may benefit from a multimodal (surgery, IMRT for loco regional control, and systemic therapy) approach. However, a majority of patients present with unresectable locoregional disease. Early palliative care involvement is inclusive of life-prolonging therapies. ATC management demands rapid, complex and integrated multidisciplinary decision making. Conclusion In this article we discuss the multidisciplinary strategies that exist to optimize the management of these patients in accordance with the recent guidelines from The American Thyroid Association. © 2013 Elsevier Ltd. All rights reserved.

Hamid O.,Angeles Clinic and Research Institute | Carvajal R.D.,Sloan Kettering Cancer Center
Expert Opinion on Biological Therapy | Year: 2013

Introduction: Multiple agents targeting the immune "checkpoint" programmed death-1 (PD-1) pathway have demonstrated early evidence of durable clinical activity and an encouraging safety profile in patients with various tumor types, including some cancers, such as non-small-cell lung cancer, historically perceived as non-immunogenic and thus nonresponsive to immunotherapy. Areas covered: Functions of the PD-1 pathway in normal immune responses are reviewed, along with the significance of expression of PD-1 and its ligands in malignant settings. Rationale for the development of PD-1 pathway-targeted therapies and associated clinical data are presented. Finally, efforts to date to identify and develop partner predictive or prognostic biomarkers for these new PD-1 pathway-targeted immunotherapies are discussed. Expert opinion: Rather than targeting the tumor directly, immunotherapies inhibiting PD-1 pathway signaling modulate the antitumor immune response. Indeed, these agents have already demonstrated promising antitumor activity and manageable toxicity in various cancers. If future data continue to support encouraging clinical profiles of anti-PD-1 and anti-programmed death-ligand 1 antibodies, the current paradigm of cancer therapy may shift. In select patient populations (ideally identified by a predictive biomarker), PD-1 pathway-targeted immunotherapy has the potential to serve as the backbone of cancer treatment, and trials evaluating combinations with chemotherapy and/or molecularly targeted therapies will determine whether additive or even synergistic responses can be achieved. © 2013 Informa UK, Ltd.

The University Of Texas System and Sloan Kettering Cancer Center | Date: 2010-09-30

Agonists to ICOS in combination with a blocking agent to a T cell inhibitory receptor (e.g., CTLA-4, PD-I, etc.) are demonstrated herein to be useful for the treatment of tumors.

The University Of Texas System and Sloan Kettering Cancer Center | Date: 2014-04-10

Agonists to ICOS in combination with a blocking agent to a T cell inhibitory receptor (e.g., CTLA-4, PD-1, etc.) are demonstrated herein to be useful for the treatment of tumors.

Sloan Kettering Cancer Center, Rockefeller University, Rutgers University and University of Bonn | Date: 2014-07-31

The present invention provides STING crystals. The present invention also provides STING modulators that interact with sites present in and/or defined by such crystals. The present invention also provides methods of making and using such crystals and modulators. Other aspects and/or features of the present invention will be apparent to those skilled in the art, reading the present specification.

The University Of Texas System and Sloan Kettering Cancer Center | Date: 2016-05-03

Agonists to ICOS in combination with a blocking agent to a T cell inhibitory receptor (e.g., CTLA-4, PD-1, etc.) are demonstrated herein to be useful for the treatment of tumors.

Rodriguez-Bravo V.,Sloan Kettering Cancer Center | Maciejowski J.,Sloan Kettering Cancer Center | Corona J.,Sloan Kettering Cancer Center | Buch H.K.,ETH Zurich | And 5 more authors.
Cell | Year: 2014

The spindle assembly checkpoint (SAC) delays anaphase until all chromosomes are bioriented on the mitotic spindle. Under current models, unattached kinetochores transduce the SAC by catalyzing the intramitotic production of a diffusible inhibitor of APC/CCdc20 (the anaphase-promoting complex/cyclosome and its coactivator Cdc20, a large ubiquitin ligase). Here we show that nuclear pore complexes (NPCs) in interphase cells also function as scaffolds for anaphase-inhibitory signaling. This role is mediated by Mad1-Mad2 complexes tethered to the nuclear basket, which activate soluble Mad2 as a binding partner and inhibitor of Cdc20 in the cytoplasm. Displacing Mad1-Mad2 from nuclear pores accelerated anaphase onset, prevented effective correction of merotelic errors, and increased the threshold of kinetochore-dependent signaling needed to halt mitosis in response to spindle poisons. A heterologous Mad1-NPC tether restored Cdc20 inhibitor production and normal M phase control. We conclude that nuclear pores and kinetochores both emit "wait anaphase" signals that preserve genome integrity. © 2014 Elsevier Inc.

Morrow M.,Sloan Kettering Cancer Center | Schnitt S.J.,Beth Israel Deaconess Medical Center | Norton L.,Sloan Kettering Cancer Center
Nature Reviews Clinical Oncology | Year: 2015

High-risk breast lesions, which comprise benign lesions and in situ carcinomas (lobular carcinoma in situ and ductal carcinoma in situ), are clinically, morphologically, and biologically heterogeneous and are associated with an increased risk of invasive breast cancer development, albeit to varying degrees. Recognition and proactive management of such lesions can help to prevent progression to invasive disease, and might, therefore, reduce breast cancer incidence, morbidity, and mortality. However, this opportunity comes with the possibility of overdiagnosis and overtreatment, necessitating risk-based intervention. Notably, despite the progress in defining the molecular changes associated with carcinogenesis, alterations identifying the individuals with high-risk lesions that will progress to invasive carcinoma remain to be identified. Thus, until reproducible clinicopathological or molecular features predicting an individual's risk of breast cancer are found, management strategies must be defined by population-level risks as determined by models such as the Gail or IBIS models, as well as patient attitudes toward the risks and benefits of interventions. Herein, we review the contemporary approaches to diagnosis and management of high-risk breast lesions. Progress in this area will ultimately be dependent on the ability to individualize risk prediction through better definition of the key drivers in the carcinogenic process. © 2015 Macmillan Publishers Limited.

Chen L.,Sloan Kettering Cancer Center | Hu J.Y.,Cumberland Skin Surgery and Dermatology | Wang S.Q.,Sloan Kettering Cancer Center
Journal of the American Academy of Dermatology | Year: 2012

Free radicals have long been studied as a contributor to aging and disease processes. Endogenous production of radicals from cellular metabolism and exogenous sources from ultraviolet radiation and pollution can damage the skin on the cellular and tissue levels. Although the body possesses an elegant defense system to prevent radical damage, this innate system can be overwhelmed and lead to a state of oxidative stress or immunosuppression, and can even trigger carcinogenesis. Topical supplementation of antioxidants can provide additional protection to neutralize reactive oxygen species from both endogenous and exogenous sources. This review will discuss our current understanding of the mechanisms of free radical damage and evaluate the potential benefit of topical antioxidants in sunscreens and skin care products. © 2012 by the American Academy of Dermatology, Inc.

Plusa B.,University of Manchester | Hadjantonakis A.-K.,Sloan Kettering Cancer Center
Nature Cell Biology | Year: 2014

Pluripotent embryonic stem cells (ESCs) can be derived from blastocyst-stage mouse embryos. However, the exact in vivo counterpart of ESCs has remained elusive. A combination of expression profiling and stem cell derivation identifies epiblast cells from late-stage blastocysts as the source, and functional equivalent, of ESCs. © 2014 Macmillan Publishers Limited. All rights reserved.

Neff T.,University of Colorado at Denver | Armstrong S.A.,Sloan Kettering Cancer Center
Blood | Year: 2013

The importance of epigenetic gene regulatory mechanisms in normal and cancer development is increasingly evident. Genome-wide analyses have revealed the mutation, deletion, and dysregulated expression of chromatin-modifying enzymes in a number of cancers, including hematologic malignancies. Genome-wide studies of DNA methylation and histone modifications are beginning to reveal the landscape of cancer-specific chromatin patterns. In parallel, recent genetic loss-of-function studies in murine models are demonstrating functional involvement of chromatin-modifying enzymes inmalignant cell proliferation and self-renewal. Paradoxically, the same chromatin modifiers can, depending on cancer type, be either hyperactive or inactivated. Increasingly, cross talk between epigenetic pathways is being identified. Leukemias carrying MLL rearrangements are quintessential cancers driven by dysregulated epigenetic mechanisms in which fusion proteins containing N-terminal sequences of MLL require few or perhaps no additional mutations to cause human leukemia. Here, we review how recent progress in the field of epigenetics opens potential mechanism-based therapeutic avenues. © 2013 by The American Society of Hematology.

Cole F.,Sloan Kettering Cancer Center | Cole F.,University of Texas M. D. Anderson Cancer Center | Baudat F.,French National Center for Scientific Research | Grey C.,French National Center for Scientific Research | And 3 more authors.
Nature Genetics | Year: 2014

The ability to examine all chromatids from a single meiosis in yeast tetrads has been indispensable for defining the mechanisms of homologous recombination initiated by DNA double-strand breaks (DSBs). Using a broadly applicable strategy for the analysis of chromatids from a single meiosis at two recombination hotspots in mouse oocytes and spermatocytes, we demonstrate here the unidirectional transfer of information-gene conversion-in both crossovers and noncrossovers. Whereas gene conversion in crossovers is associated with reciprocal exchange, the unbroken chromatid is not altered in noncrossover gene conversion events, providing strong evidence that noncrossovers arise from a distinct pathway. Gene conversion frequently spares the binding site of the hotspot-specifying protein PRDM9, with the result that erosion of the hotspot is slowed. Thus, mouse tetrad analysis demonstrates how unique aspects of mammalian recombination mechanisms shape hotspot evolutionary dynamics. © 2014 Nature America, Inc. All rights reserved.

Bidard F.-C.,Sloan Kettering Cancer Center | Bidard F.-C.,University Pierre and Marie Curie | Weigelt B.,Sloan Kettering Cancer Center | Reis-Filho J.S.,Sloan Kettering Cancer Center
Science Translational Medicine | Year: 2013

Molecular analyses of circulating tumor DNA (ctDNA) in plasma from cancer patients have the potential to deliver minimally invasive diagnostic and disease-monitoring biomarkers. Drawing from experience gained through the translation of circulating-tumor cell detection to clinical tests, we discuss ctDNA as a source of tumor material for biomarker development.

Zardavas D.,University of Waterloo | Baselga J.,Sloan Kettering Cancer Center | Piccart M.,University of Waterloo
Nature Reviews Clinical Oncology | Year: 2013

Extensive preclinical experimentation has conceptually changed the way we perceive breast cancer, with the wide spectrum of genomic alterations governing its malignant progression now being recognized. Functional genomics has helped us identify important genetic defects that can be pharmaceutically targeted in the setting of metastatic disease. Rationally chosen combination regimens are now under clinical investigation. Recent data underline the functional importance of the tumour-associated stroma, with several candidate molecular targets now emerging. Data elucidating a cellular hierarchy within the breast cancer cellular compartment support the existence of a therapy-resistant subpopulation of breast cancer stem cells. Identification of the developmental pathways that dictate their malignant phenotype and use of high-throughput screening techniques are leading to new therapeutic avenues. In this Review, we present the biological rationale for the clinical development of more than 15 different classes of targeted agents in breast cancer, along with evidence supporting rational combinations. However, metastatic breast cancer resembles a Darwinian evolutionary system, with 'driver' mutations and epigenetic changes determining clonal selection according to branching trajectories. This evolution is reflected in the molecular heterogeneity of the disease and poses severe impediments to the successful clinical development of emerging targeted agents. ©2013 Macmillan Publishers Limited. All rights reserved.

Chemaitilly W.,Childrens Hospital of Pittsburgh of UPMC | Sklar C.A.,Sloan Kettering Cancer Center
Endocrine-Related Cancer | Year: 2010

Endocrine disturbances are among the most frequently reported complications in childhood cancer survivors, affecting between 20 and 50% of individuals who survive into adulthood. Most endocrine complications are the result of prior cancer treatments, especially radiotherapy. The objective of the present review is to discuss the main endocrine complications observed in this population, including disorders of the hypothalamic - pituitary axis, disorders of pubertal development, thyroid dysfunction, gonadal dysfunction, decreased bone mineral density, obesity, and alterations in glucose metabolism with a special focus on recent findings reported from the Childhood Cancer Survivor Study. © 2010 Society for Endocrinology.

Penack O.,Charité - Medical University of Berlin | Penack O.,Sloan Kettering Cancer Center | Holler E.,University of Regensburg | Van Den Brink M.R.M.,Sloan Kettering Cancer Center
Blood | Year: 2010

Acute graft-versus-host disease (GVHD) remains the major obstacle to a more favorable therapeutic outcome of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is characterized by tissue damage in gut, liver, and skin, caused by donor T cells that are critical for antitumor and antimicrobial immunity after HSCT. One obstacle in combating GVHD used to be the lack of understanding the molecular mechanisms that are involved in the initiation phase of this syndrome. Recent research has demonstrated that interactions between microbial-associated molecules (pathogen-associated molecular patterns [PAMPs]) and innate immune receptors (pathogen recognition receptors [PRRs]), such as NOD-like receptors (NLRs) and Toll-like receptors (TLRs), control adaptive immune responses in inflammatory disorders. Polymorphisms of the genes encoding NOD2 and TLR4 are associated with a higher incidence of GVHD in HSC transplant recipients. Interestingly, NOD2 regulates GVHD through its inhibitory effect on antigen-presenting cell (APC) function. These insights identify important mechanisms regarding the induction of GVHD through the interplay of microbial molecules and innate immunity, thus opening a new area for future therapeutic approaches. This review covers current knowledge of the role of PAMPs and PRRs in the control of adaptive immuneresponses during inflammatory diseases, particularly GVHD. © 2010 by The American Society of Hematology.

Poliseno L.,Beth Israel Deaconess Medical Center | Poliseno L.,New York University | Salmena L.,Beth Israel Deaconess Medical Center | Zhang J.,Harvard University | And 3 more authors.
Nature | Year: 2010

The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs. © 2010 Macmillan Publishers Limited. All rights reserved.

Agenus, Ludwig Institute for Cancer Research and Sloan Kettering Cancer Center | Date: 2016-05-27

The instant disclosure provides antibodies that specifically bind to human CTLA-4 and antagonize CTLA-4 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

Agenus, Ludwig Institute for Cancer Research and Sloan Kettering Cancer Center | Date: 2016-05-06

The present disclosure provides antibodies that specifically bind to human OX40 receptor (OX40) and compositions comprising such antibodies. In a specific aspect, the antibodies specifically bind to human OX40 and modulate OX40 activity, e.g., enhance, activate, or induce OX40 activity, or reduce, deactivate, or inhibit OX40 activity. The present disclosure also provides methods for treating disorders, such as cancer, by administering an antibody that specifically binds to human OX40 and modulates OX40 activity, e.g., enhances, activates, or induces OX40 activity. Also provided are methods for treating autoimmune or inflammatory diseases or disorders, by administering an antibody that specifically binds to human OX40 and modulates OX40 activity, e.g., reduces, deactivates, or inhibits OX40 activity.

Otlowski M.,University of Tasmania | Taylor S.,University of Tasmania | Bombard Y.,Yale University | Bombard Y.,Sloan Kettering Cancer Center
Annual Review of Genomics and Human Genetics | Year: 2012

Genetic discrimination (GD) is a complex, multifaceted ethical, psychosocial, and legal phenomenon. It is defined as the differential treatment of asymptomatic individuals or their relatives on the basis of their real or assumed genetic characteristics. This article presents an overview of GD within the contemporary international context. It describes the concept of GD and its contextual features, reviews research evidence regarding people's experiences of GD and the impact of GD within a range of domains, and provides an overview of legal and policy responses to GD that have emerged globally. We argue that GD is a significant and internationally established phenomenon that requires multilevel responses to ensure social justice and equitable outcomes for all citizens. Future research should monitor GD and its impacts within the community as well as institutions and should evaluate the effectiveness of legislative, policy, community education, and systemic responses. © 2012 by Annual Reviews. All rights reserved.

Rajkumar S.V.,Mayo Medical School | Landgren O.,Sloan Kettering Cancer Center | Mateos M.-V.,University of Salamanca
Blood | Year: 2015

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM. © 2015 by The American Society of Hematology.

Gupta V.,University of Toronto | Tallman M.S.,Sloan Kettering Cancer Center | Weisdorf D.J.,University of Minnesota
Blood | Year: 2011

Progress in the last decade has improved the understanding of leukemia biology. Molecular markers in combinations with cytogenetics have improved the risk stratification of acute myeloid leukemia (AML) and informed decision-making. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allogeneic hematopoietic cell transplantation (HCT) for a larger number of patients. In this review, the positioning of HCT in the management of patients with AML is evaluated in view of changing risk/benefit ratios associated with both conventional treatments and transplantation, and some of the controversies are addressed in light of emerging data. Increasing data demonstrate outcomes of alternative donor transplantation approaching HLA-identical sibling donors in high-risk AML supporting the inclusion of alternative donors in trials of prospective studies evaluating post remission strategies for high-risk AML. The use of reduced-intensity conditioning has expanded the eligibility of HCT to older patients with AML, and outcome data are encouraging. Continued study of HCT versus alternative therapies is required to optimize patients' outcomes in AML. © 2011 by The American Society of Hematology.

Penack O.,Charité - Medical University of Berlin | Socie G.,Hopital Saint Louis | Van Den Brink M.R.M.,Sloan Kettering Cancer Center
Blood | Year: 2011

GVHD and tumor relapse are fundamental problems in allogeneic HSCT. Recent research has linked neovascularization to GVHD, tumor growth, and graft-versus-tumor (GVT) activity. Damage of the endothelium by the conditioning regimen provides the initiation stimulus for recruitment of donor-derived endothelial cells and their progenitors. During the early inflammatory phase of GVHD there is considerable neovascularization facilitating migration of inflammatory cells to target organs. In the course of GVHD, however, the vasculature itself becomes a target of alloreactive donor T cells. As a consequence, later stages of GVHD are characterized by fibrosis and rarefaction of blood vessels. Importantly, the inhibition of tumor-neovascularization by activated donor T cells that release antiangiogenic substances contributes to GVT and may be enhanced by pharmacologic inhibition of neovascularization. Furthermore, the therapeutic inhibition of neovascularization may improve immunotherapy for cancer by enhancing leukocyte infiltration in tumor tissue because of normalization of tumor vessels and stimulation of leukocyte-vessel wall interactions. These insights identify important mechanisms underlining the importance of neovascularization for allogeneic immune responses and move therapeutic approaches targeting neovascularization into the spotlight. This perspective covers current knowledge of the role of neovascularization during GVHD as well as GVT and its implications for HSCT. © 2011 by The American Society of Hematology.

Satagopan J.M.,Sloan Kettering Cancer Center | Elston R.C.,Case Western Reserve University
Statistics in Medicine | Year: 2013

This paper is concerned with evaluating whether an interaction between two sets of risk factors for a binary trait is removable and, when it is removable, fitting a parsimonious additive model using a suitable link function to estimate the disease odds (on the natural logarithm scale). Statisticians define the term 'interaction' as a departure from additivity in a linear model on a specific scale on which the data are measured. Certain interactions may be eliminated via a transformation of the outcome such that the relationship between the risk factors and the outcome is additive on the transformed scale. Such interactions are known as removable interactions. We develop a novel test statistic for detecting the presence of a removable interaction in case-control studies. We consider the Guerrero and Johnson family of transformations and show that this family constitutes an appropriate link function for fitting an additive model when an interaction is removable. We use simulation studies to examine the type I error and power of the proposed test and to show that, when an interaction is removable, an additive model based on the Guerrero and Johnson link function leads to more precise estimates of the disease odds parameters and a better fit. We illustrate the proposed test and use of the transformation by using case-control data from three published studies. Finally, we indicate how one can check that, after transformation, no further interaction is significant. © 2012 John Wiley & Sons, Ltd.

Joensuu H.,University of Helsinki | Dematteo R.P.,Sloan Kettering Cancer Center
Annual Review of Medicine | Year: 2012

Gastrointestinal stromal tumor (GIST) has become a model for targeted therapy in cancer. The vast majority of GISTs contain an activating mutation in either the KIT or platelet-derived growth factor A (PDGFRA) gene. GIST is highly responsive to several selective tyrosine kinase inhibitors. In fact, this cancer has been converted to a chronic disease in some patients. Considerable progress has been made recently in our understanding of the natural history and molecular biology of GIST, risk stratification, and drug resistance. Despite the efficacy of targeted therapy, though, surgery remains the only curative primary treatment and cures >50% of GIST patients who present with localized disease. Adjuvant therapy with imatinib prolongs recurrence-free survival and may improve overall survival. Combined or sequential use of tyrosine kinase inhibitors with other agents following tumor molecular subtyping is an attractive next step in the management of GIST. © 2012 by Annual Reviews. All rights reserved.

Krebs P.,Sloan Kettering Cancer Center | Prochaska J.O.,University of Rhode Island | Rossi J.S.,University of Rhode Island
Preventive Medicine | Year: 2010

Objective: Computer-tailored interventions have become increasingly common for facilitating improvement in behaviors related to chronic disease and health promotion. A sufficient number of outcome studies from these interventions are now available to facilitate the quantitative analysis of effect sizes, permitting moderator analyses that were not possible with previous systematic reviews. Method: The present study employs meta-analytic techniques to assess the mean effect for 88 computer-tailored interventions published between 1988 and 2009 focusing on four health behaviors: smoking cessation, physical activity, eating a healthy diet, and receiving regular mammography screening. Effect sizes were calculated using Hedges g. Study, tailoring, and demographic moderators were examined by analyzing between-group variance and meta-regression. Results: Clinically and statistically significant overall effect sizes were found across each of the four behaviors. While effect sizes decreased after intervention completion, dynamically tailored interventions were found to have increased efficacy over time as compared with tailored interventions based on one assessment only. Study effects did not differ across communication channels nor decline when up to three behaviors were identified for intervention simultaneously. Conclusion: This study demonstrates that computer-tailored interventions have the potential to improve health behaviors and suggests strategies that may lead to greater effectiveness of these techniques. © 2010 Elsevier Inc.

Larson S.M.,Sloan Kettering Cancer Center | Carrasquillo J.A.,Sloan Kettering Cancer Center | Cheung N.-K.V.,Sloan Kettering Cancer Center | Press O.W.,Fred Hutchinson Cancer Research Center
Nature Reviews Cancer | Year: 2015

The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types. © 2015 Macmillan Publishers Limited. All rights reserved.

Estey E.,University of Washington | Estey E.,Fred Hutchinson Cancer Research Center | Levine R.L.,Sloan Kettering Cancer Center | Lowenberg B.,Erasmus Medical Center
Blood | Year: 2015

A fundamental difficulty in testing "targeted therapies" in acute myeloid leukemia (AML) is the limitations of preclinical models in capturing inter- and intrapatient genomic heterogeneity. Clinical trials typically focus on single agents despite the routine emergence of resistant subclones and experience in blast-phase chronic myeloid leukemia and acute promyelocytic leukemia arguing against this strategy. Inclusion of only relapsed-refractory, or unfit newly diagnosed, patients risks falsely negative results. There is uncertainty as to whether eligibility should require demonstration of the putative target and regarding therapeutic end points. Although use of in vivo preclinical models employing primary leukemic cells is first choice, newer preclinical models including "organoids" and combinations of pharmacologicandgenetic approaches may better align models with human AML. We advocate earlier inclusion of combinations ± chemotherapy and of newly diagnosed patients into clinical trials. When a drug plausibly targets a pathway uniquely related to a specific genetic aberration, eligibility should begin with this subset, including patients with other malignancies, with subsequent extension to other patients. In other cases, a more open-minded approach to initial eligibility would facilitate quicker identification of responsive subsets. Complete remission without minimal residual disease seems a particularly useful short-term end point. Genotypic and phenotypic studies should be prespecified and performed routinely to distinguish responders from nonresponders. © 2015 by The American Society of Hematology.

Dobi K.C.,Sloan Kettering Cancer Center | Halfon M.S.,State University of New York at Buffalo | Baylies M.K.,Sloan Kettering Cancer Center
Cell Reports | Year: 2014

Skeletal muscles are formed in numerous shapes and sizes, and this diversity impacts function and disease susceptibility. To understand how muscle diversity is generated, we performed gene expression profiling of two muscle subsets from Drosophila embryos. By comparing the transcriptional profiles of these subsets, we identified a core group of founder cell-enriched genes. We screened mutants for muscle defects and identified functions for Sin3A and 10 other transcription and chromatin regulators in the Drosophila embryonic somatic musculature. Sin3A is required for the morphogenesis of a muscle subset, and Sin3A mutants display muscle loss and misattachment. Additionally, misexpression of identity gene transcription factors in Sin3A heterozygous embryos leads to direct transformations of one muscle into another, whereas overexpression of Sin3A results in the reverse transformation. Our data implicate Sin3A as a key buffer controlling muscle responsiveness to transcription factors in the formation of muscle identity, thereby generating tissue diversity. © 2014 The Authors.

Haeno H.,Dana-Farber Cancer Institute | Gonen M.,Sloan Kettering Cancer Center | Davis M.B.,Johns Hopkins Hospital | Herman J.M.,Johns Hopkins Hospital | And 2 more authors.
Cell | Year: 2012

Pancreatic cancer is a leading cause of cancer-related death, largely due to metastatic dissemination. We investigated pancreatic cancer progression by utilizing a mathematical framework of metastasis formation together with comprehensive data of 228 patients, 101 of whom had autopsies. We found that pancreatic cancer growth is initially exponential. After estimating the rates of pancreatic cancer growth and dissemination, we determined that patients likely harbor metastases at diagnosis and predicted the number and size distribution of metastases as well as patient survival. These findings were validated in an independent database. Finally, we analyzed the effects of different treatment modalities, finding that therapies that efficiently reduce the growth rate of cells earlier in the course of treatment appear to be superior to upfront tumor resection. These predictions can be validated in the clinic. Our interdisciplinary approach provides insights into the dynamics of pancreatic cancer metastasis and identifies optimum therapeutic interventions. © 2012 Elsevier Inc.

Weigelt B.,Sloan Kettering Cancer Center | Ghajar C.M.,Fred Hutchinson Cancer Research Center | Bissell M.J.,Lawrence Berkeley National Laboratory
Advanced Drug Delivery Reviews | Year: 2014

The recent cataloging of the genomic aberrations in breast cancer has revealed the diversity and complexity of the disease at the genetic level. To unravel the functional consequences of specific repertoires of mutations and copy number changes on signaling pathways in breast cancer, it is crucial to develop model systems that truly recapitulate the disease. Here we discuss the three-dimensional culture models currently being used or recently developed for the study of normal mammary epithelial cells and breast cancer, including primary tumors and dormancy. We discuss the insights gained from these models in regards to cell signaling and potential therapeutic strategies, and the challenges that need to be met for the generation of heterotypic breast cancer model systems that are amenable for high-throughput approaches. © 2014.

Luke J.J.,Sloan Kettering Cancer Center | Hodi F.S.,Dana-Farber Cancer Institute
Clinical Cancer Research | Year: 2012

The U.S. Food and Drug Administration recently approved vemurafenib for the treatment of BRAF valine in exon 15, at codon 600 (V600E) mutant metastatic melanoma. Vemurafenib is a competitive small-molecule serine-threonine kinase inhibitor that functions by binding to the ATP-binding domain of mutant BRAF. Compared with dacarbazine chemotherapy, vemurafenib significantly improved the 6-month overall survival of patients from 64% to 84% and exhibited a response rate of approximately 50%. Median progression-free survival was also significantly improved with vemurafenib as compared with dacarbazine (5.3 versus 1.6 months, respectively), and this was consistent among groups analyzed, including age, sex, geography, Eastern Cooperative Oncology Group status, disease stage, and serum lactate dehydrogenase. The success of targeting melanoma genomics has created a paradigm shift for future drug development. Currently, the elucidation of resistant mechanisms to vemurafenib therapy remains an important area of active investigation that will shape rational drug treatments for melanoma. The development of vemurafenib, the role of BRAF targeting, and the changing landscape of treatment for melanoma provide a new foundation for clinical investigation. ©2011 AACR.

Sima C.S.,Sloan Kettering Cancer Center | Panageas K.S.,Sloan Kettering Cancer Center | Schrag D.,Dana-Farber Cancer Institute
JAMA - Journal of the American Medical Association | Year: 2010

Context: Cancer screening has been integrated into routine primary care but does not benefit patients with limited life expectancy. Objective: To evaluate the extent to which patients with advanced cancer continue to be screened for new cancers. Design, Setting, and Participants: Utilization of cancer screening procedures (mammography, Papanicolaou test, prostate-specific antigen [PSA], and lower gastrointestinal [GI] endoscopy) was assessed in 87 736 fee-for-service Medicare enrollees aged 65 years or older diagnosed with advanced lung, colorectal, pancreatic, gastroesophageal, or breast cancer between 1998 and 2005, and reported to one of the Surveillance, Epidemiology, and End Results (SEER) tumor registries. Participants were followed up until death or December 31, 2007, whichever came first. A group of 87 307 Medicare enrollees without cancer were individually matched by age, sex, race, and SEER registry to patients with cancer and observed over the same period to evaluate screening rates in context. Demographic and clinical characteristics associated with screening were also investigated. Main Outcome Measure: For each cancer screening test, utilization rates were defined as the percentage of patients who were screened following the diagnosis of an incurable cancer. Results: Among women following advanced cancer diagnosis compared with controls, at least 1 screening mammogram was received by 8.9% (95% confidence interval [CI], 8.6%-9.1%) vs 22.0% (95% CI, 21.7%-22.5%); Papanicolaou test screening was received by 5.8% (95% CI, 5.6%-6.1%) vs 12.5% (95% CI, 12.2%-12.8%). Among men following advanced cancer diagnosis compared with controls, PSA test was received by 15.0% (95% CI, 14.7%-15.3%) vs 27.2% (95% CI, 26.8%-27.6%). For all patients following advanced diagnosis compared with controls, lower GI endoscopy was received by 1.7% (95% CI, 1.6%-1.8%) vs 4.7% (95% CI, 4.6%-4.9%). Screening was more frequent among patients with a recent history of screening (16.2% [95% CI, 15.4%-16.9%] of these patients had mammography, 14.7% [95% CI, 13.7%-15.6%] had a Papanicolaou test, 23.3% [95% CI, 22.6%-24.0%] had a PSA test, and 6.1% [95% CI, 5.2%-7.0%] had lower GI endoscopy). Conclusion: A sizeable proportion of patients with advanced cancer continue to undergo cancer screening tests that do not have a meaningful likelihood of providing benefit. ©2010 American Medical Association. All rights reserved.

Miller J.F.A.P.,Walter and Eliza Hall Institute of Medical Research | Sadelain M.,Sloan Kettering Cancer Center
Cancer Cell | Year: 2015

Recent advances in cancer immunotherapy have directly built on 50 years of fundamental and technological advances that made checkpoint blockade and Tcell engineering possible. In this review, we intend to show that research, not specifically designed to bring relief or cure to any particular disease, can, when creatively exploited, lead to spectacular results in the management of cancer. The discovery of thymus immune function, Tcells, and immune surveillance bore the seeds for today's targeted immune interventions and chimeric antigen receptors. © 2015 Elsevier Inc.

Ghobrial I.M.,Dana-Farber Cancer Institute | Landgren O.,Sloan Kettering Cancer Center
Blood | Year: 2014

Smoldering myelomais a heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as "early myeloma." It is defined as either serum M-protein ≥3 g/L or ≥10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering myeloma will become an increasingly important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity. © 2014 by The American Society of Hematology.

Momesso D.P.,Federal University of Rio de Janeiro | Tuttle R.M.,Sloan Kettering Cancer Center
Endocrinology and Metabolism Clinics of North America | Year: 2014

In this review, we demonstrate how initial estimates of the risk of disease-specific mortality and recurrent/persistent disease should be used to guide initial treatment recommendations and early management decisions and to set appropriate patient expectations with regard to likely outcomes after initial therapy of thyroid cancer. The use of ongoing risk stratification to modify these initial risk estimates is also discussed. Novel response to therapy definitions are proposed that can be used for ongoing risk stratification in thyroid cancer patients treated with lobectomy or total thyroidectomy without radioactive iodine remnant ablation. © 2014 Elsevier Inc.

Princeton University and Sloan Kettering Cancer Center | Date: 2014-07-01

Methods and compositions for treating cancer and other disorders associated with undesired cellular proliferation are provided comprising administering to a subject in need thereof an amino acid mixture, wherein the amino acid mixture comprises glycine, optionally comprising at least a 2:1 molar ratio of glycine to serine.

Chen J.,Yale University | Long J.B.,Yale University | Hurria A.,Medical Oncology and Population science | Owusu C.,Case Western Reserve University | And 2 more authors.
Journal of the American College of Cardiology | Year: 2012

Objectives: The purpose of this study was to estimate heart failure (HF) and cardiomyopathy (CM) rates after adjuvant trastuzumab therapy and chemotherapy in a population of older women with early-stage breast cancer. Background: Newer biologic therapies for breast cancer such as trastuzumab have been reported to increase HF and CM in clinical trials, especially in combination with anthracycline chemotherapy. Elderly patients, however, typically have a higher prevalence of cardiovascular risk factors and have been underrepresented in trastuzumab clinical trials. Methods: Using Surveillance, Epidemiology, and End Results-Medicare data from 2000 through 2007, we identified women 67 to 94 years of age with early-stage breast cancer. We calculated 3-year incidence rates of HF or CM for the following mutually exclusive treatment groups: trastuzumab (with or without nonanthracycline chemotherapy), anthracycline plus trastuzumab, anthracycline (without trastuzumab and with or without nonanthracycline chemotherapy), other nonanthracycline chemotherapy, or no adjuvant chemotherapy or trastuzumab therapy. HF or CM events were ascertained from administrative Medicare claims. Poisson regression was used to quantify risk of HF or CM, adjusting for sociodemographic factors, cancer characteristics, and cardiovascular conditions. Results: We identified 45,537 older women (mean age: 76.2 years, standard deviation: 6.2 years) with early-stage breast cancer. Adjusted 3-year HF or CM incidence rates were higher for patients receiving trastuzumab (32.1 per 100 patients) and anthracycline plus trastuzumab (41.9 per 100 patients) compared with no adjuvant therapy (18.1 per 100 patients, p < 0.001). Adding trastuzumab to anthracycline therapy added 12.1, 17.9, and 21.7 HF or CM events per 100 patients over 1, 2, and 3 years of follow-up, respectively. Conclusions: HF or CM are common complications after trastuzumab therapy for older women, with higher rates than those reported from clinical trials. © 2012 American College of Cardiology Foundation.

Sloan Kettering Cancer Center and Princeton University | Date: 2014-05-09

Methods and compositions for treating Ras-related cancers are provided that involve targeting lipid scavenging. Methods and compositions for identifying and/or characterizing more or less responsive cancers are also provided.

Palm W.,Sloan Kettering Cancer Center | Park Y.,Cold Spring Harbor Laboratory | Wright K.,Cold Spring Harbor Laboratory | Pavlova N.N.,Sloan Kettering Cancer Center | And 2 more authors.
Cell | Year: 2015

Summary Despite being surrounded by diverse nutrients, mammalian cells preferentially metabolize glucose and free amino acids. Recently, Ras-induced macropinocytosis of extracellular proteins was shown to reduce a transformed cell's dependence on extracellular glutamine. Here, we demonstrate that protein macropinocytosis can also serve as an essential amino acid source. Lysosomal degradation of extracellular proteins can sustain cell survival and induce activation of mTORC1 but fails to elicit significant cell accumulation. Unlike its growth-promoting activity under amino-acid-replete conditions, we discovered that mTORC1 activation suppresses proliferation when cells rely on extracellular proteins as an amino acid source. Inhibiting mTORC1 results in increased catabolism of endocytosed proteins and enhances cell proliferation during nutrient-depleted conditions in vitro and within vascularly compromised tumors in vivo. Thus, by preventing nutritional consumption of extracellular proteins, mTORC1 couples growth to availability of free amino acids. These results may have important implications for the use of mTOR inhibitors as therapeutics. © 2015 Elsevier Inc.

Steinbeck J.A.,Sloan Kettering Cancer Center | Steinbeck J.A.,Sloan Kettering Institute for Cancer Research | Studer L.,Sloan Kettering Cancer Center | Studer L.,Sloan Kettering Institute for Cancer Research
Neuron | Year: 2015

Stem cell-based therapies hold considerable promise for many currently devastating neurological disorders. Substantial progress has been made in the derivation of disease-relevant human donor cell populations. Behavioral data in relevant animal models of disease have demonstrated therapeutic efficacy for several cell-based approaches. Consequently, cGMP grade cell products are currently being developed for first in human clinical trials in select disorders. Despite the therapeutic promise, the presumed mechanism of action of donor cell populations often remains insufficiently validated. It depends greatly on the properties of the transplanted cell type and the underlying host pathology. Several new technologies have become available to probe mechanisms of action in real time and to manipulate invivo cell function and integration to enhance therapeutic efficacy. Results from such studies generate crucial insight into the nature of brain repair that can be achieved today and push the boundaries of what may be possible in the future. © 2015 Elsevier Inc.

Gaujoux S.,Cochin Hospital | Gaujoux S.,French Institute of Health and Medical Research | Brennan M.F.,Sloan Kettering Cancer Center
Surgery (United States) | Year: 2012

Background: Operative resection is the only potentially curative treatment for primary adrenocortical carcinoma (ACC), but standards of operative care are not defined with regards to the extent of local resection. We propose recommendations for operative management. Methods: Anatomic and clinical literature review focusing on local management of ACC, including lymphadenectomy and resection of adjacent organs or large vessels. Results: First-order drainage nodes of the adrenal gland include the renal hilum lymph nodes, the celiac lymph nodes, and the para-aortic and paracaval lymph nodes, mainly above the renal pedicle and ipsilateral to the adrenal glands. Lymph node involvement occurs in about 20% of patients with ACC, and is an important prognostic factor, but lymphadenectomy is performed infrequently. The adrenal glands and kidneys are contained in the same anatomic space, but systematic en bloc nephrectomy has no proven benefits for survival. Direct invasion of the kidney or adjacent organs is rare, but major venous invasion with tumor thrombus is relatively common. Both are associated with decreased survival, but complete resection can lead to long-term survival. Conclusion: Standardization of regional lymphadenectomy including first-order drainage nodes is proposed. Systematic nephrectomy is not necessary in the absence of gross local invasion, but locally involved organs or large veins should be resected en bloc, with tumor thrombus embolectomy, if R0 resection is possible. Operative standardization improves tumor staging, potentially decreases local recurrence, and may be associated with better survival. Evidence-based standards of operative care and prospective investigations within international collaborating groups are necessary. © 2012 Mosby, Inc. All rights reserved.

Saad F.,Center Hospitalier Of Luniversite Of Montreal | Segal S.,Novartis | Eastham J.,Sloan Kettering Cancer Center
European Urology | Year: 2014

Background Zoledronic acid (ZOL) is a standard therapy for the prevention of skeletal-related events (SREs) in patients with castration-resistant prostate cancer (CRPC). Although prostate-specific antigen (PSA) is an established marker for monitoring prostate cancer patients, correlations between PSA and disease outcomes during ZOL therapy are unclear. Objective To evaluate the relationships among PSA kinetics, bone-directed therapy with ZOL, and clinical outcomes in men with bone metastases from CRPC using a ZOL phase 3 trial database. Design, setting, and participants Exploratory analyses from a phase 3 trial in men with bone metastases from CRPC (n = 643) randomized to ZOL or placebo every 3 wk. Outcome measurements and statistical analysis PSA levels during the first 3 mo of the study were evaluated in linear and logarithmic (log) models stratified using prognostic factors established in a ZOL phase 3 trial and a CRPC nomogram. Relative risks of SREs, bone disease progression (BDP), and death were calculated per 1 log (nanograms per milliliter) PSA increase. Baseline PSA models used the study median (PSA: 77.3 ng/ml) as the high/low cut-off point. Results and limitations A total of 202 placebo- and 434 ZOL-treated patients were assessable. In both groups, PSA increases correlated with significantly increased risks of death, BDP, and first SRE. In the placebo and ZOL groups, associated increases in risk per 1 log (nanograms per milliliter) PSA increase were 29% (p < 0.0001) and 10% (p < 0.0074), respectively, for BDP, and 24% (p = 0.0010) and 13% (p = 0.0079), respectively, for first SRE. Limitations include the retrospective nature of these analyses and the potential confounding effects of concurrent antineoplastic therapies. Conclusions PSA is an important prognostic tool for survival in patients with bone metastases from CRPC, and these analyses show that PSA is also prognostic for BDP and SREs regardless of bone-targeted therapy. © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Wang X.,Roswell Park Cancer Institute | Jiang X.,Sloan Kettering Cancer Center
FEBS Letters | Year: 2012

Mdm2 regulates the stability, translation, subcellular localization and transcriptional activity of p53 protein. Mdm2-dependent p53 inhibition is essential in regulating p53 activity during embryonic development and in adult tissues. MdmX, an Mdm2 homolog, is also essential for p53 inhibition in vivo. Recent advances in the field from biochemical and genetic studies have revealed an essential role for the MdmX RING domain in Mdm2-dependent p53 polyubiquitination and degradation. Mdm2 on its own is a monoubiquitin E3 ligase for p53, but is converted to a p53 polyubiquitin E3 ligase by MdmX through their RING-RING domain interactions. MdmX acts as an activator as well as a substrate of Mdm2/MdmX E3 complex. The insufficiency of Mdm2 for p53 polyubiquitination also demands other p53 E3 ligases or E4 factors be incorporated into the p53 degradation arena. Deubiquitinases nullify the effects of E3 actions and reverse the ubiquitination process, which permits a diverse and dynamic pattern of p53 stability control. Unsurprisingly, stress signals target MdmX to disengage the p53/Mdm2 feedback loop for timely and appropriate p53 responses to these stresses. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Pearson S.D.,Institute for Clinical and Economic Review | Bach P.B.,Sloan Kettering Cancer Center
Health Affairs | Year: 2010

Medicare must find new ways to achieve cost control without limiting access to beneficial services. We propose a payment model incorporating comparative effectiveness research to encourage Medicare to pay equally for services that provide comparable patient outcomes. The model would include higher payments for services demonstrated by adequate evidence to provide superior health benefits compared to alternative options. New services without such evidence would receive usual reimbursement rates for a limited time but then be reevaluated as evidence emerged. In spite of the substantial political hurdles to changing Medicare reimbursement, efforts should be made to use comparative effectiveness research to reward superior services, improve incentives for cost-effective innovation, and place Medicare on a more sustainable financial footing. © 2010 Project HOPE-The People-to-People Health Foundation, Inc.

Korolev K.S.,Boston University | Xavier J.B.,Sloan Kettering Cancer Center | Gore J.,Massachusetts Institute of Technology
Nature Reviews Cancer | Year: 2014

The fight against cancer has drawn researchers from a wide variety of disciplines, ranging from molecular biology to physics, but the perspective of an ecological theorist has been mostly overlooked. By thinking about the cells that make up a tumour as an endangered species, cancer vulnerabilities become more apparent. Studies in conservation biology and microbial experiments indicate that extinction is a complex phenomenon, which is often driven by the interaction of ecological and evolutionary processes. Recent advances in cancer research have shown that tumours, like species striving for survival, harbour intricate population dynamics, which suggests the possibility to exploit the ecology of tumours for treatment. © 2014 Macmillan Publishers Limited.

Zhang Z.,Sloan Kettering Cancer Center | Sun J.,University of Missouri
Statistical Methods in Medical Research | Year: 2010

Interval-censored failure time data occur in many medical investigations as well as other studies such as demographical and sociological studies. They include the usual right-censored failure time data as a special case but provide much more complex structure and less relevant information than the right-censored data. This article reviews some basic concepts, issues and the corresponding statistical approaches related to the analysis of interval-censored data as well as recent advances. In particular, we discuss estimation of a survival function, comparison of several treatments and regression analysis as well as competing risks analysis and truncation in the presence of interval censoring. A well-known example of interval-censored data is described and analysed to illustrate some of the statistical procedures discussed.

He S.,Sloan Kettering Cancer Center | Li Z.,Sloan Kettering Cancer Center | Ge S.,SUNY at Stony Brook | Yu Y.-C.,Institute of Neurobiology | Shi S.-H.,Sloan Kettering Cancer Center
Neuron | Year: 2015

Neocortical excitatory neurons migrate radially along the glial fibers of mother radial glial progenitors (RGPs) in a birth-date-dependent inside-out manner. However, the precise functional significance of this well-established orderly neuronal migration remains largely unclear. Here, we show that strong electrical synapses selectively form between RGPs and their newborn progeny and between sister excitatory neurons in ontogenetic radial clones at the embryonic stage. Interestingly, the preferential electrical coupling between sister excitatory neurons, but not that between RGP and newborn progeny, is eliminated in mice lacking REELIN or upon clonal depletion of DISABLED-1, which compromises the inside-out radial neuronal migration pattern in the developing neocortex. Moreover, increased levels of Ephrin-A ligand or receptor that laterally disperse sister excitatory neurons also disrupt preferential electrical coupling between radially aligned sister excitatory neurons. These results suggest that RGP-guided inside-out radial neuronal migration facilitates the initial assembly of lineage-dependent precise columnar microcircuits in the neocortex. He et al. show that electrical synapses preferentially form between progenitor and newborn progeny, and between sister excitatory neurons, in the embryonic neocortex. Moreover, disruption of the birth-date-dependent inside-out radial migration impairs preferential electrical coupling between sister excitatory neurons. © 2015 Elsevier Inc.

City University of New York and Sloan Kettering Cancer Center | Date: 2014-04-21

A layered, microfluidic living cell array is disclosed. The cell array comprises a first layer comprising at least one cell culture channel; a second layer comprising at least one microfluidic channel; and a third layer, disposed between the first layer and the second layer. The third layer comprises a filter membrane with a plurality of pores, each pore fluidly connecting the microfluidic channel to the cell culture channel.

City University of New York and Sloan Kettering Cancer Center | Date: 2016-08-08

A layered, microfluidic array is disclosed. The array comprises a first layer comprising at least one culture channel; a second layer comprising at least one microfluidic channel; and a third layer, disposed between the first layer and the second layer. The third layer comprises a filter membrane with a plurality of pores, each pore fluidly connecting the microfluidic channel to the culture channel.

Sloan Kettering Cancer Center and Massachusetts Institute of Technology | Date: 2013-12-04

In certain embodiments, a nano-sized vehicle (e.g., a nanogel comprising nanoparticles) is provided herein for drug delivery with tunable biodistribution, low toxicity, and degradability, and with demonstrated targeting to bone. The composition is useful, for example, in the treatment of bone disease, particularly bone metastases from cancers such as breast, prostate, or lung cancer.

Draghi N.A.,Biochemistry and Structural Biology Program | Denzin L.K.,Immunology and Microbial Pathogenesis Program | Denzin L.K.,Sloan Kettering Cancer Center
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Upon antigen (Ag) encounter, B cells require T-cell help to enter the germinal center (GC). They obtain this help by presenting Agderived peptides onMHC class II (MHCII) for recognition by the T-cell receptor (TCR) of CD4 + T cells. Peptides are loaded onto MHCII in endosomal compartments in a process catalyzed by the MHCII-like protein H2-M (HLA-DM in humans). This process is modulated by another MHCII-like protein, H2-O (HLA-DO in humans). H2-O is a biochemical inhibitor of peptide loading onto MHCII; however, on the cellular level, it has been shown to have varying effects on Ag presentation. Thus, the function of H2-O in the adaptive immune response remains unclear. Here, we examine the effect of H2-O expression on the ability of Ag-specific B cells to enter the GC. We show that when Ag specific WT and H2-O-/- B cells are placed in direct competition, H2-O-/- B cells preferentially populate the GC. This advantage is confined to Ag-specific B cells and is due to their superior ability to obtain Ag-specific T-cell help when T-cell help is limiting. Overall, our work shows that H2-O expression reduces the ability of B cells to gain T-cell help and participate in the GC reaction.

Heller S.,Montefiore Medical Center | Zanzonico P.,Sloan Kettering Cancer Center
Seminars in Nuclear Medicine | Year: 2011

Gamma probes are now an important, well-established technology in the management of cancer, particularly in the detection of sentinel lymph nodes. Intraoperative sentinel lymph node as well as tumor detection may be improved under some circumstances by the use of beta (negatron or positron), rather than gamma detection, because the very short range (∼1 mm or less) of such particulate radiations eliminates the contribution of confounding counts from activity other than in the immediate vicinity of the detector. This has led to the development of intraoperative beta probes. Gamma camera imaging also benefits from short source-to-detector distances and minimal overlying tissue, and intraoperative small field-of-view gamma cameras have therefore been developed as well. Radiation detectors for intraoperative probes can generally be characterized as either scintillation or ionization detectors. Scintillators used in scintillation-detector probes include thallium-doped sodium iodide, thallium- and sodium-doped cesium iodide, and cerium-doped lutecium orthooxysilicate. Alternatives to inorganic scintillators are plastic scintillators, solutions of organic scintillation compounds dissolved in an organic solvent that is subsequently polymerized to form a solid. Their combined high counting efficiency for beta particles and low counting efficiency for 511-keV annihilation γ-rays make plastic scintillators well-suited as intraoperative beta probes in general and positron probes in particular Semiconductors used in ionization-detector probes include cadmium telluride, cadmium zinc telluride, and mercuric iodide. Clinical studies directly comparing scintillation and semiconductor intraoperative probes have not provided a clear choice between scintillation and ionization detector-based probes. The earliest small field-of-view intraoperative gamma camera systems were hand-held devices having fields of view of only 1.5-2.5 cm in diameter that used conventional thallium-doped sodium iodide or sodium-doped cesium iodide scintillation detectors. Later units used 2-dimensional arrays (mosaics) of scintillation crystals connected to a position-sensitive photomultiplier tube and, more recently, semiconductors such as cadmium telluride or cadmium zinc telluride. The main problems with the early units were their very small fields of view and the resulting large number of images required to interrogate the surgical field and the difficulty in holding the device sufficiently still for the duration (up to 1 min) of the image acquisition. More recently, larger field-of-view (up to 5 × 5 cm) devices have developed which are attached to an articulating arm for easy and stable positioning. These systems are nonetheless fully portable and small enough overall to be accommodated in typical surgical suites. © 2011 Elsevier Inc.

Detterbeck F.C.,Yale University | Mazzone P.J.,Cleveland Clinic | Naidich D.P.,NYU Langone Medical Center | Bach P.B.,Sloan Kettering Cancer Center
Chest | Year: 2013

Background: Lung cancer is by far the major cause of cancer deaths largely because in the majority of patients it is at an advanced stage at the time it is discovered, when curative treatment is no longer feasible. This article examines the data regarding the ability of screening to decrease the number of lung cancer deaths. Methods: A systematic review was conducted of controlled studies that address the effectiveness of methods of screening for lung cancer. Results: Several large randomized controlled trials (RCTs), including a recent one, have demonstrated that screening for lung cancer using a chest radiograph does not reduce the number of deaths from lung cancer. One large RCT involving low-dose CT (LDCT) screening demonstrated a significant reduction in lung cancer deaths, with few harms to individuals at elevated risk when done in the context of a structured program of selection, screening, evaluation, and management of the relatively high number of benign abnormalities. Whether other RCTs involving LDCT screening are consistent is unclear because data are limited or not yet mature. Conclusions: Screening is a complex interplay of selection (a population with sufficient risk and few serious comorbidities), the value of the screening test, the interval between screening tests, the availability of effective treatment, the risk of complications or harms as a result of screening, and the degree with which the screened individuals comply with screening and treatment recommendations. Screening with LDCT of appropriate individuals in the context of a structured process is associated with a significant reduction in the number of lung cancer deaths in the screened population. Given the complex interplay of factors inherent in screening, many questions remain on how to effectively implement screening on a broader scale. Copyright © by the American College of Chest Physicians 2013.

Lessnick S.L.,University of Utah | Ladanyi M.,Sloan Kettering Cancer Center
Annual Review of Pathology: Mechanisms of Disease | Year: 2012

Approximately one-third of sarcomas contain specific translocations. Ewing sarcoma is the prototypical member of this group of sarcomas; it was the first to be recognized pathologically as a singular entity and to have its signature translocation defined cytogenetically, which led to the identification of its key driver alteration, the EWS-FLI1 gene fusion that encodes this aberrant, chimeric transcription factor. We review recent progress in selected areas of Ewing sarcoma research, including the application of genome-wide chromatin immunoprecipitation analyses, to provide a comprehensive view of the EWS-FLI1 target gene repertoire, the identification of EWS-FLI1 target genes that may also point to therapeutically targetable pathways, and data from model systems as they relate to the elusive cell of origin of Ewing sarcoma and its possible similarities to mesenchymal stem cells. Copyright ©2012 by Annual Reviews. All rights reserved.

Prockop D.J.,Texas A&M University | Prockop S.E.,Sloan Kettering Cancer Center | Bertoncello I.,University of Melbourne
Stem Cells | Year: 2014

The cells referred to as mesenchymal stem/progenitor cells (MSCs) are currently being used to treat thousands of patients with diseases of essentially all the organs and tissues of the body. Strikingly positive results have been reported in some patients, but there have been few prospective controlled studies. Also, the reasons for the beneficial effects are frequently unclear. As a result there has been a heated debate as to whether the clinical trials with these new cell therapies are too far ahead of the science. The debate is not easily resolved, but important insights are provided by the 60-year history that was required to develop the first successful stem cell therapy, the transplantation of hematopoietic stem cells. The history indicates that development of a dramatically new therapy usually requires patience and a constant dialogue between basic scientists and physicians carrying out carefully designed clinical trials. It also suggests that the field can be moved forward by establishing better records of how MSCs are prepared, by establishing a large supply of reference MSCs that can be used to validate assays and compare MSCs prepared in different laboratories, and by continuing efforts to establish in vivo assays for the efficacy of MSCs. Stem Cells 2014;32:3055-3061 © 2014 The Authors. STEM CELLS Published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Cheung N.-K.V.,Sloan Kettering Cancer Center | Dyer M.A.,St Jude Childrens Research Hospital | Dyer M.A.,University of Tennessee Health Science Center | Dyer M.A.,Howard Hughes Medical Institute
Nature Reviews Cancer | Year: 2013

Neuroblastoma is a solid tumour that arises from the developing sympathetic nervous system. Over the past decade, our understanding of this disease has advanced tremendously. The future challenge is to apply the knowledge gained to developing risk-based therapies and, ultimately, improving outcome. In this Review we discuss the key discoveries in the developmental biology, molecular genetics and immunology of neuroblastoma, as well as new translational tools for bringing these promising scientific advances into the clinic. © 2013 Macmillan Publishers Limited. All rights reserved.

Huse J.T.,Sloan Kettering Cancer Center | Aldape K.D.,University of Toronto
Clinical Cancer Research | Year: 2014

While the classification of diffuse gliomas has relied on the examination of morphologic features supplemented with techniques such as immunohistochemistry, there is an increasing recognition of substantial biologic diversity within morphologically defined entities. High-throughput technologies, in particular studies that integrate genome-wide data from diverse molecular platforms, increasingly identify the existence of robust and distinct glioma subtypes. While treatment advances and improvement of outcomes for patients with diffuse glioma have been modest, there may be benefit to integrate findings from biologic studies into clinical practice to enhance the precision of treatment for these diseases. Recent examples such as the identification of mutations in IDH1 and IDH2 as an early genetic event that is predominantly in lower-grade gliomas (grades 2 and 3) underscore the importance of molecular discovery leading to the ability to develop subclassifications with prognostic and potentially therapeutic implications. In contrast, glioblastoma (grade 4), the most common and aggressive glioma, typically arises without IDH mutation, supporting the need for different therapeutic approaches. Additional genomic and epigenomic signatures are generally nonoverlapping between IDH-mutant and IDH wild-type diffuse glioma, and despite comparable histopathology, IDH-mutant gliomas can be considered as biologically distinct from IDH wild-type gliomas. In this CCR Focus article, we highlight and summarize the current understanding of recent molecular findings and the relationships of these findings to clinical trials and clinical management. © 2014 AACR.

Jones T.S.,University of Tennessee Health Science Center | Holland E.C.,Sloan Kettering Cancer Center
Oncogene | Year: 2012

Glioblastoma is the most common and deadly of the primary central nervous system tumors. Recent advances in molecular characterization have subdivided these tumors into at least three main groups. In addition, these tumors are cellularly complex with multiple stromal cell types contributing to the biology of the tumor and treatment response. Because essentially all glioma patients are treated with radiation, various chemotherapies and steroids, the tumor that finally kills them has been modified by these treatments. Most of the investigation of the effects of therapy on these tumors has focused on the glioma cells per se. However, despite the importance of the stromal cells in these tumors, little has been done to understand the effects of treatment on stromal cells and their contribution to disease. Understanding how current standard therapy affects the biology of the tumor and the tumor stroma may provide insight into the mechanisms that are important to the inhibition of tumor growth as well as the biology of recurrent tumors. © 2012 Macmillan Publishers Limited All rights reserved.

Riviere I.,Sloan Kettering Cancer Center | Dunbar C.E.,U.S. National Institutes of Health | Sadelain M.,Sloan Kettering Cancer Center
Blood | Year: 2012

The genetic engineering of hematopoietic stem cells is the basis for potentially treating a large array of hereditary and acquired diseases, and stands as the paradigm for stem cell engineering in general. Recent clinical reports support the formidable promise of this approach but also highlight the limitations of the technologies used to date, which have on occasion resulted in clonal expansion, myelodysplasia, or leukemogenesis. New research directions, predicated on improved vector designs, targeted gene delivery or the therapeutic use of pluripotent stem cells, herald the advent of safer and more effective hematopoietic stem cell therapies that may transform medical practice. In this review, we place these recent advances in perspective, emphasizing the solutions emerging from a wave of new technologies and highlighting the challenges that lie ahead.

Murphy C.G.,Bon Secours Hospital | Dickler M.N.,Sloan Kettering Cancer Center
Oncologist | Year: 2015

Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptorpositive (ER1) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia.We discuss these studies and the phase III studies that are accruing or nearingcompletion.Wedescribetheapplicationofsuchtherapy to other breast cancer settings, including HER2-positive breast cancer and the adjuvant treatment of early breast cancer.We also discuss potential concerns surrounding the combination of CDK inhibitorswith chemotherapy and their effects on repair of double-strand DNA breaks in cancer cells. Oral highly selective CDKinhibitors showgreat promiseinimprovingtheoutcomesof patientswithER1breastcancer, althoughcautionmustapply to their combination with other agents and in the early breast cancer setting. © AlphaMed Press 2015.

Yu H.A.,Sloan Kettering Cancer Center | Riely G.J.,Sloan Kettering Cancer Center | Lovly C.M.,Vanderbilt University
Clinical Cancer Research | Year: 2014

Patients with EGFR-mutant lung cancer derive significant therapeutic benefit from treatment with EGFR tyrosine kinase inhibitors (TKI). Unfortunately, acquired resistance is an inevitable consequence of this treatment strategy, with a broad variety of resistance mechanisms including acquired EGFR mutations (e.g., T790M) and activation of bypass signaling pathways, such as MET and HER2. Several therapeutic strategies hypothesized to delay or overcome resistance have been tested in clinical trials, including "nextgeneration" EGFR TKIs and rational combinations of targeted agents. However, to date, there are no FDAapproved therapies for patients with acquired resistance to first-line EGFR TKI therapy. There remains a critical need for more effective and better tailored treatments in this setting to match treatments to the individual patient and specific resistance mechanism at hand. In this review, we discuss known mechanisms of resistance to first-line EGFR TKI therapy and describe previous and ongoing strategies to overcome resistance. ©2014 AACR.

Montemurro F.,Institute of Candiolo IRCCs | Scaltriti M.,Sloan Kettering Cancer Center
Journal of Pathology | Year: 2014

The epidermal growth factor receptor family (EGFR/HER) is frequently deregulated in human cancers. Several aberrations at various levels have been successfully exploited as targets for anti-cancer therapies. However, with very few exceptions, drugs targeting HER signalling have shown only modest activity when used alone in cancers where a HER-related target can be identified. Optimization of the use of these drugs either alone or in combination with other anti-cancer agents would require a more precise definition of alterations that could predict for activity or resistance. Clinical validation of the several potential biomarkers emerging from clinical and translational studies is a challenging process. Thanks to combined efforts, collection of tumour tissues and other potentially relevant patients' materials has become more and more frequently mandatory in prospective studies with biologically targeted therapies. As a consequence, information on the value of promising biomarkers of drugs targeting HER-family receptor targeting is becoming available. This review will focus on breast cancer, where the HER2 subset has been the subject of a major research effort in the last two decades, and on gastric cancer, where HER2 targeting has emerged recently as a successful strategy. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Lee C.J.,Sloan Kettering Cancer Center | Ansell J.E.,New Hill
British Journal of Clinical Pharmacology | Year: 2011

Heparins and vitamin K antagonists have been the primary agents used for anticoagulation in certain cardiovascular and thromboembolic diseases for over 50 years. However, they can be difficult to administer and are fraught with limitations. In response to the need for new anticoagulants, direct thrombin inhibitors (DTIs) have been developed and investigated for their utility in prophylaxis and treatment of venous thromboembolism (VTE), heparin-induced thrombocytopenia (HIT), acute coronary syndromes (ACS), secondary prevention of coronary events after ACS, and nonvalvular atrial fibrillation. Currently, four parenteral direct inhibitors of thrombin activity are FDA-approved in North America: lepirudin, desirudin, bivalirudin and argatroban. Of the new oral DTIs, dabigatran etexilate is the most studied and promising of these agents. This review discusses the clinical indications and efficacy of these direct thrombin inhibitors as well as future directions in anticoagulant therapy. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Bennette C.,University of Washington | Vickers A.,Sloan Kettering Cancer Center
BMC Medical Research Methodology | Year: 2012

Background: Quantiles are a staple of epidemiologic research: in contemporary epidemiologic practice, continuous variables are typically categorized into tertiles, quartiles and quintiles as a means to illustrate the relationship between a continuous exposure and a binary outcome. Discussion. In this paper we argue that this approach is highly problematic and present several potential alternatives. We also discuss the perceived drawbacks of these newer statistical methods and the possible reasons for their slow adoption by epidemiologists. Summary. The use of quantiles is often inadequate for epidemiologic research with continuous variables. © 2012 Bennette and Vickers; licensee BioMed Central Ltd.

Gillies R.J.,H. Lee Moffitt Cancer Center and Research Institute | Kinahan P.E.,University of Washington | Hricak H.,Sloan Kettering Cancer Center
Radiology | Year: 2016

In the past decade, the field of medical image analysis has grown exponentially, with an increased number of pattern recognition tools and an increase in data set sizes. These advances have facilitated the development of processes for high-throughput extraction of quantitative features that result in the conversion of images into mineable data and the subsequent analysis of these data for decision support; this practice is termed radiomics. This is in contrast to the traditional practice of treating medical images as pictures intended solely for visual interpretation. Radiomic data contain first-, second-, and higher-order statistics. These data are combined with other patient data and are mined with sophisticated bioinformatics tools to develop models that may potentially improve diagnostic, prognostic, and predictive accuracy. Because radiomics analyses are intended to be conducted with standard of care images, it is conceivable that conversion of digital images to mineable data will eventually become routine practice. This report describes the process of radiomics, its challenges, and its potential power to facilitate better clinical decision making, particularly in the care of patients with cancer. © RSNA, 2015.

Current combination therapies for advanced breast cancer provide a modest survival benefit but with greater toxicity than with monotherapies. New combinations are needed that improve the efficacy of current treatments and have acceptable tolerability profiles. Recent clinical trials have assessed the efficacy and safety of the multikinase inhibitor sorafenib in combination with common treatments for advanced breast cancer. Sorafenib has both antiangiogenic and antiproliferative activities and is indicated for patients with unresectable hepatocellular and advanced renal cell carcinoma. Generally, sorafenib is associated with manageable, non-life-threatening adverse events. One of the more common adverse events seen with sorafenib is hand-foot skin reaction, a dermatologic toxicity usually localized to the pressure points of the palms and soles. Although hand-foot skin reaction is reversible and not life threatening, it can have a significant impact on a patient's quality of life and may necessitate dose modification. Moreover, sorafenib is being evaluated in combination with breast cancer treatments that are associated with a similar dermatologic toxicity (e.g., capecitabine-induced hand-foot syndrome). This review looks at the use of sorafenib in combination with selected chemotherapies in patients with advanced breast cancer and considers the incidence, prevention, and management of hand-foot skin reaction. © AlphaMed Press.

Hobbs G.S.,Massachusetts General Hospital | Rampal R.K.,Sloan Kettering Cancer Center
Current Opinion in Hematology | Year: 2015

PURPOSE OF REVIEW: The myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and myelofibrosis. Of these, myelofibrosis often has the most aggressive course. There is, however, often significant clinical heterogeneity among patients with myelofibrosis. We seek to summarize recent clinical and biological findings in myelofibrosis as well as review the spectrum of clinically relevant mutation in myelofibrosis and their implications. RECENT FINDINGS: The mutational spectrum in myelofibrosis includes driver mutations in genes such as JAK2, calreticulin, and myeloproliferative leukemia virus oncogene. In addition, recurrent mutations in epigenetic modifiers such as ASXL1 and TET2 have also been described. Importantly, several studies have indicated that specific mutations, as well as the number of mutations, that a patient bears may have important clinical consequences. The presence or absence of certain mutations may help to determine a patient's risk for thrombosis, leukemic transformation, and survival. SUMMARY: Myelofibrosis often has variable outcomes among patients. Prognostic systems based on clinical observations have been developed in an attempt to predict risks of disease progression and transformation. The discovery of recurrent genomic alterations in myelofibrosis, and the observation that many of these alterations may help predict clinical outcomes, has heralded a new era in the biologic understanding and clinical approach to myelofibrosis. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Pike M.C.,Sloan Kettering Cancer Center | Pike M.C.,University of Southern California | Pearce C.L.,University of Southern California
Annals of Oncology | Year: 2013

Mammographic density (MD), representing connective and epithelial tissue (fibroglandular tissue, FGT) is a major risk factor for breast cancer. In an analysis of an autopsy series (Bartow SA, Pathak DR, Mettler FA. Radiographic microcalcification and parenchymal patterns as indicators of histologic "high-risk" benign breast disease. Cancer 1990; 66: 1721-1725, Bartow SA, Pathak DR, Mettler FA et al. Breast mammographic pattern: a concatenation of confounding and breast cancer risk factors. Am J Epidemiol 1995; 142: 813-819), MD was found to be strongly correlated with the collagen and epithelial content of the breast (Li T, Sun L, Miller N et al. The association of measured breast tissue characteristics with MD and other risk factors for breast cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: 343-349), and another report showed that breast epithelium was highly concentrated in the areas of collagen concentration (Hawes D, Downey S, Pearce CL et al. Dense breast stromal tissue shows greatly increased concentration of breast epithelium but no increase in its proliferative activity. Breast Cancer Res 2006; 8: R24). Collagen comprises the overwhelming majority of the FGT, occupying an area on the slides obtained from the autopsy series some 15 times the area of glandular tissue. The relationship of MD with breast cancer risk appears likely to be due to a major extent to increasing epithelial cell numbers with increasing MD. FGT is also seen in breast magnetic resonance imaging (breast MRI) and, as expected, it has been shown that this measure of FGT (MRI-FGT) is highly correlated with MD. A contrast-enhanced breast MRI shows that normal FGT 'enhances' (background parenchymal enhancement, BPE) after contrast agent is administered(Morris EA. Diagnostic breast MR imaging: current status and future directions. Radiol Clin North Am 2007; 45: 863-880, vii., Kuhl C. The current status of breast MR imaging. Part I. Choice of technique, image interpretation, diagnostic accuracy, and transfer to clinical practice. Radiology 2007; 244: 356-378), and a recent study suggests that BPE is also a major breast cancer risk factor, possibly as important as, and independent of MD (King V, Brooks JD, Bernstein JL et al. BPE at breast MR imaging and breast cancer risk. Radiology 2011; 260: 50-60). BPE is much more sensitive to the effects of menopause and tamoxifen than is FGT (King V, Gu Y, Kaplan JB et al. Impact of menopausal status on BPE and fibroglandular tissue on breast MRI. Eur Radiol 2012; 22: 2641-2647, King V, Kaplan J, Pike MC et al. Impact of tamoxifen on amount of fibroglandular tissue, BPE, and cysts on breast MRI. Breast J 2012; 18: 527-534). Changes in MD and BPE may be most useful in predicting response to chemopreventive agents aimed at blocking breast cell proliferation. More study of the biological basis of the effects of MD and BPE is needed if we are to fully exploit these factors in developing chemopreventive approaches to breast cancer. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Gilks C.B.,University of British Columbia | Oliva E.,Massachusetts General Hospital | Soslow R.A.,Sloan Kettering Cancer Center
American Journal of Surgical Pathology | Year: 2013

Patients with high-grade subtypes of endometrial carcinoma (grade 3 endometrioid, serous, clear cell, or carcinosarcoma) have a relatively poor prognosis. The specific subtype may be used to guide patient management, but there is little information on the reproducibility of subtype diagnosis in cases of high-grade endometrial carcinoma. Fifty-six cases diagnosed as a high-grade subtype of endometrial carcinoma were identified from the pathology archives of Vancouver General Hospital. All slides for each case were reviewed independently by 3 pathologists, who diagnosed the specific tumor subtype(s) and assigned the percentage of each subtype for mixed tumors. Agreement between observers was categorized as follows: major disagreement: (A) no consensus for low-grade endometrioid versus high-grade carcinoma (any subtype), or (B) no consensus with respect to the predominant high-grade subtype present; minor disagreement: consensus was reached about the cell type of the predominant component of a mixed tumor, but there was disagreement about the subtype of the minor component. A tissue microarray was constructed from these cases and immunostained for p16, ER, PR, PTEN, and p53. In 35 of 56 (62.5%) cases, there was agreement between all 3 reviewers regarding the subtype diagnosis of the exclusive (in pure tumors) or predominant (in mixed tumors) high-grade component. Of these cases, there was a minor disagreement (ie, disagreement about the minor high-grade component subtype in a mixed tumor) in 4 cases (4/56, 7.1%). In 20 of 56 (35.8%) cases there was a major disagreement; in 17 (30.4%) of these cases there was no consensus about the major subtype diagnosis, whereas in 3 (5.4%) cases there was disagreement about whether a component of high-grade endometrial carcinoma was present. In the final case, all 3 reviewers diagnosed the case as low-grade endometrioid carcinoma, disagreeing with the original diagnosis of high-grade carcinoma. The most frequent areas of disagreement were serous versus clear cell (7 cases) and serous versus grade 3 endometrioid (6 cases). Immunostaining results using the 5-marker immunopanel were then used to adjudicate in the 6 cases in which there was disagreement between reviewers with respect to serous versus endometrioid carcinoma, and these supported a diagnosis of serous carcinoma in 4 of 6 cases and endometrioid carcinoma in 2 of 6 cases. Pairwise comparison between the reviewers for the 20 cases classified as showing major disagreement was as follows: reviewer 1 and reviewer 2 agreed in 5/20 cases, reviewer 1 and reviewer 3 agreed in 7/20 cases, and reviewer 2 and reviewer 3 agreed in 8/20 cases, indicating that disagreements were not because of a single reviewer holding outlier opinions. Diagnostic consensus among 3 reviewers about the exclusive or major subtype of high-grade endometrial carcinoma was reached in only 35/56 (62.5%) cases, and in 4 of these cases there was disagreement about the minor component present. This poor reproducibility did not reflect systematic bias on the part of any 1 reviewer. There is a need for molecular tools to aid in the accurate and reproducible diagnosis of high-grade endometrial carcinoma subtype. Copyright © 2013 by Lippincott Williams & Wilkins.

Abdel-Wahab O.,Sloan Kettering Cancer Center | Fathi A.T.,Massachusetts General Hospital
Advances in Hematology | Year: 2012

In the recent years, the discovery of a series of mutations in patients with myeloid malignancies has provided insight into the pathogenesis of myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), and acute myeloid leukemia (AML). Among these alterations have been mutations in genes, such as IDH1/2, TET2, DNMT3A, and EZH2, which appear to affect DNA and/or histone lysine methylation. Large clinical correlative studies are beginning to decipher the clinical importance, prevalence, and potential prognostic significance of these mutations. Additionally, burgeoning insight into the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. DNA demethylating agents have been demonstrated to be clinically active in a subset of patients with MDS and AML and are used extensively. However, newer, more specific agents which alter DNA and histone modification are under preclinical study and development and are likely to expand our therapeutic options for these diseases in the near future. Here, we review the current understanding of the clinical importance of these newly discovered mutations in AML and MDS patients. We also discuss exciting developments in DNA methyltransferase inhibitor strategies and the prospect of novel histone lysine methyltransferase inhibitors.

Blasberg R.,Sloan Kettering Cancer Center | Piwnica-Worms D.,University of Washington
Clinical Cancer Research | Year: 2012

At a Clinical and Translational Cancer Research Think Tank meeting sponsored by the American Association for Cancer Research in 2010, one of the breakout groups focused on new technologies and imaging. The discussions emphasized new opportunities in translational imaging and its role in the future, rather than established techniques that are currently in clinical practice. New imaging methods under development are changing the approach of imaging science from a focus on the anatomic description of disease to a focus on the molecular basis of disease. Broadly referred to as molecular imaging, these new strategies directly embrace the incorporation of cell and molecular biology concepts and techniques into image generation and can involve the introduction of genes into cells with the explicit intent to image the end products of gene expression with external imaging devices. These new methods hold the promise of providing clinicians with (i) robust linkages between cell and animal models and clinical trials, (ii) in vivo biomarkers that can be measured repeatedly and sequentially over time to observe dynamic disease processes and responses to treatment, and (iii) tools for preselection and patient population enrichment in phase II and III trials to improve outcomes and better direct treatment. These strategies provide real-time pharmacodynamic parameters and can be powerful tools to monitor therapeutic effects in a spatially and tissue-specific manner, which may reduce cost during drug development, because pharmacodynamic studies in animals can inform clinical trials and accelerate the translation process. The Imaging Response Assessment Team (IRAT) program serves as an example of how imaging techniques can be incorporated into clinical trials. IRATs work to advance the role of imaging in assessment of response to therapy and to increase the application of quantitative anatomic, functional, and molecular imaging endpoints in clinical trials, and imaging strategies that will lead to individualized patient care. ©2012 AACR.

Arvey A.,Sloan Kettering Cancer Center | Agius P.,Sloan Kettering Cancer Center | Noble W.S.,University of Washington | Leslie C.,Sloan Kettering Cancer Center
Genome Research | Year: 2012

Gene regulatory programs in distinct cell types are maintained in large part through the cell-type-specific binding of transcription factors (TFs). The determinants of TF binding include direct DNA sequence preferences, DNA sequence preferences of cofactors, and the local cell-dependent chromatin context. To explore the contribution of DNA sequence signal, histone modifications, and DNase accessibility to cell-type-specific binding, we analyzed 286 ChIP-seq experiments performed by the ENCODE Consortium. This analysis included experiments for 67 transcriptional regulators, 15 of which were profiled in both the GM12878 (lymphoblastoid) and K562 (erythroleukemic) human hematopoietic cell lines. To model TF-bound regions, we trained support vector machines (SVMs) that use flexible k-mer patterns to capture DNA sequence signals more accurately than traditional motif approaches. In addition, we trained SVM spatial chromatin signatures to model local histone modifications and DNase accessibility, obtaining significantly more accurate TF occupancy predictions than simpler approaches. Consistent with previous studies, we find that DNase accessibility can explain cell-line-specific binding for many factors. However, we also find that of the 10 factors with prominent cell-type-specific binding patterns, four display distinct cell-type-specific DNA sequence preferences according to our models. Moreover, for two factors we identify cell-specific binding sites that are accessible in both cell types but bound only in one. For these sites, cell-type-specific sequence models, rather than DNase accessibility, are better able to explain differential binding. Our results suggest that using a single motif for each TF and filtering for chromatin accessible loci is not always sufficient to accurately account for cell-type-specific binding profiles. © 2012, Published by Cold Spring Harbor Laboratory Press.

Samstein R.M.,Sloan Kettering Cancer Center | Josefowicz S.Z.,Sloan Kettering Cancer Center | Arvey A.,Sloan Kettering Cancer Center | Treuting P.M.,University of Washington | Rudensky A.Y.,Sloan Kettering Cancer Center
Cell | Year: 2012

Regulatory T (Treg) cells, whose differentiation and function are controlled by X chromosome-encoded transcription factor Foxp3, are generated in the thymus (tTreg) and extrathymically (peripheral, pTreg), and their deficiency results in fatal autoimmunity. Here, we demonstrate that a Foxp3 enhancer, conserved noncoding sequence 1 (CNS1), essential for pTreg but dispensable for tTreg cell generation, is present only in placental mammals. CNS1 is largely composed of mammalian-wide interspersed repeats (MIR) that have undergone retrotransposition during early mammalian radiation. During pregnancy, pTreg cells specific to a model paternal alloantigen were generated in a CNS1-dependent manner and accumulated in the placenta. Furthermore, when mated with allogeneic, but not syngeneic, males, CNS1-deficient females showed increased fetal resorption accompanied by increased immune cell infiltration and defective remodeling of spiral arteries. Our results suggest that, during evolution, a CNS1-dependent mechanism of extrathymic differentiation of Treg cells emerged in placental animals to enforce maternal-fetal tolerance. © 2012 Elsevier Inc.

Abramson J.S.,Massachusetts General Hospital | Zelenetz A.D.,Sloan Kettering Cancer Center
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013

Non-Hodgkin's lymphomas (NHL) represent a diverse set of diseases, with different treatment pathways based on the stage and type of hematologic cancer. In their presentation at the NCCN 18th Annual Conference, Dr. Jeremy Abramson and Dr. Andrew D. Zelenetz discuss 3 specific B-cell NHLs: follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia. They provided an overview of the treatment strategies for patients with these hematologic malignancies, and offered highlights from recent clinical trials supporting these recommendations. © JNCCN-Journal of the National Comprehensive Cancer Network.

Pietanza M.C.,Sloan Kettering Cancer Center | Byers L.A.,University of Houston | Minna J.D.,University of Texas Southwestern Medical Center | Rudin C.M.,Sloan Kettering Cancer Center
Clinical Cancer Research | Year: 2015

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with a unique natural history characterized by a short doubling time, high growth fraction, and early development of widespread metastases. Although a chemotherapy- and radiationsensitive disease, SCLC typically recurs rapidly after primary treatment, with only 6% of patients surviving 5 years from diagnosis. This disease has been notable for the absence of major improvements in its treatment: Nearly four decades after the introduction of a platinum etoposide doublet, therapeutic options have remained virtually unchanged, with correspondingly little improvement in survival rates. Here, we summarize specific barriers and challenges inherent to SCLC research and care that have limited progress in novel therapeutic development to date. We discuss recent progress in basic and translational research, especially in the development of mouse models, which will provide insights into the patterns of metastasis and resistance in SCLC. Opportunities in clinical research aimed at exploiting SCLC biology are reviewed, with an emphasis on ongoing trials. SCLC has been described as a recalcitrant cancer, for which there is an urgent need for accelerated progress. The NCI convened a panel of laboratory and clinical investigators interested in SCLC with a goal of defining consensus recommendations to accelerate progress in the treatment of SCLC, which we summarize here. © 2015 American Association for Cancer Research.

Fellmann C.,Mirimus Inc. | Lowe S.W.,Sloan Kettering Cancer Center
Nature Cell Biology | Year: 2014

RNA interference has become an indispensable tool for loss-of-function studies across eukaryotes. By enabling stable and reversible gene silencing, shRNAs provide a means to study long-term phenotypes, perform pool-based forward genetic screens and examine the consequences of temporary target inhibition in vivo. However, efficient implementation in vertebrate systems has been hindered by technical difficulties affecting potency and specificity. Focusing on these issues, we analyse current strategies to obtain maximal knockdown with minimal off-target effects. © 2014 Macmillan Publishers Limited.

Sloan Kettering Cancer Center and The General Hospital Corporation | Date: 2014-01-24

This invention is in the field of labeled peptide construction for medical treatment and analysis. The invention relates to synthetic labeled peptide compositions, methods of synthesis, and methods of use for the synthetic labeled peptide compositions for medical treatment, imaging, and research purposes.

News Article | October 28, 2016

IBM Watson first garnered worldwide attention in 2011 as the computerized "brain" that won one million dollars on the TV game show Jeopardy! by beating human contestants. Since then, IBM Watson has gained a reputation as a thinking machine that can crunch through mountains of data and turn out answers in fractions of a second. But what exactly is it? This primer on IBM Watson answers that question. SEE: Check out all of TechRepublic's smart person's guides IBM Watson is a data analytics processor that uses natural language processing, a technology that analyzes speech for meaning and syntax and translates this into actionable answers. IBM Watson was named after IBM's first CEO, Thomas J. Watson. The technology behind Watson was originally developed in an IBM research project known as DeepQA. The goal of the project was to develop a natural language-responsive system that could interpret questions asked in a human language and then analyze vast amounts of data and return answers that it would take human researchers days, weeks, or even months to derive. The 2011 Jeopardy! contest against the game show's champions Ken Jennings and Brad Rutter was IBM Watson's first public test; in the end, Watson was victorious. Two years later, IBM announced the first commercial application of Watson was designed for Sloan Kettering Cancer Center and WellPoint insurance. The application performed cost management analysis in the treatment of lung cancer. Today, IBM Watson is used in a multitude of industry sectors with specialized information needs, including veterinary science, environmental and geotechnical engineering, education, government, food and beverage, legal, and music and entertainment. What distinguishes IBM Watson from other analytics software is its direct relevance to business problem solving. Watson has the ability to rapidly analyze gargantuan repositories of data, documents, and other artifacts; it also comes with a level of human speech pattern recognition and language understanding that was elusive for many artificial intelligence applications in the past. IBM Watson uses cognitive learning practices that combine the data analytics and statistical reasoning of machines with uniquely human qualities, such as self-directed goals, common sense, and ethical values. As a top layer to all of this, IBM has packaged various versions of Watson to address the specific business concerns and questions of different industry verticals. Watson also plays a key role in managing unstructured data, which according to IBM, comprises around 80% of data under management in a majority of companies. Watson processes unstructured text and documentation by "learning" a subject by pairing questions and answers after the user loads all related materials (e.g., Word documents, .pdf files, web pages, etc.). The platform is capable of processing millions of documents, and reading 800 million pages of data per second. IBM Watson also processes natural language, which can help businesses be more efficient. For example, an insurance company or a healthcare company can use Watson to review medical reports in order to isolate key medical terms; or a physician might use Watson to pore through millions of pages of clinical research in an attempt to isolate a medical condition, and arrive at a diagnosis and treatment plan. Watson is now offered by IBM in the cloud. This means that companies can start small in their use of Watson and pay for only what they need, without having to invest in expensive on-premises computing. IBM Watson technology can apply to a broad range of companies, institutions, and public sector entities because it has been customized to many of these industries' knowledge bases. Within companies, the use of Watson can fall under the purview of, for example: IBM Watson is in operation now in many industry verticals, ranging from healthcare predictive analytics and condition diagnosis to smart city infrastructure planning and legal case outcome analysis. IBM Watson runs on IBM Power servers that are not really supercomputers in the classic sense, but that act that way when they are clustered together in groups of tens and even hundreds of servers, with a price point for an internal system that only a large enterprise or a research institute can afford. The good news for small and midsize companies is that they can use Watson, too; IBM offers a cloud-based version of Watson that companies can pay for by subscription or on demand. Companies that can afford an investment into multiple millions of dollars can purchase an in-house Watson system, which consists of futile servers tethered together into a processing cluster. For companies without these resources, Watson can be accessed through the IBM cloud. For example, IBM offers a software developer's cloud powered by Watson. It also provides a cloud-based global healthcare analytics cloud.

Pencheva N.,Rockefeller University | Tran H.,Rockefeller University | Buss C.,Rockefeller University | Huh D.,Rockefeller University | And 3 more authors.
Cell | Year: 2012

Through in vivo selection of human cancer cell populations, we uncover a convergent and cooperative miRNA network that drives melanoma metastasis. We identify miR-1908, miR-199a-5p, and miR-199a-3p as endogenous promoters of metastatic invasion, angiogenesis, and colonization in melanoma. These miRNAs convergently target apolipoprotein E (ApoE) and the heat shock factor DNAJA4. Cancer-secreted ApoE suppresses invasion and metastatic endothelial recruitment (MER) by engaging melanoma cell LRP1 and endothelial cell LRP8 receptors, respectively, while DNAJA4 promotes ApoE expression. Expression levels of these miRNAs and ApoE correlate with human metastatic progression outcomes. Treatment of cells with locked nucleic acids (LNAs) targeting these miRNAs inhibits metastasis to multiple organs, and therapeutic delivery of these LNAs strongly suppresses melanoma metastasis. We thus identify miRNAs with dual cell-intrinsic/cell-extrinsic roles in cancer, reveal convergent cooperativity in a metastatic miRNA network, identify ApoE as an anti-angiogenic and metastasis-suppressive factor, and uncover multiple prognostic miRNAs with synergistic combinatorial therapeutic potential in melanoma. © 2012 Elsevier Inc.

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