Memorial Sloan Kettering Cancer Institute

New York City, NY, United States

Memorial Sloan Kettering Cancer Institute

New York City, NY, United States
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Memorial Sloan Kettering Cancer Institute | Date: 2016-06-21

The disclosure provides compositions and methods for detecting and predicting acquired resistance to anti-EGFR treatment in colorectal cancers. Also provided are compositions and methods of preventing, reversing or delaying the acquired resistance. The present disclosure also provides kits for use in the methods described herein.

Zhu B.,Tsinghua University | Zhu X.,Tsinghua University | Wang L.,Tsinghua University | Liang Y.,Tsinghua University | And 4 more authors.
PLoS Genetics | Year: 2017

Intraflagellar transport (IFT) particles or trains are composed of IFT-A and IFT-B complexes. To assess the working mechanism of the IFT-A complex in IFT and ciliogenesis, we have analyzed ift43 mutants of Chlamydomnonas in conjunction with mutants of the other IFT-A subunits. An ift43 null mutant or a mutant with a partial deletion of the IFT43 conserved domain has no or short flagella. The mutants accumulate not only IFT-B but also IFT-Ain the short flagella, which is in contrast to an ift140 null mutant. The IFT43 conserved domain is necessary and sufficient for the function of IFT43. IFT43 directly interacts with IFT121 and loss of IFT43 results in instability of IFT-A. A construct with a partial deletion of the IFT43 conserved domain is sufficient to rescue the instability phenotype of IFT-A, but results in diminishing of IFT-A at the peri-basal body region. We have further provided evidence for the direct interactions within the IFT-A complex and shown that the integrity of IFT-A is important for its stability and cellular localization. Finally, we show that both IFT43 and IFT140 are involved in mobilizing ciliary precursors from the cytoplasmic pool during flagellar regeneration, suggesting a novel role of IFT-A in transporting ciliary components in the cytoplasm to the peri-basal body region. © 2017 Zhu et al.

Wingard J.R.,University of Florida | Carter S.L.,EMMES Corporation | Walsh T.J.,U.S. National Cancer Institute | Kurtzberg J.,Duke University | And 14 more authors.
Blood | Year: 2010

Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P =.09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and over-all survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at as NCT00075803. © 2010 by The American Society of Hematology.

News Article | December 2, 2016

Recent advance in using our body's own immune system to fight cancer may one day lead to a vaccine(Credit: luiscarceller/ Depositphotos ) Earlier this year we reported on new research that focused on training the body's own immune cells to fight cancer through a process known as adoptive immunotherapy. The process involves removing immune-system white blood cells known as T-cells, genetically modifying them to recognize certain proteins involved with cancer cells, then injecting them back in their body where they could basically hunt down and destroy tumors. In the study on which we reported, the technique was successful in destroying blood cancer in 93 percent of the patients involved in a clinical trial. While that study was focussed specifically on blood cancer in particular, T-cell therapy has shown success with regards to other types of cancer and may, in fact, one day lead to a cancer vaccine that would train our bodies to recognize and destroy cancer cells if they invade. One company working on such a vaccine is Florida-based company TapImmune. So we got ahold of TapImmune's president and COO John Bonfiglio and put this question to him as part of our ongoing series called One Big Question: "How close are we to having a cancer vaccine that people can actually get from their doctors?" The idea of developing cancer vaccines that target tumors or metastatic disease has been proposed for many years. Several companies have synthesized cancer vaccines and completed clinical studies with marginal success at best. Science, however, is an iterative process and the failures of the past could indeed lead to a viable vaccine for certain cancers. TapImmune, Inc. is leading the charge in this exciting new era of vaccine development specifically designed to target tumors and metastatic disease. The company is working diligently to bring to market agents for ovarian and breast cancer. There are approximately 30,000 ovarian cancer patients newly diagnosed every year in the US alone. More than 14,000 will die from the disease. Just as sobering, more than 41,000 people – men and women – will die this year from breast cancer. In the last several years, the science of immuno-oncology has begun to catch up to the ideas of how to develop such a vaccine. There are known to be three major components necessary to develop a strong immune response against cancer – the first is the activation of killer T-cells (CD8+ cells) against a specific target on a cancer cell. This has been known for quite some time and many vaccines that were tested earlier were designed to work by activating these cells. What has become apparent recently is the need to activate helper T-cells (CD4+ cells). These cells, together with the CD4+ cells, have been found to be essential to generating an immune response strong enough to have a therapeutic effect against cancer. The last component is the ability of the vaccine to generate memory cells capable of reactivating against metastatic disease. Recent early stage human clinical studies have shown that the TapImmune lead product, TPIV 200, may have all three key components. The development of a T-cell vaccine is at least five to 10 years from being approved. The process will begin with the clearance of a therapeutic vaccine designed to treat patients with cancer and then progress to treating potential patients prophylactically. This is a necessary progression due to regulatory requirements as well as the time and expense to complete clinical trials for a prophylaxis indication. We are also working with Memorial Sloan Kettering Cancer Institute in New York on a significant trial that combines TPIV 200 with AstraZeneca's checkpoint inhibitor, durvalumab. We expect to start an additional Phase II study in ovarian cancer patients who are responsive to platinum, in an approach to provide maintenance therapy that will reduce cancer relapse and extend progression-free survival. We received Fast Track Designation for TPIV 200 for this indication from the US FDA in February of this year.

Duhamel K.,Memorial Sloan Kettering Cancer Institute | Jandorf L.,Mount Sinai School of Medicine
Cancer Causes and Control | Year: 2010

Background: Despite the acknowledged importance of colorectal cancer (CRC) screening and its proven prognostic benefit, African American men and women simultaneously possess the highest rates of CRC-related incidence and mortality (Swan et al. in Cancer 97(6):1528-1540, 2003) and lowest screening rates in the United States (Polite et al. in Med Clin N Am 89(4):771-793, 2005). Effective, targeted interventions that promote CRC screening for this community are therefore critical. The current study evaluated the impact of a print-based educational intervention on screening behavior and associated patient-based factors, including cancer-related knowledge, fatalism, worry, and decisional balance (pros-cons). Methods: One hundred and eighteen individuals (mean age = 56.08, SD = 5.58) who had not undergone screening were recruited from two health clinics in New York City. Each participant received educational print materials regarding the need for screening, the process of undergoing screening, and the benefits of regular CRC screening. Results: One in four individuals had undergone post-intervention screening at a three-month follow-up. Whereas all participants reported a decrease in cancer-related worry (p < .05), it was a decrease in fatalism (p < .05) and an increase in decisional balance (p < .05) that was associated with post-intervention screening behavior. Discussion: These preliminary results suggest that fatalistic beliefs and an individual's assessment of the benefits and barriers of screening may be critical in the decision to undergo CRC screening. Future interventions to increase CRC-screening rates for this community may be improved by focusing on these patient-based factors. © 2010 Springer Science+Business Media B.V.

Shiyko M.P.,Northeastern University | Burkhalter J.,Memorial Sloan Kettering Cancer Institute | Li R.,Pennsylvania State University | Park B.J.,Hackensack University Medical Center
Journal of Consulting and Clinical Psychology | Year: 2014

Objective: The goal of this article is to introduce to social and behavioral scientists the generalized time-varying effect model (TVEM), a semiparametric approach for investigating time-varying effects of a treatment. The method is best suited for data collected intensively over time (e.g., experience sampling or ecological momentary assessments) and addresses questions pertaining to effects of treatment changing dynamically with time. Thus, of interest is the description of timing, magnitude, and (nonlinear) patterns of the effect. Method: Our presentation focuses on practical aspects of the model. A step-by-step demonstration is presented in the context of an empirical study designed to evaluate effects of surgical treatment on quality of life among early stage lung cancer patients during posthospitalization recovery (N = 59; 61% female, M age = 66.1 years). Frequency and level of distress associated with physical symptoms were assessed twice daily over a 2-week period, providing a total of 1,544 momentary assessments. Results: Traditional analyses (analysis of covariance [ANCOVA], repeated-measures ANCOVA, and multilevel modeling) yielded findings of no group differences. In contrast, generalized TVEM identified a pattern of the effect that varied in time and magnitude. Group differences manifested after Day 4. Conclusions: Generalized TVEM is a flexible statistical approach that offers insight into the complexity of treatment effects and allows modeling of nonnormal outcomes. The practical demonstration, shared syntax, and availability of a free set of macros aim to encourage researchers to apply TVEM to complex data and stimulate important scientific discoveries. © 2014 American Psychological Association.

Grobmyer S.R.,University of Florida | Kooby D.,Emory University | Blumgart L.H.,Memorial Sloan Kettering Cancer Institute | Hochwald S.N.,University of Florida
Journal of the American College of Surgeons | Year: 2010

Background: Pancreatic anastomotic failure has traditionally been a source of significant morbidity and potential mortality after pancreaticoduodenectomy. Both patient-derived and technical factors contribute to pancreatic anastomotic failure. From a technical standpoint, an "ideal" pancreaticojejunal anastomosis would meet the following criteria: applicable to all patients, easy to teach, and associated with a low rate of pancreatic anastomotic failure-related complications. The pancreaticojejunostomy described by one of the authors (LHB) meets the criteria for an "ideal" pancreaticojejunostomy. Study Design: We performed an audit of results of a consecutive series of patients at two institutions who underwent pancreaticojejunostomy using the described technique. Pancreaticojejunostomy after pancreaticoduodenectomy was performed in all cases using a novel two-layer technique consisting of an outer full thickness pancreas-to-seromuscular jejunal anastomosis and an inner duct-to-mucosal anastomosis. Incidences of pancreatic anastomotic failure (measured using the International Study Group of Pancreatic Fistula definition) and perioperative pancreatic anastomotic failure-related complications were analyzed. Results: One hundred eighty-seven patients underwent pancreaticojejunostomy after pancreaticoduodenectomy using the described technique. Overall mortality was 1.6%. The rate of clinically significant pancreatic anastomotic failure (International Study Group of Pancreatic Fistula grade B or C) was only 6.9%. There was no bleeding, reoperation, or mortality secondary to pancreatic anastomotic failure among patients in this series. Conclusions: The novel pancreaticojejunostomy is applicable to all patients in whom the pancreatic duct can be identified, and it is associated with very low rates of significant postoperative morbidity and mortality. These findings support its routine use for pancreaticojejunal reconstruction after pancreaticoduodenectomy. © 2010 American College of Surgeons.

Heidel F.H.,Otto Von Guericke University of Magdeburg | Arreba-Tutusaus P.,Otto Von Guericke University of Magdeburg | Armstrong S.A.,Memorial Sloan Kettering Cancer Institute | Fischer T.,Otto Von Guericke University of Magdeburg
Clinical Cancer Research | Year: 2015

Acute myelogenous leukemia stem cells (AML-LSC) give rise to the leukemic bulk population and maintain disease. Relapse can arise from residual LSCs that have distinct sensitivity and dependencies when compared with the AML bulk. AML-LSCs are driven by genetic and epigenomic changes, and these alterations influence prognosis and clonal selection. Therapies targeting these molecular aberrations have been developed and show promising responses in advanced clinical trials; however, so far success with LSCs has been limited. Besides the genetic diversity, AML-LSCs are critically influenced by the microenvironment, and a third crucial aspect has recently come to the fore: A group of evolutionarily conserved signaling pathways such as canonical Wnt signaling, Notch signaling, or the Hedgehog pathway can be essential for maintenance of AML-LSC but may be redundant for normal hematopoietic stem cells. In addition, early reports suggest also regulators of cell polarity may also influence hematopoietic stem cells and AML biology. Interactions between these pathways have been investigated recently and suggest a network of signaling pathways involved in regulation of self-renewal and response to oncogenic stress. Here, we review how recent discoveries on regulation of AML-LSC-relevant evolutionarily conserved pathways may open opportunities for novel treatment approaches eradicating residual disease. © 2015 American Association for Cancer Research.

Arndt J.,University of Missouri | Das E.,Radboud University Nijmegen | Schagen S.B.,Netherlands Cancer Institute | Reid-Arndt S.A.,University of Missouri | And 2 more authors.
Psycho-Oncology | Year: 2014

Background The potentially detrimental effects of cancer and related treatments on cognitive functioning have emerged as one of the key foci of cancer survivorship research, but little is known about how psychological variables other than depression influence these relationships. To illustrate the potential of social psychological perspectives, we examine how a self-regulatory analysis and specific self-regulatory challenges of contending with cancer-related expectancies and stereotypes provide conceptual frameworks for understanding some of the potential causes and consequences of cancer-related cognitive deficits. Methods Literatures on cancer-related cognitive deficits, self-regulatory ego depletion, expectancy stereotypes, and their points of convergence are briefly reviewed. Results A review and conceptual integration of relevant literatures suggest that coping with cancer can impair self-regulatory capacity. There is an overlap between cognitive deficits associated with self-regulatory challenge and with cancer and its treatment, and restoring self-regulatory resources can attenuate cancer-related cognitive deficits. Examination of specific regulatory challenges of contending with expectancies and stereotypes related to treatment suggests insights that can inform when and among whom cognitive deficits may most likely emerge. Conclusions Integrating social psychological ideas with a substantial knowledge base can illustrate novel research trajectories that can deepen our understanding of cancer-related cognitive deficits and their impact on psychosocial well-being. Broadening the cancer and cognition landscape: the role of self-regulatory challenges Copyright © 2013 John Wiley & Sons, Ltd.

Memorial Sloan Kettering Cancer Institute | Date: 2015-07-02

The disclosure provides compositions and methods for detecting and predicting acquired resistance to anti-EGFR treatment in colorectal cancers. Also provided are compositions and methods of preventing, reversing or delaying the acquired resistance. The present disclosure also provides kits for use in the methods described herein.

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