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Renault T.T.,Mount Sinai School of Medicine | Renault T.T.,The Tisch Cancer Institute | Renault T.T.,The Metabolism Institute | Floros K.V.,Mount Sinai School of Medicine | And 4 more authors.
Methods | Year: 2013

The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. The use of isolated mitochondria has been instrumental to understanding the key interactions necessary to engage BAK and BAX activation, MOMP, and apoptosis. Furthermore, it is possible to biochemically define the relationships between BCL-2 family function and mitochondrial physiology using isolated systems. Our laboratory uses freshly isolated mitochondria from numerous sources to better understand BCL-2 family function and requirements for BAK and BAX activation. Here, we will discuss commonly used in vitro techniques to perform MOMP and cytochrome c release assays; and provide several key methodologies to implicate BAK and BAX activity in these processes. © 2013 Elsevier Inc.

Hoeffel G.,Agency for Science, Technology and Research Singapore | Chen J.,Agency for Science, Technology and Research Singapore | Lavin Y.,The Tisch Cancer Institute | Lavin Y.,Mount Sinai School of Medicine | And 20 more authors.
Immunity | Year: 2015

Although classified as hematopoietic cells, tissue-resident macrophages (MFs) arise from embryonic precursors that seed the tissues prior to birth togenerate a self-renewing population, which is maintained independently of adult hematopoiesis. Here we reveal the identity of these embryonic precursors using an in utero MF-depletion strategy and fate-mapping of yolk sac (YS) and fetal liver (FL) hematopoiesis. We show that YS MFs are the main precursors of microglia, while most other MFs derive from fetal monocytes (MOs). Both YS MFs and fetal MOs arise from erythro-myeloid progenitors (EMPs) generated in the YS. In the YS, EMPs gave rise to MFs without monocytic intermediates, while EMP seeding the FL upon the establishment of blood circulation acquired c-Myb expression and gave rise to fetal MOs that then seeded embryonic tissues and differentiated into MFs. Thus, adult tissue-resident MFs established from hematopoietic stem cell-independent embryonic precursors arise from two distinct developmental programs. © 2015 Elsevier Inc.

News Article | December 14, 2016

(New York, NY - December 12, 2016) -- Even before tumors develop, breast cancer cells with a few defined molecular alterations can spread to organs, remain quiet for long periods of time, and then awaken to form aggressive, deadly breast cancer metastasis, says a team of investigators led by researchers at Icahn School of Medicine at Mount Sinai and the University of Regensburg in Germany. They say their finding, published in two papers in the journal Nature, and conducted in animal models and tested in human samples, now solves the mystery of how breast cancer metastasis forms without a primary tumor in this new model of early dissemination and metastasis. Furthermore, a clinical primary tumor may never develop, investigators say. The University of Regensburg team had discovered that cancer cells could spread not only from a highly mutated, overtly evolved and pathologically-defined invasive tumors, but also from early stage cancers commonly considered incapable of spreading cells. However, how these early cancer lesions could spawn cells with traits of malignant tumors was unknown. In two papers published in the journal Nature, and conducted in animal models and tested in human samples, the two teams now have identified the first mechanisms that allow cells to spread early in cancer progression and contribute to metastasis. In the study from Mount Sinai, two changes in mammary cancer cells -- a switched-on oncogene and a turned-off tumor suppressor-- motivated cells to travel from breast tissue to the lungs and other parts of the body. There, the cells stayed quiet until a growth switch was activated and metastases developed in lungs. "This research provides insight into the mechanisms of early cancer spread and may shed light into unexplained phenomena -- among them, why as many as 5 percent of cancer patients worldwide have cancer metastases but no original tumor, and most importantly, why it is so difficult to treat cancer that has spread," says the study's senior investigators, Julio A. Aguirre-Ghiso, PhD, Professor of Medicine, Hematology and Medical Oncology, Maria Soledad Sosa, PhD, Assistant Professor of Pharmacological Sciences, and graduate student Kathryn Harper of The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. "Biologically, this new model of early metastasis challenges everything we thought we knew about how cancer spreads and forms metastasis. It feels like we are going to have to adjust our ideas about the subject of metastasis," he says. "Our hope is that these findings will reshape the way we think about how metastasis should be treated." An important finding from the Mount Sinai team is that most early spread cells remain dormant and most chemotherapy and targeted therapies are aimed at those cells that are proliferative. So early spread cancer cells would escape these conventional therapies even if it kills a primary tumor, Dr. Aguirre-Ghiso says. The work also poses new questions on how early spread cancer cells support metastasis development. Do they do it on their own, do they set the soil for later arriving cells from tumors not caught early, or do they cooperate with later arriving cells? This study reveals a new biological mechanism of early dissemination that must be explored to fully understand how to target the seeds of metastasis. The companion paper headed by Dr. Christoph Klein at the University of Regensburg in Germany, published in the same issue of Nature and co-authored by Dr. Aguirre-Ghiso and members of his team provides additional key mechanistic clues on how early spread is controlled and proof in human cancer cells and tumors of the preclinical findings in this study. Researchers from both teams arrived at their findings independently and then collaborated on the project. Researchers from both teams studied very early stages of breast cancer including DCIS (ductal carcinoma in situ), a noninvasive breast lesion, since 2-3 percent of women who have been treated for DCIS die of metastasis without ever developing a primary tumor. "The best explanation for this phenomenon is that early metastasis occurs before or as DCIS develops. A key finding from this second paper is that in the mouse models, 80% of metastasis originated from the early spread cells and not from the large tumors. In fact, the Klein group identified a mechanism by which spread is more efficient in early lesions than in large tumors. In both studies, investigators found that early cancer cell spread is an extension of the normal process of creating a branching tree of breast milk ducts in females. Two major pathways are activated in this ancient process -- p38, a tumor suppressor, and HER2, an oncogene. Switching off p38 and turning on HER2 activates a module of the EMT (epithelial to mesenchymal transition) signaling pathway. EMT promotes movement of cells during embryogenesis and tissue development. The Klein paper also shows that progesterone receptor signaling, which controls branching of the mammary tree, is important for this early spread by regulating cues involved in EMT and growth programs, a mechanism that was hinted in his earlier studies. As a mammary tree develops, p38, HER2, and EMT are alternatively turned on and off. This, in cooperation with progesterone signaling, allows mammary cells to move through the mammary gland, hollow out a tubular, branching network of milk ducts that flow to the nipple. "Tweaking these pathways are a normal way of forming hollow branching tubes," Dr. Aguirre-Ghiso says. But in their experiments, they found that if HER2 is over-activated (not switched off) or mutated, and p38 is permanently turned off, EMT was continually activated, allowing cells to move out of the mammary gland and into the animal's body through the blood. "We were able to use organoids in three-dimensional cultures, and high resolution imaging directly in the live animal models to actually see these cells enter the blood stream from the mammary tree and travel to the lung, the bone marrow, and other places," he says. "We hadn't thought about oncogenes and tumor suppressors in this way before. This is a new function for these pathways." John S. Condeelis, PhD, co-Director of the Gruss Lipper Biophotonics Center and its Integrated Imaging Program at Einstein, where the high resolution intravital imaging was performed, noted that "We were surprised to learn that cancer cells from DCIS-like lesions could show such robust dissemination using similar machinery found in tumor cells from invasive carcinoma. This is a new insight with implications beyond our expectations." Also David Entenberg MSc, Director of Technological Development and Intravital Imaging who led the imaging efforts within the same Center said, "A few years ago, it would not have been possible to image these disseminating cells inside a living animal with this level of detail. We're pleased that Einstein's imaging technology could, through this collaboration, contribute to the definitive proof of early dissemination." And while both studies focus on the mechanisms of early dissemination in breast cancer, similar processes could control early dissemination and metastasis in other human cancers, including melanoma and pancreatic cancer. In fact, pancreatic cancer early dissemination has also been linked to an EMT process, Dr. Aguirre-Ghiso says. Among the critical avenues they are investigating, Mount Sinai researchers are looking for the growth switch that pushes early spread of dormant cancer cells to form metastases. "While our findings add a whole new level of complexity to the understanding of cancer, they also add energy to our efforts to finally solve the big issue in cancer -- stop the metastasis that kills patients," Dr. Aguirre-Ghiso says. Study contributors include lead co-authors Kathryn L. Harper, PhD, Maria Soledad Sosa, PhD, Julie F. Cheung, BSc, Rita Nobre MSc, Alvaro Avivar-Valderas, PhD, Chandandaneep Nagi, MD, and Eduardo F. Farias, PhD, from Icahn School of Medicine at Mount Sinai; Christoph Klein, MD and Hedayatollah Hosseini, PhD from the University of Regensburg, Germany; Nomeda Girnius, PhD and Roger J. Davis, PhD from Howard Hughes Medical Institute at the University of Massachusetts Medical School; and David Entenberg, MSc and John Condeelis, PhD from Albert Einstein College of Medicine in New York. The study was supported by grants SWCRF, CA109182, CA196521, CA163131, CA100324, F31CA183185, BC132674, BC112380, NIH 1S10RR024745 Microscopy CoRE at ISMMS, the Integrated Imaging Program at Einstein, HHMI, DFG KL 1233/10-1 and the ERC (322602). For a video on this release: https:/ The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services--from community-based facilities to tertiary and quaternary care. The System includes approximately 7,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is on the "Honor Roll" of best hospitals in America, ranked No. 15 nationally in the 2016-2017 "Best Hospitals" issue of U.S. News & World Report. The Mount Sinai Hospital is also ranked as one of the nation's top 20 hospitals in Geriatrics, Gastroenterology/GI Surgery, Cardiology/Heart Surgery, Diabetes/Endocrinology, Nephrology, Neurology/Neurosurgery, and Ear, Nose & Throat, and is in the top 50 in four other specialties. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 10 nationally for Ophthalmology, while Mount Sinai Beth Israel, Mount Sinai St. Luke's, and Mount Sinai West are ranked regionally. Mount Sinai's Kravis Children's Hospital is ranked in seven out of ten pediatric specialties by U.S. News & World Report in "Best Children's Hospitals." For more information, visit http://www. or find Mount Sinai on Facebook, Twitter and YouTube.

PubMed | McMaster University, Mount Sinai School of Medicine, The Tisch Cancer Institute, Tisch Cancer Institute and University of Alabama at Birmingham
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

111 Background: Clinical and laboratory factors, i.e. visceral metastasis, anemia, LDH, PSA, PSA-doubling time, bone scan progression, pain, performance status (PS), are recognized to be prognostic factors for overall survival (OS) in metastatic castration resistant prostate cancer (mCRPC). We sought to determine if the Charlson comorbidity Index (CCI) and hypertension (HTN) provide prognostic information independent of these known factors.We retrospectively evaluated 221 patients with mCRPC treated with docetaxel plus prednisone (DP) combined with AT-101 (bcl-2 antagonist) or placebo on a randomized phase II trial. Both arms of the trial were combined since no differences in outcomes or toxicities were observed. Wilcoxon rank sum test and Fishers exact tests were used to compare data by comorbidity groups (CCI as a continuous variable, CCI = 6 vs. CCI 7 and HTN vs. no HTN). Cox regression analysis was done to identify whether CCI or HTN independently predicted OS after adjusting for trial stratification factors (pain, performance status), nomogram, risk-groups and PCWG-2 clinical sub-types.CCI was 6 in 116 patients (52.7%) whereas it was 7 in 70 (31.8%), 8 in 23 (10.5%), 9 in (1.8%) and 10 in 7 patients (3.2%) respectively. HTN was present in 107 (48.6%) patients. Patients with HTN had increased CCI (mean CCI 7.0 vs. 6.43, p < 0.001). Patients with CCI of 7 were older and exhibited worse ECOG-PS and anemia than patients with CCI of 6 (p<0.05). CCI was not found to be independently predictive of OS on univariable and multivariable analyses. HTN alone or in combination with CCI was borderline significantly associated with OS (p~0.08) on both univariable and multivariable analyses.CCI did not predict OS independent of known prognostic factors in mCRPC. Age, performance status and anemia may adequately capture comorbidities in the context of mCRPC, given their association with higher CCI. Further analysis of HTN in a larger dataset may be warranted given its borderline independent association with OS.

Posner M.R.,The Tisch Cancer Institute | Lorch J.H.,Dana-Farber Cancer Institute | Goloubeva O.,University of Maryland, Baltimore | Tan M.,University of Maryland, Baltimore | And 4 more authors.
Annals of Oncology | Year: 2011

Background: The association between human papillomavirus (HPV) and overall survival (OS) in oropharynx cancer (OPC) was retrospectively examined in TAX 324, a phase III trial of sequential therapy for locally advanced head and neck cancer. Methods: Accrual for TAX 324 was completed in 2003 and data updated through 2008. Pretherapy tumor biopsies were studied by PCR for human papillomavirus type 16 and linked to OS, progression-free survival (PFS) and demographics. Results: Of 264 patients with OPC, 111 (42%) had evaluable biopsies; 56 (50%) were HPV+ and 55 (50%) were HPV-. HPV+ patients were significantly younger (54 versus 58 years, P = 0.02), had T1/T2 primary cancers (49% versus 20%, P = 0.001), and had a performance status of zero (77% versus 49%, P = 0.003). OS and PFS were better for HPV+ patients (OS, hazard ratio = 0.20, P < 0.0001). Local-regional failure was less in HPV+ patients (13% versus 42%, P = 0.0006); at 5 years, 82% of HPV+ patients were alive compared with 35% of HPV- patients (P < 0.0001). Conclusions: HPV+ OPC has a different biology compared with HPV- OPC; 5-year OS, PFS, and local-regional control are unprecedented. These results support the possibility of selectively reducing therapy and long-term morbidity in HPV+ OPC while preserving survival and approaching HPV- disease with more aggressive treatment. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Raje N.,Massachusetts General Hospital | Jagannath S.,The Tisch Cancer Institute
Current & Emerging Therapeutics for Multiple Myeloma | Year: 2013

The evolution of therapies for the treatment of multiple myeloma and related plasma cell dyscrasias has succeeded in transforming myeloma into a chronic disease. Conventional chemotherapy has been widely superseded by novel more targeted approaches impacting both the tumor cell and the microenvironment in which it resides. The seven chapters of this book highlight these advances and tackle the current landscape of therapies available to patients. The role of stem cell transplantation in the era of these novel agents is discussed, together with novel approaches under evaluation in early phase trials. This book provides a succinct overview of the evolving treatment paradigm of therapies in myeloma and will provide the reader with the context for use of such therapies. © 2013 Future Medicine Ltd. All rights reserved.

Baz W.,306 Hospital Drive | Najfeld V.,The Tisch Cancer Institute | Yotsuya M.,Staten Island University Hospital | Talwar J.,Staten Island University Hospital | And 2 more authors.
Clinical Medicine Insights: Oncology | Year: 2012

We report a 41 year old male with sickle cell disease who developed a myelodysplastic syndrome and acute myeloid leukemia with complex karyotype involving chromosomes 5, 7 and 17 after 15 years of hydroxyurea treatment. He responded poorly to induction chemotherapy with cytarabine/idarubicin followed by high dose cytarabine and succumbed to neutropenic sepsis. Multiple systematic reviews, observational studies and clinical trials were conducted to identify the toxicity profile of hydroxurea. Only six cases of leukemia/myelodysplastic syndrome were identified in patients with sickle cell anemia treated with hydroxyurea. Subsequently, it was concluded that hydroxyurea is not leukemogenic. However, it was noted that most of the published studies had only up to 9 years of follow-up. Our patient was started on hydroxyurea in 1990, before the widespread use of the drug and took hydroxyurea for 15 years. His presentation may reflect an outcome otherwise not yet observed because of the short follow-up of prior studies. We believe that the leukemogenic risk of hydroxyurea should be discussed with the patients and their families. Studies evaluating the adverse effects of hydroxyurea should have longer follow-up before definitive conclusions are drawn. © the author(s), publisher and licensee Libertas Academica Ltd.

Anvekar R.A.,Mount Sinai School of Medicine | Anvekar R.A.,The Tisch Cancer Institute | Asciolla J.J.,Mount Sinai School of Medicine | Asciolla J.J.,The Tisch Cancer Institute | And 4 more authors.
Frontiers in Oncology | Year: 2011

The global incidence of melanoma has dramatically increased during the recent decades, yet the advancement of primary and adjuvant therapies has not kept a similar pace. The development of melanoma is often centered on cellular signaling that hyper-activates survival pathways, while inducing a concomitant blockade to cell death. Aberrations in cell death signaling not only promote tumor survival and enhanced metastatic potential, but also create resistance to anti-tumor strategies. Chemotherapeutic agents target melanoma tumor cells by inducing a form of cell death called apoptosis, which is governed by the BCL-2 family of proteins. The BCL-2 family is comprised of anti-apoptotic proteins (e.g., BCL-2, BCL-xL, and MCL-1) and pro-apoptotic proteins (e.g., BAK, BAX, and BIM), and their coordinated regulation and function are essential for optimal responses to chemotherapeutics. Here we will discuss what is currently known about the mechanisms of BCL-2 family function with a focus on the signaling pathways that maintain melanoma tumor cell survival. Importantly, we will critically evaluate the literature regarding how chemotherapeutic strategies directly impact on BCL-2 family function and offer several suggestions for future regimens to target melanoma and enhance patient survival. © 2011 Anvekar, Asciolla, Missert and Chipuk.

Mascarenhas J.,The Tisch Cancer Institute | Navada S.,The Tisch Cancer Institute | Malone A.,The Tisch Cancer Institute | Rodriguez A.,The Tisch Cancer Institute | And 3 more authors.
Leukemia Research | Year: 2010

Myelofibrosis (MF) is a clonal stem cell disorder with the potential to transform to acute leukemia, referred to as myelofibrosis in blast phase (MF-BP). The outcome of patients with MF-BP is grave with a median survival of only 2.7 months. MF-BP is largely refractory to conventional chemotherapy and intensive induction therapy fails to have a significant impact with a median survival of 3.9 months. Eleven consecutive patients were treated at our institution with MF-BP over a 2-year period. Eligible patients with an available donor received an allogeneic stem cell transplant (ASCT) and those that were not eligible or without a donor were treated with Decitabine (DEC). The median time for follow up for the entire group was 9 months (range 5-21 month). At 9 months (range 5-45 months), 67% of the patients treated with DEC were alive and at 20 months (range 9-23 months), 53% of patients treated with ASCT remain alive. Reduced intensity conditioning allogeneic stem cell transplantation (RIC-ASCT) is a viable option that offers the potential for prolonged survival and the possibility of cure for patients with MF-BP. DEC is a tolerable outpatient chemotherapeutic regimen for MF-BP patients ineligible for transplant and deserves further prospective study. © 2010.

Misiukiewicz K.,The Tisch Cancer Institute
Anti-cancer drugs | Year: 2014

Accumulating evidence from clinical trials has shown that taxanes are among the most active antitumor agents currently available for squamous cell carcinoma of the head and neck. They are strong enhancers of the efficacy of radiotherapy in locally advanced cancer and are highly potent chemotherapeutic agents in recurrent/metastatic settings. Paclitaxel and docetaxel, prototypes of taxanes, are already well known and used in the treatment of squamous cell carcinoma of the head and neck, but a newer generation of taxanes is emerging and may possess stronger antitumor activity and/or decreased normal tissue toxicity. Acquired resistance to taxanes has become one of the major therapeutic obstacles, which hopefully will be overcome with a newer generation of taxanes, as our knowledge of the mechanism of resistance has improved.

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