Mount Sinai School Of Medicine Research Articles

Emily Steinhagen, MD, FACS, FASCRS.

Dr. Emily Steinhagen was born in New York, NY, and grew up in New Jersey prior to attending the Williams College, where she earned her BA in Political Science cum laude and played hockey. She then attended the Mount Sinai School of Medicine in New York, NY, receiving her MD in 2008. Dr. Steinhagen completed her residency in Surgery at the Mount Sinai Medical Center in 2015, spending 2 years at Memorial Sloan Kettering Cancer Center as a Clinical Research fellow from 2010 to 2012.

Editorial introductions.

Editorial introductions.

Editorial introductions.

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Editor and Section Editors for this issue. EDITOR Don RockeyDon RockeyDr Don Rockey completed internship, residency, chief residency, and fellowship at the University of California, San Francisco, USA. He is currently Director of the Medical University of South Carolina Digestive Disease Center. He has active, basic and clinical research interests in liver disease. His basic research focuses on understanding the molecular basis of fibrosis and portal hypertension. His laboratory initially demonstrated that a key player, the hepatic stellate cell, exhibits a contractile phenotype and transforms to a myofibroblast. Further, following liver injury, stellate cells not only produce increases quantities of extracellular matrix, but also exhibit exaggerated contractility, constrict liver sinusoids, and contribute to increased intrahepatic vascular resistance typical of portal hypertension. Dr Rockey also has an active clinical research program, focused on clinical management problems in gastrointestinal bleeding, drug induced liver injury, and chronic liver diseases including complications of portal hypertension. Dr Rockey and colleagues have published some 300 peer reviewed original scientific papers and over 100 editorials, reviews, and book chapters. He has served as a mentor for over 125 trainees, including students, residents, fellows, and junior faculty members - the vast majority of whom have pursued or who are pursuing careers in academic medicine. He has had a number of editorial responsibilities, including as Associate Editor for Hepatology, Liver International, and the Journal of Investigative Medicine, and has served on multiple NIH and other study sections, and editorial boards. SECTION EDITOR Anthony BuckleyAnthony BuckleyDr Anthony Buckley, PhD, is a Lecturer in Microbiology at the University of Leeds, UK, and leads the Microbiome & Nutritional Sciences group. He also holds an honorary position at the Leeds Teaching Hospital Trust, NHS, UK. Dr Buckley obtained his PhD in Molecular Microbiology at the University of Birmingham, UK, where he investigated the role of efflux pumps towards Salmonella Typhimurium in vivo pathogenicity under the supervision of Professor Laura J. V. Piddock. Dr Buckley is passionate about student education and supporting early career researchers, and he sits on the steering committees for the Leeds Biofilm Network and [email protected] Network. The research interests of his group centers on influencing disease outcome by manipulating the human microbiota through probiotics and prebiotics. His group develops novel models of the human digestive tract to study the interactions between xenobiotics, microbe, and host, and determine the efficacy of novel drugs and biotherapeutics. He is an author on over 40 primary research articles, review articles, and book chapters. Russell D. CohenRussell D. CohenRussell D. Cohen, MD. FACG, AGAF is a Professor of Medicine at the Pritzker School of Medicine, in the Department of Medicine, Section of Gastroenterology at the University of Chicago, USA. Currently he is Director of the IBD Center and the Co-Director of the Advanced IBD Fellowship Program, and serves as Illinois Governor for the American College of Gastroenterology, USA. Dr Cohen earned his BS at Cornell University, USA, his MD with honors at Mount Sinai School of Medicine, USA, and his residency in internal medicine at Beth Israel Hospital/Harvard Medical School, USA, and his fellowship in gastroenterology and senior fellowship in IBD at the University of Chicago. He has been Principal or Co-Investigator for more than 185 research projects. He is an editor of three medical textbooks, and has authored more than 200 articles, abstracts, reviews, books, book chapters, and audiotapes. He is published in prestigious journals such as Gastroenterology, American Journal of Gastroenterology, and Inflammatory Bowel Diseases. He also is a reviewer for multiple journals, including New England Journal of Medicine, Gastroenterology, Gut, and American Journal of Gastroenterology, and is a member of multiple prestigious medical societies. Dr Cohen is named in Best Doctors in America, America's Top Gastroenterologists, Top Doctors in the Chicago Metro Area, and Chicago Magazine's Top Doctor in Gastroenterology.

Implementing pathways to anesthesiology: Promoting diversity, equity, inclusion, and success.

Implementing pathways to anesthesiology: Promoting diversity, equity, inclusion, and success.

Research hotspot and frontier analysis of traditional Chinese medicine in asthma using bibliometric methods from 1991 to 2021.

Traditional Chinese medicine (TCM) has been successfully used to treat asthmatic conditions for centuries. Nevertheless, the current hotspots and research frontiers on TCM for asthma have not been systematically investigated on the basis of bibliometric analysis. In this study, a scientometric analysis (1991-2021) was carried out on 3081 journal articles obtained from the Web of Science Core Collection database to explore the basic characteristics, research hotspots, and frontiers of TCM in asthma research. The results revealed the following: (1) Research on TCM in asthma has received widespread attention since the beginning of the 21st century; perhaps 2009 was an important turning point. TCM in asthma research shows a trend of interdisciplinary development. (2) Well-known universities/institutions in China, the United States, and South Korea have conducted the main body of current TCM research in asthma. JingCheng Dong (Fudan University, China) and XiuMin Li (Mount Sinai School of Medicine, USA) are the top 2 leading authors in this field. However, there is still a lack of international cooperation in the field of TCM in asthma research, and the influence of researchers in China and South Korea still needs improvement. (3) The Journal of Allergy and Clinical Immunology ranks first in the research field on the influence of TCM in asthma. (4) Hotspots and frontiers of TCM in asthma are provided according to the timeline analyses of the research. In the former, complementary medicine, alternative treatment, allergic rhinitis, airway remodeling, Dietary Approach to Stop Hypertension diet, and eosinophilic esophagitis are in the exploratory stage. In the latter, pharmacology, essential oil, gut microbiota, and oxidative stress were investigated from 2006 until late 2021 as period B, which contradicts period A(1991-2005). Moreover, limitations of this bibliometric analysis and the study of TCM research in asthma still exist, which are sufficiently important to warrant further investigations. Finally, we propose the significant importance of the real quintessence and characteristics of TCM in clinical and future research.

MP46-10 ELUCIDATING THERAPEUTIC OPTIONS FOR TREATMENT-NAÏVE AND CISPLATIN-RESISTANT TESTICULAR CANCER

You have accessJournal of UrologyCME1 May 2022MP46-10 ELUCIDATING THERAPEUTIC OPTIONS FOR TREATMENT-NAÏVE AND CISPLATIN-RESISTANT TESTICULAR CANCER Julie-Ann Cavallo, Daniel Ranti, Elliot Merritt, Anna Tocheva, John P. Sfakianos, and Benjamin Hopkins Julie-Ann CavalloJulie-Ann Cavallo More articles by this author , Daniel RantiDaniel Ranti More articles by this author , Elliot MerrittElliot Merritt More articles by this author , Anna TochevaAnna Tocheva More articles by this author , John P. SfakianosJohn P. Sfakianos More articles by this author , and Benjamin HopkinsBenjamin Hopkins More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002612.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Platinum-based chemotherapy is the standard of care (SOC) for patients with advanced testicular cancer (TC). However, outcomes for platinum-refractory tumors remain poor. This project seeks to use functional diagnostic approach to both predict therapeutic response for patients with testicular cancer and evaluate the utility of alternate therapeutic strategies that may improve responses for patients with platinum-refractory disease. METHODS: Using an IRB-approved protocol, we obtained tissue from platinum-sensitive and -resistant TC patients. Tissue specimens were obtained from 13 tumors: 10 primary, 2 post-treatment, and 1 lymph node. To functionally model therapeutic responses for patients with TC, we used our RAPiDS (Rapid Assessment of Patient Drug Sensitivity) screens on primary patient-derived organoids (PDOs) to stratify patient response to SOC therapies and evaluate the relative sensitivity of the tumors to alternative therapeutic regimens. For these studies, we conducted screens with nine therapeutics in a clinically relevant range of concentrations to extract correlative drug response data within two weeks from dissociation. RESULTS: Using the RAPiDS protocol, we developed and evaluated drug sensitivities in five PDOs (Figure 1A). Normalized luminescence from Cell-TiterGlo cell viability assays were used to determine Area Under the Curve (AUC) as a function of drug concentration (Figure 1A and B). Heatmaps show the median centered z-score for these AUC values across the therapeutics screened in each patient to gauge relative sensitivity (Figure 1A). All of our screened TC cases showed sensitivity to one or more alternative therapies tested, regardless of PDO response to first- or second-line SOC (Figure 1B). CONCLUSIONS: This data suggests that RAPiDS could be used on TC PDOs to help guide the selection of treatment options within clinically relevant timelines, which has the potential to be useful, especially in metastatic and rare cancer settings where therapeutic options are limited. Additionally, we are currently investigating the utility of RAPiDS in refractory and metastatic TC. Source of Funding: Mount Sinai School of Medicine seed funds © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e776 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Julie-Ann Cavallo More articles by this author Daniel Ranti More articles by this author Elliot Merritt More articles by this author Anna Tocheva More articles by this author John P. Sfakianos More articles by this author Benjamin Hopkins More articles by this author Expand All Advertisement PDF DownloadLoading ...

Emergency Ambulance Utilization in Harlem, New York (July 1985)

Emergency ambulance service in Harlem, New York was studied to determine the degree to which misuse exists. Data were collected prospectively from a paramedic (ALS) ambulance and a basic life support (BLS) ambulance dispatched from Harlem Hospital. The results show that only 29.5% of the 136 calls dispatched to the ALS unit had congruent dispatch and actual priorities (r = 0.05), and only 59.6% of the 255 calls handled by both units were recommended for the unit with the proper level of the skill. 69.9% of calls assigned to the ALS unit were found not to need emergency transport (ET), the most common reason being the “unfounded” call, which represented 35.3% of the sample. ALS intervention was needed on only 20.6% of calls dispatched to the ALS unit. Paramedics were able to correctly access the need for ET 95.6% of the time, but were only willing to refuse transport 35.2% of times in which they felt it was unnecessary. Within the population studied, there exists a significant subset of nonemergency calls which could be more efficiently triaged, both at the level of dispatch and by EMS personnel on the scene. Author Perspective: This research was performed from July 1 to July 26, 1985 to fulfill the requirements of a Community Medicine rotation when the investigator was a student at the Mount Sinai School of Medicine in New York City (presently the Ican School of Medicine at Mount Sinai). Dr. Alexander E. Kuehl was the Vice President of New York City Health and Hospitals Corporation, Emergency Medical Service at the time (prior to New York City EMS moving under the Fire Department) and served as preceptor for the project. This work has not been previously published; however, the investigator was an invited presenter at the “Third International Urban Emergency Medical Service System Symposium” in September 1985 at the World Trade Center in New York City. The oral presentations at the symposium were entitled: “Paramedic Attitudes Concerning On-The-Scene Triage” and “Emergency Ambulance Utilization in Harlem.” To complete the work for this 30-day rotation, the investigator performed daily ambulance ride-alongs in Harlem, New York for 15 consecutive days and collected data prospectively from paramedics. EMTs staffing an ambulance during the same time frame provided concurrent information by survey. Some EMS terminology is now outdated; however, the terms have not been updated in order to preserve the historical perspective of the article. While the data are now historical, having been collected nearly 40 years ago, this research provides useful insights into current EMS initiatives, notably: (1) accuracy of assigned dispatch priority, (2) need for emergency transport to an emergency department, and (3) willingness of paramedics to refuse transport in cases where it is deemed unnecessary. The research questions represent many of the challenges that persist in today’s EMS world with some being particularly relevant with the advent of Community Paramedicine. Emergency Ambulance Utilization in Harlem truly illustrates “what’s old is new again!”

Editorial introductions.

Editorial introductions.

Editorial introductions

Editorial introductions

A Novel Machine Learning-Derived Dynamic Scoring System Predicts Risk of Thrombosis in Polycythemia Vera (PV) Patients

A Novel Machine Learning-Derived Dynamic Scoring System Predicts Risk of Thrombosis in Polycythemia Vera (PV) Patients

Characterization of T-Cell Exhaustion in Rapid Progressing Multiple Myeloma Using Cross Center Scrna-Seq Study

Characterization of T-Cell Exhaustion in Rapid Progressing Multiple Myeloma Using Cross Center Scrna-Seq Study

337 Intratumoral immune therapy for recurrent breast cancer with polyICLC, and tremelimumab combined with systemic durvalumab

BackgroundIntratumoral (IT) cancer therapies may enhance T cell activation and tumor infiltration when combined with systemic checkpoint blockade. This approach may improve treatment of advanced breast cancer, which is commonly resistant to immune therapy.MethodsA multicenter basket-style trial (NCT02643303) was performed in patients with advanced solid tumors, who received polyICLC IT 1mg x 6, then intramuscular (IM) x 3, combined with intravenous (IV) durvalumab 1500 mg q4W. Most were assigned to cohorts also receiving tremelimumab: 10 mg IT or 75 mg IV. Goals were to assess tolerability and clinical activity. Treated tumors were evaluated for immune infiltrates on days (d) 0, 15, and 29 by multiparameter immunofluorescence histology. A strong signal for clinical response was in breast cancer patients; thus, an expansion cohort was enrolled. We report analysis of that breast cancer subgroup.ResultsNineteen participants with treatment-refractory recurrent breast cancer with median 4 prior lines of therapy were enrolled and treated with IV durvalumab and IT/IM polyICLC. Seventeen also received tremelimumab (15 IT, 2 IV). Common treatment-related AEs were fatigue, injection site pain, and chills. There was one dose-limiting toxicity in a participant who received tremelimumab IV, and died with severe hyponatremia (DLT) and progressive disease. Objective clinical responses (1 complete; 4 partial (1 unconfirmed)) were observed in 5 (26%), including 2/9 patients with triple-negative breast cancer (TNBC) and 3/10 with non-TNBC. Median OS was longer for those with CR, PR, or SD (not reached) vs. those with PD or not evaluable (5 months): two responders remain alive at 34+ and 40+ months. In injected tumors, there were significant increases from d0 to d29 in numbers/mm2 of CD8+ T cells, CD20+ B cells, mature dendritic cells (DC), macrophages, and CD56+ NK cells, and in CD8+ cells with antigen-experience (CD45RO), cytotoxic function (granzyme B), activation (ICOS1), or proliferation (Ki67). CD8+ cells expressing LAG3 and TIM3 increased, as did PDL1+ tumor cells and stromal cells. There were no differences in cells expressing IDO, ARG1, CD39, or CD73. Among patients with objective response, vs. all others, proportions of intratumoral CD8+ cells expressing Ki67 increased (p < 0.04).ConclusionsIT tremelimumab and polyICLC plus systemic durvalumab is safe and has clinical activity in patients with advanced TNBC and non-TNBC. The therapy enhances intratumoral immune effectors and markers of T cell function in hypothesis-generating data that warrant confirmatory studies. Clinical response was associated with longer survival and increased CD8 T cell proliferation.Trial RegistrationNCT02643303Ethics ApprovalThe study has been performed with approval of the institutional review boards of each participating institution (Roswell Park Cancer Institute: STUDY 00000121/I291016; Mount Sinai School of Medicine: IRB-17-01692; University of Virginia: IRB # 19276; Cleveland Clinic: 18-694; Toledo: 300176; Dartmouth: STUDY00031630; Emory: IRB00099445). All participants give informed consent before enrolling and participating. The study was also performed with approval from the FDA

Editorial introductions.

Current Opinion in Organ Transplantation was launched in 1996. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of organ transplantation is divided into 18 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Linda S. SherLinda S. SherDr Linda S. Sher is Professor of Clinical Surgery and Director of Clinical Research in the Division of Hepatobiliary Surgery and Abdominal Organ Transplantation at Keck School of Medicine, University of Southern California (USC), USA. After completing her medical school education and surgical residency at Mount Sinai School of Medicine in New York, USA, Dr Sher undertook her fellowship training in Liver and Kidney Transplantation at the University of Pittsburgh, USA. After completing her fellowship in 1988, Dr Sher was involved in the establishment of two liver transplant programs in Los Angeles prior to joining the USC program in 2001. Dr Sher has participated in and overseen over 50 research projects and is currently very active in the development of the clinical and basic science research components of the USC Abdominal Organ Transplantation Program. She has numerous publications on immunosuppression, chronic rejection, disease recurrence, infection, and hepatobiliary surgery. Dr Sher is one of the original editors of Current Opinion in Organ Transplantation and has endeavored over the years to provide the reader with an up to date overview of the entire field of organ transplantation. Paulo N. MartinsPaulo N. MartinsDr Paulo N. Martins MD, PhD, FAST, FEBS, FACS is a transplant surgeon (Associate Professor of Surgery) and has a transplant lab focused on liver preservation at University of Massachusetts, USA. He graduated from medical school in Brazil, where he ranked first. He finished his PhD in transplant immunology at the University of Berlin-Germany in 2005 with “Summa cum Laude” and worked clinically in Berlin, Germany (Charite’-Virchow Klinikum) for over a year. He completed a post-doc research fellowship at the Brigham and Women Hospital and Massachusetts General Hospital at Harvard University, in Boston-USA, and later did a clinical hepatobiliary and Transplant Fellowship at the New York Medical School, followed by other clinical transplant fellowship at Massachusetts General Hospital, Harvard University, followed by one year as clinical instructor in the same institution. Since 2013, Dr. Martins has been working as a transplant Surgeon at the University of Massachusetts. During his career he has obtained several research awards (including the ILTS rising star award, ASTS vanguard award, ASTS rising star award, AST basic science award, an AASLD grant, and the Portuguese-American Scientific leadership award) and grants. He is the vice-chair of the ILTS Basic and Translational Science committee, associate editor of the journal "Artificial Organs, an editorial board member/reviewer of 15 scientific journals, and member of several transplant societies including (ILTS, ESOT, AST, ASTS, DTG, AASLD). Dr. Martins has published 107 peer-reviewed articles (with over 3,500 citations), one textbook, 16 book chapters, and over 100 abstracts in scientific meeting and medical journals. He has been part of Diversity committee at his institution, he is co-chair of the ASTS diversity committee, and chair of the UNOS/OPTN Minority Affairs Committee. He has been part of several initiatives to increase equity in transplantation access (e.g. policies to collect socio-economic data and to eliminate the black race coefficient for eGFR calculation, adjustments/provisions in organ allocation policies, guidelines about listing of patients with cognitive impairment among others). He is also part of the bold against racism task-force in the ASTS that aims to increase representation and equity for the transplant workforce, to build inclusive work environments, and provide culturally sensitive training. He published several articles in this field and this year he was nominated by the University of Massachusetts to the Alpha Omega Alpha honor society.

Maria O. Longas

Maria O. Longas, 76, died Jan. 7 in Hobart, Indiana. “Maria, a biochemist and native of Colombia, studied in New York and worked at the NYU Medical Center, Sloan Kettering Institute, Columbia University College of Physicians and Surgeons, and the Mount Sinai School of Medicine. She started her teaching career in 1987 at Purdue University Calumet (now Purdue University Northwest) in Hammond, Indiana. She was promoted to full professor in 1996 and retired in 2019. Her primary research interests were hyaluronic acid, aging effects of the skin, and Alzheimer’s disease. She was a long-time supporter of charities and the arts. She self-published a book of poems, Reminiscences, in 1997.”—Kay Rowberg and Hal Pinnick, colleagues Most recent title: Professor emerita of Chemistry, Purdue University Northwest Education: BA, chemistry, Hunter College, 1971; MA, chemistry, New York University, 1973; PhD, chemistry, New York University, 1978 To recognize your late loved one or colleague,

Alex Proekt, M.D., Ph.D., Recipient of the 2021 James E. Cottrell, M.D., Presidential Scholar Award

Alex Proekt, M.D., Ph.D., Recipient of the 2021 James E. Cottrell, M.D., Presidential Scholar Award

Optimal Supportive Care With Selinexor Improves Outcomes in Patients With Relapsed/Refractory Multiple Myeloma

BackgroundSupportive care improves outcomes in many cancers. In the pivotal STORM study selinexor, a first-in-class, oral, selective exportin 1 inhibitor, and low-dose dexamethasone proved to be an effective treatment for patients with triple-class refractory myeloma. We conducted a post-hoc analysis to test the hypothesis that increased utilization of supportive care measures in a sub-cohort of the STORM study prolonged treatment duration with- and improved efficacy of- selinexor. Materials and MethodsThe STORM protocol included specific recommendations for dose modifications and supportive care to mitigate selinexor most common adverse events (AEs) including nausea, fatigue, and thrombocytopenia. The Tisch Cancer Center at Mount Sinai School of Medicine (MSSM) incorporated additional supportive care strategies within the framework of the STORM protocol. ResultsOf 123 patients enrolled in STORM, 28 were enrolled at MSSM. The overall response rate was 26.2% in the overall STORM population and 53.6% in the MSSM cohort. Moreover, duration of response, progression free survival, and overall survival were longer in the MSSM cohort. AEs and dose modification events were similar in the 2 groups. The MSSM cohort had more dose reductions (67.9% vs. 50.5%), and higher use of multiple antiemetic agents (71.4% vs. 50.1%) and romiplostim (32.1% vs. 6.3%), but less discontinuations due to treatment-related AEs (3.6% vs. 25.3%). ConclusionThese results suggests that in addition to more frequent dose reductions, prompter and more aggressive supportive care may have contributed to the low discontinuation rate, longer duration therapy, and greater efficacy rates observed in the MSSM cohort. (ClinicalTrials.gov NCT02336815).

Direct-Acting Small Molecule Activators of PP2A (SMAPs) in Myeloid Malignancies: Understanding Mechanisms of Cytotoxicity to Inform Rational Combinatorial Therapeutic Strategies

The protein phosphatase 2A (PP2A) functions as a tumor suppressor by counteracting oncogenic kinase signaling. Suppression of PP2A activity represents a critical process in the development and maintenance of many neoplasms, including myeloid malignancies; PP2A inhibition de-represses numerous proliferative and survival signaling pathways. However, complete loss of PP2A is lethal to cells. As such, indirect reactivation of PP2A has emerged as a promising therapeutic strategy for myeloid leukemias. Yet the broad applicability of such a strategy remains uncertain, as it relies on targeting endogenous PP2A inhibitors. In the present work we investigated the effects of direct acting small molecule activators of PP2A (SMAPs) (Sandokar et al. JCI 2017) on myeloid leukemia cells and uncovered a novel link between PP2A reactivation and NOXA-mediated apoptosis. This mechanism explains our observation of cooperativity between SMAPs and the BH3 mimetic ABT-199 (venetoclax). Additionally, we found that SMAPs elicit a protective stress response that can be overcome by inhibition ofprotein kinase R (PKR)-like endoplasmic reticulum kinase (PERK).Given the known role of PP2A inactivation in both acute and chronic myeloid leukemia (AML and CML), we first tested the activity of SMAPs against cell lines derived from both diseases. Across all cell lines tested (CML- K562, Meg-01; AML- MOLM-14, HL-60, OCI-AML3, THP-1) SMAPs caused a dose-dependent decrease in cell viability. It is known that reactivation of PP2A induces apoptosis in myeloid leukemia cells, though this area has yet to be thoroughly investigated. Therefore, we first sought to clarify the mode of cell death in response to PP2A reactivation. Both by biochemical and flow cytometric analyses, SMAPs showed activation of the intrinsic apoptotic cascade. Furthermore, SMAP-mediated cell death was blocked by co-treatment with the caspase inhibitor z-VAD-FMK (50 μM). We previously demonstrated the target specificity of SMAPs for PP2A with methods including expression of SV40 small T antigen and PP2A alpha subunit drug-binding mutants (Sandokar et al. JCI 2017). Here, we confirmed that pre-treatment with the PP2A inhibitor okadaic acid at a dose that retains selectivity for PP2A (10 nM) attenuated SMAP-induced cell death and cleavage of PARP and caspase-3.Next, we investigated the effectors of SMAP-mediated apoptosis. To this end, we performed Western blots to detect changes in abundance and/or phosphorylation of a panel of Bcl-2 family member proteins. Interestingly, a strong upregulation of the pro-apoptotic protein NOXA occurred consistently across AML and CML cell lines. Further RT-PCR studies showed this increase to occur at the transcript level. Knockdown studies confirmed the importance of NOXA for SMAP-mediated apoptosis. These data represent the first reported link between PP2A and NOXA regulation. Since SMAPs target the NOXA-MCL1 axis of the Bcl-2 family, we next tested their efficacy in combination with the Bcl-2-selective BH3 mimetic ABT-199. We found co-treatment with SMAPs and ABT-199 to exhibit enhanced cell death compared to either agent alone.Concurrent with NOXA elevation, SMAP treatment modulated protein expression and phosphorylation levels for several known pathways downstream of PP2A. Interestingly, we additionally observed increased phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2α) in SMAP-treated cells which correlated with upregulation of mRNA and protein for the downstream transcription factor ATF4. Blockade of eIF2α phosphorylation with PERK inhibitor GSK2656157 (350 nM) prevented ATF4 elevation and enhanced SMAP-induced apoptosis. This result supports the idea that the integrated stress response (ISR) via PERK-eIF2α-ATF4 acts to counter apoptosis in the context of PP2A reactivation in myeloid leukemia cells. Thus, the efficacy of SMAPs and other PP2A-activating therapeutics may be enhanced by combination with both BH3 mimetics and inhibitors of the ISR. DisclosuresNarla:Mount Sinai School of Medicine: Patents & Royalties: patents on the small molecule PP2A activators (GN).

Small Molecule Activators of Protein Phosphatase 2A (SMAPs) Cause c-Myc Degradation and Tumor Growth Suppression in Preclinical Models of Lymphoid Malignancies

Introduction: c-myc is an oncogene implicated in the initiation and progression of multiple hematologic malignancies. Characteristic translocations of the c-myc gene with the immunoglobulin heavy chain gene (in Burkitt lymphoma and “double-hit” non-Hodgkin lymphoma) and with the T cell receptor gene (in T cell acute lymphoblastic leukemia, T-ALL) lead to constitutive expression of the c-myc transcription factor, ultimately driving dysregulated proliferation (Boxer & Dang, Oncogene 2001; 20(40):5595-5610). Strategies for inhibition of c-myc remain an area of active research; however, to date there are no approved myc-targeted agents within the cancer armamentarium, and cytotoxic chemotherapy remains the standard of care for c-myc-driven lymphoid malignancies. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase tumor suppressor protein that contributes to c-myc degradation through both direct dephosphorylation of an identified phosphodegron as well as by indirect mechanisms (Farrell & Sears, Cold Spring Harbor Perspect Med 2014; 4(3):1-15). Our laboratory has developed a series of first in class, orally bioavailable small molecule activators of PP2A (SMAPs) by derivatizing tricyclic antipsychotics to maximize antiproliferative activity and minimize psychotropic properties (Sangodkar et al., J Clin Invest 2017;127(6):2081-2090). We hypothesized that activation of PP2A with SMAPs would lead to c-myc degradation and tumor growth inhibition in models of c-myc-driven lymphoid malignancies.Methods: We investigated the effects of SMAP treatment on c-myc content, c-myc half-life (t1/2), cell viability, and xenograft tumor growth in Burkitt lymphoma (BL) and T-ALL cell lines with wild type and mutant c-myc phosphodegrons.Results: SMAP treatment induced apoptosis in Daudi (BL) cells, as evidenced by decreased viability and increased PARP and caspase cleavage. In Daudi (BL) and CCRF-CEM (T-ALL) cell lines, SMAP treatment led to rapid loss of phosphorylated and total c-myc protein. Cycloheximide (CHX)-chase experiments performed in CCRF-CEM cells confirmed that SMAP treatment affects c-myc degradation without affecting protein synthesis. This effect was abrogated by Ser to Glu mutation of residue 62 within the c-myc phosphodegron, suggesting that SMAP-mediated c-myc degradation is PP2A-dependent. Treatment of NOD/SCID mice bearing Daudi xenografts with twice daily oral SMAP decreased tumor c-myc content and inhibited tumor growth without obvious toxicity. Xenografts overexpressing c-myc with phosphodegron mutations (S62D, T58I) were resistant to SMAP treatment.Conclusions: These in vitro and in vivo observations establish PP2A activation as a potential pharmacologic strategy to target c-myc in cancers such as BL, T-ALL, and “double hit” non-Hodgkin lymphoma. SMAPs are well-tolerated, orally bioavailable activators of PP2A poised for further exploration in the treatment of c-myc-driven malignancies, either alone or in combination with other agents. Sequencing of the c-myc phosphodegron prior to initiation of treatment may facilitate patient selection in future clinical trials of PP2A activators. [Display omitted] DisclosuresNarla:Mount Sinai School of Medicine: Patents & Royalties: patents on the small molecule PP2A activators (GN).

Amisulpride: What’s Old Can Be New in the United States

Amisulpride: What’s Old Can Be New in the United States

New Alzheimer’s drug faces criticism

An effective drug for Alzheimer’s disease has long eluded doctors and the patients they treat who have this memory-robbing condition. After nearly 20 years with no new treatments for the disease, a novel Alzheimer’s drug would seem like cause for celebration. Instead, the US Food and Drug Administration’s historic and controversial approval of Biogen’s Alzheimer’s therapy, Aduhelm, left neurologists exasperated. Many believe that the drug doesn’t work and that, even if it does, its benefits are marginal at best. “I suspect there was a lot of pressure to approve, but I was quite disappointed,” says Mary Sano, director of the Alzheimer’s Disease Research Center at Mount Sinai School of Medicine. “It will be very interesting to see what will happen internationally. I am not convinced it will get approval in other countries.” Others are more optimistic. “It is a step forward,” says Oscar L. Lopez, director of the Alzheimer’s Disease