Publications by authors named "Bridget Marcellino"

25 Publications

  • Page 1 of 1

Alternatives to intensive treatment in patients with AML.

Clin Adv Hematol Oncol 2021 Aug;19(8):526-535

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

A significant proportion of patients with acute myeloid leukemia (AML) are unable to tolerate standard induction chemotherapy regimens. This is particularly true for patients who are of advanced age, have a poor performance status, and/or have significant medical comorbidities. Recent advances in understanding the genetic and molecular properties of AML have led to a spate of new treatment options for patients considered ineligible for standard chemotherapy. Here, we discuss these new treatment options, provide an overview of the completed and ongoing trials of the new agents, and highlight promising future directions in the treatment of AML in patients ineligible for intensive induction chemotherapy.
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August 2021

Recent advances in prognostication and treatment of polycythemia vera.

Fac Rev 2021 12;10:29. Epub 2021 Mar 12.

Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1079, New York, USA.

Polycythemia vera (PV) is a -negative myeloproliferative neoplasm marked by acquisition of an activating mutation of , which leads to not only erythrocytosis but also frequently to leukocytosis and thrombocytosis, and is associated with a high symptom burden and increased thrombotic risk. PV has the potential to progress to myelofibrosis or an aggressive form of acute myeloid leukemia. Mutational profiling of patients with PV has led to the development of risk stratification tools to determine an individual's risk of developing progressive disease. Although the current goals of PV treatment are to alleviate symptoms and reduce thrombotic risk, there are growing efforts to identify disease-modifying agents which will also prevent progression of disease. Here, we give an overview of the developing prognostic tools and therapeutic landscape for PV, focusing on four drug classes: pegylated interferon-alpha 2, MDM2 antagonists, hepcidin mimetics, and histone deacetylase inhibitors.
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http://dx.doi.org/10.12703/r/10-29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009192PMC
March 2021

Safety and Efficacy: Clinical Experience of Venetoclax in Combination With Hypomethylating Agents in Both Newly Diagnosed and Relapsed/Refractory Advanced Myeloid Malignancies.

Hemasphere 2021 Apr 9;5(4):e549. Epub 2021 Mar 9.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Hypomethylating agents (HMAs) in combination with venetoclax have been widely adopted as the standard of care for patients who cannot tolerate induction chemotherapy and for patients who have relapsed/refractory (R/R) acute myeloid leukemia (AML). This study retrospectively analyzed the outcomes of all patients with AML (n = 65) or myelodysplastic syndrome (n = 7) who received the combination of HMA and venetoclax at our institution. Outcomes measured included complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, duration of response (DOR), and overall survival (OS). Patient mutational profiles and transfusion requirements were also assessed. Of 26 newly diagnosed AML patients, the CR/CRi rate was 53.8%. The median DOR and OS were 6.9 months and not reached, respectively. Of 39 R/R AML patients, the CR/CRi rate was 38.5%. The median DOR and OS were both 8.1 months. Responders to HMA and venetoclax were enriched for , , and mutations, while nonresponders were associated with and mutations. Adaptive resistance was observed through various mechanisms including acquired pathway mutations. Of transfusion-dependent patients, 12.2% and 15.2% achieved red blood cell (RBC) and platelet transfusion independence, respectively, while 44.8% and 35.1% of RBC and platelet transfusion independent patients, respectively, became transfusion dependent. In total 59.1% of patients developed a ≥grade 3 infection and 46.5% neutropenic fever. HMA + venetoclax can lead to impressive response rates with moderately durable remissions and survival. However, the benefits of this combination are diminished by the significant toxicities from infection, persistent cytopenias, and transfusion requirements.
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http://dx.doi.org/10.1097/HS9.0000000000000549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951133PMC
April 2021

Clinical Course of Cancer Patients With COVID-19: A Retrospective Cohort Study.

JNCI Cancer Spectr 2021 Feb 2;5(1):pkaa085. Epub 2020 Nov 2.

Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Complications in cancer patients with coronavirus disease 2019 (COVID-19) have not been examined. This analysis aimed to compare characteristics of COVID-19 patients with and without cancer and assess whether cancer is associated with COVID-19 morbidity or mortality.

Methods: COVID-19-positive patients with an inpatient or emergency encounter at the Mount Sinai Health System between March 1, 2020, and May 27, 2020, were included and compared across cancer status on demographics and clinical characteristics. Multivariable logistic regressions were used to model the associations of cancer with sepsis, venous thromboembolism, acute kidney injury, intensive care unit admission, and all-cause mortality.

Results: There were 5556 COVID-19-positive patients included, 421 (7.6%) with cancer (325 solid, 96 nonsolid). Those with cancer were statistically significantly older, more likely to be non-Hispanic Black and to be admitted to the hospital during their encounter, and had more comorbidities than noncancer COVID-19 patients. Cancer patients were statistically significantly more likely to develop sepsis (adjusted odds ratio [OR] = 1.31, 95% confidence interval [CI] = 1.06 to 1.61) and venous thromboembolism (OR = 1.77, 95% CI = 1.01 to 3.09); there was no statistically significant difference in acute kidney injury (OR = 1.10, 95% CI = 0.87 to 1.39), intensive care unit admissions (OR = 1.04, 95% CI = 0.80 to 1.34), or mortality (OR = 1.02, 95% CI = 0.81 to 1.29).

Conclusions: COVID-19 patients with cancer may have a higher risk for adverse outcomes. Although there was no statistically significant difference in mortality, COVID-19 patients with cancer have statistically significantly higher risk of thromboembolism and sepsis. Further research is warranted into the potential effects of cancer treatments on inflammatory and immune responses to COVID-19 and on the efficacy of anticoagulant therapy in these patients.
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http://dx.doi.org/10.1093/jncics/pkaa085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665671PMC
February 2021

Prevalence of Cytopenia in the General Population-A National Health and Nutrition Examination Survey Analysis.

Front Oncol 2020 20;10:579075. Epub 2020 Nov 20.

Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Background: Cytopenia, a reduced count of blood cells manifesting as anemia, neutropenia, and/or thrombocytopenia is frequently associated with other medical conditions. However, a cytopenia may not be accompanied by a known determinant and in some of these cases, may be a precursor to pre-malignancies or hematologic cancers. Little is known about the prevalence of these unexplained cytopenias and their distribution in the population.

Materials And Methods: The National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002 was used to identify those with a cytopenia in the general population. Those without an identifiable determinant in the NHANES were classified as having unexplained cytopenia. Weighted frequencies were examined to assess the prevalence of unexplained cytopenia in the population. Distribution of blood counts comparing those with unexplained cytopenia to the general population was examined. Multivariable logistic regression was conducted to assess the association between unexplained cytopenia and demographic factors.

Results: Of the 7,962 people in the sample, 236 (2.0%) had any cytopenia and 86 (0.9%) had an unexplained cytopenia. Approximately 43% of all cytopenias were not accompanied by a clinical determinant. Unexplained cytopenia was more common in men (1.1%) than in women (0.7%) and in Non-Hispanic Black participants (3.4%). Among those with an unexplained cytopenia, the majority (74.8%) manifested as neutropenia. Compared to those with no cytopenia, those with unexplained cytopenia were significantly less likely to be female, have body mass index ≥30 kg/m, and work in the service industry, and were significantly more likely to be non-Hispanic Black.

Conclusions: This is the first study to examine the prevalence of unexplained cytopenia in a nationally representative sample and may serve as a baseline for comparison with other populations. Future research to identify risk factors for development of malignant hematological disorders among those with unexplained cytopenia is warranted.
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http://dx.doi.org/10.3389/fonc.2020.579075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714991PMC
November 2020

Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin.

Blood Adv 2020 11;4(22):5735-5744

Division of Hematology/Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.

Activation of the P53 pathway through inhibition of MDM2 using nutlins has shown clinical promise in the treatment of solid tumors and hematologic malignancies. There is concern, however, that nutlin therapy might stimulate the emergence or expansion of TP53-mutated subclones. We recently published the results of a phase 1 trial of idasanutlin in patients with polycythemia vera (PV) that revealed tolerability and clinical activity. Here, we present data indicating that idasanutlin therapy is associated with expansion of TP53 mutant subclones. End-of-study sequencing of patients found that 5 patients in this trial harbored 12 TP53 mutations; however, only 1 patient had been previously identified as having a TP53 mutation at baseline. To identify the origin of these mutations, further analysis of raw sequencing data of baseline samples was performed and revealed that a subset of these mutations was present at baseline and expanded during treatment with idasanutlin. Follow-up samples were obtained from 4 of 5 patients in this cohort, and we observed that after cessation of idasanutlin, the variant allele frequency (VAF) of 8 of 9 TP53 mutations decreased. Furthermore, disease progression to myelofibrosis or myeloproliferative neoplasm blast phase was not observed in any of these patients after 19- to 32-month observation. These data suggest that idasanutlin treatment may promote transient TP53 mutant clonal expansion. A larger study geared toward high-resolution detection of low VAF mutations is required to explore whether patients acquire de novo TP53 mutations after idasanutlin therapy.
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http://dx.doi.org/10.1182/bloodadvances.2020002379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686898PMC
November 2020

Plasma hemoglobin in COVID-19: authors' reply.

Ann Hematol 2021 08 6;100(8):2127. Epub 2020 Nov 6.

Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, ANN 24-61, 1468 Madison Ave, New York, NY, 10029, USA.

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http://dx.doi.org/10.1007/s00277-020-04335-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647886PMC
August 2021

Coombs-negative hemolytic anemia and elevated plasma hemoglobin levels in COVID-19.

Ann Hematol 2021 Mar 1;100(3):833-835. Epub 2020 Aug 1.

Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave, New York, NY, 10029, USA.

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http://dx.doi.org/10.1007/s00277-020-04202-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395213PMC
March 2021

The Myelodepletive Phenotype in Myelofibrosis: Clinical Relevance and Therapeutic Implication.

Clin Lymphoma Myeloma Leuk 2020 07 26;20(7):415-421. Epub 2020 Feb 26.

Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Myelofibrosis (MF) is a BCR-ABL1 myeloproliferative neoplasm that arises from hematopoietic stem and progenitor cells frequently harboring a somatic driver mutation in 1 of 3 genes: JAK2, CALR, or MPL. The pathologic features of this hematologic malignancy include myeloproliferation, diffuse bone marrow fibrosis, and overactivation of the JAK-STAT pathway, resulting in enhanced inflammatory cytokine release. The common clinical manifestations of MF include systemic symptoms, abnormal peripheral blood count levels, and splenomegaly. However, it has become increasingly appreciated that significant clinical heterogeneity exists among patients with MF. Two distinct MF clinical phenotypes include the myeloproliferative and myelodepletive phenotype, with peripheral blood counts being the main discerning feature. Patients with the myeloproliferative phenotype will present with elevated peripheral blood counts and often experience significant constitutional symptoms and progressive splenomegaly. In contrast, patients with the myelodepletive phenotype will have low peripheral blood counts and will frequently require transfusion support. Current frontline therapies for MF, include ruxolitinib and fedratinib, which can exacerbate cytopenias and thereby pose an impediment to effective treatment of the myelodepletive patient. The present review discusses the clinical and prognostic implications of the myelodepletive phenotype and the therapeutic options and limitations for this subset of patients, representing an unmet clinical need.
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http://dx.doi.org/10.1016/j.clml.2020.01.008DOI Listing
July 2020

SLAM dunk for myelofibrosis?

Blood 2019 09;134(10):789-791

Icahn School of Medicine at Mount Sinai.

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http://dx.doi.org/10.1182/blood.2019002119DOI Listing
September 2019

Management of advanced phase myeloproliferative neoplasms.

Clin Adv Hematol Oncol 2019 Jul;17(7):405-411

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

The BCR-ABL1-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, can evolve into a form of secondary acute myeloid leukemia termed MPN in blast phase (MPN-BP). MPN in accelerated phase (MPN-AP), which is defined by 10% to 19% myeloid blasts in the peripheral blood or bone marrow, is a precursor to MPN-BP. Alternative definitions of MPN-AP exist based on studies identifying clinical variables that portend a poor prognosis and high risk for progression to MPN-BP. Allogeneic hematopoietic stem cell transplant remains the only curative therapeutic option; however, advanced age and high comorbidity index preclude the majority of patients from receiving this treatment modality. This article reviews management considerations for the advanced-phase MPNs (MPN-AP and MPN-BP), with a special focus on MPN-AP, and highlights novel experimental therapies.
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July 2019

Myeloid Sarcoma of the Testis in Children: Clinicopathologic and Immunohistochemical Characteristics With KMT2A (MLL) Gene Rearrangement Correlation.

Appl Immunohistochem Mol Morphol 2020 08;28(7):501-507

Department of Pathology, University of Tennessee Health Science Center and Le Bonheur Children's Hospital, Memphis, TN.

Myeloid sarcoma (MS) is defined as an extramedullary mass-forming lesion composed of immature myeloid cells. It is a rare but well-known manifestation of acute myeloid leukemia. Pediatrics testicular MS may pose a possible diagnostic challenge, an issue that is underscored in the few testicular pediatric MS cases reported in the literature. Herein, we report a series of 5 cases of pediatric testicular MS that are evaluated at the morphologic and immunohistochemical levels with correlation with the KMT2A (MLL) rearrangement status. Three patients presented with no prior history of acute myeloid leukemia. All 5 cases showed monoblastic morphology; positive for CD33, CD43, CD68, CD163, CD4 (dim), and lysozyme; and negative for CD10, CD34, CD117, and myeloperoxidase. KMT2A (MLL) rearrangement was detected in 4 of the 5 cases. In the literature, 8 more cases of pediatric testicular lymphoma were reported. Most of them showed monocytic differentiation and KMT2A (MLL) rearrangement was reported in 3 of the cases. In conclusions, testicular MS in pediatric patients shows monoblastic differentiation which may be attributed to the KMT2A (MLL) rearrangement. We also highlight the importance of using an extended immunohistochemistry panel in the diagnosis of MS.
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http://dx.doi.org/10.1097/PAI.0000000000000783DOI Listing
August 2020

Acquired amegakaryocytic thrombocytopenia as a rare cause of thrombocytopenia during pregnancy.

BMJ Case Rep 2019 Jun 21;12(6). Epub 2019 Jun 21.

Hematology Oncology - BMT Department, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

A rare case of acquired amegakaryocytic thrombocytopenia (AATP) in a 35-year-old woman who presented with anaemia and thrombocytopenia at 22 weeks gestation. The first diagnostic impression was of an evolving aplastic anaemia; however, the patient was simultaneously diagnosed with severe vitamin B deficiency in the setting of vegetarianism. Once the cyanocobalamin deficiency was corrected, a repeat bone marrow biopsy revealed an isolated depletion of megakaryocytes, which suggested the diagnosis of AATP. Supportive care was provided for her anaemia and thrombocytopenia and she delivered a healthy baby girl with a normal platelet count. The patient was subsequently started on romiplostim with steady improvement in her platelet counts. This rare AATP case presentation highlights the importance of a well-structured diagnostic approach to thrombocytopenia during pregnancy and supports the successful use of thrombopoietin agonists for the management of AATP.
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http://dx.doi.org/10.1136/bcr-2019-230361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606057PMC
June 2019

A Novel t(1;9)(p36;p24.1) JAK2 Translocation and Review of the Literature.

Acta Haematol 2019 7;142(2):105-112. Epub 2019 May 7.

Departments of Medicine and Pathology, Tumor Cytogenomics, Icahn School of Medicine at Mount Sinai Hospital, New York, New York, USA,

The JAK2V617F point mutation has been implicated in the pathogenesis of the vast majority of myeloproliferative neoplasms (MPNs), but translocations involving JAK2 have increasingly been identified in patients with JAK2V617F-negativeMPNs. Here, we present a case of a patient diagnosed with JAK2V617F-negativepolycythemia vera (PV) that transformed to the MPN-blast phase. Cytogenetic and FISH analysis revealed a novel translocation of t(1;9)(p36;p24.1), causing a PEX14-JAK2 gene fusion product. The t(1;9)(p36;p24.1) represents a new addition to the list of known translocations involving JAK2that have been identified in hematologic malignancies. Although the prognostic and treatment implications of JAK2 translocations in MPNs have not been elucidated, positive outcomes have been described in case reports describing the use of JAK inhibitors in these patients. Further research into the role of JAK2 translocations in the pathogenesis and outcomes of hematologic malignancies is warranted.
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http://dx.doi.org/10.1159/000498945DOI Listing
February 2020

Eosinophilia in acute myeloid leukemia: Overlooked and underexamined.

Blood Rev 2019 07 30;36:23-31. Epub 2019 Mar 30.

Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY 10029, USA. Electronic address:

The presence of eosinophilia in acute myeloid leukemia (AML) suggests an underlying core binding factor (CBF) lesion, a platelet derived growth factor (PDGFR) translocation, or another rare translocation (such as ETV6-ABL1). Each of these cytogenetic entities carries unique diagnostic, prognostic, and therapeutic implications. CBF AML is most common and as such, its treatment is more clearly established, consisting of intensive induction chemotherapy followed by cytarabine based consolidation. Due in large part to its intrinsic chemo-sensitivity, CBF AML is associated with relatively high rates of remission and survival. PDGFR mediated AML is comparatively rare, and as such, diagnostic and treatment paradigms are not as well defined. Early identification of PDGFR translocations is essential, as they confer profound imatinib sensitivity which may, in many instances, spare the need for chemotherapy. Prompt recognition of such lesions requires a strong index of suspicion, and as such these diagnoses are often initially overlooked. Unfortunately, many cases of PDGFR associated AML, particularly those with other concurrent cytogenetic abnormalities, demonstrate treatment emergent imatinib resistance. Such patients continue to present a challenge, even with the advent of novel tyrosine kinase inhibitors (TKIs). Patients with rare translocations such as ETV6-ABL1 are not well described however seem to follow an aggressive clinical course, with limited response to imatinib, and poor outcomes. This review examines the significance of eosinophilia in the context of AML, with respect to its presentation, pathology, and cytogenetics, and with special attention to appropriate evaluation and treatment.
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http://dx.doi.org/10.1016/j.blre.2019.03.007DOI Listing
July 2019

A Rare Presentation of HIV-Negative Plasmablastic Lymphoma: A Diagnostic Dilemma.

Case Rep Hematol 2019 13;2019:2907317. Epub 2019 Feb 13.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Plasmablastic lymphoma (PBL) and plasmablastic plasma cell myeloma (PCM) have many overlapping characteristics. Clinical correlation can help make the distinction between the two entities. Human immunodeficiency virus- (HIV-) negative PBL is a rare disease, making the diagnosis more challenging. While there is no standard of care for PBL, current recommendations include dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), with or without bortezomib. We report an aggressive case of HIV-negative plasmablastic lymphoma and discuss the challenge in establishing a diagnosis. We review the literature regarding this disease and current recommendations for treatment.
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http://dx.doi.org/10.1155/2019/2907317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393929PMC
February 2019

Dietary Restriction and Glycolytic Inhibition Reduce Proteotoxicity and Extend Lifespan via NHR-49.

Curr Neurobiol 2018 Apr;9(1):1-7

Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029.

Mechanisms mediating protective effects of dietary restriction during aging are of great interest since activating such mechanisms protect against a wide range of age-related diseases. In mammals key metabolic responses to nutritional deprivation are mediated by the transcription factor PPAR-alpha, which is activated by free fatty acids and promotes lipid metabolism while inhibiting glucose metabolism. The gene appears to function similarly in Here we report that protective effects of dietary restriction and inhibition of glucose metabolism to increase lifespan wild-type and reduce toxicity in a polyQ model of Huntington's disease in are dependent on NHR-49 and its co-activator CREB-Binding Protein (CBP). We have previously demonstrated that inhibition of blocks protective effects of dietary restriction and blocks the molecular switch from glucose metabolism to alternative substrates. Conversely, increased glucose concentration and inhibition of reduce lifespan and increase proteotoxicity. Lactate and inhibition of ETC complex II mimicked toxic effects of glucose on proteotoxicity whereas pyruvate and inhibition of ETC complex I protected against glucose-enhanced proteotoxicity. These results support that PPAR-alpha-like activity mediates protective effects of dietary restriction by reducing glucose metabolism via reducing production of NADH, and corroborate and extend recent studies demonstrating that PPPAR-alpha agonists increase lifespan in dependent on NHR-49.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390974PMC
April 2018

Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53.

Blood Adv 2018 12;2(24):3581-3589

Tisch Cancer Institute, Division of Hematology/Oncology, and.

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (PMF), frequently progress to more overt forms of MF and a type of acute leukemia termed MPN-accelerated phase/blast phase (MPN-AP/BP). Recent evidence indicates that dysregulation of the tumor suppressor tumor protein p53 (TP53) commonly occurs in the MPNs. The proteins MDM2 and MDM4 alter the cellular levels of TP53. We investigated in 1,294 patients whether abnormalities involving chromosomes 1 and 12, which harbor the genes for and , respectively, and chromosome 17, where the gene for is located, are associated with MPN disease progression. Gain of 1q occurred not only in individuals with MPN-BP but also in patients with PV and ET, who, with further follow-up, eventually evolve to either MF and/or MPN-BP. These gains of 1q were most prevalent in patients with a history of PV and those who possessed the V617F driver mutation. The gains of 1q were accompanied by increased transcript levels of In contrast, 12q chromosomal abnormalities were exclusively detected in patients who presented with MF or MPN-BP, but were not accompanied by further increases in / transcript levels. Furthermore, all patients with a loss of 17p13, which leads to a deletion of , had either MF or MPN-AP/BP. These findings suggest that gain of 1q, as well as deletions of 17p, are associated with perturbations of the TP53 pathway, which contribute to MPN disease progression.
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http://dx.doi.org/10.1182/bloodadvances.2018024018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306879PMC
December 2018

Distinguishing autoimmune myelofibrosis from primary myelofibrosis.

Clin Adv Hematol Oncol 2018 Sep;16(9):619-626

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Bone marrow fibrosis (BMF) is a histologic finding in a wide range of diseases, including malignancies, endocrine disorders, autoimmune diseases, and infections. Autoimmune myelofibrosis (AIMF) is an uncommon etiology of BMF; it can be secondary to a defined autoimmune disease, or it can be primary in the absence of a clinically diagnosed autoimmune disease but the presence of serologic evidence of autoantibodies. Distinguishing between primary myelofibrosis (PMF) and non-neoplastic AIMF is of the utmost importance because the prognosis and therapeutic options are different. This distinction, however, can be complicated by overlapping findings in the 2 disease entities. Here, using the case of a patient with BMF in the setting of idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia, we present a systematic approach to distinguishing between PMF and AIMF.
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September 2018

Pharmacotherapy of Myelofibrosis.

Drugs 2017 Sep;77(14):1549-1563

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY, 10029, USA.

Myelofibrosis (MF) is a myeloproliferative neoplasm that is pathologically characterized by bone marrow myeloproliferation, reticulin and collagen fibrosis, and extramedullary hematopoiesis. Constitutive activation of the Janus associated kinase (JAK)-signal transducers and activators of transcription signaling pathway with resultant elevation in pro-inflammatory cytokine levels is the pathogenic hallmark of MF. JAK inhibitors, namely ruxolitinib, have been successful in alleviating symptoms and reducing splenomegaly, but therapy-related myelosuppression has led to the further development of highly selective JAK2 inhibitors. Additionally, ruxolitinib does not appear to affect the malignant hematopoietic clone substantially, evidenced by lack of molecular remissions, bone marrow histopathologic responses, and a proportion of treated patients developing progressive disease and leukemic transformation while receiving therapy. A number of other pharmacotherapeutic strategies are currently being explored in the clinic. Non-JAK inhibitor strategies being evaluated in MF include non-JAK signaling pathway inhibitors, epigenetic-directed therapies, immune-modulating agents, anti-fibrotic agents, and telomerase inhibitors. This review highlights the current landscape of MF pharmacotherapy and explores therapeutic advances underway.
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http://dx.doi.org/10.1007/s40265-017-0797-yDOI Listing
September 2017

Role of the hypothalamus in mediating protective effects of dietary restriction during aging.

Front Neuroendocrinol 2013 Apr 20;34(2):95-106. Epub 2012 Dec 20.

Department of Neurosciences and Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, United States.

Dietary restriction (DR) can extend lifespan and reduce disease burden across a wide range of animals and yeast but the mechanisms mediating these remarkably protective effects remain to be elucidated despite extensive efforts. Although it has generally been assumed that protective effects of DR are cell-autonomous, there is considerable evidence that many whole-body responses to nutritional state, including DR, are regulated by nutrient-sensing neurons. In this review, we explore the hypothesis that nutrient sensing neurons in the ventromedial hypothalamus hierarchically regulate the protective responses of dietary restriction. We describe multiple peripheral responses that are hierarchically regulated by the hypothalamus and we present evidence for non-cell autonomous signaling of dietary restriction gathered from a diverse range of models including invertebrates, mammalian cell culture, and rodent studies.
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http://dx.doi.org/10.1016/j.yfrne.2012.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3626742PMC
April 2013

Cell "self-eating" (autophagy) mechanism in Alzheimer's disease.

Mt Sinai J Med 2010 Jan-Feb;77(1):59-68

Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.

The autophagy pathway is the major degradation pathway of the cell for long-lived proteins and organelles. Dysfunction of autophagy has been linked to several neurodegenerative disorders that are associated with an accumulation of misfolded protein aggregates. Alzheimer's disease, the most common neurodegenerative disorder, is characterized by 2 aggregate forms, tau tangles and amyloid-beta plaques. Autophagy has been linked to Alzheimer's disease pathogenesis through its merger with the endosomal-lysosomal system, which has been shown to play a role in the formation of the latter amyloid-beta plaques. However, the precise role of autophagy in Alzheimer's disease pathogenesis is still under contention. One hypothesis is that aberrant autophagy induction results in an accumulation of autophagic vacuoles containing amyloid-beta and the components necessary for its generation, whereas other evidence points to impaired autophagic clearance or even an overall reduction in autophagic activity playing a role in Alzheimer's disease pathogenesis. In this review, we discuss the current evidence linking autophagy to Alzheimer's disease as well as the uncertainty over the exact role and level of autophagic regulation in the pathogenic mechanism of Alzheimer's disease.
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http://dx.doi.org/10.1002/msj.20161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835623PMC
April 2010

Alpha-N-acetylmannosamine (ManNAc) synthesis via rhodium(II)-catalyzed oxidative cyclization of glucal 3-carbamates.

J Org Chem 2005 May;70(10):3988-96

Department of Chemistry, Barnard College, 3009 Broadway, New York, New York 10027, USA.

[reaction: see text] Glucal 3-carbamates 1 and 7 underwent oxidative cyclization with iodobenzene diacetate or iodosobenzene in the presence of Rh2(OAc)4, providing mannosamine 2-N,3-O-oxazolidinones. With iodosobenzene, incorporation of 4-penten-1-ol provided a readily separable anomeric mixture of n-pentenyl glycosides, with the anomers exhibiting pronounced differences in reactivity as glycosyl donors. N-acylation of the sugar oxazolidinones led to alpha-selective glycosyl donors for the elaboration of various 2-mannosamine frameworks. Alternatively, the anomeric n-pentenyl glycosides of N-Cbz 2-mannosamine oxazolidinones were converted separately to oxazolidinone-opened derivatives 28alpha and 28beta. These served as stereoconvergent glycosyl donors, and the alpha-linked products were readily advanced to a variety of N-acetylmannosamine (ManNAc) frameworks, using an intramolecular O-->N acetyl transfer as the final step.
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http://dx.doi.org/10.1021/jo0500129DOI Listing
May 2005
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