Hemic and Lymphatic Diseases Commons^™

The Heme-Regulated Inhibitor Pathway Modulates Susceptibility Of Poor Prognosis B-Lineage Acute Leukemia To Bh3-Mimetics, Kaitlyn Hill Smith

Theses and Dissertations (ETD)

Anti-apoptotic MCL1 is one of the most frequently amplified genes in human cancers and its elevated expression confers resistance to many therapeutics including the BH3-mimetic agents ABT-199 and ABT-263. The anti-malarial, dihydroartemisinin (DHA) translationally represses MCL-1 and synergizes with BH3-mimetics. To explore how DHA represses MCL-1, a genome-wide CRISPR screen identified that loss of genes in the heme synthesis pathway renders mouse BCR-ABL+ B-ALL cells resistant to DHA-induced death. Mechanistically, DHA disrupts the interaction between heme and the eIF2α kinase heme regulated inhibitor (HRI) triggering the integrated stress response. Genetic ablation of Eif2ak1, which encodes HRI, blocks MCL-1 repression in ...

Lung Epithelial Cell Transcriptional Regulation As A Factor In Covid-19 Associated Coagulopathies, Ethan S. Fitzgerald, Yongzhi Chen, Katherine A. Fitzgerald, Amanda M. Jamieson

COVID-19 Publications by UMMS Authors

SARS-CoV-2 has rapidly become a global pandemic. In addition to the acute pulmonary symptoms of COVID-19 (the disease associated with SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients. Currently, the molecular pathogenesis underlying COVID-19 associated coagulopathies are unknown. Identifying the molecular basis of how SARS-CoV-2 drives coagulation is essential to mitigating short and long term thrombotic risks of sick and recovered COVID-19 patients. We aimed to perform coagulation focused transcriptome analysis of in vitro infected primary respiratory epithelial cells, patient derived bronchial alveolar lavage (BALF) cells, and circulating immune cells during SARS-CoV-2 infection. Our ...

Cohesin Mutations Alter Dna Damage Repair And Chromatin Structure And Create Therapeutic Vulnerabilities In Mds/Aml, Zuzana Tothova, Anne-Laure Valton, Sergey V. Venev, Job Dekker, Benjamin L. Ebert

Open Access Publications by UMMS Authors

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2-mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven ...

Efficacy Of The Nutritional Supplement, Evenflo, In The Management Of Sickle Cell Disease: A Randomized Controlled Trial, Richard Muga, Arthur Ajwang, James Ouma, Josephine Ojigo, Juliana Otieno, Peter Okoth, Caroline Wafula, Sophia Ajwang, David Ogolla, Abraham Hollist, James Adefisoye

Nursing & Health Sciences Research Journal

Background: In this study, we investigated if a combination of the nutraceutical supplement, EvenFlo and folic acid will be superior to the standard stand-alone use of folic acid.

Methods: We conducted a randomized double-blind, active-controlled, clinical trial. A total of 70 subjects with SCD ages 5-12 years were enrolled into the study with 35 in the intervention group and 35 in the control group; 61 completed the trial (32 from the intervention group and 29 from the control group).

Results: Participants in the intervention group were significantly less likely to experience crises compared to subjects in the control group. None ...

A Deep Learning Diagnostic Platform For Diffuse Large B-Cell Lymphoma With High Accuracy Across Multiple Hospitals, Dongguang Li, Jacob R. Bledsoe, Yu Zeng, Wei Liu, Yiguo Hu, Ke Bi, Aibin Liang, Shaoguang Li

Open Access Publications by UMMS Authors

Diagnostic histopathology is a gold standard for diagnosing hematopoietic malignancies. Pathologic diagnosis requires labor-intensive reading of a large number of tissue slides with high diagnostic accuracy equal or close to 100 percent to guide treatment options, but this requirement is difficult to meet. Although artificial intelligence (AI) helps to reduce the labor of reading pathologic slides, diagnostic accuracy has not reached a clinically usable level. Establishment of an AI model often demands big datasets and an ability to handle large variations in sample preparation and image collection. Here, we establish a highly accurate deep learning platform, consisting of multiple convolutional ...

Single-Cell Profiling Of Tuberculosis Lung Granulomas Reveals Functional Lymphocyte Signatures Of Bacterial Control [Preprint], Hannah P. Gideon, Samuel M. Behar, Alex Shalek

University of Massachusetts Medical School Faculty Publications

In humans and nonhuman primates, Mycobacterium tuberculosis lung infection yields a complex multicellular structure—the tuberculosis granuloma. All granulomas are not equivalent, however, even within the same host: in some, local immune activity promotes bacterial clearance, while in others, it allows persistence or outgrowth. Here, we used single-cell RNA-sequencing to define holistically cellular responses associated with control in cynomolgus macaques. Granulomas that facilitated bacterial killing contained significantly higher proportions of CD4+ and CD8+ T cells expressing hybrid Type1-Type17 immune responses or stem-like features and CD8-enriched T cells with specific cytotoxic functions; failure to control correlated with mast cell, plasma ...

Comparison Of Outcomes Of Hct In Blast Phase Of Bcr-Abl1- Mpn With De Novo Aml And With Aml Following Mds, Vikas Gupta, Jan Cerny

Open Access Publications by UMMS Authors

Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1- myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with ...

Changes In Selected Haematological Parameters Associated With Jak1/Jak2 Inhibition Observed In Patients With Rheumatoid Arthritis Treated With Baricitinib, Jonathan Kay, Masayoshi Harigai, Josh Rancourt, Christina Dickson, Thomas Melby, Maher Issa, Inmaculada De La Torre, Yoshitaka Isaka, Anabela Cardoso, Chadi Saifan, Edward C. Keystone, Ronald F. Van Vollenhoven, Jon T. Giles, Tom Wj. Huizinga, Joel M. Kremer

Open Access Publications by UMMS Authors

OBJECTIVE: To characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.

METHODS: Data were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492).

RESULTS: Mean absolute neutrophil counts decreased (-1.36x10(9)/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period ...

The Relationship Between Physical Activity And Lymphoma: A Systematic Review And Meta Analysis, Gwynivere A. Davies, Christopher Strader, Richa Chibbar, Stefania Papatheodorou, Adam A. Dmytriw

Open Access Publications by UMMS Authors

BACKGROUND: The literature suggests an increased risk between anthropometrics including higher body mass index and lymphoma incidence; however, the association with physical activity remains unclear. A systematic review/meta-analysis was therefore performed to examine this association with physical activity (total, recreational or occupational).

METHODS: PubMed, Web of Science and Embase were reviewed from inception to October 2019 identifying relevant observational studies. Non-Hodgkin lymphoma (NHL) including subtypes diffuse large B cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, and Hodgkin lymphoma (HL) were analyzed. Included studies reported activity, lymphoma cases, effect size and variability measures, and were restricted ...

Therapeutic Inhibition Of Fcgammariib Signaling Targets Leukemic Stem Cells In Chronic Myeloid Leukemia, Oliver Parting, Samantha Langer, Maja Kim Kuepper, Caroline Wessling, Shaoguang Li, Till Braunschweig, Nicolas Chatain, Tiago Maie, Ivan G. Costa, Martina Crysandt, Michael Huber, Tim H. Brummendorf, Steffen Koschmieder, Mirle Schemionek

Open Access Publications by UMMS Authors

Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcgammaRIIb, CD32b) for being critical in LSC resistance and show that targeting FcgammaRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcgammaRIIb upregulation in primary CML ...

Bcl11a Enhancer Edited Hematopoietic Stem Cells Persist In Rhesus Monkeys Without Toxicity, Selami Demirci, Jing Zeng, Yuxuan Wu, Naoya Uchida, Anne H. Shen, Danilo Pellin, Jackson Gamer, Morgan Yapundich, Claire Drysdale, Jasmine Bonanno, Aylin C. Bonifacino, Allen Krouse, Nathaniel Seth. Linde, Theresa Engels, Robert E. Donahue, Juan J. Haro-Mora, Alexis Leonard, Tina Nassehi, Kevin Luk, Shaina N. Porter, Cicera R. Lazzarotto, Shengdar Q. Tsai, Mitchell Weiss, Shondra M. Pruett-Miller, Scot A. Wolfe, Daniel E. Bauer, John F. Tisdale

Open Access Publications by UMMS Authors

Gene editing of the erythroid-specific BCL11A enhancer in hematopoietic stem and progenitor cells (HSPCs) from sickle cell disease (SCD) patients induces fetal hemoglobin (HbF) without detectable toxicity as assessed by mouse xenotransplant. Here, we evaluated autologous engraftment and HbF induction potential of erythroid-specific BCL11A enhancer edited HSPCs in four non-human primates. We utilized a single guide RNA (sgRNA) with identical human and rhesus target sequences to disrupt a GATA1 binding site at the BCL11A +58 erythroid enhancer. Cas9 protein and sgRNA ribonucleoprotein complex (RNP) was electroporated into rhesus HSPCs, followed by autologous infusion after myeloablation. We found that gene edits ...

Investigation Of A Peculiar Case Of Childhood Lymphadenopathy, Chade Aribo, Alonso Al, Allison Woodall, Tommy Y. Kim

HCA Healthcare Journal of Medicine

Introduction: Lymphadenopathy is a common physical finding often associated with an infectious etiology. We present a case of a patient with generalized cervical and supraclavicular lymphadenopathy diagnosed with a rare malignancy. Health care providers should be aware of some uncommon historical or physical examination findings that warrant further investigation.

Clinical Findings: A 16-year-old female presented to the emergency department with 3 days of a fever, congestion and sore throat with swelling around the jaw. Her physical examination findings included bilateral mandibular swelling and generalized cervical lymphadenopathy with palpable supraclavicular lymph nodes.

Outcomes: Complete blood count showed pancytopenia with a white ...

Epstein-Barr Virus Genomes Reveal Population Structure And Type 1 Association With Endemic Burkitt Lymphoma, Yasin Kaymaz, Cliff I. Oduor, Ozkan Aydemir, Micah A. Luftig, Juliana A. Otieno, John Michael. Ong'echa, Jeffrey A. Bailey, Ann M. Moormann

UMass Center for Clinical and Translational Science Supported Publications

Endemic Burkitt lymphoma (eBL), the most prevalent pediatric cancer in sub-Saharan Africa, is distinguished by its inclusion of Epstein-Barr virus (EBV). In order to better understand the impact of EBV variation in eBL tumorigenesis, we improved viral DNA enrichment methods and generated a total of 98 new EBV genomes from both eBL cases (n = 58) and healthy controls (n = 40) residing in the same geographic region in Kenya. Using our unbiased methods, we found that EBV type 1 was significantly more prevalent in eBL patients (74.5%) than in healthy children (47.5%) (odds ratio = 3.24, 95% confidence interval ...

Reduced Intensity Conditioning For Acute Myeloid Leukemia Using Melphalan- Vs Busulfan-Based Regimens: A Cibmtr Report, Zheng Zhou, Jan Cerny

Open Access Publications by UMMS Authors

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD ...

Medical Resource Use And Costs Of Treating Sickle Cell-Related Vaso-Occlusive Crisis Episodes: A Retrospective Claims Study, Nirmish Shah, Menaka Bhor, Lin Xie, Jincy Paulose, Huseyin Yuce

Publications and Research

Background: The study investigated the economic burden of vaso-occlusive crisis (VOC) among sickle cell disease (SCD) patients, through assessment of overall utilization and costs and costs per VOC episode (regarding the number of VOC episodes and health care setting, respectively).

Methods: Using the Medicaid Analytic Extracts database, the first SCD-related diagnosis claim (index claim) between June 1, 2009–December 31, 2012 was identified among eligible adults. Patients were required to have continuous medical and pharmacy benefits for 6 months pre- and 12 months post-index. Discrete VOC claims identified within a 3-day gap were combined as a single VOC episode. Annual ...

Cancer Pain And The Risks Of Opioid Abuse, Yarelis Diaz

College of Pharmacy Student Articles

No abstract provided.

Effectiveness Of Aerobic Exercise For Adults With Leukemia, Jalin Davis, Summer Hood, Alex Miller, Sam Stein, Kaylee Stem

Master of Occupational Therapy Student Critically Appraised Topics

We wanted to look at the most effective interventions for increasing strength and endurance in clients with Leukemia experiencing functional decline.

Survival Following Allogeneic Transplant In Patients With Myelofibrosis, Krisstina Gowin, Jan Cerny

Open Access Publications by UMMS Authors

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P < .0001; DIPSS-Int-2 and higher: HR, 0.39, P < .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P < .0001; DIPSS-Int-2 and higher: HR, 2.55, P < .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.

Covid-19 Pandemic And Impact On Hematopoietic Stem Cell Transplantation, Kamal Kant Sahu, Ahmad Daniyal Siddiqui, Jan Cerny

COVID-19 Publications by UMMS Authors

Currently, the world is witnessing a health crisis in the form of COVID-19 pandemic. For oncologists, especially for stem cell transplant specialists, the stress is high to perform to their best of capability for their cancer patients. In general, the hematopoietic stem cell transplantation (HSCT) is a high-risk procedure. The novelty of the COVID-19 disease, lack of literature, absence of antiviral agent, and vaccine has added more uncertainty while preparing for and recovering from HSCT.

Heterogeneous Nuclear Ribonucleoprotein K (Hnrnp K) Overexpression And Its Interaction With Runx1 Rna In Acute Myeloid Leukemia, Marisa Aitken

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Acute myeloid leukemia (AML) is an often devastating hematologic malignancy with 5-year overall survival lingering near 20%. Acquiring a deeper understanding of molecular underpinnings of leukemogenesis will provide a basis for developing more effective therapeutic strategies for patients with AML.

Here, we identified overexpression of hnRNP K as a recurrent abnormality in a subset (~20%) of AML patients. High levels of this RNA-binding protein associated with inferior clinical outcomes in de novo AML. Thus, to evaluate its putative oncogenic capacity in myeloid disease, we overexpressed hnRNP K in murine hematopoietic stem and progenitor cells isolated from fetal liver cells (FLCs ...