Hemic and Lymphatic Diseases Commons^™

Mir-142: A Master Regulator In Hematological Malignancies And Therapeutic Opportunities, Wilson Huang, Doru Paul, George A Calin, Recep Bayraktar

Faculty, Staff and Student Publications

MicroRNAs (miRNAs) are a type of non-coding RNA whose dysregulation is frequently associated with the onset and progression of human cancers. miR-142, an ultra-conserved miRNA with both active -3p and -5p mature strands and wide-ranging physiological targets, has been the subject of countless studies over the years. Due to its preferential expression in hematopoietic cells, miR-142 has been found to be associated with numerous types of lymphomas and leukemias. This review elucidates the multifaceted role of miR-142 in human physiology, its influence on hematopoiesis and hematopoietic cells, and its intriguing involvement in exosome-mediated miR-142 transport. Moreover, we offer a comprehensive …

Impact Of Cumulative Dose Of Brentuximab Vedotin On Outcomes Of Frontline Therapy For Advanced-Stage Hodgkin Lymphoma, Raphael E Steiner, Steven R Hwang, Arushi Khurana, Thomas M Habermann, Narendranath Epperla, Kaitlin Annunzio, Pamela Blair Allen, Katelin Baird, Darina Paulino, Juan Pablo Alderuccio, Izidore S Lossos, Kevin David, Andrew M Evens, Karan Pandya, Steven M Bair, Manali Kamdar, Sheeba Ba Aqeel, Pallawi Torka, Ryan Lynch, Stephen Smith, Lei Feng, Mansoor Noorani, Sairah Ahmed, Ranjit Nair, Francisco Vega, Susan Wu, Penny Fang, Chelsea C Pinnix, Jillian R Gunther, Bouthaina S Dabaja, Hun J Lee

Faculty, Staff and Student Publications

In the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A + AVD) demonstrated superior efficacy compared with bleomycin + AVD for the treatment of advanced-stage classic Hodgkin lymphoma (cHL). However, there are minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 patients with stage III or IV cHL treated with frontline A + AVD from January 2010 to April 2022. Treatment consisted of up to 1.2 mg/kg of BV and …

Interlaboratory Comparison Of Pseudomonas Aeruginosa Phage Susceptibility Testing, Krupa Parmar, Lauren Komarow, Damon W Ellison, Andrey A Filippov, Mikeljon P Nikolich, Joseph R Fackler, Martin Lee, Anjna Nair, Priyesh Agrawal, Pranita D Tamma, Maria Souli, Scott R Evans, Kerryl E Greenwood-Quaintance, Scott A Cunningham, Robin Patel, Antibacterial Resistance Leadership Group

Faculty, Staff and Student Publications

Standardized approaches to phage susceptibility testing (PST) are essential to inform selection of phages for study in patients with bacterial infections. There is no reference standard for assessing bacterial susceptibility to phage. We compared agreement between PST performed at three centers: two centers using a liquid assay standardized between the sites with the third, a plaque assay. Four Pseudomonas aeruginosa phages: PaWRA01ø11 (EPa11), PaWRA01ø39 (EPa39), PaWRA02ø83 (EPa83), PaWRA02ø87 (EPa87), and a cocktail of all four phages were tested against 145 P. aeruginosa isolates. Comparisons were made within measurements at the two sites performing the liquid assay and between these …

Cytogenetic Profile In Monoclonal Gammopathy Of Undetermined Significance, Smoldering And Symptomatic Multiple Myeloma: A Study Of 1087 Patients With Highly Purified Plasma Cells, Guilin Tang, Yilin Wu, Pei Lin, Gokce A Toruner, Shimin Hu, Shaoying Li, Muzaffar H Qazilbash, Robert Z Orlowski, Christine Ye, Jie Xu, Karen A Nahmod, L Jeffrey Medeiros, Zhenya Tang

Faculty, Staff and Student Publications

The aim of this study was to examine the cytogenetic profiles of plasma cell neoplasms (PCNs) at various disease stages, encompassing 1087 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), newly diagnosed multiple myeloma (NDMM), and refractory/relapsed multiple myeloma (RRMM). Fluorescence in situ hybridization (FISH) analyses were conducted on highly purified plasma cell samples, revealing that 96% of patients exhibited at least one cytogenetic abnormality. The genomic complexity escalated from MGUS to SMM and further to NDMM and RRMM, largely driven by 1q gain, del(17p), MYC-rearrangement (MYC-R), del(1p), and tetraploidy. Elevated frequencies of …

Influence Of Treatment Intensity And Medical Comorbidities In Older Adults With Peripheral T Cell Lymphoma, Max J Gordon, Zhigang Duan, Hui Zhao, Loretta Nastoupil, Samuel Ng, Alexey V Danilov, Swaminathan Iyer, Sharon H Giordano

Faculty, Staff and Student Publications

We conducted a population-based study of patients >65 years, diagnosed 2008-2017, with peripheral T-cell lymphoma (PTCL) using SEER-Medicare. Associations between PTCL subtype, treatment regimen, comorbidity, and mortality were assessed using the Kaplan-Meier method and multivariable Cox regression. Amongst the 2,546 patients, the median age was 77 years (interquartile range, 71-83). 5-year overall survival (OS) ranged from 22.2% to 37.3% depending on PTCL subtype. The most common frontline regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). 5-year OS rate was 47.0% for patients treated with etoposide + CHOP (N = 67; CHOEP), 33.7% for those treated with CHOP (N …

Safety And Efficacy Of Direct Oral Anticoagulants In Stroke Prevention In Patients With Atrial Fibrillation Complicated With Anemia And/Or Thrombocytopenia: A Retrospective Cohort Study, Wenlin Xu, Jiana Chen, Shuyi Wu, Nianxu Huang, Xia Chen, Wang Zhang, Wei Hu, Jun Su, Hengfen Dai, Ping Gu, Xiaohong Huang, Xiaoming Du, Ruijuan Li, Qiaowei Zheng, Xiangsheng Lin, Yanxia Zhang, Lang Zou, Yuxin Liu, Min Zhang, Xiumei Liu, Zhu Zhu, Jinhua Zhang

Faculty, Staff and Student Publications

BACKGROUND: There are limited data about the clinical benefits and harm of direct oral anticoagulants (DOACs) in stroke prevention in patients with atrial fibrillation (AF) complicated with anemia or thrombocytopenia.

METHODS: This is a multi-center retrospective cohort study involving 5469 AF patients from 15 hospitals in China. Patients were divided into three groups according to hemoglobin and platelet levels: Group 1 (hemoglobin male ≥ 130 g/L; female ≥ 120 g/L and platelet ≥ 100 × 10

RESULTS: Higher hemoglobin levels were associated with a reduced risk of total bleeding and major bleeding, while platelet counts were not associated with any …

Pmca Screening Of Retropharyngeal Lymph Nodes In White-Tailed Deer And Comparisons With Elisa And Ihc, Rebeca Benavente, J Hunter Reed, Mitch Lockwood, Rodrigo Morales

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) is a prion disease affecting cervids. CWD diagnosis is conducted through enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) in retropharyngeal lymph nodes. Unfortunately, these techniques have limited sensitivity against the biomarker (CWD-prions). Two in vitro prion amplification techniques, real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), have shown promise in detecting CWD-prions in tissues and bodily fluids. Recent studies have demonstrated that RT-QuIC yields similar results compared to ELISA and IHC. Here, we analyzed 1003 retropharyngeal lymph nodes (RPLNs) from Texas white-tailed deer. PMCA detected CWD at a higher rate compared to ELISA/IHC, identified …

Dhodh: A Promising Target In The Treatment Of T-Cell Acute Lymphoblastic Leukemia, Amy N Sexauer, Gabriela Alexe, Karin Gustafsson, Elizabeth Zanetakos, Jelena Milosevic, Mary Ayres, Varsha Gandhi, Yana Pikman, Kimberly Stegmaier, David B Sykes

Faculty, Staff and Student Publications

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify dihydroorotate dehydrogenase (DHODH) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, …

Effects Of Covid-19 Vaccination On Pro-Coagulant State Of A Protein S-Deficient Pediatric Patient: New Hope For Treatment Of The Deficiency, Diana Polania-Villanueva, M. Kumar, Lekha Thangada, Jone Garai, Jovanny Zabaleta, Rinku Majumder

School of Medicine Faculty Publications

ISTH 2023 Congress, June 24 - 28, 2023, Montreal, Canada

Factors Associated With Thrombo-Hemorrhagic Deaths In Patients With Acute Promyelocytic Leukemia Treated With Arsenic Trioxide And All-Trans Retinoic Acid, C. Singh, U. Yanamandra, P. Karunakaran, N. Jindal, S. Kumar, N. Saini, A. Jandial, A. Jain, D. Lad, G. Prakash, A. Khadwal, S. Naseem, Narender Kumar, J. Ahluwalia, N. Varma, S. Varma, P. Malhotra

School of Medicine Faculty Publications

ISTH 2023 Congress, June 24 - 28, 2023, Montreal, Canada

Antiphosphatidylserine/Prothrombin Antibodies In Childhood Sle Are Associated With Lupus Anticoagulant Positivity, S. Chugh, R. Pilania, A. Kler, C. Hans, Narender Kumar, S. Singh, J. Ahluwalia

School of Medicine Faculty Publications

ISTH 2023 Congress, June 24 - 28, 2023, Montreal, Canada

Pb0550 Novel Variants Of Pros1 Gene Related To Protein S Deficiency, A. Malik, M. Kumar, V. Pereira, Jovanny Zabaleta, Rinku Majumder

School of Medicine Faculty Publications

ISTH 2023 Congress June 24-28, 2023, Montreal, Canada

Unearthing The Genotype-Inhibitor Phenotype Association In Severe Hemophilia A: A North Indian Cohort Study, D. Ray, Narender Kumar, C. Hans, A. Kler, R. Sharma, M. Jamwal, H. Kishan Sene, R. Thakur, M. Singh, P. Bhatia, D. Bansal, A. Jain, P. Malhotra, J. Ahluwalia, R. Das

School of Medicine Faculty Publications

ISTH 2023 Congress June 24-28, 2023, Montreal, Canada

Pb0559 Novel Variants Of Pros1 Gene Related To Protein S Deficiency, A. Malik, M. Kumar, Jovanny Zabaleta, Rinku Majumder

School of Medicine Faculty Publications

ISTH 2023 Congress June 24-28, 2023, Montreal, Canada

Pbo575 Novel Variants Of Pros1 Gene Related To Protein S Deficiency, A. Malik, Diana Polania-Villanueva, M. Kumar, Jone Garai, Jovanny Zabaleta, Rinku Majumder

School of Medicine Faculty Publications

ISTH 2023 Congress June 24-28, 2023, Montreal, Canada

Regulation Of Protein S Gene Expression By Hypoxia Inducible Factor 1 Α And Estrogen Receptor, Mohammad Mohammad, V. Pilli, M. Kumar, Alaina Guilbeau, Narender Kumar, Rinku Majumder

School of Medicine Faculty Publications

ISTH 2023 Congress June 24-28, 2023, Montreal, Canada

A Randomized Phase Iii Study Of Standard Versus High-Dose Cytarabine With Or Without Vorinostat For Aml, Guillermo Garcia-Manero, Nikolai A Podoltsev, Megan Othus, John M Pagel, Jerald P Radich, Min Fang, David A Rizzieri, Guido Marcucci, Stephen A Strickland, Mark R Litzow, M Lynn Savoie, Bruno C Medeiros, Mikkael A Sekeres, Tara L Lin, Geoffrey L Uy, Bayard L Powell, Jonathan E Kolitz, Richard A Larson, Richard M Stone, David Claxton, James Essell, Selina M Luger, Sanjay R Mohan, Anna Moseley, Frederick R Appelbaum, Harry P Erba

Faculty, Staff and Student Publications

Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 …

Discovery, Structure-Activity Relationship And In Vitro Anticancer Activity Of Small-Molecule Inhibitors Of The Protein-Protein Interactions Between Af9/Enl And Af4 Or Dot1l, Xin Li, Xiaowei Wu, Shenyou Nie, Jidong Zhao, Yuan Yao, Fangrui Wu, Chandra Bhushan Mishra, Md Ashraf-Uz-Zaman, Bala Krishna Moku, Yongcheng Song

Faculty, Staff and Students Publications

Simple Summary

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene generate potent fusion oncogenes and cause acute myeloid leukemia or lymphocytic leukemia, which account for ~75% infant and 5–10% child/adult acute leukemia cases with a poor prognosis (5-year survival rates < 45%). Protein–protein interactions between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are critical to malignant gene expression and are therefore a potential drug target for cancer. Compound screening followed by medicinal chemistry studies identified several novel small-molecule inhibitors showing strong inhibition of these protein–protein interactions, significant suppression of characteristic gene expression, and robust cellular anticancer activities with negligible cytotoxicity. These compounds are useful chemical probes for biological studies of these protein–protein interactions, as well as pharmacological leads for further drug development against MLL-rearranged and other leukemias.

Abstract

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene cause 5–10% acute leukemias with poor clinical outcomes. Protein–protein interactions (PPI) between the most frequent MLL fusion partner proteins AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Several benzothiophene-carboxamide compounds were identified as novel inhibitors of these PPIs with IC₅₀ values as …

Automated Large Vessel Occlusion Detection Software And Thrombectomy Treatment Times: A Cluster Randomized Clinical Trial, Juan Carlos Martinez-Gutierrez, Youngran Kim, Sergio Salazar-Marioni, Muhammad Bilal Tariq, Rania Abdelkhaleq, Arash Niktabe, Anjan N Ballekere, Ananya S Iyyangar, Mai Le, Hussain Azeem, Charles C Miller, Jon E Tyson, Sandi Shaw, Peri Smith, Mallory Cowan, Isabel Gonzales, Louise D Mccullough, Andrew D Barreto, Luca Giancardo, Sunil A Sheth

Faculty, Staff and Student Publications

Importance

The benefit of endovascular stroke therapy (EVT) in large vessel occlusion (LVO) ischemic stroke is highly time dependent. Process improvements to accelerate in-hospital workflows are critical.

Objective

To determine whether automated computed tomography (CT) angiogram interpretation coupled with secure group messaging can improve in-hospital EVT workflows.

Design, Setting, and Participants

This cluster randomized stepped-wedge clinical trial took place from January 1, 2021, through February 27, 2022, at 4 comprehensive stroke centers (CSCs) in the greater Houston, Texas, area. All 443 participants with LVO stroke who presented through the emergency department were treated with EVT at the 4 CSCs. Exclusion …

Comparison Of Progression-Free Survival Outcome Of Sentinel Node Biopsy Without Ultrastaging Versus Lymphadenectomy In Endometrial Cancer: A Propensity-Matched Analysis, Dahye Lee, Yoo-Na Kim, Sang Hyun Cho, Hye Soo Yoon, Young Tae Kim, Sunghoon Kim, Sang Wun Kim

Faculty, Staff and Student Publications

OBJECTIVE: We aimed to investigate the oncologic outcomes of patients with endometrial cancer who underwent sentinel lymph node (SLN) biopsy without ultrastaging compared with that of those who underwent lymphadenectomy (LND).

METHODS: Patients with endometrial cancer who underwent staging with SLN biopsy or LND during 2006 - 2021 were analyzed using propensity score matching (PSM). SLN metastasis was examined using hematoxylin and eosin staining, without ultrastaging. Progression-free survival (PFS) was compared between the two groups before and after PSM using age, histology, and stage as covariates. Clinical variables such as recurrence patterns and lymphatic complications, were assessed.

RESULTS: After excluding …

Geographic Disparity Of Outcome In Patients With Cancer Over Decades: The Surveillance, Epidemiology, And End Results, Koji Sasaki, Kiyomi Morita, Hagop Kantarjian, Guillermo Garcia-Manero, Elias Jabbour, Farhad Ravandi, Marina Konopleva, Gautam Borthakur, William Wierda, Naval Daver, Koichi Takahashi, Courtney Dinardo, Guillermo Montalban Bravo, Ghayas C Issa, Sherry A Pierce, Kelly A Soltysiak, Martha S Tingen, Jorge E Cortes

Faculty, Staff and Student Publications

Background: Improvements in prevention, early detection, and effective cancer therapy have decreased cancer-related mortality; however, significant health disparities exist. Therefore, we investigated the impact of these disparities on survival.

Methods: In the Surveillance, Epidemiology, and End Results, we identified 784,341 patients with cancer between 1990 and 2016 in Georgia, 68,493 between 1990 and 1999; 371,353 between 2000 and 2009; and 322,932 between 2010 and 2016. We assessed the overall survival (OS) of patients with all cancers, chronic myeloid leukemia (CML), and lung cancer, given the dramatic improvement in outcomes in patients with CML since 2000 compared to the generally considerably …

The Use Of Viatorr Stent At The Thoracic Outlet To Maintain Hemodialysis Access Function, Mohammad Ghasemi-Rad, Lauren Do, Michael Collard, Jai Cui, Zubin Irani

Faculty, Staff and Students Publications

PURPOSE: Venous steno-occlusive disease at the thoracic outlet affects up to 30% of the hemodialysis population [1] causing arm swelling and hemodialysis access dysfunction. Balloon angioplasty in this region can be of limited utility given the rigid compressive effect of surrounding musculoskeletal (MSK) structures. Outcomes of using the Viatorr endoprosthesis (Gore Viatorr TIPS Endoprosthesis, Gore, Flagstaff AR, USA, Viatorr ®) within this region to salvage the HD access in patients who presented with dialysis access dysfunction is presented.

METHODS: A retrospective chart review was performed of our tertiary and quaternary care hospital system. Hemodialysis patients were included in the study …

Prospective Clinical And Biomarker Validation Of The American Society For Transplantation And Cellular Therapy Consensus Definition For Transplantation-Associated Thrombotic Microangiopathy, Shengling Ma, Saleh Bhar, Danielle Guffey, Rock Bum Kim, Mahrukh Jamil, Christopher I Amos, Stephanie J Lee, Sangeeta R Hingorani, Sarah E Sartain, Ang Li

Faculty, Staff and Students Publications

Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications after allogeneic hematopoietic cell transplantation (allo-HCT). Diagnosing TA-TMA is challenging because of the lack of standardized criteria. In this study, we aimed to evaluate the new TA-TMA consensus definition from the American Society for Transplantation and Cellular Therapy (ASTCT) panel as part of an ongoing prospective pediatric cohort study, and also to compare the impact and outcomes of using the current definition of clinical TMA (cTMA) versus the new consensus definition. We included patients age 0 to 18 years who underwent their first allo-HCT between May 2021 and January …

Market Competition And Anemia Management In The United States Following Dialysis Payment Reform, Anshul Bhatnagar, Vishnupriyadevi Parvathareddy, Wolfgang C Winkelmayer, Glenn M Chertow, Kevin F Erickson

Faculty, Staff and Students Publications

BACKGROUND: Whether market competition influences health care provider responses to national reimbursement reforms is unknown.

OBJECTIVES: We examined whether changes in anemia management after the expansion of Medicare's dialysis payment bundle varied with market competition.

RESEARCH DESIGN: With data from the US dialysis registry, we used a difference-in-differences (DID) design to estimate the independent associations of market competition with changes in anemia management after dialysis reimbursement reform.

SUBJECTS: A total of 326,150 patients underwent in-center hemodialysis in 2009 and 2012, representing periods before and after reimbursement reform.

MEASURES: Outcomes were erythropoiesis-stimulating agent (ESA) and intravenous iron dosage, the probability of …

Stigma And Patient-Controlled Analgesia: Trust Is The Essential Ingredient Of Successful Patient Education In The Patient-Doctor Relationship, Trey D. Vanaken

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Van Beers EJ, Van Tuijn CFJ, Nieuwkerk PT, et al. Patient-controlled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in sickle cell disease, a randomized controlled trial. Am J Hematol. 2007;82(11):955-960. https://doi.org/10.1002/ajh.20944.

for a patient with recurrent vaso-occlusive crisis secondary to Sickle Cell Disease.

Hepatitis B Virus And B-Cell Lymphoma: Evidence, Unmet Need, Clinical Impact, And Opportunities, Maya Rosenberg, Maria Poluch, Colin Thomas, Paola Sindaco, Alan Khoo, Pierluigi Porcu

Kimmel Cancer Center Faculty Papers

Nearly a billion people worldwide are infected with the hepatitis B Virus (HBV) and about a third of them have chronic infection. HBV is an important cause of morbidity and mortality, including acute and chronic hepatitis and hepatocellular carcinoma (HCC). Screening and control of primary HBV infection through vaccination represent a major advance in global public health, but large sections of the world population, in both developed and underdeveloped countries, remain unscreened and unvaccinated. In addition to being a global cause of liver disease, an important role of HBV in lymphoma has also emerged. First, the high risk of HBV …

Impairment Of Serine Transport Across The Blood-Brain Barrier By Deletion Of Slc38a5 Causes Developmental Delay And Motor Dysfunction, Inna Radzishevsky, Maali Odeh, Oded Bodner, Salman Zubedat, Lihi Shaulov, Maxim Litvak, Kayoko Esaki, Takeo Yoshikawa, Bella Agranovich, Wen-Hong Li, Alex Radzishevsky, Eyal Gottlieb, Avi Avital, Herman Wolosker

Faculty, Staff and Student Publications

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. …

Immune-Depleted Tumor Microenvironment Is Associated With Poor Outcomes And Btk Inhibitor Resistance In Mantle Cell Lymphoma, Preetesh Jain, Krystle Nomie, Nikita Kotlov, Vitaiy Segodin, Holly Hill, Chi Young Ok, Ahmed Fetooh, Rashmi Kanagal-Shamanna, Francisco Vega, Alexander Bagaev, Nathan Fowler, Christopher R Flowers, Michael Wang

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is a generally aggressive B cell non-Hodgkin lymphoma (B-NHL). Outcomes of patients have improved in the era of Bruton’s tyrosine kinase inhibitors (BTKi). However, MCL patients can develop resistance to BTKi over time and can progress [1]. Ibrutinib resistance in MCL is correlated with an overexpression of OXPHOS, MYC and PI3K/AKT/m-TOR pathways. Somatic mutations in TP53, KMT2D, NSD2, SMARCA4, CCND1, TRAF2, NFKBIE genes are reported with ibrutinib resistance [2]. A few reports have also demonstrated that a decrease in T cell numbers [3, 4] or a downregulation of effector/cytotoxic …

Opposing Roles For The Α Isoform Of The Catalytic Subunit Of Protein Phosphatase 1 In Inside-Out And Outside-In Integrin Signaling In Murine Platelets, Tanvir Khatlani, Subhashree Pradhan, Kimberly Langlois, Deepika Subramanyam, Rolando E Rumbaut, K Vinod Vijayan

Faculty, Staff and Students Publications

Platelet activation during hemostasis and thrombosis is facilitated by agonist-induced inside–out and integrin αIIbβ3-initiated outside–in signaling via protein kinases and phosphatases. Pharmacological inhibitor studies suggest that the serine/threonine protein phosphatase 1 (PP1) promotes platelet activation. However, since phosphatase inhibitors block all the isoforms of the catalytic subunit of PP1 (PP1c), the role of specific PP1c isoform in platelet signaling remains unclear. Here, we employed a platelet-specific PP1cα−/− mice to explore the contribution of a major PP1 isoform in platelet functions. Loss of PP1cα moderately decreased activation of integrin αIIbβ3, binding of soluble fibrinogen, and aggregation to low-dose thrombin, ADP, and …

Multiphoton In Vivo Microscopy Of Embryonic Thrombopoiesis Reveals The Generation Of Platelets Through Budding, Huan Liu, Hellen Ishikawa-Ankerhold, Julia Winterhalter, Michael Lorenz, Mykhailo Vladymyrov, Steffen Massberg, Christian Schulz, Mathias Orban

Faculty, Staff and Student Publications

Platelets are generated by specialized cells called megakaryocytes (MKs). However, MK's origin and platelet release mode have remained incompletely understood. Here, we established direct visualization of embryonic thrombopoiesis in vivo by combining multiphoton intravital microscopy (MP-IVM) with a fluorescence switch reporter mouse model under control of the platelet factor 4 promoter (Pf4CreRosa26mTmG). Using this microscopy tool, we discovered that fetal liver MKs provide higher thrombopoietic activity than yolk sac MKs. Mechanistically, fetal platelets were released from MKs either by membrane buds or the formation of proplatelets, with the former constituting the key process. In E14.5 c-Myb-deficient …