tbuckley/cabot-search huggingface dataset:
Is HBV RNA a valid marker for predicting sustained viral response for nucleoside analogue cessation?
Authors: Babu Lal Meena, Madhumita Premkumar, Akash Roy, Virendra Singh
Journal: Gut (2020)

We read with great interest the recent article by Seto et al in which the authors aimed to explore the feasibility and potential role of HBV RNA, hepatitis B core-related antigen (HBcrAg) and quantitative hepatitis B surface antigen (HBsAg) in identifying Asian patients with chronic hepatitis B suitable for the cessation of treatment.1 The study is well designed, and the results offer insight into the treatment in hepatitis B. However, certain key issues need to be highlighted.

The virological relapse was 36.6%, even if HBV RNA was not detected. This is in discordance to Fan et al , who suggested a lower virological relapse (8%) in patients who are HBV RNA negative versus higher relapse rates if RNA was positive (33.3%).2 The current study does not have clear validation for using …
Development of <i>TP53</i> Mutations over the Course of Acute Myeloid Leukemia Therapy
Authors: Yasmin Alwash, Rashmi Kanagal-Shamanna, Veronica A Guerra, Naval Daver, Marina Konopleva, Farhad Ravandi, Tapan M. Kadia, Courtney D. DiNardo, Ghayas C. Issa, Gautam Borthakur, Sanam Loghavi, Koichi Takahashi, Musa Yilmaz, Abhishek Maiti, Hagop M. Kantarjian, Steven M. Kornblau, Nicholas J. Short
Journal: Blood (2020)
Naïve Helper T-Cell and Regulatory T- and NK-Cell Subsets Are Associated with Pediatric Chronic Graft-Versus-Host Disease: Results of the ABLE / PBMTC 1202 Study
Authors: Geoff D.E. Cuvelier, Amina Kariminia, Eneida R. Nemecek, Carrie Kitko, Justin T. Wahlstrom, Andrew C Harris, Henrique Bittencourt, Victor A. Lewis, Michael A Pulsipher, Tal Schechter-Finkelstein, Sung W. Choi, Emi Caywood, Monica Bhatia, Kimberly A. Kasow, David Jacobsohn, Benjamin Oshrine, Sonali Chaudhury, Joseph H. Chewning, Flower Allyson, Don W. Coulter, Michael J. Joyce, Sureyya Savasan, Anna Pawlowska, Gail Megason, David Mitchell, Alexandra Cheerva, Anita Lawitschka, Bernard Ng, Kirk R. Schultz
Journal: Blood (2020)
Abstract 516: Homotypic Fusion Can Generate Bi- and Multi-nucleated Cardiomyocytes in the Postnatal Murine Heart
Authors: Shah R Ali, Ivan Menendez-Montes, Jane Warshaw, Feng Xiao, Hesham A Sadek
Journal: Circulation Research (2020)

Multinucleation is an important and prominent phenotype of postnatal mammalian cardiomyocytes, and its occurrence in early life correlates with the loss of regenerative potential in mice. This phenomenon is believed to be the result of mitosis followed by cytokinesis failure, although direct proof of this mechanism has not been provided for every single adult cardiomyocyte. Moreover, many multi-nucleated cells in other organs are formed after homotypic cell fusion. Although heterotypic cell fusion between cardiomyocytes and circulating cells has been described as a rare event, it is not known whether homotypic myocyte fusion occurs and if it can lead to bi- and multi-nucleation. We developed a novel mouse model wherein multi-color fluorescent protein reporter expression occurs stochastically only in cardiomyocytes (Myh6-MerCreMer;Rosa26-Confetti). Using pulse-chase experiments during development and at birth, we show that a small fraction of cardiomyocytes fuses with other myocytes to generate binucleated and multinucleated cells; we calculate a fusion rate of at least 2%, although this reflects the lower limit of the phenomenon due to technical limitations of our model. We reveal that this process occurs in the first week of life and is stable at one month of age. Our findings suggest a revision of the dogma in postnatal cardiac development by providing another mechanism for multinucleation of cardiomyocytes. Future experiments will address whether fusion is a reversible process and whether fused myocytes can undergo abscission in response to physiological or pathological cues.
Malignant transformation of wild type but not plasminogen activator inhibitor-1 gene deficient fibroblasts decreases cellular sensitivity to chemotherapy mediated apoptosis
Authors: Ulrik A. Lademann, Maria U. Romer, Nils Brünner, Peter B. Jensen, Kenneth F. Hofland, I. B. J. Christensen
Journal: Cancer Research (2005)

828  Plasminogen Activator Inhibitor-1, PAI-1, inhibits the activation of the plasminogen activator system, which is involved in cancer growth and dissemination. Increased tumor tissue levels of PAI-1 would therefore be expected to inhibit cancer cell progression. However, PAI-1 is elevated in many solid tumors and this elevation has consistently been shown to associate with shorter patient survival. In the present study we asked the question whether PAI-1 contributes to cancer cell growth by inhibiting apoptosis of tumor cells. To test this, we established fibrosarcoma cell lines from primary lung fibroblast cultures derived from PAI-1 gene-deficient and wild-type mice. We demonstrate that spontaneous transformation decreased cellular sensitivity to chemotherapy- mediated apoptosis of wild type, but not PAI-1 gene deficient fibrosarcomas. Interestingly, PAI-1 gene-deficient and wild type mice displayed similar sensitivity to treatment with etoposide, measured by weight loss and white blood cell counts, suggesting a differential effect of PAI-1 expression between cancer cells and normal cells. Thus, since PAI-1 appears to be an important factor in regulating apoptosis of cancer cells but not in normal cells, inhibitors of PAI-1 might by useful as sensitising pre-treatment to subsequent apoptosis-inducing anti-cancer therapy.
Abstract 216: Establishing an Integrated Platform to Validate Genetic Targets Associated With Atrial Remodeling
Authors: Yen-Sin Ang, John Yu, Ning Li, Joan Ndungu, Sridharan Rajamani
Journal: Circulation Research (2020)

Atrial fibrillation (AF)–the most common form of arrhythmia in the general population– is a grievous illness and a public health concern of global and epidemic scale. Current pharmacological therapies targeting ion channels or β-receptors are only partially effective and often fail to reduce AF burdens or mortality. We hypothesized that structural atrial remodeling, in addition to electrical remodeling, are key drivers of AF initiation and progression. In order to discover unrecognized drivers of AF mechanisms and reduce attrition rates in drug development, we employed Genome-Wide Association Studies (GWAS) to identify novel targets with human genetic validation. Meta-analyses of multi-ethnic patient cohorts reported 134 genetic loci, and therefore hundreds of coding variants, that are associated with AF. Atrial-specific cardiomyocytes (aCMs) differentiated from induced pluripotent stem cells (iPSCs) offer a human-relevant model system to study atrial remodeling. We combined aCMs with phenotyping platforms like Multi-Electrode Array (MEA) and Traction Force Microscopy (TFM), to evaluate whether unknown genes play a role in either cardiac conductance and/or contraction. We first devised a multi-factorial computational ranking algorithm based on WASPAS to select 50 out of 187 protein-coding targets. Next, we performed a focused loss-of-function phenotypic screen in aCMs to determine their requirement for atrial myocyte function. This resulted in the prioritization of six high value targets with diverse roles in Rho signaling, cell migration, ER stress response and integrin signaling. We also developed efficient CRISPR/Cas9 gene editing of GWAS variants as well as gain-of-function methods in aCMs. The completion of this project will establish an integrated platform for the functional validation of human genetic targets emerging from population studies associated with atrial remodeling.
Abstract 302: IL4Ra is Required for Cardiomyocyte Cell Cycle Activity and Cardiac Regeneration
Authors: Samantha J Paddock, Victor Alencar, Dylan J Wodsedalek, Caitlin Omeara
Journal: Circulation Research (2020)

Introduction: During the first week of life, neonatal mice are able to regenerate their hearts after injury with minimal scarring. Work from our lab demonstrates that IL13 signaling is required for neonatal heart regeneration, however multiple IL13 receptors exist. Here, we aim to identify the specific receptor ligand interaction that promotes regenerative healing in the heart. In vitro data suggests the IL4Ra/IL3Ra1 receptor heterodimer may mediate cardiomyocyte (CM) proliferation and heart regeneration. Thus, we aim to test the functional role of this receptor in cardiac regeneration in vivo . We hypothesize that IL13 signals through IL4Ra/IL13Ra1 directly on CMs to promote CM cell cycle activity and cardiac regeneration. Methods: To delineate IL13 signaling mechanisms in murine hearts, we utilized two knockouts of IL4Ra—global IL4Ra knockout (KO) and CM-specific IL4Ra knockout (IL4Ra fl/fl Myh6 CRE ) mice. To assess regeneration, mice received cardiac apical resection surgery at postnatal day 1 (P1). Regeneration was assessed by echocardiography and histological analysis of residual scars and CM proliferation indices. We next tested if IL13 administration could extend the regenerative window. We performed myocardial infarction (MI) on P7 mice and administered IL13 for two weeks. We assessed scar size through trichrome staining and CM cell cycle activity through immunostaining. Results: We observed impaired cardiac regeneration, determined by scar formation and decreased cardiac function in IL4Ra KO mice compared to littermate controls. Similar to global KOs, we observed decreased function in IL4Ra fl/fl Myh6 CRE mice. IL13 administration to wildtype mice after P7 MI decreased MI severity and increased CM cell cycle activity, suggesting improved reparative capacity. Interestingly, IL13 administration in IL4Ra fl/fl Myh6 CRE mice did not improve cardiac recovery phenotypes indicating that IL13 functions through IL4Ra directly on CMs to promote cardiac healing. Conclusion: These results demonstrate that the IL4Ra receptor subunit is required for cardiac regeneration, and activation of this receptor can extend the regenerative window. These findings lay the groundwork for potential therapeutic targets for promoting cardiac healing.
Effect of Age on the Efficacy and Safety of Single Agent Oral Selinexor in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): A Post-Hoc Analysis of the Sadal Pivotal Study
Authors: Michael W. Schuster, Miguel A Canales, Jason Westin, Josée M Zijlstra, George A Follows, Reem Karmali, Nagesh Kalakonda, Andre H. Goy, Rene-Olivier Casasnovas, Joost Vermaat, Eric Van Den Neste, Sylvain Choquet, Catherine Thieblemont, Federica Cavallo, Maria de Fatima De La Cruz, Brian T. Hill, Herve Tilly, Shireen Kassam, Reda Bouabdallah, Ulrich Jaeger, Ronit Gurion, Paolo Caimi, Peter Martin, Andrew Davies, Sonali M. Smith, Graham P. Collins, Fritz C. Offner, Gilles Salles, Xiwen Ma, Kelly Corona, Jean-Richard Saint-Martin, Anita A. Joshi, Kamal Chamoun, Hongwei Wang, Jatin J. Shah, Sharon Shacham, Michael G Kauffman, Marie Maerevoet
Journal: Blood (2020)
THU0099 The localisation of flice inhibitory protein (flip) in rheumatoid synovium
Authors: S Busteed, MW Bennett, M Stone, C Molloy, J O’Connell, F Shanahan, MG Molloy
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> FLICE inhibitory protein (FLIP, I-FLICE) is an inhibitor of caspase 8 (FLICE) and functions as an early mediator of apoptosis. Expression of FLIP is associated with resistance to apoptosis in differentiated macrophages and also in primary B-cells and B-cell lines. The role of FLIP in rheumatoid synovium has not been fully elucidated although it has been shown that FLIP is expressed at sites of bone and cartilage erosion in the rheumatoid joint. <h3>Objectives</h3> The aim of this study is to examine the degree of expression of FLIP in rheumatoid synovium. <h3>Methods</h3> Samples were obtained intraoperatively from patients with rheumatoid arthritis (n = 17) and osteoarthritis (n = 9). Colon sections from patients with ulcerative colitis were used as biological controls. Immunohistochemistry was carried out using a polyclonal antibody to both the long and short forms of FLIP. Sections of synovium with prominent mononuclear infiltrates were chosen for more detailed analysis of FLIP expression in inflammatory cells. Positive mononuclear cells were counted under a high-power field and the degree of positive staining was graded using the Lindblad and Hedfors scale (see Table 1). <h3>Results</h3> FLIP was strongly expressed in the synovial lining of samples from patients with both rheumatoid arthritis and osteoarthritis. There was low expression of FLIP in the rheumatoid mononuclear cells relative to the inflammatory cells in the osteoarthritis samples. Inflammatory cells in ulcerative colitis showed upregulation of FLIP. <h3>Conclusion</h3> We conclude that the infrequency of lymphocyte apoptosis in RA synovium does not appear to be due to expression of FLIP. There is high expression of FLIP in the synovial lining in both RA and OA however. This may point to differing roles for FLIP in the regulation of apoptosis in synovium and suggests that other apoptotic regulators are involved in the persistence of inflammatory cells in rheumatoid arthritis.
Combination of CS2164 and Venetoclax Shows Synergistic Antitumor Effect in High-Grade B-Cell Lymphomas with Concomitant<i>MYC</i>and<i>BCL2</i>Rearrangements
Authors: Manman Deng, Delin Yuan, Genhong Li, Yuelong Jiang, Qinwei Chen, Zhihong Fang, Bing Xu
Journal: Blood (2020)
Ruxolitinib Reduces Endothelial Pro-Adhesive Interactions: Implications for JAK2V617+ MPN Thrombosis
Authors: Angelica DaSilva, Elena Aronovich, Aithanh Nguyen, Julia Nguyen, David Reynolds, Geneva D. Doak, Gregory M. Vercellotti, David K. Wood, Joan D. Beckman
Journal: Blood (2020)
Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy
Authors: Rafael Cubas, Zia Khan, Qian Gong, Marina Moskalenko, Huizhong Xiong, Qinglin Ou, Christine Pai, Ryan Rodriguez, Jeanne Cheung, Andrew C Chan
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Cancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy. Results Here, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22 -/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4 + and CD8 + T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T ) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment. Conclusions Together, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.
Do point-of-care tests (POCTs) offer a new paradigm for the management of patients with influenza?
Authors: Elizabeth M Dickson, Maria Zambon, Richard Pebody, Simon de Lusignan, Alex J Elliot, Joanna Ellis, Angie Lackenby, Gillian Smith, Jim McMenamin
Journal: Eurosurveillance (2020)

The introduction of point-of-care tests (POCTs) has presented new opportunities for the management of patients presenting to healthcare providers with acute respiratory symptoms. This Perspective article is based on the experiences of national infection teams/those managing acute respiratory infections across the United Kingdom in terms of the challenges and opportunities that this may present for public health. This Perspective article was conceived and written pre-coronavirus disease (COVID-19), however the principles we outline here for influenza can also be translated to COVID-19 and some key points are made throughout the article. The greatest challenge for intergrating POCTs into non-traditional environments is the capture of data and samples for surveillance purposes which provides information for public health action. However, POCTs together with measures outlined in this article, offer a new paradigm for the management and public health surveillance of patients with influenza.
Role of Adoptive T- Cell Therapy in Post Hematopoietic Stem Cells Transplant Viral Infections-: A Systemic Review
Authors: Hassaan Imtiaz, Muhammad Saad Farooqi, Unaiza Faizan, Saad Ur Rehman, Muhammed Hamza Arshad, Ali Shahbaz Baloch, Syed Shahnawaz Hashmi, Abdullah Jamal, Taimoor Jaffar Ali, Ali Younas Khan, Zahoor Ahmed, Abdul Jabbar Dar, Muhammad Ali Mirza, Qasim Khurshid, Faiz Anwer
Journal: Blood (2020)
Phase I Studies in Hematologic Malignancy: 20-Year Experience from Cancer Therapy Evaluation Program (CTEP) at National Cancer Institute/National Institutes of Health
Authors: Dai Chihara, Erich P. Huang, Shanda R. Finnigan, Lisa M. Cordes, Nebojsa Skorupan, Yoko Korenaga Fukuda, Larry V. Rubinstein, Naoko Takebe
Journal: Blood (2020)
Methicillin-susceptible staphylococcus aureus in community-acquired pneumonia: Risk factors and outcomes
Authors: Catia Cilloniz, Cristina Dominedò, Albert Gabarrús, Carolina Garcia-Vidal, José Becerril, Diego Tovar, Estela Moreno, Juan.M. Pericás, Carmen Rosa Vargas, Antoni Torres
Journal: Journal of Infection (2020)
Low Dose Rituximab Plus High Dose Dexamethasone As First-Line Treatment for Autoimmune Hemolytic Anemia
Authors: Carlos Saúl Rodríguez-Roque, Andres Gomez-De Leon, Michelle Morcos-Sandino, Nelson Josafat López-Flores, David David Galindo-Calvillo, Elsa Laura Zertuche-González, Anna Cecilia Rodríguez-Zuñiga, David Gomez-Almaguer
Journal: Blood (2020)
Selinexor in Combination with Carfilzomib and Dexamethasone, All Once Weekly (SKd), for Patients with Relapsed/Refractory Multiple Myeloma
Authors: Cristina Gasparetto, Brea Lipe, Sascha A Tuchman, Natalie S. Callander, Suzanne Lentzsch, Muhamed Baljevic, Adriana C Rossi, Nizar J. Bahlis, Darrell J White, Christine I Chen, Heather J Sutherland, Rami Kotb, Richard LeBlanc, Michael Sebag, Christopher P. Venner, William I Bensinger, Heidi Sheehan, Dane Van Domelen, Kai Kazuharu, Gary J. Schiller
Journal: Blood (2020)
Diagnostic Validation of a Clinical Laboratory-Oriented Targeted RNA Sequencing System As a Comprehensive Assay for Hematologic Malignancies
Authors: Ha Jin Lim, Jun Hyung Lee, Ju-Hyeon Shin, Seung Yeob Lee, Hyun-Woo Choi, Hyun Jung Choi, Seung Jung Kee, Jong Hee Shin, Myung-Geun Shin
Journal: Blood (2020)
VIS832, a novel CD138-targeting monoclonal antibody, potently induces killing of human multiple myeloma and further synergizes with IMiDs or bortezomib in vitro and in vivo
Authors: Tengteng Yu, Bharat Chaganty, Liang Lin, Lijie Xing, Boopathy Ramakrishnan, Kenneth Wen, Phillip A. Hsieh, Andrew Wollacott, Karthik Viswanathan, Hedy Adari, Shih-Feng Cho, Yuyin Li, Hailin Chen, Wenjuan Yang, Yan Xu, Gang An, Lugui Qiu, Nikhil Munshi, Gregory Babcock, Zachary Shriver, James R. Myette, Kenneth C. Anderson, Yu-Tzu Tai
Journal: Blood Cancer Journal (2020)

Abstract Therapeutically targeting CD138, a define multiple myeloma (MM) antigen, is not yet approved for patients. We here developed and determined the preclinical efficacy of VIS832, a novel therapeutic monoclonal antibody (MoAb) with differentiated CD138 target binding to BB4 that is anti-CD138 MoAb scaffold for indatuximab ravtansine (BT062). VIS832 demonstrated enhanced CD138-binding avidity and significantly improved potency to kill MM cell lines and autologous patient MM cells regardless of resistance to current standard-of-care therapies, via robust antibody-dependent cellular cytotoxicity and phagocytosis mediated by NK and macrophage effector cells, respectively. Specifically, CD38-targeting daratumumab-resistant MM cells were highly susceptible to VIS832 which, unlike daratumumab, spares NK cells. Superior maximal cytolysis of VIS832 vs. daratumumab corresponded to higher CD138 vs. CD38 levels in MM cells. Furthermore, VIS832 acted synergistically with lenalidomide or bortezomib to deplete MM cells. Importantly, VIS832 at a sub-optimal dose inhibited disseminated MM1S tumors in vivo as monotherapy ( P &lt; 0.0001), and rapidly eradicated myeloma burden in all mice concomitantly receiving bortezomib, with 100% host survival. Taken together, these data strongly support clinical development of VIS832, alone and in combination, for the therapeutic treatment of MM in relapsed and refractory patients while pointing to its potential therapeutic use earlier in disease intervention.
Improving the Definition of Response Assessment: Prognostic Value of Minimal Residual Disease Combined with PET/CT at Day 100 Post Autologous Stem Cell Transplantation in Multiple Myeloma
Authors: Miguel Gonzalez-Velez, Mariano Arribas, Heidi E. Kosiorek, Richard Butterfield, Carlo Guerrero, Luke Mountjoy, Jeremy Larsen, Craig B. Reeder, P. Leif Bergsagel, A. Keith Stewart, Rafael Fonseca
Journal: Blood (2020)
Glioma stem cells and their roles within the hypoxic tumor microenvironment
Authors: Nathaniel H. Boyd, Anh Nhat Tran, Joshua D. Bernstock, Tina Etminan, Amber B. Jones, G. Yancey Gillespie, Gregory K. Friedman, Anita B. Hjelmeland
Journal: Theranostics (2020)

Tumor microenvironments are the result of cellular alterations in cancer that support unrestricted growth and proliferation and result in further modifications in cell behavior, which are critical for tumor progression. Angiogenesis and therapeutic resistance are known to be modulated by hypoxia and other tumor microenvironments, such as acidic stress, both of which are core features of the glioblastoma microenvironment. Hypoxia has also been shown to promote a stem-like state in both non-neoplastic and tumor cells. In glial tumors, glioma stem cells (GSCs) are central in tumor growth, angiogenesis, and therapeutic resistance, and further investigation of the interplay between tumor microenvironments and GSCs is critical to the search for better treatment options for glioblastoma. Accordingly, we summarize the impact of hypoxia and acidic stress on GSC signaling and biologic phenotypes, and potential methods to inhibit these pathways.
Continued Improvement in Survival of Patients with Newly Diagnosed Multiple Myeloma (MM)
Authors: Bharat Nandakumar, Prashant Kapoor, Moritz Binder, Francis K. Buadi, Martha Q. Lacy, Morie A. Gertz, Angela Dispenzieri, David Dingli, Yi L. Hwa, Amie Fonder, Miriam A. Hobbs, Suzanne R. Hayman, John A. Lust, Stephen J. Russell, Nelson Leung, Ronald S. Go, Yi Lin, Wilson I Gonsalves, Taxiarchis Kourelis, Rahma M Warsame, Mustaqeem A. Siddiqui, Robert A. Kyle, S. Vincent Rajkumar, Shaji K. Kumar
Journal: Blood (2020)