tbuckley/cabot-search huggingface dataset:
Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia
Authors: Sandra Kiehlmeier, Mahmoud-Reza Rafiee, Ali Bakr, Jagoda Mika, Sabrina Kruse, Judith Müller, Sabrina Schweiggert, Carl Herrmann, Gianluca Sigismondo, Peter Schmezer, Jeroen Krijgsveld, Stefan Gröschel
Journal: Leukemia (2021)

Abstract Deregulation of the EVI1 proto-oncogene by the GATA2 distal hematopoietic enhancer ( G2DHE ) is a key event in high-risk acute myeloid leukemia carrying 3q21q26 aberrations (3q-AML). Upon chromosomal rearrangement, G2DHE acquires characteristics of a super-enhancer and causes overexpression of EVI1 at 3q26.2. However, the transcription factor (TF) complex of G2DHE remains poorly characterized. The aim of this study was to unravel key components of G2DHE -bound TFs involved in the deregulation of EVI1 . We have identified several CEBPA and RUNX1 binding sites to be enriched and critical for G2DHE function in 3q-AML cells. Using ChIP-SICAP (ChIP followed by selective isolation of chromatin-associated proteins), a panel of chromatin interactors of RUNX1 and CEBPA were detected in 3q-AML, including PARP1 and IKZF1. PARP1 inhibition (PARPi) caused a reduction of EVI1 expression and a decrease in EVI1 – G2DHE interaction frequency, highlighting the involvement of PARP1 in oncogenic super-enhancer formation. Furthermore, 3q-AML cells were highly sensitive to PARPi and displayed morphological changes with higher rates of differentiation and apoptosis as well as depletion of CD34 + cells. In summary, integrative analysis of the 3q-AML super-enhancer complex identified CEBPA and RUNX1 associated proteins and nominated PARP1 as a potential new therapeutic target in EVI1 + 3q-AML.
A bivalent recombinant vaccine targeting the S1 protein induces neutralizing antibodies against both SARS‐CoV‐2 variants and wild‐type of the virus
Authors: Cai He, Jingyun Yang, Xuemei He, Weiqi Hong, Hong Lei, Zimin Chen, Guobo Shen, Li Yang, Jiong Li, Zhenling Wang, Xiangrong Song, Wei Wang, Guangwen Lu, Xiawei Wei
Journal: MedComm (2021)

The emerging variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in pandemic call for the urgent development of universal corona virus disease 2019 (COVID-19) vaccines which could be effective for both wild-type SARS-CoV-2 and mutant strains. In the current study, we formulated protein subunit vaccines with AS03 adjuvant and recombinant proteins of S1 subunit of SARS-CoV-2 (S1-WT) and S1 variant (K417N, E484K, N501Y, and D614G) subunit (S1-Mut), and immunized transgenic mice that express human angiotensin-converting enzyme 2 (hACE2). The S1 protein-specific antibody production and the neutralization capability for SARS-CoV-2 and B.1.351 variant were measured after immunization in mice. The results revealed that the S1-Mut antigens were more effective in inhibiting the receptor-binding domain and ACE2 binding in B.1.351 variant than in wild-type SARS-CoV-2. Furthermore, the development of a bivalent vaccine exhibited the ideal neutralization properties against wild-type and B.1.351 variant, as well as other variants. Our findings may provide a rationale for the development of a bivalent recombinant vaccine targeting the S1 protein that can induce the neutralizing antibodies against both SARS-CoV-2 variants and wild-type of the virus and may be of importance to explore the potential clinical use of bivalent recombinant vaccine in the future.
TREATMENT OF ASYMPTOMATIC DONOR SPECIFIC ANTIBODY AFTER HEART TRANSPLANTATION: IS IT BENEFICIAL?
Authors: Parker Rushworth, Tahli Singer-Englar, Nikhil Patel, Jignesh Patel, Michelle Kittleson, David Chang, Evan Kransdorf, Jon Kobashigawa
Journal: Journal of the American College of Cardiology (2021)
Quality of Life and Patient Reported Outcome (PRO) in Patients Receiving High and Moderate Emetogenic Chemotherapy (Ctx) - Results of a German Non-Interventional Study with NEPA - a Netupitant/Palonosetron Fixed Dose Combination
Authors: Meinolf Karthaus, P Klare, Heilmann, G Klausmann, Joerg Schilling
Journal: Blood (2017)
RATIONALE AND DESIGN FOR A PHASE 2 TRIAL OF VERINURAD PLUS ALLOPURINOL IN PATIENTS WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION AND HYPERURICEMIA
Authors: Dalane W. Kitzman, Adriaan Voors, Robert Mentz, Gregory Lewis, Shira Perl, Robin Myte, Karin Björck, Fredrik Erlandsson, Sanjiv Shah
Journal: Journal of the American College of Cardiology (2021)
AORTIC ROOT THROMBOSIS IS ASSOCIATED WITH INCREASED INCIDENCE OF AORTIC INSUFFICIENCY IN PATIENTS SUPPORTED WITH HEARTMATE 3 LEFT VENTRICULAR ASSIST DEVICE
Authors: Dylan P. Marshall, Ronald Laracuente, Matthew Carey, Kevin Clerkin, Amirali Masoumi, Jayant Raikhelkar, Jan Griffin, Jay S. Leb, Yuji Kaku, Sneha Jain, Joseph E. Sanchez, Hiroo Takayama, Melana Yuzefpolskaya, Paolo Colombo, Koji Takeda, Gabriel Sayer, Yoshifumi Naka, Nir Uriel, Veli Topkara, Justin Fried
Journal: Journal of the American College of Cardiology (2021)
The Epigenetic and Genetic Landscapes of Pediatric T-Cell Acute Lymphoblastic Leukemia (T-ALL)
Authors: Shunsuke Kimura, Masafumi Seki, Tomoko Kawai, Kenichi Yoshida, Tomoya Isobe, Hiroo Ueno, Yusuke Shiozawa, Hiromichi Suzuki, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Kentaro Ohki, Motohiro Kato, Katsuyoshi Koh, Ryoji Hanada, Ryoji Kobayashi, Takao Deguchi, Yoshiko Hashii, Toshihiko Imamura, Atsushi Sato, Nobutaka Kiyokawa, Atushi Manabe, Keizo Horibe, Akira Ohara, Masashi Sanada, Masao Kobayashi, Akira Oka, Yasuhide Hayashi, Satoru Miyano, Kenichiro Hata, Seishi Ogawa, Junko Takita
Journal: Blood (2017)
CONTEMPORARY NATIONAL PATTERNS OF ELIGIBILITY AND UTILIZATION OF NOVEL CARDIOPROTECTIVE ANTI-HYPERGLYCEMIC AGENTS IN TYPE 2 DIABETES
Authors: Arash Aghajani Nargesi, Gini Priyadharshini Jeyashanmugaraja, Nihar Desai, Kasia Lipska, Harlan Krumholz, Rohan Khera
Journal: Journal of the American College of Cardiology (2021)
IMPACT OF GENDER ON IN HOSPITAL OUTCOMES OF WATCHMAN DEVICE: INSIGHT FROM NATIONAL INPATIENT SAMPLE DATA
Authors: Jay Shah, Kritika Luthra, Sindhu Avula, Devina Adalja, Ma’En Al-Dabbas, Krunalkumar Patel, Muhammad Khan, Hemindermeet Singh, Syed Ali
Journal: Journal of the American College of Cardiology (2021)
Association between menopausal hormone therapy and incidence of psoriasis: a secondary analysis from the Women’s Health Initiative randomized clinical trials
Authors: A.A. Chan, J. Noguti, C.T. Yang, S.R. Feldman, R.B. Wallace, A.H. Shadyab, J.E. Manson, A.K. Aragaki, R.T. Chlebowski, D.J. Lee
Journal: British Journal of Dermatology (2021)
Abstract 16607: Age-induced Endoplasmic Reticulum Stress in the Heart: Role of Increased Very Long-chain Ceramides
Authors: Qun Chen, Anna Kovilakath, Jeremy Allegood, Lauren A Cowart, Edward J Lesnefsky
Journal: Circulation (2020)

Introduction: Mitochondrial function is impaired in aged hearts. Increased endoplasm reticulum (ER) stress contributes to the mitochondrial dysfunction observed during aging. Ceramides (CRMD) are sphingolipid metabolites that contribute key roles in cell signaling. Increased CRMD can lead to ER stress. Ceramide synthase enzymes (CerS) generate chain length specific CRMD with the CerS isoform 2 (Cers2) forming very long chain CRMD of ≥ 20 carbon acyl chain lengths. Hypothesis: An increase in CRMD content during aging contributes to age-related ER stress. Methods: Male mice (3, 18, 24 mo.) from the NIA colony were studied. Cardiac mitochondria (MITO), mitochondrial associated membranes (MAM), and ER were isolated from mouse hearts. CRMD content was measured using LC-MS. The contents of CerS enzymes were measured by immunoblotting in myocardial homogenates. Results: ER stress increased progressively during aging with increased contents of cleaved ATF6 and CHOP, indicators of increased ER stress, evident at 18 and 24 mo. (Panel A) (all data mean±SEM; *p&lt;0.05 vs. 3 mo., † p&lt;0.05 vs. 18 mo.). Aging increased very long-chain CRMD (≥C20) in ER (Panel B) at 18 and 24 mo. Similar CRMD trends were observed MAM (Panel C), shared membrane domains where ER and MITO interact. The content of CerS2 was increased at 24 mo. compared to 3 mo. (Panel D, n=4 each age). In contrast, the contents of CerS isoforms 4 and 5, that generate shorter chain CRMD (&lt;C20) were unchanged (not shown). CRMD contents in MITO were unaltered with age (not shown). Thus, increased generation of very long chain CRMD in the ER is the likely mechanism of increased ER stress in the aged heart. Conclusion: Aging increased ER CRMD content by enhancing the formation of very long chain CRMD in ER by an increase in CerS2 content, concomitant with the onset of ER stress. The increase in age-induced ER stress, in turn, leads to mitochondrial dysfunction in the aged heart.
Open-Label, Single-Arm, Multicenter, Phase II Trial of Lenvatinib for the Treatment of Patients With Anaplastic Thyroid Cancer
Authors: Lori J. Wirth, Marcia S. Brose, Eric J. Sherman, Lisa Licitra, Martin Schlumberger, Steven I. Sherman, Keith C. Bible, Bruce Robinson, Patrice Rodien, Yann Godbert, Christelle De La Fouchardiere, Kate Newbold, Christopher Nutting, Soamnauth Misir, Ran Xie, Ana Almonte, Weifei Ye, Maria E. Cabanillas
Journal: Journal of Clinical Oncology (2021)

Anaplastic thyroid cancer (ATC), an aggressive malignancy, is associated with a poor prognosis and an unmet need for effective treatment, especially for patients without BRAF mutations or NTRK or RET fusions. Lenvatinib is US Food and Drug Administration-approved for radioiodine-refractory differentiated thyroid cancer and has previously demonstrated activity in a small study of patients with ATC (n = 17). We aimed to further evaluate lenvatinib in ATC.This open-label, multicenter, international, phase II study enrolled patients with ATC, who had ≥ 1 measurable target lesion, to receive lenvatinib 24 mg once daily. The primary end points were objective response rate (ORR) by investigator assessment per RECIST v1.1 and safety. Responses were confirmed ≥ 4 weeks after the initial response. Additional end points included progression-free survival and overall survival (OS).The study was halted for futility as the minimum ORR threshold of 15% was not met upon interim analysis. The interim analysis set included the first 20 patients. The full analysis set includes all 34 enrolled and treated patients. In the full analysis set, one patient achieved a partial response (ORR, 2.9%; 95% CI, 0.1 to 15.3). More than half of the evaluable patients experienced tumor shrinkage; three patients experienced a > 30% tumor reduction. The median progression-free survival was 2.6 months (95% CI, 1.4 to 2.8); the median overall survival was 3.2 months (95% CI, 2.8 to 8.2). The most common treatment-related adverse events (AEs) were hypertension (56%), decreased appetite (29%), fatigue (29%), and stomatitis (29%). No major treatment-related bleeding events or grade 5 treatment-related AEs occurred.The safety profile of lenvatinib in ATC was manageable, and many AEs were attributable to the progression of ATC. The results suggest that lenvatinib monotherapy may not be an effective treatment for ATC; further investigation may be warranted.
Abstract 16178: Role of LncRNA MALAT-1 and MicroRNA-199 in Rapamycin Induced Cardioprotection Against Reperfusion Injury in Diabetic Rabbits
Authors: Arun Samidurai, Ramzi A Ockaili, Chad Cain, Sean K Roh, Donatas Kraskauskas, Fadi N Salloum, Rakesh C Kukreja, Anindita Das
Journal: Circulation (2019)

Background: Treatment with rapamycin (RAPA, mTOR inhibitor) protects diabetic (DM) hearts against ischemia/reperfusion (I/R) injury. Coordination between MALAT-1 (Metastasis Associated Lung Adenoca...
Prevention and management of allergic reactions to food in child care centers and schools: Practice guidelines
Authors: Susan Waserman, Heather Cruickshank, Kyla J. Hildebrand, Douglas Mack, Laura Bantock, Theresa Bingemann, Derek K. Chu, Carlos Cuello-Garcia, Motohiro Ebisawa, David Fahmy, David M. Fleischer, Lisa Galloway, Greg Gartrell, Matthew Greenhawt, Nicola Hamilton, Jonathan Hourihane, Michael Langlois, Richard Loh, Antonella Muraro, Lana Rosenfield, Sally Schoessler, Mimi L.K. Tang, Brenda Weitzner, Julie Wang, Jan L. Brozek
Journal: Journal of Allergy and Clinical Immunology (2021)
IS CORONARY ANGIOGRAPHY REQUIRED IN ALL PATIENTS UNDERGOING TAVR? UTILITY OF CT ANGIOGRAPHY FOR EVALUATING CORONARY ARTERY DISEASE IN PATIENTS WITH SEVERE AORTIC STENOSIS
Authors: Homam Ibrahim, Jorge Fuentes, Carlos Gonzalez-Lengua, Nakashima Makoto, Yuxin He, Stephanie Gaudio, Samantha Vidal, Joseph Tovar, Michael Querijero, Peter Neuburger, Cezar Staniloae, Hasan Jilaihawi, Mathew Williams
Journal: Journal of the American College of Cardiology (2021)
Notice of Retraction. Shimizu et al. Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome With Life-Threatening Arrhythmias in Japanese Patients. JAMA Cardiol. 2019;4(3):246-254.
Authors: Wataru Shimizu, Takeshi Aiba
Journal: JAMA Cardiology (2021)

encourage broader adoption of this approach to cardiovascular risk reduction in clinical practice.
Inner retinal injury in experimental glaucoma is prevented upon AAV mediated Shp2 silencing in a caveolin dependent manner
Authors: Mojdeh Abbasi, Vivek K. Gupta, Nitin Chitranshi, Veer Gupta, Reza Ranjbaran, Rashi Rajput, Kanishka Pushpitha, Devaraj KB, Yuyi You, Ghasem Hosseini Salekdeh, Robert G. Parton, Mehdi Mirzaei, Stuart L. Graham
Journal: Theranostics (2021)

SH2 domain containing tyrosine phosphatase 2 (Shp2; PTPN11) regulates several intracellular pathways downstream of multiple growth factor receptors. Our studies implicate that Shp2 interacts with Caveolin-1 (Cav-1) protein in retinal ganglion cells (RGCs) and negatively regulates BDNF/TrkB signaling. This study aimed to investigate the mechanisms underlying the protective effects of shp2 silencing in the RGCs in glaucomatous conditions. Methods: Shp2 was silenced in the Cav-1 deficient mice and the age matched wildtype littermates using adeno-associated viral (AAV) constructs. Shp2 expression modulation was performed in an acute and a chronic mouse model of experimental glaucoma. AAV2 expressing Shp2 eGFP-shRNA under a strong synthetic CAG promoter was administered intravitreally in the animals' eyes. The contralateral eye received AAV-eGFP-scramble-shRNA as control. Animals with Shp2 downregulation were subjected to either microbead injections or acute ocular hypertension experimental paradigm. Changes in inner retinal function were evaluated by measuring positive scotopic threshold response (pSTR) while structural and biochemical alterations were evaluated through H&E staining, western blotting and immunohistochemical analysis of the retinal tissues. Results: A greater loss of pSTR amplitudes was observed in the WT mice compared to Cav-1-/- retinas in both the models. Silencing of Shp2 phosphatase imparted protection against inner retinal function loss in chronic glaucoma model in WT mice. The functional rescue also translated to structural preservation of ganglion cell layer in the chronic glaucoma condition in WT mice which was not evident in Cav-1-/- mice retinas. Conclusions: This study indicates that protective effects of Shp2 ablation under chronic experimental glaucoma conditions are dependent on Cav-1 in the retina, suggesting in vivo interactions between the two proteins.
Effects of Low-Dose Gestational TCDD Exposure on Behavior and on Hippocampal Neuron Morphology and Gene Expression in Mice
Authors: Talia E. Gileadi, Abhyuday K. Swamy, Zoe Hore, Stuart Horswell, Jacob Ellegood, Conor Mohan, Keiko Mizuno, Anne-Katrine Lundebye, K. Peter Giese, Brigitta Stockinger, Christer Hogstrand, Jason P. Lerch, Cathy Fernandes, M. Albert Basson
Journal: Environmental Health Perspectives (2021)

Background: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans. Objectives: The aim of the study was to establish a dietary low-dose gestational TCDD exposure protocol and performed an initial characterization of the effects on offspring behavior, neurodevelopmental phenotypes, and gene expression. Methods: Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD (9 ng TCDD/kg body weight per day) or a control diet. The offspring were tested in a battery of behavioral tests, and structural brain alterations were investigated by magnetic resonance imaging. The dendritic morphology of pyramidal neurons in the hippocampal Cornu Ammonis (CA)1 area was analyzed. RNA sequencing was performed on hippocampi of postnatal day 14 TCDD-exposed and control offspring. Results: TCDD-exposed females displayed subtle deficits in motor coordination and reversal learning. Volumetric difference between diet groups were observed in regions of the hippocampal formation, mammillary bodies, and cerebellum, alongside higher dendritic arborization of pyramidal neurons in the hippocampal CA1 region of TCDD-exposed females. RNA-seq analysis identified 405 differentially expressed genes in the hippocampus, enriched for genes with functions in regulation of microtubules, axon guidance, extracellular matrix, and genes regulated by SMAD3. Discussion: Exposure to 9 ng TCDD/kg body weight per day throughout gestation was sufficient to cause specific behavioral and structural brain phenotypes in offspring. Our data suggest that alterations in SMAD3-regulated microtubule polymerization in the developing postnatal hippocampus may lead to an abnormal morphology of neuronal dendrites that persists into adulthood. These findings show that environmental low-dose gestational exposure to TCDD can have significant, long-term impacts on brain development and function. https://doi.org/10.1289/EHP7352
The Landscape of Cell-Free HBV Integrations and Mutations in Cirrhosis and Hepatocellular Carcinoma Patients
Authors: Bo Zheng, Xiao-Long Liu, Rong Fan, Jian Bai, Hao Wen, Lu-Tao Du, Guo-Qing Jiang, Chun-Ying Wang, Xiao-Tang Fan, Yi-Nong Ye, Yun-Song Qian, Ying-Chao Wang, Gao-Jing Liu, Guo-Hong Deng, Feng Shen, He-Ping Hu, Hui Wang, Qing-Zheng Zhang, Lan-Lan Ru, Jing Zhang, Yan-Hang Gao, Jie Xia, Hua-Dong Yan, Min-Feng Liang, Yan-Long Yu, Fu-Ming Sun, Yu-Jing Gao, Jian Sun, Chun-Xiu Zhong, Yin Wang, Fei Kong, Jin-Ming Chen, Dan Zheng, Yuan Yang, Chuan-Xin Wang, Lin Wu, Jin-Lin Hou, Jing-Feng Liu, Hong-Yang Wang, Lei Chen
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Intratumoral hepatitis B virus (HBV) integrations and mutations are related to hepatocellular carcinoma (HCC) progression. Circulating cell-free DNA (cfDNA) has shown itself as a powerful noninvasive biomarker for cancer. However, the HBV integration and mutation landscape on cfDNA remains unclear. Experimental Design: A cSMART (Circulating Single-Molecule Amplification and Resequencing Technology)-based method (SIM) was developed to simultaneously investigate HBV integration and mutation landscapes on cfDNA with HBV-specific primers covering the whole HBV genome. Patients with HCC (n = 481) and liver cirrhosis (LC; n = 517) were recruited in the study. Results: A total of 6,861 integration breakpoints including TERT and KMT2B were discovered in HCC cfDNA, more than in LC. The concentration of circulating tumor DNA (ctDNA) was positively correlated with the detection rate of these integration hotspots and total HBV integration events in cfDNA. To track the origin of HBV integrations in cfDNA, whole-genome sequencing (WGS) was performed on their paired tumor tissues. The paired comparison of WGS data from tumor tissues and SIM data from cfDNA confirmed most recurrent integration events in cfDNA originated from tumor tissue. The mutational landscape across the whole HBV genome was first generated for both HBV genotype C and B. A region from nt1100 to nt1500 containing multiple HCC risk mutation sites (OR &amp;gt; 1) was identified as a potential HCC-related mutational hot zone. Conclusions: Our study provides an in-depth delineation of HBV integration/mutation landscapes at cfDNA level and did a comparative analysis with their paired tissues. These findings shed light on the possibilities of noninvasive detection of virus insertion/mutation.
Polypeptides–Drug Conjugates for Anticancer Therapy
Authors: Yu Zhang, Pan He, Peng Zhang, Xuan Yi, Chunsheng Xiao, Xuesi Chen
Journal: Advanced Healthcare Materials (2021)

Abstract Polypeptides are an important class of biodegradable polymers that have been widely used in drug delivery field. Owing to the controllable synthesis and robust side chain‐functionalization ability, polypeptides have long been ideal candidates for conjugation with anticancer drugs. The chemical conjugation of anticancer drugs with polypeptides, termed polypeptides–drug conjugates, has demonstrated several advantages in improving pharmacokinetics, enhancing drug targeting, and controlling drug release, thereby leading to enhanced therapeutic outcomes with reduced side toxicities. This review focuses on the recent advances in the design and preparation of polypeptides–drug conjugates for enhanced anticancer therapy. Strategies for conjugation of different types of drugs, including small‐molecule chemotherapeutic drugs, proteins, vascular disrupting agents, and gas molecules, onto polypeptides backbone are summarized. Finally, the challenges and future perspectives on the development of innovative polypeptides–drug conjugates for clinical cancer treatment are also presented.
Diagnostic accuracy of rapid nucleic acid tests for group A streptococcal pharyngitis: systematic review and meta-analysis
Authors: Constance Dubois, Pierre R Smeesters, Yacine Refes, Corinne Levy, Philippe Bidet, Robert Cohen, Martin Chalumeau, Julie Toubiana, Jérémie F Cohen
Journal: Clinical Microbiology and Infection (2021)
CARDIOVASCULAR ADVERSE EVENTS ASSOCIATED WITH NIVOLUMAB VERSUS STANDARD CHEMOTHERAPY IN PATIENTS WITH CANCER. A META-ANALYSIS OF RAMDOMIZED CONTROL TRIALS
Authors: Eder Cativo Calderon, Nehemias Guevara, Noemy Coreas, Persio Lopez Loyo, Diana P. Cativo, Hasitha Manohar, Anurag Gaddam, Steven Atlas, Clive Rosendorff
Journal: Journal of the American College of Cardiology (2021)