tbuckley/cabot-search huggingface dataset:
Peptide vaccine targeting mutated<i>GNAS</i>: a potential novel treatment for pseudomyxoma peritonei
Authors: Kjersti Flatmark, Annette Torgunrud, Karianne G Fleten, Ben Davidson, Hedvig V Juul, Nadia Mensali, Christin Lund-Andersen, Else Marit Inderberg
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Pseudomyxoma peritonei (PMP) is a rare, slow-growing abdominal cancer with no efficacious treatment options in non-resectable and recurrent cases. Otherwise, rare activating mutations in the GNAS oncogene are remarkably frequent in PMP and the mutated gene product, guanine nucleotide-binding protein α subunit (Gsα), is a potential tumor neoantigen, presenting an opportunity for targeting by a therapeutic cancer vaccine. Methods Tumor and blood samples were collected from 25 patients undergoing surgery for PMP ( NCT02073500 ). GNAS mutation analysis was performed by next-generation targeted sequencing or digital droplet PCR. Responses to stimulation with Gsα mutated (point mutations R201H and R201C) 30 mer peptides were analyzed in peripheral blood T cells derived from patients with PMP and healthy donors. Fresh PMP tumor samples were analyzed by mass cytometry using a panel of 35 extracellular markers, and cellular subpopulations were clustered and visualized using the visual stochastic network embedding analysis tool. Results GNAS mutations were detected in 22/25 tumor samples (88%; R201H and R201C mutations detected in 16 and 6 cases, respectively). Strong T cell proliferation against Gsα mutated peptides was observed in 18/24 patients with PMP. Mass cytometry analysis of tumor revealed infiltration of CD3 +T cells in most samples, with variable CD4+:CD8 + ratios. A large proportion of T cells expressed immune checkpoint molecules, in particular programmed death receptor-1 and T cell immunoreceptor with Ig and ITIM, indicating that these T cells were antigen experienced. Conclusion These findings point to the existence of a pre-existing immunity in patients with PMP towards mutated Gsα, which has been insufficient to control tumor growth, possibly because of inhibition of antitumor T cells by upregulation of immune checkpoint molecules. The results form a rationale for exploring peptide vaccination with Gsα peptides in combination with immune checkpoint inhibiton as a possible curative treatment for PMP and other GNAS mutated cancers.
Abstract 11508: T Peak - T End Interval on the Prehospital 12-lead ECG is a Strong Predictor of Adverse Cardiac Events in Patients With Suspected Acute Coronary Syndrome
Authors: Mohammad Alhamaydeh, Abdullah Ahmad, Ziad Faramand, Samir Saba, Richard Gregg, Christian Martin-Gill, Clifton W Callaway, Salah S Al-Zaiti
Journal: Circulation (2019)

Introduction: QTc interval prolongation is a well-established marker of adverse cardiac events in a wide range of clinical and population-based populations. This interval, however, has been found t...
An insight on how to survive COVID-19
Authors: Rose Worrell
Journal: The Lancet Infectious Diseases (2021)

It was during the writing of Dying to live: the story of Grant McIntyre, COVID's sickest patient, Grant McIntyre's detailed account of his illness with COVID-19, that he discovered that the average length of a hospital stay of a COVID-19 patient in the UK was 8 days. This must have been a painful realisation for the author, whose own battle with the illness lasted an arduous 4 months, and who was branded the sickest survivor of COVID-19 in Scotland. The book charts the story of McIntyre's journey, from contracting COVID-19 as a healthy man aged 49 years during the first UK wave in March, 2020, his subsequent admission to an intensive care unit, the serious medical complications he had to endure (including kidney failure, a collapsed lung, and sepsis) and finally, against all odds, his incredible recovery.
TCT-124 Spontaneous Coronary Artery Dissection: Effect of Angiographic Type 1 SCAD on Percutaneous Intervention and Clinical Outcomes
Authors: Cameron McAlister, Mesfer Alfadhel, Rohit Samuel, Thomas Nestelberger, Tejana Grewal, Johandra Argote, Andrew Starovoytov, Eve Aymong, Jacqueline Saw
Journal: Journal of the American College of Cardiology (2021)
Peroral endoscopic myotomy for management of cricopharyngeal bars (CP-POEM): a retrospective evaluation
Authors: Sarah S. Al Ghamdi, Michael Bejjani, Oscar V. Hernández Mondragón, Nasim Parsa, Muhammad N. Yousaf, Mohammad Aghaie Meybodi, Bachir Ghandour, Chonlada Krustri, Chainarong Phalanusitthepha, Saowanee Ngamruengphong, Jose M. Nieto, Mouen A. Khashab
Journal: Endoscopy (2021)

Cricopharyngeal bars (CPBs) are a unique etiology of oropharyngeal dysphagia. Symptomatic patients are managed with endoscopic dilation or surgical myotomy. Cricopharyngeal peroral endoscopic myotomy (CP-POEM) is an emerging technique for the management of dysphagia due to CPBs. This study evaluated technical success, clinical success, adverse events, and long-term recurrence following CP-POEM.Consecutive patients who underwent POEM for management of CPBs between May 2015 and December 2020 at four tertiary care centers were included. Primary outcome was clinical success (defined as improvement of dysphagia score to ≤ 1). Secondary outcomes were technical success, rate and severity of adverse events, procedure duration, and symptom recurrence.27 patients (mean age 69 years; 10 female) underwent CP-POEM during the study period. The most common presenting symptoms at the time of index procedure were dysphagia (26; 96.3 %) and regurgitation (20; 74.1 %). Clinical and technical success were achieved in all patients. Mild/moderate adverse events occurred in two patients (7.4 %). CP-POEM significantly reduced the median dysphagia score.CP-POEM was a safe and effective treatment for symptomatic CPBs. Although symptom recurrence was low, long-term outcome data are needed. CP-POEM should be considered as a management option for symptomatic CPBs at centers with POEM expertise.
Covid-19 vaccination should be mandatory for healthcare workers
Authors: Daniel Sokol
Journal: BMJ (2021)

The Royal College of Physicians and the Royal Pharmaceutical Society have spoken out against mandatory covid vaccinations for healthcare staff.The Royal College of Nursing has "significant concerns" about it.On 14 October 2021, the Nuffield Council on Bioethics called for more evidence of the need for mandatory vaccination before resorting to coercion. 1 In contrast, countries such as France, Greece, Italy, and Hungary have already made covid vaccination mandatory for healthcare workers and last week the UK's secretary of state for health and social care, Sajid Javid, said that he was "leaning towards" compulsory vaccination.So who is right?
Real-World Outcomes for Standard-of-Care Treatments in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Michel Delforge, Marie-Christiane Vekemans, Sébastien Anguille, Julien Depaus, Nathalie Meuleman, Ann Van de Velde, Isabelle Vande Broek, Danielle Strens, Sandra Van Hoorenbeeck, Evelien J Moorkens, Joris Diels, Francesca Ghilotti, Sander Dalhuisen, Sophie Vandervennet
Journal: Blood (2021)
Plasma TNFR1 Predicts Major Adverse Kidney Events in Hospitalized Patients with COVID-19
Authors: Steven Menez, Steven G. Coca, Dennis G. Moledina, Yumeng Wen, Lili Chan, Heather Thiessen Philbrook, Wassim Obeid, Evren U. Azeloglu, Francis P. Wilson, Chirag R. Parikh
Journal: Journal of the American Society of Nephrology (2021)

Background: Patients hospitalized with COVID-19 are at risk for major adverse kidney events (MAKE). Predicting which patients will experience progression of disease and poor outcomes remains elusive. We sought to develop a biomarker-based risk model for predicting MAKE in patients hospitalized with COVID-19. Methods: We applied least absolute shrinkage and regression methodology (LASSO) to a prospectively enrolled cohort of 432 patients admitted with COVID-19 who had blood specimens collected (median 2 days [IQR 2-4 days] from admission) from March 2020-January 2021, at three large academic medical centers. Clinical variables and 26 plasma biomarkers were used as candidate features in the prediction models for the outcome of MAKE, defined as KDIGO stage 3 AKI, dialysis-requiring AKI, or in hospital mortality. Cross-validation was used for optimal shrinkage parameter selection and model AUCs were optimism-corrected using bootstrapping. Results: MAKE occurred in 85 (20%) patients within 60 days of admission. Application of LASSO to the 26 biomarkers selected IL-12, IL-13, IL-6, Tie2, FLT1, NGAL, MCP1, YKL40, Ang1, Ang2, and TNFR1, which yielded an AUC of 0.88 (95% CI 0.85-0.91). Plasma TNFR-1 alone had an AUC of 0.88 (0.84,0.91). When LASSO was applied on the clinical variables and TNFR1, 4 clinical variables (age, black race, obesity, WHO COVID severity score) and TNFR1 were selected with an AUC was 0.88 (95% CI 0.87-0.89). Random Forest models of biomarkers and clinical variables had similar prediction performance. A cutoff of TNFR1 at 3005 pg/ml had a sensitivity of 69%, specificity of 89%, PPV of 60% and NPV of 92% for occurrence of MAKE over 60 days. Conclusions: In this multi-center cohort study, plasma TNFR1 by itself produced a robust prediction for MAKE in patients hospitalized with COVID-19 that did not improve when combined with multiple clinical variables and was equivalent to combined inputs of 10 other plasma biomarkers.
Long-Term Morbidity Associated with Chronic Graft Vs. Host Disease (cGvHD) - a Blood or Marrow Transplant Survivor Study (BMTSS)
Authors: Mukta Arora, Yanjun Chen, Jessica Wu, Lindsey Hageman, Liton F. Francisco, Emily Ness, Mariel Parman, Michelle Kung, Alysia Bosworth, Manju Nayar, Ravi Bhatia, Stephen J. Forman, Daniel J. Weisdorf, Saro H. Armenian, Smita Bhatia
Journal: Blood (2017)
XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells
Authors: Adam Wahida, Madeleine Müller, Andreas Hiergeist, Bastian Popper, Katja Steiger, Caterina Branca, Markus Tschurtschenthaler, Thomas Engleitner, Sainitin Donakonda, Jordy De Coninck, Rupert Öllinger, Marie K. Pfautsch, Nicole Müller, Miguel Silva, Sinem Usluer, Erik Thiele Orberg, Jan P. Böttcher, Nicole Pfarr, Martina Anton, Julia B. Slotta-Huspenina, Andreas G. Nerlich, Tobias Madl, Marijana Basic, André Bleich, Geert Berx, Jürgen Ruland, Percy A. Knolle, Roland Rad, Timon E. Adolph, Peter Vandenabeele, Hirokazu Kanegane, André Gessner, Philipp J. Jost, Monica Yabal
Journal: Science Immunology (2021)

In XIAP deficiency, ileitis is driven by TNFR1- and TNFR2-dependent targeting of TLR5-expressing Paneth and dendritic cells.
Lower Statistical Support with Larger Data Sets: Insights from the Ochrophyta Radiation
Authors: Arnaud Di Franco, Denis Baurain, Gernot Glöckner, Michael Melkonian, Hervé Philippe
Journal: Molecular Biology and Evolution (2021)

Abstract It is commonly assumed that increasing the number of characters has the potential to resolve evolutionary radiations. Here, we studied photosynthetic stramenopiles (Ochrophyta) using alignments of heterogeneous origin mitochondrion, plastid, and nucleus. Surprisingly while statistical support for the relationships between the six major Ochrophyta lineages increases when comparing the mitochondrion (6,762 sites) and plastid (21,692 sites) trees, it decreases in the nuclear (209,105 sites) tree. Statistical support is not simply related to the data set size but also to the quantity of phylogenetic signal available at each position and our ability to extract it. Here, we show that this ability for current phylogenetic methods is limited, because conflicting results were obtained when varying taxon sampling. Even though the use of a better fitting model improved signal extraction and reduced the observed conflicts, the plastid data set provided higher statistical support for the ochrophyte radiation than the larger nucleus data set. We propose that the higher support observed in the plastid tree is due to an acceleration of the evolutionary rate in one short deep internal branch, implying that more phylogenetic signal per position is available to resolve the Ochrophyta radiation in the plastid than in the nuclear data set. Our work therefore suggests that, in order to resolve radiations, beyond the obvious use of data sets with more positions, we need to continue developing models of sequence evolution that better extract the phylogenetic signal and design methods to search for genes/characters that contain more signal specifically for short internal branches.
A Phase II Study of Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Older Patients Using Fludarabine and Total Body Irradiation
Authors: Omer Hassan Jamy, Sankalp Arora, Donna Salzman, Antonio Di Stasi, Kentaro Minagawa, Shin Mineishi, Ayman Saad
Journal: Blood (2021)
TCT-489 Three-Year Outcomes of Patients Treated With the Firehawk Stent Versus XIENCE Stent on the Basis of Diabetes Status: Subgroup Analysis of the TARGET All Comers Trial
Authors: Yasin Hussain, William Wijns, Bo Xu, Henning Kelbæk, Paul Knaapen, Ming Zheng, Ton Slagboom, Thomas Johnson, Pieter Smits, Karin Arkenbout, Lene Holmvang, Luc Janssens, Andrzej Ochala, Salvatore Brugaletta, Thomas Schmitz, Richard Anthony Anderson, Harald Rittger, Sergio Berti, Emanuele Barbato, Gabor Toth, Luc Maillard, Christian Valina, Paweł Buszman, Holger Thiele, Volker Schachinger, Andreas Baumbach, Alexandra Lansky
Journal: Journal of the American College of Cardiology (2021)
Single-dose replicating poxvirus vector-based RBD vaccine drives robust humoral and T cell immune response against SARS-CoV-2 infection
Authors: Stephen Boulton, Joanna Poutou, Nikolas T. Martin, Taha Azad, Ragunath Singaravelu, Mathieu J.F. Crupi, Taylor Jamieson, Xiaohong He, Ricardo Marius, Julia Petryk, Christiano Tanese de Souza, Bradley Austin, Zaid Taha, Jack Whelan, Sarwat T. Khan, Adrian Pelin, Reza Rezaei, Abera Surendran, Sarah Tucker, Emily E.F. Fekete, Jaahnavi Dave, Jean-Simon Diallo, Rebecca Auer, Jonathan B. Angel, D. William Cameron, Jean-Francois Cailhier, Réjean Lapointe, Kyle Potts, Douglas J. Mahoney, John C. Bell, Carolina S. Ilkow
Journal: Molecular Therapy (2021)

The coronavirus disease 2019 (COVID-19) pandemic requires the continued development of safe, long-lasting, and efficacious vaccines for preventive responses to major outbreaks around the world, and especially in isolated and developing countries. To combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we characterize a temperature-stable vaccine candidate (TOH-Vac1) that uses a replication-competent, attenuated vaccinia virus as a vector to express a membrane-tethered spike receptor binding domain (RBD) antigen. We evaluate the effects of dose escalation and administration routes on vaccine safety, efficacy, and immunogenicity in animal models. Our vaccine induces high levels of SARS-CoV-2 neutralizing antibodies and favorable T cell responses, while maintaining an optimal safety profile in mice and cynomolgus macaques. We demonstrate robust immune responses and protective immunity against SARS-CoV-2 variants after only a single dose. Together, these findings support further development of our novel and versatile vaccine platform as an alternative or complementary approach to current vaccines.
DNA crosslinking and recombination‐activating genes 1/2 (RAG1/2) are required for oncogenic splicing in acute lymphoblastic leukemia
Authors: Hao Zhang, Nuo Cheng, Zhihui Li, Ling Bai, Chengli Fang, Yuwen Li, Weina Zhang, Xue Dong, Minghao Jiang, Yang Liang, Sujiang Zhang, Jianqing Mi, Jiang Zhu, Yu Zhang, Sai‐Juan Chen, Yajie Zhao, Xiang‐Qin Weng, Weiguo Hu, Zhu Chen, Jinyan Huang, Guoyu Meng
Journal: Cancer Communications (2021)

Abstract Background Abnormal alternative splicing is frequently associated with carcinogenesis. In B‐cell acute lymphoblastic leukemia (B‐ALL), double homeobox 4 fused with immunoglobulin heavy chain (DUX4/IGH) can lead to the aberrant production of E‐26 transformation‐specific family related gene abnormal transcript (ERG alt ) and other splicing variants. However, the molecular mechanism underpinning this process remains elusive. Here, we aimed to know how DUX4/IGH triggers abnormal splicing in leukemia. Methods The differential intron retention analysis was conducted to identify novel DUX4/IGH‐driven splicing in B‐ALL patients. X‐ray crystallography, small angle X‐ray scattering (SAXS), and analytical ultracentrifugation were used to investigate how DUX4/IGH recognize double DUX4 responsive element (DRE)‐DRE sites. The ERG alt biogenesis and B‐cell differentiation assays were performed to characterize the DUX4/IGH crosslinking activity. To check whether recombination‐activating gene 1/2 (RAG1/2) was required for DUX4/IGH‐driven splicing, the proximity ligation assay, co‐immunoprecipitation, mammalian two hybrid characterizations, in vitro RAG1/2 cleavage, and shRNA knock‐down assays were performed. Results We reported previously unrecognized intron retention events in C‐type lectin domain family 12, member A abnormal transcript (CLEC12A alt ) and chromosome 6 open reading frame 89 abnormal transcript (C6orf89 alt ), where also harbored repetitive DRE‐DRE sites. Supportively, X‐ray crystallography and SAXS characterization revealed that DUX4 homeobox domain (HD)1‐HD2 might dimerize into a dumbbell‐shape trans configuration to crosslink two adjacent DRE sites. Impaired DUX4/IGH‐mediated crosslinking abolishes ERG alt , CLEC12A alt , and C6orf89 alt biogenesis, resulting in marked alleviation of its inhibitory effect on B‐cell differentiation. Furthermore, we also observed a rare RAG1/2‐mediated recombination signal sequence‐like DNA edition in DUX4/IGH target genes. Supportively, shRNA knock‐down of RAG1/2 in leukemic Reh cells consistently impaired the biogenesis of ERG alt , CLEC12A alt , and C6orf89 alt . Conclusions All these results suggest that DUX4/IGH‐driven DNA crosslinking is required for RAG1/2 recruitment onto the double tandem DRE‐DRE sites, catalyzing V(D)J‐like recombination and oncogenic splicing in acute lymphoblastic leukemia.
Anakinra Targeting Cytokine Release Syndrome Associated with Chimeric Antigen Receptor T-Cell Therapies
Authors: Sandy W. Wong, Shambavi Richard, Yi Lin, Deepu Madduri, Carolyn C. Jackson, Enrique Zudaire, Vadim Romanov, Michael Trigg, Martin Vogel, Ashraf Garrett, Lisa Hullinger, Tonia Nesheiwat, Thomas Martin, Sundar Jagannath
Journal: Blood (2021)
Risk of Incident Dementia According to Glycemic Status and Comorbidities of Hyperglycemia: A Nationwide Population-Based Cohort Study
Authors: Woo Jung Kim, Seo Jung Lee, Eun Lee, Eun Y. Lee, Kyungdo Han
Journal: Diabetes Care (2021)

OBJECTIVE To investigate the risk of incident dementia according to fasting glucose levels and presence of comorbidities. RESEARCH DESIGN AND METHODS Using a health insurance claims database and the results of biennial health examinations in South Korea, we selected 8,400,950 subjects aged ≥40 years who underwent health examinations in 2009–2010. We followed them until 2016. Subjects’ baseline characteristics were categorized by presence of diabetes (yes/no) and glycemic status as normoglycemia, impaired fasting glucose (IFG), new-onset diabetes, or known diabetes (duration &amp;lt;5 years or ≥5 years). We estimated adjusted hazard ratios (aHRs) for dementia occurrence in each category. RESULTS During the observation period of 48,323,729 person-years, all-cause dementia developed in 353,392 subjects (4.2%). Compared with normoglycemia, aHRs (95% CI) were 1.01 (1.01–1.02) in IFG, 1.45 (1.44–1.47) in new-onset diabetes, 1.32 (1.30–1.33) in known diabetes &amp;lt;5 years, and 1.62 (1.60–1.64) in known diabetes ≥5 years. We found that associations between ischemic heart disease and chronic kidney disease with incident dementia were affected by the presence of diabetes. Ischemic stroke showed a greater association with incident dementia than diabetes. CONCLUSIONS Mild degrees of hyperglycemia and presence of comorbidities were associated with incident dementia. Intervention during the prodromal stage of a chronic disease (e.g., prediabetes) could be considered for dementia prevention.
TCT-501 Impact of TAVR Implantation Technique on Need for Permanent Pacemaker Implantation
Authors: Immad Sadiq, Muhammad Umair Bakhsh, Sarfaraz Memon, Hossein Ouranos, Hadi Mahmaljy, Sidhanta Gurung, Nicole Hoover, Asad Rizvi, Robert Hagberg, Talhat Azemi
Journal: Journal of the American College of Cardiology (2021)
Beta RBD boost broadens antibody-mediated protection against SARS-CoV-2 variants in animal models
Authors: Daniel J. Sheward, Marco Mandolesi, Egon Urgard, Changil Kim, Leo Hanke, Laura Perez Vidakovics, Alec Pankow, Natalie L. Smith, Xaquin Castro Dopico, Gerald M. McInerney, Jonathan M. Coquet, Gunilla B. Karlsson Hedestam, Ben Murrell
Journal: Cell Reports Medicine (2021)

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with resistance to neutralizing antibodies are threatening to undermine vaccine efficacy. Vaccination and infection have led to widespread humoral immunity against the pandemic founder (Wu-Hu-1). Against this background, it is critical to assess the outcomes of subsequent immunization with variant antigens. It is not yet clear whether heterotypic boosts would be compromised by original antigenic sin, where pre-existing responses to a prior variant dampen responses to a new one, or whether the memory B cell repertoire would bridge the gap between Wu-Hu-1 and VOCs. We show, in macaques immunized with Wu-Hu-1 spike, that a single dose of adjuvanted beta variant receptor binding domain (RBD) protein broadens neutralizing antibody responses to heterologous VOCs. Passive transfer of plasma sampled after Wu-Hu-1 spike immunization only partially protects K18-hACE2 mice from lethal challenge with a beta variant isolate, whereas plasma sampled following heterotypic RBD boost protects completely against disease.