tbuckley/cabot-search huggingface dataset:
Tbx5 variants disrupt Nav1.5 function differently in patients diagnosed with Brugada or Long QT Syndrome
Authors: Paloma Nieto-Marín, David Tinaquero, Raquel G Utrilla, Jorge Cebrián, Andrés González-Guerra, Teresa Crespo-García, Anabel Cámara-Checa, Marcos Rubio-Alarcón, María Dago, Silvia Alfayate, David Filgueiras-Rama, Rafael Peinado, José Luis López-Sendón, José Jalife, Juan Tamargo, Juan Antonio Bernal, Ricardo Caballero, Eva Delpón, F Arribas, J Pérez-Villacastín, J J Alonso-Martín, F Atienza, J L López-Sendón, J Toquero, A Hernández-Madrid, E Delpón
Journal: Cardiovascular Research (2021)

Abstract Aims The transcription factor Tbx5 controls cardiogenesis and drives Scn5a expression in mice. We have identified two variants in TBX5 encoding p. D111Y and p. F206L Tbx5, respectively, in two unrelated patients with structurally normal hearts diagnosed with long QT (LQTS) and Brugada (BrS) syndrome. Here, we characterized the consequences of each variant to unravel the underlying disease mechanisms. Methods and results We combined clinical analysis with in vivo and in vitro electrophysiological and molecular techniques in human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs), HL-1 cells, and cardiomyocytes from mice trans-expressing human wild-type (WT) or mutant proteins. Tbx5 increased transcription of SCN5A encoding cardiac Nav1.5 channels, while repressing CAMK2D and SPTBN4 genes encoding Ca/calmodulin kinase IIδ (CaMKIIδ) and βIV-spectrin, respectively. These effects significantly increased Na current (INa) in hiPSC-CMs and in cardiomyocytes from mice trans-expressing Tbx5. Consequently, action potential (AP) amplitudes increased and QRS interval narrowed in the mouse electrocardiogram. p. F206L Tbx5 bound to the SCN5A promoter failed to transactivate it, thus precluding the pro-transcriptional effect of WT Tbx5. Therefore, p. F206L markedly decreased INa in hiPSC-CM, HL-1 cells and mouse cardiomyocytes. The INa decrease in p. F206L trans-expressing mice translated into QRS widening and increased flecainide sensitivity. p. D111Y Tbx5 increased SCN5A expression but failed to repress CAMK2D and SPTBN4. The increased CaMKIIδ and βIV-spectrin significantly augmented the late component of INa (INaL) which, in turn, significantly prolonged AP duration in both hiPSC-CMs and mouse cardiomyocytes. Ranolazine, a selective INaL inhibitor, eliminated the QT and QTc intervals prolongation seen in p. D111Y trans-expressing mice. Conclusions In addition to peak INa, Tbx5 critically regulates INaL and the duration of repolarization in human cardiomyocytes. Our original results suggest that TBX5 variants associate with and modulate the intensity of the electrical phenotype in LQTS and BrS patients.
Prevalence and spectrum of germline mutations in children with high-risk cancer
Authors: Paulette Barahona, Alexandra Sherstyuk, Mark Cowley, Paul Ekert, Judy Kirk, Khuong-Quang Dong-Anh, Amit Kumar, Loretta Lau, Chelsea Mayoh, Glenn Marshall, Emily Moud, Tracey O'Brien, Mark Pinese, David Thomas, Vanessa Tyrell, David Ziegler, Michelle Haber, Katherine Tucker, Noemi Auxiliadora Fuentes-Bolanos, Meera Warby
Journal: Cancer Research (2020)
HuR-targeted Inhibition Impairs Th2 Proinflammatory Responses in Asthmatic CD4+ T cells
Authors: Fatemeh Fattahi, Jason Ellis, Michael Sylveste, Kristin Bahelda, Samuel Hietanen, Luis Correa, Njira Lugogo, Ulus Atasoy
Journal: Journal of Allergy and Clinical Immunology (2021)
Applications of CRISPR Genome Editing to Advance the Next Generation of Adoptive Cell Therapies for Cancer
Authors: Samantha M. Fix, Amir A. Jazaeri, Patrick Hwu
Journal: Cancer Discovery (2021)

Adoptive cell therapy (ACT) for cancer shows tremendous potential; however, several challenges preclude its widespread use. These include poor T-cell function in hostile tumor microenvironments, a lack of tumor-specific target antigens, and the high cost and poor scalability of cell therapy manufacturing. Creative genome-editing strategies are beginning to emerge to address each of these limitations, which has initiated the next generation of cell therapy products now entering clinical trials. CRISPR is at the forefront of this revolution, offering a simple and versatile platform for genetic engineering. This review provides a comprehensive overview of CRISPR applications that have advanced ACT. SIGNIFICANCE: The clinical impact of ACT for cancer can be expanded by implementing specific genetic modifications that enhance the potency, safety, and scalability of cellular products. Here we provide a detailed description of such genetic modifications, highlighting avenues to enhance the therapeutic efficacy and accessibility of ACT for cancer. Furthermore, we review high-throughput CRISPR genetic screens that have unveiled novel targets for cell therapy enhancement.
Abstract 9915: Atrio-ventricular Synchronicity Improves Fontan Hemodynamics
Authors: Hirofumi Saiki, Seiko Kuwata, Manabu Takanashi, Satoshi Masutani, Hideaki Senzaki
Journal: Circulation (2019)

Introduction: Impaired preload reserve coupled with augmented venous congestion is increasingly subject to therapies to prevent cardiovascular remodeling and end organ failure in the Fontan circula...
The BEAT-PCD (Better Experimental Approaches to Treat Primary Ciliary Dyskinesia) Clinical Research Collaboration
Authors: Myrofora Goutaki, Suzanne Crowley, Eleonora Dehlink, René Gaupmann, Katie L. Horton, Panayiotis Kouis, Yin Ting Lam, Niki T. Loges, Jane S. Lucas, Jobst F. Roehmel, Amelia Shoemark
Journal: European Respiratory Journal (2021)

<b>The BEAT-PCD ERS CRC is a large multidisciplinary network of researchers and healthcare professionals aiming to advance clinical and translational research in different areas of primary ciliary dyskinesia building upon previous collaborative initiatives</b>https://bit.ly/39h3veZ
Successful non-exposed endoscopic wall-inversion surgery for gastric stromal tumor and gastric ESD for dysplastic lesion during a single procedure
Authors: Arnaud Pasquer, Gilles Poncet, Florian Rostain, Jérôme Rivory, Valérie Hervieu, Julie Périnel, Mathieu Pioche
Journal: Endoscopy (2021)

For gastrointestinal stromal tumors, the risk of lymph node metastasis is considered negligible and partial gastric resection without lymphadenectomy is accepted [1]. However, conventional gastric wall resections are associated with intentional perforation with a risk of bacterial contamination and tumor cell seeding into the peritoneum. To avoid this dissemination, non-exposed endoscopic wall-inversion surgery has been developed [2] [3] but never reproduced outside Japan [4].
Clinical conditions of patients with chronic urticaria during the pandemic caused by the 2019 Novel Coronavirus Disease (COVID-19)
Authors: Paula Argolo, Grazielly Pereira, G.F. Pereira, Jorge Kalil, Antonio Motta, Rosana Agondi
Journal: Journal of Allergy and Clinical Immunology (2021)

Chronic urticaria (CU) frequently compromises patients' quality of life and stress can be a major factor. This becomes even more important in the current worldwide COVID-19 pandemic scenario. This study aimed to assess how much this disease had compromised patients with CU. This is a retrospective study with data collected from electronic medical records of patients with CU. As routine outpatient visits were suspended due to COVID-19 pandemic, patients received phone calls to reschedule their outpatient visits and during those calls, some questions were asked to assess clinical condition related to CU and possible infection with SARS-CoV-2. From april to july, 2020, 140 patients received phone calls. Nervousness was reported by 80 patients (57.1%), of which 30% reported worsening of urticaria. The use of corticosteroids was more frequent among patients with emotional stress due to the pandemic (20%). Obesity was the other comorbidity most frequently seen in these patients with CU (35%). Of the 22 patients who visited the Emergency Room, 9 (40.9%), only five patients underwent specific investigation to COVID-19 and 2 (22.2%) of them tested positive – one obese patient was intubated for 24 days. During the COVID-19 pandemic, our patients with CU presented more frequently new episodes of emotional stress and these were a factor associated with worsening urticaria and greater use of corticosteroids. Obesity, in our group of patients, was very prevalent and the only patient with CU admitted to an intensive care unit was not elderly but was obese with BMI> 35 kg/m2.
Cellular and humoral immunity in patients infected with the SARS-CoV-2 virus at general hospital
Authors: Valéria Brandão, Thaís T. Saito, Débora S. Guterres, Grasiele Lima, Sara Tencarte, Ana Carolina Dos Santos, Marina Laubi, Roselene Lourenço, Octavio Grecco, Myrthes Toledo Barros, Myrthes T. Barros, Cristina Kokron, Ana Karolina Marinho
Journal: Journal of Allergy and Clinical Immunology (2021)

The cellular immune response seems to have a central role in the pathophysiology of COVID-19. Few studies have analyzed lymphocyte subpopulations and clinical outcomes. We evaluated clinical and immunological characteristics of patients infected with the SARS-CoV-2 virus and described the outcomes during hospitalization. Prospective and descriptive study carried with adult patients, admitted with a diagnosis of COVID-19 confirmed by RT-PCR. We evaluated lymphocytes subsets (CD3+, CD4+, CD8+, CD19), serum immunoglobulin levels (IgG, IgM, IgA) and described the mean hospital stay outcomes, need for intensive care, mechanical ventilation and death. Of the 165 patients included, 65% were male, with an average of 58.7 years. The most related initial symptoms were dyspnea (80%), fever (74%) and cough (70%). Among the reported comorbidities, 58% had obesity, 47% systemic arterial hypertension and 25% diabetes. We observed that 40% lymphopenia, 43% reduction in CD3+, 46% reduction in CD4+, 50% reduction in CD8+ and 39% reduction in CD19+. The average levels of IgG, IgM and IgA were 1,285, 121 and 296mg / dL, respectively. We identified 3 patients with selective IgA deficiency and all were discharged. Regarding the outcome, 28% required intensive care unit, 24% mechanical ventilation conditions and 23% of the patients died. Lymphopenia, reduction of CD8+, CD4+ and CD3+ cells were frequent in hospitalized patients, inferring greater clinical severity. However, we identified three patients with selective IgA deficiency whose outcome was hospital discharge.
Shared Decision-making in Dermatologic Care
Authors: Carrie C. Coughlin, Mary C. Politi
Journal: JAMA Dermatology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Reduction in Attacks in Hereditary Angioedema (HAE) With Berotralstat is Consistent Regardless of Prior Prophylactic Treatment: A Subgroup Analysis of the Phase 3 APeX-2 Trial
Authors: John Anderson, Remi Gagnon, Jessica Best, Sharon Murray, Heather Iocca, Karl Sitz
Journal: Journal of Allergy and Clinical Immunology (2021)
Abstract 14540: Discharge Pharmacological Prophylaxis and 90-Day Outcomes for Venous Thromboembolism After Hip and Knee Replacements in Older Adults
Authors: Darae Ko, Alok Kapoor, Adam Rose, Amresh Hanchate, Donald Miller, Michael Winter, Joseph Palmisano, Lori Henault, Yorghos Tripodis, Anita Karcz, Elaine Hylek
Journal: Circulation (2017)

Background: Venous thromboembolism (VTE) after total hip and knee replacement (THR and TKR) is a major patient safety threat. We sought to report trends in the selection of prophylaxis agents at th...
Millions face potential health risks from climate change in UK, report warns
Authors: Gareth Iacobucci
Journal: BMJ (2021)

Almost a third of people report suffering from post-traumatic stress disorder (PTSD) after having their house flooded, highlighting the potential health risks from climate change for millions of UK residents, a new report1 has warned.

In a joint report published on 5 February, the Climate Coalition and the Priestley International Centre for Climate estimate that more than 12 million people in the UK are vulnerable to adverse health because of events made more likely by climate change such as heatwaves and major flooding.

Around 1.8 million people in the UK live in areas at significant risk of flooding, and this …
NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models
Authors: Stephanie A. Moquin, Oliver Simon, Ratna Karuna, Suresh B. Lakshminarayana, Fumiaki Yokokawa, Feng Wang, Chandra Saravanan, Jin Zhang, Craig W. Day, Katherine Chan, Qing-Yin Wang, Siyan Lu, Hongping Dong, Kah Fei Wan, Siew Pheng Lim, Wei Liu, Cheah Chen Seh, Yen-Liang Chen, Haoying Xu, David T. Barkan, Cyrille S. Kounde, Wei Lin Sandra Sim, Gang Wang, Hui-Quan Yeo, Bin Zou, Wai Ling Chan, Mei Ding, Jae-Geun Song, Min Li, Colin Osborne, Francesca Blasco, Christopher Sarko, David Beer, Ghislain M. C. Bonamy, Vito G. Sasseville, Pei-Yong Shi, Thierry T. Diagana, Bryan K. S. Yeung, Feng Gu
Journal: Science Translational Medicine (2021)

Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility. The lead compound, NITD-688, showed strong potency against all four serotypes of DENV and demonstrated excellent oral efficacy in infected AG129 mice. There was a 1.44-log reduction in viremia when mice were treated orally at 30 milligrams per kilogram twice daily for 3 days starting at the time of infection. NITD-688 treatment also resulted in a 1.16-log reduction in viremia when mice were treated 48 hours after infection. Selection of resistance mutations and binding studies with recombinant proteins indicated that the nonstructural protein 4B is the target of NITD-688. Pharmacokinetic studies in rats and dogs showed a long elimination half-life and good oral bioavailability. Extensive in vitro safety profiling along with exploratory rat and dog toxicology studies showed that NITD-688 was well tolerated after 7-day repeat dosing, demonstrating that NITD-688 may be a promising preclinical candidate for the treatment of dengue.
Detection of genetic alterations in non-small cell lung cancer (NSCLC) using inter-simple sequence repeat PCR
Authors: David M. Broomhead, Peter Jenkins, Sarah L. Morgan, Tracey A. Bailey, Anthony C. Woodman
Journal: Cancer Research (2004)

1705  Lung cancer remains the number one cause of cancer death in the United Kingdom Despite advances in surgery, radiotherapy and chemotherapy the prognosis for lung cancer remains poor, in part due to poor early detection. The analysis of tumours for molecular markers can not only help with a specific diagnosis, but also be used to follow the progression and remission of disease. Such genetic abnormalities in lung cancer are being increasingly recognised, although a multi-stage model similar to that described in other cancers, most notably colorectal, has not yet been defined. Genomic instability is thought to play an important part in cancer progression specifically in the early stages, even before the appearance of any morphological changes. By means of non-radioactive inter-simple-sequence-repeat PCR (InterSSR-PCR) we have assessed the extent of genomic abnormalities occurring in the progression of non-small cell lung cancer (NSCLC). Inter-SSR PCR amplifies regions located between repeated sequences and allows the detection of chromosomal alterations found in DNA segments. DNA was extracted from a variety of cell lines, blood and pinch biopsies from formally consented patients with various types and stages of NSCLC, then amplified using the inter-SSR PCR technique described. Band differences between normal and neoplastic samples were identified by resolution of PCR products on an 8% non-denaturating polyacrylamide electrophoresis gel, following silver staining. By comparing fingerprinting patterns between samples from cell lines of similar lineage or involved/non-involved from the same patient, a number of intensity changes could be visualized. These results demonstrate the first step in characterising molecular events, which may be indicative of carcinoma development, which in turn may allow more precise and earlier risk assessment for individual patients, enabling more effective therapy.
A Phase 2 Study of Capmatinib in Patients With MET-Altered Lung Cancer Previously Treated With a MET Inhibitor
Authors: Ibiayi Dagogo-Jack, Philicia Moonsamy, Justin F. Gainor, Jochen K. Lennerz, Zofia Piotrowska, Jessica J. Lin, Inga T. Lennes, Lecia V. Sequist, Alice T. Shaw, Kelly Goodwin, Sara E. Stevens, Andrew Do, Subba R. Digumarthy, Kristin Price, Alona Muzikansky, Aaron N. Hata, Rebecca S. Heist
Journal: Journal of Thoracic Oncology (2021)
Undiagnosed, familial cold auto-inflammatory syndrome (FCAS) masquerading as COVID-19 cytokine storm
Authors: Dilawar Khokhar, James Baker
Journal: Journal of Allergy and Clinical Immunology (2021)

A patient presented in early April with fever and markers for acute inflammation that appeared to be cytokine storm from COVID-19. Molecular and antibody testing for COVID-19 and other infections were negative. Genetic testing was undertaken to identify a cause for his symptoms. The patient is a 49-year-old male who initially presented In April with a high fever, apparent pneumonia and elevated inflammatory markers suggestive of cytokine storm from COVID-19. His history was notable for a prolonged hospitalization complicated by hyponatremia, hypokalemia, pulmonary embolism and peripheral neuropathy. Extensive evaluation by Endocrinology, Rheumatology, Neurology and Infectious Disease failed to identify a cause for his symptoms. During our evaluation we obtained a history of cold sensitivity and frequent febrile illness during his childhood in Bulgaria. He also reported fever symptoms during winters in Michigan and after minor trauma, and these were associated with arthralgias. Screening of 201 immune associated genes revealed a variant in PLCG2; c.1596 G>T, which causes as sequence change replacing tryptophan with cysteine at amino acid 532 of the PLCG2 protein. While this variant has not been previously described, it is in an exon area associated with FCAS. Patients with FCAS can have a clinical presentation compatible with COVID-19 cytokine storm. Broad ranging genetic screening is important to perform on patients with non-COVID-19, cytokine storm-like presentations to identify novel gene variants potentially causing these symptoms. The findings in this patient suggest that this variant may be pathogenic and associated with a FCAS phenotype.
Heart Rate and Heart Rate Variability Changes Are Not Related to Future Cardiovascular Disease and Death in People With and Without Dysglycemia: A Downfall of Risk Markers? The Whitehall II Cohort Study
Authors: Christian S. Hansen, Marit E. Jørgensen, Marek Malik, Daniel R. Witte, Eric J. Brunner, Adam G. Tabák, Mika Kivimäki, Dorte Vistisen
Journal: Diabetes Care (2021)

OBJECTIVE Higher resting heart rate (rHR) and lower heart rate variability (HRV) are associated with increased risk of cardiovascular disease (CVD) and all-cause mortality in people with and without diabetes. It is unknown whether temporal changes in rHR and HRV may contribute to this risk. We investigated associations between 5-year changes in rHR and HRV and risk of future CVD and death, taking into account participants’ baseline glycemic state. RESEARCH DESIGN AND METHODS In this prospective, population-based cohort study we investigated 4,611 CVD-free civil servants (mean [SD] age, 60 [5.9] years; 70% men). We measured rHR and/or six indices of HRV. Associations of 5-year change in 5-min rHR and HRV with fatal and nonfatal CVD and all-cause mortality or the composite of the two were assessed, with adjustments made for relevant confounders. Effect modification by glycemic state was tested. RESULTS At baseline, 63% of participants were normoglycemic, 29% had prediabetes, and 8% had diabetes. During a median (interquartile range) follow-up of 11.9 (11.4; 12.3) years, 298 participants (6.5%) experienced a CVD event and 279 (6.1%) died of non–CVD-related causes. We found no association between 5-year changes in rHR and HRV and future events. Only baseline rHR was associated with all-cause mortality. A 10 bpm–higher baseline HR level was associated with an 11.4% higher rate of all-cause mortality (95% CI 1.0–22.9%; P = 0.032). Glycemic state did not modify associations. CONCLUSIONS Changes in rHR and HRV and possibly also baseline values of these measures are not associated with future CVD or death in people with or without dysglycemia.
Abstract IA013: Endometrial carcinomas with a mutation in DNA polymerase epsilon: A pathologist view
Authors: Tjalling Bosse
Journal: Clinical Cancer Research (2021)

Abstract POLE exonuclease domain mutations (referred to as ‘POLE mutations’) are found in a wide variety of human malignancies, including endometrial cancer (EC). In all tumor types, cancers with POLE mutations are characterized by an exceptionally high mutational burden and a specific mutational signature. Despite their so-called ‘ultramutated’ phenotype, patients with POLE-mutant cancers have significantly better outcomes compared to patients with POLE-wild-type tumors. This prognostic benefit has thus far been shown for early-stage EC and stage II/III colorectal cancers, and has been suggested for glioblastomas. I will discuss the gained insight into somatic POLE mutations, the underlying mechanism(s) by which these POLE mutations contribute to low risk of recurrence and the possible ways for clinical implementation. Citation Format: Tjalling Bosse. Endometrial carcinomas with a mutation in DNA polymerase epsilon: A pathologist view [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA013.