tbuckley/cabot-search huggingface dataset:
Pharmacology of TRPC Channels and Its Potential in Cardiovascular and Metabolic Medicine
Authors: Robin S. Bon, David J. Wright, David J. Beech, Piruthivi Sukumar
Journal: The Annual Review of Pharmacology and Toxicology (2021)

Transient receptor potential canonical (TRPC) proteins assemble to form homo- or heterotetrameric, nonselective cation channels permeable to K+, Na+, and Ca2+. TRPC channels are thought to act as complex integrators of physical and chemical environmental stimuli. Although the understanding of essential physiological roles of TRPC channels is incomplete, their implication in various pathological mechanisms and conditions of the nervous system, kidneys, and cardiovascular system in combination with the lack of major adverse effects of TRPC knockout or TRPC channel inhibition is driving the search of TRPC channel modulators as potential therapeutics. Here, we review the most promising small-molecule TRPC channel modulators, the understanding of their mode of action, and their potential in the study and treatment of cardiovascular and metabolic disease.
Integrated Biomarkers for the Management of Indeterminate Pulmonary Nodules
Authors: Michael N. Kammer, Dhairya A. Lakhani, Aneri B. Balar, Sanja L. Antic, Amanda K. Kussrow, Rebekah L. Webster, Shayan Mahapatra, Udaykamal Barad, Chirayu Shah, Thomas Atwater, Brenda Diergaarde, Jun Qian, Alexander Kaizer, Melissa New, Erin Hirsch, William J. Feser, Jolene Strong, Matthew Rioth, York E. Miller, Yoganand Balagurunathan, Dianna J. Rowe, Sherif Helmey, Sheau-Chiann Chen, Joseph Bauza, Stephen A. Deppen, Kim Sandler, Fabien Maldonado, Avrum Spira, Ehab Billatos, Matthew B. Schabath, Robert J. Gillies, David O. Wilson, Ronald C. Walker, Bennett Landman, Heidi Chen, Eric L. Grogan, Anna E. Barón, Darryl J. Bornhop, Pierre P. Massion
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Patients with indeterminate pulmonary nodules (IPNs) at risk of cancer undergo high rates of invasive, costly, and morbid procedures. Objectives: To train and externally validate a risk prediction model that combined clinical, blood, and imaging biomarkers to improve the noninvasive management of IPNs. Methods: In this prospectively collected, retrospective blinded evaluation study, probability of cancer was calculated for 456 patient nodules using the Mayo Clinic model, and patients were categorized into low-, intermediate-, and high-risk groups. A combined biomarker model (CBM) including clinical variables, serum high sensitivity CYFRA 21-1 level, and a radiomic signature was trained in cohort 1 (n = 170) and validated in cohorts 2–4 (total n = 286). All patients were pooled to recalibrate the model for clinical implementation. The clinical utility of the CBM compared with current clinical care was evaluated in 2 cohorts. Measurements and Main Results: The CBM provided improved diagnostic accuracy over the Mayo Clinic model with an improvement in area under the curve of 0.124 (95% bootstrap confidence interval, 0.091–0.156; P < 2 × 10−16). Applying 10% and 70% risk thresholds resulted in a bias-corrected clinical reclassification index for cases and control subjects of 0.15 and 0.12, respectively. A clinical utility analysis of patient medical records estimated that a CBM-guided strategy would have reduced invasive procedures from 62.9% to 50.6% in the intermediate-risk benign population and shortened the median time to diagnosis of cancer from 60 to 21 days in intermediate-risk cancers. Conclusions: Integration of clinical, blood, and image biomarkers improves noninvasive diagnosis of patients with IPNs, potentially reducing the rate of unnecessary invasive procedures while shortening the time to diagnosis.
CARs and beyond: tailoring macrophage-based cell therapeutics to combat solid malignancies
Authors: Shifaa M. Abdin, Daniela Paasch, Michael Morgan, Nico Lachmann
Journal: Journal for ImmunoTherapy of Cancer (2021)

Recent understanding of the role and contribution of immune cells in disease onset and progression has pioneered the field of immunotherapies. Use of genetic engineering to deliver, correct or enhance immune cells has been clinically successful, especially in the field of cancer immunotherapy. Indeed, one of the most attractive approaches is the introduction of chimeric antigen receptors (CARs) to immune cells, such as T cells. Recent studies revealed that adapting this platform for use in macrophages may widen the spectrum of CAR applications for better control of solid tumors and, thus, extend this treatment strategy to more patients with cancer. Given the novel insights into tumor-associated macrophages and new targeting strategies to boost anticancer therapy, this review aims to provide an overview of the current status of the role of macrophages in cancer therapy. The various genetic engineering approaches that can be used to optimize macrophages for use in oncology are discussed, with special attention dedicated to the implication of the CAR platform on macrophages for anticancer therapy. The current clinical status, challenges and future perspective of macrophage-based drugs are highlighted.
Two Functional Epithelial Sodium Channel Isoforms Are Present in Rodents despite Pronounced Evolutionary Pseudogenization and Exon Fusion
Authors: Sean M Gettings, Stephan Maxeiner, Maria Tzika, Matthew R D Cobain, Irina Ruf, Fritz Benseler, Nils Brose, Gabriela Krasteva-Christ, Greetje Vande Velde, Matthias Schönberger, Mike Althaus
Journal: Molecular Biology and Evolution (2021)

Abstract The epithelial sodium channel (ENaC) plays a key role in salt and water homeostasis in tetrapod vertebrates. There are four ENaC subunits (α, β, γ, δ), forming heterotrimeric αβγ- or δβγ-ENaCs. Although the physiology of αβγ-ENaC is well understood, for decades the field has stalled with respect to δβγ-ENaC due to the lack of mammalian model organisms. The SCNN1D gene coding for δ-ENaC was previously believed to be absent in rodents, hindering studies using standard laboratory animals. We analyzed all currently available rodent genomes and discovered that SCNN1D is present in rodents but was independently lost in five rodent lineages, including the Muridae (mice and rats). The independent loss of SCNN1D in rodent lineages may be constrained by phylogeny and taxon-specific adaptation to dry habitats, however habitat aridity does not provide a selection pressure for maintenance of SCNN1D across Rodentia. A fusion of two exons coding for a structurally flexible region in the extracellular domain of δ-ENaC appeared in the Hystricognathi (a group that includes guinea pigs). This conserved pattern evolved at least 41 Ma and represents a new autapomorphic feature for this clade. Exon fusion does not impair functionality of guinea pig (Cavia porcellus) δβγ-ENaC expressed in Xenopus oocytes. Electrophysiological characterization at the whole-cell and single-channel level revealed conserved biophysical features and mechanisms controlling guinea pig αβγ- and δβγ-ENaC function as compared with human orthologs. Guinea pigs therefore represent commercially available mammalian model animals that will help shed light on the physiological function of δ-ENaC.
Receipt of mRNA Covid-19 Vaccines and Risk of Spontaneous Abortion
Authors: Lauren H Zauche, Bailey Wallace, Ashley N Smoots, Christine K Olson, Titilope Oduyebo, Shin Y Kim, Emily E Petersen, Jun Ju, Jennifer Beauregard, Allen J Wilcox, Charles E Rose, Dana M Meaney-Delman, Sascha R Ellington
Journal: New England Journal of Medicine (2021)

mRNA Covid-19 Vaccines and Risk of Spontaneous Abortion In this updated analysis from the CDC v-safe pregnancy registry, the cumulative risk of pregnancy loss at 6 to less than 20 weeks of gestatio...
Abstract 16087: Vitamin D May be Associated With the Renal Effects of Angiotensin II Receptor Blocker in African Americans
Authors: Li Chen, Haidong Zhu, Ying Huang, Gregory Harshfield, Yanbin Dong
Journal: Circulation (2019)

Objective: Angiotensin II receptor blocker (ARB), a first-line treatment for hypertension, is less effective in African Americans, probably due to the negative effect on renal function. We aimed to...
Fragile X Syndrome: Lessons Learned and What New Treatment Avenues Are on the Horizon
Authors: Randi J. Hagerman, Paul J. Hagerman
Journal: The Annual Review of Pharmacology and Toxicology (2021)

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading single-gene form of autism spectrum disorder, encompassing cognitive, behavioral, and physical forms of clinical involvement. FXS is caused by large expansions of a noncoding CGG repeat (&gt;200 repeats) in the FMR1 gene, at which point the gene is generally silenced. Absence of FMR1 protein (FMRP), important for synaptic development and maintenance, gives rise to the neurodevelopmental disorder. There is, at present, no therapeutic approach that directly reverses the loss of FMRP; however, there is an increasing number of potential treatments that target the pathways dysregulated in FXS, including those that address the enhanced activity of the mGluR5 pathway and deficits in GABA pathways. Based on studies of targeted therapeutics to date, the prospects are good for one or more effective therapies for FXS in the near future.
Liquid Biopsy for Cancer Detection: Clinical and Epidemiologic Considerations
Authors: Nicolas Wentzensen, Megan A. Clarke
Journal: Clinical Cancer Research (2021)

Abstract Detection of circulating nucleic acids, also referred to as liquid biopsy, has been evaluated for detection of cancer in a variety of settings. We describe important clinical and epidemiologic considerations for liquid biopsy applications in cancer early detection and for monitoring of cancer recurrence. See related article by Jeannot et al., p. 5869
SARS-CoV-2-specific T cells in infection and vaccination
Authors: Antonio Bertoletti, Nina Le Bert, Martin Qui, Anthony T. Tan
Journal: Cellular and Molecular Immunology (2021)

During viral infections, antibodies and T cells act together to prevent pathogen spread and remove virus-infected cells. Virus-specific adaptive immunity can, however, also trigger pathological processes characterized by localized or systemic inflammatory events. The protective and/or pathological role of virus-specific T cells in SARS-CoV-2 infection has been the focus of many studies in COVID-19 patients and in vaccinated individuals. Here, we review the works that have elucidated the function of SARS-CoV-2-specific T cells in patients and in vaccinated individuals. Understanding whether SARS-CoV-2-specific T cells are more linked to protection or pathogenesis is pivotal to define future therapeutic and prophylactic strategies to manage the current pandemic.
The effect of immunosuppressants on the prognosis of SARS-CoV-2 infection
Authors: Daniel Ward, Sanne Gørtz, Martin Thomson Ernst, Nynne Nyboe Andersen, Susanne K. Kjær, Jesper Hallas, Steffen Christensen, Christian Fynbo Christiansen, Simone Bastrup Israelsen, Thomas Benfield, Anton Pottegård, Tine Jess
Journal: European Respiratory Journal (2021)

Background Immunosuppression may worsen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a nationwide cohort study of the effect of exposure to immunosuppressants on the prognosis of SARS-CoV-2 infection in Denmark. Methods We identified all SARS-CoV-2 test-positive patients from February 2020 to October 2020 and linked healthcare data from nationwide registers, including prescriptions for the exposure (immunosuppressant drugs). We estimated relative risks of hospital admission, intensive care unit (ICU) admission and death (each studied independently up to 30 days from testing) with a log-linear binomial regression adjusted for confounders using a propensity score-based matching weights model. Results A composite immunosuppressant exposure was associated with a significantly increased risk of death (adjusted relative risk 1.56 (95% CI 1.10–2.22)). The increased risk of death was mainly driven by exposure to systemic glucocorticoids (adjusted relative risk 2.38 (95% CI 1.72–3.30)), which were also associated with an increased risk of hospital admission (adjusted relative risk 1.34 (95% CI 1.10–1.62)), but not of ICU admission (adjusted relative risk 1.76 (95% CI 0.93–3.35)); these risks were greater for high cumulative doses of glucocorticoids than for moderate doses. Exposure to selective immunosuppressants, tumour necrosis factor inhibitors or interleukin inhibitors was not associated with an increased risk of hospitalisation, ICU admission or death, nor was exposure to calcineurin inhibitors, other immunosuppressants, hydroxychloroquine or chloroquine. Conclusions Exposure to glucocorticoids was associated with increased risks of hospital admission and death. Further investigation is needed to determine the optimal management of coronavirus disease 2019 (COVID-19) in patients with pre-morbid glucocorticoid usage, specifically whether these patients require altered doses of glucocorticoids.
Compression-Only Versus Rescue-Breathing Cardiopulmonary Resuscitation After Pediatric Out-of-Hospital Cardiac Arrest
Authors: Maryam Y Naim, Heather M Griffis, Robert A Berg, Richard N Bradley, Rita V Burke, David Markenson, Bryan F McNally, Vinay M Nadkarni, Lihai Song, Kimberly Vellano, Victoria Vetter, Joseph W Rossano
Journal: Journal of the American College of Cardiology (2021)
Ichthyosiform Rashes and Joint Pain in a Boy
Authors: Hsuan Ning Wang, Chao-Yi Wu, Chun-Bing Chen
Journal: JAMA Dermatology (2021)

A school-aged boy presents with generalized erythematous rashes for 4 years and ichthyosiform brownish plaques on his lower extremities and multiple erythematous confluent papules and plaques on his trunk and face. What is your diagnosis?
Fundamentals and developments in fluorescence-guided cancer surgery
Authors: J. Sven D. Mieog, Friso B. Achterberg, Aimen Zlitni, Merlijn Hutteman, Jacobus Burggraaf, Rutger-Jan Swijnenburg, Sylvain Gioux, Alexander L. Vahrmeijer
Journal: Nature Reviews Clinical Oncology (2021)
Managing Pulmonary Oligometastatic Disease With Stereotactic Body Radiation Therapy—Moving the Field Forward 1 Organ at a Time
Authors: Arya Amini
Journal: JAMA Oncology (2021)

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Downregulation of a mitochondrial micropeptide, MPM, promotes hepatoma metastasis by enhancing mitochondrial complex I activity
Authors: Man-Huan Xiao, Yi-Fang Lin, Peng-Peng Xie, Hua-Xing Chen, Jun-Wen Deng, Wei Zhang, Na Zhao, Chen Xie, Yu Meng, Xingguo Liu, Shi-Mei Zhuang, Ying Zhu, Jian-Hong Fang
Journal: Molecular Therapy (2021)

We and others have shown that MPM (micropeptide in mitochondria) regulates myogenic differentiation and muscle development. However, the roles of MPM in cancer development remain unknown. Here we revealed that MPM was downregulated significantly in human hepatocellular carcinoma (HCC) tissues and its decrease was associated with increased metastasis potential and HCC recurrence. Gain- and loss-of-function investigations disclosed that in vitro migration/invasion and in vivo liver/lung metastasis of hepatoma cells were repressed by restoring MPM expression and increased by silencing MPM. Mechanism investigations revealed that MPM interacted with NDUFA7. Mitochondrial complex I activity was inhibited by overexpressing MPM and enhanced by siMPM, and this effect of siMPM was attenuated by knocking down NDUFA7. The NAD+/NADH ratio, which was regulated by complex I, was reduced by MPM but increased by siMPM. Treatment with the NAD+ precursor nicotinamide abrogated the inhibitory effect of MPM on hepatoma cell migration. Further investigations showed that miR-17-5p bound to MPM and inhibited MPM expression. miR-17-5p upregulation was associated with MPM downregulation in HCC tissues. These findings indicate that a decrease in MPM expression may promote hepatoma metastasis by increasing mitochondrial complex I activity and the NAD+/NADH ratio.
Call for Emergency Action to Limit Global Temperature Increases, Restore Biodiversity, and Protect Health
Authors: Lukoye Atwoli, Abdullah H. Baqui, Thomas Benfield, Raffaella Bosurgi, Fiona Godlee, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Carlos Augusto Monteiro, Ian Norman, Kirsten Patrick, Nigel Praities, Marcel G.M. Olde Rikkert, Eric J. Rubin, Peush Sahni, Richard Smith, Nick Talley, Sue Turale, Damián Vázquez
Journal: New England Journal of Medicine (2021)

Call for Emergency Action on Climate Crisis A joint editorial published simultaneously in biomedical journals across the globe calls for swift and decisive action, noting that only fundamental and ...
SARS-CoV-2 infection after vaccination in patients with inflammatory rheumatic and musculoskeletal diseases
Authors: Saskia Lawson-Tovey, Kimme L Hyrich, Laure Gossec, Anja Strangfeld, Loreto Carmona, Bernd Raffeiner, Gözde Kübra Yardımcı, Ludovic Trefond, Nicolas Roux, Ana Rodrigues, Charalampos Papagoras, Elsa F Mateus, Xavier Mariette, Pedro M Machado
Journal: Annals of the Rheumatic Diseases (2021)

Patients with inflammatory rheumatic and musculoskeletal diseases (iRMDs) are often treated with immunomodulatory or immunosuppressive medications; consequently, they have been excluded alongside other immunocompromised patients from late stages of SARS-CoV-2 vaccine trials. SARS-CoV-2 vaccine efficacy in this population is unclear, though initial data are reassuring overall.

However, a slightly lower SARS-CoV-2 immunogenicity of vaccines has been documented in some patients with iRMD.1 2 Some common rheumatic and musculoskeletal disease (RMD) medications have been highlighted as possible influential factors on immunogenicity, particularly rituximab (RTX), mycophenolate mofetil (MMF), methotrexate (MTX), abatacept and glucocorticoids.3–7

The European Alliance of Associations for Rheumatology (EULAR) launched a COVID-19 registry in March 2020, capturing COVID-19 outcomes in the European RMD population. Questions on reinfection and vaccination were added in January 2021. A further EULAR registry (COVAX) was launched in February 2021 to collect data on COVID-19 vaccination and related adverse events among patients with RMD. Here we describe a series of patients who contracted SARS-CoV-2 infection after COVID-19 vaccination between 19 January 2021 and 27 July 2021.

The series consists of 38 adults with iRMDs, 8 from the COVID-19 registry (<1%, out of 9118 patients with iRMD diagnosed with COVID-19) and 30 from the COVAX registry (<1%, out of 4393). Cases were deemed eligible if they were ‘partially vaccinated’ (≥14 days after dose 1 to <14 days after dose 2) or ‘fully vaccinated’ (≥14 days after dose 2/single dose), as per Centers for Disease Control and Prevention definitions8 (17 cases were excluded for this reason). A quarter (26%) were fully vaccinated and 28 cases (74%) were partially vaccinated.

As shown in table 1, 76% of the series is female, with a median age of 58 (IQR 49–65) from 12 countries. The most frequent iRMD …
Population genomics of the critically endangered kākāpō
Authors: Nicolas Dussex, Tom van der Valk, Hernán E. Morales, Christopher W. Wheat, David Díez-del-Molino, Johanna von Seth, Yasmin Foster, Verena E. Kutschera, Katerina Guschanski, Arang Rhie, Adam M. Phillippy, Jonas Korlach, Kerstin Howe, William Chow, Sarah Pelan, Joanna D. Mendes Damas, Harris A. Lewin, Alex R. Hastie, Giulio Formenti, Olivier Fedrigo, Joseph Guhlin, Thomas W.R. Harrop, Marissa F. Le Lec, Peter K. Dearden, Leanne Haggerty, Fergal J. Martin, Vamsi Kodali, Françoise Thibaud-Nissen, David Iorns, Michael Knapp, Neil J. Gemmell, Fiona Robertson, Ron Moorhouse, Andrew Digby, Daryl Eason, Deidre Vercoe, Jason Howard, Erich D. Jarvis, Bruce C. Robertson, Love Dalén
Journal: Cell Genomics (2021)

The kākāpō is a flightless parrot endemic to New Zealand. Once common in the archipelago, only 201 individuals remain today, most of them descending from an isolated island population. We report the first genome-wide analyses of the species, including a high-quality genome assembly for kākāpō, one of the first chromosome-level reference genomes sequenced by the Vertebrate Genomes Project (VGP). We also sequenced and analyzed 35 modern genomes from the sole surviving island population and 14 genomes from the extinct mainland population. While theory suggests that such a small population is likely to have accumulated deleterious mutations through genetic drift, our analyses on the impact of the long-term small population size in kākāpō indicate that present-day island kākāpō have a reduced number of harmful mutations compared to mainland individuals. We hypothesize that this reduced mutational load is due to the island population having been subjected to a combination of genetic drift and purging of deleterious mutations, through increased inbreeding and purifying selection, since its isolation from the mainland ∼10,000 years ago. Our results provide evidence that small populations can survive even when isolated for hundreds of generations. This work provides key insights into kākāpō breeding and recovery and more generally into the application of genetic tools in conservation efforts for endangered species.