tbuckley/cabot-search huggingface dataset:
Mutations in the exocyst component EXOC2 cause severe defects in human brain development
Authors: Nicole J. Van Bergen, Syed Mukhtar Ahmed, Felicity Collins, Mark Cowley, Annalisa Vetro, Russell C. Dale, Daniella H. Hock, Christian de Caestecker, Minal Menezes, Sean Massey, Gladys Ho, Tiziana Pisano, Seana Glover, Jovanka Gusman, David A. Stroud, Marcel Dinger, Renzo Guerrini, Ian G. Macara, John Christodoulou
Journal: The Journal of Experimental Medicine (2020)

The exocyst, an octameric protein complex, is an essential component of the membrane transport machinery required for tethering and fusion of vesicles at the plasma membrane. We report pathogenic variants in an exocyst subunit, EXOC2 (Sec5). Affected individuals have severe developmental delay, dysmorphism, and brain abnormalities; variability associated with epilepsy; and poor motor skills. Family 1 had two offspring with a homozygous truncating variant in EXOC2 that leads to nonsense-mediated decay of EXOC2 transcript, a severe reduction in exocytosis and vesicle fusion, and undetectable levels of EXOC2 protein. The patient from Family 2 had a milder clinical phenotype and reduced exocytosis. Cells from both patients showed defective Arl13b localization to the primary cilium. The discovery of mutations that partially disable exocyst function provides valuable insight into this essential protein complex in neural development. Since EXOC2 and other exocyst complex subunits are critical to neuronal function, our findings suggest that EXOC2 variants are the cause of the patients’ neurological disorders.
Abstract 16916: Right Ventricular Function in Aortic Stenosis: Early Marker of Decompensation and Left Ventricular Recovery
Authors: Marzia Rigolli, Sanjay Sivalokanathan, Sacha Bull, Rohan S Wijesurendra, Rina Ariga, Margaret Loudon, Jane M Francis, Theodoros D Karamitsos, Stefan Neubauer, Masliza Mahmod, Saul G Myerson
Journal: Circulation (2017)

Introduction: The right ventricle (RV) in aortic stenosis (AS) has been largely neglected due to the belief that changes occur only late in association with left ventricular (LV) dysfunction and pu...
P-96 Levels of sex hormones and sex steroid receptors in pathological tissues in gastric cancer patients
Authors: O. Kit, E. Frantsiyants, V. Bandovkina, Y. Gevorkyan, N. Soldatkina, N. Samoylenko, N. Cheryarina, E. Dzhenkova, A. Shaposhnikov
Journal: Annals of Oncology (2020)
PTU-064 Online searches for information about alcohol in the uk and worldwide: an exploratory time series analysis using google trends
Authors: S Haroon, A Mittal, N Bhala
Journal: Gut (2017)

Introduction  Alcohol is the leading cause of liver disease in the UK, and is a major cause of preventable morbidity and mortality globally. Public health campaigns that aim to encourage people to reduce their alcohol consumption are typically launched in January, such as Public Health England’s Dry January campaign. We aimed to use publicly available data on the volume and temporal trends of web searches to investigate whether January is the most appropriate month to launch alcohol-related health campaigns in the UK and internationally.  Method  We used Google Trends to analyse the volume and temporal trends of the use of the search term “alcohol” entered into Google over the last 5 years from 19/02/2012 to 12/02/2017. We also used synonyms of alcohol including “booze” and “drinking”. The volume of search activity was measured as a percentage of the peak popularity for a given region and time. We also examined whether there was a significant change in this search activity when the UK Chief Medical Officers’ (CMO) Low Risk Drinking Guidelines were published for consultation on 8thJan 2016.  Results  Google Trends showed regular and recurring annual peaks in web searches for “alcohol”, both in the UK and worldwide, starting at the beginning of December and peaking during Christmas and New Year’s Day (Figure 1). This search activity then fell back to baseline levels within the first two weeks of January. Similar trends were seen when using synonyms of alcohol. Search activity for “alcohol” increased in the UK but this trend was less marked worldwide. There was also a peak in search activity for the term ‘alcohol’ following the publication of the CMO consultation on low risk drinking on the 8th of January 2016, which was similar in intensity to the December peak but which decayed rapidly to baseline levels within 48 hours.  Conclusion  There is a regular annual peak in online searches for information about alcohol in December, a pattern that is seen both in the UK and globally. This potentially represents the optimal time for the implementation of national online campaigns to reduce alcohol misuse in the UK and worldwide. There may be additional benefit in disseminating the CMOs’ low risk drinking guidelines and other alcohol-related health campaigns throughout December when online interest in alcohol is at peak levels and relatively more sustained.  References  UK Chief Medical Officers’ Alcohol Guidelines Review: Summary of the proposed new guidelines. January 2016  Figure 1 Web searches for the term “alcohol” in the Google search engine over the previous 5 years in the UK and worldwide (volume of search activity is expressed as a percentage of the peak popularity for a given region and time  Disclosure of Interest  None Declared
The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: A prospective cohort study
Authors: Adam Shardlow, Natasha J. McIntyre, Nitin V. Kolhe, Laura B. Nellums, Richard J. Fluck, Christopher W. McIntyre, Maarten W. Taal
Journal: PLoS Medicine (2020)

Background Tissue advanced glycation end product (AGE) accumulation has been proposed as a marker of cumulative metabolic stress that can be assessed noninvasively by measurement of skin autofluorescence (SAF). In persons on haemodialysis, SAF is an independent risk factor for cardiovascular events (CVEs) and all-cause mortality (ACM), but data at earlier stages of chronic kidney disease (CKD) are inconclusive. We investigated SAF as a risk factor for CVEs and ACM in a prospective study of persons with CKD stage 3. Methods and findings Participants with estimated glomerular filtration rate (eGFR) 59 to 30 mL/min/1.73 m2 on two consecutive previous blood tests were recruited from 32 primary care practices across Derbyshire, United Kingdom between 2008 and 2010. SAF was measured in participants with CKD stage 3 at baseline, 1, and 5 years using an AGE reader (DiagnOptics). Data on hospital admissions with CVEs (based on international classification of diseases [ICD]-10 coding) and deaths were obtained from NHS Digital. Cox proportional hazards models were used to investigate baseline variables associated with CVEs and ACM. A total of 1,707 of 1,741 participants with SAF readings at baseline were included in this analysis: The mean (± SD) age was 72.9 ± 9.0 years; 1,036 (60.7%) were female, 1,681 (98.5%) were of white ethnicity, and mean (±SD) eGFR was 53.5 ± 11.9 mL/min/1.73 m2. We observed 319 deaths and 590 CVEs during a mean of 6.0 ± 1.5 and 5.1 ± 2.2 years of observation, respectively. Higher baseline SAF was an independent risk factor for CVEs (hazard ratio [HR] 1.12 per SD, 95% CI 1.03–1.22, p = 0.01) and ACM (HR 1.16, 95% CI 1.03–1.30, p = 0.01). Additionally, increase in SAF over 1 year was independently associated with subsequent CVEs (HR 1.11 per SD, 95% CI 1.00–1.22; p = 0.04) and ACM (HR 1.24, 95% CI 1.09–1.41, p = 0.001). We relied on ICD-10 codes to identify hospital admissions with CVEs, and there may therefore have been some misclassification. Conclusions We have identified SAF as an independent risk factor for CVE and ACM in persons with early CKD. These findings suggest that interventions to reduce AGE accumulation, such as dietary AGE restriction, may reduce cardiovascular risk in CKD, but this requires testing in prospective randomised trials. Our findings may not be applicable to more ethnically diverse or younger populations.
Current Intake and Demographic Disparities in the Association of Fructose-Rich Foods and Metabolic Syndrome
Authors: Kristie J. Lancaster
Journal: JAMA Network Open (2020)

Zhila Semnani-Azad, BSc; Tauseef A. Khan, PhD; Sonia Blanco Mejia, MD; Russell J. de Souza, ScD; Lawrence A. Leiter, MD; Cyril W. C. Kendall, PhD; Anthony J. Hanley, PhD; John L. Sievenpiper, MD, PhD
Single-Cell RNA Sequencing Reveals mRNA Splice Isoform Switching during Kidney Development
Authors: Yishay Wineberg, Tali Hana Bar-Lev, Anna Futorian, Nissim Ben-Haim, Leah Armon, Debby Ickowicz, Sarit Oriel, Efrat Bucris, Yishai Yehuda, Naomi Pode-Shakked, Shlomit Gilad, Sima Benjamin, Peter Hohenstein, Benjamin Dekel, Achia Urbach, Tomer Kalisky
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Kidney development is a complex process involving multiple interacting and transitioning cell types. Drop-seq single-cell technology, which measures gene expression from many thousands of individual cells, has been used to characterize these cellular differentiation changes that underlie organ development. However, the alternative splicing of many genes creates an additional layer of cellular heterogeneity that Drop-seq technology cannot measure. Therefore, in this study, full transcript length single-cell RNA sequencing was used to characterize alternative splicing in the mouse embryonic kidney, with particular attention to the identification of genes that are alternatively spliced during the transition from mesenchymal to epithelial cell states, as well as their splicing regulators. These results improve our understanding of the molecular mechanisms that underlie kidney development. Background During mammalian kidney development, nephron progenitors undergo a mesenchymal-to-epithelial transition and eventually differentiate into the various tubular segments of the nephron. Recently, Drop-seq single-cell RNA sequencing technology for measuring gene expression from thousands of individual cells identified the different cell types in the developing kidney. However, that analysis did not include the additional layer of heterogeneity that alternative mRNA splicing creates. Methods Full transcript length single-cell RNA sequencing characterized the transcriptomes of 544 individual cells from mouse embryonic kidneys. Results Gene expression levels measured with full transcript length single-cell RNA sequencing identified each cell type. Further analysis comprehensively characterized splice isoform switching during the transition between mesenchymal and epithelial cellular states, which is a key transitional process in kidney development. The study also identified several putative splicing regulators, including the genes Esrp1/2 and Rbfox1/2 . Conclusions Discovery of the sets of genes that are alternatively spliced as the fetal kidney mesenchyme differentiates into tubular epithelium will improve our understanding of the molecular mechanisms that drive kidney development.
Long‐term efficacy of certolizumab pegol for the treatment of plaque psoriasis: 3‐year results from two randomized phase III trials (CIMPASI‐1 and CIMPASI‐2)
Authors: K.B. Gordon, R.B. Warren, A.B. Gottlieb, A. Blauvelt, D. Thaçi, C. Leonardi, Y. Poulin, M. Boehnlein, F. Brock, C. Ecoffet, K. Reich
Journal: British Journal of Dermatology (2020)

Certolizumab pegol (CZP) is an Fc-free, PEGylated anti-tumour necrosis factor biologic.To report the 3-year efficacy of CZP in plaque psoriasis, pooled from the CIMPASI-1 (NCT02326298) and CIMPASI-2 (NCT02326272) phase III trials.Adults with moderate-to-severe psoriasis for ≥ 6 months were randomized 2 : 2 : 1 to CZP 200 mg, CZP 400 mg or placebo, every 2 weeks (Q2W) for up to 48 weeks. Patients entering the open-label period (weeks 48-144) from double-blinded CZP initially received CZP 200 mg Q2W. Patients not achieving ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50) at week 16 entered an open-label CZP 400 mg Q2W escape arm (weeks 16-144). Dose adjustments based on PASI response were permitted during open-label treatment. Outcomes included PASI 75, PASI 90 and Physician's Global Assessment (PGA) 0/1 responder rates, based on a logistic regression model (missing data imputed using Markov Chain Monte Carlo methodology).In total, 186 patients were randomized to CZP 200 mg Q2W and 175 to CZP 400 mg Q2W. At week 48, PASI 75/90 was achieved by 72·7%/51·3% of patients randomized to CZP 200 mg and 84·4%/62·7% randomized to CZP 400 mg. Patients entering the open-label period at week 48, from blinded treatment, received CZP 200 mg Q2W. At week 144, PASI 75/90 was achieved by 70·6%/48·7% patients randomized to CZP 200 mg and 72·9%/42·7% randomized to CZP 400 mg. At week 16, 72 placebo-randomized patients entered the CZP 400 mg Q2W escape arm; 75.7%/58.5% achieved PASI 75/90 at week 144.Both CZP 200 mg and 400 mg Q2W demonstrated sustained, durable efficacy, with numerically higher responses for some outcomes with 400 mg Q2W.
Myocardial infarction accelerates breast cancer via innate immune reprogramming
Authors: Graeme J. Koelwyn, Alexandra A. C. Newman, Milessa S. Afonso, Coen van Solingen, Emma M. Corr, Emily J. Brown, Kathleen B. Albers, Naoko Yamaguchi, Deven Narke, Martin Schlegel, Monika Sharma, Lianne C. Shanley, Tessa J. Barrett, Karishma Rahman, Valeria Mezzano, Edward A. Fisher, David S. Park, Jonathan D. Newman, Daniela F. Quail, Erik R. Nelson, Bette J. Caan, Lee W. Jones, Kathryn J. Moore
Journal: Nature Medicine (2020)
Incidence of Secondary Malignancies in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) in the Era of Tyrosine Kinase Inhibitors (TKI)
Authors: Koji Sasaki, Hagop M. Kantarjian, Susan M. O'Brien, Farhad Ravandi, Marina Konopleva, Gautam Borthakur, Guillermo Garcia-Manero, William G Wierda, Naval Daver, Alessandra Ferrajoli, Koichi Takahashi, Preetesh Jain, Mary B. Rios, Sherry Pierce, Elias J. Jabbour, Jorge E. Cortes
Journal: Blood (2017)
Evaluation of the Use of Capecitabine for the Treatment and Prevention of Actinic Keratoses, Squamous Cell Carcinoma, and Basal Cell Carcinoma
Authors: David M. Schauder, Jinwan Kim, Rajiv I. Nijhawan
Journal: JAMA Dermatology (2020)

<h3>Importance</h3> Certain patient groups, such as solid organ transplant recipients (SOTRs), have a significantly increased risk of developing skin cancers. The chemotherapeutic drug capecitabine has been used off label as a chemopreventive modality to suppress the development of precancerous skin lesions and squamous cell carcinomas (SCCs). <h3>Objective</h3> To systematically review published studies on the use of capecitabine for the treatment and prevention of precancerous and cancerous skin lesions, with a focus on cutaneous SCC. <h3>Evidence Review</h3> For this systematic review, a literature search was performed using the PubMed and Embase databases in December 2019 for all articles published between January 1, 1998, and December 31, 2019, using the search term<i>capecitabine</i>paired with each of the following terms:<i>actinic keratosis, actinic keratoses, squamous cell carcinoma</i>, and<i>basal cell carcinoma</i>. Articles on the use of capecitabine for the treatment and prevention of actinic keratoses (AKs), SCCs, and basal cell carcinomas (BCCs) were selected for inclusion. <h3>Findings</h3> Sixteen publications met the criteria for inclusion, with 8 case reports describing the inflammation of AKs in patients with solid organ cancer treated with capecitabine (2 patients with breast cancer and 6 patients with colorectal cancer). One case report and 1 case series of 4 patients investigated the use of capecitabine for the treatment of advanced or widespread cutaneous SCCs. A total of 6 publications (3 case reports and 3 case series) described the use of capecitabine to prevent development of SCCs in SOTRs. Of these case series, 2 studies found a significant reduction in SCC incidence rate during treatment with capecitabine compared with before treatment. Adverse effects, such as fatigue, nausea, vomiting, diarrhea, elevated creatinine level, hand-foot syndrome, hyperuricemia, weight loss, anemia, and cardiomyopathy, limited the duration of chemoprevention in several patients. <h3>Conclusions and Relevance</h3> Capecitabine treatment may be associated with a decrease in the incidence of SCCs in SOTRs. Capecitabine treatment may also be associated with a decrease in AK and BCC incidence. However, practitioners must weigh this benefit against the risk of adverse effects for each patient individually. Further investigation with a prospective clinical trial is warranted.
Genes adapt to outsmart gene-targeting strategies in mutant mouse strains by skipping exons to reinitiate transcription and translation
Authors: Vishnu Hosur, Benjamin E. Low, Daniel Li, Grace A. Stafford, Vivek Kohar, Leonard D. Shultz, Michael V. Wiles
Journal: Genome biology (2020)

Abstract Background Gene disruption in mouse embryonic stem cells or zygotes is a conventional genetics approach to identify gene function in vivo. However, because different gene disruption strategies use different mechanisms to disrupt genes, the strategies can result in diverse phenotypes in the resulting mouse model. To determine whether different gene disruption strategies affect the phenotype of resulting mutant mice, we characterized Rhbdf1 mouse mutant strains generated by three commonly used strategies—definitive-null, targeted knockout (KO)-first, and CRISPR/Cas9. Results We find that Rhbdf1 responds differently to distinct KO strategies, for example, by skipping exons and reinitiating translation to potentially yield gain-of-function alleles rather than the expected null or severe hypomorphic alleles. Our analysis also revealed that at least 4% of mice generated using the KO-first strategy show conflicting phenotypes. Conclusions Exon skipping is a widespread phenomenon occurring across the genome. These findings have significant implications for the application of genome editing in both basic research and clinical practice.
Chekhov on Epic
Authors: Samuel C. Durso
Journal: Annals of Internal Medicine (2020)

On Being a Doctor1 September 2020Chekhov on EpicSamuel C. Durso, MD, MBASamuel C. Durso, MD, MBAJohns Hopkins University School of Medicine, Baltimore, Maryland (S.C.D.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-0992 Audio Reading - “Chekhov on Epic” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Chekhov on Epic” by Samuel C. Durso, MD, MBA Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail It is well known that many great writers have been physicians. I suspect that this is the case because much of the physician's work requires telling a patient's story. This process—storytelling, captured in the clinical note—is (or can be) more than a record. With craft, it becomes a device with a voice, connecting the physician to the patient.Imagine for a moment that you are the physician-writer Anton Chekhov. You staff the intake ward of a hospital. A servant brings in a young girl; she is the nursemaid of a couple for whom the servant works. You examine the patient. ... Author, Article, and Disclosure InformationAffiliations: Johns Hopkins University School of Medicine, Baltimore, Maryland (S.C.D.)Corresponding Author: Samuel C. Durso, MD, MBA, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Baltimore, MD 21224; e-mail, [email protected]edu.This article was published at Annals.org on 14 July 2020. PreviousarticleNextarticle Advertisement Audio Reading - “Chekhov on Epic” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Chekhov on Epic” by Samuel C. Durso, MD, MBA Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetailsSee AlsoRestoring the Story and Creating a Valuable Clinical Note Heather E. Gantzer , Brian L. Block , Lacy C. Hobgood , and Janice Tufte Metrics 1 September 2020Volume 173, Issue 5Page: 399-400KeywordsEmotionsPainPatient advocacySleepSleep deprivationSmellSurgeryTeaTicksTouch ePublished: 14 July 2020 Issue Published: 1 September 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
P-198 The AST/ALT ratio predicts clinical outcome in pancreatic cancer patients treated with capecitabine and gemcitabine: A single institution experience in the west of Algeria
Authors: A. Bengueddach, M. Kaid, H. Kehili, A. Tidjane, N. Boudjenan Serradj, B. Tabeti, K. Rekai
Journal: Annals of Oncology (2020)
Transcatheter Aortic Valve Implantation Represents an Anti-Inflammatory Therapy Via Reduction of Shear Stress–Induced, Piezo-1–Mediated Monocyte Activation
Authors: Sara Baratchi, Maria T.K. Zaldivia, Maria Wallert, Julia Loseff-Silver, Sefaa Al-Aryahi, Jalal Zamani, Peter Thurgood, Agus Salim, Nay M. Htun, Dion Stub, Parisa Vahidi, Stephen J. Duffy, Antony Walton, Thanh Ha Nguyen, Anthony Jaworowski, Khashayar Khoshmanesh, Karlheinz Peter
Journal: Circulation (2020)

Aortic valve stenosis is an increasingly prevalent degenerative and inflammatory disease. Transcatheter aortic valve implantation (TAVI) has revolutionized its treatment, thereby avoiding its life-threatening/disabling consequences. Whether aortic valve stenosis is accelerated by inflammation and whether it is itself a cause of inflammation are unclear. We hypothesized that the large shear forces exerted on circulating cells, particularly on the largest circulating cells, monocytes, while passing through stenotic aortic valves result in proinflammatory effects that are resolved with TAVI.TAVI provides a unique opportunity to compare the activation status of monocytes under high shear stress (before TAVI) and under low shear stress (after TAVI). The activation status of monocytes was determined with a single-chain antibody, MAN-1, which is specific for the activated β2-integrin Mac-1. Monocyte function was further characterized by the adhesion of myocytes to stimulated endothelial cells, phagocytic activity, uptake of oxidized low-density lipoprotein, and cytokine expression. In addition, we designed a microfluidic system to recapitulate the shear rate conditions before and after TAVI. We used this tool in combination with functional assays, Ca2+ imaging, siRNA gene silencing, and pharmacological agonists and antagonists to identify the key mechanoreceptor mediating the shear stress sensitivity of monocytes. Last, we stained for monocytes in explanted stenotic aortic human valves.The resolution of high shear stress through TAVI reduces Mac-1 activation, cellular adhesion, phagocytosis, oxidized low-density lipoprotein uptake, and expression of inflammatory markers in monocytes and plasma. Using microfluidics and pharmacological and genetic studies, we could recapitulate high shear stress effects on isolated human monocytes under highly controlled conditions, showing that shear stress-dependent calcium influx and monocyte adhesion are mediated by the mechanosensitive ion channel Piezo-1. We also demonstrate that the expression of this receptor is shear stress dependent and downregulated in patients receiving TAVI. Last, we show monocyte accumulation at the aortic side of leaflets of explanted aortic valves.We demonstrate that high shear stress, as present in patients with aortic valve stenosis, activates multiple monocyte functions, and we identify Piezo-1 as the mainly responsible mechanoreceptor, representing a potentially druggable target. We demonstrate an anti-inflammatory effect and therefore a novel therapeutic benefit of TAVI.