tbuckley/cabot-search huggingface dataset:
Building a portfolio for specialty applications
Authors: Clara Salice
Journal: BMJ (2020)

Clara Salice shares her experience of building a portfolio for specialty applications The medical portfolio is something you will hear about from day 1 of medical school. Lecturers, clinicians, and other students might promote certain experiences as being “great for your portfolio.” Starting your portfolio early and updating it regularly will save time in the long run. Knowing the relevant scoring criteria for applications and collating your existing achievements will enable you to make strategic choices about how to allocate your limited time to maximise points. Medical students and junior doctors are increasingly asked to record their achievements in a mandatory training portfolio.1 Progression to the next stage of training depends on completion of the necessary learning outcomes. This portfolio based assessment is designed for learners to take a more active and autonomous role in their learning and assessment. A well known example is the foundation programme’s Horus e-portfolio, where doctors must record several case based discussions and mini clinical evaluation exercises, and have a minimum attendance at teaching sessions. Revalidation, which doctors complete every five years, requires a portfolio of evidence to show they are up to date and providing a good level of care. Another kind of portfolio is used as part of the job application process. This article focuses on the portfolio needed when applying to core or specialty training. Applicants are asked to bring a physical portfolio of evidence to interview, where the evidence will be given a total score based on defined criteria (see box 1). Box 1 ### An example scoring system for the achievements documented in a portfolio , taken from Internal Medicine Training entry 20202RETURN TO TEXT
Author Correction: AHR is a Zika virus host factor and a candidate target for antiviral therapy
Authors: Federico Giovannoni, Irene Bosch, Carolina Manganeli Polonio, María F. Torti, Michael A. Wheeler, Zhaorong Li, Leonardo Romorini, María S. Rodriguez Varela, Veit Rothhammer, Andreia Barroso, Emily C. Tjon, Liliana M. Sanmarco, Maisa C. Takenaka, Seyed Mohamad Sadegh Modaresi, Cristina Gutiérrez-Vázquez, Nágela Ghabdan Zanluqui, Nilton Barreto dos Santos, Carolina Demarchi Munhoz, Zhongyan Wang, Elsa B. Damonte, David Sherr, Lee Gehrke, Jean Pierre Schatzmann Peron, Cybele C. Garcia, Francisco J. Quintana
Journal: Nature Neuroscience (2020)
Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy
Authors: Daniel B. Rubin, Ali Al Jarrah, Karen Li, Sarah LaRose, Andrew D. Monk, Ali Basil Ali, Lauren N. Spendley, Sarah Nikiforow, Caron Jacobson, Henrikas Vaitkevicius
Journal: JAMA Neurology (2020)

Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion.To identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk.This single-center diagnostic/prognostic accuracy study was conducted at Brigham and Women's Hospital/Dana Farber Cancer Institute from April 2015 to February 2020. A consecutive sample of all patients undergoing CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma were assessed for inclusion (n = 213). Patients who had previously received CAR T cells or who were treated for mantle cell lymphoma were excluded (n = 9). Patients were followed up for a minimum of 30 days from the date of CAR T-cell infusion.The primary outcomes were measures of performance (accuracy, sensitivity, specificity, area under the curve) of a diagnostic tool to predict the occurrence of CAR-associated neurotoxicity, as graded by the Common Terminology Criteria for Adverse Events criteria.Two hundred four patients (127 men [62.2%]; mean [SD] age, 60.0 [12.1] years) were included in the analysis, of which 126 (61.8%) comprised a derivation cohort and 78 (38.2%), an internal validation cohort. Seventy-three patients (57.9%) in the derivation cohort and 45 patients (57.7%) in the validation cohort experienced neurotoxicity. Clinical and laboratory values obtained early in admission were used to develop a multivariable score that can predict the subsequent development of neurotoxicity; when tested on an internal validation cohort, this score had an area under the curve of 74%, an accuracy of 77%, a sensitivity of 82%, and a specificity of 70% (positive:negative likelihood ratio, 2.71:0.26).The score developed in this study may help predict which patients are likely to experience CAR T-cell-associated neurotoxicity. The score can be used for triaging and resource allocation and may allow a large proportion of patients to be discharged from the hospital early.
Divergent Evolution of a Protein–Protein Interaction Revealed through Ancestral Sequence Reconstruction and Resurrection
Authors: Louise Laursen, Jelena Čalyševa, Toby J Gibson, Per Jemth
Journal: Molecular Biology and Evolution (2020)

Abstract The postsynaptic density extends across the postsynaptic dendritic spine with discs large (DLG) as the most abundant scaffolding protein. DLG dynamically alters the structure of the postsynaptic density, thus controlling the function and distribution of specific receptors at the synapse. DLG contains three PDZ domains and one important interaction governing postsynaptic architecture is that between the PDZ3 domain from DLG and a protein called cysteine-rich interactor of PDZ3 (CRIPT). However, little is known regarding functional evolution of the PDZ3:CRIPT interaction. Here, we subjected PDZ3 and CRIPT to ancestral sequence reconstruction, resurrection, and biophysical experiments. We show that the PDZ3:CRIPT interaction is an ancient interaction, which was likely present in the last common ancestor of Eukaryotes, and that high affinity is maintained in most extant animal phyla. However, affinity is low in nematodes and insects, raising questions about the physiological function of the interaction in species from these animal groups. Our findings demonstrate how an apparently established protein–protein interaction involved in cellular scaffolding in bilaterians can suddenly be subject to dynamic evolution including possible loss of function.
CD163<sup>+</sup>cytokine-producing cDC2 stimulate intratumoral type 1 T cell responses in HPV16-induced oropharyngeal cancer
Authors: Saskia J Santegoets, Chantal L Duurland, Ekaterina J Jordanova, Vanessa J van Ham, Ilina Ehsan, Nikki M Loof, Vipin Narang, Charles A Dutertre, Florent Ginhoux, Sylvia L van Egmond, Marij J P Welters, Sjoerd H van der Burg
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct clinical entity with a much better prognosis after (chemo)radiotherapy than HPV-negative OPSCC, especially in patients with a concomitant intratumoral HPV-specific and type-1 cytokine-oriented T cell response. However, knowledge on the type of myeloid cells and their coordination with intratumoral T cells and influence on patient outcome in OPSCC is lacking. Methods We analyzed the presence of intratumoral myeloid cells and their relationship to tumor-infiltrating T cells and patient outcome in a well-described cohort of HPV16 + patients with OPSCC using multispectral immunofluorescence, flow cytometry and functional analyses. Results We show that the tumor microenvironment of HPV16 + OPSCC tumors with such an ongoing HPV16-specific T cell response is highly infiltrated with a newly defined CD163 + cytokine-producing subset of conventional dendritic cell type 2 (cDC2), called DC3. These CD163 + cDC2 predominantly stimulated type 1 T cell polarization and produced high levels of interleukin-12 (IL-12) and IL-18, required for IFNγ and IL-22 production by T cells after cognate antigen stimulation. Tumor-infiltration with these CD163 + cDC2 positively correlated with the infiltration by Tbet + and tumor-specific T cells, and with prolonged survival. Conclusions These data suggest an important role for intratumoral CD163 + cDC2 in stimulating tumor-infiltrating T cells to exert their antitumor effects.
Abstract 10215: Percutaneous Coronary Intervention to Unprotected Left Main Trunk Lesion in Patients With Acute Coronary Syndrome
Authors: Hideki Wada, Manabu Ogita, Satoru Suwa, Ryota Nishio, Kentaro Yasuda, Mitsuhiro Takeuchi, Shoichiro Yatsu, Katsumi Miyauchi, Hiroyuki Daida
Journal: Circulation (2019)

Background: Acute coronary syndrome (ACS) due to left main trunk (LMT) lesion has been associated with cardiogenic shock and higher mortality. The aim of this study was to evaluate clinical outcome...
Evolutionary History of Major Chemosensory Gene Families across Panarthropoda
Authors: Joel Vizueta, Paula Escuer, Cristina Frías-López, Sara Guirao-Rico, Lars Hering, Georg Mayer, Julio Rozas, Alejandro Sánchez-Gracia
Journal: Molecular Biology and Evolution (2020)

Abstract Chemosensory perception is a fundamental biological process of particular relevance in basic and applied arthropod research. However, apart from insects, there is little knowledge of specific molecules involved in this system, which is restricted to a few taxa with uneven phylogenetic sampling across lineages. From an evolutionary perspective, onychophorans (velvet worms) and tardigrades (water bears) are of special interest since they represent the closest living relatives of arthropods, altogether comprising the Panarthropoda. To get insights into the evolutionary origin and diversification of the chemosensory gene repertoire in panarthropods, we sequenced the antenna- and head-specific transcriptomes of the velvet worm Euperipatoides rowelli and analyzed members of all major chemosensory families in representative genomes of onychophorans, tardigrades, and arthropods. Our results suggest that the NPC2 gene family was the only family encoding soluble proteins in the panarthropod ancestor and that onychophorans might have lost many arthropod-like chemoreceptors, including the highly conserved IR25a receptor of protostomes. On the other hand, the eutardigrade genomes lack genes encoding the DEG-ENaC and CD36-sensory neuron membrane proteins, the chemosensory members of which have been retained in arthropods; these losses might be related to lineage-specific adaptive strategies of tardigrades to survive extreme environmental conditions. Although the results of this study need to be further substantiated by an increased taxon sampling, our findings shed light on the diversification of chemosensory gene families in Panarthropoda and contribute to a better understanding of the evolution of animal chemical senses.
Association of Opioid Prescription Initiation During Adolescence and Young Adulthood With Subsequent Substance-Related Morbidity
Authors: Patrick D. Quinn, Kimberly L. Fine, Martin E. Rickert, Ayesha C. Sujan, Katja Boersma, Zheng Chang, Johan Franck, Paul Lichtenstein, Henrik Larsson, Brian M. D’Onofrio
Journal: JAMA Pediatrics (2020)

Concerns about adverse outcomes associated with opioid analgesic prescription have led to major guideline and policy changes. Substantial uncertainty remains, however, regarding the association between opioid prescription initiation and increased risk of subsequent substance-related morbidity.To examine the association of opioid initiation among adolescents and young adults with subsequent broadly defined substance-related morbidity.This cohort study analyzed population-register data from January 1, 2007, to December 31, 2013, on Swedish individuals aged 13 to 29 years by January 1, 2013, who were naive to opioid prescription. To account for confounding, the analysis compared opioid prescription recipients with recipients of nonsteroidal anti-inflammatory drugs as an active comparator, compared opioid-recipient twins and other multiple birth individuals with their nonrecipient co-multiple birth offspring (co-twin control), examined dental prescription as a specific indication, and included individual, parental, and socioeconomic covariates. Data were analyzed from March 30, 2019, to January 22, 2020.Opioid prescription initiation, defined as first dispensed opioid analgesic prescription.Substance-related morbidity, assessed as clinically diagnosed substance use disorder or overdose identified from inpatient or outpatient specialist records, substance use disorder or overdose cause of death, dispensed pharmacotherapy for alcohol use disorder, or conviction for substance-related crime.Among the included cohort (n = 1 541 862; 793 933 male [51.5%]), 193 922 individuals initiated opioid therapy by December 31, 2013 (median age at initiation, 20.9 years [interquartile range, 18.2-23.6 years]). The active comparator design included 77 143 opioid recipients without preexisting substance-related morbidity and 229 461 nonsteroidal anti-inflammatory drug recipients. The adjusted cumulative incidence of substance-related morbidity within 5 years was 6.2% (95% CI, 5.9%-6.5%) for opioid recipients and 4.9% (95% CI, 4.8%-5.1%) for nonsteroidal anti-inflammatory drug recipients (hazard ratio, 1.29; 95% CI, 1.23-1.35). The co-twin control design produced comparable results (3013 opioid recipients and 3107 nonrecipients; adjusted hazard ratio, 1.43; 95% CI, 1.02-2.01), as did restriction to analgesics prescribed for dental indications and additional sensitivity analyses.Among adolescents and young adults analyzed in this study, initial opioid prescription receipt was associated with an approximately 30% to 40% relative increase in risk of subsequent substance-related morbidity in multiple designs that adjusted for confounding. These findings suggest that this increase may be smaller than previously estimated in some other studies.
Covid lockdown: England sees fewer cases of colds, flu, and bronchitis
Authors: Gareth Iacobucci
Journal: BMJ (2020)

Covid lockdown: England sees fewer cases of colds, flu, and bronchitis Gareth IacobucciCases of common cold, flu, and other respiratory diseases in England are substantially lower than average for this time of year, GP surveillance data show.The Royal College of General Practitioners, which published the figures, derived from data from 500 practices across England, 1 said that lockdown and physical distancing measures to prevent the spread of covid-19 were the probable cause of the trend.But although there were fewer respiratory diseases and other viral infections for this time of year than in previous years, the college said that since lockdown measures have eased recorded rates of illnesses such as the common cold have begun to rise as more people start to return to their general practice seeking medical treatment.
MDM2 is a direct, p53-independent, negative regulator of p21
Authors: Zhuo Zhang, Hui Wang, Mao Li, Xinbin Chen, Sudhir Agrawal, Ruiwen Zhang
Journal: Cancer Research (2004)

2534  MDM2 oncoprotein is overexpressed in many human malignancies and high MDM2 levels are associated with poor prognosis. The MDM2 oncogene has been shown to have both p53-dependent and p53-independent activities. We have previously reported that antisense MDM2 inhibitors have significant antitumor activity in multiple human cancer models with various p53 statuses (PNAS, 2003; 100: 11636-11641). We have also hypothesized that MDM2 has a direct role in regulation of p21WAF1/CIP1, which belongs to the CIP/KIP1 family of cyclin-dependent kinase inhibitors.P21 has long been characterized as an inhibitor of cell proliferation, but increasing evidence suggests that it plays a role in cell differentiation, senescence and modulation of apoptosis. Its transcription can be regulated through p53-dependent and -independent pathways; its degradation is also processed by ubiquitin-dependent and -independent pathways via proteasome-mediated mechanisms. In the present study, we provided evidence supporting direct interaction between MDM2 and p21 in vitro and in vivo. Since both MDM2 and p21 are p53 target genes, we have accomplished these experiments in human prostate cancer PC3 cells that are p53 null. At least four novel and significant results were generated. First, the treatment of parental PC3 cells with the novel, mixed-backbone anti-MDM2 antisense oligonucleotide or siRNA targeting MDM2 significantly activated p21 protein levels. In contrast, the transfection of pcDNA3-MDM2 decreased p21 levels in PC3 cells, shortening p21 half-life, which was reversed by the MDM2 antisense oligonucleotide. Second, MDM2 was shown to facilitate p21 degradation independent of ubiquitination and its E3 ligase function. Instead, MDM2 promoted p21 degradation via facilitating binding of p21 with the proteasomal C8-subunit. Third, the physical interaction between p21 protein and MDM2 protein was demonstrated both in vitro and in vivo. The binding region was mapped to the region of AA 180-297 of the MDM2 protein. Fourth, the p21 protein has been shown to play an important role in tumor inhibitory effects induced by MDM2 inhibition. In summary, we provide evidence supporting the direct interaction of MDM2 and p21 and the function of MDM2 as a negative regulator of p21 by reducing p21 protein stability, an effect independent of p53 and ubiquitination. The newly identified mechanism may have therapeutic potential. (Supported by NIH/NCI grant CA80698.)
Reviewing the global burden of acne: how could we improve care to reduce the burden?*
Authors: A.M. Layton, D. Thiboutot, J. Tan
Journal: British Journal of Dermatology (2020)

Acne (also known as acne vulgaris) remains the most common inflammatory dermatosis treated worldwide, as estimated by global skin disease prevalence studies. Latest reports suggest that the prevalence may be increasing in adolescents and adults, particularly female adults. The concept of ‘burden of skin disease’ is multidimensional and can be difficult to quantify in light of different healthcare systems across the globe. In acne, the resulting burden may vary according to patient demographics, access to treatments and duration of the disease. The visible nature of acne, symptoms and sequelae all contribute physically and psychosocially to the overall burden of disease, as do the costs required for management. Acne typically presents in adolescence at a time of significant transition. Profound effects on functional status have been demonstrated, along with a strong impact on interpersonal relationships, social functioning and mental health. The high prevalence of acne also presents an economic burden for society. The widespread and prolonged use of antibiotics introduces a potential added burden through resulting antimicrobial resistance. A James Lind Alliance Acne Priority Setting Partnership has identified numerous areas to inform future research, which would help to improve acne management and reduce the burden. The lack of standardized assessments is a major issue in acne trials and challenges the ability to compare treatments and perform meta-analyses. This paper reviews the current literature on burden of acne, identifies areas of treatment uncertainties and summarizes the work of the Acne Core Outcome Research Network as a means of supporting a reduction in the burden of disease.
Treatment of muscle‐invasive and advanced bladder cancer in 2020
Authors: Vaibhav G. Patel, William K. Oh, Matthew D. Galsky
Journal: CA A Cancer Journal for Clinicians (2020)

Abstract Bladder cancer accounts for nearly 170,000 deaths worldwide annually. For over 4 decades, the systemic management of muscle‐invasive and advanced bladder cancer has primarily consisted of platinum‐based chemotherapy. Over the past 10 years, innovations in sequencing technologies have led to rapid genomic characterization of bladder cancer, deepening our understanding of bladder cancer pathogenesis and exposing potential therapeutic vulnerabilities. On the basis of its high mutational burden, immune checkpoint inhibitors were investigated in advanced bladder cancer, revealing durable responses in a subset of patients. These agents are now approved for several indications and highlight the changing treatment landscape of advanced bladder cancer. In addition, commonly expressed molecular targets were leveraged to develop targeted therapies, such as fibroblast growth factor receptor inhibitors and antibody‐drug conjugates. The molecular characterization of bladder cancer and the development of novel therapies also have stimulated investigations into optimizing treatment approaches for muscle‐invasive bladder cancer. Herein, the authors review the history of muscle‐invasive and advanced bladder cancer management, highlight the important molecular characteristics of bladder cancer, describe the major advances in treatment, and offer future directions for therapeutic development.
Tau induces PSD95–neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration
Authors: Laibaik Park, Karin Hochrainer, Yorito Hattori, Sung Ji Ahn, Antoine Anfray, Gang Wang, Ken Uekawa, James Seo, Victoria Palfini, Ismary Blanco, Diana Acosta, David Eliezer, Ping Zhou, Josef Anrather, Costantino Iadecola
Journal: Nature Neuroscience (2020)
Concurrent Treatment with Pim Kinase Inhibitor Downregulates Alternative Non-Homologous End-Joining Repair and Decreases Genomic Instability in FLT3-ITD Cells Treated with Topoisomerase 2 Inhibitor Chemotherapy Drugs
Authors: Kshama A. Doshi, Shivani Kapoor, Ying Zou, Xiang Li, Mario Scarpa, Nidal Muvarak, Pratik Nagaria, Olga Goloubeva, Adriana E. Tron, Charles J. Bieberich, Feyruz V. Rassool, Maria R. Baer
Journal: Blood (2017)
Direct Assessment of IgA and IgG Paraprotein By Hevylite Assay and Correlation to IMWG Response and Progression-Free Survival in Newly Diagnosed, Transplant-Eligible Multiple Myeloma Patients in the Prospective Phase III GMMG-MM5 Trial
Authors: Christof Scheid, Anja Seckinger, Jan Dürig, Katja C. Weisel, Christina Kunz, Uta Bertsch, Thomas Hielscher, Markus Munder, Hans-Walter Lindemann, Barbara Huegle-Doerr, Stefanie Huhn, Elias K Mai, Anna Jauch, Bernhard Rabold, Christian Gerecke, Peter Brossart, Martin Goerner, Helga Bernhard, Martin Hoffmann, Jens Hillengass, Marc-Steffen S Raab, Igor Wolfgang Blau, Mathias Haenel, Dirk Hose, Hartmut Goldschmidt, Hans Jürgen Salwender
Journal: Blood (2017)