tbuckley/cabot-search huggingface dataset:
Histoplasmosis acquired in Alberta, Canada: an epidemiological and genomic study
Authors: Tanis C Dingle, Matthew A Croxen, Sumana Fathima, Sandy Shokoples, Ashlesha Sonpar, Lynora Saxinger, Ilan S Schwartz
Journal: The Lancet Microbe (2021)

The classic geographical range of histoplasmosis in North America primarily includes the states and provinces adjacent to the Ohio, Mississippi, and St Lawrence riverways. Although Alberta, Canada is not typically considered a region of risk for histoplasmosis, cases with suspected local acquisition have been reported. We aimed to investigate the epidemiology and geographical distribution of cases of histoplasmosis in Alberta to assess evidence for local acquisition of infections, using genomic analysis for corroboration.We did an epidemiological and genomic investigation, in which laboratory-confirmed cases of histoplasmosis were reviewed in Alberta from 2011, when the disease became reportable, until 2018. We used data attained from Alberta Health. Travel and exposure histories and clinical features were reviewed. Definite local acquisition was defined as a case without previous travel outside Alberta or associated with a common-source outbreak within the province, whereas probable local acquisition was a sporadic case with travel outside Alberta but compelling local exposures. Genomes of selected case isolates were analysed, including those from cases suspected to have been locally acquired and imported.Between Jan 1, 2011, and June 30, 2018, 45 cases of histoplasmosis were identified. Participants had a median age of 53 years (range 17-77) and 32 [71%] were male. Among 34 patients with documented travel histories, ten (29%) had never left the province. 11 cases were of definite local acquisition, including eight cases from three common-source outbreaks and three sporadic cases in patients who had never travelled outside Alberta. The common-source outbreaks all involved exposure to bats or their droppings in chimneys or attics of private dwellings or churches. Four patients had travelled outside Alberta but compelling evidence was seen for local exposure to bat guano. Genome sequencing showed that isolates from cases of definite and probable local acquisition clustered together and were genetically distinct from isolates from suspected imported cases and other published isolates.Using epidemiological and genomic analyses, we established that cases of histoplasmosis have been acquired in Alberta, thus expanding the geographical range of Histoplasma spp much further northwest than was previously appreciated. Histoplasmosis should be considered in patients with compatible symptoms outside areas of classic geographical risk.None.
Genomic landscape of <i>CDK12</i> mutated metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Petros Grivas, Gennady Bratslavsky, Joseph M Jacob, Andrea Necchi, Philippe E. Spiess, Natalie Danziger, Richard Huang, Douglas A Mata, Brennan James Decker, Ethan Sokol, Meagan Montesion, Hanna Tukachinsky, Jeffrey Michael Venstrom, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2021)

165 Background: Identifying prostate cancer patients likely to benefit from immune checkpoint inhibitors (ICPI) remains an unmet need. Specific loss-of-function genomic alterations (GA) in CDK12 are associated with focal tandem duplications linked to fusion-induced production of neoantigens and are a promising candidate biomarker for ICPI. Using comprehensive genomic profiling (CGP) we compared the GA landscape of CDK12 altered (CDK12mut+) and unaltered (CDK12mut-) tumors. Methods: 4,918 mCRPC tumors were sequenced using a hybrid capture-based FDA-approved CGP assay. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining -49% and high staining ≥50% expression. Results: Overall, 315 (6.4%) of the mCRPC cases were CDK12mut+ (Table). CDKmut+ cases had significantly fewer GA in TMPRSS2: ERG (P &lt; .0001), TP53 (P &lt; .0001), PTEN (P &lt; .0001), ATM (P = .001), PIK3CA (P = .003), RB1 (P = .02), BRCA2 (P &lt; .0001) and APC (P = .002). CDK12mut+ cases featured higher frequencies only in CCND1 (P &lt; .0001), BRAF (P = .007) and ERBB2 (P &lt; .001) as well as in cell cycle regulatory genes including MDM2/4 (P &lt; .0001), CDK4 (P &lt; .0001) and CDK6 (P = .002). CDK12mut+ cases featured more frequent MSI-H status (P = .007), significantly higher median TMB (P &lt; .001) and more frequent low positive (1-49% staining) PD-L1 expression (P = .02). High (≥50%) PD-L1 expression was rarely identified in either cohort. Conclusions: CDK12mut+ mCRPC demonstrates a unique genomic profile with significant differences compared with CDK12mut- mCRPC. Lower frequencies of GA associated with homologous recombination defect and mTOR pathway may impact the use of platinum agents, as well as PARPi and PIK3CA/Akt/mTOR inhibitors. Opportunities for targeted therapies for BRAF and ERBB2 driven mCRPC may be enriched in the CDK12mut+ tumors and raise the possibility of combination therapy strategies although the numbers of patients are small and validation is needed. The slightly higher MSI High status, median TMB and PD-L1 staining may be associated with additional benefit from ICPI and warrants further prospective investigation. [Table: see text]
Abstract IA014: Regulation of disseminated tumor cell dormancy in brain by the perivascular niche
Authors: Cyrus M. Ghajar
Journal: Cancer Research (2021)

Abstract The brain provides compelling evidence that tumour dormancy is not simply an intriguing biological phenomenon. Given effective therapy, it may emerge as a culprit of lethality. To date, the mechanism by which the brain microenvironment drives disseminated tumor cells (DTCs) into a dormant state remain elusive. Here, I describe our studies leveraging serial intravital imaging to demonstrate that a large fraction of disseminated breast tumor cells within brain persist as single cells, and that every one of these cells is physically associated with microvasculature. Despite occupying a vascular niche, however, the burden for enforcing dormancy does not lie with endothelium. Instead, perivascular astrocytes are the dominant effector. Specifically, we show that astrocytic laminin-211 signals through DTC dystroglycan to suppress proliferation. Transcriptomic data suggest quiescence may ultimately be driven by sequestration of the Hippo effector yes-associated protein. We view these findings as a first step towards therapies that maintain DTC dormancy to prevent brain metastasis. Citation Format: Cyrus M. Ghajar. Regulation of disseminated tumor cell dormancy in brain by the perivascular niche [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA014.
Thyroid cancer incidence trends by histology in 25 countries: a population-based study
Authors: Adalberto Miranda-Filho, Joannie Lortet-Tieulent, Freddie Bray, Bochen Cao, Silvia Franceschi, Salvatore Vaccarella, Luigino Dal Maso
Journal: The Lancet Diabetes & Endocrinology (2021)
Children’s mental health: the UK government needs to be far more ambitious
Authors: Michael Craig Watson, John Lloyd
Journal: BMJ (2021)

England’s children’s commissioner is right to highlight the gulf between what children need and what is being provided.12 Before the pandemic, mental health problems were common and growing in the child and adolescent population. Lockdowns have added further concerns associated with school closures, social isolation, and lack of access to support services.3 Moreover, children from disadvantaged backgrounds are at …
Covid-19: Highest death rates seen in countries with most overweight populations
Authors: Jacqui Wise
Journal: BMJ (2021)

Covid-19: Highest death rates seen in countries with most overweight populations Jacqui WiseCovid-19 death rates are 10 times higher in countries where more than half of the adult population is classified as overweight, a comprehensive report from the World Obesity Federation has found.The report analysed mortality data from Johns Hopkins University and the WHO Global Health Observatory data on obesity. 1 Of the 2.5 million covid-19 deaths reported by the end of February 2021, 2.2 million were in countries where over half the population is classified as overweight-defined as a body mass index above 25.
Abstract 15814: 30-Day Readmission Causes and Rates After Heart Transplant: A Nationwide Cohort Study
Authors: Fahed Darmoch, Yasser Al-khadra, Homam Moussa Pacha, Mohamad Soud, M Chadi M Alraies
Journal: Circulation (2019)

Introduction: The predictors and national readmissions rates after heart transplant is not well studied. We sought to evaluate the causes and predictors of 30-day readmission rate of patients who u...
Microbiome Analysis of More Than 2,000 NHS Bowel Cancer Screening Programme Samples Shows the Potential to Improve Screening Accuracy
Authors: Caroline Young, Henry M. Wood, Alba Fuentes Balaguer, Daniel Bottomley, Niall Gallop, Lyndsay Wilkinson, Sally C. Benton, Martin Brealey, Cerin John, Carole Burtonwood, Kelsey N. Thompson, Yan Yan, Jennifer H. Barrett, Eva J.A. Morris, Curtis Huttenhower, Philip Quirke
Journal: Clinical Cancer Research (2021)

Abstract Purpose: There is potential for fecal microbiome profiling to improve colorectal cancer screening. This has been demonstrated by research studies, but it has not been quantified at scale using samples collected and processed routinely by a national screening program. Experimental Design: Between 2016 and 2019, the largest of the NHS Bowel Cancer Screening Programme hubs prospectively collected processed guaiac fecal occult blood test (gFOBT) samples with subsequent colonoscopy outcomes: blood-negative [n = 491 (22%)]; colorectal cancer [n = 430 (19%)]; adenoma [n = 665 (30%)]; colonoscopy-normal [n = 300 (13%)]; nonneoplastic [n = 366 (16%)]. Samples were transported and stored at room temperature. DNA underwent 16S rRNA gene V4 amplicon sequencing. Taxonomic profiling was performed to provide features for classification via random forests (RF). Results: Samples provided 16S amplicon-based microbial profiles, which confirmed previously described colorectal cancer–microbiome associations. Microbiome-based RF models showed potential as a first-tier screen, distinguishing colorectal cancer or neoplasm (colorectal cancer or adenoma) from blood-negative with AUC 0.86 (0.82–0.89) and AUC 0.78 (0.74–0.82), respectively. Microbiome-based models also showed potential as a second-tier screen, distinguishing from among gFOBT blood-positive samples, colorectal cancer or neoplasm from colonoscopy-normal with AUC 0.79 (0.74–0.83) and AUC 0.73 (0.68–0.77), respectively. Models remained robust when restricted to 15 taxa, and performed similarly during external validation with metagenomic datasets. Conclusions: Microbiome features can be assessed using gFOBT samples collected and processed routinely by a national colorectal cancer screening program to improve accuracy as a first- or second-tier screen. The models required as few as 15 taxa, raising the potential of an inexpensive qPCR test. This could reduce the number of colonoscopies in countries that use fecal occult blood test screening.
Cytokine-like protein 1–induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML
Authors: Margaux Sevin, Franck Debeurme, Lucie Laplane, Séverine Badel, Margot Morabito, Hanna L. Newman, Miguel Torres-Martin, Qin Yang, Bouchra Badaoui, Orianne Wagner-Ballon, Véronique Saada, Dorothée Sélimoglu-Buet, Laurence Kraus-Berthier, Sébastien Banquet, Alix Derreal, Pierre Fenaux, Raphael Itzykson, Thorsten Braun, Gabriel Etienne, Celine Berthon, Sylvain Thépot, Oliver Kepp, Guido Kroemer, Eric Padron, Maria E. Figueroa, Nathalie Droin, Eric Solary
Journal: Blood (2021)
Rash after consumption of game meat
Authors: Yuka Maya, Yasuyuki Fujita, Fumihiro Kodama, Satoko Shimizu
Journal: BMJ (2021)

This is a disseminated maculopapular rash due to trichinellosis in a woman in her 50s, secondary to eating undercooked meat (fig 1). She presented at the dermatology department with a 10 day history of pyrexia, eosinophilia, malaise, and abdominal …
Hypoxic Tumor Radiosensitization Using Engineered Probiotics
Authors: Chunyu Huang, Fu‐Bing Wang, Lei Liu, Wei Jiang, Wei Liu, Wang Ma, Huan Zhao
Journal: Advanced Healthcare Materials (2021)

Abstract Owing to their ability to rapidly proliferate in specific niches and their amenability to genetic manipulation, bacteria are frequently studied as potential diagnostic or therapeutic bioagents in a range of pathological contexts. A sustained oxygen supply within solid tumors is essential in order to achieve positive radiotherapy (RT) outcomes, as these intratumoral oxygen levels are necessary to facilitate RT‐induced reactive oxygen species (ROS) generation. In this study, a genetically engineered variant of the tumor‐targeting probiotic E. coli Nissle 1917 bacteria that secret catalase is utilized to alleviate intratumoral hypoxia and to thereby enhance tumor radiosensitivity. These engineered bacteria are able to facilitate robust O 2 evolution and consequent ROS generation in response to X‐ray irradiation both in vitro and in vivo, significantly inhibiting tumor growth. Overall, the study highlights a novel and practical approach to enhance the efficacy of tumor RT, underscoring the value of future research in the field of probiotic medicine.
Data-driven Derivation and Validation of Novel Phenotypes for Acute Kidney Transplant Rejection using Semi-supervised Clustering
Authors: Thibaut Vaulet, Gillian Divard, Olivier Thaunat, Evelyne Lerut, Aleksandar Senev, Olivier Aubert, Elisabet Van Loon, Jasper Callemeyn, Marie-Paule Emonds, Amaryllis Van Craenenbroeck, Katrien De Vusser, Ben Sprangers, Maud Rabeyrin, Valérie Dubois, Dirk Kuypers, Maarten De Vos, Alexandre Loupy, Bart De Moor, Maarten Naesens
Journal: Journal of the American Society of Nephrology (2021)

Over the past decades, an international group of experts iteratively developed a consensus classification of kidney transplant rejection phenotypes, known as the Banff classification. Data-driven clustering of kidney transplant histologic data could simplify the complex and discretionary rules of the Banff classification, while improving the association with graft failure.The data consisted of a training set of 3510 kidney-transplant biopsies from an observational cohort of 936 recipients. Independent validation of the results was performed on an external set of 3835 biopsies from 1989 patients. On the basis of acute histologic lesion scores and the presence of donor-specific HLA antibodies, stable clustering was achieved on the basis of a consensus of 400 different clustering partitions. Additional information on kidney-transplant failure was introduced with a weighted Euclidean distance.Based on the proportion of ambiguous clustering, six clinically meaningful cluster phenotypes were identified. There was significant overlap with the existing Banff classification (adjusted rand index, 0.48). However, the data-driven approach eliminated intermediate and mixed phenotypes and created acute rejection clusters that are each significantly associated with graft failure. Finally, a novel visualization tool presents disease phenotypes and severity in a continuous manner, as a complement to the discrete clusters.A semisupervised clustering approach for the identification of clinically meaningful novel phenotypes of kidney transplant rejection has been developed and validated. The approach has the potential to offer a more quantitative evaluation of rejection subtypes and severity, especially in situations in which the current histologic categorization is ambiguous.
Radiomic features of renal cell carcinoma primary and metastatic sites as predictors of <i>TERT</i> and <i>BAP1</i> mutations.
Authors: Luis A Meza, Aleksandr Filippov, Sohaib Naim, Nazli Dizman, Alex Chehrazi-Raffle, Errol James Philip, Jasnoor Maholtra, Ramya Muddasani, Neal Shiv Chawla, Chi Wah Wong, Sabrina Salgia, Misagh Karimi, Jeffrey M. Trent, Sara Ann Byron, Ammar Chaudhry, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2021)

282 Background: TERT and BAP1 mutations are associated with poor clinical outcome in patients (pts) with metastatic renal cell carcinoma (mRCC) (Dizman et al JITC 2020; Joseph et al J Urol 2016). In this study we explore radiogenomics as a non-invasive method to identify these alterations. Methods: Pts with mRCC who had genomic testing in the course of routine clinical care were included in the current analysis. Pts were assessed with the GEM Extra assay, a CAP-accredited, CLIA-certified test encompassing paired tumor-normal whole exome sequencing (WES) and tumor whole transcriptome sequencing (TGen; Phoenix, AZ). Pts underwent CT imaging; radiomic analysis was performed on the segmented metastatic and primary lesions. Features were independently correlated with TERT and BAP1 mutation status to generate Pearson correlation values (PCVs). Results: 92 pts (65:27 M: F) were included in the analysis; of these, the majority of pts (84%) had clear cell histology. Alterations in the TERT gene were seen in 12 pts. In these pts 1,325 radiomic features of the primary tissue were examined and 251 features correlated with a PCV ≥ |0.2|. Of these, 42 features were correlated with a PCV ≥ |0.3|. Highest correlation with TERT mutation was seen with Gray Level Cooccurrence Matrix (GLCM) and First Order Features (FOF). 9 pts had BAP1 mutation with 5 detected in primary tumor and 4 in metastatic sites. Analysis of primary tumor imaging yielded no significant associations between radiomic features and BAP1 mutation. However, out of approximately 1,500 radiomic features noted in metastatic sites, 111 features correlated with BAP1 mutation with a PCV ≥ 0.2. Of these, 15 features correlated with a PCV ≥ 0.3. The radiomic features with the highest correlation with BAP1mt were Gray Level Dependence Matrix (GLDM) and GLCM. Conclusions: By identifying a correlation between radiomic features of TERT mutation in primary tumors and BAP1 mutation in metastatic sites, our work may ultimately yield a non-invasive method of discerning mutational status in patents with mRCC. Efforts are ongoing to validate our findings within The Cancer Imaging Archive.
T‐cell changes induced by desensitisation to BRAF inhibitors in two patients with DRESS
Authors: Maria Salas, Miguel‐Angel Berciano‐Guerrero, Francisca Palomares, Antonio Rueda, Tahia D. Fernandez, Cristobalina Mayorga, Maria Jose Torres
Journal: Allergy (2021)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19
Authors: Eduardo López-Medina, Pío López, Isabel C. Hurtado, Diana M Dávalos, Oscar Ramirez, Ernesto Martínez, Jesus A. Díazgranados, José M. Oñate, Hector Chavarriaga, Sócrates Herrera, Beatriz Parra, Gerardo Libreros, Roberto Jaramillo, Ana C. Avendaño, Dilian F. Toro, Miyerlandi Torres, Maria C. Lesmes, Carlos A. Rios, Isabella Caicedo
Journal: JAMA (2021)

Ivermectin is widely prescribed as a potential treatment for COVID-19 despite uncertainty about its clinical benefit.To determine whether ivermectin is an efficacious treatment for mild COVID-19.Double-blind, randomized trial conducted at a single site in Cali, Colombia. Potential study participants were identified by simple random sampling from the state's health department electronic database of patients with symptomatic, laboratory-confirmed COVID-19 during the study period. A total of 476 adult patients with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between July 15 and November 30, 2020, and followed up through December 21, 2020.Patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200).Primary outcome was time to resolution of symptoms within a 21-day follow-up period. Solicited adverse events and serious adverse events were also collected.Among 400 patients who were randomized in the primary analysis population (median age, 37 years [interquartile range {IQR}, 29-48]; 231 women [58%]), 398 (99.5%) completed the trial. The median time to resolution of symptoms was 10 days (IQR, 9-13) in the ivermectin group compared with 12 days (IQR, 9-13) in the placebo group (hazard ratio for resolution of symptoms, 1.07 [95% CI, 0.87 to 1.32]; P = .53 by log-rank test). By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The most common solicited adverse event was headache, reported by 104 patients (52%) given ivermectin and 111 (56%) who received placebo. The most common serious adverse event was multiorgan failure, occurring in 4 patients (2 in each group).Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.ClinicalTrials.gov Identifier: NCT04405843.
Abstract 763: Human Cardiac Beta1-Adrenergic Receptors Are Desensitized By Receptor-Mediated Activation Of Phosphatidylinositol-3 Kinase and Phosphodiesterase-4
Authors: Christoph Maack, Illkyu O Lee, Philip Böhmer, Monika Dudenhöffer-Pfeifer, Mathias Hohl, Heiko Kilter, Hans J Schäfers, Michael Böhm
Journal: Circulation (2007)

Background: Cardiac β-adrenergic receptors (β-ARs) couple to the stimulatory G-protein (Gs), activating adenylyl cyclase to produce cAMP and increase force of contraction. Animal models suggested a...
National Trends in the Use of Neoadjuvant Therapy Before Cancer Surgery in the US From 2004 to 2016
Authors: Christopher T. Aquina, Aslam Ejaz, Allan Tsung, Timothy M. Pawlik, Jordan M. Cloyd
Journal: JAMA Network Open (2021)

This cohort study uses information obtained from the US National Cancer Database to evaluate trends in the use of neoadjuvant therapy before tumor resection for various types of cancer from 2004 to 2016.