tbuckley/cabot-search huggingface dataset:
Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium
Authors: Jack F. Shern, Joanna Selfe, Elisa Izquierdo, Rajesh Patidar, Hsien-Chao Chou, Young K. Song, Marielle E. Yohe, Sivasish Sindiri, Jun Wei, Xinyu Wen, Erin R. Rudzinski, Donald A. Barkauskas, Tammy Lo, David Hall, Corinne M. Linardic, Debbie Hughes, Sabri Jamal, Meriel Jenney, Julia Chisholm, Rebecca Brown, Kristine Jones, Belynda Hicks, Paola Angelini, Sally George, Louis Chesler, Michael Hubank, Anna Kelsey, Susanne A. Gatz, Stephen X. Skapek, Douglas S. Hawkins, Janet M. Shipley, Javed Khan
Journal: Journal of Clinical Oncology (2021)

PURPOSE Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAX-FOXO1 fusion status, no genomic markers are available for risk stratification. We present an international consortium study designed to determine the incidence of driver mutations and their association with clinical outcome. PATIENTS AND METHODS Tumor samples collected from patients enrolled on Children's Oncology Group trials (1998-2017) and UK patients enrolled on malignant mesenchymal tumor and RMS2005 (1995-2016) trials were subjected to custom-capture sequencing. Mutations, indels, gene deletions, and amplifications were identified, and survival analysis was performed. RESULTS DNA from 641 patients was suitable for analyses. A median of one mutation was found per tumor. In FOXO1 fusion-negative cases, mutation of any RAS pathway member was found in &gt; 50% of cases, and 21% had no putative driver mutation identified. BCOR (15%), NF1 (15%), and TP53 (13%) mutations were found at a higher incidence than previously reported and TP53 mutations were associated with worse outcomes in both fusion-negative and FOXO1 fusion-positive cases. Interestingly, mutations in RAS isoforms predominated in infants &lt; 1 year (64% of cases). Mutation of MYOD1 was associated with histologic patterns beyond those previously described, older age, head and neck primary site, and a dismal survival. Finally, we provide a searchable companion database ( ClinOmics ), containing all genomic variants, and clinical annotation including survival data. CONCLUSION This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.
Rupatadine fumarate is effective in the treatment of persistent allergic rhinitis: A multicentre study
Authors: Olavo de Godoy Mion, J. Mello, F. Castro, A. Cruz, Marcos Mocellin, P. Bogart, Maria Letícia Chavarria, Martti Antila, Dirceu Solé, Luc Wexler, R. Guimaraes, A. Miniti
Journal: Allergy (2007)
More than COVID19
Authors: L. Lee, C. Okorie
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Introduction: COVID19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents with widely varying severity of disease, with pediatric patients experiencing milder disease than adults. Most children requiring mechanical ventilation had underlying comorbidities, most commonly cardiovascular abnormality or obesity. We report an adolescent with severe obesity with COVID19 pneumonia, requiring mechanical ventilation, incidentally, found to have a Morgagni hernia. Case: A 15-year-old male, with severe obesity (BMI 67) presented with acute hypoxemic respiratory failure secondary to SARS-CoV-2 infection leading to severe COVID19 pneumonia. Chest X-ray on admission was significant for bilateral reticulonodular opacities consistent with COVID19. His respiratory failure rapidly progressed despite high-flow nasal oxygen, leading to intubation for high pressure mechanical ventilation and adjunct inhaled nitric oxide to improve oxygenation. He was treated with Remdesivir and dexamethasone. He developed pulmonary edema, which was managed with aggressive diuresis and fluid restriction. He developed right axillary and basilic occlusive thrombi associated with hypercoagulability and was treated with subcutaneous enoxaparin sodium. Subsequent chest X-ray showed significant left hemidiaphragm elevation, concerning for diaphragmatic eventration. After 15 days of intubation, he was extubated to continuous non-invasive ventilation (NIV) before weaning to room air when awake and empiric nocturnal NIV with supplemental oxygen due to hypoxemia attributed to previously undiagnosed severe obstructive sleep apnea and atelectasis secondary to his illness and deconditioning. CT Chest demonstrated a massive Morgagni hernia containing mesenteric fat and multiple loops of bowel, with associated left lung compression and displacement of the heart and mediastinum into the right hemithorax. Lung parenchyma had scattered areas of air trapping and small airway obstruction. Gated cardiac CT showed low to normal systolic function without pulmonary hypertension. The patient was discharged with nocturnal NIV with supplemental oxygen with plans for outpatient polysomnography and titration. Surgical correction of the diaphragmatic defect was deferred as patient had no gastrointestinal symptoms and follow up CT Chest at discharge showed no evidence of obstruction or strangulation. Discussion: Limited data exists regarding risk factors for severe COVID19 disease in pediatric patients, but describes chronic cardiac conditions, respiratory disease and obesity as prominent risk factors, similarly described in adult populations. Despite severity of presentation, a high proportion of adolescents recover without sequelae thus far. We present a case of severe COVID19 in an adolescent with multiple comorbidities, incidentally, found to have a Morgagni hernia. This case represents a favorable outcome despite multiple risk factors and severe presentation requiring mechanical ventilation.
Low-dose total body irradiation facilitates antitumoral Th1 immune responses
Authors: Dominik Sonanini, Christoph M. Griessinger, Barbara F. Schörg, Philipp Knopf, Klaus Dittmann, Martin Röcken, Bernd J. Pichler, Manfred Kneilling
Journal: Theranostics (2021)

CD4+ T helper cells are capable of mediating long-term antitumoral immune responses. We developed a combined immunotherapy (COMBO) using tumor antigen-specific T helper 1 cells (Tag-Th1), dual PD-L1/LAG-3 immune checkpoint blockade, and a low-dose total body irradiation (TBI) of 2 Gy, that was highly efficient in controlling the tumor burden of non-immunogenic RIP1-Tag2 mice with late-stage endogenous pancreatic islet carcinomas. In this study, we aimed to explore the impact of 2 Gy TBI on the treatment efficacy and the underlying mechanisms to boost CD4+ T cell-based immunotherapies. Methods: Heavily progressed RIP1-Tag2 mice underwent COMBO treatment and their survival was compared to a cohort without 2 Gy TBI. Positron emission tomography/computed tomography (PET/CT) with radiolabeled anti-CD3 monoclonal antibodies and flow cytometry were applied to investigate 2 Gy TBI-induced alterations in the biodistribution of endogenous T cells of healthy C3H mice. Migration and homing properties of Cy5-labeled adoptive Tag-Th1 cells were monitored by optical imaging and flow cytometric analyses in C3H and tumor-bearing RIP1-Tag2 mice. Splenectomy or sham-surgery of late-stage RIP1-Tag2 mice was performed before onset of COMBO treatment to elucidate the impact of the spleen on the therapy response. Results: First, we determined a significant longer survival of RIP1-Tag2 mice and an increased CD4+ T cell tumor infiltrate when 2 Gy TBI was applied in addition to Tag-Th1 cell PD-L1/LAG-3 treatment. In non-tumor-bearing C3H mice, TBI induced a moderate host lymphodepletion and a tumor antigen-independent accumulation of Tag-Th1 cells in lymphoid and non-lymphoid organs. In RIP1-Tag2, we found increased numbers of effector memory-like Tag-Th1 and endogenous CD4+ T cells in the pancreatic tumor tissue after TBI, accompanied by a tumor-specific Th1-driven immune response. Furthermore, the spleen negatively regulated T cell effector function by upregulation PD-1/LAG-3/TIM-3 immune checkpoints, providing a further rationale for this combined treatment approach. Conclusion: Low-dose TBI represents a powerful tool to foster CD4+ T cell-based cancer immunotherapies by favoring Th1-driven antitumoral immunity. As TBI is a clinically approved and well-established technique it might be an ideal addition for adoptive cell therapy with CD4+ T cells in the clinical setting.
Association of Lifetime Earning Potential and Workforce Distribution Among Pediatric Subspecialists
Authors: Eva Catenaccio, Jonathan M. Rochlin, Harold K. Simon
Journal: JAMA Pediatrics (2021)

Differences in lifetime earning potential between pediatric subspecialties may contribute to shortages in the subspecialty workforce.To evaluate the association between lifetime earning potential and workforce distribution and to investigate the potential role of a pediatric subspecialist-specific loan repayment program (LRP) in workforce expansion.This study was performed on publicly available mean debt and compensation data from national physician surveys from 2018 to 2019 of pediatric subspecialists in academic practice. Linear regression analysis was used to evaluate the association between lifetime earning potential and measures of workforce distribution in 2019, including distance to subspecialists, percentage of hospital referral regions with a subspecialist, and ratio of subspecialists to the regional child population as well as between lifetime earning potential in 2018 to 2019 and mean subspecialty fellowship fill rates between 2014 and 2018. The association between the change in lifetime earning potential from 2007 to 2018 and the change in workforce distribution metrics from 2003 to 2019 was also examined. The potential role of a pediatric subspecialist-specific LRP was modeled.Lifetime earning potential by subspecialty.Measures of workforce distribution and fellowship fill rates.This study included mean compensation data representing 7539 pediatric subspecialists, workforce distribution data representing 24 375 pediatric subspecialists, and fellowship fill rates representing a mean of 1344 pediatric subspecialty fellows per year. Higher lifetime earning potential was associated with shorter distance to subspecialists (-0.59 miles/$100 000 increase in lifetime earning potential; 95% CI, -1.10 to -0.09), higher percentage of hospital referral regions with a subspecialist (+1.17%/$100 000 increase in lifetime earning potential; 95% CI, 0.34-2.00), and higher ratio of subspecialists to regional child population (+0.11 subspecialists/100 000 children/$100 000 increase in lifetime earning potential; 95% CI, 0.04-0.19). The subspecialties for which lifetime earning potential increased the least between 2007 and 2018 experienced the least growth in the ratio of subspecialists to regional child population from 2003 to 2019 (+0.11 subspecialists/100 000 children/$100 000 increase in lifetime earning potential; 95% CI, 0.07-0.16). Higher lifetime earning potential was associated with higher mean fellowship fill rates (+0.96% spots filled/$100 000 increase in lifetime earning potential; 95% CI, 0.15-1.77). Implementing a pediatric subspecialist-specific LRP could increase fellowship fill rates and improve workforce distribution.Lifetime earning potential based on subspecialty may contribute to imbalances in both the current and future pediatric subspecialty workforce. Pediatric subspecialist-specific LRPs, especially for underfilled subspecialties, are potential tools for policy makers to target workforce shortages.
Abstract 50: DNA Methylation Signatures in Blood Distinguish Patients at Risk of Post-operative Atrial Fibrillation Following Cardiopulmonary Bypass
Authors: Emma Monte, Matthew A Fischer, Nicholas Wisniewski, Jennifer Scovotti, Kimberly Howard-Quijano, Todd Kimball, Ira Hofer, Yibin Wang, Matteo Pellegrini, Aman Mahajan, Thomas Vondriska
Journal: Circulation Research (2016)

Post-operative atrial fibrillation (AF) is the most common complication for cardiac surgery, with an incidence of 27-40% and is associated with increased 30-day mortality. Several models exist to predict post-op AF using clinical data, however none have been widely implemented, and all have room for improvement (average area under ROC curve is ~0.70). We tested whether DNA methylation, assayed from pre-operative blood draws, could add predictive value. We enrolled a cohort of 55 adult patients undergoing cardiopulmonary bypass, with a 36% incidence of post-op AF. Reduced representative bisulfite sequencing provided single-base resolution for an average of 3 million CpGs with 10x sequencing coverage per sample. We first tested whether these CpGs were correlated with AF. Of the 809,569 CpGs that passed thresholds in all samples, 16,774 were significantly correlated with AF (corrected p-value &lt;=0.01 using methylKit in R). We used the R package Glmnet to perform logistic regression on the 16,774 CpGs in 40 of the 55 patients using 5-fold cross validation to build a model and selecting the 381 CpGs which were included in 95% of the 5,000 models. Our assumption being that these 381 CpGs were predictive no matter the subset of patients selected in the randomly generated groups employed during cross validation. Using these 381 CpGs as inputs we built a final model that ultimately incorporated 51 CpGs. None of the 51 CpGs were significantly correlated with age (corrected p-value &lt;=0.01), ruling out age as a confounding factor. We tested our model on the remaining 15 patients. Our model correctly predicted 5 of the 5 AF cases, and 9 of the 10 AF-free cases. Validation of our model in a larger cohort is ongoing, and future directions will incorporate our epigenomic signature with readily available clinical risk factors to further optimize the model.
Effects of brilliant green on human erythroleukemic K562 and breast adenocarcinoma MCF7 cell growth and on inhibition of human topoisomerase IIα
Authors: Xing Wu, Jack Yalowich, Brian Hasinoff
Journal: Cancer Research (2008)

780  Brilliant green (BG), ([4-[(4-diethylaminophenyl)-phenylmethylidene]-1-cyclohexa-2,5-dienylidene]-diethylazanium; hydrogen sulfate), is a pH indicator, a topical antiseptic and a selective bacteriostatic agent in culture media. It has also been used to dye silk and wool. In this study, we showed that BG strongly inhibited the growth of human erythroleukemia K562 and breast adenocarcinoma MCF7 cells with IC50 values in the nanomolar concentration range. BG also inhibited the DNA decatenation activity of human topoisomerase IIα (topo II) in the micromolar concentration range. BG stabilized the DNA-topo II covalent complex, and thus may act as a topo II poison. The growth inhibitory effects of BG on K562 and K/VP.5 cells (an etoposide-resistant cell line containing one-fifth the topo II content of the parental K562 cells) were not significantly different, a result which suggested that BG acted differently than etoposide. GB induced apoptosis in K562 cells as measured by flow cytometry using annexin V-FITC and PI staining. When K562 cells were treated with GB, the fraction of cells in S phase were increased. However, cells were not able to complete the G2/M phase. BG may directly react with DNA since it increased the DNA melting temperature of sonicated calf thymus DNA. In conclusion, our results indicate that BG may have potent antitumor activity. BG may exert its action by inhibiting the decatenation activity of topo II, by acting as a topo II poison and by directly reacting with DNA. Support: CIHR and a Canada Research Chair in Drug Development to BH, and NIH RO1 CA90787 to JCY.
Sounds of COVID-19: exploring realistic performance of audio-based digital testing
Authors: Jing Han, Tong Xia, Dimitris Spathis, Erika Bondareva, Chloë Brown, Jagmohan Chauhan, Ting Dang, Andreas Grammenos, Apinan Hasthanasombat, Andres Floto, Pietro Cicuta, Cecilia Mascolo
Journal: npj Digital Medicine (2022)

Abstract To identify Coronavirus disease (COVID-19) cases efficiently, affordably, and at scale, recent work has shown how audio (including cough, breathing and voice) based approaches can be used for testing. However, there is a lack of exploration of how biases and methodological decisions impact these tools’ performance in practice. In this paper, we explore the realistic performance of audio-based digital testing of COVID-19. To investigate this, we collected a large crowdsourced respiratory audio dataset through a mobile app, alongside symptoms and COVID-19 test results. Within the collected dataset, we selected 5240 samples from 2478 English-speaking participants and split them into participant-independent sets for model development and validation. In addition to controlling the language, we also balanced demographics for model training to avoid potential acoustic bias. We used these audio samples to construct an audio-based COVID-19 prediction model. The unbiased model took features extracted from breathing, coughs and voice signals as predictors and yielded an AUC-ROC of 0.71 (95% CI: 0.65–0.77). We further explored several scenarios with different types of unbalanced data distributions to demonstrate how biases and participant splits affect the performance. With these different, but less appropriate, evaluation strategies, the performance could be overestimated, reaching an AUC up to 0.90 (95% CI: 0.85–0.95) in some circumstances. We found that an unrealistic experimental setting can result in misleading, sometimes over-optimistic, performance. Instead, we reported complete and reliable results on crowd-sourced data, which would allow medical professionals and policy makers to accurately assess the value of this technology and facilitate its deployment.
Thiol-ene cross-linked alginate hydrogel encapsulation modulates the extracellular matrix of kidney organoids by reducing abnormal type 1a1 collagen deposition
Authors: Thomas Geuens, Floor A.A. Ruiter, Anika Schumacher, Francis L.C. Morgan, Timo Rademakers, Loes E. Wiersma, Cathelijne W. van den Berg, Ton J. Rabelink, Matthew B. Baker, Vanessa L.S. LaPointe
Journal: Biomaterials (2021)

Differentiated kidney organoids from induced pluripotent stem cells hold promise as a treatment for patients with kidney diseases. Before these organoids can be translated to the clinic, shortcomings regarding their cellular and extracellular compositions, and their developmental plateau need to be overcome. We performed a proteomic analysis on kidney organoids cultured for a prolonged culture time and we found a specific change in the extracellular matrix composition with increased expression of types 1a1, 2 and 6a1 collagen. Such an excessive accumulation of specific collagen types is a hallmark of renal fibrosis that causes a life-threatening pathological condition by compromising key functions of the human kidney. Here we hypothesized the need for a three-dimensional environment to grow the kidney organoids, which could better mimic the in vivo surroundings of the developing kidney than standard culture on an air–liquid interface. Encapsulating organoids for four days in a soft, thiol-ene cross-linked alginate hydrogel resulted in decreased type 1a1 collagen expression. Furthermore, the encapsulation did not result in any changes of organoid structural morphology. Using a biomaterial to modulate collagen expression allows for a prolonged kidney organoid culture in vitro and a reduction of abnormal type 1a1 collagen expression bringing kidney organoids closer to clinical application.
Correspondence on ‘Safety and efficacy of faecal microbiota transplantation for active peripheral psoriatic arthritis: an exploratory randomised placebo-controlled trial’
Authors: Dennis G McGonagle, Charlie Bridgewood, Helena Marzo-Ortega
Journal: Annals of the Rheumatic Diseases (2021)

Did the first randomised trial of faecal microbiotal transplantation in psoriatic arthritis have a negative outcome due to the paradoxical triggering of a reactive type arthritis disease flare?

We read with great interest the report by Kragsnaes et al on faecal microbiota transplantation (FMT) in active psoriatic arthritis (PsA).1 The authors cited the example of reactive arthritis (ReA) as an exemplar of how dysregulation of the intestinal microbiome may contribute to the immunopathogenesis of human arthritis by disturbance of the gut–joint axis. We appreciate that limitations in word count may have constrained Kragsnaes et al on commenting further on gut dysbiosis in arthritis. PsA, ankylosing spondylitis (AS), the related inflammatory bowel disease (IBD)-associated arthropathies and ReA all fit within the umbrella term …
Epicardial origin of cardiac arrhythmias: clinical evidences and pathophysiology
Authors: Corentin Chaumont, Nadine Suffee, Estelle Gandjbakhch, Elise Balse, Frédéric Anselme, Stéphane N Hatem
Journal: Cardiovascular Research (2021)

Recent developments in imaging, mapping, and ablation techniques have shown that the epicardial region of the heart is a key player in the occurrence of ventricular arrhythmic events in several cardiac diseases, such as Brugada syndrome, arrhythmogenic cardiomyopathy, or dilated cardiomyopathy. At the atrial level as well, the epicardial region has emerged as an important determinant of the substrate of atrial fibrillation, pointing to common underlying pathophysiological mechanisms. Alteration in the gradient of repolarization between myocardial layers favouring the occurrence of re-entry circuits has largely been described. The fibro-fatty infiltration of the subepicardium is another shared substrate between ventricular and atrial arrhythmias. Recent data have emphasized the role of the epicardial reactivation in the formation of this arrhythmogenic substrate. There are new evidences supporting this structural remodelling process to be regulated by the recruitment of epicardial progenitor cells that can differentiate into adipocytes or fibroblasts under various stimuli. In addition, immune-inflammatory processes can also contribute to fibrosis of the subepicardial layer. A better understanding of such 'electrical fragility' of the epicardial area will open perspectives for novel biomarkers and therapeutic strategies. In this review article, a pathophysiological scheme of epicardial-driven arrhythmias will be proposed.