tbuckley/cabot-search huggingface dataset:
Decrease in tumor content assessed in biopsies is associated with improved treatment outcome response to pembrolizumab in patients with rare tumors
Authors: Coya Tapia, Phyu P. Aung, Sinchita Roy-Chowdhuri, Mingxuan Xu, Fengying Ouyang, Anas Alshawa, Joud Hajjar, Gopal Singh, Vincent Yang, Lilibeth Castillo, Hung Le, Ravi Murthy, Bettzy Stephen, Kenneth R Hess, Ignacio Wistuba, Aung Naing
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Decreased tumor content (TC) in resection specimens after neoadjuvant therapy is used to predict prognosis. We investigated whether TC assessed in biopsy specimens or the shift in TC from baseline to on-treatment can be used accordingly to predict response in patients with rare tumors who were treated with pembrolizumab. Methods A total of 57 tumors (represented by 173 baseline and 179 on-treatment biopsies) from 57 patients with rare tumors participating in an ongoing phase II clinical trial of pembrolizumab were evaluated. TC was estimated on H&amp;E-stained slides and tumors were dichotomized into low and high TC according to a cut-off of 10%. Necrosis, proliferative fibrosis (PF) and normal tissue were assessed in on-treatment biopsies. TC at baseline and on-treatment, as well as the shift in TC from baseline to on-treatment, was correlated with clinical response defined according to Response Evaluation Criteria in Solid Tumors. Results A decrease in TC was seen in 14% (n=8); no change in TC was seen in 75% (n=43); and an increase in TC from baseline to on-treatment was seen in 11% (n=6). Objective response was significantly associated with decrease in TC from baseline to on-treatment (38%, 3/8) compared with no change/increase in TC (6%, 3/49) (p=0.031). Patients with a decrease in TC had a significantly increased time to progression (TTP) (75% probability) compared with patients with an increase (20% probability) or no change in TC (19% probability) (p=0.0042). Low TC was seen in 23% (13/57) of the tumors at baseline and in 26% (15/57) on-treatment. High TC was seen in 77% (44/57) of tumors at baseline and in 74% (42/57) on-treatment. No significant associations with response were seen for necrosis, PF or normal tissue in on-treatment biopsies. Conclusion Patients with a decrease in TC from baseline to on-treatment had a significant improvement in objective response and a longer TTP. Our data suggest that the shift in TC might be used to predict response to pembrolizumab in rare tumors. However, further investigations in larger cohorts are needed to determine the clinical value of TC, the shift in TC and the cut-off of 10% assessed in biopsies. Trial registration number NCT02721732
Author Correction: Targeted pharmacological therapy restores β-cell function for diabetes remission
Authors: Stephan Sachs, Aimée Bastidas-Ponce, Sophie Tritschler, Mostafa Bakhti, Anika Böttcher, Miguel A. Sánchez-Garrido, Marta Tarquis-Medina, Maximilian Kleinert, Katrin Fischer, Sigrid Jall, Alexandra Harger, Erik Bader, Sara Roscioni, Siegfried Ussar, Annette Feuchtinger, Burcak Yesildag, Aparna Neelakandhan, Christine B. Jensen, Marion Cornu, Bin Yang, Brian Finan, Richard D. DiMarchi, Matthias H. Tschöp, Fabian J. Theis, Susanna M. Hofmann, Timo D. Müller, Heiko Lickert
Journal: Nature Metabolism (2020)
Abstract A21: Promotion of colorectal cancer by <i>Streptococcus gallolyticus</i>—a novel mechanism
Authors: John Taylor, Ritesh Kumar, Amir Sarshekeh, Jennifer Davies, Scott Kopetz, Juan Xu, Yi Xu
Journal: Cancer Research (2020)

Abstract Streptococcus gallolyticus subsp. gallolyticus (Sgg) is an opportunistic gut pathobiont. It has a longstanding clinical association with colorectal cancer (CRC). We previously demonstrated that Sgg stimulates CRC cell proliferation and promotes tumor growth in mouse models of CRC (Kumar et al., 2017). Recent studies also indicated that Sgg induced an immune-tolerant environment in the mouse colon conductive for tumor development (Zhang et al., 2018). These results provide strong experimental support for Sgg being an active promoter of tumor development. The molecular mechanism underlying Sgg’s tumor promoting activity was unknown. We investigated the effect of Sgg on CRC cells by analyzing mass spectrometry proteomics data. We found that several types of collagen were upregulated in Sgg-treated cells compared to cells cultured in media only. The upregulation was further confirmed by RT-qPCR and Western blot. Transforming growth factor beta (TGFbeta) is a master regulator of the extracellular matrix. Therefore, we examined the effect of Sgg on the TGFbeta signaling pathway. The results showed that Sgg-treated cells had significantly higher level of phosphorylated Smad2. Sgg treatment also induced the expression of TGFbeta target genes. The effects of Sgg on CRC cells were significantly decreased in the presence of inhibitors for TGFbeta signaling. In addition, we observed that Sgg induced similar effects in mouse colon. Together, these results demonstrate that Sgg activates the TGFbeta signaling pathway in vitro and in vivo. Furthermore, we found that activation of TGFbeta by Sgg is mediated by specific Sgg genes. Deletion of these genes abolished the effect of Sgg on CRC cells in vitro and its ability to promote tumor growth in a mouse model of CRC. These results suggest that TGFbeta activation is a mechanism underlying Sgg’s contribution to tumor growth. Next, we tried to determine if these findings are relevant to CRC patients. Examination of tumor tissues from CRC patients revealed that Sgg-positive tumors exhibit significantly enhanced TGFbeta activity compared to Sgg-negative tumors, suggesting that Sgg-positivity correlates with stronger TGFbeta signaling activities in CRC patients. Taken together, our results highlight a previously unrecognized mechanism in which a colonic microbe activates the TGFbeta signaling pathway to promote the development of CRC. Studies to further delineate this novel mechanism are currently under way. Citation Format: John Taylor, Ritesh Kumar, Amir Sarshekeh, Jennifer Davies, Scott Kopetz, Juan Xu, Yi Xu. Promotion of colorectal cancer by Streptococcus gallolyticus—a novel mechanism [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A21.
El Niño/Southern Oscillation (ENSO) and stunting in children under 5 years in Peru: a double-difference analysis
Authors: Oliver A Elorreaga, Luis Huicho, Andres G Lescano
Journal: The Lancet Global Health (2020)

BackgroundThe 1997–98 El Niño/Southern Oscillation (ENSO) was one of the most important natural disasters in 20th century Peru, associated with heavy rainfall and flooding. It affected 502 000 people, ruined 944 km of roads, and damaged 580 health centres and 956 schools. Almost a quarter of all people affected (23%) came from Piura, in the northwest of Peru. In this study, we assessed the association between the 1997–98 ENSO and growth stunting in children younger than 5 years on Peru's north coast.MethodsWe analysed Peruvian Demographic and Health Survey (DHS) data, from 1996 and 2000, using a double-difference approach. Our primary outcome was childhood growth stunting, and our exposure was the ENSO phenomenon. The exposed group was from Peru's Piura coast, and the unexposed group was from southern coastal regions, which were less affected by the events associated with ENSO 1997–98. First, we conducted a regional comparison. Secondly, we used propensity score matching (PSM) to explore similarities between the exposed and non-exposed groups. We then estimated adjusted prevalence ratios (PR) of childhood growth stunting using generalised linear models. Finally, we conducted a subanalysis by childhood age.FindingsWe studied 2270 and 1349 children younger than 5 years from 1996 and 2000, respectively. Regression without matching showed a PR of 1·37 (95% CI 0·93–2·01), and a PSM regression 1-to-2 PR of 1·45 (0·66–3·18), obtaining a PR greater than 1 but with a confidence interval that included the null value. Furthermore, we found a possible effect on children aged 0–11 months. In the regressions without PSM, analysis for this age group showed a PR of 2·48 (1·11–5·54); whereas, after PSM 1-to-2, the PR was 2·69 (1·03–7·03); alternative PSM was also consistent with these results. Analysis of the other age groups yielded results that were not statistically significant.InterpretationOur results suggest that the ENSO phenomenon could have increased childhood stunting on the coast of Piura. More specifically, children who were aged 0 to 11 months during the worst and most disruptive period of the El Niño phenomenon were at increased risk of growth stunting. Our results were consistent with and without PSM. Factors that might have contributed to our results include increased childhood morbidity with concurrent reductions in maternal and familial access to health care, and diminished household incomes due to El Niño's devastating effects during the disaster period. Our findings outline a need to prevent harm to people and their health during weather and natural events associated with ENSO. Specifically, there is a need for childhood-focused social protection systems, especially during critical stages of growth and development. Childhood-focused social protection and delivery systems will be instrumental in preventing downstream effects of similar climatic events.FundingFogarty 2D43 TW007393.
Genetic Disruption of □pdl and □pdlr Phospholipases in Mice Leads to Impaired Platelet Adhesion and Aggregation
Authors: DingYan Wang, Adili Reheman, Phil Connelly, Youdong Wang, Graham Maguire, Feng He, Armand Keating, Heyu Ni, Xiao-Yan Wen
Journal: Blood (2008)
Cellular Pathology of Atherosclerosis
Authors: Samantha P. Tull, Steve I. Anderson, Sascha C. Hughan, Steve P. Watson, Gerard B. Nash, G. Ed Rainger
Journal: Circulation Research (2005)

Although platelets do not ordinarily bind to endothelial cells (EC), pathological interactions between platelets and arterial EC may contribute to the propagation of atheroma. Previously, in an in vitro model of atherogenesis, where leukocyte adhesion to EC cocultured with smooth muscle cells was greatly enhanced, we also observed attachment of platelets to the EC layer. Developing this system to specifically model platelet adhesion, we show that EC cocultured with smooth muscle cells can bind platelets in a process that is dependent on EC activation by tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1. Recapitulating the model using EC alone, we found that a combination of TGF-beta1 and TNF-alpha promoted high levels of platelet adhesion compared with either agent used in isolation. Platelet adhesion was inhibited by antibodies against GPIb-IX-V or alpha(IIb)beta3 integrin, indicating that both receptors are required for stable adhesion. Platelet activation during interaction with the EC was also essential, as treatment with prostacyclin or theophylline abolished stable adhesion. Confocal microscopy of the surface of EC activated with TNF-alpha and TGF-beta1 revealed an extensive matrix of von Willebrand factor that was able to support the adhesion of flowing platelets at wall shear rates below 400 s(-1). Thus, we have demonstrated a novel route of EC activation which is relevant to the atherosclerotic microenvironment. EC activated in this manner would therefore be capable of recruiting platelets in the low-shear environments that commonly exist at points of atheroma formation.
Immunotherapy to treat malignancy in patients with pre-existing autoimmunity
Authors: Patrick Boland, Anna C Pavlick, Jeffrey Weber, Sabina Sandigursky
Journal: Journal for ImmunoTherapy of Cancer (2020)

In the past 10 years, immune checkpoint inhibitors (ICIs) have become an additional pillar of cancer therapy by activating the immune system to treat a number of different malignancies. Many patients receiving ICIs develop immune-related adverse events (irAEs) that mimic some features of classical autoimmune diseases. Unfortunately, patients with underlying autoimmune conditions, many of whom have an increased risk for malignancy, have been excluded from clinical trials of ICIs due to a concern that they will have an increased risk of irAEs. Retrospective data from patients with autoimmune diseases and concomitant malignancy treated with ICIs are encouraging and suggest that ICIs may be tolerated safely in patients with specific autoimmune diseases, but there are no prospective data to guide management. In this manuscript, we review the relationship between pre-existing autoimmune disease and irAEs from checkpoint inhibitors. In addition, we assess the likelihood of autoimmune disease exacerbations in patients with pre-existing autoimmunity receiving ICI.
Magnetic Resonance Imaging for Acute Minor Neurological Symptoms
Authors: Paul Bentley
Journal: JAMA Neurology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Improving AML Classification Using Splicing Signatures
Authors: Teresa V. Bowman
Journal: Clinical Cancer Research (2020)

Mutations in spliceosomal components are prevalent in myelodysplastic syndromes, but less so in acute myeloid leukemia (AML). However, aberrant splicing is prolific in AML, suggesting deregulated splicing could contribute broadly to tumorigenesis. Elevated stress responses correlate with splicing dysfunction across myeloid malignancies, representing potentially novel therapeutic targets.See related article by Anande et al., p. 3597.
Evaluation of a low-cost undergraduate digital medical curriculum platform in Rwanda: a mixed methods study
Authors: O Clarke, M Thomas, J Owolabi, D Seifu, T Le, A Bekele, R Ojiambo
Journal: The Lancet Global Health (2020)

BackgroundThe University of Global Health Equity (UGHE) is a new medical school in Rwanda that aims to train new physicians with competencies in global health delivery for Africa. As part of an effort to deliver high-quality, preclinical medical education, UGHE has implemented a low-cost, modular digital curricular platform called ScholarRx Bricks, which has already been well evaluated in the USA. We aim to test whether Rwandan medical students will find the Bricks to be an acceptable curricular resource.MethodsBricks are self-contained, integrated basic science learning units consisting of learning objectives, illustrated narrative text, and interactive self-assessment items delivered through a web browser. The Bricks have been assigned as flipped classroom pre-work in a course that includes integrated topics in anatomy, histology, embryology, biochemistry, and physiology. Students are in the first year of a 6-year MBBS programme. We used a Kirkpatrick programme evaluation model to measure student use and satisfaction (level 1 outcome). We also conducted a student focus group for qualitative feedback.FindingsWe included responses from all 27 students, all of whom had used the Bricks in some capacity in the course; 18 students (67%) agreed that the Bricks were a helpful resource, and 19 (70%) would recommend the Bricks to other students. Key themes that arose from qualitative questions and the focus group were that the Bricks provided detailed and useful information for the course, and were valued as a curricular resource, but that information was often viewed as too advanced for this foundational stage of the medical school programme.InterpretationThe Bricks appeared to be generally well accepted by Rwandan medical students and may be a viable, low-cost curricular option in Africa. We identified potential adjustments that may improve the learner experience.FundingScholarRx provided in-kind support access to the Bricks.
Functional decellularized fibrocartilaginous matrix graft for rotator cuff enthesis regeneration: A novel technique to avoid in-vitro loading of cells
Authors: Can Chen, Yang Chen, Muzh Li, Han Xiao, Qiang Shi, Tao Zhang, Xing Li, Chunfeng Zhao, Jianzhong Hu, Hongbin Lu
Journal: Biomaterials (2020)
COVID-19: minimising risk to healthcare workers during aerosol-producing respiratory therapy using an innovative constant flow canopy
Authors: Yochai Adir, Ori Segol, Dmitry Kompaniets, Hadas Ziso, Yechiam Yaffe, Irina Bergman, Erez Hassidov, Arieh Eden
Journal: European Respiratory Journal (2020)

Noninvasive ventilation (NIV), continuous positive airway pressure (CPAP) and high-flow nasal cannula (HFNC) can be used as the first line of treatment in coronavirus disease 2019 (COVID-19) patients with respiratory failure, postponing and maybe even avoiding the need for intubation and mechanical ventilation [1]. Recent systematic review and meta-analysis demonstrated that HFNC reduces the need for intubation compared with conventional oxygen, with no change in the death risk or length of stay in the intensive care unit [2, 3]. No direct evidence supports the use of NIV, due to a high failure rate [4]. However, when resources become limited, with no option of invasive ventilation, the use of NIV may be justified. The major caveat of using noninvasive respiratory support in the face of the COVID-19 pandemic is the generation of aerosols, composed of small virus-containing particles, which may remain suspended in the air, with increased risk for healthcare workers [5, 6]. The risk of aerosolisation depends on many variables, including duration of use, flow velocity, mask leakage and patient coughing and cooperation. An innovative constant flow canopy enables noninvasive respiratory support with minimal risk of healthcare worker infection <https://bit.ly/3eqgoVZ>
HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis
Authors: Marta Palomo-Irigoyen, Encarni Pérez-Andrés, Marta Iruarrizaga-Lejarreta, Adrián Barreira-Manrique, Miguel Tamayo-Caro, Laura Vila-Vecilla, Leire Moreno-Cugnon, Nagore Beitia, Daniela Medrano, David Fernández-Ramos, Juan José Lozano, Satoshi Okawa, José L. Lavín, Natalia Martín-Martín, James D. Sutherland, Virginia Guitiérez de Juan, Monika Gonzalez-Lopez, Nuria Macías-Cámara, David Mosén-Ansorena, Liyam Laraba, C. Oliver Hanemann, Emanuela Ercolano, David B. Parkinson, Christopher W. Schultz, Marcos J. Araúzo-Bravo, Alex M. Ascensión, Daniela Gerovska, Haizea Iribar, Ander Izeta, Peter Pytel, Philipp Krastel, Alessandro Provenzani, Pierfausto Seneci, Ruben D. Carrasco, Antonio Del Sol, María Luz Martinez-Chantar, Rosa Barrio, Eduard Serra, Conxi Lazaro, Adrienne M. Flanagan, Myriam Gorospe, Nancy Ratner, Ana M. Aransay, Arkaitz Carracedo, Marta Varela-Rey, Ashwin Woodhoo
Journal: Journal of Clinical Investigation (2020)

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment.
Rapid Cardiovascular Magnetic Resonance for Ischemic Heart Disease Investigation (RAPID-IHD)
Authors: James R.J. Foley, Caroline Richmond, Graham J. Fent, Malenka Bissell, Eylem Levelt, Erica Dall’armellina, Peter P. Swoboda, Sven Plein, John P. Greenwood
Journal: JACC. Cardiovascular imaging (2020)
French research strategy to tackle antimicrobial resistance
Authors: Evelyne Jouvin-Marche, Guia Carrara, Céline Pulcini, Antoine Andremont, Corinne Danan, Céline Couderc-Obert, Christian Lienhardt, Marie-Paule Kieny, Yazdan Yazdanpanah
Journal: The Lancet (2020)
20-Year Trends in the Pharmacologic Treatment of Bipolar Disorder by Psychiatrists in Outpatient Care Settings
Authors: Taeho Greg Rhee, Mark Olfson, Andrew A. Nierenberg, Samuel T. Wilkinson
Journal: American Journal of Psychiatry (2020)

Pharmacological options for treating bipolar disorder have increased over the past 20 years, with several second-generation antipsychotics receiving regulatory approval in the 1990s. The authors describe trends in use of pharmacological agents in the outpatient management of bipolar disorder.Using nationally representative data from the 1997-2016 National Ambulatory Medical Care Surveys, the authors examined trends in the use of mood stabilizers, first- and second-generation antipsychotics, and antidepressants among psychiatrist visits for which bipolar disorder was listed among the primary diagnoses. A logistic regression model was used to identify statistically significant trends, with covariates including age, gender, race/ethnicity, and primary insurance.Antipsychotics were increasingly more commonly prescribed, increasing from 12.4% of outpatient visits for bipolar disorder in the 1997-2000 period to 51.4% in the 2013-2016 period (adjusted odds ratio=5.05, 95% CI=3.65-7.01). Use of mood stabilizers decreased from 62.3% of visits for bipolar disorder in the 1997-2000 period to 26.4% in the 2013-2016 period (adjusted odds ratio=0.18, 95% CI=0.13-0.27). Prescription of antidepressants occurred in 47.0% of visits for bipolar disorder in the 1997-2000 period and 57.5% in the 2013-2016 period. Prescription of an antidepressant without a mood stabilizer increased substantially, from 17.9% in the 1997-2000 period to 40.9% in the 2013-2016 period (adjusted odds ratio=2.88, 95% CI=2.06-4.03).Substantial changes have occurred in the treatment of bipolar disorder over the past 20 years, with second-generation antipsychotics in large measure supplanting traditional mood stabilizers. Antidepressant prescriptions persisted despite a lack of evidence for their efficacy in bipolar disorder and concerns about increasing the risk of mania. Research is needed to compare the real-world effectiveness and tolerability of newer antipsychotics with those of traditional mood stabilizers.