tbuckley/cabot-search huggingface dataset:
Characterization of fructooligosaccharide metabolism and fructooligosaccharide-degrading enzymes in human commensal butyrate producers
Authors: Hiroki Tanno, Tadashi Fujii, Katsuaki Hirano, Shintaro Maeno, Takashi Tonozuka, Mitsuo Sakamoto, Moriya Ohkuma, Takumi Tochio, Akihito Endo
Journal: Gut Microbes (2021)

Butyrate produced by gut microbiota has multiple beneficial effects on host health, and oligosaccharides derived from host diets and glycans originating from host mucus are major sources of its production. A significant reduction of butyrate-producing bacteria has been reported in patients with inflammatory bowel diseases and colorectal cancers. Although gut butyrate levels are important for host health, oligosaccharide metabolic properties in butyrate producers are poorly characterized. We studied the metabolic properties of fructooligosaccharides (FOSs) and other prebiotic oligosaccharides (i.e. raffinose and xylooligosaccharides; XOSs) in gut butyrate producers. 1-Kestose (kestose) and nystose, FOSs with degrees of polymerization of 3 and 4, respectively, were also included. Fourteen species of butyrate producers were divided into four groups based on their oligosaccharide metabolic properties, which are group A (two species) metabolizing all oligosaccharides tested, group F (four species) metabolizing FOSs but not raffinose and XOSs, group XR (four species) metabolizing XOSs and/or raffinose but not FOSs, and group N (four species) metabolizing none of the oligosaccharides tested. Species assigned to groups A and XR are rich glycoside hydrolase (GH) holders, whereas those in groups F and N are the opposite. In total, 17 enzymes assigned to GH32 were observed in nine of the 14 butyrate producers tested, and species that metabolized FOSs had at least one active GH32 enzyme. The GH32 enzymes were divided into four clusters by phylogenetic analysis. Heterologous gene expression analysis revealed that the GH32 enzymes in each cluster had similar FOS degradation properties within clusters, which may be linked to the conservation/substitution of amino acids to bind with substrates in GH32 enzymes. This study provides important knowledge to understand the impact of FOS supplementation on the activation of gut butyrate producers.Abbreviations: SCFA, short chain fatty acid; FOS, fructooligosaccharide; XOS, xylooligosaccharide; CAZy, Carbohydrate Active Enzymes; CBM, carbohydrate-binding module; PUL, polysaccharide utilization locus; S6PH sucrose-6-phosphate hydrolase.
PPARα/RXRα downregulates amino acid catabolism in the liver via interaction with HNF4α promoting its proteasomal degradation
Authors: Sandra Tobón-Cornejo, Ariana Vargas-Castillo, Alekxa Leyva-Martínez, Victor Ortíz, Lilia G. Noriega, Laura A. Velázquez-Villegas, Gabriela Aleman, Janette Furosawa-Carballeda, Nimbe Torres, Armando R. Tovar
Journal: Metabolism (2021)
Abstract 18049: The Relation Between Coronary Endothelial Dysfunction and High Platelet Aggregability
Authors: Masafumi Takae, Koichiro Fujisue, Eiichiro Yamamoto, Daisuke Sueta, Taiki Nishihara, Kenji Sakamoto, Koichi Kaikita, Kenichi Tsujita
Journal: Circulation (2017)

Background: Thrombosis formation and endothelial dysfunction are the pathogenesis of myocardial infarction. However, the relation between coronary endothelial dysfunction and platelet aggregability...
Cost-effectiveness of Prostate Radiation Therapy for Men With Newly Diagnosed Low-Burden Metastatic Prostate Cancer
Authors: Nataniel H. Lester-Coll, Steven Ades, James B. Yu, Adam Atherly, H. James Wallace, Brian L. Sprague
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Prostate radiation therapy (PRT) is a treatment option in men with low-volume metastatic prostate cancer based on the results of the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy Arm H (STAMPEDE-H) trial. However, the cost-effectiveness of this treatment remains unaddressed. <h3>Objective</h3> To assess the cost-effectiveness of PRT when added to androgen deprivation therapy (ADT) for men with low-volume metastatic hormone-sensitive prostate cancer (mHSPC). <h3>Design, Setting, and Participants</h3> This economic evaluation used microsimulation modeling to evaluate the cost-effectiveness of adding PRT to ADT. A simulated cohort of 10 000 individuals with low-volume mHSPC was created. Data from men with low-volume mHSPC were extracted and analyzed from January 18, 2019, through July 4, 2020. Transition probabilities were extracted from the STAMPEDE-H study. Health states included stable disease, progression, second progression, and death. Individual grade 2 or higher genitourinary and gastrointestinal toxic events associated with PRT were tracked. Univariable deterministic and probabilistic sensitivity analyses explored uncertainty with regard to the model assumptions. Health state utility estimates were based on the published literature. <h3>Exposures</h3> The combination of PRT and ADT using regimens of 20 fractions and 6 weekly fractions. <h3>Main Outcomes and Measures</h3> Outcomes included net quality-adjusted life-years (QALYs), costs in US dollars, and incremental cost-effectiveness ratios. A strategy was classified as dominant if it was associated with higher QALYs at lower costs than the alternative and dominated if it was associated with fewer QALYs at higher costs than the alternative. <h3>Results</h3> For the base case scenario of men 68 years of age with low-volume mHSPC, the modeled outcomes were similar to the target clinical data for overall survival, failure-free survival, and rates of PRT-related toxic effects. The addition of PRT was a dominant strategy compared with ADT alone, with a gain of 0.16 QALYs (95% CI, 0.15-0.17 QALYs) and a reduction in net costs by $19 472 (95% CI, $16 333-$22 611) at 37 months of follow-up and a gain of 0.81 QALYs (95% CI, 0.73-0.89 QALYs) and savings of $30 229 (95% CI, $23 096-$37 362) with lifetime follow-up. <h3>Conclusions and Relevance</h3> In the economic evaluation, PRT was a dominant treatment strategy compared with ADT alone. These findings suggest that addition of PRT to ADT is a cost-effective treatment for men with low-volume mHSPC.
Covid-19: Doctors’ leaders call for revised PPE guidance to reflect new variants
Authors: Gareth Iacobucci
Journal: BMJ (2021)

Medical leaders have urged Public Health England to strengthen its guidance on personal protective equipment (PPE) to reflect the more transmissible forms of SARS-CoV-2 that healthcare staff are being exposed to.

Current guidance says that higher grade FFP3 masks should be provided to staff who are involved in aerosol generating procedures, but other staff looking after patients with covid-19 are only required to wear fluid resistant surgical masks.

In a letter to Public Health England sent on 13 January, BMA council chair Chaand Nagpaul said that, in light of the identification of the new variant of SARS-CoV-2, increased spread of the virus, and growing evidence of aerosol transmission, Public Health England should …
Insulinemic and Inflammatory Dietary Patterns and Risk of Prostate Cancer
Authors: Benjamin C. Fu, Fred K. Tabung, Claire H. Pernar, Weike Wang, Amparo G. Gonzalez-Feliciano, Ilkania M. Chowdhury-Paulino, Steven K. Clinton, Edmund Folefac, Mingyang Song, Adam S. Kibel, Edward L. Giovannucci, Lorelei A. Mucci
Journal: European Urology (2021)
Circulating cardiovascular <scp>microRNAs</scp> in critically ill <scp>COVID</scp> ‐19 patients
Authors: Ankita Garg, Benjamin Seeliger, Anselm A. Derda, Ke Xiao, Anika Gietz, Kristian Scherf, Kristina Sonnenschein, Isabell Pink, Marius M. Hoeper, Tobias Welte, Johann Bauersachs, Sascha David, Christian Bär, Thomas Thum
Journal: European Journal of Heart Failure (2021)

Abstract Aims Coronavirus disease 2019 (COVID‐19) is a still growing pandemic, causing many deaths and socio‐economic damage. Elevated expression of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) entry receptor angiotensin‐converting enzyme 2 on cardiac cells of patients with heart diseases may be related to cardiovascular burden. We have thus analysed cardiovascular and inflammatory microRNAs (miRs), sensitive markers of cardiovascular damage, in critically ill, ventilated patients with COVID‐19 or influenza‐associated acute respiratory distress syndrome (Influenza‐ARDS) admitted to the intensive care unit and healthy controls. Methods and results Circulating miRs (miR‐21, miR‐126, miR‐155, miR‐208a, and miR‐499) were analysed in a discovery cohort consisting of patients with mechanically‐ventilated COVID‐19 ( n = 18) and healthy controls ( n = 15). A validation study was performed in an independent cohort of mechanically‐ventilated COVID‐19 patients ( n = 20), Influenza‐ARDS patients ( n = 13) and healthy controls ( n = 32). In both cohorts, RNA was isolated from serum and cardiovascular disease/inflammatory‐relevant miR concentrations were measured by miR‐specific TaqMan PCR analyses. In both the discovery and the validation cohort, serum concentration of miR‐21, miR‐155, miR‐208a and miR‐499 were significantly increased in COVID‐19 patients compared to healthy controls. Calculating the area under the curve using receiver operating characteristic analysis miR‐155, miR‐208a and miR‐499 showed a clear distinction between COVID‐19 and Influenza‐ARDS patients. Conclusion In this exploratory study, inflammation and cardiac myocyte‐specific miRs were upregulated in critically ill COVID‐19 patients. Importantly, miR profiles were able to differentiate between severely ill, mechanically‐ventilated Influenza‐ARDS and COVID‐19 patients, indicating a rather specific response and cardiac involvement of COVID‐19.
Stem cells for treatment of cardiovascular diseases: An umbrella review of randomized controlled trials
Authors: Jacopo Demurtas, Giuseppe Nicolò Fanelli, Simone Lorenzo Romano, Marco Solari, Lin Yang, Pinar Soysal, Guillermo F. López Sánchez, Igor Grabovac, Lee Smith, Alessandro Zorzi, Claudio Luchini, Nicola Veronese
Journal: Ageing Research Reviews (2021)
Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma
Authors: Selin Merdan, Kritika Subramanian, Turgay Ayer, Johan Van Weyenbergh, Andres Chang, Jean L. Koff, Christopher Flowers
Journal: Blood Cancer Journal (2021)

Abstract The clinical risk stratification of diffuse large B-cell lymphoma (DLBCL) relies on the International Prognostic Index (IPI) for the identification of high-risk disease. Recent studies suggest that the immune microenvironment plays a role in treatment response prediction and survival in DLBCL. This study developed a risk prediction model and evaluated the model’s biological implications in association with the estimated profiles of immune infiltration. Gene-expression profiling of 718 patients with DLBCL was done, for which RNA sequencing data and clinical covariates were obtained from Reddy et al. (2017). Using unsupervised and supervised machine learning methods to identify survival-associated gene signatures, a multivariable model of survival was constructed. Tumor-infiltrating immune cell compositions were enumerated using CIBERSORT deconvolution analysis. A four gene-signature-based score was developed that separated patients into high- and low-risk groups. The combination of the gene-expression-based score with the IPI improved the discrimination on the validation and complete sets. The gene signatures were successfully validated with the deconvolution output. Correlating the deconvolution findings with the gene signatures and risk score, CD8+ T-cells and naïve CD4+ T-cells were associated with favorable prognosis. By analyzing the gene-expression data with a systematic approach, a risk prediction model that outperforms the existing risk assessment methods was developed and validated.
Fueling the Fire: Inflammatory Forms of Cell Death and Implications for Cancer Immunotherapy
Authors: Sheera R. Rosenbaum, Nicole A. Wilski, Andrew E. Aplin
Journal: Cancer Discovery (2021)

Abstract Unleashing the immune system with immune checkpoint inhibitors (ICI) has significantly improved overall survival for subsets of patients with stage III/IV cancer. However, many tumors are nonresponsive to ICIs, in part due to a lack of tumor-infiltrating lymphocytes (TIL). Converting these immune “cold” tumors to “hot” tumors that are thus more likely to respond to ICIs is a major obstacle for cancer treatment. Triggering inflammatory forms of cell death, such as necroptosis and pyroptosis, may alter the tumor immune microenvironment and the influx of TILs. We present an emerging view that promoting tumor-localized necroptosis and pyroptosis may ultimately enhance responses to ICI. Significance: Many tumor types respond poorly to ICIs or respond but subsequently acquire resistance. Effective therapies for ICI-nonresponsive tumors are lacking and should be guided by evidence from preclinical studies. Promoting inflammatory cell death mechanisms within the tumor may alter the local immune microenvironment toward an ICI-responsive state.
DPP-4 Inhibitors and Respiratory Infection: A Systematic Review and Meta-analysis of the Cardiovascular Outcomes Trials
Authors: Guillaume Grenet, Samia Mekhaldi, Sabine Mainbourg, Marine Auffret, Catherine Cornu, Jean-Luc Cracowski, François Gueyffier, Jean-Christophe Lega, Michel Cucherat
Journal: Diabetes Care (2021)

From before the coronavirus disease 2019 (COVID-19) pandemic, the effect of dipeptidyl peptidase 4 inhibitors (DPP-4i) on respiratory infections (RI) remains unclear. The meta-analysis of Yang et al. (1) specifically assessed the risk of infection with DPP-4i. However, cardiovascular outcomes trials (CVOTs) did not appear in their meta-analysis for RI (1). In addition, the meta-analyses of CVOTs did not report assessment of RI for DPP-4i. Meta-analyses and pharmacovigilance studies showed some discrepancies (2). Recently published practical recommendations did not suggest discontinuation of DPP-4i because of the COVID-19 pandemic (3,4). The dipeptidyl peptidase 4 enzyme could be a target for treating COVID-19 (2). We aimed to provide a powerful and less biased estimate of the effect of DPP-4i on the overall risk of RI and thus verify the validity of the recent recommendations for the management of diabetes during the COVID-19 pandemic (3,4).

We updated a previous systematic review and meta-analysis, focusing our primary analysis on RI in placebo-controlled CVOTs assessing a DPP-4i in patients with type 2 diabetes, using PubMed and Cochrane Central Register of Controlled Trials (CENTRAL), up to 27 January 2020. In line with the previous meta-analysis of Yang et al. (1), our primary outcome was “any respiratory infection” (defined as influenza, nasopharyngitis, sinusitis, pharyngotonsillitis, pharyngitis, bronchitis, respiratory tract infection [RTI], upper RTI, lower RTI, or pneumonia). Secondary outcomes …
Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma
Authors: Shuichi Aoki, Koetsu Inoue, Sebastian Klein, Stefan Halvorsen, Jiang Chen, Aya Matsui, Mohammad R Nikmaneshi, Shuji Kitahara, Tai Hato, Xianfeng Chen, Kazumichi Kawakubo, Hadi T Nia, Ivy Chen, Daniel H Schanne, Emilie Mamessier, Kohei Shigeta, Hiroto Kikuchi, Rakesh R Ramjiawan, Tyge CE Schmidt, Masaaki Iwasaki, Thomas Yau, Theodore S Hong, Alexander Quaas, Patrick S Plum, Simona Dima, Irinel Popescu, Nabeel Bardeesy, Lance L Munn, Mitesh J Borad, Slim Sassi, Rakesh K. Jain, Andrew X Zhu, Dan G Duda
Journal: Gut (2021)

Objective Intrahepatic cholangiocarcinoma (ICC)—a rare liver malignancy with limited therapeutic options—is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression. Design We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. Results PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC. Conclusion PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.
Abstract 12463: Apolipoprotein (Apo) AI Stability Determines High Density Lipoprotein Function
Authors: Yaliu Yang, Corina Rosales, Baiba Gillard, Antonio Gotto, Henry Pownall
Journal: Circulation (2015)

Introduction Atherosclerosis is characterized by the accumulation of free and esterified cholesterol in the subendothelial space of the arterial wall. Reverse cholesterol transport reduces the burden of cholesterol in the arterial wall in three steps including selective uptake by hepatic scavenger receptor class B member 1 (SR-BI). The mechanism for HDL-lipid uptake is distinct from that of low density lipoproteins, which are removed by endocytosis of the holo particle; in contrast, SR-BI selectively extracts lipids from HDL and leaves remnant HDL as an obligatory lipid-poor particle. Hypothesis HDL resides in a kinetic trap from which it escapes via perturbations that transfer apo AI into the surrounding aqueous phase as a lipid-free (LF) protein. Given that apo AI but not other HDL apos nor apo B-100 is labile and readily released by HDL, we hypothesized that apo AI lability is necessary or at least permitting for HDL function, including selective CE uptake. Methods HDL-protein lipophilicity was increased by lysine acylation. HDL stability was tested by chaotropic perturbation with guanidinium chloride (GdmCl), and with Streptococcal serum opacity factor (SOF) and phospholipid transfer protein (PLTP), which are functional perturbants of HDL structure. Production of LF apo AI was quantified by size exclusion chromatography; SOF reaction kinetics vs. HDL was determined turbidimetrically; selective [ 3 H]CE HDL uptake was determined in human hepatoma Huh7 cells, and in SR-BI over expressing Chinese hamster ovary (CHO-SR-BI) and the parent CHO-ldlA7 cells. Results Hexanoylation of HDL profoundly reduces release of apo AI vs. the chemical perturbant–GdmCl, and biochemical perturbants–SOF and PLTP. The rate of [ 3 H]CE uptake from polyhexanoylated HDL by Huh7 and CHO-SR-BI cells was respectively 32% and 38% lower than that of control HDL. The rate of [ 3 H]CE uptake by the parent CHO-ldlA7 cells was 7% to 13% of that of CHO-SR-BI cells and similar for control and polyhexanoylated HDL. Conclusions We have developed and validated an HDL mechanism, reaction with hexanoic anhydride, which reduces the loss of LF apo AI. Our data support the hypothesis that apo AI lability in HDL is a permitting factor in multiple HDL functions, including selective hepatic CE uptake.
Perspective for Future Medicine: Multidisciplinary Computational Anatomy-Based Medicine with Artificial Intelligence
Authors: Makoto Hashizume
Journal: Cyborg and Bionic Systems (2021)

Multidisciplinary computational anatomy (MCA) is a new frontier of science that provides a mathematical analysis basis for the comprehensive and useful understanding of "dynamic living human anatomy." It defines a new mathematical modeling method for the early detection and highly intelligent diagnosis and treatment of incurable or intractable diseases. The MCA is a method of scientific research on innovative areas based on the medical images that are integrated with the information related to: (1) the spatial axis, extending from a cell size to an organ size; (2) the time series axis, extending from an embryo to post mortem body; (3) the functional axis on physiology or metabolism which is reflected in a variety of medical image modalities; and (4) the pathological axis, extending from a healthy physical condition to a diseased condition. It aims to integrate multiple prediction models such as multiscale prediction model, temporal prediction model, anatomy function prediction model, and anatomy-pathology prediction model. Artificial intelligence has been introduced to accelerate the calculation of statistic mathematical analysis. The future perspective is expected to promote the development of human resources as well as a new MCA-based scientific interdisciplinary field composed of mathematical statistics, information sciences, computing data science, robotics, and biomedical engineering and clinical applications. The MCA-based medicine might be one of the solutions to overcome the difficulties in the current medicine.
When the Signal From Phase 2 Research Should Be a Warning Sign
Authors: Howard (Jack) West
Journal: JAMA Oncology (2021)

Hiroaki Akamatsu, MD, PhD; Yukihiro Toi, MD; Hidetoshi Hayashi, MD, PhD; Daichi Fujimoto, MD; Motoko Tachihara, MD, PhD; Naoki Furuya, MD, PhD; Sakiko Otani, MD, PhD; Junichi Shimizu, MD, PhD; Nobuyuki Katakami, MD, PhD; Koichi Azuma, MD, PhD; Naoko Miura, MD, PhD; Kazumi Nishino, MD, PhD; Satoshi Hara, MD; Shunsuke Teraoka, MD; Satoshi Morita, PhD; Kazuhiko Nakagawa, MD, PhD; Nobuyuki Yamamoto, MD, PhD
Machine learning-based prediction of COVID-19 diagnosis based on symptoms
Authors: Yazeed Zoabi, Shira Deri-Rozov, Noam Shomron
Journal: npj Digital Medicine (2021)

Abstract Effective screening of SARS-CoV-2 enables quick and efficient diagnosis of COVID-19 and can mitigate the burden on healthcare systems. Prediction models that combine several features to estimate the risk of infection have been developed. These aim to assist medical staff worldwide in triaging patients, especially in the context of limited healthcare resources. We established a machine-learning approach that trained on records from 51,831 tested individuals (of whom 4769 were confirmed to have COVID-19). The test set contained data from the subsequent week (47,401 tested individuals of whom 3624 were confirmed to have COVID-19). Our model predicted COVID-19 test results with high accuracy using only eight binary features: sex, age ≥60 years, known contact with an infected individual, and the appearance of five initial clinical symptoms. Overall, based on the nationwide data publicly reported by the Israeli Ministry of Health, we developed a model that detects COVID-19 cases by simple features accessed by asking basic questions. Our framework can be used, among other considerations, to prioritize testing for COVID-19 when testing resources are limited.