tbuckley/cabot-search huggingface dataset:
The vicK gene of Streptococcus mutans mediates its cariogenicity via exopolysaccharides metabolism
Authors: Yalan Deng, Yingming Yang, Bin Zhang, Hong Chen, Yangyu Lu, Shirui Ren, Lei Lei, Tao Hu
Journal: International Journal of Oral Science (2021)

Abstract Streptococcus mutans ( S. mutans ) is generally regarded as a major contributor to dental caries because of its ability to synthesize extracellular polysaccharides (EPS) that aid in the formation of plaque biofilm. The VicRKX system of S. mutans plays an important role in biofilm formation. The aim of this study was to investigate the effects of vicK gene on specific characteristics of EPS in S. mutans biofilm. We constructed single-species biofilms formed by different mutants of vicK gene. Production and distribution of EPS were detected through atomic force microscopy, scanning electron microscopy and confocal laser scanning microscopy. Microcosmic structures of EPS were analyzed by gel permeation chromatography and gas chromatography-mass spectrometry. Cariogenicity of the vicK mutant was assessed in a specific pathogen-free rat model. Transcriptional levels of cariogenicity-associated genes were confirmed by quantitative real-time polymerase chain reaction. The results showed that deletion of vicK gene suppressed biofilm formation as well as EPS production, and EPS were synthesized mostly around the cells. Molecular weight and monosaccharide components underwent evident alterations. Biofilms formed in vivo were sparse and contributed a decreased degree of caries. Moreover, expressional levels of genes related to EPS synthesis were down-regulated, except for gtfB . Our report demonstrates that vicK gene enhances biofilm formation and subsequent caries development. And this may due to its regulations on EPS metabolism, like synthesis or microcosmic features of EPS. This study suggests that vicK gene and EPS can be considered as promising targets to modulate dental caries.
The future doctor and the future patient—reaching a true partnership
Authors: David J Hunter
Journal: BMJ (2021)

The growing crisis in the NHS adds greater urgency to our efforts to create a future doctor-patient relationship that is both equal and effective.The current arrangement is no longer fit for purpose, if it ever was, with patients often left feeling disempowered. 1Too often, efforts to engage the public and patients in their health have amounted to symbolic gesturing, with plans for hospitals and practices excluding their voices.Such hubristic activity has been termed "engagement camouflage" for decisions that are still largely taken elsewhere without patient or public input.In a classic study 50 years ago, the American political scientist Robert Alford referred to patients and the public as "repressed interests," while doctors remained the "dominant interests." 2 Little has changed over the years, although with the arrival of managers and managerialism (the "challenging interests"), doctors may feel themselves to hold less sway than they once did.
Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial
Authors: Benjamin A Fisher, Tonny Veenith, Daniel Slade, Charlotte Gaskell, Matthew Rowland, Tony Whitehouse, James Scriven, Dhruv Parekh, Madhu S Balasubramaniam, Graham Cooke, Nick Morley, Zoe Gabriel, Matthew P Wise, Joanna Porter, Helen McShane, Ling-Pei Ho, Philip N Newsome, Anna Rowe, Rowena Sharpe, David R Thickett, Julian Bion, Simon Gates, Duncan Richards, Pamela Kearns, Bryan Williams, Rebecca Turner, Vincenzo Libri, Francis Mussai, Gary Middleton, Sarah Bowden, Mansoor Bangash, Fang Gao-Smith, Jaimin Patel, Elizabeth Sapey, Mark Thomas, Mark Coles, Peter Watkinson, Naj Rahman, Brian Angus, Alexander J. Mentzer, Alex Novak, Marc Feldman, Alex Richter, Sian Faustini, Camilla Bathurst, Joseph Van de Wiel, Susie Mee, Karen James, Bushra Rahman, Karen Turner, Adam Hill, Anthony Gordon, Christina Yap, Michael Matthay, Danny McAuley, Andrew Hall, Paul Dark, Andrew McMichael
Journal: The Lancet Respiratory Medicine (2021)
Relative environmental and social disadvantage in patients with idiopathic pulmonary fibrosis
Authors: Na'ama Avitzur, Elizabeth M Noth, Mubasiru Lamidi, Steven D Nathan, Harold R Collard, Alison M DeDent, Neeta Thakur, Kerri A Johannson
Journal: Thorax (2021)

Background Air pollution exposure is associated with disease severity, progression and mortality in patients with idiopathic pulmonary fibrosis (IPF). Combined impacts of environmental and socioeconomic factors on outcomes in patients with IPF are unknown. The objectives of this study were to characterise the relationships between relative environmental and social disadvantage with clinical outcomes in patients with IPF. Methods Patients with IPF were identified from a longitudinal database at University of California, San Francisco. Residential addresses were geocoded and linked to the CalEnviroScreen 3.0 (CES), a tool that quantifies environmental burden in California communities, combining population, environmental and pollution vulnerability into individual and composite scores (higher scores indicating greater disadvantage). Unadjusted and adjusted linear and logistic regression and Fine and Gray proportional hazards models were used. Results 603 patients were included. Higher CES was associated with lower baseline forced vital capacity ( β =−0.073, 95% CI −0.13 to −0.02; p=0.006) and diffusion capacity of the lung for carbon monoxide ( β =−0.11, 95% CI −0.16 to −0.06; p&lt;0.001). Patients in the highest population vulnerability quartile were less likely to be on antifibrotic therapy (OR=0.33; 95% CI 0.18 to 0.60; p=0.001) at time of enrolment, compared with those in the lowest quartile. An association between CES and mortality was suggested, but sensitivity analyses demonstrated inconsistent results. Relative disadvantage of the study cohort appeared lower compared with the general population. Conclusions Higher environmental exposures and vulnerability were associated with lower baseline lung function and lower antifibrotic use, suggesting that relative socioenvironmental disadvantage has meaningful impacts on patients with IPF.
Unequal global vaccine coverage is at the heart of the current covid-19 crisis
Authors: Fatima Hassan, Leslie London, Gregg Gonsalves
Journal: BMJ (2021)

Unequal global vaccine coverage is at the heart of the current covid-19 crisisThe emergence of the omicron variant shows the risks of vaccine inequity, and the response of the global North has been to further discriminate against and isolate the global South
Real-World Ravulizumab Dosing Patterns Among Patients with Paroxysmal Nocturnal Hemoglobinuria in a US Population
Authors: Wendy Y. Cheng, Jesse Fishman, Sujata P. Sarda, Sangeeta Krishnan, Colin Kunzweiler, Jensen Duy Vu, Mihran Yenikomshian, Mei Sheng Duh
Journal: Blood (2021)
Pharmacological modulation of autophagy for Alzheimer's disease therapy: Opportunities and obstacles
Authors: Zhiqiang Deng, Yu Dong, Xiaoting Zhou, Jia-Hong Lu, Zhenyu Yue
Journal: Acta Pharmaceutica Sinica B (2021)

Alzheimer's disease (AD) is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. By far, the precise mechanisms of AD are not fully understood and no interventions are available to effectively slow down progression of the disease. Autophagy is a conserved degradation pathway that is crucial to maintain cellular homeostasis by targeting damaged organelles, pathogens, and disease-prone protein aggregates to lysosome for degradation. Emerging evidence suggests dysfunctional autophagy clearance pathway as a potential cellular mechanism underlying the pathogenesis of AD in affected neurons. Here we summarize the current evidence for autophagy dysfunction in the pathophysiology of AD and discuss the role of autophagy in the regulation of AD-related protein degradation and neuroinflammation in neurons and glial cells. Finally, we review the autophagy modulators reported in the treatment of AD models and discuss the obstacles and opportunities for potential clinical application of the novel autophagy activators for AD therapy.
Abstract 11809: Trans-Endothelial Electrical Resistance to Assess Cell Layer Integrity in Coronary Artery Endothelial Cells After Hypoxia/Reoxygenation Injury
Authors: Matthew J Hampton, Insha H Maknojia, zhu li, Matthew B Barajas, Matthias L Riess
Journal: Circulation (2021)

Introduction: Cardiovascular disease remains one of the leading causes of complications and death worldwide. Therefore, accurate and reliable methods of mimicking ischemia/reperfusion (IR) injury in cardiac cells in vivo are crucial when testing drugs/substances for prevention and treatment. Coronary artery endothelial cells play a critical role in not only supplying blood to myocardial cells but protecting them from insult as well. However, the endothelial layer can be compromised by ischemic injury, heightening damage to the heart during reperfusion. Hypothesis: Varied ischemic insult of mouse coronary artery endothelial cells (MCAECs) affects cell layer integrity as measured by Trans-Endothelial Electrical Resistance (TEER). Methods: MCAECs were cultured on Grenier Bio-One ThinCert™-cell culture inserts for 72 hrs to allow for adequate confluency. Cells were then subjected to either continued normoxic conditions or hypoxia for 3, 6, 12, or 24 hrs, with a 2-hr reperfusion period immediately following. TEER was used to measure the integrity of the endothelial cell layer on the insert. Results: Our data showed a significant decrease in TEER between control and hypoxic groups after 6 hrs (p = 0.0400), 12 hrs (p = 0.0179) and 24 hrs (p = 0.0103), but not after 3 hrs (p = 0.4453) of hypoxia. Conclusion: This indicates that titrating the hypoxia time to a sufficient duration is necessary to achieve an adequate H/R injury which can then be used for potential cardioprotective agents and/or strategies to be tested. Furthermore, TEER is a reliable and reproducible method to assess the role of endothelial cell membrane integrity in cardioprotection.
Abstract 9899: Sex-Related Differences in Severe Cerebral Edema Development in Comatose Cardiac Arrest Patients
Authors: Annelise M Kulpanowski, William A Copen, Brandon L Hancock, Eric S Rosenthal, David A Schoenfeld, Brian L Edlow, W Taylor T Kimberly, Edilberto Amorim, Michael B Westover, Mingming Ning, Pamela W Schaefer, Rajeev Malhotra, Joseph T Giacino, David M Greer, Ona Wu
Journal: Circulation (2021)

Introduction: Previous studies have shown that women have poorer neurological outcomes than men following out-of-hospital cardiac arrest (OHCA). However, those studies focused on survival, a measure that may be confounded by withdrawal of life-sustaining therapy (WLST) decisions. We sought to assess sex differences in severe cerebral edema development following cardiac arrest. Methods: Data from adult OHCA patients presenting between 2007-2019 were retrospectively analyzed. Patients with multiple concomitant acute neurologic dysfunctions were excluded. Severe cerebral edema was classified as herniation or more than minimal ventricular effacement in MRI or CT radiology reports. Arrest types were categorized as shockable (VT/VF) or non-shockable (PEA, asystole). Poor outcomes were defined as Cerebral Performance Category &gt; 3 at discharge. Multivariable backward stepwise logistic regression was performed. Results: 359 patients met our inclusion criteria. Demographics, imaging and clinical outcomes are summarized in Table 1. Women were more likely than men to have a non-shockable initial rhythm (P=0.003) and develop severe cerebral edema (P=0.005). Backwards stepwise logistic regression of an initial model including age, sex, rhythm, witnessed arrest and TTM-treatment, produced a final model that showed younger age (P&lt;0.001), female sex (P=0.01), and non-shockable rhythm (P&lt;0.001) as significant predictors of severe cerebral edema development. Patients with severe cerebral edema had worse outcomes (89/91 vs 176/268, P&lt;0.001), and greater in-hospital mortality (82/91 vs 166/268, P&lt;0.001), with a higher proportion of deaths due to brain death (15/82 vs 3/166 P&lt;0.001). Conclusion: For OHCA patients who are initially comatose, women are more likely than men to have non-shockable rhythms and severe cerebral brain edema. These differences may be responsible for the poorer discharge outcomes that have been observed by other studies.
Gab2 deficiency prevents Flt3-ITD driven acute myeloid leukemia in vivo
Authors: Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schönberger, Nina Cabezas-Wallscheid, Melanie Boerries, Sebastian Halbach, Anna L. Illert, Tilman Brummer
Journal: Leukemia (2021)

Internal tandem duplications (ITD) of the FMS-like tyrosine kinase 3 (FLT3) predict poor prognosis in acute myeloid leukemia (AML) and often co-exist with inactivating DNMT3A mutations. In vitro studies implicated Grb2-associated binder 2 (GAB2) as FLT3-ITD effector. Utilizing a Flt3-ITD knock-in, Dnmt3a haploinsufficient mouse model, we demonstrate that Gab2 is essential for the development of Flt3-ITD driven AML in vivo, as Gab2 deficient mice displayed prolonged survival, presented with attenuated liver and spleen pathology and reduced blast counts. Furthermore, leukemic bone marrow from Gab2 deficient mice exhibited reduced colony-forming unit capacity and increased FLT3 inhibitor sensitivity. Using transcriptomics, we identify the genes encoding for Axl and the Ret co-receptor Gfra2 as targets of the Flt3-ITD/Gab2/Stat5 axis. We propose a pathomechanism in which Gab2 increases signaling of these receptors by inducing their expression and by serving as downstream effector. Thereby, Gab2 promotes AML aggressiveness and drug resistance as it incorporates these receptor tyrosine kinases into the Flt3-ITD signaling network. Consequently, our data identify GAB2 as a promising biomarker and therapeutic target in human AML.
Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors
Authors: Clint A. Stalnecker, Kajal R. Grover, A. Cole Edwards, Michael F. Coleman, Runying Yang, Jonathan M. DeLiberty, Björn Papke, Craig M. Goodwin, Mariaelena Pierobon, Emanuel F. Petricoin, Prson Gautam, Krister Wennerberg, Adrienne D. Cox, Channing J. Der, Stephen D. Hursting, Kirsten L. Bryant
Journal: Cancer Research (2021)

Abstract The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development of improved therapies. As KRAS mutations are found in 95% of PDAC and are critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. The macrometabolic process of autophagy is upregulated in KRAS-mutant PDAC, and PDAC growth is reliant on autophagy. However, inhibition of autophagy as monotherapy using the lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy. To identify strategies that can improve PDAC sensitivity to HCQ, we applied a CRISPR-Cas9 loss-of-function screen and found that a top sensitizer was the receptor tyrosine kinase (RTK) insulin-like growth factor 1 receptor (IGF1R). Additionally, reverse phase protein array pathway activation mapping profiled the signaling pathways altered by chloroquine (CQ) treatment. Activating phosphorylation of RTKs, including IGF1R, was a common compensatory increase in response to CQ. Inhibition of IGF1R increased autophagic flux and sensitivity to CQ-mediated growth suppression both in vitro and in vivo. Cotargeting both IGF1R and pathways that antagonize autophagy, such as ERK–MAPK axis, was strongly synergistic. IGF1R and ERK inhibition converged on suppression of glycolysis, leading to enhanced dependence on autophagy. Accordingly, concurrent inhibition of IGF1R, ERK, and autophagy induced cytotoxicity in PDAC cell lines and decreased viability in human PDAC organoids. In conclusion, targeting IGF1R together with ERK enhances the effectiveness of autophagy inhibitors in PDAC. Significance: Compensatory upregulation of IGF1R and ERK–MAPK signaling limits the efficacy of autophagy inhibitors chloroquine and hydroxychloroquine, and their concurrent inhibition synergistically increases autophagy dependence and chloroquine sensitivity in pancreatic ductal adenocarcinoma.
Tafenoquine exposure assessment, safety, and relapse prevention efficacy in children with Plasmodium vivax malaria: open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial
Authors: Iván D Vélez, Tran T Hien, Justin A Green, Ana Martin, Hema Sharma, Victoria M Rousell, John J Breton, Terry B Ernest, Katie Rolfe, Maxine Taylor, Khadeeja Mohamed, Siôn W Jones, Nguyen Hoang Chau, Nhu Thi Hoa, Stephan Duparc, Lionel K Tan, Navin Goyal
Journal: The Lancet Child & Adolescent Health (2021)
Identification of human LDHC4 as a potential target for anticancer drug discovery
Authors: Hong Tan, Huali Wang, Jinhu Ma, Hui Deng, Qinghua He, Qiang Chen, Qinglian Zhang
Journal: Acta Pharmaceutica Sinica B (2021)

One of the distinct hallmarks of cancer cells is aerobic glycolysis (Warburg effect). Lactate dehydrogenase A (LDHA) is thought to play a key role in aerobic glycolysis and has been extensively studied, while lactate dehydrogenase C (LDHC), an isoform of LDHA, has received much less attention. Here we showed that human LDHC was significantly expressed in lung cancer tissues, overexpression of Ldhc in mice could promote tumor growth, and knock-down of LDHC could inhibit the proliferation of lung cancer A549 cells. We solved the first crystal structure of human LDHC4 and found that the active-site loop of LDHC4 adopted a distinct conformation compared to LDHA4 and lactate dehydrogenase B4 (LDHB4). Moreover, we found that (ethylamino) (oxo)acetic acid shows about 10 times selective inhibition against LDHC4 over LDHA4 and LDHB4. Our studies suggest that LDHC4 is a potential target for anticancer drug discovery and (ethylamino) (oxo)acetic acid provides a good start to develop lead compounds for selective drugs targeting LDHC4.
Imaging diagnosis of hepatocellular carcinoma: Future directions with special emphasis on hepatobiliary magnetic resonance imaging and contrast-enhanced ultrasound
Authors: Junghoan Park, Jeong Min Lee, Tae-Hyung Kim, Jeong Hee Yoon
Journal: Clinical and Molecular Hepatology (2021)

Hepatocellular carcinoma (HCC) is a unique cancer entity that can be noninvasively diagnosed using imaging modalities without pathologic confirmation. In 2018, several major guidelines for HCC were updated to include hepatobiliary contrast agent magnetic resonance imaging (HBA-MRI) and contrast-enhanced ultrasound (CEUS) as major imaging modalities for HCC diagnosis. HBA-MRI enables the achievement of high sensitivity in HCC detection using the hepatobiliary phase (HBP). CEUS is another imaging modality with real-time imaging capability, and it is reported to be useful as a second-line modality to increase sensitivity without losing specificity for HCC diagnosis. However, until now, there is an unsolved discrepancy among guidelines on whether to accept “HBP hypointensity” as a definite diagnostic criterion for HCC or include CEUS in the diagnostic algorithm for HCC diagnosis. Furthermore, there is variability in terminology and inconsistencies in the definition of imaging findings among guidelines; therefore, there is an unmet need for the development of a standardized lexicon. In this article, we review the performance and limitations of HBA-MRI and CEUS after guideline updates in 2018 and briefly introduce some future aspects of imaging-based HCC diagnosis.
Retinal Displacement after Pneumatic Retinopexy versus Vitrectomy for Rhegmatogenous Retinal Detachment (ALIGN)
Authors: Carolina L.M. Francisconi, Samara B. Marafon, Natalia A. Figueiredo, Verena R. Juncal, Sufiyan Shaikh, Nishaant Bhambra, David T. Ta Kim, Koby Brosh, Jenny Qian, Varun Chaudhary, Alan R. Berger, Louis R. Giavedoni, David T. Wong, Filiberto Altomare, David R. Chow, Sandro Di Simplicio, Mustafa R. Kadhim, Deven Deonarain, Roxane J. Hillier, Rajeev H. Muni
Journal: Ophthalmology (2021)
Promotion of Oral Health and Prevention of Dental Caries Among Children in Primary Care
Authors: Melinda B. Clark, Patricia A. Braun
Journal: JAMA (2021)

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Whole gut virome analysis of 476 Japanese revealed a link between phage and autoimmune disease
Authors: Yoshihiko Tomofuji, Toshihiro Kishikawa, Yuichi Maeda, Kotaro Ogawa, Takuro Nii, Tatsusada Okuno, Eri Oguro-Igashira, Makoto Kinoshita, Kenichi Yamamoto, Kyuto Sonehara, Mayu Yagita, Akiko Hosokawa, Daisuke Motooka, Yuki Matsumoto, Hidetoshi Matsuoka, Maiko Yoshimura, Shiro Ohshima, Shota Nakamura, Hidenori Inohara, Hideki Mochizuki, Kiyoshi Takeda, Atsushi Kumanogoh, Yukinori Okada
Journal: Annals of the Rheumatic Diseases (2021)

Objective The relationship between autoimmune diseases and the gut microbiome has been intensively studied, and several autoimmunity-associated bacterial taxa have been identified. However, much less is known about the roles of the gut virome in autoimmune diseases. Methods Here, we performed a whole gut virome analysis based on the shotgun sequencing of 476 Japanese which included patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis and healthy control subjects. Results Our case–control comparison of the viral abundance revealed that crAss-like phages, which are one of the main components of a healthy gut virome, significantly decreased in the gut of the patients with autoimmune disease, specifically the patients with RA and SLE. In addition, Podoviridae significantly decreased in the gut of the patients with SLE. To understand how these viruses affected the bacteriome, we performed a quantitative virus–bacterium association analysis and clustered regularly interspaced short palindromic repeat-based virus–bacterium interaction analysis. We identified a symbiosis between Podovirida e and Faecalibacterium . In addition, multiple bacterial targets of crAss-like phages were identified (eg, Ruminococcus spp). Conclusion Our data suggest that the gut virome can affect our body either directly or via bacteria. Our analyses have elucidated a previously missing part of the autoimmunity-associated gut microbiome and presented new candidates that contribute to the development of autoimmune diseases.