tbuckley/cabot-search huggingface dataset:
An increase in the<i>Akkermansia</i>spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice
Authors: Na-Ri Shin, June-Chul Lee, Hae-Youn Lee, Min-Soo Kim, Tae Woong Whon, Myung-Shik Lee, Jin-Woo Bae
Journal: Gut (2013)

<h3>Background</h3> Recent evidence indicates that the composition of the gut microbiota contributes to the development of metabolic disorders by affecting the physiology and metabolism of the host. Metformin is one of the most widely prescribed type 2 diabetes (T2D) therapeutic agents. <h3>Objective</h3> To determine whether the antidiabetic effect of metformin is related to alterations of intestinal microbial composition. <h3>Design</h3> C57BL/6 mice, fed either a normal-chow diet or a high-fat diet (HFD), were treated with metformin for 6 weeks. The effect of metformin on the composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing. Adipose tissue inflammation was examined by flow cytometric analysis of the immune cells present in visceral adipose tissue (VAT). <h3>Results</h3> Metformin treatment significantly improved the glycaemic profile of HFD-fed mice. HFD-fed mice treated with metformin showed a higher abundance of the mucin-degrading bacterium <i>Akkermansia</i> than HFD-fed control mice. In addition, the number of mucin-producing goblet cells was significantly increased by metformin treatment (p&lt;0.0001). Oral administration of <i>Akkermansia muciniphila</i> to HFD-fed mice without metformin significantly enhanced glucose tolerance and attenuated adipose tissue inflammation by inducing Foxp3 regulatory T cells (Tregs) in the VAT. <h3>Conclusions</h3> Modulation of the gut microbiota (by an increase in the <i>Akkermansia</i> spp. population) may contribute to the antidiabetic effects of metformin, thereby providing a new mechanism for the therapeutic effect of metformin in patients with T2D. This suggests that pharmacological manipulation of the gut microbiota in favour of <i>Akkermansia</i> may be a potential treatment for T2D.
Water Exchange Is the Least Painful Colonoscope Insertion Technique and Increases Completion of Unsedated Colonoscopy
Authors: Sergio Cadoni, Přemysl Falt, Paolo Gallittu, Mauro Liggi, Donatella Mura, Vit Smajstrla, Matteo Erriu, Felix W. Leung
Journal: Clinical Gastroenterology and Hepatology (2015)
The TNF family member APRIL dampens collagen-induced arthritis
Authors: Leticia Fernandez, Gabriela Franco Salinas, Cecilia Rocha, Carla E Carvalho-Pinto, Nataliya Yeremenko, Laura Papon, Jan Paul Medema, Bernard Combe, Jacques Morel, Dominique Baeten, Michael Hahne
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> The tumour necrosis factor (TNF)-family members B cell activating factor (BAFF) and A PRoliferation-Inducing Ligand (APRIL) play important roles in B cell biology, and share binding to B cell maturation antigen and transmembrane activator and cyclophilin ligand interactor, both receptors of the TNF-family. However, while it is reported that BAFF can break B cell tolerance, the role of APRIL in autoimmunity remains elusive. <h3>Objective</h3> To evaluate the role of APRIL on collagen-induced arthritis (CIA). <h3>Methods</h3> CIA was induced in APRIL-transgenic (Tg) DBA/1 mice and littermates. Disease progression was evaluated by clinical and histological signs of arthritis. In another experimental setting mice were exposed to the collagen antibody-induced arthritis. In addition, we tested T cell dependent humoral responses in APRIL-Tg mice. <h3>Results</h3> We found that APRIL-Tg displayed a strongly reduced incidence and severity of CIA compared with littermates, with decreases in collagen-specific autoantibody titres, immune complex deposition and downstream mast cell activation in joints. Notably, ectopic APRIL-expression was also found to negatively regulate T cell dependent humoral responses. The lower autoantibody production in APRIL-Tg mice during CIA appears to be crucial, as arthritis induced by administration of anti-collagen antibodies developed similar in APRIL-Tg and control mice, thus demonstrating that the downstream effector pathways induced by anti-collagen antibodies remain intact in APRIL-Tg mice. This protective effect was specifically mediated by APRIL, as adenoviral delivery of APRIL decreased CIA in a therapeutic setting. <h3>Conclusions</h3> Collectively, our data identify APRIL as a negative regulator of CIA by regulating autoantibody production. These findings are of important clinical relevance, as the therapeutic potential of transmembrane activator and cyclophilin ligand interactor-Fc (atacicept) is presently evaluated in clinical trials.
Associated factors in recurrent groin and hamstring injuries.
Authors: D. S. Muckle
Journal: British Journal of Sports Medicine (1982)

Recurrent groin and hamstring injuries are amongst the most difficult and refractory problems in sports medicine.Although accounting for only 14% of all sports injuries the amount of playing time lost is dispro- portionately high; thus, in one soccer season they were responsible for almost thirty per cent of missed match- units (Muckle, 1982).
Adventures in Cardiovascular Research
Authors: Eugene Braunwald
Journal: Circulation (2009)

This article, derived from an invited Distinguished Scientist lecture presented at the American Heart Association Scientific Sessions in 2007, reviews 4 themes (adventures) in clinical cardiovascular research carried out over a period of 58 years. It begins with the author's introduction to cardiovascular hemodynamics during a medical school elective in 1951. The 4 adventures include valvular heart disease, hypertrophic cardiomyopathy, heart failure (HF), and myocardial ischemia. In each of these adventures, the author describes briefly what was known when he entered each field, followed by the author's contribution to the field (the adventure), and ends with comments about the current status of the field. Of particular interest are the changes in the technologies used in clinical cardiovascular research over the past half century, commencing with pressure tracings in left heart chambers with the use of needle puncture in the operating room to genetic technologies designed to understand differences between drugs that inhibit platelet activation. The article ends with some general comments on conducting research and the rewards that can come with this activity.
Antiproteinuric Therapy while Preventing the Abnormal Protein Traffic in Proximal Tubule Abrogates Protein- and Complement-Dependent Interstitial Inflammation in Experimental Renal Disease
Authors: MAURO ABBATE, CARLA ZOJA, DANIELA ROTTOLI, DANIELA CORNA, NORBERTO PERICO, TULLIO BERTANI, GIUSEPPE REMUZZI
Journal: Journal of the American Society of Nephrology (1999)

Abstract. In proteinuric glomerulopathies, the excess traffic of proteins into the renal tubule is a candidate trigger of interstitial inflammatory and immune events leading to progressive injury, and a key target for the renoprotective action of antiproteinuric drugs. Among proteins trafficked to the proximal tubule, the third component of complement (C3) can be activated locally and contribute to inflammation at sites of protein reabsorption. Experiments were performed in rats with renal mass reduction (RMR, 5/6 nephrectomy) with the following aims: ( 1 ) to study Ig (IgG) and complement deposition in proximal tubules, and interstitial macrophage infiltration and MHC class II expression at intervals after surgery by double immunofluorescence analysis; ( 2 ) to assess whether lisinopril (angiotensin-converting enzyme inhibitor [ACEi], 25 mg/L in the drinking water, from either day 1 or day 7) limited IgG and C3 accumulation and interstitial inflammation at day 30. In 7-d remnant kidneys, intracellular staining for both IgG and C3 was detectable in proximal tubules in focal areas; C3 was restricted to IgG-positive tubular cells, and there were no interstitial ED-1 macrophage and MHC II-positive cellular infiltrates. In 14-d and 30-d remnant kidneys, proximal tubular IgG and C3 staining was associated with the appearance of interstitial infiltrates that preferentially localized to areas of tubules positive for both proteins. RMR rats given ACEi had no or limited increases in levels of urinary protein excretion, tubular IgG, and C3 reactivity, and interstitial cellular infiltrates in kidneys at 30 d, even when ACEi was started from day 7 after surgery. These findings document that ( 1 ) in RMR, IgG and C3 accumulation in proximal tubular cells is followed by leukocyte infiltration and MHC II overexpression in the adjacent interstitium; ( 2 ) ACEi while preventing proteinuria limits both tubular accumulation of IgG and C3 and interstitial inflammation. The data suggest that ACE inhibition can be renoprotective by limiting the early abnormal protein traffic in proximal tubule and consequent deleterious effects of excess protein reabsorption, including the accumulation and local activation of complement as well as the induction of chemokines and endothelin genes known to promote interstitial inflammation and fibrosis.
Gene Expression Profile Associated with Response to Doxorubicin-Based Therapy in Breast Cancer
Authors: Maria Aparecida Azevedo Koike Folgueira, Dirce Maria Carraro, Helena Brentani, Diogo Ferreira da Costa Patrão, Edson Mantovani Barbosa, Mário Mourão Netto, José Roberto Fígaro Caldeira, Maria Lucia Hirata Katayama, Fernando Augusto Soares, Célia Tosello Oliveira, Luiz Fernando Lima Reis, Jane Haruko Lima Kaiano, Luiz Paulo Camargo, Ricardo Zorzetto Nicoliello Vêncio, Igor Moysés Longo Snitcovsky, Fabiana Baroni Alves Makdissi, Paulo José da Silva e Silva, João Carlos Guedes Sampaio Góes, Maria Mitzi Brentani
Journal: Clinical Cancer Research (2005)

Abstract Purpose: This study was designed to identify genes that could predict response to doxorubicin-based primary chemotherapy in breast cancer patients. Experimental Design: Biopsy samples were obtained before primary treatment with doxorubicin and cyclophosphamide. RNA was extracted and amplified and gene expression was analyzed using cDNA microarrays. Results: Response to chemotherapy was evaluated in 51 patients, and based on Response Evaluation Criteria in Solid Tumors guidelines, 42 patients, who presented at least a partial response (≥30% reduction in tumor dimension), were classified as responsive. Gene profile of samples, divided into training set (n = 38) and independent validation set (n = 13), were at first analyzed against a cDNA microarray platform containing 692 genes. Unsupervised clustering could not separate responders from nonresponders. A classifier was identified comprising EMILIN1, FAM14B, and PBEF, which however could not correctly classify samples included in the validation set. Our next step was to analyze gene profile in a more comprehensive cDNA microarray platform, containing 4,608 open reading frame expressed sequence tags. Seven samples of the initial training set (all responder patients) could not be analyzed. Unsupervised clustering could correctly group all the resistant samples as well as at least 85% of the sensitive samples. Additionally, a classifier, including PRSS11, MTSS1, and CLPTM1, could correctly distinguish 95.4% of the 44 samples analyzed, with only two misclassifications, one sensitive sample and one resistant tumor. The robustness of this classifier is 2.5 greater than the first one. Conclusion: A trio of genes might potentially distinguish doxorubicin-responsive from nonresponsive tumors, but further validation by a larger number of samples is still needed.
Ureteric Morphogenesis Requires Fgfr1 and Fgfr2/Frs2α Signaling in the Metanephric Mesenchyme
Authors: Sunder Sims-Lucas, Valeria Di Giovanni, Caitlin Schaefer, Brian Cusack, Veraragavan P. Eswarakumar, Carlton M. Bates
Journal: Journal of the American Society of Nephrology (2012)

Conditional deletion of fibroblast growth factor receptors (Fgfrs) 1 and 2 in the metanephric mesenchyme (MM) of mice leads to a virtual absence of MM and unbranched ureteric buds that are occasionally duplex. Deletion of Fgfr2 in the MM leads to kidneys with cranially displaced ureteric buds along the Wolffian duct or duplex ureters. Mice with point mutations in Fgfr2’s binding site for the docking protein Frs2α (Fgfr2LR/LR), however, have normal kidneys; the roles of the Fgfr2/Frs2α signaling axis in MM development and regulating the ureteric bud induction site are incompletely understood. Here, we generated mice with both Fgfr1 deleted in the MM and Fgfr2LR/LR point mutations (Fgfr1Mes−/−Fgfrf2LR/LR). Unlike mice lacking both Fgfr1 and Fgfr2 in the MM, these mice had no obvious MM defects but had cranially displaced or duplex ureteric buds, probably as a result of decreased Bmp4 expression. Fgfr1Mes−/−Fgfr2LR/LR mice also had subsequent defects in ureteric morphogenesis, including dilated, hyperproliferative tips and decreased branching. Ultimately, they developed progressive renal cystic dysplasia associated with abnormally oriented cell division. Furthermore, mutants had increased and ectopic expression of Ret and its downstream targets in ureteric trunks, and exhibited upregulation of Ret/Etv4/5 signaling effectors, including Met, Myb, Cxcr4, and Crlf1. These defects were associated with reduced expression of Bmp4 in mesenchymal cells near mutant ureteric bud tips. Taken together, these results demonstrate that Fgfr2/Frs2α signaling in the MM promotes Bmp4 expression, which represses Ret levels and signaling in the ureteric bud to ensure normal ureteric morphogenesis.
Acquired Neuromuscular Disorders in the Intensive Care Unit
Authors: Steven Deem, Catherine M. Lee, J. Randall Curtis
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Patients are occasionally admitted to the intensive care unit (ICU) with respiratory failure or other pulmonary complications secondary to neuromuscular weakness that is chronic or newly acquired. However, the development of neuromuscular weakness in the ICU as a result of critical illness or therapy is an under-recognized but common problem. Indeed, neuromuscular abnormalities can be found in virtually all patients hospitalized in the ICU for a week or more, and more than one-half of mechanically ventilated patients develop clinically overt weakness. In the latter group, weakness appears to prolong time on the mechanical ventilator, increase hospital costs and increase mortality. Acquired neuromuscular disorders may also account for the majority of cases of prolonged ventilatory failure. It is therefore imperative to understand the potential causes of acquired neuromuscular disorders in the ICU so that inciting factors can be avoided if possible.
Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma
Authors: David T Yang, Ken H Young, Brad S Kahl, Stephanie Markovina, Shigeki Miyamoto
Journal: Molecular Cancer (2008)

The proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-kappaB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL). However, NF-kappaB can be activated through many distinct mechanisms, including proteasome independent pathways. While MCL cells have been shown to harbor constitutive NF-kappaB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear.Proteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-kappaB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA). Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231) and a breast carcinoma cell line (MDA-MB-468), the bortezomib-resistant NF-kappaB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10) displayed bortezomib-resistant constitutive NF-kappaB activity.Our findings show that bortezomib-resistant NF-kappaB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.
Multiple Reaction Monitoring to Identify Site-Specific Troponin I Phosphorylated Residues in the Failing Human Heart
Authors: Pingbo Zhang, Jonathan A. Kirk, Weihua Ji, Cristobal G. dos Remedios, David A. Kass, Jennifer E. Van Eyk, Anne M. Murphy
Journal: Circulation (2012)

Background— Human cardiac troponin I is known to be phosphorylated at multiple amino acid residues by several kinases. Advances in mass spectrometry allow sensitive detection of known and novel phosphorylation sites and measurement of the level of phosphorylation simultaneously at each site in myocardial samples. Methods and Results— On the basis of in silico prediction and liquid chromatography/mass spectrometry data, 14 phosphorylation sites on cardiac troponin I, including 6 novel residues (S4, S5, Y25, T50, T180, S198), were assessed in explanted hearts from end-stage heart failure transplantation patients with ischemic heart disease or idiopathic dilated cardiomyopathy and compared with samples obtained from nonfailing donor hearts (n=10 per group). Thirty mass spectrometry–based multiple reaction monitoring quantitative tryptic peptide assays were developed for each phosphorylatable and corresponding nonphosphorylated site. The results show that in heart failure there is a decrease in the extent of phosphorylation of the known protein kinase A sites (S22, S23) and other newly discovered phosphorylation sites located in the N-terminal extension of cardiac troponin I (S4, S5, Y25), an increase in phosphorylation of the protein kinase C sites (S41, S43, T142), and an increase in phosphorylation of the IT-arm domain residues (S76, T77) and C-terminal domain novel phosphorylation sites of cardiac troponin I (S165, T180, S198). In a canine dyssynchronous heart failure model, enhanced phosphorylation at 3 novel sites was found to decline toward control after resynchronization therapy. Conclusions— Selective, functionally significant phosphorylation alterations occurred on individual residues of cardiac troponin I in heart failure, likely reflecting an imbalance in kinase/phosphatase activity. Such changes can be reversed by cardiac resynchronization.
Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab
Authors: N. Nishimoto, J. Hashimoto, N. Miyasaka, K. Yamamoto, S. Kawai, T. Takeuchi, N. Murata, D. van der Heijde, T. Kishimoto
Journal: Annals of the Rheumatic Diseases (2007)

To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA.In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method.Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively.Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.
Genetic Testing and Youth Sports
Authors: M. Alison Brooks, Beth A. Tarini
Journal: JAMA (2011)

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Intratumoral Recombinant Human Interleukin-12 Administration in Head and Neck Squamous Cell Carcinoma Patients Modifies Locoregional Lymph Node Architecture and Induces Natural Killer Cell Infiltration in the Primary Tumor
Authors: Carla M.L. van Herpen, Jeroen A.W.M. van der Laak, I. Jolanda M. de Vries, Johan H. van Krieken, Peter C. de Wilde, Michiel G.J. Balvers, Gosse J. Adema, Pieter H.M. De Mulder
Journal: Clinical Cancer Research (2005)

The objective of this study was to evaluate the histologic and immunohistopathologic effects of intratumorally given recombinant human interleukin-12 on the immune cells in the primary tumors and regional lymph nodes. Ten previously untreated patients with head and neck squamous cell carcinoma (HNSCC) were injected in the primary tumor twice to thrice, once weekly, at two dose levels of 100 or 300 ng/kg, before surgery. These patients were compared with 20 non-IL-12-treated control HNSCC patients. In the primary tumor, the number of CD56+ natural killer (NK) cells was increased in IL-12-treated patients compared with control patients. In some IL-12-treated patients, an impressive peritumoral invasion of CD20+ B cells was noticed. No differences were seen in the CD8+ or CD4+ T lymphocytes. Interestingly, major differences were apparent in the architecture of the enlarged lymph nodes of IL-12-treated patients; in particular, the distribution of B cells differed and fewer primary and secondary follicles with smaller germinal centers were observed. In addition, a decrease of dendritic cell lysosyme-associated membrane glycoprotein-positive cells in the paracortex was noted, resulting in a reduction of paracortical hyperplasia. In the lymph nodes, especially the CD56+ NK cells but also the CD8+ and CD4+ T lymphocytes, produced a high amount of IFN-gamma. Patients, irrespectively of IL-12 treatment, with a high number of CD56+ cells in the primary tumor had a better overall survival than those with a low number. In conclusion, after i.t. IL-12 treatment in HNSCC patients, the largest effect was seen on the NK cells, with a higher number in the primary tumor and a high IFN-gamma mRNA expression in the lymph nodes. Significant effects were noted on B cells, with altered lymph node architecture in every IL-12-treated patient and excessive peritumoral infiltration in some patients.