tbuckley/cabot-search huggingface dataset:
Nod2 is essential for temporal development of intestinal microbial communities
Authors: A. Rehman, C. Sina, O. Gavrilova, R. Hasler, S. Ott, J. F. Baines, S. Schreiber, P. Rosenstiel
Journal: Gut (2011)

<h3>Objective</h3> The mammalian commensal gut microbiota is highly diverse and displays an individual-specific composition determined by host genotype and environmental factors. The temporal development of host–microbial homeostasis in the digestive tract is recognised as a major function of the immune system. However, the underlying cellular and molecular mechanisms are just beginning to come to light. Nucleotide-binding, oligomerisation domain 2 (NOD2) recognises bacterial muramyl dipeptide and is regarded as a pivotal sensor molecule of the intestinal barrier. The aim of this study was to investigate its influence on the development and composition of the intestinal microbiota using a <i>Nod2</i>-deficient mouse model. <h3>Methods</h3> The dynamics of faecal and ileal microbial composition were investigated in <i>Nod2</i><sup>+/+</sup>and <i>Nod2</i><sup>−/−</sup> mice on a C57BL/6J background. We assessed microbial diversity and composition using 16S ribosomal RNA gene-based clone library sequencing and high throughput pyrosequencing and quantified the observed changes by real-time PCR. Changes in the major bacterial phyla were investigated in human samples by quantitative real-time PCR. <h3>Results</h3> We found that adult <i>Nod2</i>-deficient mice display a substantially altered microbial community structure and a significantly elevated bacterial load in their faeces and terminal ileum compared to their wild-type counterparts. Interestingly, we demonstrate that these findings are also present in weaning mice, indicating a profound influence of <i>Nod2</i> on the early development and composition of the intestinal microbiota. We demonstrate that NOD2 genotypes also influence the microbial composition in humans. <h3>Conclusions</h3> Our results point to an essential role of <i>Nod2</i> for the temporal development and composition of the host microbiota, both in mice and in humans, which may contribute to the complex role of NOD2 for the aetiopathogenesis of Crohn9s disease.
REDOX REGULATION OF <i>c-Ha-ras</i> AND OSTEOPONTIN SIGNALING IN VASCULAR SMOOTH MUSCLE CELLS: Implications in Chemical Atherogenesis
Authors: Kenneth S. Ramos
Journal: The Annual Review of Pharmacology and Toxicology (1999)

▪ Abstract Reduction/oxidation (redox) reactions play a central role in the regulation of vascular cell functions. Recent studies in this laboratory have identified c-Ha-ras and osteopontin genes as critical molecular targets during oxidant-induced atherogenesis. This review focuses on the deregulation of gene transcription by redox-activated trans-acting factors after benzo(a)pyrene challenge and the modulation of extracellular matrix signaling in vascular smooth muscle cells by allylamine-induced oxidative injury. The induction of atherogenic vascular smooth muscle cell phenotypes by chemical injury exhibits remarkable parallels with those seen in other forms of atherogenesis.
The possible role of dartoic muscle degeneration in the pathogenesis of idiopathic scrotal calcinosis
Authors: U. Pabuccuoglu, M.S. Canda, M. Guray, A. Kefi, E. Canda
Journal: British Journal of Dermatology (2003)

Sir, We report an otherwise healthy 63‐year‐old man with no systemic metabolic disorders, who presented with multiple slowly growing scrotal nodules that had been present since his childhood. There was a recurrent discharge of chalky material from these nodules. Serum calcium and phosphate levels were within normal ranges. The involved scrotal skin was completely excised. Healing was uneventful. The specimen received for pathological examination consisted of eight pieces of polypoid tissues covered with skin, with the largest being 4 × 3·5 × 2·5 cm in size. Cut sections of the tissues revealed multiple firm nodules, some of which were heavily calcified. Microscopic examination showed multiple cystic or duct‐like spaces with an amorphous, periodic acid–Schiff (PAS)‐positive and von Kossa‐negative central content along with prominent nodules of partially calcified PAS‐positive amorphous material in the dermis (Fig. 1a). Nodules were surrounded by fibrous tissue and a foreign body giant cell reaction was focally present in the vicinity of the calcified material. No keratinous material was observed in the histological slides. Immunohistochemistry for carcinoembryonic antigen and cytokeratin failed to show any positive reaction (epithelial lining) either in the duct‐like spaces or around the calcified nodules. A thorough histological examination revealed degenerative changes in the dartoic muscle bundles, with a gradual transition to necrotic forms, which also corresponded to the central amorphous substance in the dilated duct‐like spaces. Gomori's reticulin stain revealed the presence of collapsed reticular fibres within the central substance (Fig. 1b). The silhouette of the necrotic bundles was morphologically comparable with the vital dartoic muscle fibres. Smooth muscle actin was intensely positive in dartoic muscle and showed faint or no staining in the degenerated and necrotic muscle bundles. The histopathological diagnosis was that of idiopathic scrotal calcinosis.
RAE1ε Ligand Expressed on Pancreatic Islets Recruits NKG2D Receptor-Expressing Cytotoxic T Cells Independent of T Cell Receptor Recognition
Authors: Mary A. Markiewicz, Erica L. Wise, Zachary S. Buchwald, Amelia K. Pinto, Biljana Zafirova, Bojan Polic, Andrey S. Shaw
Journal: Immunity (2012)
Development of the Manchester early morning symptoms index in COPD
Authors: Janelle Yorke, Adam Garrow, Mat Khan, Sarah Tyson, Dave Singh, Jorgen Vestbo
Journal: European Respiratory Journal (2014)

Aim: In COPD early morning symptoms (EMS) are associated with poorer health status, impaired daily activities and increased exacerbation risk. We are currently developing a new measure to quantify EMS in COPD – the Manchester EMS Index in COPD (MEMSI-C). Methods: Identification of potential items was guided by interviews and focus groups with COPD patients. Potential items for inclusion in the final questionnaire were extracted from focus group transcripts. Cognitive interviewing was then used with a different group of patients to assess the relevance and understanding of the different items. A cross-sectional study then identified items for final inclusion. Participants completed the draft item list twice (day 0 and day 7) and the St George9s Respiratory Questionnaire (SGRQ). Hierarchical methods were used to inform stage one of item deletion. Rasch analysis is now planned to enable the development of a unidimensional scale. Results: Qualitative data from 45 patients with COPD informed the initial item-list (items = 22). The cross sectional study included 204 COPD patients (GOLD: 1: 17% 2:48% 3:26% 4: 9% ; male 62%, mean age 65 sd 7 years). Eight items were removed during hierarchical methods. Provisional results suggest that the MEMSI-C demonstrates good internal consistency (Cronbach9s alpha 0.9) and test-retest repeatability (>0.7). Conclusion: The MEMSI-C shows good internal consistency and stability over time. Rash analysis will be used to assess the unidimentionality of the index. The final instrument should lead to a better understanding of the impact that EMS have on patients with COPD.
Variations on a Theme
Authors: Zachary D. Goldberger, Steven E. Weinberger, Roberto F. Nicosia, Sanjay Saint, Bessie A. Young
Journal: New England Journal of Medicine (2008)

A 57-year-old man presented to the emergency department with a 2-week history of progressive dyspnea on exertion, edema of the legs, a nonproductive cough, and scant hemoptysis. He also reported occasional passage of bright red blood from his rectum and intermittent nausea and vomiting during the previous 4 days.
Heparin: A Mucopolysaccharide and an Active Antithrombotic Drug
Authors: J. ERIK JORPES
Journal: Circulation (1959)

in 1916 trying to isolate a thromboplastin, an accelerator of the coagulation of the blood, from the phosphatide fraction of the liver and the heart.His co-worker, Jay AMcLean, found instead a substance, later called heparin, which retarded the coagulation of blood.Also unexpected was the finding made almost 20 years later in 1935 that heparin is a muco- polysaceharide esterified with sulfuric acid to a quite extraordinary degree.
Alterations in the epidermal-dermal melanin axis and factor XIIIa melanophages in senile lentigo and ageing skin
Authors: N. Ünver, P. Freyschmidt-Paul, S. Hörster, H. Wenck, F. Stäb, T. Blatt, H-P. Elsässer
Journal: British Journal of Dermatology (2006)

Senile lentigo (SL) is a pigmentation disorder that occurs predominantly on the dorsa of the hands, the forearms and the face; its incidence increases with age. Histological hallmarks of SL lesions are hyperpigmentation of the epidermis and elongation of the epidermal rete ridges. Various factors such as alpha-melanocyte-stimulating hormone, endothelin-1 or stem cell factor are involved in the onset and maintenance of the increased pigmentation. Alterations of the dermal compartment have not yet been analysed in detail in SL.To study the occurrence and distribution of melanin in the dermis from SL and aged skin, biopsies from 12 subjects were morphologically analysed by light and electron microscopy in comparison with unaffected skin.Punch biopsies of SL and adjacent skin from 12 male or female volunteers aged 52-81 years were prepared for light and electron microscopy and samples were analysed by morphological, morphometric, histochemical and immunohistochemical methods.The epidermis from SL revealed morphological features such as hyperpigmentation of basal keratinocytes and the formation of elongated rete ridges. S100+ melanocytes in the stratum basale were not markedly increased, indicating that the hyperpigmentation is predominantly due to changes in melanin synthesis, distribution or turnover. Quantification of epidermal cells expressing the proliferation marker Ki67 did not show an increase of this parameter in SL, indicating that at least in the established lesion cell proliferation is not enhanced. We further focused on the dermal compartment and observed granulated cells which were more abundant in SL. Electron microscopic and histochemical analysis revealed that the granulation of these cells is based on melanosomes, mostly present in large melanosomal complexes. Immunohistochemistry using antibodies to CD68 and factor XIIIa (FXIIIa) showed these melanophages to be predominantly FXIIIa+ dermal dendrocytes, which were about six times more abundant than CD68+ macrophages.In SL an increased number of melanophages was found compared with unaffected skin from the same subject. These melanophages were identified as FXIIIa+ dermal dendrocytes. Possible functional consequences of the massive melanin uptake by dermal dendrocytes are discussed.
LKB1 Is Recruited to the p21/WAF1 Promoter by p53 to Mediate Transcriptional Activation
Authors: Ping-Yao Zeng, Shelley L. Berger
Journal: Cancer Research (2006)

The tumor suppressor LKB1 is an evolutionarily conserved serine/threonine kinase. In humans, LKB1 can be inactivated either by germ-line mutations resulting in Peutz-Jeghers syndrome or by somatic mutations causing predisposition to multiple sporadic cancers. LKB1 has wide-ranging functions involved in tumor suppression and cell homeostasis, including establishing cell polarity, setting energy metabolic balance (via phosphorylation of AMP-dependent kinase), regulating the cell cycle, and promoting apoptosis. LKB1 function was previously linked to the tumor suppressor p53 and shown to activate the p53 target gene p21/WAF1. In this study, we further investigated LKB1 activation of the p21/WAF1 gene and addressed whether LKB1 is directly involved at the gene promoter. We find that, consistent with previous studies, LKB1 stabilizes p53 in vivo, correlating with activation of p21/WAF1. We show that LKB1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 Ser15 (previously shown to be phosphorylated by AMP-dependent kinase) and p53 Ser392. Further, these two p53 residues are required for LKB1-dependent cell cycle G(1) arrest. Chromatin immunoprecipitation analyses show that LKB1 is recruited directly to the p21/WAF1 promoter, as well as to other p53 activated promoters, in a p53-dependent fashion. Finally, a genetic fusion of LKB1 to defective p53, deleted for its activation domains, promotes activation of p21/WAF1. These results indicate that LKB1 has a direct role in activation of p21/WAF1 gene.
T helper type 1–specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-γ promoter are Stat4 dependent
Authors: Fuping Zhang, Mark Boothby
Journal: The Journal of Experimental Medicine (2006)

Transcriptional competence of the interferon-γ (IFN-γ) locus is enhanced as Th1 effectors develop from naive CD4 T lymphocytes; conversely, this gene is repressed during Th2 differentiation. We now show that the Switch (Swi)–sucrose nonfermenter (SNF) component Brahma-related gene 1 (Brg1) is recruited, and positioned nucleosomes are remodeled, in a Th1-specific manner that is dependent on the transcription factor Stat4 and calcineurin phosphatase activity. Interference with specific components of mammalian Swi–SNF complexes decreased CD4 T cell differentiation into IFN-γ–positive Th1 cells. These findings reveal a collaborative mechanism of IFN-γ gene regulation during Th1 differentiation and suggest that a Th1-specific chromatin structure is created by early recruitment of Swi–SNF complexes and nucleosome remodeling dependent on Stat4 and calcineurin activation.
Chronic Progression of Tubulointerstitial Damage in Proteinuric Renal Disease Is Mediated by Complement Activation
Authors: Stephen I-Hong Hsu, William G Couser
Journal: Journal of the American Society of Nephrology (2003)

The mechanisms by which increased urinary protein concentrations lead to nephrotoxic injury are certain to be multifactorial and involve complex interactions between numerous pathways of cellular damage mediated by both cellular and humoral pathways. These may include a major role for the podocyte in glomerular diseases leading to chronic renal failure, the loss of microvascular endothelium, the albumin-induced upregulation of renal cytokines and growth factors that promote tubulointerstitial injury by inflammation and fibrogenesis, and the role of complement-mediated tubulointerstitial injury due to proteinuria. This review will focus on the last mechanism, and emphasize recent studies implicating a primary role for activation of complement in proteinuric urine as the principal mediator of tubulointerstitial damage and progressive renal disease in various experimental animal models of nephrosis. It will be our contention that intraluminal activation of the terminal complement cascade leading to the formation of the C5b-9 membrane attack complex is the principal mediator of chronic progressive interstitial damage and progressive renal failure irrespective of the type of primary glomerular injury. This paradigm has important implications for the potential therapeutic role of complement inhibitors that are currently being developed.
Vascular Endothelial Growth Factor–Mediated Decrease in Plasma Soluble Vascular Endothelial Growth Factor Receptor-2 Levels as a Surrogate Biomarker for Tumor Growth
Authors: John M.L. Ebos, Christina R. Lee, Elena Bogdanovic, Jennifer Alami, Paul Van Slyke, Giulio Francia, Ping Xu, Anthony J. Mutsaers, Daniel J. Dumont, Robert S. Kerbel
Journal: Cancer Research (2008)

Abstract Vascular endothelial growth factor (VEGF) is a potent proangiogenic protein that activates VEGF receptor (VEGFR) tyrosine kinases expressed by vascular endothelial cells. We previously showed that one of these receptors, VEGFR-2, has a truncated soluble form (sVEGFR-2) that can be detected in mouse and human plasma. Because activation of VEGFR-2 plays an important role in tumor angiogenesis, clinical interest in monitoring plasma sVEGFR-2 levels in cancer patients has focused on its potential exploitation as a surrogate biomarker for disease progression as well as assessing efficacy/activity of antiangiogenic drugs, particularly those that target VEGF or VEGFR-2. However, no preclinical studies have been done to study sVEGFR-2 during tumor growth or the mechanisms involved in its modulation. Using spontaneously growing tumors and both localized and metastatic human tumor xenografts, we evaluated the relationship between sVEGFR-2 and tumor burden as well as underlying factors governing protein level modulation in vivo. Our results show an inverse relationship between the levels of sVEGFR-2 and tumor size. Furthermore, using various methods of VEGF overexpression in vivo, including cell transfection and adenoviral delivery, we found plasma sVEGFR-2 decreases to be mediated largely by tumor-derived VEGF. Finally, in vitro studies indicate VEGF-mediated sVEGFR-2 modulation is the result of ligand-induced down-regulation of the VEGFR-2 from the cell surface. Taken together, these findings may be pertinent to further clinical exploitation of plasma sVEGFR-2 levels as a surrogate biomarker of VEGF-dependent tumor growth as well as an activity indicator of antiangiogenic drugs that target the VEGFR system. [Cancer Res 2008;68(2):521–9]
Chronic Renal Failure and Shortened Lifespan in COL4A3+/− Mice
Authors: Bogdan Beirowski, Manfred Weber, Oliver Gross
Journal: Journal of the American Society of Nephrology (2006)

A heterozygous mutation in autosomal Alport genes <i>COL4A3</i> and <i>COL4A4</i> can be found in 20 to 50% of individuals with familial benign hematuria and diffuse glomerular basement membrane thinning (thin basement membrane nephropathy [TBMN]). Approximately 1% of humans are heterozygous carriers of mutations in the autosomal Alport genes and at risk for developing renal failure as a result of TBMN. The incidence and pathogenesis of renal failure in heterozygous COL4A3/4 mutation carriers is still unclear and was examined further in this study using COL4A3 knockout mice. In heterozygous COL4A3<sup>+/−</sup> mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot. Lifespan of COL4A3<sup>+/−</sup> mice was found to be significantly shorter than in healthy controls (21.7 <i>versus</i> 30.3 mo). Persistent glomerular hematuria was detected starting in week 9; proteinuria of &gt;0.1 g/L started after 3 mo of life and increased to &gt;3 g/L after 24 mo. The glomerular basement membrane was significantly thinned (167 <i>versus</i> 200 nm in wild type) in 30-wk-old mice, coinciding with focal glomerulosclerosis, tubulointerstitial fibrosis, and increased levels of TGF-β and connective tissue growth factor. The renal phenotype in COL4A3<sup>+/−</sup> mice resembled the clinical and histopathologic phenotype of human cases of TBMN with concomitant progression to chronic renal failure. Therefore, the COL4A3<sup>+/−</sup> mouse model will help in the understanding of the pathogenesis of TBMN in humans and in the evaluation of potential therapies.
Allergy to Galacto-Oligosaccharides in an Atopic Population in Singapore
Authors: Jian Yi Soh, Chiung-Hui Huang, Wen Chin Chiang, Genevieve Llanora, Alison Joanne Lee, Wenyin Loh, Cherlyn Yue Lin Chin, Victoria Yu Jia Tay, Yiong Huak Chan, Dianne Delsing, Bee-Wah Lee
Journal: Journal of Allergy and Clinical Immunology (2015)
Prevalence of rheumatic diseases in a rheumatological outpatient practice
Authors: J Vanhoof
Journal: Annals of the Rheumatic Diseases (2002)

Objective: To assess the prevalence and distribution of rheumatic diseases in a community based rheumatological outpatient practice. Methods: Rheumatological diagnoses of 3751 consecutive new and returning patients were recorded using a standard diagnosis form. Results: 6264 rheumatological diagnoses were made in 3751 patients, of whom 1097 were newly referred; 69% of all patients were female. Inflammatory joint and spine diseases were diagnosed in 42% of all patients (including 5% with connective tissue diseases), soft tissue rheumatism in 37%, degenerative joint and spine diseases in 36%, and metabolic bone diseases in 17% of all patients. In new patients soft tissue rheumatism was most prevalent (51%), 45% had osteoarthritis, 24% had inflammatory joint and spine disease (including 2% with connective tissue disease), and 13% had metabolic bone disease. One of 10 new patients was diagnosed with definite rheumatoid arthritis. In returning patients the prevalence of inflammatory rheumatic diseases was higher (49%, including 6% with connective tissue diseases). 28% of the returning patients had rheumatoid arthritis. Osteoarthritis was present in 33% and metabolic bone disease in 19% of the returning patients. Conclusions: Soft tissue rheumatism and degenerative joint and spine diseases are the most common rheumatological diagnoses in newly referred patients visiting a community based rheumatological outpatient practice. Inflammatory rheumatic diseases were most prevalent in returning patients.
Immunosuppressive and Prometastatic Functions of Myeloid-Derived Suppressive Cells Rely upon Education from Tumor-Associated B Cells
Authors: Monica Bodogai, Kanako Moritoh, Catalina Lee-Chang, Christine M. Hollander, Cheryl A. Sherman-Baust, Robert P. Wersto, Yoshihiko Araki, Ichiro Miyoshi, Li Yang, Giorgio Trinchieri, Arya Biragyn
Journal: Cancer Research (2015)

Myeloid-derived suppressive cells (MDSC) have been reported to promote metastasis, but the loss of cancer-induced B cells/B regulatory cells (tBreg) can block metastasis despite MDSC expansion in cancer. Here, using multiple murine tumor models and human MDSC, we show that MDSC populations that expand in cancer have only partially primed regulatory function and limited prometastatic activity unless they are fully educated by tBregs. Cancer-induced tBregs directly activate the regulatory function of both the monocyte and granulocyte subpopulations of MDSC, relying, in part, on TgfβR1/TgfβR2 signaling. MDSC fully educated in this manner exhibit an increased production of reactive oxygen species and NO and more efficiently suppress CD4(+) and CD8(+) T cells, thereby promoting tumor growth and metastasis. Thus, loss of tBregs or TgfβR deficiency in MDSC is sufficient to disable their suppressive function and to block metastasis. Overall, our data indicate that cancer-induced B cells/B regulatory cells are important regulators of the immunosuppressive and prometastatic functions of MDSC.
Inhibition of δ-Protein Kinase C Protects Against Reperfusion Injury of the Ischemic Heart In Vivo
Authors: Koichi Inagaki, Leon Chen, Fumiaki Ikeno, Felix H. Lee, Ken-ichi Imahashi, Donna M. Bouley, Mehrdad Rezaee, Paul G. Yock, Elizabeth Murphy, Daria Mochly-Rosen
Journal: Circulation (2003)

Current treatment for acute myocardial infarction (AMI) focuses on reestablishing blood flow (reperfusion). Paradoxically, reperfusion itself may cause additional injury to the heart. We previously found that delta-protein kinase C (deltaPKC) inhibition during simulated ischemia/reperfusion in isolated rat hearts is cardioprotective. We focus here on the role for deltaPKC during reperfusion only, using an in vivo porcine model of AMI.An intracoronary application of a selective deltaPKC inhibitor to the heart at the time of reperfusion reduced infarct size, improved cardiac function, inhibited troponin T release, and reduced apoptosis. Using 31P NMR in isolated perfused mouse hearts, we found a faster recovery of ATP levels in hearts treated with the deltaPKC inhibitor during reperfusion only.Reperfusion injury after cardiac ischemia is mediated, at least in part, by deltaPKC activation. This study suggests that including a deltaPKC inhibitor at reperfusion may improve the outcome for patients with AMI.