tbuckley/cabot-search huggingface dataset:
Self-reactive human CD4 T cell clones form unusual immunological synapses
Authors: David A. Schubert, Susana Gordo, Joseph J. Sabatino, Santosh Vardhana, Etienne Gagnon, Dhruv K. Sethi, Nilufer P. Seth, Kaushik Choudhuri, Helena Reijonen, Gerald T. Nepom, Brian D. Evavold, Michael L. Dustin, Kai W. Wucherpfennig
Journal: The Journal of Experimental Medicine (2012)

Recognition of self–peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases. We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes. All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling. However, they showed little or no visible pMHC accumulation or transport of TCR–pMHC complexes into a central supramolecular activation cluster (cSMAC). In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities. The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells. 2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC. These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus. However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease.
Autonomic Renal Denervation Ameliorates Experimental Glomerulonephritis
Authors: Roland Veelken, Eva-Maria Vogel, Karl Hilgers, Kerstin Amann, Andrea Hartner, Gabriele Sass, Winfried Neuhuber, Gisa Tiegs
Journal: Journal of the American Society of Nephrology (2008)

Increasing evidence indicates that inflammation of visceral organs is significantly affected by the autonomic nervous system. Such neuroimmune interactions have not been studied in the kidney. Here, we show that the rat kidney is innervated by both tyrosine hydroxylase–positive sympathetic efferent nerve fibers and calcitonin gene-related peptide–positive primary afferent nerve fibers, both of which are found in proximity to macrophages and dendritic cells. Complete surgical bilateral renal denervation was performed 2 d before glomerulonephritis was induced by injecting the monoclonal anti–Thy-1.1 antibody OX-7. Denervation significantly reduced albuminuria, mesangiolysis, formation of microaneurysms, deposition of glomerular collagen IV, and expression of TGF-β compared with sham-operated controls. Accordingly, inflammation, identified by accumulation of interstitial macrophages and renal expression of TNF-α, and mesangial cell proliferation were significantly reduced. These findings indicate that autonomic renal denervation ameliorates and, by inference, innervation exacerbates acute inflammation in the kidney; therefore, neurotransmitters or neuropeptides and their receptors might represent novel targets for the treatment of acute glomerulonephritis.
Thrombospondin-1 Is the Key Activator of TGF-β1 in Human Mesangial Cells Exposed to High Glucose
Authors: NATALIA YEVDOKIMOVA, NADIA ABDEL WAHAB, ROGER M. MASON
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Elevated levels of transforming growth factor-β1 (TGF-β1) are synthesized by human mesangial cells that are cultured in medium that contains high concentrations of glucose and mediate increased synthesis of fibronectin (FN), plasminogen activator inhibitor-1 (PAI-1), and changes in the expression of other genes. TGF-β1 is synthesized as a latent complex. Previous work indicated that high-glucose conditions also upregulate expression of thrombospondin-1 (TSP-1), a potential activator of latent TGF-β1. With the use of the synthetic peptide GGWSHW, an inhibitor of the TSP-1 activation mechanism, endogenous TSP-1 is shown to be responsible for converting high levels of latent TGF-β1 to bioactive growth factor over 3 wk of exposure of mesangial cells to 30 mM D-glucose. Peptide inhibition of TGF-β1 activation by TSP-1 in high-glucose conditions completely suppressed increases in FN and PAI-1 expression. Treating mesangial cells maintained in high glucose with a TSP-1 antisense oligonucleotide reduced TSP-1 expression to levels found in 4 mM D-glucose cultures, prevented TGF-β1 activation, and normalized expression of FN.
HER2 Protein and Gene Variation between Primary and Metastatic Breast Cancer: Significance and Impact on Patient Care
Authors: Alessandra Fabi, Anna Di Benedetto, Giulio Metro, Letizia Perracchio, Cecilia Nisticò, Franco Di Filippo, Cristiana Ercolani, Gianluigi Ferretti, Elisa Melucci, Simonetta Buglioni, Isabella Sperduti, Paola Papaldo, Francesco Cognetti, Marcella Mottolese
Journal: Clinical Cancer Research (2011)

To analyze HER2 status in primary breast cancer (PBC) compared with correspondent metachronous metastases and to investigate whether BC phenotype may be predictive of change in HER2 expression.HER2 was investigated by immunohistochemistry, silver in situ hybridization (SISH), and FISH, in a series of 137 tumors, building up a tissue microarray to concurrently analyze each single PBC and metastatic (MBC) on the same slide.HER2 status was discordant in 14 cases (10%): 12 negative in PBC and positive in metastases and two positive in PBC and negative in metastases (P = 0.04). These findings were confirmed by a PCR based test termed Multiplex Ligation-dependent Probe Amplification (MLPA). HER2 status changed in hormone receptor-positive BC more frequently than in negative ones (P = 0.002). In addition, we evaluated HER2 gene and chromosome 17 copy number by SISH in the 123 cases with unchanged HER2 status during progression. We found consistent HER2 gene copy number stability in the 100 nonamplified cases. Conversely, of the 23 amplified PBC, 13 (57%) demonstrated a significant increase in the HER2 gene and chromosome 17 copy number in their paired metastases (P = 0.01), as defined by SISH (k = 0.54, P < 0.0001) and MLPA. Patients who changed HER2 status from negative to positive, presented significant longer time to progression when treated with trastuzumab compared to those who were untreated (P = 0.04).When feasible, HER2 reassessment in metastatic lesions should be carefully taken into account, especially for metastases coming from primary hormone receptor-positive BC.
Detection of proliferating liver cells in various diseases by a monoclonal antibody against DNA polymerase-α: With special reference to the relationship between hepatocytes and sinusoidal cells
Authors: Shuichi Seki, Hiroki Sakaguchi, Nobuyoshi Kawakita, Atsushi Yanai, Tetsuo Kuroki, Yasuhiro Mizoguchi, Kenzo Kobayashi, Takeyuki Monna
Journal: Hepatology (1991)

Proliferating cells in liver specimens from patients with various diseases were detected by use of a monoclonal antibody against human DNA polymerase-alpha, which is present in the nuclei of cells in the G1, S, M and G2 phases of the mitotic cell cycle and absent in the G0 phase, to clarify the kinetics and morphological characteristics of these cells. This monoclonal antibody was supernatant derived from clone CL22-2-42B, and the peroxidase antiperoxidase method was used. Not only epithelial cells (hepatocytes, biliary epithelial cells and hepatocellular carcinoma cells) but also nonepithelial cells (Kupffer cells and other macrophages, endothelial cells, fat-storing cells, lymphocytes and fibroblasts) were stained for DNA polymerase-alpha. In acute viral hepatitis with confluent necrosis, small hepatocytes with basophilic cytoplasm next to the necrosis accounted for most of the proliferating cells. In these areas, Kupffer cells and other macrophages and lymphocytes had often proliferated. Hepatocellular carcinoma cells were frequently stained for DNA polymerase-alpha, in addition to endothelial cells, macrophages and lymphocytes. These nonepithelial cells were stained more frequently in specimens with many stained carcinoma cells than in those with only a few cells stained. In fibrotic areas, fibroblasts were often stained for this enzyme. In proliferating bile ducts, both small epithelial cells and large mature cells were stained. The differences between stained and nonstained cells that were not hepatocytes could not be defined by their ultrastructural characteristics. From these findings, it seemed possible that sinusoidal cells, especially Kupffer cells and other macrophages, might be much involved in hepatocytic proliferation during regeneration of the liver and also in the occurrence of malignant tumors.
Effects of Liver Biopsy Sample Length and Number of Readings on Sampling Variability in Nonalcoholic Fatty Liver Disease
Authors: Raj Vuppalanchi, Aynur Ünalp, Mark L. Van Natta, Oscar W. Cummings, Kumar E. Sandrasegaran, Tariq Hameed, James Tonascia, Naga Chalasani
Journal: Clinical Gastroenterology and Hepatology (2008)
Tissue factor is rapidly induced in arterial smooth muscle after balloon injury.
Authors: J D Marmur, M Rossikhina, A Guha, B Fyfe, V Friedrich, M Mendlowitz, Y Nemerson, M B Taubman
Journal: Journal of Clinical Investigation (1993)

Tissue factor (TF) is a major activator of the coagulation cascade and may play a role in initiating thrombosis after intravascular injury. To investigate whether medial vascular smooth muscle provides a source of TF following arterial injury, the induction of TF mRNA and protein was studied in balloon-injured rat aorta. After full length aortic injury, aortas were harvested at various times and the media and adventitia separated using collagenase digestion and microscopic dissection. In uninjured aortic media, TF mRNA was undetectable by RNA blot hybridization. 2 h after balloon injury TF mRNA levels increased markedly. Return to near baseline levels occurred at 24 h. In situ hybridization with a 35S-labeled antisense rat TF cRNA probe detected TF mRNA in the adventitia but not in the media or endothelium of uninjured aorta. 2 h after balloon dilatation, a marked induction of TF mRNA was observed in the adventitia and media. Using a functional clotting assay, TF procoagulant activity was detected at low levels in uninjured rat aortic media and rose by approximately 10-fold 2 h after balloon dilatation. Return to baseline occurred within 4 d. These data demonstrate that vascular injury rapidly induces active TF in arterial smooth muscle, providing a procoagulant that may result in thrombus initiation or propagation.
Molecular Phylogeny of Euthyneura (Mollusca: Gastropoda)
Authors: C. Grande
Journal: Molecular Biology and Evolution (2003)

A new phylogenetic hypothesis for Euthyneura is proposed based on the analysis of primary sequence data (mitochondrial cox1, trnV, rrnL, trnL(cun), trnA, trnP, nad6, and nad5 genes) and the phylogenetic utility of two rare genomic changes (the relative position of the mitochondrial trnP gene, and an insertion/deletion event in a conserved region of the mitochondrial Cox1 protein) is addressed. Both sources of phylogenetic information clearly rejected the monophyly of pulmonates, a group of gastropods well supported so far by morphological evidence. The marine basommatophoran pulmonate Siphonaria was placed within opisthobranchs and shared with them the insertion of a Glycine in the Cox 1 protein. The marine systellommatophoran pulmonate Onchidella was recovered at the base of the opisthobranch + Siphonaria clade. Opisthobranchs, Siphonaria, and Onchidella shared the relative position of the mitochondrial trnP gene between the mitochondrial trnA and nad6 genes. The land snails and slugs (stylommatophoran pulmonates) were recovered as an early split in the phylogeny of advanced gastropods. The monophyly of the Euthyneura (Opisthobranchia + Pulmonata) was rejected by the inclusion of the heterostrophan Pyramidella.
Limited generalisability of UPLIFT findings to clinical practice: Table 1
Authors: Steven Walker, James Fingleton, Mark Weatherall, Richard Beasley
Journal: Thorax (2013)

<h3>Background</h3> The findings of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) study may be poorly generalisable to tiotropium use in clinical practice. <h3>Methods</h3> An audit of 226 patients admitted to Wellington Hospital with a chronic obstructive pulmonary disease exacerbation determined the proportion of patients prescribed tiotropium on discharge that would have been ineligible for inclusion in the UPLIFT study. <h3>Results</h3> Among 100 patients prescribed tiotropium, 38/100; 38% (95% CI 28.5% to 48.3%) would have been ineligible for UPLIFT at the time of the hospital discharge due to recent cardiovascular comorbidity or moderate to severe renal impairment. <h3>Conclusions</h3> The UPLIFT findings have limited generalisability to over a third of patients prescribed tiotropium following a hospital admission with a chronic obstructive pulmonary disease exacerbation in New Zealand.
Mechanistic Elucidation of the Antitumor Properties of Withaferin A in Breast Cancer
Authors: Arumugam Nagalingam, Panjamurthy Kuppusamy, Shivendra V. Singh, Dipali Sharma, Neeraj K. Saxena
Journal: Cancer Research (2014)

Abstract Withaferin A (WFA) is a steroidal lactone with antitumor effects manifested at multiple levels that are mechanistically obscure. Using a phospho-kinase screening array, we discovered that WFA activated phosphorylation of the S6 kinase RSK (ribosomal S6 kinase) in breast cancer cells. Pursuing this observation, we defined activation of extracellular signal–regulated kinase (ERK)–RSK and ETS-like transcription factor 1 (Elk1)–CHOP (C-EBP homologous protein) kinase pathways in upregulating transcription of the death receptor 5 (DR5). Through this route, WFA acted as an effective DR5 activator capable of potentiating the biologic effects of celecoxib, etoposide, and TRAIL. Accordingly, WFA treatment inhibited breast tumor formation in xenograft and mouse mammary tumor virus (MMTV)-neu mouse models in a manner associated with activation of the ERK/RSK axis, DR5 upregulation, and elevated nuclear accumulation of Elk1 and CHOP. Together, our results offer mechanistic insight into how WFA inhibits breast tumor growth. Cancer Res; 74(9); 2617–29. ©2014 AACR.
Pedometers and Text Messaging to Increase Physical Activity
Authors: Kirsty H. Newton, Esko J. Wiltshire, C. Raina Elley
Journal: Diabetes Care (2009)

OBJECTIVE To assess whether pedometers and text messaging increase physical activity in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS A 12-week randomized controlled trial was conducted. A total of 78 subjects participated in the trial (mean ± SD age 14.4 ± 2.37 years, 36 [47%] male). Intervention participants wore an open pedometer and received regular motivational text messages. Control participants received usual care. Primary outcomes were daily step count (4-day closed pedometer) and physical activity questionnaire. RESULTS Baseline median step count was 11,063 steps/day (range 1,541–20,158). At 12 weeks, mean daily step count reduced by 840 (95% CI −1,947 to 266) in the control group and by 22 (−1,407 to 1,364) in the intervention group (P = 0.4). Mean self-reported moderate or vigorous physical activity increased by 38.5 min/week in the control group and by 48.4 in the intervention group (P = 0.9). CONCLUSIONS A 12-week intervention using pedometers and text messaging as motivational tools in adolescents with type 1 diabetes did not increase physical activity.
Vitamin D Supplementation for Cardiovascular Disease Prevention
Authors: James H. O’Keefe
Journal: JAMA (2011)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Spontaneous Aortic Lesions in Rabbits I. Morphologic Characteristics
Authors: ERIC A. SCHENK, ELIZABETH GAMAN, A. S. FEIGENBAUM
Journal: Circulation Research (1966)

A number of morphologically distinct, spontaneously occurring lesions are present in the rabbit aorta. Intimal atheromata occur in newborn rabbits, decrease in incidence as the rabbit becomes weaned, and are a rarity in the adult. Intimal mesenchymal thickening is first seen in weanling rabbits and is almost universally present in the adult. Medial sclerotic changes involving exclusively the inner one-half of the media and termed "type A" lesions are present in weanling and adult, but not in newborn rabbits. Type A lesions have a variable gross appearance, but a fairly uniform microscopic appearance, which shows principally fragmentation and calcification of elastic lamina and accumulation of acid mucopolysaccharides. "Type B" lesions, medial sclerosis involving exclusively the outer half of the media, usually occur throughout the entire aorta, and only in adult rabbits.
Type C oncornavirus isolation studies in systemic lupus erythematosus. II. Attempted detection by viral RNA-dependent DNA polymerase assay.
Authors: P E Phillips, R Hargrave-Granda
Journal: Annals of the Rheumatic Diseases (1978)

Isolation of type C oncornavirus was attempted from 20 tissues and cell cultures of patients with systemic lupus erythematosus. Chemical inducers, cocultivation and fusion with cells from multiple other species, prolonged subculturing, and the RNA-dependent DNA polymerase assay for virus detection were used. A type C virus was isolated, but was shown to be the endogenous rat virus. Thus the methods, although generally appropriate, were not specifically permissive for replication of a human type C virus. This agrees with the failure of other investigators to isolate a virus of undisputed human origin. Combining available evidence, a fundamental role for type C viruses in lupus erythematosus remains an attractive hypothesis.
Poor Outcome of Hormone Receptor–Positive Breast Cancer at Very Young Age Is Due to Tamoxifen Resistance: Nationwide Survival Data in Korea—A Report From the Korean Breast Cancer Society
Authors: Sei Hyun Ahn, Byung Ho Son, Seok Won Kim, Seung Il Kim, Joon Jeong, Seung-Sang Ko, Wonshik Han
Journal: Journal of Clinical Oncology (2007)

Purpose Breast cancer in very young women (age &lt; 35 years) is uncommon and poorly understood. We sought to evaluate the prognosis and treatment response of these patients compared with women ages 35 to 50 years. Patients and Methods We analyzed data from 9,885 breast cancer patients age ≤ 50 years who were part of the Korean Breast Cancer Society registration program between 1992 and 2001. The overall survival (OS) and breast cancer-specific survival (BCSS) were compared between age groups. Results One thousand four hundred forty-four patients (14.6%) were younger than age 35 and 8,441 (85.4%) patients were between 35 and 50 years of age. Younger patients had significantly higher T-stage and higher lymph node positivity and lower hormone receptor expression than older patients. Younger patients had a greater probability of death than older patients, regardless of tumor size or lymph node status. The survival difference was significant for patients with positive or unknown hormone receptor status (P &lt; .0001), but not for patients with negative hormone receptor status. In a multivariate analysis, the interaction term of young age and hormone receptor positivity was significant for OS and BCSS with a hazard ratio for OS of 2.13 (95% CI, 1.52 to 2.98). The significant survival benefit from adjuvant hormone therapy after chemotherapy observed in older patients (hazard ratio for OS, 0.61; 95% CI, 0.47 to 0.79; P = .001) could not be seen in younger patients (P &gt; .05). Conclusion Younger patients (age &lt; 35) showed worse prognosis than older patients (age, 35 to 50 years) only in the hormone receptor–unknown or hormone receptor–positive subgroups. Adjuvant tamoxifen therapy might provide less survival benefit when added to chemotherapy in very young breast cancer patients.
Seeking Worldwide Professional Consensus on the Principles of End-of-Life Care for the Critically Ill. The Consensus for Worldwide End-of-Life Practice for Patients in Intensive Care Units (WELPICUS) Study
Authors: Charles L. Sprung, Robert D. Truog, J. Randall Curtis, Gavin M. Joynt, Mario Baras, Andrej Michalsen, Josef Briegel, Jozef Kesecioglu, Linda Efferen, Edoardo De Robertis, Pierre Bulpa, Philipp Metnitz, Namrata Patil, Laura Hawryluck, Constantine Manthous, Rui Moreno, Sara Leonard, Nicholas S. Hill, Elisabet Wennberg, Robert C. McDermid, Adam Mikstacki, Richard A. Mularski, Christiane S. Hartog, Alexander Avidan
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Great differences in end-of-life practices in treating the critically ill around the world warrant agreement regarding the major ethical principles. This analysis determines the extent of worldwide consensus for end-of-life practices, delineates where there is and is not consensus, and analyzes reasons for lack of consensus. Critical care societies worldwide were invited to participate. Country coordinators were identified and draft statements were developed for major end-of-life issues and translated into six languages. Multidisciplinary responses using a web-based survey assessed agreement or disagreement with definitions and statements linked to anonymous demographic information. Consensus was prospectively defined as >80% agreement. Definitions and statements not obtaining consensus were revised based on comments of respondents, and then translated and redistributed. Of the initial 1,283 responses from 32 countries, consensus was found for 66 (81%) of the 81 definitions and statements; 26 (32%) had >90% agreement. With 83 additional responses to the original questionnaire (1,366 total) and 604 responses to the revised statements, consensus could be obtained for another 11 of the 15 statements. Consensus was obtained for informed consent, withholding and withdrawing life-sustaining treatment, legal requirements, intensive care unit therapies, cardiopulmonary resuscitation, shared decision making, medical and nursing consensus, brain death, and palliative care. Consensus was obtained for 77 of 81 (95%) statements. Worldwide consensus could be developed for the majority of definitions and statements about end-of-life practices. Statements achieving consensus provide standards of practice for end-of-life care; statements without consensus identify important areas for future research.
Diagnostic usefulness of dermatoscopy in differentiating lichen sclerous et atrophicus from morphea
Authors: Woo-Haing Shim, Seung-Wook Jwa, Margaret Song, Hoon-Soo Kim, Hyun-Chang Ko, Moon-Bum Kim, Byung-Soo Kim
Journal: Journal of the American Academy of Dermatology (2012)