tbuckley/cabot-search huggingface dataset:
High Frequency of Vα24+ Vβ11+ T-Cells Observed in Type 1 Diabetes
Authors: Yoichi Oikawa, Akira Shimada, Satoru Yamada, Yoshiko Motohashi, Yoshinori Nakagawa, Jun-ichiro Irie, Taro Maruyama, Takao Saruta
Journal: Diabetes Care (2002)

Natural killer T-cells (NKT cells) are believed to play an important role in the regulation of immune response, and a numerical and functional deficit of NKT cells has been reported to be associated with the pathogenesis of autoimmune diseases. Thus far, it has been shown that subjects with type 1 diabetes have a lower frequency of NKT cells than nondiabetic subjects. In this study, we measured the frequency of peripheral Valpha24(+) Vbeta11(+) T-cells, which include human NKT cells, in Japanese diabetic patients.Peripheral blood samples were obtained from 164 Japanese diabetic patients and 67 healthy subjects. The diabetic patients were classified into four categories as follows: islet-associated autoantibody-positive (Ab(+)) and -negative (Ab(-)) classic type 1 diabetes, latent autoimmune diabetes in adults (LADA), and type 2 diabetes. We measured the frequency of peripheral Valpha24(+) Vbeta11(+) CD3(+) triple-positive cells.Unexpectedly, a higher frequency of Valpha24(+) Vbeta11(+) T-cells was observed in Ab(+) and Ab(-) patients compared with LADA patients (P = 0.0294 and P = 0.0021), type 2 diabetic patients (P < 0.0001 and P < 0.0001), and healthy subjects (P = 0.0046 and P = 0.0001). Moreover, an inverse correlation between Valpha24(+) Vbeta11(+) T-cell frequency and disease duration was observed in Ab(+) (rho = -0.455; P = 0.0023) and Ab(-) (rho = -0.432; P = 0.0162) patients.Our findings indicate that a high frequency of Valpha24(+) Vbeta11(+) T-cells is a unique finding in recent-onset classic type 1 diabetes, and measurement of Valpha24(+) Vbeta11(+) T-cell frequency may be useful to assess the disease activity of classic type 1 diabetes.
Neuroimaging of Cognitive Dysfunction and Depression in Aging Retired National Football League Players
Authors: John Hart, Michael A. Kraut, Kyle B. Womack, Jeremy Strain, Nyaz Didehbani, Elizabeth Bartz, Heather Conover, Sethesh Mansinghani, Hanzhang Lu, C. Munro Cullum
Journal: JAMA Neurology (2013)

OBJECTIVES To assess cognitive impairment and depression in aging former professional football (National Football League [NFL]) players and to identify neuroimaging correlates of these dysfunctions. DESIGN We compared former NFL players with cognitive impairment and depression, cognitively normal retired players who were not depressed, and matched healthy control subjects. SETTING Research center in the North Texas region of the United States. PATIENTS Cross-sectional sample of former NFL players with and without a history of concussion recruited from the North Texas region and age-, education-, and IQ-matched controls. Thirty-four retired NFL players (mean age, 61.8 years) underwent neurological and neuropsychological assessment. A subset of 26 players also underwent detailed neuroimaging; imaging data in this subset were compared with imaging data acquired in 26 healthy matched controls. MAIN OUTCOME MEASURES Neuropsychological measures, clinical diagnoses of depression, neuroimaging mea-sures of white matter pathology, and a measure of cerebral blood flow. RESULTS Of the 34 former NFL players, 20 were cognitively normal. Four were diagnosed as having a fixed cognitive deficit; 8, mild cognitive impairment; 2, dementia; and 8, depression. Of the subgroup in whom neuroimaging data were acquired, cognitively impaired participants showed the greatest deficits on tests of naming, word finding, and visual/verbal episodic memory. We found significant differences in white matter abnormalities in cognitively impaired and depressed retired players compared with their respective controls. Regional blood flow differences in the cognitively impaired group (left temporal pole, inferior parietal lobule, and superior temporal gyrus) corresponded to regions associated with impaired neurocognitive performance (problems with memory, naming, and word finding). CONCLUSIONS Cognitive deficits and depression appear to be more common in aging former NFL players compared with healthy controls. These deficits are correlated with white matter abnormalities and changes in regional cerebral blood flow.
Agonist and Antagonist of Retinoic Acid Receptors Cause Similar Changes in Gene Expression and Induce Senescence-like Growth Arrest in MCF-7 Breast Carcinoma Cells
Authors: Yuhong Chen, Milos Dokmanovic, Wilfred D. Stein, Robert J. Ardecky, Igor B. Roninson
Journal: Cancer Research (2006)

Abstract Biological effects of retinoids are mediated via retinoic acid (RA) receptors (RAR) and retinoid X receptors (RXR). The best-characterized mechanism of retinoid action is stimulation of transcription from promoters containing RA response elements (RARE). Retinoids induce senescence-like growth arrest in MCF-7 breast carcinoma cells; this effect is associated with the induction of several growth-inhibitory genes. We have now found that these genes are induced by RAR-specific but not by RXR-specific ligands. Genome-scale microarray analysis of gene expression was used to compare the effects of two pan-RAR ligands, one of which is a strong agonist of RARE-dependent transcription, whereas the other induces such transcription only weakly and antagonizes the inducing effect of RAR agonists. Both RAR ligands, however, produced very similar effects on gene expression in MCF-7 cells, suggesting that RARE-dependent transcription is only a minor component of retinoid-induced changes in gene expression. The effects of RAR ligands on gene expression parallel changes associated with damage-induced senescence, and both ligands induced G1 arrest and the senescent phenotype in MCF-7 cells. The RAR ligands up-regulated many tumor-suppressive genes and down-regulated multiple genes with oncogenic activities. Genes that are strongly induced by RAR ligands encode secreted bioactive proteins, including several tumor-suppressing factors. In agreement with these observations, retinoid-treated MCF-7 cells inhibited the growth of retinoid-insensitive MDA-MB-231 breast carcinoma cells in coculture. These results indicate that RARE-independent transcriptional effects of RAR ligands lead to senescence-like growth arrest and paracrine growth-inhibitory activity in MCF-7 breast carcinoma cells. (Cancer Res 2006; 66(17): 8749-61)
Neighboring Genes Show Interchromosomal Colocalization after Their Separation
Authors: Zhiming Dai, Yuanyan Xiong, Xianhua Dai
Journal: Molecular Biology and Evolution (2014)

The order of genes on eukaryotic chromosomes is nonrandom. Some neighboring genes show order conservation among species, while some neighboring genes separate during evolution. Here, we investigated whether neighboring genes show interactions after their separation. We found that neighboring gene pairs tend to show interchromosomal colocalization (i.e., nuclear colocalization) in the species in which they separate. These nuclear colocalized separated neighboring gene pairs 1) show neighborhood conservation in more species, 2) tend to be regulated by the same transcription factor, and 3) tend to be regulated by the same histone modification. These results suggest a mechanism by which neighboring genes could retain nuclear proximity after their separation.
The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim
Authors: Chun-Rong Chen, Pavel Pichurin, Yuji Nagayama, Francesco Latrofa, Basil Rapoport, Sandra M. McLachlan
Journal: Journal of Clinical Investigation (2003)

Graves disease, a common organ-specific autoimmune disease affecting humans, differs from all other autoimmune diseases in being associated with target organ hyperfunction rather than organ damage. Clinical thyrotoxicosis is directly caused by autoantibodies that activate the thyrotropin receptor (TSHR). The etiology of Graves disease is multifactorial, with nongenetic factors playing an important role. Of the latter, there is the intriguing possibility that the molecular structure of the target antigen contributes to the development of thyroid-stimulatory autoantibodies (TSAb’s). Among the glycoprotein hormone receptors, only the TSHR undergoes intramolecular cleavage into disulfide-linked subunits with consequent shedding of some of the extracellular, autoantibody-binding A subunits. Functional autoantibodies do not arise to the noncleaving glycoprotein hormone receptors. Recently, TSAb’s were found to preferentially recognize shed, rather than attached, A subunits. Here we use a new adenovirus-mediated animal model of Graves disease to show that goiter and hyperthyroidism occur to a much greater extent when the adenovirus expresses the free A subunit as opposed to a genetically modified TSHR that cleaves minimally into subunits. These data show that shed A subunits induce or amplify the immune response leading to hyperthyroidism and provide new insight into the etiology of Graves disease.
Community-acquired pneumonia in Chile: the clinical relevance in the detection of viruses and atypical bacteria
Authors: Vivian Luchsinger, Mauricio Ruiz, Enna Zunino, María Angélica Martínez, Clarisse Machado, Pedro A Piedra, Rodrigo Fasce, María Teresa Ulloa, Maria Cristina Fink, Pamela Lara, Mónica Gebauer, Fernando Chávez, Luis F Avendaño
Journal: Thorax (2013)

<h3>Background</h3> Adult community-acquired pneumonia (CAP) is a relevant worldwide cause of morbidity and mortality, however the aetiology often remains uncertain and the therapy is empirical. We applied conventional and molecular diagnostics to identify viruses and atypical bacteria associated with CAP in Chile. <h3>Methods</h3> We used sputum and blood cultures, IgG/IgM serology and molecular diagnostic techniques (PCR, reverse transcriptase PCR) for detection of classical and atypical bacteria (<i>Mycoplasma pneumoniae</i>, <i>Chlamydia pneumoniae</i>, <i>Legionella pneumoniae</i>) and respiratory viruses (adenovirus, respiratory syncytial virus (RSV), human metapneumovirus, influenza virus, parainfluenzavirus, rhinovirus, coronavirus) in adults &gt;18 years old presenting with CAP in Santiago from February 2005 to September 2007. Severity was qualified at admission by Fine9s pneumonia severity index. <h3>Results</h3> Overall detection in 356 enrolled adults were 92 (26%) cases of a single bacterial pathogen, 80 (22%) cases of a single viral pathogen, 60 (17%) cases with mixed bacterial and viral infection and 124 (35%) cases with no identified pathogen. <i>Streptococcus pneumoniae</i> and RSV were the most common bacterial and viral pathogens identified. Infectious agent detection by PCR provided greater sensitivity than conventional techniques. To our surprise, no relationship was observed between clinical severity and sole or coinfections. <h3>Conclusions</h3> The use of molecular diagnostics expanded the detection of viruses and atypical bacteria in adults with CAP, as unique or coinfections. Clinical severity and outcome were independent of the aetiological agents detected.
Metalloproteinases and tissue inhibitors of metalloproteinases in exudative pleural effusions
Authors: D. Iglesias, J. Alegre, C. Alemán, E. Ruíz, T. Soriano, L. I. Armadans, R. M. Segura, A. Anglés, J. Monasterio, T. Fernández de Sevilla
Journal: European Respiratory Journal (2005)

The aim of this study was to assess the expression of several metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in exudative pleural effusions, and their relationship with inflammatory and fibrinolytic mediators in parapneumonic effusions. The study included 51 parapneumonic effusions (30 empyema or complicated parapneumonic, 21 noncomplicated parapneumonic), 28 tuberculous, 30 malignant and 30 transudates. Inflammatory markers (tumour necrosis factor-α, interleukin-8, polymorphonuclear elastase), fibrinolytic system variables (tissue plasminogen activator (PA), urokinase PA (u-PA), plasminogen activation inhibitor (PAI)-1, PAI-2), and several MMPs (MMP-1, MMP-2, MMP-8, MMP-9) and TIMPs (TIMP-1, TIMP-2) were determined by ELISA in plasma and pleural fluid. Elevated MMP-2 and TIMP-1 concentrations were observed in all the pleural fluid samples studied. The group of empyema or complicated parapneumonic effusions showed higher MMP-1, MMP-8 and MMP-9 concentrations than the remaining exudates. There was no correlation between MMP and TIMP levels in plasma and pleural fluid in this group of effusions. In parapneumonic effusions, MMP-1, MMP-8 and MMP-9 showed a positive correlation with the inflammatory markers and with u-PA and PAI-1. Moreover, there was a relationship between MMP-8 concentration in pleural fluid and pleural thickening at the end of treatment. In conclusion, elevated metalloproteinase-1, -8 and -9 expression was found in parapneumonic pleural effusions. These metalloproteinases could be implicated in the local inflammatory response existing in this group of effusions.
Prospection and the brain
Authors: Randy L. Buckner
Journal: Behavioral and Brain Sciences (2007)

Abstract Suddendorf &amp; Corballis (S&amp;C) propose that the capacity to flexibly forsee the future was a critical step in human evolution and is accomplished by a set of component processes that can be likened to a theater production. Understanding the brain-bases of these functions may help to clarify the hypothesized component processes, inform us of how and when they are used adaptively, and also provide empirical ways of exploring to what degree these abilities exist and are implemented similarly (or differently) across species.
Perfectionism in Anorexia Nervosa: Variation by Clinical Subtype, Obsessionality, and Pathological Eating Behavior
Authors: Katherine A. Halmi, Suzanne R. Sunday, Michael Strober, Alan Kaplan, D. Blake Woodside, Manfred Fichter, Janet Treasure, Wade H. Berrettini, Walter H. Kaye
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: The purpose of this study was to examine the role of perfectionism as a phenotypic trait in anorexia nervosa and its relevance across clinical subtypes of this illness. METHOD: The Multidimensional Perfectionism Scale and the perfectionism subscale of the Eating Disorder Inventory were administered to 322 women with a history of anorexia nervosa who were participating in an international, multicenter genetic study of anorexia nervosa. All participants were additionally interviewed with the Yale-Brown Obsessive Compulsive Scale and the Yale-Brown-Cornell Eating Disorder Scale. Mean differences on dependent measures among women with anorexia nervosa and comparison subjects were examined by using generalized estimating equations. RESULTS: Persons who had had anorexia nervosa had significantly higher total scores on the Multidimensional Perfectionism Scale than did the healthy comparison subjects. In addition, scores of the anorexia subjects on the Eating Disorder Inventory-2 perfectionism subscale exceeded Eating Disorder Inventory-2 normative data. For the anorexia nervosa participants, the total score on the Multidimensional Perfectionism Scale and the Eating Disorder Inventory-2 perfectionism subscale score were highly correlated. Total score on the Multidimensional Perfectionism Scale was also significantly related to the total score and the motivation-for-change subscale score of the Yale-Brown-Cornell Eating Disorder Scale. CONCLUSIONS: These data show that perfectionism is a robust, discriminating characteristic of anorexia nervosa. Perfectionism is likely to be one of a cluster of phenotypic trait variables associated with a genetic diathesis for anorexia nervosa.
High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200
Authors: B. J. Giantonio, P. J. Catalano, N. J. Meropol, P. J. O’Dwyer, E. P. Mitchell, S. R. Alberts, M. A. Schwartz, A. B. Benson
Journal: Journal of Clinical Oncology (2005)

2 Background: The humanized monoclonal antibody bevacizumab (BEV) binds VEGF, inhibits angiogenesis, and improves survival when combined with chemotherapy for advanced colorectal cancer. Methods: E3200 is a randomized phase 3 trial of high-dose BEV (10 mg/kg, IV, biweekly) either alone, or in combination with FOLFOX4 (biweekly administration of: oxaliplatin 85 mg/m2, day 1; leucovorin 200 mg/m2 IV 2hrs and fluorouracil 400 mg/m2 IV bolus followed by fluorouracil 600 mg/m2 CIV for 22hrs, days 1 & 2), compared to FOLFOX4 alone, in patients with previously treated advanced colorectal cancer. Eligible patients had an ECOG PS of 0–2 and must have been treated with a fluoropyrimidine and an irinotecan-based regimen used either alone or in combination. Prior BEV use was not allowed. The endpoints of E3200 include survival (OS), progression free survival (PFS) and response rate (RR). Results: 829 patients were accrued from November 2001 to April 2003. The bevacizumab alone arm of the study was closed in March 2003. Median follow-up is 18.7 months. Efficacy results and limited toxicity findings of E3200 will be presented. Bowel perforation was infrequent (1.1%) but occurred only in patients on E3200 treated with BEV. Conclusion: BEV administered at 10 mg/kg in combination with FOLFOX4 is well tolerated and improves OS and PFS in advanced colorectal cancer patients previously treated with irinotecan and a fluoropyrimidine. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech BioOncology, Sanofi-Synthelabo Genentech BioOncology, Pfizer, Sanofi-Synthelabo Genentech BioOncology, Sanofi-Synthelabo Genentech, Sanofi-Synthelabo
Facial Papules in a Patient With Long-Term Cystinosis
Authors: Michael S. Stevens, Shachar Sade, Scott Walsh
Journal: JAMA Dermatology (2015)

specimen from the patient's cutaneous SCC lesions was strongly positive for PD-L1 (Figure 2), suggesting that blockade of the PD-1/PD-L1 pathway might be a therapeutic option.After considering several factors-adaptive immunotherapy in the form of PD-1 inhibitors had recently been approved by the FDA for metastatic melanoma and was now commercially available; early data in head and neck squamous cells showed potential efficacy 5,6 ; and no good treatment options were available that would preserve quality of life-the patient decided to pursue an off-label trial of pembrolizumab (intravenous infusions, 2 mg/kg every 3 weeks).He tolerated the treatment with adverse effects of mild fatigue, chills, malaise, arthralgias, and weight loss.After 2 cycles, dramatic tumor response was observed (Figure 2).After 6 cycles, the patient was still progression free.Discussion | A recent retrospective study of patients with unresectable cutaneous SCC showed that only 30% responded to therapy of any kind, and overall survival of such patients was only 10.9 months. 1,3Hence, unresectable cutaneous SCCs represent an unmet medical need.This case highlights the potential for immunotherapy in the form of PD-1/PD-L1 inhibition to address this need, a finding that requires further investigation through clinical trials.
Insights into the Evolution of Vitamin B12 Auxotrophy from Sequenced Algal Genomes
Authors: K. E. Helliwell, G. L. Wheeler, K. C. Leptos, R. E. Goldstein, A. G. Smith
Journal: Molecular Biology and Evolution (2011)

Vitamin B12 (cobalamin) is a dietary requirement for humans because it is an essential cofactor for two enzymes, methylmalonyl-CoA mutase and methionine synthase (METH). Land plants and fungi neither synthesize or require cobalamin because they do not contain methylmalonyl-CoA mutase, and have an alternative B12-independent methionine synthase (METE). Within the algal kingdom, approximately half of all microalgal species need the vitamin as a growth supplement, but there is no phylogenetic relationship between these species, suggesting that the auxotrophy arose multiple times through evolution. We set out to determine the underlying cellular mechanisms for this observation by investigating elements of B12 metabolism in the sequenced genomes of 15 different algal species, with representatives of the red, green, and brown algae, diatoms, and coccolithophores, including both macro- and microalgae, and from marine and freshwater environments. From this analysis, together with growth assays, we found a strong correlation between the absence of a functional METE gene and B12 auxotrophy. The presence of a METE unitary pseudogene in the B12-dependent green algae Volvox carteri and Gonium pectorale, relatives of the B12-independent Chlamydomonas reinhardtii, suggest that B12 dependence evolved recently in these lineages. In both C. reinhardtii and the diatom Phaeodactylum tricornutum, growth in the presence of cobalamin leads to repression of METE transcription, providing a mechanism for gene loss. Thus varying environmental conditions are likely to have been the reason for the multiple independent origins of B12 auxotrophy in these organisms. Because the ultimate source of cobalamin is from prokaryotes, the selective loss of METE in different algal lineages will have had important physiological and ecological consequences for these organisms in terms of their dependence on bacteria.
15-Lipoxygenases and its metabolites 15(S)-HETE and 13(S)-HODE in the development of non-small cell lung cancer
Authors: H. Yuan, M.-Y. Li, L. T Ma, M. K Y Hsin, T. S K Mok, M. J Underwood, G. G Chen
Journal: Thorax (2010)

15-S-Hydroxyeicosatetraenoic acid (15(S)-HETE) and 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), both of which are metabolites of 15-lipoxygenases (15-LOXs), are endogenous ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). The activation of PPARgamma inhibits cell growth and induces apoptosis in some cancers. The role of 15(S)-HETE) and 13(S)-HODE in the development of lung cancer is not clear.15-LOXs, 15(S)-HETE and 13(S)-HODE were monitored during the development of mouse lung tumours induced by the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the levels of these markers were determined in 54 human non-small cell lung cancers.15-LOXs, 15(S)-HETE and 13(S)-HODE levels were significantly reduced in human lung cancer tissue compared with non-tumour lung tissue (p=0.011 and p=0.022, respectively). In mouse experiments, 15(S)-HETE and 13(S)-HODE started to reduce at 26 and 30 weeks, respectively, after NNK treatment. The time frame of 15(S)-HETE reduction was in line with the decrease in 12/15-LOX mRNA and protein. A significant difference in the number of tumours in NNK-treated mice and controls was not observed until week 34 (p<0.05) and week 38 (p<0.01). The reduction in 12/15-LOX and 15(S)-HETE therefore predated the appearance of lung tumour. Furthermore, PPARgamma activity was decreased in NNK-treated mouse lungs compared with the control, and the decreased PPARgamma activity occurred at the same time points as the reduction in 12/15-LOX and 15(S)-HETE.These findings indicate that the reduction in 15-LOX, 15(S)-HETE and 13(S)-HODE results in the decreased PPARgamma activity seen in lung tumours and contributes to the development of lung tumours induced by tobacco smoking.