tbuckley/cabot-search huggingface dataset:
A prospective study of respiratory symptoms associated with chronic arsenic exposure in Bangladesh: findings from the Health Effects of Arsenic Longitudinal Study (HEALS)
Authors: F. Parvez, Y. Chen, P. W. Brandt-Rauf, V. Slavkovich, T. Islam, A. Ahmed, M. Argos, R. Hassan, M. Yunus, S. E. Haque, O. Balac, J. H. Graziano, H. Ahsan
Journal: Thorax (2010)

<h3>Background and aims</h3> A prospective cohort study was conducted to evaluate the effect of arsenic (As) exposure from drinking water on respiratory symptoms using data from the Health Effects of Arsenic Exposure Longitudinal Study (HEALS), a large prospective cohort study established in Ariahazar, Bangladesh in 2000–2002. A total of 7.31, 9.95 and 2.03% of the 11 746 participants completing 4 years of active follow-up reported having a chronic cough, breathing problem or blood in their sputum, respectively, as assessed by trained physicians. <h3>Methods</h3> Cox regression models were used to estimate HRs for respiratory symptoms during the follow-up period in relation to levels of chronic As exposure assessed at baseline, adjusting for age, gender, smoking, body mass index, education and arsenic-related skin lesion status. <h3>Results</h3> Significant positive associations were found between As exposure and respiratory symptoms. As compared with those with the lowest quintile of water As level (≤7 μg/l), the HRs for having respiratory symptoms were 1.27 (95% CI 1.09 to 1.48), 1.39 (95% CI 1.19 to 1.63), 1.43 (95% CI 1.23 to 1.68) and 1.43 (95% CI 1.22 to 1.68) for the second to fifth quintiles of baseline water As concentrations (7–40, 40–90, 90–178 and &gt;178 μg/l), respectively. Similarly, the corresponding HRs in relation to the second to fifth quintiles of urinary arsenic were 1.10 (95% CI 0.94 to 1.27), 1.11 (95% CI 0.95 to 1.29), 1.29 (95% CI 1.11 to 1.49) and 1.35 (95% CI 1.16 to 1.56), respectively. These associations did not differ appreciably by cigarette smoking status. <h3>Conclusions</h3> This prospective cohort study found a dose–response relationship between As exposure and clinical symptoms of respiratory diseases in Bangladesh. In particular, these adverse respiratory effects of As were clearly evident in the low to moderate dose range, suggesting that a large proportion of the country9s population may be at risk of developing serious lung diseases in the future.
The Psychiatrist and Huntington's Disease (Chorea)
Authors: JOHN R. WHITTIER, AUDREY HEIMLER, CHARLES KORENYI
Journal: American Journal of Psychiatry (1972)

Huntington's disease is inherited and is usually not detectable until after the affected individual marries and produces children. As genetic knowledge increases there will be a growing awareness of its personal significance to members of kindreds having a history of this disease and more requests for psychiatrists' involvement in genetic counseling. For these reasons it is important that the psychiatric profession be alerted to the particular needs of this group of patients.
Cytoprotective Effects of Nitroglycerin in Ischemia–Reperfusion-Induced Lung Injury
Authors: MASAHIRO KAWASHIMA, TORU BANDO, TAKAYUKI NAKAMURA, NORITAKA ISOWA, MINGYAO LIU, SHINYA TOYOKUNI, SHIGEKI HITOMI, HIROMI WADA
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Prevention of ischemia-reperfusion (IR) injury is crucial for successful lung transplantation. We investigated whether a nitric oxide donor, nitroglycerin (NTG), could suppress the oxidative stress of IR injury and improve pulmonary function after reperfusion in an ex vivo rat lung perfusion model. In Fresh group of animals, the lungs were flushed with perfusate, followed immediately by reperfusion, and no lung injury was observed. In NTG- and NTG+ groups of animals, the lungs were flushed with perfusate alone or perfusate containing NTG, respectively. Harvested lung and heart blocks from these latter two groups were immersed in the corresponding perfusate at 4 degrees C for 15 h, and were then reperfused for 60 min. Reperfusion induced pulmonary edema in the NTG- group, but not in the NTG+ group. Shunt fractions in NTG+ group were significantly lower than in the NTG- group throughout reperfusion. NTG had no effect on pulmonary arterial pressure or myeloperoxidase activity. In contrast, oxidative DNA damage assessed immunohistochemically with a monoclonal antibody against 8-hydroxy-2'-deoxyguanosine (8-OHdG) was significantly increased in the NTG- group, in the order alveolar epithelium > pulmonary endothelium > bronchial epithelium. NTG treatment significantly decreased staining with the anti-8-OHdG antibody in all three areas of tissue. Therefore, administration of NTG attenuates the oxidative stress of IR injury, and may improve pulmonary function after reperfusion.
Biomarkers in solid organ transplantation: establishing personalized transplantation medicine
Authors: Silke Roedder, Matthew Vitalone, Purvesh Khatri, Minnie M Sarwal
Journal: Genome Medicine (2011)

Technological advances in molecular and in silico research have enabled significant progress towards personalized transplantation medicine. It is now possible to conduct comprehensive biomarker development studies of transplant organ pathologies, correlating genomic, transcriptomic and proteomic information from donor and recipient with clinical and histological phenotypes. Translation of these advances to the clinical setting will allow assessment of an individual patient's risk of allograft damage or accommodation. Transplantation biomarkers are needed for active monitoring of immunosuppression, to reduce patient morbidity, and to improve long-term allograft function and life expectancy. Here, we highlight recent pre- and post-transplantation biomarkers of acute and chronic allograft damage or adaptation, focusing on peripheral blood-based methodologies for non-invasive application. We then critically discuss current findings with respect to their future application in routine clinical transplantation medicine. Complement-system-associated SNPs present potential biomarkers that may be used to indicate the baseline risk for allograft damage prior to transplantation. The detection of antibodies against novel, non-HLA, MICA antigens, and the expression of cytokine genes and proteins and cytotoxicity-related genes have been correlated with allograft damage and are potential post-transplantation biomarkers indicating allograft damage at the molecular level, although these do not have clinical relevance yet. Several multi-gene expression-based biomarker panels have been identified that accurately predicted graft accommodation in liver transplant recipients and may be developed into a predictive biomarker assay.
Functioning and Evolutionary Significance of Nutrient Transceptors
Authors: J. M. Thevelein, K. Voordeckers
Journal: Molecular Biology and Evolution (2009)

The discovery of nutrient transceptors, transporter-like proteins with a receptor function, suggests that receptors for chemical signals may have been derived in evolution from nutrient transporters. Several examples are now available of nutrient transporters with an additional nutrient signaling function, nutrient receptors with a transporter-like sequence and structure but without transport capacity, and G protein–coupled receptors (GPCRs) that have nutrients as ligands. Recent results have revealed that transceptor signaling requires a specific ligand-induced conformational change, which indicates that transceptors function in a similar way as regular receptors. Advanced bioinformatic analysis for detection of homology in distantly related proteins identifies the nontransporting glucose transceptor Rgt2 as the closest homologue of the glucose-sensing GPCR Gpr1 in yeast. This supports an intermediate position for nutrient transceptors in evolution, between nutrient transporters and classical receptors for chemical signals.
Loss of α3/α4(IV) Collagen from the Glomerular Basement Membrane Induces a Strain-Dependent Isoform Switch to α5α6(IV) Collagen Associated with Longer Renal Survival in Col4a3 −/− Alport Mice
Authors: Jeong Suk Kang, Xu-Ping Wang, Jeffrey H. Miner, Roy Morello, Yoshikazu Sado, Dale R. Abrahamson, Dorin-Bogdan Borza
Journal: Journal of the American Society of Nephrology (2006)

Mutations in COL4A3/4/5 genes that affect the normal assembly of the alpha3/4/5(IV) collagen network in the glomerular basement membrane (GBM) cause Alport syndrome. Patients progress to renal failure at variable rates that are determined by the underlying mutation and putative modifier genes. Col4a3(-/-) mice, a model for autosomal recessive Alport syndrome, progress to renal failure significantly slower on the C57BL/6 than on the 129X1/Sv background. Reported here is a novel strain-specific alternative collagen IV isoform switch that is associated with the differential renal survival in Col4a3(-/-) Alport mice. The downregulation or the absence of alpha3/4(IV) collagen chains in the GBM of Lmx1b(-/-) and Col4a3(-/-) mice was found to induce ectopic deposition of alpha5/6(IV) collagen. The GBM deposition of alpha5/6(IV) collagen was abundant in C57BL/6 Col4a3(-/-) mice but almost undetectable in 129X1/Sv Col4a3(-/-) mice. This strain difference was due to overall low expression of alpha6(IV) chain and alpha5/6(IV) protomers in the tissues of 129X1/SvJ mice, a natural Col4a6 knockdown. In (129 x B6)F1 Col4a3(-/-) mice, the amount of alpha5/6(IV) collagen in the GBM was inherited in a mother-to-son manner, suggesting that it is controlled by one or more X-linked loci, possibly Col4a6 itself. Importantly, high levels of ectopic alpha5/6(IV) collagen in the GBM were associated with approximately 46% longer renal survival. These findings suggest that alpha5/6(IV) collagen, the biologic role of which has been hitherto unknown, may partially substitute for alpha3/4/5(IV) collagen. Therapeutically induced GBM deposition of alpha5/6(IV) collagen may provide a novel strategy for delaying renal failure in patients with autosomal recessive Alport syndrome.
PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis
Authors: Hayley Mylroie, Odile Dumont, Andrea Bauer, Clare C. Thornton, John Mackey, Damien Calay, Shahir S. Hamdulay, Joan R. Choo, Joseph J. Boyle, Allen M. Samarel, Anna M. Randi, Paul C. Evans, Justin C. Mason
Journal: Cardiovascular Research (2015)

Vascular injury leading to endothelial dysfunction is a characteristic feature of chronic renal disease, diabetes mellitus, and systemic inflammatory conditions, and predisposes to apoptosis and atherogenesis. Thus, endothelial dysfunction represents a potential therapeutic target for atherosclerosis prevention. The observation that activity of either protein kinase C epsilon (PKCε) or haem oxygenase-1 (HO-1) enhances endothelial cell (EC) resistance to inflammation and apoptosis led us to test the hypothesis that HO-1 is a downstream target of PKCε. Expression of constitutively active PKCε in human EC significantly increased HO-1 mRNA and protein, whereas conversely aortas or cardiac EC from PKCε-deficient mice exhibited reduced HO-1 when compared with wild-type littermates. Angiotensin II activated PKCε and induced HO-1 via a PKCε-dependent pathway. PKCε activation significantly attenuated TNFα-induced intercellular adhesion molecule-1, and increased resistance to serum starvation-induced apoptosis. These responses were reversed by the HO antagonist zinc protoporphyrin IX. Phosphokinase antibody array analysis identified CREB1(Ser133) phosphorylation as a PKCε signalling intermediary, and cAMP response element-binding protein 1 (CREB1) siRNA abrogated PKCε-induced HO-1 up-regulation. Likewise, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was identified as a PKCε target using nuclear translocation and DNA-binding assays, and Nrf2 siRNA prevented PKCε-mediated HO-1 induction. Moreover, depletion of CREB1 inhibited PKCε-induced Nrf2 DNA binding, suggestive of transcriptional co-operation between CREB1 and Nrf2. PKCε activity in the vascular endothelium regulates HO-1 via a pathway requiring CREB1 and Nrf2. Given the potent protective actions of HO-1, we propose that this mechanism is an important contributor to the emerging role of PKCε in the maintenance of endothelial homeostasis and resistance to injury.
N-Acetylcysteine Decreases Angiotensin II Receptor Binding in Vascular Smooth Muscle Cells
Authors: Michael E. Ullian, Andrew K. Gelasco, Wayne R. Fitzgibbon, C. Nicole Beck, Thomas A. Morinelli
Journal: Journal of the American Society of Nephrology (2005)

Antioxidants seem to inhibit angiotensin II (Ang II) actions by consuming stimulated reactive oxygen species. An alternative hypothesis was investigated: Antioxidants that are also strong reducers of disulfide bonds inhibit the binding of Ang II to its surface receptors with consequent attenuation of signal transduction and cell action. Incubation of cultured vascular smooth muscle cells, which possess Ang II type 1a receptors, with the reducing agent n-acetylcysteine (NAC) for 1 h at 37 degrees C resulted in decreased Ang II radioligand binding in a concentration-dependent pattern. NAC removal restored Ang II binding within 30 min. Incubation with n-acetylserine, a nonreducing analogue of NAC, did not lower Ang II binding, and oxidized NAC was less effective than reduced NAC in lowering Ang II binding. NAC did not decrease Ang II type 1a receptor protein content. Other antioxidants regulated Ang II receptors differently: alpha-Lipoic acid lowered Ang II binding after 24 h, and vitamin E did not lower Ang II binding at all. NAC inhibited Ang II binding in cell membranes at 21 or 37 but not 4 degrees C. Dihydrolipoic acid (the reduced form of alpha-lipoic acid), which contains free sulfhydryl groups as NAC does, decreased Ang II receptor binding in cell membranes, whereas alpha-lipoic acid, which does not contain free sulfhydryl groups, did not. Ang II-stimulated inositol phosphate formation was decreased by preincubation with NAC (1 h) or alpha-lipoic acid (24 h) but not vitamin E. In conclusion, certain antioxidants that are reducing agents lower Ang II receptor binding, and Ang II-stimulated signal transduction is decreased in proportion to decreased receptor binding.
From mRNA Metabolism to Cancer Therapy: Chronic Myelogenous Leukemia Shows the Way
Authors: Danilo Perrotti, Paolo Neviani
Journal: Clinical Cancer Research (2007)

Abstract Altered mRNA metabolism is a feature of many cancers including blast crisis chronic myelogenous leukemia. Indeed, loss of function of many tumor suppressors regulating cell proliferation, survival, and differentiation results from aberrant mRNA processing, nuclear export, and/or translation. Here, we summarize the effects of increased BCR/ABL oncogenic activity on the expression and function of RNA binding proteins (e.g., FUS, hnRNP A1, hnRNP E2, hnRNP K, and La/SSB) with posttranscriptional and translational regulatory activities and their importance for the phenotype of BCR/ABL-transformed hematopoietic progenitors. We also provide evidence that these studies not only advance our understanding on the molecular mechanisms contributing to tumor/leukemia emergence, maintenance, and/or progression but they also serve for the identification of novel molecular targets useful for the development of alternative therapies for imatinib-resistant and blast crisis chronic myelogenous leukemia and, perhaps, for other cancers characterized by similar alterations in the mRNA metabolism.
The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL
Authors: K Balakrishnan, M Peluso, M Fu, N Y Rosin, J A Burger, W G Wierda, M J Keating, K Faia, S O'Brien, J L Kutok, V Gandhi
Journal: Leukemia (2015)
The monoclonality of human B-cell lymphomas.
Authors: R Levy, R Warnke, R F Dorfman, J Haimovich
Journal: The Journal of Experimental Medicine (1977)

Human tissues involved with lymphoma have been examined in frozen sections for immunoglobulin-bearing cells by a technique involving double-label immunofluorescence with mixed anti-kappa and anti-lambda antibodies. F (ab')2 fragments of purified antibodies were employed to avoid any binding via Fc receptors. B cell lymphomas were shown to be composed of monoclonal populations of Ig bearing cells, whereas normal or reactive lymphoid follicles contained a mosaic of Ig-bearing cells derived from multiple clones. Nodules of lymphoma were often surrounded by normal polyclonal B cell populations. We anticipates that the approach described here will be useful in the diagnosis of lymphoma, differentiating it from reactive lymphoid hyperplasia by the demostration of monoclonality. In addition, it should provide a sensitive and reliable tool for investigating the immunobiology of human lymphoma.
Causes of Fecal and Urinary Incontinence After Total Mesorectal Excision for Rectal Cancer Based on Cadaveric Surgery: A Study From the Cooperative Clinical Investigators of the Dutch Total Mesorectal Excision Trial
Authors: Christian Wallner, Marilyne M. Lange, Bert A. Bonsing, Cornelis P. Maas, Charles N. Wallace, Noshir F. Dabhoiwala, Harm J. Rutten, Wouter H. Lamers, Marco C. DeRuiter, Cornelis J.H. van de Velde
Journal: Journal of Clinical Oncology (2008)

Total mesorectal excision (TME) for rectal cancer may result in anorectal and urogenital dysfunction. We aimed to study possible nerve disruption during TME and its consequences for functional outcome. Because the levator ani muscle plays an important role in both urinary and fecal continence, an explanation could be peroperative damage of the nerve supply to the levator ani muscle.TME was performed on cadaver pelves. Subsequently, the anatomy of the pelvic floor innervation and its relation to the pelvic autonomic innervation and the mesorectum were studied. Additionally, data from the Dutch TME trial were analyzed to relate anorectal and urinary dysfunction to possible nerve damage during TME procedure.Cadaver TME surgery demonstrated that, especially in low tumors, the pelvic floor innervation can be damaged. Furthermore, the origin of the levator ani nerve was located in close proximity of the origin of the pelvic splanchnic nerves. Analysis of the TME trial data showed that newly developed urinary and fecal incontinence was present in 33.7% and 38.8% of patients, respectively. Both types of incontinence were significantly associated with each other (P = .027). Low anastomosis was significantly associated with urinary incontinence (P = .049). One third of the patients with newly developed urinary and fecal incontinence also reported difficulty in bladder emptying, for which excessive perioperative blood loss was a significant risk factor.Perioperative damage to the pelvic floor innervation could contribute to fecal and urinary incontinence after TME, especially in case of a low anastomosis or damage to the pelvic splanchnic nerves.
Epicardial calcineurin–NFAT signals through Smad2 to direct coronary smooth muscle cell and arterial wall development
Authors: Jin Yang, Miriam Zeini, Chieh-Yu Lin, Chien-Jung Lin, Yiqin Xiong, Ching Shang, Pei Han, Wei Li, Thomas Quertermous, Bin Zhou, Ching-Pin Chang
Journal: Cardiovascular Research (2013)

Congenital coronary artery anomalies produce serious events that include syncope, arrhythmias, myocardial infarction, or sudden death. Studying the mechanism of coronary development will contribute to the understanding of the disease and help design new diagnostic or therapeutic strategies. Here, we characterized a new calcineurin–NFAT signalling which specifically functions in the epicardium to regulate the development of smooth muscle wall of the coronary arteries. Using tissue-specific gene deletion, we found that calcineurin–NFAT signals in the embryonic epicardium to direct coronary smooth muscle cell development. The smooth muscle wall of coronary arteries fails to mature in mice with epicardial deletion of calcineurin B1 (Cnb1), and accordingly these mutant mice develop cardiac dysfunction with reduced exercise capacity. Inhibition of calcineurin at various developmental windows shows that calcineurin–NFAT signals within a narrow time window at embryonic Day 12.5–13.5 to regulate coronary smooth muscle cell development. Within the epicardium, NFAT transcriptionally activates the expression of Smad2, whose gene product is critical for transducing transforming growth factor β (TGFβ)–Alk5 signalling to control coronary development. Our findings demonstrate new spatiotemporal and molecular actions of calcineurin–NFAT that dictate coronary arterial wall development and a new mechanism by which calcineurin–NFAT integrates with TGFβ signalling during embryonic development.
Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45
Authors: Hyun-Joo Nam, Florence Poy, Haruo Saito, Christin A. Frederick
Journal: The Journal of Experimental Medicine (2005)

CD45 is the prototypic member of transmembrane receptor-like protein tyrosine phosphatases (RPTPs) and has essential roles in immune functions. The cytoplasmic region of CD45, like many other RPTPs, contains two homologous protein tyrosine phosphatase domains, active domain 1 (D1) and catalytically impaired domain 2 (D2). Here, we report crystal structure of the cytoplasmic D1D2 segment of human CD45 in native and phosphotyrosyl peptide-bound forms. The tertiary structures of D1 and D2 are very similar, but doubly phosphorylated CD3ζ immunoreceptor tyrosine-based activation motif peptide binds only the D1 active site. The D2 “active site” deviates from the other active sites significantly to the extent that excludes any possibility of catalytic activity. The relative orientation of D1 and D2 is very similar to that observed in leukocyte common antigen–related protein with both active sites in an open conformation and is restrained through an extensive network of hydrophobic interactions, hydrogen bonds, and salt bridges. This crystal structure is incompatible with the wedge model previously suggested for CD45 regulation.
A new class of cell surface antigens. Quantitative absorption studies defining cell-lineage-specific antigens on hemopoietic cells.
Authors: M V Berridge
Journal: The Journal of Experimental Medicine (1979)

A new class of cell surface antigens are described which are expressed on cells within a particular differentiation pathway. These antigens, termed cell-lineage-specific antigens, are shown to be distinct from differentiation antigens and from histocompatibility antigens. The presence of these antigens was demonstrated by raising antisera against terminally differentiated hemopoietic cells such as platelets, thymocytes, and macrophages and showing cross-reaction with the pluripotent stem cells from which these cells were derived. Quantitative absorption studies of each antiserum showed the antigens to be largely cell-lineage-specific. For example, the anti-stem cell activity in anti-platelet serum was not absorbed out with thymocytes or macrophages from the same mouse strain but was removed by absorption with platelets. Absorption of each antiserum with nonhemopoietic mouse tissues such as brain, kidney, liver, and testis did not reduce anti-stem cell activity. Thus, each antiserum was shown to be tissue specific and species specific. Hemopoietic cells from mouse strains other than CBA absorbed out most of the anti-stem cell activity indicating cell-lineage-specific antigens to be common to the mouse strains tested.