tbuckley/cabot-search huggingface dataset:
New ways to turn on NKT cells
Authors: Dale Ian Godfrey, Jamie Rossjohn
Journal: The Journal of Experimental Medicine (2011)

Natural killer T (NKT) cells are CD1d-restricted, lipid antigen–reactive T cells with powerful immunoregulatory potential. The prototypic antigen for NKT cells is a marine sponge–derived glycolipid, α-galactosylceramide (α-GalCer), but this is not normally encountered in the mammalian environment. Thus, there is great interest in the identification of more physiological stimuli for NKT cells, and numerous studies have shown that NKT cells are capable of responding to a range of microbial lipid-based antigens. Two new studies expand our understanding of environmental NKT cell stimuli, with one showing that CD1d-restricted NKT cell antigens are present within common house dust extract (HDE), whereas the other shows that NKT cells can respond to innate stimuli irrespective of the presence of foreign microbial antigens. Collectively, these two investigations indicate that NKT cells are far more likely to encounter foreign antigens, or innate activating signals, than previously recognized, suggesting a more central role for these cells in the immune system.
Presence of the neuropeptide Y1 receptor in tenocytes and blood vessel walls in the human Achilles tendon
Authors: D Bjur, H Alfredson, S Forsgren
Journal: British Journal of Sports Medicine (2009)

Questions remain concerning the mechanisms of the development of chronic pain and impaired function of tendons (tendinosis). Aspects known to occur are cell proliferation, angiogenesis and altered blood flow regulation. Neuropeptide Y (NPY) is widely distributed in the body and has powerful effects in relation to these processes. NPY has its effects via the G-protein-coupled Y receptors. There is no information concerning the presence or absence of NPY receptors in Achilles tendons or other tendons.To clarify the expression patterns of the NPY receptors Y1 and Y2 in normal and tendinosis Achilles tendons of humans.Immunohistochemical methods were used. Examination on NPY was carried out in parallel.The tenocytes showed strong immunoreactions for the Y1 receptor. The immunoreactions were more intense in the tenocytes of tendinosis tendons than in non-tendinosis tendons. The rounded/oval tenocytes typically seen in tendinosis tendons exhibited marked Y1 receptor reactions on their exterior. Pronounced Y1 reactions were seen in the smooth muscle of the arterioles of both tendinosis and non-tendinosis tendons. No reactions for the Y2 receptor were noted. NPY was detected in nerve fascicles and in perivascular innervation.This study shows that there is a morphological correlate for the occurrence of pronounced NPY effects via the Y1 receptor in both tenocytes, especially for tendinosis tendons, and blood vessel walls in the Achilles tendon. The findings are of particular interest as NPY is known to have proliferative, angiogenic and blood vessel-regulating effects. The effects of targeting the Y1 receptor in tendinosis is an interesting task to be evaluated further.
On the mechanism of parathyroid hormone stimulation of calcium uptake by mouse distal convoluted tubule cells.
Authors: F A Gesek, P A Friedman
Journal: Journal of Clinical Investigation (1992)

PTH stimulates transcellular Ca2+ absorption in renal distal convoluted tubules. The effect of PTH on membrane voltage, the ionic basis of the change in voltage, and the relations between voltage and calcium entry were determined on immortalized mouse distal convoluted tubule cells. PTH (10(-8) M) significantly increased 45Ca2+ uptake from basal levels of 2.81 +/- 0.16 to 3.88 +/- 0.19 nmol min-1 mg protein-1. PTH-induced 45Ca2+ uptake was abolished by the dihydropyridine antagonist, nifedipine (10(-5) M). PTH did not affect 22Na+ uptake. Intracellular calcium activity ([Ca2+]i) was measured in cells loaded with fura-2. Control [Ca2+]i averaged 112 +/- 21 nM. PTH increased [Ca2+]i over the range of 10(-11) to 10(-7) M. Maximal stimulation to 326 +/- 31 nM was achieved at 10(-8) M PTH. Resting membrane voltage measured with the potential sensitive dye DiO6(3) averaged -71 +/- 2 mV. PTH hyperpolarized cells by 19 +/- 4 mV. The chloride-channel blocker NPPB prevented PTH-induced hyperpolarization. PTH decreased and NPPB increased intracellular chloride, measured with the fluorescent dye SPQ. Chloride permeability was estimated by measuring the rate of 125I- efflux. PTH increased 125I- efflux and this effect was blocked by NPPB. Clamping voltage with K+/valinomycin; depolarizing membrane voltage by reducing extracellular chloride; or addition of NPPB prevented PTH-induced calcium uptake. In conclusion, PTH increases chloride conductance in distal convoluted tubule cells leading to decreased intracellular chloride activity, membrane hyperpolarization, and increased calcium entry through dihydropyridine-sensitive calcium channels.
Analysis of ErbB Receptors in Pulmonary Carcinoid Tumors
Authors: Otis B. Rickman, Pawan K. Vohra, Bharati Sanyal, Julie A. Vrana, Marie-Christine Aubry, Dennis A. Wigle, Charles F. Thomas
Journal: Clinical Cancer Research (2009)

Abstract Purpose: This study aimed to investigate the expression of the ErbB family of receptor tyrosine kinases in pulmonary typical carcinoid and atypical carcinoid tumors and to understand the role of epidermal growth factor receptor (EGFR) signaling in pulmonary carcinoid tumor proliferation. Experimental Design: Surgically resected typical carcinoid (n = 24) and atypical carcinoid (n = 7) tumor tissues were analyzed by immunohistochemical staining for EGFR, ErbB2, ErbB3, and ErbB4. Sequencing of tumor DNA of exons 18 to 21 of the EGFR gene and the KRAS gene was carried out. Biochemical analysis of lung carcinoid cell lines was used to investigate EGFR signal transduction and response to erlotinib inhibition. Results: The analysis showed that 45.8% of typical carcinoid and 28.6% of atypical carcinoid tumors express EGFR, 100% of the tumors lack expression of ErbB2, and 100% have moderate to intense staining for ErbB3 and ErbB4. Sequencing of tumor DNA of exons 18 to 21 of the EGFR gene revealed the absence of tyrosine kinase domain mutations in these tumors. Instead, 80.6% tumors harbored a synonymous single nucleotide polymorphism in exon 20. Because EGFR and KRAS mutations tend not to be present at the same time, we sequenced the KRAS gene from pulmonary carcinoid tumor DNA and found that 100% were wild-type. Using a lung carcinoid cell line that expresses EGFR, we found that erlotinib reduced proliferation by inhibiting EGFR signal transduction. Conclusions: Our findings suggest clinical potential for the use of EGFR inhibitors in the treatment of patients with pulmonary carcinoid tumors, particularly for patients with EGFR-positive pulmonary carcinoid tumors not amenable to surgical resection.
Creating a honey bee consensus gene set
Authors: Christine G Elsik, Aaron J Mackey, Justin T Reese, Natalia V Milshina, David S Roos, George M Weinstock
Journal: Genome biology (2007)

Abstract Background We wished to produce a single reference gene set for honey bee ( Apis mellifera ). Our motivation was twofold. First, we wished to obtain an improved set of gene models with increased coverage of known genes, while maintaining gene model quality. Second, we wished to provide a single official gene list that the research community could further utilize for consistent and comparable analyses and functional annotation. Results We created a consensus gene set for honey bee ( Apis mellifera ) using GLEAN, a new algorithm that uses latent class analysis to automatically combine disparate gene prediction evidence in the absence of known genes. The consensus gene models had increased representation of honey bee genes without sacrificing quality compared with any one of the input gene predictions. When compared with manually annotated gold standards, the consensus set of gene models was similar or superior in quality to each of the input sets. Conclusion Most eukaryotic genome projects produce multiple gene sets because of the variety of gene prediction programs. Each of the gene prediction programs has strengths and weaknesses, and so the multiplicity of gene sets offers users a more comprehensive collection of genes to use than is available from a single program. On the other hand, the availability of multiple gene sets is also a cause for uncertainty among users as regards which set they should use. GLEAN proved to be an effective method to combine gene lists into a single reference set.
What is Indigestion?<sup>1</sup>
Authors: J G C Kingham, P D Fairclough, A M Dawson
Journal: Journal of the Royal Society of Medicine (1983)

Ninety patients and 30 senior hospital doctors were questioned about indigestion and dyspepsia. There were marked discrepancies between the views of patients and doctors. Most doctors considered indigestion to be synonymous with dyspepsia and associated it with peptic ulcer. Patients, however, were not generally conversant with the term dyspepsia and linked indigestion with psychological factors, feeding patterns and bowel function rather than physical illness. The patients' concept of indigestion corresponded closely with medically-accepted features of irritable bowel syndrome. Uncritical use of these terms may lead to misinterpretation of the patient's complaint and inappropriate management.
Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal Antibody to Tumor Necrosis Factor-α, in Patients With Moderate-to-Severe Heart Failure
Authors: Eugene S. Chung, Milton Packer, Kim Hung Lo, Adedigbo A. Fasanmade, James T. Willerson
Journal: Circulation (2003)

Preclinical and preliminary clinical data have suggested that tumor necrosis factor-alpha (TNFalpha) may play a role in the evolution and progression of heart failure and that inhibition of TNFalpha may favorably modify the course of the disease. We evaluated the efficacy and safety of infliximab, a chimeric monoclonal antibody to TNFalpha, in patients with moderate-to-severe heart failure.One hundred fifty patients with stable New York Heart Association class III or IV heart failure and left ventricular ejection fraction <or=35% were randomly assigned to receive placebo (n=49), infliximab 5 mg/kg (n=50), or infliximab 10 mg/kg (n=51) at 0, 2, and 6 weeks after randomization and were followed-up prospectively for 28 weeks. Neither dose of infliximab improved clinical status at 14 weeks, the primary endpoint of the study, despite suppression of inflammatory markers (C-reactive protein and interleukin-6) and a modest increase in ejection fraction in the patients receiving 5 mg/kg (P=0.013). Furthermore, after 28 weeks, 13, 10, and 20 patients were hospitalized for any reason in the placebo, 5 mg/kg infliximab, and 10 mg/kg infliximab groups, respectively. The combined risk of death from any cause or hospitalization for heart failure through 28 weeks was increased in the patients randomized to 10 mg/kg infliximab (hazard ratio 2.84, 95% confidence interval 1.01 to 7.97; nominal P=0.043).Short-term TNFalpha antagonism with infliximab did not improve and high doses (10 mg/kg) adversely affected the clinical condition of patients with moderate-to-severe chronic heart failure.
DH admits insufficient resources were put into cutting health inequalities
Authors: A. O'Dowd
Journal: BMJ (2010)

The resources and focus given to reducing health inequalities in the United Kingdom in the past were lacking, Department of Health leaders have admitted.

MPs on the parliamentary public accounts select committee held on 14 September quizzed department officials as part on their inquiry to examine the National Audit Office (NAO) report Tackling inequalities in life expectancy in areas with the worst health and deprivation , published in July ( BMJ 2010; 341:c3558 doi: 10.1136/bmj.c3558).

That report concluded that the government had made a serious attempt to tackle health inequalities, but having set targets, it took too long to embed the issue in policy and to develop an evidence base of cost effective interventions.

Consequently, although …
Urokinase Receptor Modulates Cellular and Angiogenic Responses in Obstructive Nephropathy
Authors: Guoqiang Zhang, Heungsoo Kim, Xiaohe Cai, Jesus M. Lopez-Guisa, Peter Carmeliet, Allison A. Eddy
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Interstitial cells have been implicated in the pathogenesis of renal fibrosis. Given that the urokinase receptor (uPAR) is known to play a role in cell adhesion, migration, and angiogenesis, the present study was designed to evaluate the role of uPAR in the regulation of the phenotypic composition of interstitial cells (macrophages, myofibroblasts, capillaries) in response to chronic renal injury. Groups of uPAR wild-type (+/+) and knockout (−/−) mice were investigated between 3 and 14 d after unilateral ureteral obstruction (UUO) or sham surgery (n = 8 mice per group). The density of F4/80+ interstitial macrophages (Mφ) was significantly lower in the −/− mice (3.3 ± 0.4 versus 6.9 ± 1.7% area at day 3 UUO; 10.8 ± 1.6 versus 15.7 ± 1.0% at day 14 UUO; −/− versus +/+). In contrast, in the −/− mice there were significantly more α smooth muscle actin (αSMA)–positive cells (12.9 ± 3.2 versus 7.8 ± 1.5% area at day 3 UUO; 21.0 ± 4.7 versus 9.7 ± 1.9% at day 14 UUO) and CD34-positive endothelial cells (8.4 ± 1.9 versus 4.0 ± 1.1% area at day 14 UUO). These differences were associated with significantly more interstitial fibrosis in the −/− mice based on Sirius red staining (4.6 ± 0.9 versus 2.3 ± 0.9% area at 14 d UUO). Absence of the uPAR scavenger receptor was associated with significantly greater accumulation of plasminogen activator inhibitor-1 protein (PAI-1) (20.5 ± 3.5 versus 9.1 ± 2.9% area, day 14 UUO) and vitronectin protein (2.4 ± 1.1 versus 0.9 ± 0.4% area, day 14 UUO). By immunostaining αSMA+ cells, CD34+ cells, vitronectin and PAI-1 co-localized to the same tubulointerstitial area. The number of apoptotic cells increased in response to UUO but was significantly higher in the −/− mice (2.0 ± 0.2 versus 1.2 ± 0.2 per 100 tubulointerstitial cells, day 14 UUO) while the number of proliferating cells was significantly lower in the uPAR−/− mice. These data suggest that uPAR deficiency suppresses renal Mφ recruitment, but the absence of this scavenger receptor actually accentuates the fibrogenic response, likely due in part to the delayed clearance of angiogenic/profibrotic molecules such as PAI-1 and decreased receptor-associated uPA activity. E-mail: [email protected]
Pivotal Role of Dermal IL-17-Producing γδ T Cells in Skin Inflammation
Authors: Yihua Cai, Xiaoyan Shen, Chuanlin Ding, Chunjian Qi, Kejia Li, Xia Li, Venkatakrishna R. Jala, Huang-ge Zhang, Tian Wang, Jie Zheng, Jun Yan
Journal: Immunity (2011)
Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/<i>lpr</i>mice
Authors: Jason S Knight, Venkataraman Subramanian, Alexander A O'Dell, Srilakshmi Yalavarthi, Wenpu Zhao, Carolyne K Smith, Jeffrey B Hodgin, Paul R Thompson, Mariana J Kaplan
Journal: Annals of the Rheumatic Diseases (2014)

Objectives An imbalance between neutrophil extracellular trap (NET) formation and degradation has been described in systemic lupus erythematosus (SLE), potentially contributing to autoantigen externalisation, type I interferon synthesis and endothelial damage. We have demonstrated that peptidylarginine deiminase (PAD) inhibition reduces NET formation and protects against lupus-related vascular damage in the New Zealand Mixed model of lupus. However, another strategy for inhibiting NETs—knockout of NOX2 —accelerates lupus in a different murine model, MRL/ lpr . Here, we test the effects of PAD inhibition on MRL/ lpr mice in order to clarify whether some NET inhibitory pathways may be consistently therapeutic across models of SLE. Methods NET formation and autoantibodies to NETs were characterised in lupus-prone MRL/ lpr mice. MRL/ lpr mice were also treated with two different PAD inhibitors, Cl-amidine and the newly described BB-Cl-amidine. NET formation, endothelial function, interferon signature, nephritis and skin disease were examined in treated mice. Results Neutrophils from MRL/ lpr mice demonstrate accelerated NET formation compared with controls. MRL/ lpr mice also form autoantibodies to NETs and have evidence of endothelial dysfunction. PAD inhibition markedly improves endothelial function, while downregulating the expression of type I interferon-regulated genes. PAD inhibition also reduces proteinuria and immune complex deposition in the kidneys, while protecting against skin disease. Conclusions PAD inhibition reduces NET formation, while protecting against lupus-related damage to the vasculature, kidneys and skin in various lupus models. The strategy by which NETs are inhibited will have to be carefully considered if human studies are to be undertaken.
Defective Regulation of Interdomain Interactions Within the Ryanodine Receptor Plays a Key Role in the Pathogenesis of Heart Failure
Authors: Tetsuro Oda, Masafumi Yano, Takeshi Yamamoto, Takahiro Tokuhisa, Shinichi Okuda, Masahiro Doi, Tomoko Ohkusa, Yasuhiro Ikeda, Shigeki Kobayashi, Noriaki Ikemoto, Masunori Matsuzaki
Journal: Circulation (2005)

According to our hypothesis, 2 domains within the ryanodine receptor (RyR) of sarcoplasmic reticulum (SR) (N-terminal [0 to 600] and central [2000 to 2500] domains), where many mutations have been found in patients with polymorphic ventricular tachycardia, interact with each other as a regulatory switch for channel gating. Here, we investigated whether the defective FKBP12.6-mediated stabilization of RyR in heart failure is produced by an abnormal interdomain interaction.SR vesicles were isolated from dog left ventricular muscles, and then the RyR moiety of the SR was fluorescently labeled with methylcoumarin acetate (MCA) using DPc10, a synthetic peptide corresponding to Gly2460-Pro2495 of RyR (one of the mutable domains in polymorphic ventricular tachycardia), as a site-directing carrier; the carrier was removed from the RyR after MCA labeling. Addition of DPc10 induced an unzipped state of the interacting N-terminal and central domains, as evidenced by an increase in the accessibility of the RyR-bound MCA fluorescence to a large fluorescence quencher. Domain unzipping resulted in Ca2+ leak through the RyR and facilitated cAMP-dependent hyperphosphorylation of RyR and FKBP12.6 dissociation from RyR. When DPc10 was introduced into the isolated myocytes, the magnitude of intracellular Ca2+ transient decreased, and its decay time was prolonged. In the SR isolated from pacing-induced dog failing hearts, the domain unzipping has already occurred, together with FKBP12.6 dissociation and Ca2+ leak.The specific domain interaction within the RyR regulates the channel gating property, and the defectiveness in the mode of the interdomain interaction seems to be the initial critical step of the pathogenesis of heart failure.
Ventriculoarterial coupling in normal and failing heart in humans.
Authors: H Asanoi, S Sasayama, T Kameyama
Journal: Circulation Research (1989)

To investigate coupling between the heart and arterial system in normal subjects and cardiac patients, we determined both the slope of the left ventricular end-systolic pressure-volume relation (ventricular elastance) and the slope of the arterial end-systolic pressure-stroke volume relation (effective arterial elastance) in three groups of subjects: group A, 12 subjects with ejection fraction of 60% or more; group B, seven patients with ejection fraction of 40-59%; and group C, nine patients with ejection fraction of less than 40%. We also determined the left ventricular stroke work, end-systolic potential energy, and the ventricular work efficiency defined as stroke work per pressure-volume area (stroke work + potential energy). In group A, ventricular elastance was nearly twice as large as arterial elastance. This is a condition for a maximal mechanical efficiency. In group B, ventricular elastance was almost equal to arterial elastance. This is a condition for maximal stroke work from a given end-diastolic volume. In group C, ventricular elastance was less than one half of arterial elastance, which resulted in increased potential energy and decreased work efficiency. Thus, the present study suggests that ventriculoarterial coupling is normally set toward higher left ventricular work efficiency, whereas in patients with moderate cardiac dysfunction, ventricular and arterial properties are so matched as to maximize stroke work at the expense of the work efficiency. Neither the stroke work nor the work efficiency is near maximum for patients with severe cardiac dysfunction.
Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes
Authors: Ding-Wu Shen, Lynn M. Pouliot, Matthew D. Hall, Michael M. Gottesman
Journal: Pharmacological Reviews (2012)

Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis.