tbuckley/cabot-search huggingface dataset:
Human T cell clones define S1 subunit as the most immunogenic moiety of pertussis toxin and determine its epitope map.
Authors: M T De Magistris, M Romano, A Bartoloni, R Rappuoli, A Tagliabue
Journal: The Journal of Experimental Medicine (1989)

Human T lymphocyte clones specific for pertussis toxin (PT) were used to analyze the fine specificity of the response to PT, the basic component of new acellular vaccines against whooping cough. The majority (83%) of the clones specific for PT recognized S1, the subunit that in animal models has been shown to be highly immunogenic. To map T cell epitopes on S1, 18 S1-specific clones were tested for recognition of recombinant fragments representing NH2-terminal and COOH-terminal deletions of S1 and two recombinant S1 subunits containing amino acid substitutions. This approach led to the identification of three regions of the protein as the sequences containing T cell antigenic sites: 1-42, 181-211, and 212-235. Synthetic peptides were eventually used for a finer localization of the T cell epitopes. Two peptides, one of 13 residues (27-39) at the NH2 terminus and one of 24 residues (171-194) at the COOH terminus, stimulated proliferation of three and four clones, respectively. Both peptides are recognized in association with HLA DR1 molecules. These results stress the role of S1 in the immune response to PT and provide data useful for the development of a recombinant or synthetic antipertussis vaccine containing T cell epitopes from S1.
Activation of Protein Kinase G Is Sufficient to Induce Apoptosis and Inhibit Cell Migration in Colon Cancer Cells
Authors: Atsuko Deguchi, W. Joseph Thompson, I. Bernard Weinstein
Journal: Cancer Research (2004)

Abstract The activation of protein kinase G (PKG) by cGMP has become of considerable interest as a novel molecular mechanism for the induction of apoptosis in cancer cells, because sulindac sulfone (exisulind, Aptosyn) and certain derivatives that inhibit cGMP-phosphodiesterases and thereby increase cellular levels of cGMP appear to induce apoptosis via this mechanism. However, other effects of these compounds have not been excluded, and the precise mechanism by which PKG activation induces apoptosis has not been elucidated in detail. To directly examine the effects of PKG on cell growth and apoptosis, we generated a series of mutants of PKG Iα: PKG IαS65D, a constitutively activated point mutant; PKG IαΔ, a constitutively activated N-terminal truncated mutant; and PKG IαK390R, a dominant-negative point mutant. A similar series of mutants of PKG Iβ were also constructed (Deguchi et al., Mol. Cancer Ther., 1: 803–809, 2002). The present study demonstrates that when transiently expressed in SW480 colon cancer, the constitutively activated mutants of PKG Iβ, and to a lesser extent PKG Iα, inhibit colony formation and induce apoptosis. We were not able to obtain derivatives of SW480 cells that stably expressed these constitutively activated mutants, presumably because of toxicity. However, derivatives that stably overexpressed wild-type PKG Iβ displayed growth inhibition, whereas derivatives that stably expressed the dominant-negative mutant (KR) of PKG Iβ grew more rapidly and were more resistant to Aptosyn-induced growth inhibition than vector control cells. Stable overexpression of PKG Iβ was associated with decreased cellular levels of β-catenin and cyclin D1 and increased levels of p21CIP1. Reporter assays indicated that activation of PKG Iβ inhibits the transcriptional activity of the cyclin D1 promoter. We also found that transient expression of the constitutively activated mutants of PKG Iβ inhibited cell migration. Taken together, these results indicate that activation of PKG Iβ is sufficient to inhibit growth and cell migration and induce apoptosis in human colon cancer cells and that these effects are associated with inhibition of the transcription of cyclin D1 and an increase in the expression of p21CIP1.
Investigation of Microcystin Congener–Dependent Uptake into Primary Murine Neurons
Authors: Daniel Feurstein, Julia Kleinteich, Alexandra H. Heussner, Kerstin Stemmer, Daniel R. Dietrich
Journal: Environmental Health Perspectives (2010)

Contamination of natural waters by toxic cyanobacteria is a growing problem worldwide, resulting in serious water pollution and human health hazards. Microcystins (MCs) represent a group of > 80 cyclic heptapeptides, mediating cytotoxicity via specific protein phosphatase (PP) inhibition at equimolar concentrations (comparable toxicodynamics). Because of the structure and size of MCs, active uptake into cells occurs via organic anion-transporting polypeptides (OATP/Oatp), as confirmed for liver-specific human OATP1B1 and OATP1B3, mouse Oatp1b2 (mOatp1b2), skate Oatp1d1, and the more widely distributed OATP1A2 expressed, for example, at the blood-brain barrier. Tissue-specific and cell-type-specific expression of OATP/Oatp transporters and specific transport of MC congeners (toxicokinetics) therefore appear prerequisite for the reported toxic effects in humans and other species upon MC exposure. Beyond hepatotoxicity induced by the MC-LR congener, the effects of other MC congeners, especially neuronal uptake and toxicity, are unknown.In this study we examined the expression of mOatps and the uptake of congeners MC-LR, MC-LW, and MC-LF in primary murine neurons.Intracellular MC accumulation was indicated indirectly via uptake inhibition experiments and directly confirmed by Western blot analysis and a PP inhibition assay. Neuronal mOatp expression was verified at the mRNA and protein level.MCs can cross neuronal cell membranes, with a subsequent decrease of PP activity. Of 15 mOatps, 12 were expressed at the mRNA level, but we found detectable protein levels for only two: mOatp1a5 (Slco1a5) and the known MC-LR transporter mOatp1b2 (Slco1b2).These data suggest mOatp-mediated uptake of MC congeners into neurons, thus corroborating earlier assumptions of the neurotoxic potential of MCs.
Hepatocyte Nuclear Factor-1β
Authors: MARIA KOLATSI-JOANNOU, CORALIE BINGHAM, SIAN ELLARD, MICHAEL P. BULMAN, LISA I. S. ALLEN, ANDREW T. HATTERSLEY, ADRIAN S. WOOLF
Journal: Journal of the American Society of Nephrology (2001)

The hepatocyte nuclear factor—1β (HNF-1β) transcription factor controls endoderm development. Human mutations cause early-onset diabetes mellitus and have recently been associated with dysplastic, hypoplastic, and glomerulocystic kidneys. A new kindred with this "renal cysts and diabetes" syndrome is described, and nephrogenic HNF-1β expression is defined. The proband had congenital cystic kidneys: over the next 12 yr, his renal function was impaired, but he was normoglycemic. His mother developed diabetes during pregnancy: renal ultrasonography at age 24 yr was normal, but she subsequently developed cysts. Both subjects have a heterozygous frameshift mutation in HNF-1β that results from a 1-bp insertion in exon 5 (Y352fsinsA). When reverse-transcription PCR and in situ hybridization were used, HNF-1β mRNA was detected in normal human metanephroi, with the highest levels of transcripts localized to fetal medullary and cortical collecting ducts and low levels of expression in nephrogenic cortex mesenchyme, primitive nephron tubules, and immature glomeruli. These results constitute the first demonstration of HNF-1β expression during human nephrogenesis and emphasize a disease spectrum associated with HNF-1β mutation.
Effect of Inhibitors of Prostaglandin Synthesis On Induced Diuresis in Cirrhosis
Authors: Daniel Mirouze, Robert D. Zipser, Telfer B. Reynolds
Journal: Hepatology (1983)

The effect of inhibitors of prostaglandin synthesis on diuretic action was examined in patients with ascites due to chronic liver disease and in normal subjects. In patients with ascites, natriuresis after 80 mg i.v. furosemide was reduced 82% by pretreatment with indomethacin. Creatinine clearance was reduced only 16%. These effects were likely due to inhibition of renal prostaglandin synthesis, since urinary prostaglandin E2 fell and there was also reduction in natriuresis with naproxen (52%). The effects were not specific for furosemide since spironolactone–induced natriuresis was also reduced by indomethacin (82%), naproxen (52%), and aspirin (33%). In normal subjects, indomethacin reduced furosemide natriuresis by only 14% while creatinine clearance was not affected. The mechanisms of these, drug interactions are uncertain but probably involve renal hemodynamics which appear to be supported importantly by renal prostaglandins in patients with ascites due to liver disease.
Move to local control has led to poorer care for neurological patients
Authors: A. O'Dowd
Journal: BMJ (2012)

Local control of neurological care has allowed standards to fall in contrast to successful national targets on cancer and stroke, according to MPs.

The parliamentary public accounts committee has criticised poor coordination of care for the estimated two million people in the UK who have a neurological condition and the variation in quality of care around the country.

The committee’s report on services for people with neurological conditions says efforts to improve services in recent years have made some difference, but have not worked as well as similar efforts to improve cancer and stroke care.

In 2005, the government published its National Service Framework for long term conditions, containing 11 quality indicators, designed to improve …
Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids
Authors: Jiaxi Wu, Zhijian J. Chen
Journal: Annual Review of Immunology (2014)

The innate immune system utilizes pattern-recognition receptors (PRRs) to detect the invasion of pathogens and initiate host antimicrobial responses such as the production of type I interferons and proinflammatory cytokines. Nucleic acids, which are essential genetic information carriers for all living organisms including viral, bacterial, and eukaryotic pathogens, are major structures detected by the innate immune system. However, inappropriate detection of self nucleic acids can result in autoimmune diseases. PRRs that recognize nucleic acids in cells include several endosomal members of the Toll-like receptor family and several cytosolic sensors for DNA and RNA. Here, we review the recent advances in understanding the mechanism of nucleic acid sensing and signaling in the cytosol of mammalian cells as well as the emerging role of cytosolic nucleic acids in autoimmunity.
Phosphate Regulation of Vascular Smooth Muscle Cell Calcification
Authors: Shuichi Jono, Marc D. McKee, Charles E. Murry, Atsushi Shioi, Yoshiki Nishizawa, Katsuhito Mori, Hirotoshi Morii, Cecilia M. Giachelli
Journal: Circulation Research (2000)

Abstract —Vascular calcification is a common finding in atherosclerosis and a serious problem in diabetic and uremic patients. Because of the correlation of hyperphosphatemia and vascular calcification, the ability of extracellular inorganic phosphate levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro was examined. HSMCs cultured in media containing normal physiological levels of inorganic phosphate (1.4 mmol/L) did not mineralize. In contrast, HSMCs cultured in media containing phosphate levels comparable to those seen in hyperphosphatemic individuals (&gt;1.4 mmol/L) showed dose-dependent increases in mineral deposition. Mechanistic studies revealed that elevated phosphate treatment of HSMCs also enhanced the expression of the osteoblastic differentiation markers osteocalcin and Cbfa-1. The effects of elevated phosphate on HSMCs were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor phosphonoformic acid, to dose dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. With the use of polymerase chain reaction and Northern blot analyses, the NPC in HSMCs was identified as Pit-1 (Glvr-1), a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMCs to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. The full text of this article is available at http://www.circresaha.org.
Course setting and selected biomechanical variables related to injury risk in alpine ski racing: an explorative case study
Authors: Jörg Spörri, Josef Kröll, Hermann Schwameder, Christian Schiefermüller, Erich Müller
Journal: British Journal of Sports Medicine (2012)

Course setting has often been discussed as a potential preventative measure in the World Cup ski-racing community. However, there is limited understanding of how it is related to injury risk.This study was undertaken to investigate the effect of increased horizontal gate distance on energy-related and injury mechanism-related variables.During a video-based three-dimensional (3D)-kinematic field measurement, a top world-class racer performed giant slalom runs at two course settings with different horizontal gate distances. A full-body segment model was reconstructed in 3D and selected biomechanical parameters were calculated.For the analysed turn, no significant differences were found in turn speed for increased horizontal gate distance. However, a large effect size was observed for speed reduction towards the end of the turn. Turn forces were by tendency higher at the beginning and significantly higher towards the end of the turn. Additionally, significant differences were found in higher inward leaning, and large effect sizes were observed for a decreased fore/aft position after gate passage.On the basis of the data of this study, no final conclusion can be made about whether, for a section of consecutive turns, increasing horizontal gate distance is an effective tool for speed reduction. However, this study pointed out two major drawbacks of this course setting modification: (1) it may increase fatigue as a consequence of loading forces acting over a longer duration; (2) it may increase the risk of out-of-balance situations by forcing the athlete to exhaust his backward and inward leaning spectrum.
Effect of the Endecapeptide Eledoisin on the Coronary Blood Flow: Comparison with Nitroglycerin, Bradykinin and Epinephrine in the Dog
Authors: MARIO BERGAMASCHI, ALFREDO H. GLÄSSER
Journal: Circulation Research (1963)

The effects on coronary blood flow of the endecapeptide Eledoisin have been studied in the anesthetized dog. Eledoisin increases coronary blood flow without increasing myocardial contractility and heart rate. Nitroglycerin and the polypeptide bradykinin increase coronary blood flow in the same way, but are markedly less active than Eledoisin. l -Epinephrine increases coronary blood flow, but at the same time produces a stimulating action on the myocardium.
Novel angiotensin peptides regulate blood pressure, endothelial function, and natriuresis.
Authors: C M Ferrario, M C Chappell, R H Dean, S N Iyer
Journal: Journal of the American Society of Nephrology (1998)

Accumulating evidence suggests that angiotensin-(1-7) is an important component of the renin-angiotensin system, having actions that are either identical to or opposite that of angiotensin II. Angiotensin I can be directly converted to angiotensin-(1-7), bypassing formation of angiotensin II. This pathway is under the control of three enzymes: neutral endopeptidases 24.11 (neprilysin) and 24.15 and prolyl-endopeptidase 24.26. Two of the three angiotensin-forming enzymes (neprilysin and endopeptidase 24.15) also contribute to the breakdown of bradykinin and the atrial natriuretic peptide. Furthermore, angiotensin-(1-7) is a major substrate for angiotensin-converting enzyme. These observations suggest that the process of biotransformation between the various Ang peptides of the renin-angiotensin system and other vasodepressor peptides are intertwined through this enzymatic pathway. Substantial evidence suggests that angiotensin-(1-7) stimulates the synthesis and release of vasodilator prostaglandins, and nitric oxide, while also augmenting the metabolic actions of bradykinin. In addition, angiotensin-(1-7) alters tubular sodium and bicarbonate reabsorption, decreases Na+-K+-ATPase activity, induces diuresis, and exerts a vasodilator effect. These physiologic effects of angiotensin-(1-7) favor a blood pressure-lowering effect. The majority of the data currently available suggest that angiotensin-(1-7) mediates its effects through a novel non-AT1/AT2 receptor subtype.
Increased Vascular Permeability in Organs Mediated by the Systemic Administration of Lymphokine-Activated Killer Cells and Recombinant Interleukin-2 in Mice
Authors: S. E. Ettinghausen, R. K. Puri, S. A. Rosenberg
Journal: JNCI Journal of the National Cancer Institute (1988)

Significant tumor regressions in mice with established carcinomas, sarcomas, and melanomas and in humans with advanced cancers have been observed following immunotherapy with lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (IL-2). However, dose escalations of LAK cells and IL-2 have been prevented by the development of a vascular leak syndrome (VLS). Although IL-2 alone can produce this VLS, we investigated the role of transferred LAK cells, generated by the incubation of syngeneic splenocytes in IL-2, in mediating this phenomenon. We used a murine model to quantitate the vascular leak by measuring the extravasation of iv injected 125I-bovine serum albumin. A permeability index (PI) was calculated by dividing the mean cpm of tissues from treated mice by those from control animals. The systemic transfer of LAK cells and IL-2 produced a significantly greater extravasation of albumin in the lungs, liver, and kidneys than after Hanks' balanced salt solution, IL-2, or LAK cells alone (in the lungs, for example, PI = 4.7, 1.4, and 1.6 after LAK cells and IL-2, LAK cells alone, and IL-2 alone, respectively). To eliminate the contribution to the leak by host lymphocytes, we irradiated mice before cell transfer. As compared to controls, LAK cells and IL-2 resulted in higher extravasation in the lungs, liver, kidneys, and spleen. However, a similar vascular leak was not observed in the lungs, liver, and kidneys after treatment with IL-2 plus fresh or cultured (without IL-2) splenocytes. Moreover, the combination of IL-2 excipient and LAK cells or IL-2 and irradiated LAK cells did not produce a fluid leak. The development of the VLS by LAK cells was directly related to the dose of concurrently administered IL-2 and the number of injected cells. Depletion of Thy 1.2-positive lymphocytes using antibody and complement prior to generating the LAK cells used in adoptive transfer did not abrogate the VLS in any of the organs tested. Similarly, depletion of L3T4 and Lyt-2 positive cells in vivo using monoclonal antibodies prior to harvesting spleens for generation of LAK cells also had no impact on the VLS. In contrast, in vitro treatment of LAK precursor cells with antibody to asialo-GM-1 plus complement completely eliminated the VLS when the depleted cells were cultured in IL-2 and subsequently transferred.(ABSTRACT TRUNCATED AT 400 WORDS)
Epac-Rap Signaling Reduces Oxidative Stress in the Tubular Epithelium
Authors: Geurt Stokman, Yu Qin, Tijmen H. Booij, Sreenivasa Ramaiahgari, Marie Lacombe, M. Emmy M. Dolman, Kim M.A. van Dorenmalen, Gwendoline J.D. Teske, Sandrine Florquin, Frank Schwede, Bob van de Water, Robbert J. Kok, Leo S. Price
Journal: Journal of the American Society of Nephrology (2014)

Activation of Rap1 by exchange protein activated by cAMP (Epac) promotes cell adhesion and actin cytoskeletal polarization. Pharmacologic activation of Epac-Rap signaling by the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP during ischemia-reperfusion (IR) injury reduces renal failure and application of 8-pCPT-2'-O-Me-cAMP promotes renal cell survival during exposure to the nephrotoxicant cisplatin. Here, we found that activation of Epac by 8-pCPT-2'-O-Me-cAMP reduced production of reactive oxygen species during reoxygenation after hypoxia by decreasing mitochondrial superoxide production. Epac activation prevented disruption of tubular morphology during diethyl maleate-induced oxidative stress in an organotypic three-dimensional culture assay. In vivo renal targeting of 8-pCPT-2'-O-Me-cAMP to proximal tubules using a kidney-selective drug carrier approach resulted in prolonged activation of Rap1 compared with nonconjugated 8-pCPT-2'-O-Me-cAMP. Activation of Epac reduced antioxidant signaling during IR injury and prevented tubular epithelial injury, apoptosis, and renal failure. Our data suggest that Epac1 decreases reactive oxygen species production by preventing mitochondrial superoxide formation during IR injury, thus limiting the degree of oxidative stress. These findings indicate a new role for activation of Epac as a therapeutic application in renal injury associated with oxidative stress.
Phase II Trial of Paclitaxel, Carboplatin, and Etoposide in Advanced Poorly Differentiated Neuroendocrine Carcinoma: A Minnie Pearl Cancer Research Network Study
Authors: John D. Hainsworth, David R. Spigel, Sharlene Litchy, F. Anthony Greco
Journal: Journal of Clinical Oncology (2006)

Purpose To evaluate the efficacy of chemotherapy with paclitaxel, carboplatin, and etoposide in advanced adult poorly differentiated neuroendocrine carcinomas. Patients and Methods Patients eligible for this multicenter, phase II trial had metastatic poorly differentiated neuroendocrine carcinoma and had received no previous treatment. Patients with a variety of known primary sites (excepting small-cell lung cancer) and patients with unknown primary site were eligible. Patients received four courses of chemotherapy with paclitaxel, carboplatin, and etoposide, administered at 3-week intervals. After completing four courses of treatment, patients with objective response or stable disease received three courses (24 weeks) of weekly paclitaxel. Results Seventy-eight patients were treated; 62% had unknown primary site. Forty-one patients (53%) had major responses (complete response rate, 15%), and five patients remain disease free from 18 to 66 months after therapy. Response rates were similar regardless of histology (small-cell v poorly differentiated carcinoma) or primary site. The median, 2-year, and 3-year survivals for the entire group were 14.5 months, 33%, and 24%, respectively. Myelosuppression was the major toxicity, as has been reported previously with this regimen. Conclusion This prospective phase II trial provides additional evidence that this family of relatively uncommon carcinomas is initially chemosensitive, with a high overall response rate to combination chemotherapy and a minority of complete responses. The three-drug regimen evaluated in this trial is moderately toxic, and has no obvious efficacy advantages when compared with standard platinum/etoposide regimens. Treatment for advanced poorly differentiated neuroendocrine carcinoma should parallel treatments used for small-cell lung cancer.