tbuckley/cabot-search huggingface dataset:
CARD8 p.C10X polymorphism is associated with inflammatory activity in early rheumatoid arthritis
Authors: A. Kastbom, M. Johansson, D. Verma, P. Soderkvist, S. Rantapaa-Dahlqvist
Journal: Annals of the Rheumatic Diseases (2009)

<h3>Objectives</h3> CARD8 and NLRP3 are constituents of the inflammasome which regulates interleukin 1β production. The influence of polymorphisms in <i>CARD8</i> and <i>NLRP3</i> on rheumatoid arthritis (RA) susceptibility and severity were evaluated. <h3>Methods</h3> <i>CARD8</i> p.C10X and <i>NLRP3</i> p.Q705K genotypes were assessed in &gt;500 controls and patients with early RA from northern Sweden. The patients were monitored regularly over a 2–year period. The 28-joint disease activity score (DAS28) and its separate components were compared across genotypes. <h3>Results</h3> Patients with one or more variant alleles in <i>CARD8</i> (CARD8-X) had increased DAS28, tender joint count and erythrocyte sedimentation rate during the 2-year follow-up period despite receiving disease-modifying antirheumatic drugs to a greater extent. CARD8-X was significantly over-represented among patients who received anti-tumour necrosis factor therapy during the first 2 years. <i>CARD8</i> and <i>NLRP3</i> genotypes did not influence radiological joint damage and were not associated with an increased susceptibility. <h3>Conclusions</h3> Carriage of CARD8-X is associated with a worse disease course in early RA.
Epac Regulates UT-A1 to Increase Urea Transport in Inner Medullary Collecting Ducts
Authors: Yanhua Wang, Janet D. Klein, Mitsi A. Blount, Christopher F. Martin, Kimilia J. Kent, Vladimir Pech, Susan M. Wall, Jeff M. Sands
Journal: Journal of the American Society of Nephrology (2009)

Urea plays a critical role in the concentration of urine, thereby regulating water balance. Vasopressin, acting through cAMP, stimulates urea transport across rat terminal inner medullary collecting ducts (IMCD) by increasing the phosphorylation and accumulation at the apical plasma membrane of UT-A1. In addition to acting through protein kinase A (PKA), cAMP also activates Epac (exchange protein activated by cAMP). In this study, we tested whether the regulation of urea transport and UT-A1 transporter activity involve Epac in rat IMCD. Functional analysis showed that an Epac activator significantly increased urea permeability in isolated, perfused rat terminal IMCD. Similarly, stimulating Epac by adding forskolin and an inhibitor of PKA significantly increased urea permeability. Incubation of rat IMCD suspensions with the Epac activator significantly increased UT-A1 phosphorylation and its accumulation in the plasma membrane. Furthermore, forskolin-stimulated cAMP significantly increased ERK 1/2 phosphorylation, which was not prevented by inhibiting PKA, indicating that Epac mediated this phosphorylation of ERK 1/2. Inhibition of MEK 1/2 phosphorylation decreased the forskolin-stimulated UT-A1 phosphorylation. Taken together, activation of Epac increases urea transport, accumulation of UT-A1 at the plasma membrane, and UT-A1 phosphorylation, the latter of which is mediated by the MEK-ERK pathway.
Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies
Authors: Ravi Salgia, Premal Patel, John Bothos, Wei Yu, Steve Eppler, Priti Hegde, Shuang Bai, Surinder Kaur, Ihsan Nijem, Daniel V.T. Catenacci, Amy Peterson, Mark J. Ratain, Blase Polite, Janice M. Mehnert, Rebecca A. Moss
Journal: Clinical Cancer Research (2014)

This first-in-human study evaluated the safety, immunogenicity, pharmacokinetics, and antitumor activity of onartuzumab, a monovalent antibody against the receptor tyrosine kinase MET.This 3+3 dose-escalation study comprised three stages: (i) phase Ia dose escalation of onartuzumab at doses of 1, 4, 10, 20, and 30 mg/kg intravenously every 3 weeks; (ii) phase Ia cohort expansion at the recommended phase II dose (RP2D) of 15 mg/kg; and (iii) phase Ib dose escalation of onartuzumab at 10 and 15 mg/kg in combination with bevacizumab (15 mg/kg intravenously every 3 weeks). Serum samples were collected for evaluation of pharmacokinetics, potential pharmacodynamic markers, and antitherapeutic antibodies.Thirty-four patients with solid tumors were treated in phase Ia and 9 in phase Ib. Onartuzumab was generally well tolerated at all dose levels evaluated; the maximum tolerated dose was not reached. The most frequent drug-related adverse events included fatigue, peripheral edema, nausea, and hypoalbuminemia. In the phase Ib cohort, onartuzumab at the RP2D was combined with bevacizumab and no dose-limiting toxicities were seen. Onartuzumab showed linear pharmacokinetics in the dose range from 4 to 30 mg/kg. The half-life was approximately 8 to 12 days. There were no apparent pharmacokinetic interactions between onartuzumab and bevacizumab, and antitherapeutic antibodies did not seem to affect the safety or pharmacokinetics of onartuzumab. A patient with gastric carcinoma in the 20-mg/kg dose cohort achieved a durable complete response for nearly 2 years.Onartuzumab was generally well tolerated as a single agent and in combination with bevacizumab in patients with solid tumors.
Guanylyl Cyclase C Messenger RNA Is a Biomarker for Recurrent Stage II Colorectal Cancer
Authors: B Cagir, A Gelmann, J Park, T Fava, A Tankelevitch, E W Bittner, E J Weaver, J P Palazzo, D Weinberg, R D Fry, S A Waldman
Journal: Annals of Internal Medicine (1999)

Background: Patients with stage II colorectal cancer and no histologic evidence of lymph node invasion develop recurrent disease, presumably because of undetected micrometastases. Guanylyl cyclase C is expressed by intestinal and colorectal cancer cells but not by extraintestinal tissues or tumors. Objective: To examine the expression of guanylyl cyclase C messenger RNA (mRNA) in lymph nodes of patients with node-negative colorectal cancer who did and did not have recurrent disease. Design: Case-control study. Setting: Tertiary care academic medical center. Patients: Paraffin-embedded lymph nodes were obtained from 21 patients with histologically confirmed node-negative colorectal cancer who had undergone resection. Controls included 11 patients without disease recurrence 6 or more years after resection, and case-patients included 10 patients whose disease recurred up to 3 years after resection. Measurements: Sections of paraffin-embedded lymph nodes were obtained from each patient and were pooled, and their RNA was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR). Results: Guanylyl cyclase C mRNA was expressed in lymph nodes from all patients with recurrent disease but not in those from patients without recurrent disease (P = 0.004). Nested RT-PCR that used primers for carcinoembryonic antigen, a marker for colorectal cancer, identified carcinoembryonic antigen mRNA in lymph nodes from only 1 of 10 patients with recurrent disease and those from 0 of 11 patients without recurrent disease. The odds ratio for death associated with expression of guanylyl cyclase C mRNA in regional lymph nodes was 15.0 (95% CI, 1.1 to 756.7). Conclusions: Expression of guanylyl cyclase C mRNA in lymph nodes is associated with recurrence of colorectal cancer in patients with stage II disease. Analysis of guanylyl cyclase mRNA expression by RT-PCR may be useful for colorectal cancer staging.
Epigenetic Modifications of <i>RASSF1A</i> Gene through Chromatin Remodeling in Prostate Cancer
Authors: Ken Kawamoto, Steven T. Okino, Robert F. Place, Shinji Urakami, Hiroshi Hirata, Nobuyuki Kikuno, Toshifumi Kawakami, Yuichiro Tanaka, Deepa Pookot, Zhong Chen, Shahana Majid, Hideki Enokida, Masayuki Nakagawa, Rajvir Dahiya
Journal: Clinical Cancer Research (2007)

The RAS-association domain family 1, isoform A (RASSF1A) gene is shown to be inactivated in prostate cancers. However, the molecular mechanism of silencing of the RASSFIA gene is not fully understood. The present study was designed to investigate the mechanisms of inactivation of the RASSF1A gene through the analysis of CpG methylation and histone acetylation and H3 methylation associated with the RASSF1A promoter region.Methylation status of the RASSF1A gene was analyzed in 131 samples of prostate cancer, 65 samples of benign prostate hypertrophy (BPH), and human prostate cell lines using methylation-specific PCR. Histone acetylation (acetyl-H3, acetyl-H4) and H3 methylation (dimethyl-H3-K4, dimethyl-H3-K9) status associated with the promoter region in prostate cells were analyzed by chromatin immunoprecipitation (ChIP) assay.Aberrant methylation was detected in 97 (74.0%) prostate cancer samples and 12 (18.5%) BPH samples. The methylation frequency of RASSF1A showed a significant increase with high Gleason sum and high stage. The ChIP assays showed enhancement of histone acetylation and dimethyl-H3-K4 methylation on the unmethylated RASSF1A promoter. TSA alone was unable to alter key components of the histone code. However, after 5-aza-2'-deoxy-cytidine treatment, there was a complete reversal of the histone components in the hypermethylated promoter. Levels of acetyl-H3, acetyl-H4, and dimethyl-H3-K4 became more enriched, whereas H3K9me2 levels were severely depleted.This is the first report suggesting that reduced histone acetylation or H3K4me2 methylation and increased dimethyl-H3-K9 methylation play a critical role in the maintenance of promoter DNA methylation-associated RASSF1A gene silencing in prostate cancer.
Absence of ghrelin protects against early-onset obesity
Authors: K. E. Wortley
Journal: Journal of Clinical Investigation (2005)

The gut peptide ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, has been implicated not only in the regulation of pituitary growth hormone (GH) secretion but in a number of endocrine and nonendocrine functions, including appetitive behavior and carbohydrate substrate utilization. Nevertheless, recent genetic studies have failed to show any significant defects in GH levels, food intake, or body weight in adult ghrelin-deficient (Ghrl-/-) mice. Here we demonstrate that male Ghrl-/- mice are protected from the rapid weight gain induced by early exposure to a high-fat diet 3 weeks after weaning (6 weeks of age). This reduced weight gain was associated with decreased adiposity and increased energy expenditure and locomotor activity as the animals aged. Despite the absence of ghrelin, these Ghrl-/- mice showed a paradoxical preservation of the GH/IGF-1 axis, similar to that reported in lean compared with obese humans. These findings suggest an important role for endogenous ghrelin in the metabolic adaptation to nutrient availability.
CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer
Authors: S. Ripka, A. Neesse, J. Riedel, E. Bug, A. Aigner, R. Poulsom, S. Fulda, J. Neoptolemos, W. Greenhalf, P. Barth, T. M. Gress, P. Michl
Journal: Gut (2010)

<h3>Background and aims</h3> The transcription factor CUX1 is known as a regulator of cell differentiation and cell cycle progression. Previously, CUX1 was identified as a modulator of invasiveness in various cancers. Based on expression profiles suggesting a role for CUX1 in mediating chemoresistance, the aim of this study was to characterise the effect of CUX1 on apoptosis as well as its regulation by signalling pathways modulating drug resistance in pancreatic cancer. <h3>Methods</h3> The effect of CUX1 on TRAIL- (tumour necrosis factor-related apoptosis-inducing ligand) and drug-induced apoptosis was analysed using overexpression and knock-down strategies. Regulation of CUX1 by phosphatidylinositol-3-kinase (PI3K)/Akt signalling was examined at the mRNA and protein level. The effect of CUX1 knock-down by nanoparticle-complexed small interfering RNA (siRNA) in vivo was analysed in a murine xenograft model. Furthermore, <i>CUX1</i> RNA and protein expression was evaluated in human pancreatic cancer and adjacent normal tissues. <h3>Results</h3> Knock-down of CUX1 resulted in significantly enhanced TRAIL- and drug-induced apoptosis, associated with increased PARP (poly ADP-ribose polymerase) cleavage and caspase activity. Vice versa, overexpression of CUX1 inhibited apoptosis. CUX1 expression was induced by activation of Akt/protein kinase B signalling, and decreased by PI3K inhibitors. The antiapoptotic effect of CUX1 was associated with upregulation of BCL2 and downregulation of tumour necrosis factor α. CUX1 was significantly overexpressed in pancreatic cancers, as analysed by in situ hybridisation and immunohistochemistry. In vivo, silencing of CUX1 by intratumourally administered polyethylenimine-complexed siRNA led to reduced tumour growth and increased apoptosis in pancreatic cancer xenografts. <h3>Conclusion</h3> CUX1 was identified as an important mediator of tumour cell survival in pancreatic cancer in vitro and in vivo.
Cardiovascular Endocrinology: Introduction
Authors: John D. Baxter, William F. Young, Paul Webb
Journal: Endocrine Reviews (2003)

s (maximum 200 words) must be sent to: Prof. J. R. PASQUALINI by Monday, February 9th, 2004 (postmark) (Original 4 copies). For further details please contact: General Scientific Secretariat: Prof. J. R. PASQUALINI Steroid Hormone Research Unit Institut de Puericulture
Vinegar Decreases Postprandial Hyperglycemia in Patients With Type 1 Diabetes
Authors: Panayota Mitrou, Athanasios E. Raptis, Vaia Lambadiari, Eleni Boutati, Eleni Petsiou, Filio Spanoudi, Emilia Papakonstantinou, Eirini Maratou, Theofanis Economopoulos, George Dimitriadis, Sotirios A. Raptis
Journal: Diabetes Care (2010)

Although previous studies show that vinegar improves insulin sensitivity in healthy or insulin-resistant subjects (1,2), information on the effect of vinegar in type 1 diabetes is absent. Given the beneficial effects of maintaining tight glycemic control on the development of complications, there is much interest in identifying diet patterns that could possibly reduce hyperglycemia. The aim of this study was to investigate the effect of vinegar in type 1 diabetes.

Ten men with type 1 diabetes (aged 32 ± 3 years, BMI 24 ± 1 kg/m2, diabetes duration 14 ± 3 years, A1C 6.7 ± 0.2%) treated with rapid-acting insulin preprandially and long-acting insulin once daily were studied after an overnight fast.

The study was approved by …
THE RÔLE OF ANHYDREMIA AND THE NATURE OF THE TOXIN IN INTESTINAL OBSTRUCTION
Authors: Thorsten Ingvaldsen, Allen O. Whipple, Louis Bauman, Beverly C. Smith
Journal: The Journal of Experimental Medicine (1924)

1. Data are presented which show that anhydremia does not play a leading rôle in the causation of symptoms in intestinal obstruction. 2. Chemical changes in the blood corresponding with those noted by previous investigators were observed. 3. Additional data regarding the chemistry of the toxin found in the obstructed intestine of dogs were obtained.
Prevalence of Neuropathy and Peripheral Arterial Disease and the Impact of Treatment in People With Screen-Detected Type 2 Diabetes
Authors: Morten Charles, Niels Ejskjaer, Daniel R. Witte, Knut Borch-Johnsen, Torsten Lauritzen, Annelli Sandbaek
Journal: Diabetes Care (2011)

There is limited evidence on how intensive multifactorial treatment (IT) improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. We examined the effects of early detection and IT of type 2 diabetes in primary care on the prevalence of diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) 6 years later in a pragmatic, cluster-randomized parallel group trial.A stepwise screening program in 190 general practices in Denmark was used to identify 1,533 people with type 2 diabetes. General practices were randomized to deliver either IT or routine care (RC) as recommended through national guidelines. Participants were followed for 6 years and measures of DPN and PAD were applied.We found no statistically significant effect of IT on the prevalence of DPN and PAD compared with RC. The prevalence of an ankle brachial index ≤0.9 was 9.1% (95% CI 6.0-12.2) in the RC arm and 7.3% (5.0-9.6) in the IT arm. In participants tested for vibration detection threshold and light touch sensation, the prevalence of a least one abnormal test was 34.8% (26.7-43.0) in the RC arm and 30.1% (24.1-36.1) in the IT arm.In a population with screen-detected type 2 diabetes, we did not find that screening followed by IT led to a statistically significant difference in the prevalence of DPN and PAD 6 years after diagnosis. However, treatment levels were high in both groups.
Differential effect of agonistic anti-CD40 on human mature and immature dendritic cells: the Janus face of anti-CD40
Authors: Marie-Ghislaine de Goër de Herve, Deniz Durali, Tú-Anh Tran, Gwénola Maigné, Federico Simonetta, Philippe Leclerc, Jean-François Delfraissy, Yassine Taoufik
Journal: Blood (2005)
A DWARF MUTATION IN THE RABBIT
Authors: Harry S. N. Greene
Journal: The Journal of Experimental Medicine (1940)

An hereditary type of dwarfism in the rabbit has been described. In contrast to the dwarfs described in other animals, this type is evident at birth and conforms to the classification, nannosomia primordialis, as used in human pathology. In homozygous form the variation is lethal and produces a miniature individual approximately one-third the size of its normal sibs. Heterozygous animals are approximately two-thirds the size of normal sibs at birth and never attain an equal stature. The expression of the variation is modified by genetic factors carried by a line of cretinoid animals and, rarely, dwarfs derived from crosses with this line survive for 1 to 2 months. The striking changes in such survivors are hypertrophy and hyperplasia of the acidophilic cells of the pituitary and atrophy of the gonads. Such changes are not present in ordinary dwarfs and it is concluded that the acidophilic hyperplasia represents the influence of the modifying factors of the cretinoid line and supplies the growth hormone responsible for survival. The gonadotropic hormone is not supplied by the secretory activity of these cells and as a result the gonads atrophy. The evidence at hand indicates that the primary effect of the dwarfing gene is an inhibition of the secretory functions of the pituitary. In homozygous individuals, the inhibition is complete and the variation is expressed as a lethal dwarf. In heterozygous animals, the function of the organ is altered, producing an undersized individual. The modifying factors of the cretinoid line act either to partially remove the inhibition or to alter the constitution of the animal so that life is possible for a short period without the full complement of pituitary hormones.
Varicella Disease After Introduction of Varicella Vaccine in the United States, 1995-2000
Authors: Jane F Seward, Barbara M Watson, Carol L Peterson, Laurene Mascola, Jan W Pelosi, John X Zhang, Teresa J Maupin, Gary S Goldman, Laura J Tabony, Kimberly G Brodovicz, Aisha O Jumaan, Melinda Wharton
Journal: JAMA (2002)

Before licensure of varicella vaccine in 1995, varicella was a universal childhood disease in the United States, causing 4 million cases, 11,000 hospitalizations, and 100 deaths every year.To examine population-based disease surveillance data in 3 communities to document the impact of the varicella vaccination program.Active surveillance for varicella conducted among the populations of Antelope Valley, Calif; Travis County, Tex; and West Philadelphia, Pa; from January 1, 1995, to December 31, 2000. Reporting sites included child care centers, schools, universities, physicians, public health clinics, hospitals, emergency departments, and households.Trends in number and rate of varicella cases and hospitalizations; varicella vaccine coverage.From 1995 through 1998, in each surveillance area, the number of verified varicella cases varied from year to year with marked springtime seasonality. In 1999, the number and rates of varicella cases and hospitalizations declined markedly. From 1995 through 2000, in Antelope Valley, Travis County, and West Philadelphia, varicella cases declined 71%, 84%, and 79%, respectively. Cases declined to the greatest extent among children aged 1 to 4 years, but cases declined in all age groups, including infants and adults. In the combined 3 surveillance areas, hospitalizations due to varicella declined from a range of 2.7 to 4.2 per 100,000 population in 1995 through 1998 to 0.6 and 1.5 per 100,000 population in 1999 and 2000, respectively (P =.15). By 2000, vaccine coverage among children aged 19 to 35 months was 82.1%, 73.6%, and 83.8% in Los Angeles County, Texas, and Philadelphia County, respectively.Varicella disease has declined dramatically in surveillance areas with moderate vaccine coverage. Continued implementation of existing vaccine policies should lead to further reductions of varicella disease in these communities and throughout the United States.
Integration of 3-Dimensional Cardiac Computed Tomography Images With Real-Time Electroanatomic Mapping to Guide Catheter Ablation of Atrial Fibrillation
Authors: Brad J. Mikaelian, Zachary J. Malchano, Petr Neuzil, Jiri Weichet, Shephal K. Doshi, Jeremy N. Ruskin, Vivek Y. Reddy
Journal: Circulation (2005)
Curcumin Suppresses the Paclitaxel-Induced Nuclear Factor-κB Pathway in Breast Cancer Cells and Inhibits Lung Metastasis of Human Breast Cancer in Nude Mice
Authors: Bharat B. Aggarwal, Shishir Shishodia, Yasunari Takada, Sanjeev Banerjee, Robert A. Newman, Carlos E. Bueso-Ramos, Janet E. Price
Journal: Clinical Cancer Research (2005)

Abstract Currently, there is no effective therapy for metastatic breast cancer after surgery, radiation, and chemotherapy have been used against the primary tumor. Because curcumin suppresses nuclear factor-κB (NF-κB) activation and most chemotherapeutic agents activate NF-κB that mediates cell survival, proliferation, invasion, and metastasis, we hypothesized that curcumin would potentiate the effect of chemotherapy in advanced breast cancer and inhibit lung metastasis. We tested this hypothesis using paclitaxel (Taxol)-resistant breast cancer cells and a human breast cancer xenograft model. As examined by electrophoretic mobility gel shift assay, paclitaxel activated NF-κB in breast cancer cells and curcumin inhibited it; this inhibition was mediated through inhibition of IκBα kinase activation and IκBα phosphorylation and degradation. Curcumin also suppressed the paclitaxel-induced expression of antiapoptotic (XIAP, IAP-1, IAP-2, Bcl-2, and Bcl-xL), proliferative (cyclooxygenase 2, c-Myc, and cyclin D1), and metastatic proteins (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1). It also enhanced apoptosis. In a human breast cancer xenograft model, dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-κB, cyclooxygenase 2, and matrix metalloproteinase-9. Overall, our results indicate that curcumin, which is a pharmacologically safe compound, has a therapeutic potential in preventing breast cancer metastasis possibly through suppression of NF-κB and NF-κB–regulated gene products.
Clinical Course in Crohn’s Disease: Results of a Norwegian Population-Based Ten-Year Follow-Up Study
Authors: Inger Camilla Solberg, Morten H. Vatn, Ole Høie, Njaal Stray, Jostein Sauar, Jørgen Jahnsen, Bjørn Moum, Idar Lygren
Journal: Clinical Gastroenterology and Hepatology (2007)