tbuckley/cabot-search huggingface dataset:
The Selective Cyclooxygenase-2 Inhibitor Nimesulide Prevents <b> <i>Helicobacter pylori</i> </b>-Associated Gastric Cancer Development in a Mouse Model
Authors: Ki Taek Nam, Ki-Baik Hahm, Sang-Yeon Oh, Marie Yeo, Sang-Uk Han, Byeongwoo Ahn, Young-Bae Kim, Jin Seok Kang, Dong Deuk Jang, Ki-Hwa Yang, Dae-Yong Kim
Journal: Clinical Cancer Research (2004)

Helicobacter pylori infection can lead to gastric cancer, and cyclooxygenase-2 (COX-2) is overexpressed in the stomach during H. pylori infection. Therefore, we investigated whether nonsteroidal anti-inflammatory drugs might protect against this form of cancer. Specifically, we examined the chemopreventive effect of the COX-2 inhibitor nimesulide on H. pylori-associated gastric carcinogenesis in mice.C57BL/6 mice were treated with the carcinogen N-methyl-N-nitrosourea (MNU) and/or H. pylori. To determine the effect of COX-2 inhibition, nimesulide was mixed with feed pellets and administered for the duration of the experiment. All of the mice were sacrificed 50 weeks after the start of the experiment. Histopathology, immunohistochemistry, and Western blotting for COX-2, Bax and Bcl-2 were performed in stomach tissues. In vitro experiments with the human gastric cancer cell line AGS were also performed to identify mechanisms underlying cancer chemoprevention by nimesulide.Gastric tumors developed in 68.8% of mice that were given both MNU and H. pylori, whereas less than 10% developed gastric tumors when given either MNU or H. pylori alone. These findings indicate that H. pylori promotes carcinogen-induced gastric tumorigenesis. In mice treated with both MNU and H. pylori, nimesulide administration substantially reduced H. pylori-associated gastric tumorigenesis, whereas substantial inductions of apoptosis were observed. In vitro studies demonstrated that nimesulide and H. pylori when combined acted synergistically to induce more apoptosis than either alone.Our data show that nimesulide prevents H. pylori-associated gastric carcinogenesis, and suggest that COX-2 may be a target for chemoprevention of gastric cancer.
COMPATIBILITY OF ELECTROANATOMICAL MAPPING SYSTEMS WITH A CONCURRENT PERCUTANEOUS AXIAL FLOW VENTRICULAR ASSIST DEVICE
Authors: Vaibhav Vaidya, Malini Madhavan, Amit Noheria, Christopher DeSimone, Mohammed Shahid, Dorothy Ladewig, Susan Mikell, Scott Suddendorf, Susan Johnson, Tomas Konecny, Juna Misiri, Samuel Asirvatham
Journal: Journal of the American College of Cardiology (2014)
Relationship of Retinal Vascular Caliber With Diabetes and Retinopathy
Authors: Thanh Tan Nguyen, Jie Jin Wang, A. Richey Sharrett, F.M. Amirul Islam, Ronald Klein, Barbara E.K. Klein, Mary Frances Cotch, Tien Yin Wong
Journal: Diabetes Care (2008)

OBJECTIVE—To examine the relationship of retinal vascular caliber with diabetes, glycemia, and diabetic retinopathy. RESEARCH DESIGN AND METHODS—Population-based study using data from the Multi-Ethnic Study of Atherosclerosis (MESA), comprising 5,976 individuals (whites, blacks, Hispanics, and Chinese) residing in six U.S. communities who were free of clinical cardiovascular disease at baseline. Retinal vascular caliber was measured from digital retinal photographs. RESULTS—There were 4,585 individuals with normal fasting glucose (NFG), 499 with impaired fasting glucose (IFG), 165 with diabetes with retinopathy signs, and 727 with diabetes without retinopathy signs. After multivariate analysis, retinal arteriolar caliber increased from 143.8 μm in subjects with NFG to 144.5 μm in IFG and 146.1 μm in diabetes (P &amp;lt; 0.001 for trend). Retinal venular caliber increased from 214.4 μm in NFG to 216.7 μm in IFG and 218.0 μm in diabetes (P &amp;lt; 0.001 for trend). Retinal venular caliber was significantly larger with increasing levels of fasting glucose and A1C. In a subgroup analysis by ethnicity, the association between wider arteriolar caliber and diabetes was evident in whites only, whereas wider venular caliber and diabetes was evident in Hispanics and Chinese only. In people with diabetes, eyes with retinopathy had larger retinal venular but not arteriolar caliber. CONCLUSIONS—Retinal arteriolar and venular calibers are larger in individuals with diabetes, but the pattern of associations appears to vary by ethnicity. Retinal venular caliber is additionally associated with retinopathy signs. These findings add further to the concept that variations in retinal vascular caliber may reflect early diabetic microvascular damage.
Development of ultra short‐acting muscle relaxant agents: History, research strategies, and challenges
Authors: Laszlo Gyermek
Journal: Medicinal Research Reviews (2005)

Abstract Author has reviewed the literature and his own work related to the chemistry, pharmacology, and clinical aspects of new muscle relaxants. Emphasis has been placed on the basic science concepts and technologies (e.g. structure–activity relationships, nicotinic receptor pharmacology, and investigation of side effects) behind the development of rapidly and short acting nondepolarizing muscle relaxants. © 2005 Wiley Periodicals, Inc.
Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression
Authors: Svetlana Usanova, Andrea Piée-Staffa, Ulrike Sied, Jürgen Thomale, Astrid Schneider, Bernd Kaina, Beate Köberle
Journal: Molecular Cancer (2010)

Abstract Background Cisplatin based chemotherapy cures over 80% of metastatic testicular germ cell tumours (TGCT). In contrast, almost all other solid cancers in adults are incurable once they have spread beyond the primary site. Cell lines derived from TGCTs are hypersensitive to cisplatin reflecting the clinical response. Earlier findings suggested that a reduced repair capacity might contribute to the cisplatin hypersensitivity of testis tumour cells (TTC), but the critical DNA damage has not been defined. This study was aimed at investigating the formation and repair of intrastrand and interstrand crosslinks (ICLs) induced by cisplatin in TTC and their contribution to TTC hypersensitivity. Results We observed that repair of intrastrand crosslinks is similar in cisplatin sensitive TTC and resistant bladder cancer cells, whereas repair of ICLs was significantly reduced in TTC. γH2AX formation, which serves as a marker of DNA breaks formed in response to ICLs, persisted in cisplatin-treated TTC and correlated with sustained phosphorylation of Chk2 and enhanced PARP-1 cleavage. Expression of the nucleotide excision repair factor ERCC1-XPF, which is implicated in the processing of ICLs, is reduced in TTC. To analyse the causal role of ERCC1-XPF for ICL repair and cisplatin sensitivity, we over-expressed ERCC1-XPF in TTC by transient transfection. Over-expression increased ICL repair and rendered TTC more resistant to cisplatin, which suggests that ERCC1-XPF is rate-limiting for repair of ICLs resulting in the observed cisplatin hypersensitivity of TTC. Conclusion Our data indicate for the first time that the exceptional sensitivity of TTC and, therefore, very likely the curability of TGCT rests on their limited ICL repair due to low level of expression of ERCC1-XPF.
Requirement of p21-activated Kinase (PAK) for <i>Salmonella typhimurium</i>–induced Nuclear Responses
Authors: Li-Mei Chen, Shubha Bagrodia, Richard A. Cerione, Jorge E. Galán
Journal: The Journal of Experimental Medicine (1999)

Salmonella typhimurium has sustained a long-standing association with its host and therefore has evolved sophisticated strategies to multiply and survive within this environment. Central to Salmonella pathogenesis is the function of a dedicated type III secretion system that delivers bacterial effector proteins into the host cell cytoplasm. These effectors stimulate nuclear responses and actin cytoskeleton reorganization leading to the production of proinflammatory cytokines and bacterial internalization. The stimulation of these responses requires the function of Cdc42, a member of the Rho family of small molecular weight GTPases, and SopE, a bacterial effector protein that stimulates guanine nucleotide exchange on Rho GTPases. However, nothing is known about the role of Cdc42 effector proteins in S. typhimurium–induced responses. We showed here that S. typhimurium infection of cultured epithelial cells results in the activation of p21-activated kinase (PAK), a serine/threonine kinase that is an effector of Cdc42-dependent responses. Transient expression of a kinase-defective PAK blocked both S. typhimurium– and SopE-induced c-Jun NH2-terminal kinase (JNK) activation but did not interfere with bacteria-induced actin cytoskeleton rearrangements. Similarly, expression of SH3-binding mutants of PAK did not block actin-mediated S. typhimurium entry into cultured cells. However, expression of an effector loop mutant of Cdc42Hs (Cdc42HsC40) unable to bind PAK and other CRIB (for Cdc42/Rac interacting binding)-containing target proteins resulted in abrogation of both S. typhimurium–induced nuclear and cytoskeletal responses. These results show that PAK kinase activity is required for bacteria-induced nuclear responses but it is not required for cytoskeletal rearrangements, indicating that S. typhimurium stimulates cellular responses through different Cdc42 downstream effector activities. In addition, these results demonstrate that the effector loop of Cdc42 implicated in the binding of PAK and other CRIB-containing target proteins is required for both responses.
Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (Modified FOLFOX6) as First-line Treatment of Metastatic Colorectal Cancer: The RESPECT Trial
Authors: Josep Tabernero, Rocio Garcia-Carbonero, James Cassidy, Alberto Sobrero, Eric Van Cutsem, Claus-Henning Köhne, Sabine Tejpar, Oleg Gladkov, Irina Davidenko, Ramon Salazar, Liubov Vladimirova, Sergey Cheporov, Olga Burdaeva, Fernando Rivera, Leslie Samuel, Irina Bulavina, Vanessa Potter, Yu-Lin Chang, Nathalie A. Lokker, Peter J. O'Dwyer
Journal: Clinical Cancer Research (2013)

This randomized, double-blind, placebo-controlled, phase IIb study evaluated adding sorafenib to first-line modified FOLFOX6 (mFOLFOX6) for metastatic colorectal cancer (mCRC).Patients were randomized to sorafenib (400 mg b.i.d.) or placebo, combined with mFOLFOX6 (oxaliplatin 85 mg/m(2); levo-leucovorin 200 mg/m(2); fluorouracil 400 mg/m(2) bolus and 2400 mg/m(2) continuous infusion) every 14 days. Primary endpoint was progression-free survival (PFS). Target sample was 120 events in 180 patients for >85% power (two-sided α = 0.20) to detect an HR = 0.65.Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1 months versus 8.7 months for placebo plus mFOLFOX6 (HR = 0.88; 95% CI, 0.64-1.23; P = 0.46). There was no difference between treatment arms for overall survival. Subgroup analyses of PFS and overall survival showed no difference between treatment arms by KRAS or BRAF status (mutant and wild type). The most common grade 3/4 adverse events in the sorafenib and placebo arms were neutropenia (48% vs. 22%), peripheral neuropathy (16% vs. 21%), and grade 3 hand-foot skin reaction (20% vs. 0%). Treatment discontinuation because of adverse events was 9% and 6%, respectively. Generally, dose intensity (duration and cumulative doses) was lower in the sorafenib arm than in the placebo arm.This study did not detect a PFS benefit with the addition of sorafenib to first-line mFOLFOX6 for mCRC. KRAS and BRAF status did not seem to impact treatment outcomes but the subgroups were small. These results do not support further development of sorafenib in combination with mFOLFOX6 in molecularly unselected patients with mCRC.
A Nationwide Study on the Risk of Autoimmune Diseases in Individuals With a Personal or a Family History of Schizophrenia and Related Psychosis
Authors: Michael E. Benros, Marianne G. Pedersen, Helle Rasmussen, William W. Eaton, Merete Nordentoft, Preben B. Mortensen
Journal: American Journal of Psychiatry (2013)

Previous research has found an increased risk of schizophrenia in individuals with autoimmune diseases and smaller but significant associations with a family history of autoimmune diseases. This study investigates, for the first time, the association between schizophrenia and subsequent autoimmune diseases (the reverse temporality) and also considers the effect of infections, a possible risk factor for both schizophrenia and autoimmune diseases.Danish nationwide registers were linked to establish a cohort of 3.83 million people, identifying 39,364 individuals with schizophrenia-like psychosis and 142,328 individuals with autoimmune disease. Data were analyzed using survival analysis and adjusted for calendar year, age, and sex.Individuals with schizophrenia had an elevated risk of subsequent autoimmune diseases, with an incidence rate ratio of 1.53 (95% CI=1.46-1.62). Among persons without hospital contacts for infections, the effect of having schizophrenia was smaller, with an increased incidence rate ratio of 1.32 (95% CI=1.22-1.43) for autoimmune diseases. For individuals with schizophrenia as well as hospital contacts for infections, the combined risk of autoimmune diseases was 2.70 (95% CI=2.51-2.89). A family history of schizophrenia slightly increased the overall risk of developing autoimmune diseases (incidence rate ratio=1.06, 95% CI=1.02-1.09). Autoimmune diseases developed subsequently in 3.6% of people with schizophrenia, and 3.1% of people with autoimmune diseases had a family history of schizophrenia.The increased risk of subsequent autoimmune diseases in individuals with schizophrenia may involve neuropsychiatric manifestations from the undiagnosed autoimmune disease, medical treatment or lifestyle associated with schizophrenia, or common etiological mechanisms, such as infections and shared genetic factors.
Should we screen adults with osteoporotic fractures for coeliac disease?
Authors: A A Fisher
Journal: Gut (2003)

Cyclooxygenase 2 selective inhibitor induced bowel stricture: a case report Several reports have mentioned the role of non-steroidal anti-inflammatory drugs (NSAID) in inducing diaphragm disease and strictures in the small and large bowel. [1]2][3] To our knowledge, there is no such report in patients treated with cyclooxygenase 2 (COX-2) selective inhibitors.We report the case of a 55 year old man with a past history of axial spondylarthropathy, successfully treated with NSAID from 1975 to 2001; from February 2001, he was treated with celecoxib 400 mg per day for three weeks and then 200 mg/day for two years.He had previous abdominal surgery (appendicectomy) in 1965.He presented with a 24 hour history of central abdominal pain with persistent vomiting.Clinical and radiological examination confirmed small bowel obstruction.At laparoscopy, a distal ileal obstruction was identified.Coelioscopic laparotomy was then performed, showing evidence of bowel wall stricture; 10 cm of the distal ileum was spared.Macroscopic and microscopic examination of the resected specimen was consistent with a diagnosis of stricture on submucosal ulceration of the small bowel.This condition is known to be associated with long term use of NSAID.The COX-2 specific inhibitors have been developed in order to improve the gastrointestinal safety of therapy with NSAID.In various clinical trials, COX-2 selective inhibitors have been shown to have similar efficacy to NSAID, with a concomitant association with fewer endoscopic ulcers and serious lower gastrointestinal events. 3 This case suggests that COX-2 selective inhibitors can induce bowel wall ulcerations, followed by submucosa fibrosis, which may cause strictures or diaphragm-like disease.
Detection of cases of inflammatory rheumatic disorders: performance of a telephone questionnaire designed for use by patient interviewers
Authors: F Guillemin
Journal: Annals of the Rheumatic Diseases (2003)

To assess the performance in the detection of cases of rheumatoid arthritis (RA) and the spondyloarthropathies (SpA) of a questionnaire suitable for use in telephone surveys conducted by patient interviewers.A questionnaire was designed with reference to the signs, symptoms, and epidemiological criteria for RA (ACR 1987) and SpA (ESSG 1991). Three groups of respondents were recruited from the rheumatology outpatient clinics of 10 university hospitals: 235 with RA, 175 with SpA, and 195 controls with other rheumatological disorders. All diagnoses were confirmed by a rheumatologist. Patient from self help groups and social organisations were trained by a polling company professional to conduct a standard telephone interview using the new questionnaire.In an RA-control comparison, logistic regression showed that a set of five items, predominantly ACR criteria, were the most informative. Self reported diagnosis performed best (sensitivity 0.99, specificity 0.87). In an SpA-control comparison, a set of three items from the ESSG criteria were the most informative, with self reported diagnosis again performing best (sensitivity 0.85, specificity 0.96). Overall agreements with clinical diagnoses were 97.7% for RA and 94.4% SpA, dropping to 90.4% and 79.1%, respectively, when self reported diagnosis was excluded. Without self reported diagnosis, questions about peripheral joint and spinal pain made significant contributions to diagnostic performance.A questionnaire in plain language was developed for use in detecting cases of RA and SpA. It performed satisfactorily when administered by patient interviewers and is now available for epidemiological surveys of the general population.
Nonalbuminuric Renal Impairment in Type 2 Diabetic Patients and in the General Population (National Evaluation of the Frequency of Renal Impairment cO-existing with NIDDM [NEFRON] 11)
Authors: Merlin C. Thomas, Richard J. MacIsaac, George Jerums, Andrew Weekes, John Moran, Jonathan E. Shaw, Robert C. Atkins
Journal: Diabetes Care (2009)

OBJECTIVE Most diabetic patients with impaired renal function have a urinary albumin excretion rate in the normal range. In these patients, the etiology of renal impairment is unclear, and it is also unclear whether this nonalbumunuric renal impairment is unique to diabetes. RESEARCH DESIGN AND METHODS In this study, we examined the frequency and predictors of nonalbumunuric renal impairment (estimated glomerular filtration rate [eGFR] &amp;lt;60 ml/min per 1.73 m2) in a nationally representative cohort of 3,893 patients with type 2 diabetes and compared our findings with rates observed in the general population from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) survey (n = 11,247). RESULTS Of the 23.1% of individuals with type 2 diabetes who had eGFR &amp;lt;60 ml/min per 1.73 m2 (95% CI 21.8–24.5%), more than half (55%) had a urinary albumin excretion rate that was persistently in the normal range. This rate of renal impairment was predictably higher than that observed in the general population (adjusted odds ratio 1.3, 95% CI 1.1–1.5, P &amp;lt; 0.01) but was solely due to chronic kidney disease associated with albuminuria. In contrast, renal impairment in the absence of albuminuria was less common in those with diabetes than in the general population, independent of sex, ethnicity, and duration of diabetes (0.6, 0.5–0.7, P &amp;lt; 0.001). CONCLUSIONS Nonalbuminuric renal impairment is not more common in those with diabetes. However, its impact may be more significant. New studies are required to address the pathogenesis, prevention, and treatment of nonalbuminuric renal disease.
Mannose-binding lectin is present in the infected airway: a possible pulmonary defence mechanism
Authors: K J Fidler, T N Hilliard, A Bush, M Johnson, D M Geddes, M W Turner, E W F W Alton, N J Klein, J C Davies
Journal: Thorax (2008)

Mannose-binding lectin (MBL) deficiency has been associated with infections of the respiratory tract and with increased disease severity in cystic fibrosis (CF). The mechanism is uncertain, and could relate either to systemic or local effects. The aim of this study was to determine, in a large cohort of children, whether MBL is present on the airway surface in health or disease.Bronchoalveolar lavage (BAL) fluid from children with and without respiratory infection (some with underlying disease) was analysed for MBL and neutrophil elastase (NE). Levels were compared between groups, and correlations were examined with local and systemic inflammatory markers, infective organisms and load.85 children were recruited to the study. MBL was absent in the lavage of all 7 children without lung infection but present in 62% (8/13) of those with acute pneumonia/pneumonitis, 23% (5/22) with recurrent respiratory tract infections, 17% (1/6) with primary ciliary dyskinesia and 8% (3/37) with CF (p<0.01). Children with acute pneumonia/pneumonitis had significantly higher levels than those in the other groups. There was no relationship with organisms cultured or systemic markers of inflammation, although in the group with detectable MBL in the BAL fluid, the levels correlated positively with levels of NE.MBL is undetectable in the non-infected airway but is present in a significant number of samples from children with lung infection. The levels found in the BAL fluid could be physiologically active and the protein may therefore be playing a role in host defence.
Inducible Gene Expression and Gene Modification in Transgenic Mice
Authors: FRE[Combining Acute Accent]DE[Combining Acute Accent]RIC JAISSER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Animal transgenesis has proven to be useful for physiologic as well as pathophysiologic studies. Animal models with conditional expression of a transgene of interest or with a conditional gene mutation can be generated. This permits spatial and temporal control of the expression of the transgene or of gene mutations previously introduced by gene targeting. These approaches allow the generation of models suitable for physiologic analysis or models mimicking disease states.
Molecular Mechanisms for Memory: Second-Messenger Induced Modifications of Protein Kinases in Nerve Cells
Authors: J H Schwartz, S M Greenberg
Journal: Annual Review of Neuroscience (1987)

The protein kinases that are activated by Ca2+ /calmodulin, Ca2+ /phos­ pholipid, and cAMP are now thought to govern many types of slow (or modulatory) synaptic mechanisms and to mediate many forms of short. term synaptic plasticity (Reichardt & Kelly 1983, Nairn et a1 1985, Nish­ izuka 1986). These processes, which do not depend on the synthesis of new proteins and can endure from minutes to a substantial part of an hour, are the neurophysiological correlates of short-term memory (see Kandel & Schwartz 1982, Schwartz et a1 1983, Goelet et aI1986). Unlike the rapid conformational changes in the polypeptides that constitute chemically gated ion channels and that last only fractions of seconds after the stimu­ lating ligand is removed, the slow onset of short-term synaptic mechan­ isms on the one hand and their persistence for periods of time exceeding even the longest allosteric rearrangements of protein molecules on the other (Frieden 1970) reflect the receptor stimulated appearance, accumu­ lation, and relatively slow dissipation of free Ca2+, diacylglycerol, or cAMP within the stimulated nerve cell. As second messengers, these mol-