tbuckley/cabot-search huggingface dataset:
Chemopreventive and Therapeutic Efficacy of Orally Active Tyrosine Kinase Inhibitors in a Transgenic Mouse Model of Gallbladder Carcinoma
Authors: Kaoru Kiguchi, Lynnsie Ruffino, Toru Kawamoto, Tetsuo Ajiki, John DiGiovanni
Journal: Clinical Cancer Research (2005)

Abstract Biliary tract cancer (BTC) is the second most common primary hepatobiliary cancer after hepatocellular cancer. At the time of diagnosis, most BTC are at an advanced stage and are unresectable. There is presently no effective curative treatment of the advanced disease nor is there any effective clinical therapy that will prevent the development of BTC. All of these factors render gallbladder cancer nearly incurable with a poor survival rate. The aim of our study was to provide a better understanding of the mechanisms involved in the development of gallbladder carcinoma as the advancement of more effective treatment options would significantly improve prognosis. In the present study, we examined the effect of gefitinib, a selective epidermal growth factor receptor/tyrosine kinase inhibitor (EGFR/TKI), on the development of gallbladder carcinoma in BK5.erbB2 mice. In addition, we examined the effect of another quinazoline derivative, GW2974, which is able to block the activation of both the EGFR and erbB2, in this model. Animals were treated with either 400 ppm gefitinib or 200 ppm GW2974 as a supplement in the diet using either a chemopreventive or therapeutic protocol. The results show that both compounds were potent chemopreventive and therapeutic agents in this mouse model of human BTC. The results also suggest that activation of the EGFR plays an important role in development of BTC in this model and that targeting both the EGFR and erbB2 may be an effective strategy for treatment of this disease.
Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study
Authors: M. J Redondo, M. Rewers, L. Yu, S. Garg, C. C Pilcher, R. B Elliott, G. S Eisenbarth
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objective:</b> To test the hypothesis that non-diabetic dizygotic and monozygotic twin siblings of patients with type 1 diabeteshave a similar high prevalence of islet cell autoantibodies, thus suggesting that islet cell autoimmunity is mainly environmentally determined. <b>Design:</b> Prospective twin study. <b>Setting:</b> Two specialist centres for diabetes in the United States. <b>Participants:</b> Non-diabetic monozygotic twin (n=53), dizygotic twin (n=30), and non-twin (n=149) siblings of patients with type 1 diabetes; 101 controls. <b>Main outcome measures:</b> Analysis of progression to diabetes and expression of anti-islet autoantibodies. <b>Results:</b> Monozygotic twin siblings had a higher risk of progression to diabetes (12/53) than dizygotic twin siblings (0/30; P&lt;0.005). At the last follow up 22 (41.5%) monozygotic twin siblings expressed autoantibodies compared with 6 (20%) dizygotic twin siblings (P&lt;0.05), 16 (10.7%) non-twin siblings (P&lt;0.0001), and 6 (5.9%) controls (P&lt;0.0001). Monozygotic twin siblings expressed multiple (≤2) antibodies more often than dizygotic twin siblings (10/38 <i>v</i> 1/23; P&lt;0.05). By life table analysis the probability of developing positive autoantibodies was higher among the monozygotic twin siblings bearing the diabetes associated HLA DQ8/DQ2 genotype than in those without this genotype (64.2% (95% confidence interval 32.5% to 96%) <i>v</i> 23.5% (7% to 40%) at 10 years of discordance; P&lt;0.05). <b>Conclusion:</b> Monozygotic and dizygotic twins differ in progression to diabetes and expression of islet cell autoantibodies. Dizygotic twin siblings are similar to non-twin siblings. These two observations suggest that genetic factors play an important part in determination of islet cell autoimmunity, thus rejecting the hypothesis. In addition, there is a high penetrance of islet cell autoimmunity in DQ8/DQ2 monozygotic twin siblings.
Age-period-cohort analysis of tuberculosis notifications in Hong Kong from 1961 to 2005
Authors: P Wu, B J Cowling, C M Schooling, I O L Wong, J M Johnston, C-C Leung, C-M Tam, G M Leung
Journal: Thorax (2007)

Despite its wealth, excellent vital indices and robust health care infrastructure, Hong Kong has a relatively high incidence of tuberculosis (TB) (85.4 per 100 000). Hong Kong residents have also experienced a very rapid and recent epidemiological transition; the population largely originated from migration by southern Chinese in the mid 20th century. Given the potentially long latency period of TB infection, an investigation was undertaken to determine the extent to which TB incidence rates reflect the population history and the impact of public health interventions.An age-period-cohort model was used to break down the Hong Kong TB notification rates from 1961 to 2005 into the effects of age, calendar period and birth cohort.Analysis by age showed a consistent pattern across all the cohorts by year of birth, with a peak in the relative risk of TB at 20-24 years of age. Analysis by year of birth showed an increase in the relative risk of TB from 1880 to 1900, stable risk until 1910, then a linear rate of decline from 1910 with an inflection point at 1990 for a steeper rate of decline. Period effects yielded only one inflection during the calendar years 1971-5.Economic development, social change and the World Health Organisation's short-course directly observed therapy (DOTS) strategy have contributed to TB control in Hong Kong. The linear cohort effect until 1990 suggests that a relatively high, but slowly falling, incidence of TB in Hong Kong will continue into the next few decades.
Multiple functions of gingival and mucoperiosteal fibroblasts in oral wound healing and repair
Authors: Matthias Chiquet, Christos Katsaros, Dimitris Kletsas
Journal: Periodontology 2000 (2015)

Abstract Fibroblasts are cells of mesenchymal origin. They are responsible for the production of most extracellular matrix in connective tissues and are essential for wound healing and repair. In recent years, it has become clear that fibroblasts from different tissues have various distinct traits. Moreover, wounds in the oral cavity heal under very special environmental conditions compared with skin wounds. Here, we reviewed the current literature on the various interconnected functions of gingival and mucoperiosteal fibroblasts during the repair of oral wounds. The MEDLINE database was searched with the following terms: (gingival OR mucoperiosteal) AND fibroblast AND (wound healing OR repair). The data gathered were used to compare oral fibroblasts with fibroblasts from other tissues in terms of their regulation and function during wound healing. Specifically, we sought answers to the following questions: (i) what is the role of oral fibroblasts in the inflammatory response in acute wounds; (ii) how do growth factors control the function of oral fibroblasts during wound healing; (iii) how do oral fibroblasts produce, remodel and interact with extracellular matrix in healing wounds; (iv) how do oral fibroblasts respond to mechanical stress; and (v) how does aging affect the fetal‐like responses and functions of oral fibroblasts? The current state of research indicates that oral fibroblasts possess unique characteristics and tightly controlled specific functions in wound healing and repair. This information is essential for developing new strategies to control the intraoral wound‐healing processes of the individual patient.
Genetic basis of transcriptome differences between the founder strains of the rat HXB/BXH recombinant inbred panel
Authors: Marieke Simonis, Santosh S Atanur, Sam Linsen, Victor Guryev, Frans-Paul Ruzius, Laurence Game, Nico Lansu, Ewart de Bruijn, Sebastiaan van Heesch, Steven JM Jones, Michal Pravenec, Tim J Aitman, Edwin Cuppen
Journal: Genome biology (2012)

Abstract Background With the advent of next generation sequencing it has become possible to detect genomic variation on a large scale. However, predicting which genomic variants are damaging to gene function remains a challenge, as knowledge of the effects of genomic variation on gene expression is still limited. Recombinant inbred panels are powerful tools to study the cis and trans effects of genetic variation on molecular phenotypes such as gene expression. Results We generated a comprehensive inventory of genomic differences between the two founder strains of the rat HXB/BXH recombinant inbred panel: SHR/OlaIpcv and BN- Lx /Cub. We identified 3.2 million single nucleotide variants, 425,924 small insertions and deletions, 907 copy number changes and 1,094 large structural genetic variants. RNA-sequencing analyses on liver tissue of the two strains identified 532 differentially expressed genes and 40 alterations in transcript structure. We identified both coding and non-coding variants that correlate with differential expression and alternative splicing. Furthermore, structural variants, in particular gene duplications, show a strong correlation with transcriptome alterations. Conclusions We show that the panel is a good model for assessing the genetic basis of phenotypic heterogeneity and for providing insights into possible underlying molecular mechanisms. Our results reveal a high diversity and complexity underlying quantitative and qualitative transcriptional differences.
Risk of Current Asthma among Adult Smokers with Respiratory Syncytial Virus Illnesses in Early Life
Authors: Nipasiri Voraphani, Debra A. Stern, Anne L. Wright, Stefano Guerra, Wayne J. Morgan, Fernando D. Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Rationale: Risk of subsequent asthma-like symptoms after early-life lower respiratory illness (LRI) caused by respiratory syncytial virus (RSV) is increased during the first decade of childhood and diminished thereafter by adolescence.Objectives: To determine the relation of early-life RSV-LRI on adult asthma-like symptoms and its interactive role with adult smoking.Methods: A total of 1,246 nonselected infants were enrolled at birth and prospectively followed. Virologically confirmed RSV-LRIs were assessed during the first 3 years of life. At age 22, 24, 26, and 29 years, current asthma and smoking behavior were evaluated by questionnaire. Peak flow variability was assessed at age 26 and expressed as amplitude % mean. A longitudinal analysis was used to investigate the relation of RSV-LRI and active smoking to adult outcomes.Measurements and Main Results: Neither RSV-LRI nor active smoking were directly associated with increased current adult asthma or peak flow variability. However, there was a significant interaction between RSV-LRI and active smoking in relation to current asthma (P for interaction = 0.004) and peak flow variability (P for interaction = 0.04). Among subjects with early RSV-LRI, those who actively smoked were 1.7 times more likely to have current asthma (95% confidence interval, 1.2–2.3; P = 0.003) and had greater amplitude % mean (10.0% vs. 6.4%; P = 0.02) than nonsmokers. Among subjects without early RSV-LRI, there was no difference in asthma risk or peak flow variability between active smokers and nonsmokers.Conclusions: Smoking is associated with increased risk of having asthma in young adults who had RSV-LRI in early life but not among subjects without these illnesses.
Diabetic LDL inhibits cell-cycle progression via STAT5B and p21waf
Authors: Maria Felice Brizzi, Patrizia Dentelli, Marzia Pavan, Arturo Rosso, Roberto Gambino, Maria Grazia De Cesaris, Giovanni Garbarino, Giovanni Camussi, Gianfranco Pagano, Luigi Pegoraro
Journal: Journal of Clinical Investigation (2002)

Modified LDL is a major cause of injury to the endothelium in diabetes. In the present study, we analyzed the effects on endothelial cells of LDL recovered from type 2 diabetic patients (dm-LDL) or from nondiabetic subjects (n-LDL). Treatment of human umbilical vein endothelial cells with dm-LDL, but not n-LDL, led to the accumulation of cells in G1. To dissect the molecular mechanisms of this effect, we analyzed the expression and function of the cyclin-dependent kinase inhibitor p21waf, a cell cycle regulator known to be a target of the signal transducers and activators of transcription (STATs). dm-LDL led to transient STAT5 phosphorylation and the formation of a STAT5-containing complex and activated p21waf expression at the transcriptional level. Expression of the dominant-negative form of STAT5B, but not of STAT5A, significantly decreased both p21waf expression and the fraction of cells in G1. Finally, immunofluorescence analysis demonstrated that activated STAT5 is expressed in newly formed intraplaque vessels and in endothelial cells lining the luminal side of the plaque. Similarly, p21waf immunoreactivity was found in the neointimal vasculature. Our results suggest a role of STAT5B as a regulator of gene expression in diabetes-associated vascular disease.
RECURRING DISLOCATION OF THE SHOULDER-JOINT
Authors: T. L. Sandes
Journal: BMJ (1921)

r MTOALTOUUWI 321XBotlh of tllese cases are liable to frequent attacks of 2aetit mal, but they assure me that these attacks are not more frequent than they were under the bromide treat- ment.Botli patients say that they feel infinitely better and -brighter than when takina bromides.Cases 3, 4, 5 and 6 were, after some months' treatment with luminal, placed on bromide treatment for a fortnight.In all four cases the number of fits increased witllin two days, and I lhad to yield to their solicitations to discontinue the experiment.Cases 8 and 9 are two children, both mentally def&ttive.Case 8 slhowed no improvement when treated with luminal, whilst Case 9 became decidedly worse.Some weeks after the luminal treatment was abandoned, and this clhild again put on bromides, she began to improve, and during the past three montlhs has not hiad more than one fit a montb.CLASS B.-Cases wvith mnore than Four Flits a Month.The results of treatment of cases in this class are recorded in the following table.Of the 51 cases, 4 were no better witlh luminal than with bromides, as evidenced by the number of fits, and 5 cases had an increased number of fits.Table showing Averaqge rincidentce of Fits during Precedinig Nine Mlolnths 'under Brom11ide Treatmenit, anld during the last T'hree Month,s of a Yeat of Luvninal 'treatnteiit.No. of Bromide Treatment.Lumiinal Cases.ITreatment.
Development of vascular pole-associated glomerulosclerosis in the Fawn-hooded rat.
Authors: W Kriz, H Hosser, B Hähnel, J L Simons, A P Provoost
Journal: Journal of the American Society of Nephrology (1998)

Fawn-hooded hypertensive (FHH) rats constitute a spontaneous model of chronic renal failure with early systemic and glomerular hypertension, proteinuria, and development of focal and segmental glomerulosclerosis. The goal of the present study was to elucidate a step-by-step sequence of histopathologic events leading from an initial glomerular injury to segmental sclerosis. Segmental sclerosis in the FHH rat is consistently associated with the glomerular vascular pole. The initial injury involves the expansion of primary branches of the afferent arteriole. Apposition of those capillaries to Bowman's capsule, together with the degeneration and detachment of corresponding podocytes, allows parietal cells to attach to the naked glomerular basement membrane of this capillary, i.e., allows the formation of a tuft adhesion to Bowman's capsule. The adhesion enlarges to a broad synechia by encroaching to neighboring capillaries, apparently based on progressive podocyte degeneration at the flanks of the adhesion. Capillaries inside the adhesion--before undergoing collapse or hyalinization--appear to stay perfused for some time and to maintain some kind of filtration misdirected toward the cortical interstitium. Thereby, a prominent paraglomerular space comes into existence, enlarging in parallel with the adhesion. Toward the cortical interstitium this space is delimited by a layer of sheetlike fibroblast processes, which has obviously been assembled in response to the formation of this space. Toward the urinary space, the paraglomerular space is demarcated by the parietal epithelium and by the interface between the adhesion and the "intact" tuft remnant. Thus, the sclerotic tuft portions all become enclosed within the paraglomerular space.
Direct Effects of Smooth Muscle Relaxation and Contraction on In Vivo Human Brachial Artery Elastic Properties
Authors: Alan J. Bank, Robert F. Wilson, Spencer H. Kubo, James E. Holte, Thomas J. Dresing, Hongyu Wang
Journal: Circulation Research (1995)

Abstract The direct effect of smooth muscle relaxation on arterial elastic properties is controversial. Studies in animals show both a decrease and an increase in elastic modulus. In human subjects, the contribution of smooth muscle to arterial elastic mechanics has been limited by difficulty in separating the direct effects of a vasodilator drug on the arterial wall from the indirect effects due to reduced blood pressure. The purpose of the present study was to assess the direct contribution of vascular smooth muscle to brachial artery elastic mechanics in normal human subjects in vivo. We measured brachial artery compliance and incremental elastic modulus (E inc ) in eight normal subjects (age, 22 to 51 years) by using intravascular ultrasound. A 3.5F 30-MHz intravascular ultrasound catheter was placed through a sheath into the brachial artery, and intra-arterial pressure, cross-sectional area, and wall thickness were measured simultaneously under baseline conditions and after the administration of intra-arterial nitroglycerin (100 μg) and norepinephrine (1.2 μg). A pressurized cuff surrounding the brachial artery was inflated to reduce transmural brachial artery pressure. Using this technique, we were able to measure the following arterial characteristics for the first time in human subjects in vivo: (1) the effective unstressed arterial radius and (2) the pressure-area, stress-strain, and pressure-E inc relations over a wide pressure range (0 to 100 mm Hg). Intra-arterial nitroglycerin increased brachial artery area by 22% and intra-arterial norepinephrine decreased brachial artery area by 17% at 100 mm Hg transmural pressure ( P &lt;.001 versus baseline). Nitroglycerin produced a significant ( P &lt;.01) nonparallel upward shift of the compliance pressure curve compared with baseline, and norepinephrine produced a smaller downward shift of the compliance-pressure curve. Pulse-wave velocity was decreased from 15.1±1.1 m/s at baseline to 13.2±0.7 m/s at 100 mm Hg after the administration of nitroglycerin ( P &lt;.05). Nitroglycerin and norepinephrine also significantly shifted the brachial artery stress-strain and E inc -strain curves in opposite directions. However, nitroglycerin did not significantly change E inc under isobaric conditions. This study describes and validates a new technique for determining brachial artery elastic properties in vivo over a wide pressure range. At constant pressure, nitroglycerin-induced smooth muscle relaxation increased brachial artery compliance and decreased pulse-wave velocity without significantly altering E inc .
Protection from Obesity and Diabetes by Blockade of TGF-β/Smad3 Signaling
Authors: Hariom Yadav, Celia Quijano, Anil K. Kamaraju, Oksana Gavrilova, Rana Malek, Weiping Chen, Patricia Zerfas, Duan Zhigang, Elizabeth C. Wright, Christina Stuelten, Peter Sun, Scott Lonning, Monica Skarulis, Anne E. Sumner, Toren Finkel, Sushil G. Rane
Journal: Cell Metabolism (2011)
Pattern of Serum Autoantibodies Allows Accurate Distinction between a Tumor and Pathologies of the Same Organ
Authors: Nicole Ludwig, Andreas Keller, Nicole Comtesse, Stefanie Rheinheimer, Christian Pallasch, Ulrike Fischer, Klaus Fassbender, Wolf Ingo Steudel, Hans-Peter Lenhof, Eckart Meese
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Recent studies impressively showed the diagnostic potential of seroreactivity patterns for different tumor types, offering the prospect for low-cost screening of numerous tumor types simultaneously. One of the major challenges toward this goal is to prove that seroreactivity profiles do not only allow for identifying a tumor but also allow for distinguishing tumors from other pathologies of the same organ. Experimental Design: We chose glioma as a model system and tested 325 sera (88 glioma, 95 intracranial tumors, 60 other brain pathologies, and 82 healthy controls) for seroreactivity on a panel of 35 antigens. Results: We were able to discriminate between glioma and all other sera with cross-validated specificity of 86.1%, sensitivity of 85.2%, and accuracy of 85.8%. We obtained comparably good results for the separation of glioma versus nontumor brain pathologies and glioma versus other intracranial tumors. Conclusion: Our study provides first evidence that seroreactivity patterns allow for an accurate discrimination between a tumor and pathologies of the same organ even between different tumor types of the same organ.
Downregulation of Protein Kinase C Inhibits Activation of Mitochondrial K <sub>ATP</sub> Channels by Diazoxide
Authors: Yigang Wang, En Takashi, Meifeng Xu, Ahmar Ayub, Muhammad Ashraf
Journal: Circulation (2001)

Background —The mitochondrial K ATP (mitoK ATP ) channel has been shown to confer short- and long-term cardioprotection against prolonged ischemia via protein kinase C (PKC) signaling pathways. However, the exact association between PKC or its isoforms and mitoK ATP channels has not yet been clarified. The present study tested the hypothesis that the activity and translocation of PKC to the mitochondria are important for cardiac protection elicited by mitoK ATP channels. Methods and Results —PKC was downregulated by prolonged (24-hour) treatment with phorbol 12-myristate 13-acetate (4 μg/kg body weight) before subsequent experiments in rats. Langendorff-perfused rat hearts were subjected to 40 minutes of ischemia followed by 30 minutes of reperfusion. Effects of PKC downregulation on the activation of mitoK ATP channels and other interventions on hemodynamic, biochemical, and pathological changes were assessed. Subcellular localization of PKC isoforms by Western blot analysis and immunocytochemistry demonstrated that PKC-α and PKC-δ were translocated to the sarcolemma and that PKC-δ was translocated to the mitochondria after diazoxide treatment. In hearts treated with diazoxide (80 μmol/L), a significant improvement in cardiac function and an attenuation of cell injury were observed. In PKC-downregulated hearts, protection was abolished because mitoK ATP channels could not be activated by diazoxide. Conclusions —These data suggest that PKC activation is required for the opening of mitoK ATP channels during protection against ischemia and that this effect is linked to isoform-specific translocation of PKC-δ to the mitochondria.