tbuckley/cabot-search huggingface dataset:
Impaired Preneoplastic Changes and Liver Tumor Formation in Tumor Necrosis Factor Receptor Type 1 Knockout Mice
Authors: Belinda Knight, George C.T. Yeoh, Kirsten L. Husk, Tina Ly, Lawrence J. Abraham, Changpu Yu, Jonathan A. Rhim, Nelson Fausto
Journal: The Journal of Experimental Medicine (2000)

Hepatic stem cells (oval cells) proliferate within the liver after exposure to a variety of hepatic carcinogens and can generate both hepatocytes and bile duct cells. Oval cell proliferation is commonly seen in the preneoplastic stages of liver carcinogenesis, often accompanied by an inflammatory response. Tumor necrosis factor (TNF), an inflammatory cytokine, is also important in liver regeneration and hepatocellular growth. The experiments reported here explore the relationship among the TNF inflammatory pathway, liver stem cell activation, and tumorigenesis. We demonstrate that TNF is upregulated during oval cell proliferation induced by a choline-deficient, ethionine-supplemented diet and that it is expressed by oval cells. In TNF receptor type 1 knockout mice, oval cell proliferation is substantially impaired and tumorigenesis is reduced. Oval cell proliferation is impaired to a lesser extent in interleukin 6 knockout mice and is unchanged in TNF receptor type 2 knockout mice. These findings demonstrate that TNF signaling participates in the proliferation of oval cells during the preneoplastic phase of liver carcinogenesis and that loss of signaling through the TNF receptor type 1 reduces the incidence of tumor formation. The TNF inflammatory pathway may be a target for therapeutic intervention during the early stages of liver carcinogenesis.
Significant male predisposition in extramammary Paget disease: a nationwide population-based study in Taiwan
Authors: P.S. Cheng, C.L. Lu, C.L. Cheng, F.J. Lai
Journal: British Journal of Dermatology (2014)

P.C. and C.L. contributed equally to this work. Funding sources: this study was supported by the National Science Council of Taiwan (NSC 99‐2314‐B‐384‐002‐MY3, NSC 102‐2320‐B‐384‐003) and Chi Mei Medical Center (CMFHR9952, CMFHR10227). Conflicts of interest: none declared. Dear Editor, Extramammary Paget disease (EMPD) was first described by Crocker in 1889.1 It is a rare intraepithelial malignancy that affects mainly the apocrine‐gland‐bearing skin including the vulva, perianal region, perineum and scrotum. Increasing frequency of the disease appears in patients aged 50–80 years. It occurs most frequently in the white population, and has been reported to have a female predominance (male‐to‐female ratios between 1 : 2 and 1 : 7).2 3 4 5 6 However, a male predominance had been reported by single‐ or multicentre studies in Japan, Korea and China (male‐to‐female ratios between 2 : 1 and 4 : 1).7 8 9 10 Although the prevalence of EMPD in different sexes seems to be reversed between Asian and Western populations, there is a lack of large series of studies to support the male preponderance and incidence trends of EMPD in Taiwan.
mini-PAT (Peer Assessment Tool): a well kept secret?
Authors: Julian Archer
Journal: Journal of the Royal Society of Medicine (2008)

I read with interest the article by Dr Abdulla about the use of mini-PAT (JRSM 2008;101:22–26).1 The author raises a number of important points about the utility of multi-source feedback (MSF) but fails to recognize that mini-PAT has been published.2,3 The paper reports an evaluation including 553 trainees and answers many of the questions raised.

Assessor selection does indeed seem important as a source of bias that can undermine validity,3,4 with less-senior doctors and nurses scoring colleagues more leniently. This informs the online selection process from Healthcare Assessment and Training (HcAT), which is now limited by occupational group. Local training must continue and be targeted correctly, with 60% of assessments currently being assessed by senior trainees, not consultants.

Linking good assessment practices to better patient outcomes will never be a clear outcome measure as the naturalistic world of medical practice is too confounded for such study designs. However, the author quite rightly points out the lack of patient involvement in Foundation assessment, a PMETB assessment principle which does need addressing.

The work on MSF in medicine is in its infancy. Much is yet to be understood and sadly the work is under threat. There appears to be a move towards assessment as simply an ‘add on’ to online portfolios. Without large, regulated databases, further research to assure validity and reliability will simply support the ‘no evidence’ view held by critics of recent postgraduate initiatives.5

I welcome the opportunity to debate all these issues as I remain concerned about widespread, unsupported implementation of MSF. MSF can be – when well-supported, well-implemented and quality assured – an important educational instrument, but our profession will be quick to dismiss it if it is poorly supported and lacks evidence.
Association between preterm birth and intrauterine growth retardation and child asthma
Authors: Bengt Källén, Orvar Finnström, Karl-Gösta Nygren, Petra Otterblad Olausson
Journal: European Respiratory Journal (2012)

An association between preterm birth and an increased risk of childhood asthma has been demonstrated, but the importance of intrauterine growth retardation on asthma risk is unclear. Using data from Swedish health registers, infant characteristics and childhood asthma were studied. Analyses were made using Mantel-Haenszel methodology with adjustment for year of birth, maternal age, parity, smoking in early pregnancy and maternal body mass index. Preterm birth, birth weight and birth weight for gestational week were analysed and childhood asthma was evaluated from prescriptions of anti-asthmatic drugs. Neonatal respiratory problems and treatment for them were studied as mediating factors. Both short gestational duration and intrauterine growth retardation appeared to be risk factors and seemed to act separately. The largest effect was seen from short gestational duration. Use of mechanical ventilation in the newborn period and bronchopulmonary dysplasia were strong risk factors. A moderately increased risk was also seen in infants born large for gestational age. We conclude that preterm birth is a stronger risk factor for childhood asthma than intrauterine growth disturbances; however, the latter also affects the risk, and is also seen in infants born at term.
Effect of Pneumococcal Conjugate Vaccine on Pneumococcal Meningitis
Authors: Heather E. Hsu, Kathleen A. Shutt, Matthew R. Moore, Bernard W. Beall, Nancy M. Bennett, Allen S. Craig, Monica M. Farley, James H. Jorgensen, Catherine A. Lexau, Susan Petit, Arthur Reingold, William Schaffner, Ann Thomas, Cynthia G. Whitney, Lee H. Harrison
Journal: New England Journal of Medicine (2009)

Invasive pneumococcal disease declined among children and adults after the introduction of the pediatric heptavalent pneumococcal conjugate vaccine (PCV7) in 2000, but its effect on pneumococcal meningitis is unclear.We examined trends in pneumococcal meningitis from 1998 through 2005 using active, population-based surveillance data from eight sites in the United States. Isolates were grouped into PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), PCV7-related serotypes (6A, 9A, 9L, 9N, 18A, 18B, 18F, 19B, 19C, 23A, and 23B), and non-PCV7 serotypes (all others). Changes in the incidence of pneumococcal meningitis were assessed against baseline values from 1998-1999.We identified 1379 cases of pneumococcal meningitis. The incidence declined from 1.13 cases to 0.79 case per 100,000 persons between 1998-1999 and 2004-2005 (a 30.1% decline, P<0.001). Among persons younger than 2 years of age and those 65 years of age or older, the incidence decreased during the study period by 64.0% and 54.0%, respectively (P<0.001 for both groups). Rates of PCV7-serotype meningitis declined from 0.66 case to 0.18 case (a 73.3% decline, P<0.001) among patients of all ages. Although rates of PCV7-related-serotype disease decreased by 32.1% (P=0.08), rates of non-PCV7-serotype disease increased from 0.32 to 0.51 (an increase of 60.5%, P<0.001). The percentages of cases from non-PCV7 serotypes 19A, 22F, and 35B each increased significantly during the study period. On average, 27.8% of isolates were nonsusceptible to penicillin, but fewer isolates were nonsusceptible to chloramphenicol (5.7%), meropenem (16.6%), and cefotaxime (11.8%). The proportion of penicillin-nonsusceptible isolates decreased between 1998 and 2003 (from 32.0% to 19.4%, P=0.01) but increased between 2003 and 2005 (from 19.4% to 30.1%, P=0.03).Rates of pneumococcal meningitis have decreased among children and adults since PCV7 was introduced. Although the overall effect of the vaccine remains substantial, a recent increase in meningitis caused by non-PCV7 serotypes, including strains nonsusceptible to antibiotics, is a concern.
Efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA)
Authors: Gerd R Burmester, Andrea Rubbert-Roth, Alain Cantagrel, Stephen Hall, Piotr Leszczynski, Daniel Feldman, Madura J Rangaraj, Georgia Roane, Charles Ludivico, Min Bao, Lucy Rowell, Claire Davies, Eduardo F Mysler
Journal: Annals of the Rheumatic Diseases (2015)

To evaluate the long-term efficacy and safety of subcutaneous (SC) tocilizumab (TCZ) versus intravenous (IV) TCZ, including switching formulations, in patients with rheumatoid arthritis (RA) and inadequate response to disease-modifying antirheumatic drugs (DMARDs).Patients (n=1262) were randomised 1:1 to receive TCZ-SC 162 mg weekly (qw)+placebo-IV every four weeks (q4w) or TCZ-IV 8 mg/kg q4w+placebo-SC qw in combination with DMARD(s). After a 24-week double-blind period, patients receiving TCZ-SC were re-randomised 11:1 to TCZ-SC (n=521) or TCZ-IV (TCZ-SC-IV, n=48), and patients receiving TCZ-IV were re-randomised 2:1 to TCZ-IV (n=372) or TCZ-SC (TCZ-IV-SC; n=186). Maintenance of clinical responses and safety through week 97 were assessed.The proportions of patients who achieved American College of Rheumatology (ACR)20/50/70 responses, Disease Activity Score in 28 joints remission and improvement from baseline in Health Assessment Questionnaire Disability Index ≥0.3 were sustained through week 97 and comparable across arms. TCZ-SC had a comparable safety profile to TCZ-IV through week 97, except that injection site reactions (ISRs) were more common with TCZ-SC. Safety profiles in patients who switched were similar to those in patients who received continuous TCZ-SC or TCZ-IV treatment. The proportion of patients who developed anti-TCZ antibodies remained low across treatment arms. No association between anti-TCZ antibody development and clinical response or adverse events was observed.The long-term efficacy and safety of TCZ-SC was maintained and comparable to that of TCZ-IV, except for ISRs. Profiles in patients who switched formulations were comparable to those in patients who received TCZ-IV or TCZ-SC. TCZ-SC provides additional treatment options for patients with RA.NCT01194414.
International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma
Authors: M Dimopoulos, E Terpos, R L Comenzo, P Tosi, M Beksac, O Sezer, D Siegel, H Lokhorst, S Kumar, S V Rajkumar, R Niesvizky, L A Moulopoulos, B G M Durie
Journal: Leukemia (2009)
Enhanced contractility and myosin phosphorylation induced by Ca2+-independent MLCK activity in hypertensive rats
Authors: Y.-E. Cho, D.-S. Ahn, K. G. Morgan, Y.-H. Lee
Journal: Cardiovascular Research (2011)

The role of Ca2+ sensitization induced by a Ca2+-independent myosin light chain kinase (MLCK) in hypertension has not been determined. The aim of this study was to clarify the role of possible Ca2+-independent MLCK activity in hypertension. We compared increases in contractile force and phosphorylation of myosin light chain (MLC) evoked by calyculin A, a phosphatase inhibitor, in β-escin-permeabilized mesenteric arteries at pCa 9.0 between spontaneously hypertensive rat (SHR) and Wistar Kyoto rat (WKY). We found that there was no detectable phosphorylation of MLC at pCa 9.0, but that the administration of 1 μM calyculin A gradually increased force and mono- and di-phosphorylation of MLC. This contraction was inhibited by staurosporine but not by wortmannin, Y-27632, or calphostin-C. The calyculin A-induced contraction was significantly greater in the SHR than in the WKY and was associated with an increase in mono- and di-phosphorylation of MLC. SM-1, a zipper-interacting protein kinase (ZIPK)-inhibiting peptide, significantly inhibited the amplitude of the calyculin A-induced contraction and di-phosphorylation. Total ZIPK expression (54 + 32 kDa) was greater in the SHR than in the WKY. Phosphorylation of myosin phosphatase target subunit at Thr697, but not at Thr855, was consistently stronger in the SHR than in the WKY in calyculin A-treated tissues at pCa 9.0. Our results suggest that Ca2+-independent MLCK activity is enhanced in the SHR, and that ZIPK plays, at least in part, an important role as a candidate for this kinase in rat mesenteric arteries.
Glycine N-methyltransferase−/− mice develop chronic hepatitis and glycogen storage disease in the liver
Authors: Shih-Ping Liu, Ying-Shiuan Li, Yann-Jang Chen, En-Pei Chiang, Anna Fen-Yau Li, Ying-Hue Lee, Ting-Fen Tsai, Michael Hsiao, Shiu-Feng Hwang, Yi-Ming Arthur Chen
Journal: Hepatology (2007)

Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. To establish a Gnmt knockout mouse model, 2 lambda phage clones containing a mouse Gnmt genome were isolated. At 11 weeks of age, the Gnmt−/− mice had hepatomegaly, hypermethioninemia, and significantly higher levels of both serum alanine aminotransferase and hepatic S-adenosylmethionine. Such phenotypes mimic patients with congenital GNMT deficiencies. A real-time polymerase chain reaction analysis of 10 genes in the one-carbon metabolism pathway revealed that 5,10-methylenetetrahydrofolate reductase, S-adenosylhomocysteine hydrolase (Ahcy), and formiminotransferase cyclodeaminase (Ftcd) were significantly down-regulated in Gnmt−/− mice. This report demonstrates that GNMT regulates the expression of both Ftcd and Ahcy genes. Results from pathological examinations indicated that 57.1% (8 of 14) of the Gnmt−/− mice had glycogen storage disease (GSD) in their livers. Focal necrosis was observed in male Gnmt−/− livers, whereas degenerative changes were found in the intermediate zones of female Gnmt−/− livers. In addition, hypoglycemia, increased serum cholesterol, and significantly lower numbers of white blood cells, neutrophils, and monocytes were observed in the Gnmt−/− mice. A real-time polymerase chain reaction analysis of genes involved in the gluconeogenesis pathways revealed that the following genes were significantly down-regulated in Gnmt−/− mice: fructose 1,6-bisphosphatase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphate transporter. Conclusion: Because Gnmt−/− mice phenotypes mimic those of patients with GNMT deficiencies and share several characteristics with GSD Ib patients, we suggest that they are useful for studies of the pathogenesis of congenital GNMT deficiencies and the role of GNMT in GSD and liver tumorigenesis. (HEPATOLOGY 2007.)
Acute Myocardial Infarction and Kidney Transplantation
Authors: Bertram L Kasiske, J Ross Maclean, Jon J Snyder
Journal: Journal of the American Society of Nephrology (2006)

Although the risk for acute myocardial infarction (AMI) is lower after transplantation than on the waiting list, this risk may vary by patient population and may be different early versus late after transplantation. Risk factors for AMI were examined among 53,297 Medicare beneficiaries who were placed on the deceased-donor waiting list in 1995 to 2002. Early (<or=3 mo) and late (>3 mo) effects of receiving a deceased- or living-donor kidney transplant were examined using time-dependent covariates in Cox nonproportional hazards analysis. Overall, transplantation was associated with a 17% lower adjusted risk for AMI (0.83; 95% confidence interval [CI] 0.77 to 0.90) versus the waiting list. However, the relative risk (versus the waiting list) for AMI was greater for deceased- compared to living-donor transplants, with both being much greater early (deceased-donor 3.57 [95% CI 3.21 to 3.96] compared to living-donor 2.81 [95% CI 2.31 to 3.42]) than late (deceased-donor 0.45 [95% CI 0.41 to 0.50] compared to living-donor 0.39 [95% CI 0.33 to 0.47]) posttransplantation. Individuals who were >or=65 yr of age had a much higher risk (versus 18- to 34-yr-olds) for AMI early posttransplantation (8.01; 95% CI 5.12 to 12.53) compared with the waiting list (3.68; 95% CI 3.98 to 4.54) or late posttransplantation (4.37; 95% CI 3.07 to 6.20). Black patients had less reduction in AMI risk (versus white patients) late posttransplantation (0.78; 95% CI 0.64 to 0.95) compared with early posttransplantation (0.60; 95% CI 0.48 to 0.74) or on the waiting list (0.62; 95% CI 0.56 to 0.68). The AMI risk that was associated with chronic kidney disease from diabetes (versus glomerulonephritis) was relatively greater on the waiting list (1.64; 95% CI 1.45 to 1.85) compared with early (1.34; 95% CI 1.08 to 1.68) and late (1.39; 95% CI 1.12 to 1.72) posttransplantation. Thus the risk reduction for AMI with transplantation versus the waiting list varies by patient population and time after transplantation.
Transitions in Early Embryonic Atrioventricular Valvular Function Correspond With Changes in Cushion Biomechanics That Are Predictable by Tissue Composition
Authors: Jonathan T. Butcher, Tim C. McQuinn, David Sedmera, Debi Turner, Roger R. Markwald
Journal: Circulation Research (2007)

Endocardial cushions are critical to maintain unidirectional blood flow under constantly increasing hemodynamic forces, but the interrelationship between endocardial cushion structure and the mechanics of atrioventricular junction function is poorly understood. Atrioventricular (AV) canal motions and blood velocities of embryonic chicks at Hamburger and Hamilton (HH) stages 17, 21, and 25 were quantified using ultrasonography. Similar to the embryonic zebrafish heart, the HH17 AV segment functions like a suction pump, with the cushions expanding in a wave during peak myocardial contraction and becoming undetectable during the relaxation phase. By HH25, the AV canal contributes almost nothing to the piston-like propulsion of blood, but the cushions function as stoppers apposing blood flow with near constant thickness. Using a custom built mesomechanical testing system, we quantified the nonlinear pseudoelastic biomechanics of developing AV cushions, and found that both AV cushions increased in effective modulus between HH17 and HH25. Enzymatic digestion of major structural constituent collagens or glycosaminoglycans resulted in distinctly different stress-strain curves suggestive of their individual contributions. Mixture theory using histologically determined volume fractions of cells, collagen, and glycosaminoglycans showed good prediction of cushion material properties regardless of stage and cushion position. These results have important implications in valvular development, as biomechanics may play a larger role in stimulating valvulogenic events than previously thought.
Crohn's disease and the ‘white plague’: a hypothesis
Authors: Kshaunish Das
Journal: Gut (2013)

The article by Yang et al 1 contributes to the emerging evidence that genetic predisposition to Crohn's Disease (CD) has an ethnicity-specific variation.s1–s4 The genetic architecture of autoimmune and inflammatory diseases has been subject to recent positive selection in human history, probably driven by the historical exposure to pathogens.2 s5–s7 Thus, the differing genetic susceptibilities in East Asians (Koreans and Japanese) vis-a-vis the Caucasoid Euro-Americans might reflect the differences in their historical exposure to predominant pathogens occurring during the historical migrations of anatomically modern humans (AMH) while they populated the globe.s8 Gene(s) or gene pathways involved in innate immune control of intracellular bacteria (eg, NOD2, ATG16L1, IRGM) and in the IL-23/Th17 pathway are predominant susceptibility loci for Crohn's in Caucasoid, but characteristically not so in East Asians.s1, s4 Interestingly, these gene(s) or gene pathways play a primary role in the immune response to human mycobacterial infections, …
Octreotide, a Somatostatin Analogue, Mediates Its Antiproliferative Action in Pituitary Tumor Cells by Altering Phosphatidylinositol 3-Kinase Signaling and Inducing Zac1 Expression
Authors: Marily Theodoropoulou, Jing Zhang, Sandra Laupheimer, Marcelo Paez-Pereda, Christophe Erneux, Tullio Florio, Uberto Pagotto, Günter K. Stalla
Journal: Cancer Research (2006)

Abstract Somatostatin limits cell growth by inhibiting the proliferative activity of growth factor receptors. In this study, it is shown that in pituitary tumor cells, the somatostatin analogue octreotide produces its antiproliferative action by inducing the expression the tumor suppressor gene Zac1. ZAC/Zac1 induces cell cycle arrest and apoptosis and is highly expressed in normal pituitary, mammary, and ovarian glands but is down-regulated in pituitary, breast, and ovarian tumors. Knocking down Zac1 by RNA interference abolished the antiproliferative effect of octreotide in pituitary tumor cells, indicating that Zac1 is necessary for the action of octreotide. The effect of octreotide on Zac1 expression was pertussis toxin sensitive and was abolished after transfection with a dominant negative vector for SHP-1. Zac1 is a target of the phosphatidylinositol 3-kinase (PI3K) survival pathway. Octreotide treatment decreased the tyrosine phosphorylation levels of the PI3K regulatory subunit p85, induced dephosphorylation of phosphoinositide-dependent kinase 1 (PDK1) and Akt, and activated glycogen synthase kinase 3β (GSKβ). Therefore, in pituitary tumor cells, somatostatin analogues produce their antiproliferative action by acting on the PI3K/Akt signaling pathway and increasing Zac1 gene expression. (Cancer Res 2006; 66(3): 1576-82)
The Ancient and Widespread Nature of the ER–Mitochondria Encounter Structure
Authors: Jeremy G. Wideman, Ryan M.R. Gawryluk, Michael W. Gray, Joel B. Dacks
Journal: Molecular Biology and Evolution (2013)

Mitochondria are the result of a billion years of integrative evolution, converting a once free-living bacterium to an organelle deeply linked to diverse cellular processes. One way in which mitochondria are integrated with nonendosymbiotically derived organelles is via endoplasmic reticulum (ER)-mitochondria contact sites. The ER membrane is physically tethered to the mitochondrial outer membrane by the ER-mitochondria encounter structure (ERMES). However, to date, ERMES has only ever been found in the fungal lineage. Here, we bioinformatically demonstrate that ERMES is present in lineages outside Fungi and validate this inference by mass spectrometric identification of ERMES components in Acanthamoeba castellanii mitochondria. We further demonstrate that ERMES is retained in hydrogenosome-bearing but not mitosome-bearing organisms, yielding insight into the process of reductive mitochondrial evolution. Finally, we find that the taxonomic distribution of ERMES is most consistent with rooting the eukaryotic tree between Amorphea (Animals + Fungi + Amoebozoa) + Excavata and all other eukaryotes (Diaphoratickes).