tbuckley/cabot-search huggingface dataset:
Decreased DNA synthesis by cultured osteoblastic cells in eugonadal osteoporotic men with defective bone formation.
Authors: P J Marie, M C de Vernejoul, D Connes, M Hott
Journal: Journal of Clinical Investigation (1991)

To determine the osteoblastic dysfunction that may be involved in the pathophysiology of osteoporosis in men we have compared histomorphometric indices of bone formation with in vitro characteristics of osteoblastic cells isolated from the trabecular bone surface in 23 untreated men with eugonadal osteoporosis. In most patients (n = 14), trabecular bone loss resulted from decreased bone formation evidenced by a lower than normal osteoblast surface, double tetracycline labeled surface, bone formation rate, and mean wall thickness. In these patients, DNA synthesis by cultured osteoblastic cells was altered. The peak of [3H]thymidine incorporation into DNA, the maximal DNA synthesis, and the area under the curve of cell proliferation were lower than the values in normal bone cells from age-matched controls. Parameters of bone cell growth were decreased in correlation with the extent of actively bone forming surfaces. By contrast, in patients (n = 9) with normal histomorphometric indices of bone formation, bone cell proliferation in vitro was not different from normal. Parameters of osteoblastic differentiation in vitro such as osteocalcin production and alkaline phosphatase activity were normal in the two groups of patients. This study shows that the trabecular bone loss resulting from defective bone formation in eugonadal osteoporotic men is associated with a lower than normal proliferative capacity of osteoblastic cells lining the trabecular bone surface.
FMRP Regulates Neurotransmitter Release and Synaptic Information Transmission by Modulating Action Potential Duration via BK Channels
Authors: Pan-Yue Deng, Ziv Rotman, Jay A. Blundon, Yongcheol Cho, Jianmin Cui, Valeria Cavalli, Stanislav S. Zakharenko, Vitaly A. Klyachko
Journal: Neuron (2013)
MicroRNA-21 Integrates Pathogenic Signaling to Control Pulmonary Hypertension
Authors: Victoria N. Parikh, Richard C. Jin, Sabrina Rabello, Natali Gulbahce, Kevin White, Andrew Hale, Katherine A. Cottrill, Rahamthulla S. Shaik, Aaron B. Waxman, Ying-Yi Zhang, Bradley A. Maron, Jochen C. Hartner, Yuko Fujiwara, Stuart H. Orkin, Kathleen J. Haley, Albert-László Barabási, Joseph Loscalzo, Stephen Y. Chan
Journal: Circulation (2012)

Pulmonary hypertension (PH) is driven by diverse pathogenic etiologies. Owing to their pleiotropic actions, microRNA molecules are potential candidates for coordinated regulation of these disease stimuli.Using a network biology approach, we identify microRNA associated with multiple pathogenic pathways central to PH. Specifically, microRNA-21 (miR-21) is predicted as a PH-modifying microRNA, regulating targets integral to bone morphogenetic protein (BMP) and Rho/Rho-kinase signaling as well as functional pathways associated with hypoxia, inflammation, and genetic haploinsufficiency of BMP receptor type 2. To validate these predictions, we have found that hypoxia and BMP receptor type 2 signaling independently upregulate miR-21 in cultured pulmonary arterial endothelial cells. In a reciprocal feedback loop, miR-21 downregulates BMP receptor type 2 expression. Furthermore, miR-21 directly represses RhoB expression and Rho-kinase activity, inducing molecular changes consistent with decreased angiogenesis and vasodilation. In vivo, miR-21 is upregulated in pulmonary tissue from several rodent models of PH and in humans with PH. On induction of disease in miR-21-null mice, RhoB expression and Rho-kinase activity are increased, accompanied by exaggerated manifestations of PH.A network-based bioinformatic approach coupled with confirmatory in vivo data delineates a central regulatory role for miR-21 in PH. Furthermore, this study highlights the unique utility of network biology for identifying disease-modifying microRNA in PH.
Appraising the quality of sub-Saharan African cancer registration systems that contributed to GLOBOCAN 2008: a review of the literature and critical appraisal
Authors: Tim Crocker-Buque, Allyson M Pollock
Journal: Journal of the Royal Society of Medicine (2015)

Objective To critically appraise the quality of sub-Saharan African cancer registration systems that submitted data to GLOBOCAN 2008 with respect to population coverage using publicly available information and to show the use of GLOBOCAN statistics in determining global health priorities. Design Sources of cancer registration data for twenty-six sub-Saharan African cancer registries were identified from GLOBOCAN 2008 factsheets. Additional information was extracted from International Agency for Research on Cancer publications. A literature search was conducted to identify studies that reported additional information on data collection methods and provided 27 studies. The websites of the 10 largest funders of development assistance for health were searched for GLOBOCAN citations. Setting and participants Twenty-six sub-Saharan African cancer registration systems submitting data to GLOBOCAN 2008 in relation to 21 countries. Main outcome measures Information on 15 quality variables were extracted and compared with the international gold standard for cancer registration systems. Results Population coverage of the cancer registries ranged from from 2.3% of the population in Kenya to 100% in The Gambia, with a heavy urban bias in all countries. However, 20 countries (300 million people) had no cancer registration systems. Nineteen of the 26 registries failed to meet more than five of the 15 quality criteria and only one country met more than 10. Seven of the 10 largest funders of development assistance for health cite GLOBOCAN statistics in support of policy priorities. Conclusions GLOBOCAN 2008 estimates are based on data drawn from poor quality cancer registration systems, with limited or no population registry coverage. It is essential the GLOBOCAN 2012 estimates should provide information on the quality of the data collection and explain the limitations of the estimates. Development organisations and the World Health Organization need to take a more cautious approach when using these data to determine priorities and allocating resources.
Withdrawal of Cyclosporine or Prednisone Six Months after Kidney Transplantation in Patients on Triple Drug Therapy
Authors: Peter J. H. Smak Gregoor, Ruud G. L. de Sévaux, Gerry Ligtenberg, Andries J. Hoitsma, Ronald J. Hené, Willem Weimar, Luuk B. Hilbrands, Teun van Gelder
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Uncertainty exists regarding the necessity of continuing triple therapy consisting of mycophenolate mofetil (MMF), cyclosporine (CsA), and prednisone (Pred) after kidney transplantation (RTx). At 6 mo after RTx, 212 patients were randomized to stop CsA ( n = 63), stop Pred ( n = 76), or continue triple drug therapy ( n = 73). The MMF dose was 1000 mg twice daily, target CsA trough levels were 150 ng/ml, and Pred dose was 0.10 mg/kg per d. Follow-up was until 24 mo after RTx. Biopsy-proven acute rejection occurred in 14 (22%) of 63 patients after CsA withdrawal compared with 3 (4%) of 76 in the Pred withdrawal group ( P = 0.001) and 1 (1.4%) of 73 in the control group ( P = 0.0001). Biopsy-proven chronic rejection was present in one patient in the control group, in nine patients after CsA withdrawal ( P = 0.006 versus control group); and in four patients after discontinuation of Pred (NS). Graft loss occurred in two versus one patient after CsA or Pred withdrawal, respectively, and in two patients in the control group (NS). Patients who successfully withdrew CsA had a significantly lower serum creatinine during follow-up. Pred withdrawal resulted in a reduction in mean arterial pressure, and the total cholesterol/HDL ratio increased. In conclusion, rapid CsA withdrawal at 6 mo after RTx results in a significantly increased incidence of biopsy-proven acute and chronic rejection. Pred withdrawal was safe and resulted in a reduction in mean arterial pressure. However, patient and graft survival and renal function 2 yr after RTx were not different among groups.
GenoType MTBDR assays for the diagnosis of multidrug-resistant tuberculosis: a meta-analysis
Authors: D. I. Ling, A. A. Zwerling, M. Pai
Journal: European Respiratory Journal (2008)

The global extensively drug-resistant tuberculosis (TB) response plan calls for implementation of rapid tests to screen patients at risk of drug-resistant TB. Currently, two line probe assays exist, the INNO-LiPA(R)Rif.TB assay (Innogenetics, Ghent, Belgium) and the GenoType MTBDR assay (Hain LifeScience GmbH, Nehren, Germany). While LiPA studies have been reviewed, the accuracy of GenoType assays has not been systematically reviewed. The present authors carried out a systematic review and used meta-analysis methods appropriate for diagnostic accuracy. After the literature searches, 14 comparisons for rifampicin and 15 comparisons for isoniazid were identified in 10 articles that used GenoType MTBDR assays. Accuracy results were summarised in forest plots and pooled using bivariate random-effects regression. The pooled sensitivity (98.1%, 95% confidence interval (CI) 95.9-99.1) and specificity (98.7%, 95% CI 97.3-99.4) estimates for rifampicin resistance were very high and consistent across all subgroups, assay versions and specimen types. The accuracy for isoniazid was variable, with lower sensitivity (84.3%, 95% CI 76.6-89.8) and more inconsistent than specificity (99.5%, 95% CI 97.5-99.9). GenoType MDTBR assays demonstrate excellent accuracy for rifampicin resistance, even when used on clinical specimens. While specificity is excellent for isoniazid, sensitivity estimates were modest and variable. Together with data from demonstration projects, the meta-analysis provides evidence for policy making and clinical practice.
Gamma interferon is the lymphokine and beta interferon the monokine responsible for inhibition of fibroblast collagen production and late but not early fibroblast proliferation.
Authors: M R Duncan, B Berman
Journal: The Journal of Experimental Medicine (1985)

Human peripheral blood mononuclear cells activated with concanavalin A (Con A) or lipopolysaccharide (LPS) produce, respectively, lymphokines (LK) of 50,000 Mr or monokines (MK) of 20,000 Mr that inhibit the growth and collagen production of cultured human dermal fibroblasts. Because antigenic typing of the antiviral activity of these LK and MK preparations revealed that LK contained mainly gamma interferon (IFN-gamma), and MK, primarily IFN-beta, we investigated if any of the fibroblast-inhibiting activities could be attributed to human IFN. Unlike LK and MK, which act within 24 h to inhibit the growth of subconfluent foreskin and adult dermal fibroblasts, samples of purified, natural derived IFN-alpha, -beta, and -gamma and recombinant DNA-derived IFN-alpha 2 and -gamma were ineffective inhibitors at 24 h and required 48-72 h to significantly inhibit growth. However, all IFN did mimic LK/MK action in causing concentration-dependent inhibition of collagen production by confluent fibroblast microcultures. Furthermore, the collagen production-inhibiting activity of Con A-induced LK supernatant and its 50,000 Mr fraction was completely suppressed by 10(3) neutralizing U/ml of either polyclonal or monoclonal antibody to IFN-gamma, while polyclonal antibodies to IFN-alpha and -beta had no effect. Similarly, the collagen production-inhibiting activity of LPS-induced MK supernatant and its 20,000 Mr fraction was suppressed by polyclonal anti-IFN-beta but not by anti-IFN-alpha or -gamma. Anti-IFN failed to reverse early-acting LK or MK growth-inhibiting activities. These data suggest collagen production-inhibiting LK and MK are IFN-gamma and IFN-beta, respectively, and that early acting, growth-inhibiting LK and MK are not IFN.
Decreased Conflict- and Error-Related Activity in the Anterior Cingulate Cortex in Subjects With Schizophrenia
Authors: John G. Kerns, Jonathan D. Cohen, Angus W. MacDonald, Melissa K. Johnson, V. Andrew Stenger, Howard Aizenstein, Cameron S. Carter
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: People with schizophrenia have exhibited reduced functional activity in the anterior cingulate cortex during the performance of many types of cognitive tasks and during the commission of errors. According to conflict theory, the anterior cingulate cortex is involved in the monitoring of response conflict, acting as a signal for a need for greater cognitive control. This study examined whether impaired conflict monitoring in people with schizophrenia could underlie reduced anterior cingulate activity during both correct task performance and error-related activity. METHOD: Functional activity in the anterior cingulate of 13 schizophrenia patients and 13 healthy comparison subjects was investigated by using event-related fMRI and a Stroop task that allowed simultaneous examination of activity during both conflict (incongruent trials) and error (commission of error trials). RESULTS: In the presence of comparable reaction time measures for conflict as well as comparable error rates, the schizophrenia subjects showed both decreased conflict- and error-related activity in the same region of the anterior cingulate cortex. Moreover, those with schizophrenia did not exhibit significant post-conflict or post-error behavioral adjustments. CONCLUSIONS: Concurrently reduced conflict- and error-related activity in the anterior cingulate cortex along with reduced trial-to-trial adjustments in performance has not previously been reported in schizophrenia. The current results suggest that impaired conflict monitoring by the anterior cingulate cortex might play an important role in contributing to cognitive control deficits in patients with schizophrenia.
Family-Based Association Study Showing that Immunoglobulin A Nephropathy Is Associated with the Polymorphisms 2093C and 2180T in the 3′ Untranslated Region of the Megsin Gene
Authors: You-Ji Li, Yong Du, Cai-Xia Li, Hui Guo, Joseph C.K. Leung, Man F. Lam, Niansheng Yang, Fengxian Huang, Yun Chen, Ji-Qian Fang, Patrick H. Maxwell, Kar N. Lai, Yiming Wang
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Immunoglobulin A nephropathy (IgAN) is considered to be a multifactorial disease with genetic and environmental factors contributing to its pathogenesis. The genes involved in susceptibility and progression of the disease have not yet been clearly elucidated. Megsin (SERPINB7) is an important candidate gene, predominantly expressed in glomerular mesangium and upregulated in IgAN. To investigate the potential role of this and other genes in IgAN, patients with biopsy-proven IgAN were recruited, as were family members, for a family-based association study. The genotypes of the polymorphisms C2093T and C2180T within the 3′ untranslated region of the gene were determined by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. The results were analyzed by transmission disequilibrium test (TDT) and haplotype relative risk (HRR). TDT analyses revealed that Megsin 2093C and 2180T alleles were significantly more transmitted from heterozygous parents to patients than expected (C2093T: 127 trios, P = 0.034, C2180T: 100 trios, P = 0.002). Extended TDT showed increased cotransmission of the 2093C and 2180T alleles (232 families, P < 0.001). HRR revealed that the 2093C and 2180T alleles were more often transmitted to patients (P = 0.014, <0.001, respectively). Genetic variation in Megsin confers susceptibility to IgAN.
Statistics Notes: Missing outcomes in randomised trials
Authors: A. J. Vickers, D. G. Altman
Journal: BMJ (2013)

In most randomised trials, some patients fail to provide data for study endpoints.1 We have previously described the analysis of a trial of acupuncture versus sham acupuncture for the treatment of shoulder pain.2 All 52 randomised patients provided baseline data on pain and range of motion, but only 45 returned for follow-up testing. The statistical question is how to handle those seven patients with missing data. The most straightforward approach is simply to ignore the seven patients and do what is known as an “available case analysis” (often confusingly known as “complete case analysis”). As not all randomised patients are included in the analysis, this leads to reduced statistical power.1

A method that attempts to include all randomised patients is “last observation carried forward,” in which the last measurement obtained from the patient is used for all data points that were subsequently missed. This method is attractive because it is simple, but it has little else to recommend it. Substituting a missing data point with a value is known as “imputation,”1 and the data analyst needs a clear rationale for the …
Leveraging population admixture to characterize the heritability of complex traits
Authors: Noah Zaitlen, Bogdan Pasaniuc, Sriram Sankararaman, Gaurav Bhatia, Jianqi Zhang, Alexander Gusev, Taylor Young, Arti Tandon, Samuela Pollack, Bjarni J Vilhjálmsson, Themistocles L Assimes, Sonja I Berndt, William J Blot, Stephen Chanock, Nora Franceschini, Phyllis G Goodman, Jing He, Anselm J M Hennis, Ann Hsing, Sue A Ingles, William Isaacs, Rick A Kittles, Eric A Klein, Leslie A Lange, Barbara Nemesure, Nick Patterson, David Reich, Benjamin A Rybicki, Janet L Stanford, Victoria L Stevens, Sara S Strom, Eric A Whitsel, John S Witte, Jianfeng Xu, Christopher Haiman, James G Wilson, Charles Kooperberg, Daniel Stram, Alex P Reiner, Hua Tang, Alkes L Price
Journal: Nature Genetics (2014)
Mechanism of decreased forward stroke volume in children and swine with ventricular septal defect and failure to thrive.
Authors: W J Corin, M M Swindle, J F Spann, K Nakano, M Frankis, R W Biederman, A Smith, A Taylor, B A Carabello
Journal: Journal of Clinical Investigation (1988)

Children with ventricular septal defect (VSD) often demonstrate failure to thrive (FTT). Such patients usually have reduced systemic cardiac output which has been postulated as a cause for their growth retardation. This study was conducted to ascertain the mechanism of the reduced cardiac output in children with VSD and FTT and also in a porcine model of VSD. Forward stroke volume was reduced in VSD-FTT children, 31 +/- 8 ml/m2, compared to normal children, 49 +/- 15 ml/m2 (P less than 0.05), but was not reduced in children with VSD and normal growth and development (41 +/- 16 ml/m2). Forward stroke volume was also reduced in swine with VSD compared to controls. Contractility assessed by mean velocity of circumferential shortening (Vcf) corrected for afterload was similar in normals and VSD-FTT children. Contractile performance was also similar in normal and VSD swine. Afterload assessed as systolic stress was similar in FTT-VSD children and normal subjects. Preload assessed as end-diastolic stress was increased in the VSD-FTT group. End-diastolic volume was not larger in the VSD-FTT group. We conclude that the reduced stroke volume seen in VSD-FTT children and VSD-swine was not due to reduced contractility, increased afterload or reduced preload. The reduced stroke volume may have been due to failure of end-diastolic volume to increase adequately.
Distinct functions of monoclonal IgG antibody depend on antigen-site specificities.
Authors: W Schalch, J K Wright, L S Rodkey, D G Braun
Journal: The Journal of Experimental Medicine (1979)

Intraveneous hyperimmunization of selectivity bred rabbits with streptococcal group A-variant vaccines elicits antibody responses of restricted heterogeneity at high antibody levels. All antisera contain two functionally distinct antibody populations, which can be isolated in single-band purity upon analytical isoelectric focusing. Typical examples of these two kinds of single-band antibodies were investigated in great detail for several parameters by a variety of methods. 85--99% of the streptococcal group A-variant polysaccharide (Av-CHO)-specific antibody in the antisera does not precipitate the isolated 5,000 daltons poly-L-rhamnose antigen, neither agglutinates nor lyses in the presence of complement Av-CHO-coated sheep erythrocytes (SRBC), binds the radio-labeled Av-CHO with an association constant in the ragne of 10(5)--10(6) M-1, and is of terminal specificity (nonreducing end) for the linear Av-CHO. In contrast, the minor fraction of Av-CHO-specific antibody (1--15%) does precipitate the linear Av-CHO, both agglutinates and lyses Av-CHO-coated SRBC in the presence of complement, has an affinity range of 10(8)--10(9) M-1, and is of internal specificity for the Av-CHO. The antigenic determinants of the Av-CHO for the antibodies are nonoverlapping, only one Fab of the low affinity antibody can be bound whereas four Fab of the high affinity antibody are accommodated. Hence, the determinant specificity explains the functional differences observed, for there is no indication of subclass differences. A mechanistic model of the A-variant carbohydrate presentation on the vaccine appears to account best for the unbalanced levels of low and high affinity antibody.
Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer
Authors: Martin P Barr, Steven G Gray, Kathy Gately, Emily Hams, Padraic G Fallon, Anthony Mitchell Davies, Derek J Richard, Graham P Pidgeon, Kenneth J O'Byrne
Journal: Molecular Cancer (2015)

The VEGF pathway has become an important therapeutic target in lung cancer, where VEGF has long been established as a potent pro-angiogenic growth factor expressed by many types of tumors. While Bevacizumab (Avastin) has proven successful in increasing the objective tumor response rate and in prolonging progression and overall survival in patients with NSCLC, the survival benefit is however relatively short and the majority of patients eventually relapse. The current use of tyrosine kinase inhibitors alone and in combination with chemotherapy has been underwhelming, highlighting an urgent need for new targeted therapies. In this study, we examined the mechanisms of VEGF-mediated survival in NSCLC cells and the role of the Neuropilin receptors in this process. NSCLC cells were screened for expression of VEGF and its receptors. The effects of recombinant VEGF and its blockade on lung tumor cell proliferation and cell cycle were examined. Phosphorylation of Akt and Erk1/2 proteins was examined by high content analysis and confocal microscopy. The effects of silencing VEGF on cell proliferation and survival signaling were also assessed. A Neuropilin-1 stable-transfected cell line was generated. Cell growth characteristics in addition to pAkt and pErk1/2 signaling were studied in response to VEGF and its blockade. Tumor growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells. Inhibition of the VEGF pathway with anti-VEGF and anti-VEGFR-2 antibodies or siRNA to VEGF, NP1 and NP2 resulted in growth inhibition of NP1 positive tumor cell lines associated with down-regulation of PI3K and MAPK kinase signaling. Stable transfection of NP1 negative cells with NP1 induced proliferation in vitro, which was further enhanced by exogenous VEGF. In vivo, NP1 over-expressing cells significantly increased tumor growth in xenografts compared to controls. Our data demonstrate that VEGF is an autocrine growth factor in NSCLC signaling, at least in part, through NP1. Targeting this VEGF receptor may offer potential as a novel therapeutic approach and also support the evaluation of the role of NP1 as a biomarker predicting sensitivity or resistance to VEGF and VEGFR-targeted therapies in the clinical arena.