tbuckley/cabot-search huggingface dataset:
The TGFβ superfamily in cardiovascular biology
Authors: J MEHTA, H ATTRAMADAL
Journal: Cardiovascular Research (2007)

This issue of Cardiovascular Research is focused on the TGFβ superfamily and cardiovascular disease. It is timely to comment on some of the unique aspects of this potent cytokine family in relation to cardiovascular disease. There are three structurally similar isoforms of TGFβ, encoded by three distinct genes, in mammalian species; of these, TGFβ1 is the most prevalent. The TGFβ superfamily also includes several other related growth factors, including activin, GDF-15, several bone morphogenetic protein (BMP) isoforms, and nodal. Apparently, all TGFβ superfamily members bind to heterodimeric receptor isomers that belong to the same family, i.e. dimeric complexes of various type I receptor serine/threonine kinases (ALK 1-7) and type II receptor proteins (5 isoforms). These receptors subsequently activate different intracellular Smad proteins to elicit various biological responses [1]. Besides activation of Smads, TGFβ mediates its effects via activation of a number of signals including p38 MAPK, Erk, JNK, and TAK1. This pathway has been reviewed elegantly by Bujak and Frangogiannis in this issue of the Journal [2]. Except for TGFβ itself, the biological functions of the other TGFβ superfamily ligands are poorly understood or have only been partly elucidated.

TGFβs are among the most multifunctional cytokines known; they affect a variety of cell types and modulate multiple biological processes. TGFβ1 knockout mice have a defect in embryonic Development and immune regulation [3]. With regard to the cardiovascular system, low concentrations of TGFβ are growth promoting, and high concentrations are growth inhibitory via modulation … 

*Corresponding author. Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., Slot 532, Little Rock, 72205-7199 AR, USA. Tel.: +1 501 296 1401; fax: +1 501 686 8319. Email address: MehtaJL{at}uams.edu
When is a further clinical trial justified?
Authors: M. L. Ferreira, R. D. Herbert, M. J. Crowther, A. Verhagen, A. J. Sutton
Journal: BMJ (2012)

When is a further clinical trial justified?High quality randomised trials provide unbiased estimates of the effects of health interventions, but the findings of a single trial are rarely conclusive.Usually data from several similar trials must be pooled together to draw firm conclusions about the effectiveness of an intervention.This article considers how to determine whether data from existing trials are conclusive and, if not, whether a further trial is justified.
Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression.
Authors: N M Anstey, J B Weinberg, M Y Hassanali, E D Mwaikambo, D Manyenga, M A Misukonis, D R Arnelle, D Hollis, M I McDonald, D L Granger
Journal: The Journal of Experimental Medicine (1996)

Nitric oxide (NO)-related activity has been shown to be protective against Plasmodium falciparum in vitro. It has been hypothesized, however, that excess NO production contributes to the pathogenesis of cerebral malaria. The purpose of this study was to compare markers of NO production [urinary and plasma nitrate + nitrite (NOx)], leukocyte-inducible nitric oxide synthase type 2 (NOS2), and plasma TNF-alpha and IL-10 levels with disease severity in 191 Tanzanian children with and without malaria. Urine NOx excretion and plasma NOx levels (corrected for renal impairment) were inversely related to disease severity, with levels highest in subclinical infection and lowest in fatal cerebral malaria. Results could not be explained by differences in dietary nitrate ingestion among the groups. Plasma levels of IL-10, a cytokine known to suppress NO synthesis, increased with disease severity. Leukocyte NOS2 antigen was detectable in all control children tested and in all those with subclinical infection, but was undetectable in all but one subject with cerebral malaria. This suppression of NO synthesis in cerebral malaria may contribute to pathogenesis. In contrast, high fasting NOx levels and leukocyte NOS2 in healthy controls and asymptomatic infection suggest that increased NO synthesis might protect against clinical disease. NO appears to have a protective rather than pathological role in African children with malaria.
Effect of low-dose tamoxifen after surgical excision of ductal intraepithelial neoplasia: results of a large retrospective monoinstitutional cohort study
Authors: A. Guerrieri-Gonzaga, M. Lazzeroni, E. Botteri, D. Serrano, N. Rotmensz, M.-C. Varricchio, M. Cazzaniga, G. Bollani, S. Mora, C. Montefrancesco, G. Pruneri, G. Viale, M. Intra, V. Galimberti, A. Goldhirsch, V. Bagnardi, B. Bonanni, A. DeCensi
Journal: Annals of Oncology (2013)
High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis
Authors: Steve Eyre, John Bowes, Dorothée Diogo, Annette Lee, Anne Barton, Paul Martin, Alexandra Zhernakova, Eli Stahl, Sebastien Viatte, Kate McAllister, Christopher I Amos, Leonid Padyukov, Rene E M Toes, Tom W J Huizinga, Cisca Wijmenga, Gosia Trynka, Lude Franke, Harm-Jan Westra, Lars Alfredsson, Xinli Hu, Cynthia Sandor, Paul I W de Bakker, Sonia Davila, Chiea Chuen Khor, Khai Koon Heng, Robert Andrews, Sarah Edkins, Sarah E Hunt, Cordelia Langford, Deborah Symmons, Pat Concannon, Suna Onengut-Gumuscu, Stephen S Rich, Panos Deloukas, Miguel A Gonzalez-Gay, Luis Rodriguez-Rodriguez, Lisbeth Ärlsetig, Javier Martin, Solbritt Rantapää-Dahlqvist, Robert M Plenge, Soumya Raychaudhuri, Lars Klareskog, Peter K Gregersen, Jane Worthington
Journal: Nature Genetics (2012)
Ancestral Sequence Reconstruction in Primate Mitochondrial DNA: Compositional Bias and Effect on Functional Inference
Authors: Neeraja M. Krishnan, Hervé Seligmann, Caro-Beth Stewart, A. P. Jason de Koning, David D. Pollock
Journal: Molecular Biology and Evolution (2004)

Reconstruction of ancestral DNA and amino acid sequences is an important means of inferring information about past evolutionary events. Such reconstructions suggest changes in molecular function and evolutionary processes over the course of evolution and are used to infer adaptation and convergence. Maximum likelihood (ML) is generally thought to provide relatively accurate reconstructed sequences compared to parsimony, but both methods lead to the inference of multiple directional changes in nucleotide frequencies in primate mitochondrial DNA (mtDNA). To better understand this surprising result, as well as to better understand how parsimony and ML differ, we constructed a series of computationally simple "conditional pathway" methods that differed in the number of substitutions allowed per site along each branch, and we also evaluated the entire Bayesian posterior frequency distribution of reconstructed ancestral states. We analyzed primate mitochondrial cytochrome b (Cyt-b) and cytochrome oxidase subunit I (COI) genes and found that ML reconstructs ancestral frequencies that are often more different from tip sequences than are parsimony reconstructions. In contrast, frequency reconstructions based on the posterior ensemble more closely resemble extant nucleotide frequencies. Simulations indicate that these differences in ancestral sequence inference are probably due to deterministic bias caused by high uncertainty in the optimization-based ancestral reconstruction methods (parsimony, ML, Bayesian maximum a posteriori). In contrast, ancestral nucleotide frequencies based on an average of the Bayesian set of credible ancestral sequences are much less biased. The methods involving simpler conditional pathway calculations have slightly reduced likelihood values compared to full likelihood calculations, but they can provide fairly unbiased nucleotide reconstructions and may be useful in more complex phylogenetic analyses than considered here due to their speed and flexibility. To determine whether biased reconstructions using optimization methods might affect inferences of functional properties, ancestral primate mitochondrial tRNA sequences were inferred and helix-forming propensities for conserved pairs were evaluated in silico. For ambiguously reconstructed nucleotides at sites with high base composition variability, ancestral tRNA sequences from Bayesian analyses were more compatible with canonical base pairing than were those inferred by other methods. Thus, nucleotide bias in reconstructed sequences apparently can lead to serious bias and inaccuracies in functional predictions.
Block of AIDS-Kaposi's sarcoma (KS) cell growth, angiogenesis, and lesion formation in nude mice by antisense oligonucleotide targeting basic fibroblast growth factor. A novel strategy for the therapy of KS.
Authors: B Ensoli, P Markham, V Kao, G Barillari, V Fiorelli, R Gendelman, M Raffeld, G Zon, R C Gallo
Journal: Journal of Clinical Investigation (1994)

Kaposi's sarcoma (KS) is the most frequent tumor of HIV-1-infected individuals (AIDS-KS). Typical features of KS are proliferating spindle-shaped cells, considered to be the tumor cells of KS, and endothelial cells forming blood vessels. Basic fibroblast growth factor (bFGF), a potent angiogenic factor, is highly expressed by KS spindle cells in vivo and after injection in nude mice it induces vascular lesions closely resembling early KS in humans. Similar lesions are induced by inoculating nude mice with cultured spindle cells from AIDS-KS lesions (AIDS-KS cells) which produce and release bFGF. Here we show that phosphorothioate antisense (AS) oligonucleotides directed against bFGF mRNA (ASbFGF) inhibit both the growth of AIDS-KS cells derived from different patients and the angiogenic activity associated with these cells, including the induction of KS-like lesions in nude mice. These effects are due to the block of the production of bFGF which is required by AIDS-KS cells to enter the cell cycle and which, after release, mediates angiogenesis. The effects of ASbFGF are specific, dose dependent, achieved at low (0.1-1 microM), nontoxic, oligomer concentrations, and are reversed by the addition of bFGF to the cells, suggesting that ASbFGF oligomers are promising drug candidates for KS therapy.
Efficacy and Safety of Second-Generation Antidepressants in the Treatment of Major Depressive Disorder
Authors: Richard A. Hansen, Gerald Gartlehner, Kathleen N. Lohr, Bradley N. Gaynes, Timothy S. Carey
Journal: Annals of Internal Medicine (2005)

Background: Reviews have compared the efficacy and tolerability of newer second-generation antidepressants with those of placebo or older treatments, but comparative evidence for use of second-generation antidepressants to treat major depressive disorder has not been evaluated. Purpose: To systematically evaluate comparative data on the efficacy, effectiveness, and tolerability of commonly prescribed second-generation antidepressants (selective serotonin reuptake inhibitors, bupropion, duloxetine, mirtazapine, and venlafaxine) in the treatment of major depressive disorder. Data Sources: MEDLINE, EMBASE, and PsychLit; the Cochrane Library; and the International Pharmaceutical Abstracts were searched from January 1980 through February 2005 for reviews; randomized, controlled trials; meta-analyses; and observational studies. Study Selection: The authors reviewed 46 head-to-head randomized, controlled trials comparing one second-generation antidepressant with another. Twenty-four observational studies and placebo-controlled trials were also included for assessment of safety and tolerability. Data Extraction: Two researchers independently reviewed titles and abstracts. Trained reviewers abstracted data from each study and assigned an initial quality rating. A second reviewer verified the data extraction and quality rating. Data Synthesis: According to fair to good evidence, the second-generation antidepressants that were compared had only minimal differences in efficacy, and 88% of comparative efficacy studies reported no statistically significant difference in any outcome measure at the end of the study. One effectiveness trial rated good and 2 effectiveness trials rated fair reported no statistically significant differences in primary outcome measures for compared drugs. Meta-analyses showed a modest but statistically significant additional treatment effect for sertraline and venlafaxine compared with fluoxetine. About 96% of comparative trials were sponsored by or had at least 1 author affiliated with a pharmaceutical company; the remaining trials did not report funding sources. Adverse event profiles differed among drugs; however, the degree and quality of adverse event assessment varied and only 13% of trials used a standardized scale to assess adverse events. Limitations: Quantitative analyses could not be done for many drug comparisons because the quantity and quality of the evidence were inadequate. Most published evidence was from trials sponsored by pharmaceutical companies, and publication bias may have occurred. Conclusions: Overall, second-generation antidepressants probably do not differ substantially for treatment of major depressive disorder. Choosing the agent that is most appropriate for a given patient is difficult.
Insulin, Insulin-Like Growth Factor-I, and Risk of Breast Cancer in Postmenopausal Women
Authors: M. J. Gunter, D. R. Hoover, H. Yu, S. Wassertheil-Smoller, T. E. Rohan, J. E. Manson, J. Li, G. Y. F. Ho, X. Xue, G. L. Anderson, R. C. Kaplan, T. G. Harris, B. V. Howard, J. Wylie-Rosett, R. D. Burk, H. D. Strickler
Journal: JNCI Journal of the National Cancer Institute (2008)

BackgroundThe positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level.
Recurrence of endometriosis and its control
Authors: S.-W. Guo
Journal: Human Reproduction Update (2009)

BACKGROUNDAlthough surgery is currently the treatment of choice for managing endometriosis, recurrence poses a formidable challenge. To delay or to eliminate the recurrence is presently an unmet medical need in the management of endometriosis. To this end, proposals to investigate patterns of recurrence, to develop biomarkers for recurrence and to carry out biomarker-based intervention have been made.
The Promise of Patient-Derived Xenografts: The Best Laid Plans of Mice and Men
Authors: Scott Kopetz, Robert Lemos, Garth Powis
Journal: Clinical Cancer Research (2012)

Abstract Compared with xenografts from previously established cell lines, patient-derived xenografts may more faithfully recapitulate the molecular diversity, cellular heterogeneity, and histology seen in patient tumors, although other limitations of murine models remain. The ability of these models to inform clinical development and answer mechanistic questions will determine their ultimate use. Clin Cancer Res; 18(19); 5160–2. ©2012 AACR.
Countervailing Influence of Tumor Necrosis Factor-α and Nitric Oxide in Endotoxemia
Authors: EDGAR A. JAIMES, DOMINGO DEL CASTILLO, MARK S. RUTHERFORD, LEOPOLDO RAIJ
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Tumor necrosis factor-α (TNF-α), a crucial mediator in sepsis, elicits multiple biologic effects, including intravascular thrombosis and circulatory shock. TNF-α exerts its biologic effects through two distinct cell surface receptors, TNF-R1 and TNF-R2. The pathophysiologic interaction between TNF-α and nitric oxide (NO) in glomerular thrombosis caused by endotoxemia in rats and wild-type mice (C57BL6) as well as in knockout mice that are deficient in TNF-R1 (R1 —/—), TNF-R2 (R2 —/—), or both receptors (R1R2 —/—) was studied. Administration of lipopolysaccharide (LPS; Escherichia coli endotoxin) resulted in increased NO and TNF-α production but failed to induce glomerular thrombosis. Concomitant administration of LPS + NG-nitro-L-arginine methyl ester (L-NAME; an NO synthesis inhibitor) resulted in glomerular thrombosis in rats and in wild-type mice. Intraperitoneal administration of pentoxifylline before LPS inhibited TNF-α synthesis and prevented glomerular thrombosis in rats given LPS + L-NAME. In contrast to the results observed in rats and wild-type mice, administration of LPS + L-NAME did not result in glomerular thrombosis in knockout mice with either single or double TNF-α receptor deletion. Thus, during endotoxemia, (1) TNF-α fosters glomerular thrombosis if there is deficiency of NO synthesis and (2) both TNF-α receptors are necessary for TNF-α's prothrombogenic action. Clinically, these novel studies suggest that in gram-negative endotoxemia, inhibition of NO synthesis and selective blockade of TNF-α receptors may provide unique therapeutic approaches for mitigation of glomerular thrombosis and restitution of vascular tone.
Response to Cabozantinib in Patients with <i>RET</i> Fusion-Positive Lung Adenocarcinomas
Authors: Alexander Drilon, Lu Wang, Adnan Hasanovic, Yoshiyuki Suehara, Doron Lipson, Phil Stephens, Jeffrey Ross, Vincent Miller, Michelle Ginsberg, Maureen F. Zakowski, Mark G. Kris, Marc Ladanyi, Naiyer Rizvi
Journal: Cancer Discovery (2013)

Abstract The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes. In an unselected population of non–small cell lung carcinomas (NSCLCs), RET fusions are present in 1% to 2% of cases. This incidence increases substantially, however, in never-smokers with lung adenocarcinomas that lack other known driver oncogenes. Although preclinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors, clinical data on response are lacking. We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase II trial for patients with RET fusion-positive NSCLCs (NCT01639508). Confirmed partial responses were observed in 2 patients, including one harboring a novel TRIM33–RET fusion. A third patient with a KIF5B–RET fusion has had prolonged stable disease approaching 8 months (31 weeks). All three patients remain progression-free on treatment. Significance: Driver oncogene discovery in lung cancers has dramatically changed today's therapeutic landscape. This report of the activity of cabozantinib in RET fusion-positive disease provides early clinical validation of RET fusions as drivers in lung cancers and suggests that RET inhibition may represent a new treatment paradigm in this molecular cohort. Cancer Discov; 3(6); 630–5. ©2013 AACR. See related commentary by Gainor and Shaw, p. 604 This article is highlighted in the In This Issue feature, p. 591
Identification of miR-133b and RB1CC1 as Independent Predictors for Biochemical Recurrence and Potential Therapeutic Targets for Prostate Cancer
Authors: Xia Li, Xuechao Wan, Hongbing Chen, Shu Yang, Yiyang Liu, Wenjuan Mo, Delong Meng, Wenting Du, Yan Huang, Hai Wu, Jingqiang Wang, Tao Li, Yao Li
Journal: Clinical Cancer Research (2014)

We aimed to investigate the contribution of microRNA-133b (miR-133b) in prostate cancer cell proliferation, cell cycle, and apoptosis. We also examined expression of miR-133b in prostate cancer tissues, and evaluated the prognostic significance of miR-133b, as well as its target gene RB1CC1 in patients with prostate cancer after radical prostatectomy.miR-133b mimics (miR-133bm) and anti-miR-133b were transfected into LNCaP and PC-3 cells. CCK-8 was used to look at cell proliferation, flow cytometric analysis was carried out to study cell cycle, and apoptosis was determined by caspase-3 activity. miR-133b expression was assessed by real-time reverse transcription PCR and in situ hybridization in prostatic cell lines and 178 prostate tissue samples, respectively. The protein level of RB1CC1 was examined by Western blot and immunohistochemistry in prostatic cell lines and prostate tissue samples, respectively.Overexpression of miR-133b in LNCaP cells boosted cell proliferation and cell-cycle progression, but inhibited apoptosis; in contrast, miR-133bm promoted cell apoptosis, but suppressed cell proliferation and cell-cycle progression in PC-3 cells. In LNCaP cells, silencing of RB1CC1, a target of miR-133b, inhibited cell apoptosis, and promoted cell-cycle progression. Moreover, miR-133b expression was significantly inversely correlated with RB1CC1 expression in prostate cancer tissues. Multivariate Cox analysis indicated that miR-133b and RB1CC1 might be two independent prognostic factors of biochemical recurrence.miR-133b might enhance tumor-promoting properties in less aggressive LNCaP cells, whereas this miR may act as a tumor suppressor in more aggressive PC-3 cells. miR-133b and RB1CC1 were independent prognostic indicators for prostate cancer.
The use of bedaquiline in regimens to treat drug-resistant and drug-susceptible tuberculosis: a perspective from tuberculosis-affected communities
Authors: Laia Ruiz Mingote, Dorothy Namutamba, Francis Apina, Nomampondo Barnabas, Carmen Contreras, Taharqa Elnour, Mike Watson Frick, Cynthia Lee, Barbara Seaworth, Debra Shelly, Natalie Skipper, Ezio Tavora dos Santos Filho
Journal: The Lancet (2014)
Na+,K+-ATPase concentration in rodent and human heart and skeletal muscle: apparent relation to muscle performance
Authors: K. KJELDSEN, P. BJERREGAARD, E. A. RICHTER, P. E. B. THOMSEN, A. NORGAARD
Journal: Cardiovascular Research (1988)

To investigate whether the sodium-potassium pump or Na+,K+-ATPase concentration in muscles is related to the capacity for muscle performance, the 3H-ouabain binding site concentration or 3-O-methylflourescein phosphatase activity was determined in samples of heart ventricular muscles from trained rats, cardiomyopathic hamsters, and human subjects. These methods have earlier been shown to quantify the Na+,K+-ATPase concentration in muscle tissue with high accuracy.
The Lumleian Lectures on some Problems in Connection with Aphasia and Other Speech Defects: Delivered before the Royal College of Physicians, April 8th, 1897
Authors: H. C. Bastian
Journal: BMJ (1897)

This is the exact point at which Sabouraud leaves us for the moment; but he promites us before long another memoir toontaining the results of experiments not yet completed.If 'We retrace the ground covered by this analysis we find (i) that the microbial origin of baldness is certaini; (2) that the micro-organism of baldness is the same as that of seborrhaea;(3) that it is identical with that of the seborrhoeic plugs of the orifices of the hair follicles in alopecia areata.To render the whole work complete, to prove that these results are definitely allied to each other, it would suffice if the following could be added to the third conclusion: The bacillus which is the cause of both seborrhea and lo8s of hair acts according to its greater or less virulence under vary- ing conditions in a manner either violent and fulminating, producing what has hitherto been known as alopecia areata, or moderately gentle, giving rise to that progressive loss of hair which in ten or twenty years ends in baldness.This last deduction Sabouraud does not give, in spite of certain favourable experiments.For prudence sake he does not wish to state it yet, because lfe has till now perhaps been unable to produce in an animal the true patch of alopecia areata, that is to say, the typical disease with the club-shaped Ihairs.There is probably, however, but a shade of difference to overcome, and we are convinced that after what has gone before Sabouraud's last scruples will soon prove to be base- less.Thus from this work, besides all the other discoveries which it comprises, we hope to see arise at the same time the key to the much-sought solution of the problem of alopecia areata in the definitely and finally established dis- covery of the microbe of the disease.