tbuckley/cabot-search huggingface dataset:
Amphetamine activates connexin43 gene expression in cultured neonatal rat cardiomyocytes through JNK and AP-1 pathway
Authors: K SHYU, B WANG, Y YANG, S TSAI, S LIN, C LEE
Journal: Cardiovascular Research (2004)

Objective: Amphetamine has been known to induce cardiac dysrhythmia and sudden death. However, the molecular mechanism for the induction of dysrhythmia is not known. Connexin43 (Cx43) plays an important role for arrhythmogenesis. This study was undertaken to test the hypothesis that amphetamine could induce Cx43 expression in cardiac myocytes. Methods: Neonatal Wistar rat cardiac myocytes were cultured under the stimulation of amphetamine. Cx43 mRNA and protein expression were examined by Northern and Western blots, respectively. We used c-Jun N-terminal kinase (JNK) inhibitor, SP600125, and JNK1 dsRNAi to investigate the signal pathway of amphetamine-induced expression of Cx43. Results: The level of Cx43 protein significantly increased from 4 to 24 h after addition of amphetamine (10 μM). The Cx43 mRNA increased maximally to 4.2-fold at 6 h after addition of amphetamine and returned to the baseline level at 48 h. These increases of Cx43 protein at 24 h were completely attenuated (P<0.001) by SP600125 (20 μM) and JNK1 dsRNAi. Amphetamine increased and SP600125 decreased the immunohistochemical labeling of Cx43. Amphetamine increased and SP600125 decreased the phosphorylated JNK and c-Jun proteins. Gel-shifting assay showed that DNA-binding activity of AP-1 increased after addition of amphetamine and SP600125 and JNK1 dsRNAi abolished the binding activity induced by amphetamine. Conclusions: These findings indicate that amphetamine activates Cx43 gene expression in cultured rat neonatal cardiac myocytes. Amphetamine mediates the Cx43 gene expression, at least in part, through the JNK pathway. These findings from our study suggest that Cx43 plays a role for the molecular mechanism of amphetamine-induced cardiac dysrhythmias.
Diversity of airway epithelial cell targets for in vivo recombinant adenovirus-mediated gene transfer.
Authors: A Mastrangeli, C Danel, M A Rosenfeld, L Stratford-Perricaudet, M Perricaudet, A Pavirani, J P Lecocq, R G Crystal
Journal: Journal of Clinical Investigation (1993)

A variety of pulmonary disorders, including cystic fibrosis, are potentially amenable to treatment in which a therapeutic gene is directly transferred to the bronchial epithelium. This is difficult to accomplish because the majority of airway epithelial cells replicate slowly and/or are terminally differentiated. Adenovirus vectors may circumvent this problem, since they do not require target cell proliferation to express exogenous genes. To evaluate the diversity of airway epithelial cell targets for in vivo adenovirus-directed gene transfer, a replication deficient recombinant adenovirus containing the Escherichia coli lacZ (beta-galactosidase [beta-gal]) gene (Ad.RSV beta gal) was used to infect lungs of cotton rats. In contrast to uninfected animals, intratracheal Ad.RSV beta gal administration resulted in beta-gal activity in lung lysate and cytochemical staining in all cell types forming the airway epithelium. The expression of the exogenous gene was dose-dependent, and the distribution of the beta-gal positive airway epithelial cells in Ad.RSV beta gal-infected animals was similar to the normal cell differential of the control animals. Thus, a replication deficient recombinant adenovirus can transfer an exogenous gene to all major categories of airway epithelial cells in vivo, suggesting that adenovirus vectors may be an efficient strategy for in vivo gene transfer in airway disorders such as cystic fibrosis.
Overexpression of Insulin-Like Growth Factor-1 Attenuates the Myocyte Renin-Angiotensin System in Transgenic Mice
Authors: Annarosa Leri, Yu Liu, Xiaowei Wang, Jan Kajstura, Ashwani Malhotra, Leonard G. Meggs, Piero Anversa
Journal: Circulation Research (1999)

Abstract —Constitutive overexpression of insulin-like growth factor-1 (IGF-1) in myocytes protects them from apoptosis and interferes with myocyte hypertrophy in the normal and pathological heart. Conversely, angiotensin II (Ang II) triggers cell death and promotes myocyte hypertrophy. Moreover, activation of p53 upregulates the cellular renin-angiotensin system (RAS). Therefore, IGF-1 overexpression in FVB. Igf +/− mice may downregulate the local RAS through the attenuation of p53 and p53-inducible genes. On this basis, p53 DNA binding activity to angiotensinogen (Aogen), bax, and the AT 1 receptor was determined in left ventricular myocytes from FVB. Igf −/− and FVB. Igf +/− mice. The quantity of Bax, Bcl-2, Aogen, and AT 1 receptor in these cells was evaluated. The presence of Mdm2-p53 complexes was also established. Finally, Ang II levels in myocytes were measured. Upregulation of IGF-1 in myocytes was associated with a protein-to-protein interaction between Mdm2 and p53, which attenuated p53 transcriptional activity for bax, Aogen, and AT 1 receptor. Similarly, the amount of Bax, Aogen, and AT 1 receptor proteins in these cells decreased. In contrast, the expression of Bcl-2 remained constant. The downregulation of Aogen in myocytes from FVB. Igf +/− mice was characterized by a reduction in Ang II. In conclusion, IGF-1 negatively influences the myocyte RAS through the upregulation of Mdm2 and its binding to p53. This may represent the molecular mechanism responsible for the effects of IGF-1 on cell viability and myocyte hypertrophy in the nonpathological and pathological heart in vivo.
DIVERSE EXPRESSION OF GROUP a ALLOTYPE SPECIFICITIES ON THE HEAVY CHAINS OF HOMOGENEOUS RABBIT ANTIBODIES
Authors: Thomas J. Kindt, Rochelle K. Seide, Brian F. Tack, Charles W. Todd
Journal: The Journal of Experimental Medicine (1973)

Variations in the ability of homogeneous antibodies to absorb group a allotype antisera suggest that these V(H) region allotypes comprise a spectrum of specificities. While no homogeneous antibody tested would completely absorb antisera to the group a specificities, the total IgG preparations from individual rabbits was capable of doing so, including preimmune IgG from the rabbits that produced the homogeneous antibodies. Differences in the serologic reactivities of homogeneous antibodies indicate that each possesses only a portion of the spectrum of the allotypic specificities expressed by the total IgG.
Users' Guides to the Medical Literature
Authors: Gordon H. Guyatt
Journal: JAMA (1995)

THE ULTIMATE PURPOSE of applied health research is to improve health care. Summarizing the literature to adduce recommendations for clinical practice is an important part of the process. Recently, the health sciences community has reduced the bias and imprecision of traditional literature summaries and their associated recommendations through the development of rigorous criteria for both literature overviews<sup>1-3</sup>and practice guidelines.<sup>4,5</sup>Even when recommendations come from such rigorous approaches, however, it is important to differentiate between those based on weak vs strong evidence. Recommendations based on inadequate evidence often require reversal when sufficient data become available,<sup>6</sup>while timely implementation of recommendations based on strong evidence can save lives.<sup>6</sup>In this article, we suggest an approach to classifying strength of recommendations. We direct our discussion primarily at clinicians who make treatment recommendations that they hope their colleagues will follow. However, we believe that any clinician who attends to
Risk factors for acute hepatitis B and its progression to chronic hepatitis in Shanghai, China
Authors: H W Zhang, J H Yin, Y T Li, C Z Li, H Ren, C Y Gu, H Y Wu, X S Liang, P Zhang, J F Zhao, X J Tan, W Lu, S Schaefer, G W Cao
Journal: Gut (2008)

<h3>Background and aims:</h3> The major risk factors for acute hepatitis B (AHB) in China and the viral factors determining the progression from acute to chronic hepatitis B remain largely unknown. <h3>Methods:</h3> Epidemiological studies within a population-based surveillance for AHB in adults were performed in Shanghai, China, including 294 patients, 588 matched controls and 572 family members of the patients. <h3>Results:</h3> Invasive medical procedures, household contact with hepatitis B virus (HBV) carriers, body care and beauty treatments, and lack of HBV vaccination were independently associated with AHB. Among those risks, pedicure in bath centres emerged. Sixty-eight of 128 patients with AHB were genotyped including 33 with HBV B2 and 35 with HBV C2. Twenty-five (8.50%) of the 294 patients, including 20 with HBV C2 and 5 with HBV B2 (p = 0.013), progressed to chronic infection. Multivariate analysis showed that HBV C2 was independently associated with chronicification of AHB. Patients with HBV B2 were younger and there was a higher proportion of women than those with HBV C2. The prevalence of HBV B2 was higher in the patients than in neighbourhood chronic carriers. The chronic carriers with HBV B2 showed higher viral loads, higher hepatitis B e antigen (HBeAg) seropositivity, and with higher proportion in men than those with HBV C2, implying that sexual contact plays a role in the transmission of HBV B2. Phylogenetic analysis showed that HBV C2 was frequently involved in transmissions within households. <h3>Conclusions:</h3> Despite lower viral load and HBeAg status in the chronic carriers, HBV C2 was more prone to causing chronic infection than was HBV B2.
Study of the role of functional variants of SLC22A4, RUNX1 and SUMO4 in systemic lupus erythematosus
Authors: G Orozco
Journal: Annals of the Rheumatic Diseases (2005)

Functional polymorphisms of the solute carrier family 22, member 4 (SLC22A4), runt related transcription factor 1 (RUNX1) and small ubiquitin-like modifier 4 (SUMO4) genes have been shown to be associated with several autoimmune diseases.To test the possible role of these variants in susceptibility to or severity of systemic lupus erythematosus (SLE), on the basis that common genetic bases are shared by autoimmune disorders.597 SLE patients and 987 healthy controls of white Spanish origin were studied. Two additional cohorts of 228 SLE patients from Sweden and 122 SLE patients from Colombia were included. A case-control association study was carried out with six single nucleotide polymorphisms (SNP) spanning the SLC22A4 gene, one SNP in RUNX1 gene, and one additional SNP in SUM04 gene.No significant differences were observed between SLE patients and healthy controls when comparing the distribution of the genotypes or alleles of any of the SLC22A4, RUNX1, or SUMO4 polymorphisms tested. Significant differences were found in the distribution of the SUMO4 genotypes and alleles among SLE patients with and without nephritis, but after multiple testing correction, the significance of the association was lost. The association of SUMO4 with nephritis could not be verified in two independent SLE cohorts from Sweden and Colombia.These results suggest that the SLC22A4, RUNX1, and SUMO4 polymorphisms analysed do not play a role in the susceptibility to or severity of SLE.
How sustainable agriculture can address the environmental and human health harms of industrial agriculture.
Authors: Leo Horrigan, Robert S Lawrence, Polly Walker
Journal: Environmental Health Perspectives (2002)

The industrial agriculture system consumes fossil fuel, water, and topsoil at unsustainable rates. It contributes to numerous forms of environmental degradation, including air and water pollution, soil depletion, diminishing biodiversity, and fish die-offs. Meat production contributes disproportionately to these problems, in part because feeding grain to livestock to produce meat--instead of feeding it directly to humans--involves a large energy loss, making animal agriculture more resource intensive than other forms of food production. The proliferation of factory-style animal agriculture creates environmental and public health concerns, including pollution from the high concentration of animal wastes and the extensive use of antibiotics, which may compromise their effectiveness in medical use. At the consumption end, animal fat is implicated in many of the chronic degenerative diseases that afflict industrial and newly industrializing societies, particularly cardiovascular disease and some cancers. In terms of human health, both affluent and poor countries could benefit from policies that more equitably distribute high-protein foods. The pesticides used heavily in industrial agriculture are associated with elevated cancer risks for workers and consumers and are coming under greater scrutiny for their links to endocrine disruption and reproductive dysfunction. In this article we outline the environmental and human health problems associated with current food production practices and discuss how these systems could be made more sustainable.
Psychosocial and Biobehavioral Factors and Their Interplay in Coronary Heart Disease
Authors: Redford B. Williams
Journal: Annual Review of Clinical Psychology (2008)

Recent epidemiological research has confirmed that psychosocial factors are associated with increased risk of developing coronary heart disease (CHD), a major cause of death and disability worldwide. This association is probably mediated by changes in health risk behaviors and neuroendocrine and autonomic functions that affect metabolic, hemostatic, inflammatory, and cardiovascular functions that are the proximal agents in CHD pathogenesis over time as well as the precipitation of acute disease events. Recent developments in genomics have now made it possible to begin the process of identifying specific genetic variants that act either independently or via moderation of the impact of exposures to stressful environmental situations to increase the expression of these health-damaging psychosocial factors and the accompanying behavioral and physiological changes that lead to disease. It will be possible ultimately to use the knowledge emerging from research on gene x environment interactions that affect expression of psychosocial risk factors, health risk behaviors, and biological changes inside the body to speed the development of a new field of prospective medicine-a field where instead of spending the majority of health care resources on the treatment of chronic diseases at the end of life, it will be possible to allocate more resources to develop, test, and implement earlier in the disease process cost-effective, proactive interventions that target persons at high risk.
Diagnosing CF: sweat, blood and years
Authors: J S Elborn
Journal: Thorax (2006)

Use of algorithms for the diagnosis of CF

The diagnosis of cystic fibrosis (CF) is usually straightforward. The accepted criteria for the diagnosis of CF is one phenotypic characteristic of CF (such as lung disease or pancreatic malabsorption), or a positive neonatal screening result, or a positive history of CF in a sibling plus a raised sweat chloride level, positive nasal potential difference (PD) test, or two mutations in the CFTR gene.1 In countries with neonatal screening the diagnosis is made in most cases using either an immunoreactive trypsinogen (IRT) test on a heel prick blood sample or direct detection of genetic mutations.2 Missed cases (false negatives) from screening are almost all pancreatic sufficient with minimal lung disease, and may have a consequent delay in diagnosis.2 In countries which do not yet have neonatal screening for CF, most children present in the first year of life with failure to thrive, recurrent respiratory infections, or both.2 For such children a sweat test is the most important investigation to confirm the diagnosis. Some patients also present with clinical disease later in childhood and into adult life and diagnosis can be more difficult for a number of reasons.

In late diagnosed patients there is a wider range of presenting phenotypes in addition to the common presentations with respiratory infection and pancreatic malabsorption.3 Some present with single organ pulmonary disease (bronchiectasis), pancreatitis, severe sinusitis, or infertility. The explanation for this is that some mutations of the CFTR gene are associated with an atypical phenotype, usually with less severe lung disease. Over 1000 …
Prospective Multicenter Phase II Trial of Systemic ADH-1 in Combination With Melphalan via Isolated Limb Infusion in Patients With Advanced Extremity Melanoma
Authors: Georgia M. Beasley, Jonathan C. Riboh, Christina K. Augustine, Jonathan S. Zager, Steven N. Hochwald, Stephen R. Grobmyer, Bercedis Peterson, Richard Royal, Merrick I. Ross, Douglas S. Tyler
Journal: Journal of Clinical Oncology (2011)

Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity.Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one).To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.
A Phase II Multicenter, Randomized, Double-Blind, Safety Trial Assessing the Pharmacokinetics, Pharmacodynamics, and Efficacy of Oral 2-Methoxyestradiol Capsules in Hormone-Refractory Prostate Cancer
Authors: Christopher Sweeney, Glenn Liu, Constantin Yiannoutsos, Jill Kolesar, Dorothea Horvath, Mary Jane Staab, Karen Fife, Victoria Armstrong, Anthony Treston, Carolyn Sidor, George Wilding
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To determine whether the preclinical antitumor and antiangiogenic activity of 2-methoxyestradiol can be translated to the clinic. Experimental Design: Men with hormone-refractory prostate cancer were enrolled into this phase II randomized, double-blind trial of two doses of oral 2-methoxyestradiol capsules (400 and 1,200 mg/d) given in 4-week cycles. Pharmacokinetic sampling was done on day 1 of cycles 1 and 2 and trough samples were obtained weekly. Results: Thirty-three men were accrued between February and September 2001. The notable toxicity related to therapy was one grade 2 and two grade 3 episodes of liver transaminase elevation, which resolved with continued treatment in two patients. There were two cases of deep venous thromboses. The drug had nonlinear pharmacokinetic, rapid conversion to 2-methoxyestrone and ∼85% conjugation. Trough plasma levels of unconjugated 2-methoxyestradiol and 2-methoxyestrone were ∼4 and 40 ng/mL, respectively. Prostate-specific antigen declines between 21% and 40% were seen in seven patients in the 1,200 mg group and in one patient in the 400 mg group. The higher-dose group showed significantly decreased prostate-specific antigen velocity (P = 0.037) and compared with the 400 mg dose had a longer median time to prostate-specific antigen progression (109 versus 67 days; P = 0.094) and time on study (126 versus 61 days; P = 0.024). There was a 2.5- and 4-fold increase in sex hormone-binding globulin for the 400 and 1,200 mg dose levels, respectively, at days 28 and 56. Conclusion: 2-Methoxyestradiol is well tolerated and, despite suboptimal plasma levels and limited oral bioavailability with this capsule formulation, still showed some anticancer activity at 1,200 mg/d.
An Expression-Based Site of Origin Diagnostic Method Designed for Clinical Application to Cancer of Unknown Origin
Authors: Richard W. Tothill, Adam Kowalczyk, Danny Rischin, Alex Bousioutas, Izhak Haviv, Ryan K. van Laar, Paul M. Waring, John Zalcberg, Robyn Ward, Andrew V. Biankin, Robert L. Sutherland, Susan M. Henshall, Kwun Fong, Jonathan R. Pollack, David D.L. Bowtell, Andrew J. Holloway
Journal: Cancer Research (2005)

Abstract Gene expression profiling offers a promising new technique for the diagnosis and prognosis of cancer. We have applied this technology to build a clinically robust site of origin classifier with the ultimate aim of applying it to determine the origin of cancer of unknown primary (CUP). A single cDNA microarray platform was used to profile 229 primary and metastatic tumors representing 14 tumor types and multiple histologic subtypes. This data set was subsequently used for training and validation of a support vector machine (SVM) classifier, demonstrating 89% accuracy using a 13-class model. Further, we show the translation of a five-class classifier to a quantitative PCR–based platform. Selecting 79 optimal gene markers, we generated a quantitative-PCR low-density array, allowing the assay of both fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tissue. Data generated using both quantitative PCR and microarray were subsequently used to train and validate a cross-platform SVM model with high prediction accuracy. Finally, we applied our SVM classifiers to 13 cases of CUP. We show that the microarray SVM classifier was capable of making high confidence predictions in 11 of 13 cases. These predictions were supported by comprehensive review of the patients' clinical histories.