tbuckley/cabot-search huggingface dataset:
Synergistic Interaction between Histone Deacetylase and Topoisomerase II Inhibitors Is Mediated through Topoisomerase IIβ
Authors: Douglas C. Marchion, Elona Bicaku, Joel G. Turner, Adil I. Daud, Daniel M. Sullivan, Pamela N. Munster
Journal: Clinical Cancer Research (2005)

Abstract Background: DNA topoisomerase II inhibitors and poisons are among the most efficacious drugs for the treatment of cancer. Sensitivity of cancer cells to the cytotoxic effects of topoisomerase II targeting agents is thought to depend on the expression of the topoisomerase IIα isoform, and drug resistance is often associated with loss or mutation of topoisomerase IIα. Histone deacetylase inhibitors (HDACi) are a novel class of compounds that potentiate the antitumor effects of topoisomerase II–targeting agents. Methods: The interaction between HDACi and topoisomerase II–targeting agents in cancer cells was evaluated as a function of topoisomerase IIα and topoisomerase IIβ expression. Topoisomerase II isoforms were selectively depleted using small interfering RNA and antisense. Drug-induced formation of cleavable complexes involving topoisomerase IIα and topoisomerase IIβ was evaluated by trapped-in-agarose DNA immunostaining and band depletion assays in the presence and absence of HDACi. Results: Preexposure to HDACi increased the cytotoxicity of topoisomerase II poisons. This was associated with a down-regulation of topoisomerase IIα expression but had no effects on topoisomerase IIβ. In the setting of HDACi-induced chromatin decondensation and topoisomerase IIα depletion, topoisomerase II poison cytotoxicity was mediated through topoisomerase IIβ cleavable complex formation. The HDACi-induced sensitization was also observed in cells with target-specific resistance to topoisomerase II poisons. Conclusions: The recruitment of topoisomerase IIβ as a target may overcome primary or emergent drug resistance to topoisomerase II–targeting agents and hence may broaden the applicability of this important class of anticancer agents.
Granulocytosis and increased adhesion molecules after resistive loading of the diaphragm
Authors: X. Wang, T-X. Jiang, J. D. Road, D. M. Redenbach, W. D. Reid
Journal: European Respiratory Journal (2005)

Upregulation of endothelial cell adhesion molecules, followed by an influx of granulocytes and macrophages, can contribute to exertion-induced skeletal muscle injury. The purpose of this study was to quantify circulating leukocyte subsets, diaphragm injury and infiltrating leukocyte subsets, and surface expression of vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1 in the diaphragm after inspiratory resistive loading (IRL). Eight New Zealand white rabbits underwent 1.5 h of IRL and seven control rabbits underwent a sham procedure. Blood samples, taken at baseline and 2, 6, 12, 24, 48 and 72 h after the onset of IRL or sham, showed that band cell counts had increased at 6 h post-IRL. Point counting of haematoxylin and eosin-stained cross-sections, sampled at 72 h post-IRL, showed greater injury in diaphragms from IRL rabbits compared with controls. Immunohistochemical processing showed increased expression of ICAM-1 and VCAM-1, and higher granulocyte and macrophage counts in IRL diaphragms than control diaphragms. Macrophages were the predominant inflammatory cells. Increased intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, and infiltration of granulocytes and macrophages may contribute to inspiratory resistive loading-induced diaphragm injury.
Book: The Human Effect in Medicine: Theory, Research and Practice
Authors: I. Heath
Journal: BMJ (2001)

Michael Dixon, Kieran Sweeney Radcliffe Medical Press, £17.95, pp 176 ISBN 1 85775 369 0 Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> Ever since the Enlightenment, medical science has sought to regard the human body as an object that can be analysed scientifically, and its “defects” have been treated accordingly. The subjective experience of the human mind has been marginalised and the inextricable mutual dependence of body and mind within a unique individual ignored. Only now are we rediscovering the extent to which the objective body responds to the values, aspirations, and emotions of the subjective mind. Each individual has the … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
Neutrophil dysfunction and repeated infections: influence of levamisole and ascorbic acid
Authors: A. REBORA, F. DALLEGRI, F. PATRONE
Journal: British Journal of Dermatology (1980)

Neutrophil function was studied in several patients with recurrent infections, mainly of the skin. Twelve patients showed impairment of neutrophil functions, either chemotaxis or bacterial killing and phagocytosis. Levamisole was given in four cases: improvement of neutrophil function and long-lasting clinical remission occurred in three of them, whilst in the fourth the drug was not tolerated. Ascorbic acid was administered to three other patients, with satisfactory improvement of neutrophil function and long-lasting clinical remission.
SNPs in TSPYL-4, NT5DC1 genes are associated with susceptibility to COPD in a southern Chinese Han population
Authors: Yi Guo, Yi Gong, Guochao Shi, Kun Yang, Chunming Pan, Min Li, Qingyun Li, Qijian Cheng, Ranran Dai, Liang Fan, Huanying Wan
Journal: European Respiratory Journal (2012)

Background The risk of developing chronic obstructive pulmonary disease(COPD) is partially genetically determined as well as environmental. Many published candidate gene studies had conflicting results due to different races and sample sizes.

Objectives To investigate candidate genes and haplotype in susceptibility to COPD in a southern Chinese Han population.

Methods We performed genotyping of DNA samples in 200 COPD patients and 250 control subjects according to 54 single nucleotide polymorphisms (SNPs) in 23 genes associated with development of COPD and/or pulmonary function identified by GWAS. We also made linkage disequilibrium (LD) and haplotype analysis according the results of genotyping.

Results The frequencies of the SNP(rs3749893 of testis specific protein Y encoded like 4 (TSPYL-4) gene) G allele and SNP (rs1052443 of 5'-nucleotidase domain containing 1 (NT5DC1) gene) A allele were significantly higher in cases than in controls (p=0.032, p<0.05,OR=0.692, 95%CI=0.495-0.970; P=0.0205, p<0.05, OR=0.670, 95%CI=0.477-0.941, respectively). There were two blocks of SNPs (rs1052443 and rs3749893; rs11155242 and rs6937121) that had sufficient precision to warrant construction of a haplotype block. We constructed the TSPYL-4 and NT5DC1 haplotypes of cases and controls, but with no significantly difference between the two groups. rs3749893 A allele of TSPYL-4 and rs1052443 C allele of NT5DC1 were associated with a protective effect from the deterioration of pulmonary function.

Conclusion TSPYL-4, NT5DC1 genes polymorphism are associated with susceptibility to COPD and pulmonary function in a southern Chinese Han population.
Survival analysis versus event count
Authors: Laurent Arnaud, Herve Devilliers, Zahir Amoura
Journal: Annals of the Rheumatic Diseases (2014)

We read with great interest the article ‘The prognostic value of routinely performed minor salivary gland assessments in primary Sjogren’s syndrome’ by Risselada et al. 1

One of the main findings of the paper is that lymphocytic focus score (LFS) ≥3 contributes significantly and independently to …
Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis
Authors: JB Rasmussen, C Glennow
Journal: European Respiratory Journal (1988)

The clinical effect of N-acetylcysteine (NAC) controlled-release tablets, 300 mg b.i.d., and placebo, in chronic bronchitis was investigated. The study was performed as a double-blind six month comparison between active drug and placebo in two parallel groups, with statistical evaluation after four and six months. The patients were chosen from nine centres. One hundred and sixteen out-patients were included and ninety one of them completed the six month study. The acetylcysteine-treated group had a significantly reduced number of sick-leave days caused by exacerbations of chronic bronchitis after the four winter months December-March compared with the control group (NAC 173, placebo 456). The number of exacerbation days was also very much reduced, however, not significantly (NAC 204, placebo 399). At the end of the six month trial, including also two spring months, the absolute numbers of sick-leave days and exacerbation days were still fewer in the acetylcysteine-treated group, (NAC 260, placebo 739) and (NAC 378, placebo 557) respectively. This study demonstrates a significant reduction in sick-leave days after four months of NAC-treatment. A constant tendency to reduction in the number of exacerbations and exacerbation days was also registered after four and six months. The differences in these parameters were, however, not statistically significant. This was probably due to the small number of patients participating.
Systematic review of interferon-gamma release assays in tuberculosis: focus on likelihood ratios
Authors: K. C. Chang, C. C. Leung
Journal: Thorax (2010)

<h3>Background</h3> Clinical roles of QuantiFERON-TB Gold (QFT-G)/Gold in-Tube (QFT-G-IT) and T-SPOT.TB in tuberculosis require clarification. <h3>Methods</h3> MEDLINE and EMBASE were searched for relevant English papers. Summary estimates of likelihood ratios (LR) of QFT-G/QFT-G-IT and T-SPOT.TB for latent tuberculosis infection (LTBI) and tuberculosis disease in adults were obtained by bivariate and univariate random effects meta-analyses after assessing heterogeneity. Probable ranges of prevalence for LTBI and tuberculosis disease were estimated. Critical values of positive LR (PLR) and negative LR (NLR) corresponding to a 90% certainty threshold were calculated over probable prevalence ranges. It was considered reliable to rule in when the best estimated PLR exceeds the corresponding critical value and to rule out when the best estimated NLR is less than the corresponding critical value. <h3>Results</h3> 35 studies involving predominantly immunocompetent adults were identified. Based on bivariate meta-analysis, PLR (95% CI) for LTBI were 7.9 (3.6 to 17.3) for T-SPOT.TB and 48.1 (19.7 to 117.6) and 10.8 (5.3 to 21.8) for QFT-G/QFT-G-IT based on Japanese and other studies, respectively. Corresponding NLR (95% CI) were 0.10 (0.06 to 0.18), 0.11 (0.07 to 0.18) and 0.23 (0.16 to 0.32). PLR (95% CI) for tuberculosis disease were 3.6 (2.3 to 5.6) for QFT-G, 2.1 (1.1 to 4.0) for QFT-G-IT and 4.7 (2.4 to 9.1) and 2.3 (1.3 to 4.0) for T-SPOT.TB based on studies with mean or median age &gt;47. 1 years and ≤47.1 years, respectively. Corresponding NLR (95% CI) were 0.18 (0.12 to 0.27), 0.38 (0.22 to 0.68), 0.11 (0.06 to 0.20) and 0.20 (0.10 to 0.40). Estimated prevalence ranges were 10–55% for LTBI and 40–60% for tuberculosis disease. <h3>Conclusions</h3> At a 90% certainty threshold, LTBI is best diagnosed by QFT-G/QFT-G-IT and excluded by T-SPOT.TB or QFT-G/QFT-G-IT; none can diagnose tuberculosis disease, whereas. T-SPOT.TB can exclude tuberculosis disease among middle-aged and older patients.
Advances in tuberculosis 2011–2012
Authors: Heather J Zar, Zarir F Udwadia
Journal: Thorax (2013)

Renewed global interest and funding for tuberculosis (TB) has led to increased research and publications, with several recent advances. The increased incidence of drug resistant TB and emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB globally has strengthened the need for improved rapid diagnostics and better treatment regimens. The HIV and TB epidemics have further impacted on TB research, necessitating the development of better preventive and treatment strategies. Important recent strides in adult TB include more widespread validation of molecular techniques and advances in therapeutics, including major drug trials with existing and novel agents and even a putative new regimen. Studies in childhood TB have led to increased understanding of the paediatric burden, new possibilities for rapid diagnosis and advances in preventive strategies. There are still several research priorities that must be addressed including development of better diagnostics, defining biomarkers of TB disease or correlates of protection, shorter more effective regimens for prophylaxis and for treatment, and development of an improved safe vaccine that offers protection against pulmonary disease. Operational research to inform more widespread implementation of research findings is needed in order to benefit optimally from recent advances.
Phase III Trial of Androgen Ablation With or Without Three Cycles of Systemic Chemotherapy for Advanced Prostate Cancer
Authors: Randall E. Millikan, Sijin Wen, Lance C. Pagliaro, Melissa A. Brown, Brenda Moomey, Kim-Anh Do, Christopher J. Logothetis
Journal: Journal of Clinical Oncology (2008)

We conducted a phase III trial in patients with previously untreated metastatic prostate cancer to test the hypothesis that three 8-week cycles of ketoconazole and doxorubicin alternating with vinblastine and estramustine, given in addition to standard androgen deprivation, would delay the appearance of castrate-resistant disease.Eligible patients had metastatic prostate cancer threatening enough to justify sustained androgen ablation and were fit enough for chemotherapy. The primary end point was time to castrate-resistant progression as shown by increasing prostate-specific antigen, new radiographic lesions, worsening cancer-related symptoms, or receipt of any other systemic therapy.Three hundred six patients were registered; 286 are reported. Median time to progression was 24 months (95% CI, 18 to 39 months) in the standard therapy arm, and 35 months (95% CI, 26 to 44 months) in the chemohormonal group (P = .39). At median follow-up of 6.4 years, overall survival was 5.4 years (95% CI, 4.7 to 7.8 years) in the standard therapy arm versus 6.1 years (95% CI, 5.1 to 10.1 years; P = .41). Prostate-specific antigen kinetics at the time of androgen ablation and the nadir after hormone treatment were strongly correlated with survival. Chemotherapy significantly increased the burden of therapy, with 51% of patients experiencing an adverse event of grade 3 or worse, especially thromboembolic events.There is no role for ketoconazole and doxorubicin alternating with vinblastine and estramustine before emergence of a castrate-resistant phenotype.
Health professionals call for urgent halt to fracking because of public health concerns
Authors: J. Pakpoor
Journal: BMJ (2015)

A health professionals’ campaigning group has called for an immediate moratorium on fracking for shale gas in the United Kingdom until a comprehensive assessment of the effects on public health and the environment is completed.

The report from Medact described fracking as an “inherently risky” practice.1 It highlights numerous potential health hazards associated with hydraulic fracturing for shale gas, or “fracking,” including air pollution and water contamination; negative effects on health associated with noise, traffic, spoilage of the natural environment, and local and socioeconomic disruption; and the indirect effects of climate change as a …
Risk for Cancer in Parents of Patients With Schizophrenia
Authors: Susanne Oksbjerg Dalton, Thomas Munk Laursen, Lene Mellemkjær, Christoffer Johansen, Preben Bo Mortensen
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: This study attempted to determine whether a genetic protection against cancer might be manifest in parents of offspring with schizophrenia. METHOD: Using data from the Danish Central Population Registry, the authors identified 1,999,072 parents of offspring born after 1935. By linking this nationwide population-based parent cohort to the Danish Psychiatric Central Register, they identified 19,856 parents of offspring with schizophrenia. Follow-up for cancer in the Danish Cancer Registry began on the date of birth of the oldest child or April 1, 1969, and ended on the date of cancer diagnosis, death, or Dec. 31, 1997, yielding a total of 48,343,430 person-years at risk and 211,681 cases of cancer. The relative risk for cancer among parents with schizophrenic offspring compared to parents with no schizophrenic offspring was estimated by Poisson regression analysis and adjusted for age, period, and number of children. RESULTS: The risk for all cancer was 1.01 for fathers and 1.00 for mothers of schizophrenics. Mothers of schizophrenic patients had an increased risk of 1.20 for lung cancer and a nonsignificant risk of 1.14 for tobacco-related cancers combined. Apart from a reduced risk for leukemia in both mothers and fathers of schizophrenics, there was no difference in risk for any other cancer. DISCUSSION: This study does not confirm a previously reported reduced risk for cancer in parents of schizophrenic patients and provides no support for genetic protection against cancer in families with schizophrenia.
Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy
Authors: Lin Zhong, Manuel Chiusa, Adrian G. Cadar, Angel Lin, Susan Samaras, Jeffrey M. Davidson, Chee C. Lim
Journal: Cardiovascular Research (2015)

Accumulating evidence suggest that sarcomere signalling complexes play a pivotal role in cardiomyocyte hypertrophy by communicating stress signals to the nucleus to induce gene expression. Ankyrin repeat domain 1 (ANKRD1) is a transcriptional regulatory protein that also associates with sarcomeric titin; however, the exact role of ANKRD1 in the heart remains to be elucidated. We therefore aimed to examine the role of ANKRD1 in cardiomyocyte hypertrophic signalling. In neonatal rat ventricular myocytes, we found that ANKRD1 is part of a sarcomeric signalling complex that includes ERK1/2 and cardiac transcription factor GATA4. Treatment with hypertrophic agonist phenylephrine (PE) resulted in phosphorylation of ERK1/2 and GATA4 followed by nuclear translocation of the ANKRD1/ERK/GATA4 complex. Knockdown of Ankrd1 attenuated PE-induced phosphorylation of ERK1/2 and GATA4, inhibited nuclear translocation of the ANKRD1 complex, and prevented cardiomyocyte growth. Mice lacking Ankrd1 are viable with normal cardiac function. Chronic PE infusion in wild-type mice induced significant cardiac hypertrophy with reactivation of the cardiac fetal gene program which was completely abrogated in Ankrd1 null mice. In contrast, ANKRD1 does not play a role in haemodynamic overload as Ankrd1 null mice subjected to transverse aortic constriction developed cardiac hypertrophy comparable to wild-type mice. Our study reveals a novel role for ANKRD1 as a selective regulator of PE-induced signalling whereby ANKRD1 recruits and localizes GATA4 and ERK1/2 in a sarcomeric macro-molecular complex to enhance GATA4 phosphorylation with subsequent nuclear translocation of the ANKRD1 complex to induce hypertrophic gene expression.
Pulmonary sarcoidosis presenting as a granulomatous tattoo reaction
Authors: P. COLLINS, A.T. EVANS, W. GRAY, D.A. LEVISON
Journal: British Journal of Dermatology (1994)

Summary A 29-year-old man presented with nodular skin lesions localized to areas of navy-blue pigmentation within a tattoo. Light microscopy demonstrated well-defined epithelioid granulomata in close relation to blue and black pigment. Although the patient was asymptomatic, a chest X-ray showed bilateral pulmonary shadowing, and histology of a transbronchial biopsy specimen showed features compatible with a diagnosis of sarcoidosis. X-ray energy dispersive spectroscopy identified copper and titanium in the tattoo pigment. These elements were not found in tissue from the lung biopsy. The cutaneous eruption resolved with oral steroid therapy. Our observations suggest that the granulomatous reaction in the tattoo was a manifestation of sarcoidosis. Rather than a specific reaction to pigment.
Neural Control of the Lower Esophageal Sphincter INFLUENCE OF THE VAGUS NERVES
Authors: Satish Rattan, Raj K. Goyal
Journal: Journal of Clinical Investigation (1974)

We performed studies in the opossum to define the influence of the vagi in the control of lower esophageal sphincter (LES) function. Bilateral vagotomy caused transient sphincter hypertension which was prevented by phentolamine and by atropine. Stimulation of the peripheral end of vagus, after bilateral cervical vagotomy, caused relaxation of the LES over a wide range of frequency and intensity of electrical stimulation. The relaxation was less marked at the lower frequencies of stimulation, and atropine treatment did not enhance this relaxation. In other experiments, atropine treatment reversed the rise in gastric (fundic) pressure with the vagal stimulation, but atropine did not enhance the degree of LES relaxation. Stimulation of the central end of the vagus caused an increase in LES pressure due to a centrally mediated reflex; the efferents for this motor response were not present in the vagi, as the reflex contraction persisted after bilateral vagotomy. The LES contraction with the stimulation of the vagal afferents was antagonized by phentolamine as well as by atropine. These studies suggest that: (a) the vagi do not mediate any cholinergic excitatory influences to the LES and the vagal influence of the sphincter is entirely inhibitory; (b) the vagi carry afferent fibres for a centrally mediated neural reflex which contracts the LES, but the efferent path of this reflex arc does not lie in the vagi.
A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells.
Authors: F Powrie, J Carlino, M W Leach, S Mauze, R L Coffman
Journal: The Journal of Experimental Medicine (1996)

A T helper type 1 (Th1)-mediated colitis with similarities to inflammatory bowel disease in humans developed in severe combined immunodeficiency mice reconstituted with CD45RB(high) CD4+ splenic T cells and could be prevented by cotransfer of CD45RB(low) CD4+ T cells. Inhibition of this Th1 response by the CD45RB(low) T cell population could be reversed in vivo by an anti-transforming growth factor (TGF) beta antibody. Interleukin (IL) 4 was not required for either the differentiation of function of protective cells as CD45RB(low) CD4+ cells from IL-4-deficient mice were fully effective. These results identify a subpopulation of peripheral CD4+ cells and TGF-beta as critical components of the natural immune regulatory mechanism, which prevents the development of pathogenic Th1 responses in the gut, and suggests that this immunoregulatory population is distinct from Th2 cells.