tbuckley/cabot-search huggingface dataset:
Fixing cystic fibrosis CFTR with correctors and potentiators. Off to a good start
Authors: J Stuart Elborn
Journal: Thorax (2011)

Since the cloning of the cystic fibrosis transmembrane regulator (CFTR) protein in the late 1980s and subsequent significant advances in understanding the pathophysiology of cystic fibrosis (CF) there have been high expectations that transformative, disease-modifying therapies could be developed.1 2 Dysfunction of the CFTR protein results in significant reduction or absence of chloride transport and dysregulation of sodium transport.3–5 Other cationic ions such as bicarbonate may also be transported by CFTR and the interaction with the epithelial sodium channel ENaC still remains to be elucidated.6 7 However, a significant number of in vitro and animal studies strongly support the premise that correction of CFTR function is possible and will make a significant impact on the CF phenotype, particularly in the lung, which accounts for most of the morbidity and mortality from this condition.7 Two approaches to correction of CFTR function are currently being pursued: one based on gene transfer therapy and the other on small molecule modulators.

Gene therapy attempts to correct CFTR dysfunction in CF by transfection of airway cells with the wild-type CFTR gene to enable cells to express functional CFTR.8 Progress with this approach has been slow and methodical. Early studies suggest that it is possible to transfect nasal and bronchial epithelial cells and this results in a modest electrophysiological improvement.9 10 To date, there are no clinical studies in humans to determine if sufficient gene transfer can be achieved to result in a clinically meaningful benefit. A two-centre, double-blind, placebo-controlled trial of CF gene therapy is due to commence in the UK in 2012 using a specifically designed plasmid and a GL67 liposome complex. The results of this proof of concept study will help determine if gene therapy has the potential to provide a treatment which will benefit all mutation …
Haplotypes, Loss of Heterozygosity, and Expression Levels of Glycine <i>N</i>-Methyltransferase in Prostate Cancer
Authors: Yu-Chuen Huang, Cheng-Ming Lee, Marcelo Chen, Ming-Yi Chung, Yen-Hwa Chang, William Ji-Shian Huang, Donald Ming-Tak Ho, Chin-Chen Pan, Tony T. Wu, Stone Yang, Ming-Wei Lin, Jer-Tsong Hsieh, Yi-Ming Arthur Chen
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. In a previous study, we showed that GNMT acts as a susceptibility gene for hepatocellular carcinoma. Here, we report on our efforts to characterize the haplotypes, loss of heterozygosity (LOH), and expression levels of the GNMT in prostate cancer. Experimental Design: Peripheral blood mononuclear cell DNA collected from 326 prostate cancer patients and 327 age-matched controls was used to determine GNMT haplotypes. Luciferase reporter constructs were used to compare the promoter activity of different GNMT haplotypes. GNMT LOH rates in tumorous specimens were investigated via a comparison with peripheral blood mononuclear cell genotypes. Immunohistochemical staining was used to analyze GNMT expression in tissue specimens collected from 5 normal individuals, 33 benign prostatic hyperplasia patients, and 45 prostate cancer patients. Results: Three major GNMT haplotypes were identified in 92% of the participants: A, 16GAs/DEL/C (58%); B, 10GAs/INS/C (19.9%); and C, 10GAs/INS/T (14.5%). Haplotype C carriers had significantly lower risk for prostate cancer compared with individuals with haplotype A (odds ratio, 0.68; 95% confidence interval, 0.48-0.95). Results from a phenotypic analysis showed that haplotype C exhibited the highest promoter activity (P &amp;lt; 0.05, ANOVA test). In addition, 36.4% (8 of 22) of the prostatic tumor tissues had LOH of the GNMT gene. Immunohistochemical staining results showed abundant GNMT expression in normal prostatic and benign prostatic hyperplasia tissues, whereas it was diminished in 82.2% (37 of 45) of the prostate cancer tissues. Conclusions: Our findings suggest that GNMT is a tumor susceptibility gene for prostate cancer.
Adenosine, adenosine receptors and myocardial protection An updated overview
Authors: K Mubagwa
Journal: Cardiovascular Research (2001)

Adenosine (Ado) accumulates in tissues under metabolic stress. On myocardial cells, the nucleoside interacts with various receptor subtypes (A1, A3, and probably A2A and A2B) that are coupled, via G proteins, to multiple effectors, including enzymes, channels, transporters and cytoskeletal components. Studies using Ado receptor agonists and antagonists, as well as animals overexpressing the A1 receptor indicate that Ado exerts anti-ischemic action. Ado released during preconditioning (PC) by short periods of ischemia followed by reperfusion induces cardioprotection to a subsequent sustained ischemia. This protective action is mediated by A1 and A3 receptor subtypes and involves the activation and translocation of PKC to sarcolemmal and to mitochondrial membranes. PKC activation leads to an increased opening of ATP-sensitive K+ (KATP) channels. Recent studies implicate mitochondrial rather than sarcolemmal KATP channels in the protective action of PC. Other effectors possibly contributing to cardioprotection by Ado or PC, and which seem particularly involved in the delayed (second window of) protection, include MAP kinases, heat shock proteins and iNOS. Because of its anti-ischemic effects, Ado has been tested as a protective agent in clinical interventions such as PTCA, CABG and tissue preservation, and was found in most cases to enhance the post-ischemic recovery of function. The mechanisms underlying the role of Ado and of mitochondrial function in PC are not completely clear, and uncertainties remain concerning the role played by newly identified potential effectors such as free radicals, the sarcoplasmic reticulum, etc. In addition, more studies are needed to clarify the signalling mechanisms by which A3 receptor activation or overexpression may promote apoptosis and cellular injury, as reported by a few recent studies.
S0356: A Phase II Clinical and Prospective Molecular Trial With Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy Before Surgery for Patients With Esophageal Adenocarcinoma
Authors: Lawrence P. Leichman, Bryan H. Goldman, Pierre O. Bohanes, Heinz J. Lenz, Charles R. Thomas, Kevin G. Billingsley, Christopher L. Corless, Syma Iqbal, Philip J. Gold, Jacqueline K. Benedetti, Kathleen D. Danenberg, Charles D. Blanke
Journal: Journal of Clinical Oncology (2011)

Purpose Pathologic complete response (pCR) after neoadjuvant therapy for locally advanced esophageal adenocarcinoma is associated with improved survival. The Southwest Oncology Group designed a trimodality, phase II, single-arm trial with objectives of achieving a pCR rate of 40% with prospective exploratory analyses of intratumoral molecular markers postulated to affect response and survival. Patients and Methods Patients with clinically staged II or III esophageal adenocarcinoma received oxaliplatin 85 mg/m 2 on days 1, 15, and 29; protracted-infusion fluorouracil (PI-FU) 180 mg/m 2 /d on days 8 through 43; and external-beam radiation therapy (EBRT) 5 days a week at 1.8 Gy/d for 25 fractions; surgery was performed 28 to 42 days after neoadjuvant therapy. Chemotherapy was planned after surgery. Tumors were analyzed for mRNA expression and polymorphisms in genes involved in drug metabolism and DNA repair. Results Ninety-three patients were evaluable. Two deaths (2.2%) were attributable to preoperative therapy, and two deaths (2.2%) were attributable to surgery. Grade 3 and 4 toxicities were recorded for 47.3% and 19.4% of patients, respectively. Seventy-nine patients (84.9%) underwent surgery; 67.7% of patients had R0 resections. Twenty-six patients (28.0%) had confirmed pCR (95% CI, 19.1% to 38.2%). At a median follow-up of 39.2 months, estimates of median and 3-year overall survival (OS) were 28.3 months and 45.1%, respectively. Intratumoral ERCC-1 gene expression was inversely related to progression-free survival and OS. Conclusion Neoadjuvant oxaliplatin, PI-FU, and EBRT for esophageal adenocarcinoma is active and tolerable. Because the regimen failed to meet the primary end point, it does not define a new standard. However, future trials can be built on this platform to validate the role of ERCC-1 in determining the best systemic regimen for individual patients.
Identifying Muir-Torre syndrome in a patient with glioblastoma multiforme
Authors: Deric M. Park, Gabrielle A. Yeaney, Ronald L. Hamilton, Jennifer Mabold, Nikki Urban, Leonard Appleman, John Flickinger, Frank Lieberman, Arlan Mintz
Journal: Neuro-Oncology (2008)

Patients with Muir-Torre syndrome, an autosomal-dominant familial tumor condition caused by germline mutation of the DNA mismatch repair genes, MSH2 or MLH1, present with tumors of the sebaceous gland and visceral malignancies characterized by microsatellite instability. Here we show development of glioblastoma multiforme in a patient with Muir-Torre syndrome. Immunohistochemical analysis of the brain tumor and colon cancer revealed loss of the DNA mismatch repair gene detected by the genetic test, suggesting a pathogenic link.
Telomere Shortening in Familial and Sporadic Pulmonary Fibrosis
Authors: Jennifer T. Cronkhite, Chao Xing, Ganesh Raghu, Kelly M. Chin, Fernando Torres, Randall L. Rosenblatt, Christine Kim Garcia
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres.
The Precompetitive Space: Time to Move the Yardsticks
Authors: Thea Norman, Aled Edwards, Chas Bountra, Stephen Friend
Journal: Science Translational Medicine (2011)

Industry, government, patient advocacy groups, public funders, and academic thought leaders met in Toronto, Canada, to set into motion an initiative that addresses some of the scientific and organizational challenges of modern therapeutics discovery. What emerged from the meeting was a public-private partnership that seeks to establish proof of clinical mechanism (POCM) for selected "pioneer" disease targets using lead compounds-all accomplished in the precompetitive space. The group will reconvene in April 2011 to create a business plan that specifies the generation of two positive POCM results per year.
Load Independence of the Instantaneous Pressure-Volume Ratio of the Canine Left Ventricle and Effects of Epinephrine and Heart Rate on the Ratio
Authors: HIROYUKI SUGA, KIICHI SAGAWA, ARTIN A. SHOUKAS
Journal: Circulation Research (1973)

As a means of assessing ventricular performance, we analyzed the time-varying ratio of instantaneous pressure, P(t), to instantaneous volume, V(t), in the canine left ventricle. Intraventricular volume was measured by plethysmography, while the right heart was totally bypassed. The cardiac nerves were sectioned, and an epinephrine infusion was used to alter the contractile state. The instantaneous pressure-volume ratio was defined as E(t) = P(t)/[V(t) - V d ], where V d is an experimentally determined correction factor. We found that (1) all the E(t) curves thus defined were similar in their basic shape and attained their peak near the end of the ejection phase regardless of the mechanical load, the contractile state, or the heart rate, (2) under a constant heart rate and contractile state extensive changes in preload, afterload, or both did not alter the peak value of E(t), Emax, or the time to Emax from the onset of systole, Tmax, and (3) these parameters of E(t) markedly changed with epinephrine infusion or increases in heart rate. At an epinephrine infusion rate of 2 µg/kg min -1 , Emax increased to 12.2 ± 4.5 ( SD ) mm Hg/ml (N = 9) from its control value of 6.6 ± 1.2 mm Hg/ml before the infusion. Simultaneously, Tmax shortened from 191 ± 29 msec to 157 ± 26 msec. Increases in the paced heart rate proportionally shortened Tmax (45% per 100-beats/min change in heart rate) without any effect on Emax. We concluded that E(t), represented by Emax and Tmax, explicitly reflects the ventricular contractility.
Recent Clinical Advances in Lung Cancer Management
Authors: David H. Johnson, Joan H. Schiller, Paul A. Bunn
Journal: Journal of Clinical Oncology (2014)

Progress in lung cancer therapy has been slow but steady and has accelerated due to improvements in scientific basis for the disease and to technologic advances in diagnosis and therapy. The elusive goal of reduced mortality rates can be achieved in the next 50 years through continued interdisciplinary research efforts.
Cryotherapy versus salicylic acid for the treatment of plantar warts (verrucae): a randomised controlled trial
Authors: S. Cockayne, C. Hewitt, K. Hicks, S. Jayakody, A. R. Kang'ombe, E. Stamuli, G. Turner, K. Thomas, M. Curran, G. Denby, F. Hashmi, C. McIntosh, N. McLarnon, D. Torgerson, I. Watt
Journal: BMJ (2011)

<b>Objective</b> To compare the clinical effectiveness of cryotherapy versus salicylic acid for the treatment of plantar warts. <b>Design</b> A multicentre, open, two arm randomised controlled trial. <b>Setting</b> University podiatry school clinics, NHS podiatry clinics, and primary care in England, Scotland, and Ireland. <b>Participants</b> 240 patients aged 12 years and over, with a plantar wart that in the opinion of the healthcare professional was suitable for treatment with both cryotherapy and salicylic acid. <b>Interventions</b> Cryotherapy with liquid nitrogen delivered by a healthcare professional, up to four treatments two to three weeks apart. Patient self treatment with 50% salicylic acid (Verrugon) daily up to a maximum of eight weeks. <b>Main outcome measures</b> Complete clearance of all plantar warts at 12 weeks. Secondary outcomes were (<i>a</i>) complete clearance of all plantar warts at 12 weeks controlling for age, whether the wart had been treated previously, and type of wart, (<i>b</i>) patient self reported clearance of plantar warts at six months, (<i>c</i>) time to clearance of plantar wart, (<i>d</i>) number of plantar warts at 12 weeks, and (<i>e</i>) patient satisfaction with the treatment. <b>Results</b> There was no evidence of a difference between the salicylic acid and cryotherapy groups in the proportions of participants with complete clearance of all plantar warts at 12 weeks (17/119 (14%) <i>v</i> 15/110 (14%), difference 0.65% (95% CI –8.33 to 9.63), P=0.89). The results did not change when the analysis was repeated but with adjustment for age, whether the wart had been treated previously, and type of plantar wart or for patients' preferences at baseline. There was no evidence of a difference between the salicylic acid and cryotherapy groups in self reported clearance of plantar warts at six months (29/95 (31%) <i>v</i> 33/98 (34%), difference –3.15% (–16.31 to 10.02), P=0.64) or in time to clearance (hazard ratio 0.80 (95% CI 0.51 to 1.25), P=0.33). There was also no evidence of a difference in the number of plantar warts at 12 weeks (incident rate ratio 1.08 (0.81 to 1.43), P=0.62). <b>Conclusions</b> Salicylic acid and the cryotherapy were equally effective for clearance of plantar warts. <b>Trial registration</b> Current Controlled Trials ISRCTN18994246, National Research Register N0484189151.
Expression of the Brn-3b Transcription Factor Correlates with Expression of HSP-27 in Breast Cancer Biopsies and Is Required for Maximal Activation of the HSP-27 Promoter
Authors: Sonia A. Lee, Daniel Ndisang, Chandrakant Patel, Jonathan H. Dennis, David J. Faulkes, Corrado D'Arrigo, Laila Samady, Saleha Farooqui-Kabir, Richard J. Heads, David S. Latchman, Vishwanie S. Budhram-Mahadeo
Journal: Cancer Research (2005)

Abstract In breast cancer, overexpression of the small heat shock protein, HSP-27, is associated with increased anchorage-independent growth, increased invasiveness, and resistance to chemotherapeutic drugs and is associated with poor prognosis and reduced disease-free survival. Therefore, factors that increase the expression of HSP-27 in breast cancer are likely to affect the prognosis and outcome of treatment. In this study, we show a strong correlation between elevated levels of the Brn-3b POU transcription factor and high levels of HSP-27 protein in manipulated MCF-7 breast cancer cells as well as in human breast biopsies. Conversely, HSP-27 is decreased on loss of Brn-3b. In cotransfection assays, Brn-3b can strongly transactivate the HSP-27 promoter, supporting a role for direct regulation of HSP-27 expression. Brn-3b also cooperates with the estrogen receptor (ER) to facilitate maximal stimulation of the HSP-27 promoter, with significantly enhanced activity of this promoter observed on coexpression of Brn-3b and ER compared with either alone. RNA interference and site-directed mutagenesis support the requirement for the Brn-3b binding site on the HSP-27 promoter, which facilitates maximal transactivation either alone or on interaction with the ER. Chromatin immunoprecipitation provides evidence for association of Brn-3b with the HSP-27 promoter in the intact cell. Thus, Brn-3b can, directly and indirectly (via interaction with the ER), activate HSP-27 expression, and this may represent one mechanism by which Brn-3b mediates its effects in breast cancer cells.
The Low Evolutionary Rate of Human T-Cell Lymphotropic Virus Type-1 Confirmed by Analysis of Vertical Transmission Chains
Authors: S. Van Dooren
Journal: Molecular Biology and Evolution (2003)

The evolutionary rate of the human T-cell lymphotropic virus type-1 (HTLV-1) is considered to be very low, in strong contrast to the related human retrovirus HIV. However, current estimates of the HTLV-1 rate rely on the anthropological calibration of phylogenies using assumed dates of human migration events. To obtain an independent rate estimate, we analyzed two variable regions of the HTLV-1 genome (LTR and env) from eight infected families. Remarkable genetic stability was observed, as only two mutations in LTR (756 bp) and three mutations in env (522 bp) occurred within the 16 vertical transmission chains, including one ambiguous position in each region. The evolutionary rate in HTLV-1 was then calculated using a maximum-likelihood approach that used the highest and lowest possible times of HTLV-1 shared ancestry, given the known transmission histories. The rates for the LTR and env regions were 9.58 x 10(-8)-1.25 x 10(-5) and 7.84 x 10(-7) -2.33 x 10(-5)nucleotide substitutions per site per year, respectively. A more precise estimate was obtained for the combined LTR-env data set, which was 7.06 x 10(-7)-1.38 x 10(-5)substitutions per site per year. We also note an interesting correlation between the occurrence of mutations in HTLV-1 and the age of the individual infected.
A phase I–II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer
Authors: G.A. Masters, A.M. Mauer, Ph.C. Hoffman, D. Wyka, B.L. Samuels, S.A. Krauss, S. Watson, H. Golomb, E.E. Vokes
Journal: Annals of Oncology (1998)
Restrictive lung disease in rats exposed chronically to an urban profile of ozone.
Authors: D L Costa, J S Tepper, M A Stevens, W P Watkinson, D L Doerfler, T R Gelzleichter, J A Last
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

The potential for irreversible lung impairment resulting from life-long ozone (O3) exposure remains uncertain. To address this question, young adult rats (male, F-344) were exposed to a simulated urban profile of O3 for 1, 3, 13, 52, or 78 wk, after which pulmonary function tests were performed. To assess reversibility of effects, cohorts from the 13-, 52-, and 78-wk groups were evaluated, respectively, after an additional 6, 27, and 17 wk of clean air. Static and dynamic lung properties were based on measurements of lung volume apportionment, respiratory system compliance (Crs), DLCO, multibreath N2 washout, and maximum expiratory flow-volume relationships. Electrocardiography was also performed in unanesthetized, restrained rats after 52 and 78 wk, as were determinations of wet and dry lung weights, lung collagen, and associated connective tissue crosslinks. Small (< 10%) but significant reductions in TLC and RV were noted after 13, 52, and 78 wk of O3 exposure. At 13 and 52 wk, N2 washout was enhanced, though at 78 wk it was similar to control. None of these changes appeared progressive with continued O3 exposure. Post exposure to clean air did not completely reverse the reduction in TLC. Additionally, Crs, though not affected during O3 exposure, decreased during the air recovery. No O3-related changes in collagen were apparent, however. Thus, near life-long exposure of F-344 rats to a worse-case, urban profile of O3 appears to have led to a functionally restrictive, i.e. "stiffened," lung without overt fibrosis. Furthermore, certain aspects of the O3-induced effect were not fully reversible.
Pulmonary fibrosis with predominant CD8 lymphocytic alveolitis and anti-Jo-1 antibodies
Authors: A Sauty, T Rochat, OD Schoch, J Hamacher, AM Kurt, JM Dayer, LP Nicod
Journal: European Respiratory Journal (1997)

Interstitial lung disease (ILD) is a complication of polymyositis (PM) and dermatomyositis (DM). It often manifests itself in association with myositis-specific antisynthetase autoantibodies, among which anti-Jo-1 antibodies are the most commonly encountered. In contrast, ILD associated with anti-Jo-1 antibodies without muscle involvement is rare and not well characterized. We report four patients presenting with ILD associated with anti-Jo-1 antibodies. Histological findings of transbronchial biopsies disclosed a pattern consistent with nonspecific interstitial pneumonitis, a CD8+ lymphocytosis was found in bronchoalveolar lavage. Only one of these patients developed an "antisynthetase syndrome" with PM, after nearly 2 yrs of severe ILD. The clinical conditions of all four cases showed stabilization or improvement when cyclosporine was added to their immunosuppressive treatment. These cases confirm that a CD8+ lymphocytic interstitial lung disease may be the first, and sole manifestation of autoimmune disease associated with anti-Jo-1 antibodies. Furthermore, they suggest that this form of interstitial lung disease apparently has a poor response to steroids and cytotoxic drugs, but may respond to moderate doses of cyclosporine and azathioprine in addition to low doses of steroids.