tbuckley/cabot-search huggingface dataset:
Randomized Phase II Trial of a Toll-Like Receptor 9 Agonist Oligodeoxynucleotide, PF-3512676, in Combination With First-Line Taxane Plus Platinum Chemotherapy for Advanced-Stage Non–Small-Cell Lung Cancer
Authors: Christian Manegold, Donald Gravenor, Donald Woytowitz, Jörg Mezger, Vera Hirsh, Gary Albert, Mohammed Al-Adhami, David Readett, Arthur M. Krieg, Cynthia Gail Leichman
Journal: Journal of Clinical Oncology (2008)

Purpose This study assessed the efficacy of the combination of standard taxane plus platinum chemotherapy with the synthetic Toll-like receptor 9–activating oligodeoxynucleotide PF-3512676 in patients with non–small-cell lung cancer (NSCLC). Patients and Methods Chemotherapy-naive patients with stage IIIB to IV NSCLC were randomly assigned (one to two ratio) to receive four to six cycles of taxane/platinum chemotherapy alone or with 0.2 mg/kg of subcutaneous PF-3512676 on days 8 and 15 of each 3-week cycle. The primary end point was objective response rate (ORR). Results Baseline demographics were similar between treatment arms, although significantly more patients in the PF-3512676 arm had stage IV disease (85% compared with 62% in the chemotherapy-alone arm). The modified intent-to-treat analysis (n = 111) demonstrated a 38% ORR (confirmed and unconfirmed) in the PF-3512676 arm (n = 74) and 19% in the chemotherapy-alone arm (n = 37) by investigator evaluation. Blinded, independent radiologic review for 90 patients showed a similar trend in confirmed response rate (19% and 11%, respectively). Median survival was 12.3 months in the PF-3512676 arm and 6.8 months in the chemotherapy-alone arm, and 1-year survival was 50% and 33%, respectively. Mild to moderate local injection site reactions and flu-like symptoms were the most common PF-3512676–related adverse events, but grade 3/4 neutropenia, thrombocytopenia, and anemia were all reported more commonly for patients in the PF-3512676 arm. Conclusion The addition of PF-3512676 to taxane plus platinum chemotherapy for first-line treatment of NSCLC improves objective response and may improve survival. Confirmatory phase III trials are ongoing.
Familial primary spontaneous pneumothorax consistent with true autosomal dominant inheritance.
Authors: P J Morrison, R C Lowry, N C Nevin
Journal: Thorax (1998)

A family exhibiting spontaneous pneumothorax in a father and three offspring (two sons, and one daughter) is described. The mode of inheritance is apparently autosomal dominant with two episodes of male to male transmission in one family. The age of onset varied by up to 13 years within the family. Isolated autosomal dominant pneumothorax appears to be a distinct clinical entity.
A Study of Seventy Cases.
Authors: C. M. R. VESEY, D. S. WILKINSON
Journal: British Journal of Dermatology (1959)

Journal Article A Study of Seventy Cases. Get access C. M. R. VESEY, M.B., B.S., D.C.H., C. M. R. VESEY, M.B., B.S., D.C.H. Aylesbury and High Wycombe Area Hospitals Search for other works by this author on: Oxford Academic Google Scholar D. S. WILKINSON, M.D., M.R.C.P. D. S. WILKINSON, M.D., M.R.C.P. Aylesbury and High Wycombe Area Hospitals Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 71, Issue 4, 1 April 1959, Pages 139–155, https://doi.org/10.1111/j.1365-2133.1959.tb13399.x Published: 01 April 1959
Expression of KCNA10, a Voltage-Gated K Channel, in Glomerular Endothelium and at the Apical Membrane of the Renal Proximal Tubule
Authors: Xiaoqiang Yao, Shulan Tian, Ho-Yu Chan, Daniel Biemesderfer, Gary V. Desir
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Potassium (K) channels regulate cell membrane potential and modulate a number of important cellular functions. KCNA10 is a cyclic nucleotide-gated, voltage-activated K channel that is detected in kidney, heart, and aorta by Northern blot and postulated to participate in renal K metabolism and to regulate vascular tone. The aim of this study was to establish the cellular and subcellular localization of KCNA10 in kidney and vascular tissues. An anti-KCNA10 polyclonal antibody was generated, and immunocytochemical studies were performed on rat kidney. KCNA10 protein was easily detectable at the apical membrane of rat proximal tubular cells, and a weaker signal was also evident in the glomerulus. In situ hybridization experiments confirmed the immunocytochemical studies and revealed KCNA10 expression in human proximal tubular cells, glomerular and vascular endothelial cells, and also in vascular smooth muscle cells. The data suggest that KCNA10 may facilitate proximal tubular sodium absorption by stabilizing cell membrane voltage. Furthermore, its presence in endothelial and vascular smooth muscle cells supports the notion that it also regulates vascular tone.
Genes That Escape X-Inactivation in Humans Have High Intraspecific Variability in Expression, Are Associated with Mental Impairment but Are Not Slow Evolving
Authors: Yuchao Zhang, Atahualpa Castillo-Morales, Min Jiang, Yufei Zhu, Landian Hu, Araxi O. Urrutia, Xiangyin Kong, Laurence D. Hurst
Journal: Molecular Biology and Evolution (2013)

In female mammals most X-linked genes are subject to X-inactivation. However, in humans some X-linked genes escape silencing, these escapees being candidates for the phenotypic aberrations seen in polyX karyotypes. These escape genes have been reported to be under stronger purifying selection than other X-linked genes. Although it is known that escape from X-inactivation is much more common in humans than in mice, systematic assays of escape in humans have to date employed only interspecies somatic cell hybrids. Here we provide the first systematic next-generation sequencing analysis of escape in a human cell line. We analyzed RNA and genotype sequencing data obtained from B lymphocyte cell lines derived from Europeans (CEU) and Yorubans (YRI). By replicated detection of heterozygosis in the transcriptome, we identified 114 escaping genes, including 76 not previously known to be escapees. The newly described escape genes cluster on the X chromosome in the same chromosomal regions as the previously known escapees. There is an excess of escaping genes associated with mental retardation, consistent with this being a common phenotype of polyX phenotypes. We find both differences between populations and between individuals in the propensity to escape. Indeed, we provide the first evidence for there being both hyper- and hypo-escapee females in the human population, consistent with the highly variable phenotypic presentation of polyX karyotypes. Considering also prior data, we reclassify genes as being always, never, and sometimes escape genes. We fail to replicate the prior claim that genes that escape X-inactivation are under stronger purifying selection than others.
Access to bone densitometry increases general practitioners' prescribing for osteoporosis in steroid treated patients
Authors: A L Dolan
Journal: Annals of the Rheumatic Diseases (2004)

Availability of access to bone densitometry in the UK varies widely and there are concerns as to appropriate prescribing. Studies suggest inadequate use of osteoporosis prophylaxis in steroid users, despite recent guidelines.To examine in a case-control study whether access to bone densitometry affects GPs' osteoporosis prescribing in high risk steroid users.10 general practices were included, five from primary care trusts (PCTs) with access to bone densitometry and five with limited access. Patients receiving prednisolone for >3 months were identified by database search. Patients receiving no prophylaxis other than calcium and vitamin D (Ca/D) were subsequently included. Appropriate patients in five practices were offered DXA scan (cases) and review. Patients in practices without access to scans (controls) were reviewed. GPs' opinions leading to treatment were sought by structured questionnaire.132 (0.12%) patients were receiving prednisolone for >/=3 months, but no osteoporosis prophylaxis other than Ca/D. Pre-study prophylaxis ranged from 18 to 36%. Of 48 patients scanned, 21 (44%) were abnormal and 18 (38%) received new treatment. 13/44 (30%) controls received new treatment. 10/21 (48%) with abnormal scans started a bisphosphonate, compared with 7/44 (16%) controls (RR = 3, p = 0.004). No difference in risk factors for fracture was found in treated and untreated controls.GPs were three times more likely to start potent osteoporosis treatment after abnormal scans than GPs relying on clinical information. In practice, risk factors were not adequately assessed. Database searches may identify patients needing osteoporosis prophylaxis; however, DXA enables more appropriate patient treatment.
Protein transport and processing by human HT29-19A intestinal cells: effect of interferon gamma
Authors: K Terpend, F Boisgerault, M A Blaton, J F Desjeux, M Heyman
Journal: Gut (1998)

<i>Background</i>—The nature of the breakdown products produced in enterocytes during epithelial transport of intact proteins may be critical in determining the functional consequences of protein absorption. <i>Aim</i>—(<i>a</i>) To measure the transepithelial transport of horseradish peroxidase (HRP) and to identify the nature of HRP breakdown products released on the basal side of enterocytes and (<i>b</i>) to assess the role of interferon γ (IFNγ) on HRP transport and processing. <i>Methods</i>—HT29-19A intestinal cells were used to assess transepithelial transport of HRP in Ussing chambers, and the nature of breakdown products in the basal compartment was analysed by high performance liquid chromatography (HPLC). <i>Results</i>—(1) In control conditions, [<sup>3</sup>H]HRP equivalent fluxes (3135 (219) ng/h per cm<sup>2</sup>; mean (SEM)) comprised 50% amino acids, 40% peptides, and 10% intact HRP. Steric exclusion HPLC of the breakdown products indicated a wide range of molecular masses including a major peptide of about 1150 Da. Lysosomal aspartyl and thiol proteases were expressed but no HLA-DR surface expression was noted. (2) At 48 to 72 hours after IFNγ stimulation, [<sup>3</sup>H]HRP equivalent fluxes increased significantly (7392 (1433) ng/h per cm<sup>2</sup>) without modification of the relative proportions of amino acids, peptides, and intact HRP, and without modification of the distribution of breakdown products in HPLC. Lysosomal protease activities were not modified by IFNγ but HLA-DR expression was increased. <i>Conclusion</i>—Intestinal cells are able to process HRP into peptides potentially capable of stimulating the immune system. IFNγ stimulates the transport and processing of HRP thus increasing the antigenic load in the intestinal mucosa.
Human limbal biopsy–derived stromal stem cells prevent corneal scarring
Authors: Sayan Basu, Andrew J. Hertsenberg, Martha L. Funderburgh, Michael K. Burrow, Mary M. Mann, Yiqin Du, Kira L. Lathrop, Fatima N. Syed-Picard, Sheila M. Adams, David E. Birk, James L. Funderburgh
Journal: Science Translational Medicine (2014)

Human stromal stem cells isolated from limbal biopsies prevented corneal scarring in a murine model of corneal wounding.
β1-Integrins Mediate Enhancement of Airway Smooth Muscle Proliferation by Collagen and Fibronectin
Authors: Trang T.-B. Nguyen, Jeremy P. T. Ward, Stuart J. Hirst
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Airway smooth muscle (ASM) accumulation and enrichment of the extracellular matrix (ECM) with type I collagen and fibronectin are major pathologic features of airway remodeling in asthma. These ECM components confer enhanced ASM proliferation in vitro, but a requirement for specific integrin ECM receptors has not been examined. Here, we examined the mitogen platelet-derived growth factor (PDGF)-BB on beta1-integrin expression on human ASM cells cultured on these ECM substrates and defined the involvement of specific integrins in cell attachment and proliferation using integrin-neutralizing antibodies. PDGF-BB-dependent proliferation was enhanced two- to threefold by monomeric type I collagen or fibronectin and to a lesser extent by vitronectin; other interstitial ECM components (fibrillar type I and III collagen and tenascin-C) had no effect. Except for increased alpha3 expression induced by PDGF-BB and monomeric type I collagen or fibronectin, alpha1, alpha2, alpha4, alpha5, alphav, and alphavbeta3 integrins were unchanged compared with unstimulated cells on plastic. Blocking antibodies revealed alpha2beta1- and alphavbeta3-mediated attachment to monomeric type I collagen, whereas attachment to fibronectin required alpha5beta1. In contrast, enhancement of PDGF-BB-dependent proliferation by either monomeric type I collagen or fibronectin required alpha2beta1, alpha4beta1, and alpha5beta1 integrins. These data suggest multiple beta1-integrins regulate enhanced ASM proliferative responses.
The Transport of Exogenous Cholesterol in the Rabbit
Authors: L. L. Rudel, M. D. Morris, J. M. Felts
Journal: Journal of Clinical Investigation (1972)

Thoracic lymph duct cannulations were performed shortly after a meal in rabbits trained to ingest a moderate fat, low cholesterol diet. A tracer dose of cholesterol-(3)H was administered to label exogenous (dietary) cholesterol during absorption. Sequential lymph samples were collected up to 24 hr postprandially, after which ultracentrifugal fractionation of lymph lipoproteins was carried out. The d < 1.006 lipoproteins were separated into two classes, chylomicra and very low density lipoproteins (VLDL).A comparison was made between chylomicra and VLDL of lymph in the transport of exogenous cholesterol after ingestion of a single meal. The per cent of exogenous cholesterol present in VLDL of sequential lymph collections progressively increased with time after a meal and by 18 hr had reached a value of 80% or greater. In chylomicra the per cent of exogenous cholesterol of sequential lymph collections progressively decreased. Therefore, exogenous cholesterol was preferentially transported in VLDL compared with chylomicra. Cholesterol ester specific activity (CESA) of lymph chylomicra and VLDL increased at a more rapid rate than free cholesterol specific activity (FCSA). CESA of VLDL was three times higher than FCSA at the maximum. Exogenous cholesterol which appeared in both chylomicra and VLDL was consistently 80% esterified. while the per cent of total cholesterol esterified decreased with time and was significantly lower than that for exogenous cholesterol from 6 to 24 hr postprandially. These results demonstrate preferential esterification of exogenous cholesterol during absorption and indicate that a mechanism exists within the intestinal mucosal cell to maintain both free and esterified exogenous cholesterol in a chemically distinct pool from endogenous cholesterol during incorporation into both chylomicra and VLDL.
Effect of Epidermal Growth Factor Receptor Tyrosine Kinase Domain Mutations on the Outcome of Patients with Non–Small Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Authors: Pasi A. Jänne, Bruce E. Johnson
Journal: Clinical Cancer Research (2006)

Abstract Somatic mutations in the epidermal growth factor receptor (EGFR) have been identified in patients with advanced non–small cell lung cancer who achieve dramatic clinical and radiographic response to the EGFR tyrosine kinase inhibitors (TKI) gefitinib and erlotinib. These mutations in EGFR are found more frequently in patients with adenocarcinomas, nonsmokers, patients of Asian ethnicity, and in females: the same populations that are the most likely to have a clinical response when treated with EGFR TKIs. Retrospective studies comparing the outcomes of patients with and without EGFR mutations treated with EGFR TKIs show a significant clinical benefit of EGFR TKIs in patients with EGFR mutations. These findings suggest that for patients with advanced non–small cell lung cancer bearing EGFR mutations, treatment with an EGFR TKI should be incorporated as at least part of their initial therapy. These approaches are being studied in ongoing clinical trials and will spur the development of additional technology for EGFR mutation detection.
Television viewing time and reduced life expectancy: a life table analysis
Authors: J Lennert Veerman, Genevieve N Healy, Linda J Cobiac, Theo Vos, Elisabeth A H Winkler, Neville Owen, David W Dunstan
Journal: British Journal of Sports Medicine (2012)

Prolonged television (TV) viewing time is unfavourably associated with mortality outcomes, particularly for cardiovascular disease, but the impact on life expectancy has not been quantified. The authors estimate the extent to which TV viewing time reduces life expectancy in Australia, 2008.The authors constructed a life table model that incorporates a previously reported mortality risk associated with TV time. Data were from the Australian Bureau of Statistics and the Australian Diabetes, Obesity and Lifestyle Study, a national population-based observational survey that started in 1999-2000. The authors modelled impacts of changes in population average TV viewing time on life expectancy at birth.The amount of TV viewed in Australia in 2008 reduced life expectancy at birth by 1.8 years (95% uncertainty interval (UI): 8.4 days to 3.7 years) for men and 1.5 years (95% UI: 6.8 days to 3.1 years) for women. Compared with persons who watch no TV, those who spend a lifetime average of 6 h/day watching TV can expect to live 4.8 years (95% UI: 11 days to 10.4 years) less. On average, every single hour of TV viewed after the age of 25 reduces the viewer's life expectancy by 21.8 (95% UI: 0.3-44.7) min. This study is limited by the low precision with which the relationship between TV viewing time and mortality is currently known.TV viewing time may be associated with a loss of life that is comparable to other major chronic disease risk factors such as physical inactivity and obesity.
Phase I/II Study of Inhaled Doxorubicin Combined with Platinum-Based Therapy for Advanced Non–Small Cell Lung Cancer
Authors: Gregory A. Otterson, Miguel A. Villalona-Calero, William Hicks, Xueliang Pan, John A. Ellerton, Scott N. Gettinger, John R. Murren
Journal: Clinical Cancer Research (2010)

Abstract Purpose: We have shown the feasibility of administering inhaled doxorubicin to patients with cancer. This study evaluated inhaled doxorubicin combined with cisplatin and docetaxel in patients with non–small cell lung cancer. The principal objective was to determine safety and, secondarily, efficacy. Experimental Design: Patients who had chemo-naïve advanced non–small cell lung cancer were enrolled in the study. Adequate organ and pulmonary function was required: diffusing capacity for carbon monoxide/forced expiratory volume in 1 second/forced vital capacity ≥50%, resting/exercise O2 saturation ≥90%/85%. In phase I, doxorubicin was escalated: dose level 1 (6 mg/m2) and level 2 (7.5 mg/m2). Escalation was permitted if ≤2 of 6 patients experienced pulmonary dose-limiting toxicity (grade 2 Radiation Therapy Oncology Group lung morbidity; resting O2 saturation of &amp;lt;85%; decrease in diffusing capacity for carbon monoxide, forced vital capacity, or forced expiratory volume in 1 second of ≥20% from baseline or ≤30% of predicted; or grade 3 Common Terminology Criteria for Adverse Events version 3.0 pulmonary toxicity). Doses of cisplatin and docetaxel were 75 mg/m2. Treatments and pulmonary function tests were repeated every 21 days, with up to eight cycles for responding patients. Results: Twenty-eight patients were treated at level 1 and eight patients at level 2. Doxorubicin was escalated to 7.5 mg/m2, however, after two patients developed pulmonary dose-limiting toxicity; the remainder were treated at 6.0 mg/m2. Twenty-four evaluable patients received at least two courses or had progressive disease following the first course at the phase II dose. Toxicity was associated with i.v. chemotherapy although one patient had delayed pulmonary toxicity responding to corticosteroids and oxygen. Seven (29%) evaluable patients responded (six partial responses and one complete response) and 13 (54%) patients had stable disease for up to eight cycles. Conclusion: Although this combination was safe, the primary objective was not met and will not be pursued further. Clin Cancer Res; 16(8); 2466–73. ©2010 AACR.
Lack of strategy on forensic science risks damaging ability to catch criminals, say MPs
Authors: A. O'Dowd
Journal: BMJ (2013)

The ability to convict serious criminals and ensure justice is done is at risk because of the government’s lack of a strategy for forensic science, MPs have claimed.

A report published on 25 July by the parliamentary science and technology committee warns that changes to forensic science could jeopardise the criminal justice system.1

The government closed the Forensic Science Service (FSS)—the government owned company that analysed crime scene evidence for police forces and government agencies in England and Wales—in March 2012.

As the service was wound down, the government transferred its work …
Selective Expansion of the Newly Evolved Genomic Variants of Retrotransposon 1731 in the Drosophila Genomes
Authors: A. I. Kalmykova
Journal: Molecular Biology and Evolution (2004)

The structural variants of the regulatory and coding regions of the LTR-retrotransposon 1731 are described. Two classes of genomic copies of retrotransposon 1731, with and without frameshifting strategy to express Gag and Pol proteins, were earlier revealed in the D. melanogaster genome. Copies without frameshifting are shown to be evolved from an ancient variant with frameshifting and are widespread in the genomes of the melanogaster complex species. Position of a rare codon responsible for ribosome pausing and efficient frameshifting is identified. Two structural variants of 1731 LTRs were detected in the melanogaster complex species: the predominant structural variant A1A2 of 1731 LTR in the D. melanogaster, D. simulans, and D. sechellia genomes contains duplicated and diverged copies of 28 bp in the U3 region, whereas A1 variant lacking this duplication is expanded in the D. mauritiana genome. Selective expansion of the A1A2 variant was detected in the independently established D. melanogaster cell cultures. A1A2 variant is expressed in embryos, cell culture, and testes, whereas A1 is expressed only in testes of D. melanogaster. Relief of expression of the A1A2 but not A1 variant in the ovaries as a result of mutation in the RNA interference (RNAi) spn-E gene is shown. Thus, expansion of the recently evolved genomic variants of the LTR retrotransposon 1731 possessing a new translation strategy, duplication in the U3 region, and extended profile of expression is revealed.