tbuckley/cabot-search huggingface dataset:
Can EGFR-TKIs be used in first line treatment for advanced non-small cell lung cancer based on selection according to clinical factors ? -- A literature-based meta-analysis
Authors: Chongrui Xu, Qing Zhou, Yi-long Wu
Journal: Journal of Hematology & Oncology (2012)

Abstract Background In the first line treatment of non-small cell lung cancer (NSCLC), several clinical trials have shown that not all NSCLC patients can benefit from treatment with tyrosine kinase inhibitors (TKIs) than receiving chemotherapy. Some trials treated patients with TKI according to their clinical characteristics. A few studies only chose patients with an epidermal grouth factor receptor (EGFR) mutation for TKI therapy. We aimed to determine whether patients could be treated with TKIs based on clinical factors in the first-line setting. Methods We performed a meta-analysis of randomized trials involving patients with advanced NSCLC treated with chemotherapy or TKIs by different selections. Efficacy outcomes of interest were the objective response rate (ORR), progression-free survival (PFS) and the overall survival (OS) of each treatment arm. Results Four trials enrolled unselected patients, and two trials selected East Asian patients using the clinical factors of gender and smoking history. Five trials chose patients with an EGFR mutation who were randomized for treatment with TKI or chemotherapy. For unselected patients, the risk ratio (RR) of the ORR was 3.52, the hazard ratio (HR) of the PFS was 1.29 and the HR of the OS was 1.35. For the clinically selected patients, the RR of the ORR was 0.64. The HRs of the PFS and OS were 0.83 and 0.92, respectively. The ORR and PFS were better for TKIs than for chemotherapy in patients with an EGFR mutation. The ORR was 0.47, and the HRs of the PFS and OS were 0.36 and 1.00, respectively. Conclusions Advanced NSCLC patients with an EGFR mutation benefit most from TKIs. EGFR-TKI treatment is justified for patients with unknown EGFR status,and those who cannot tolerate chemotherapy owing to age, poor performance status (PS) or other medical conditions, when selected according to clinical factors in the first-line setting.
Interval versus continuous training in patients with severe COPD: a randomized clinical trial
Authors: R Coppoolse, A.M.W.j Schols, E.m Baarends, R Mostert, M.a Akkermans, P.p Janssen, E.F.m Wouters
Journal: European Respiratory Journal (1999)

Limited information is available regarding the physiological responses to different types of exercise training in patients with severe chronic obstructive pulmonary disease (COPD). The aim of this study was two fold: firstly, to investigate the physiological response to training at 60% of achieved peak load in patients with severe COPD; and secondly to study the effects of interval (I) versus continuous (C) training in these patients. Twenty-one patients with COPD (mean+/-SD forced expiratory volume in one second: 37+/-15% of predicted, normoxaemic at rest) were evaluated at baseline and after 8 weeks' training. Patients were randomly allocated to either I or C training. The training was performed on a cycle ergometer, 5 days a week, 30 min daily. The total work load was the same for both training programmes. C training resulted in a significant increase in oxygen consumption (V'O2) (17%, p<0.05) and a decrease in minute ventilation (V'E)/V'O2 (p<0.01) and V'E/carbon dioxide production (V'CO2) (p<0.05) at peak exercise capacity, while no changes in these measures were observed after interval training. During submaximal exercise a significant decrease was observed in lactic acid production, being most pronounced in the C-trained group (-31%, p<0.01 versus -20%, p<0.05). Only in the I-trained group did a significant increase in peak work load (17%, p<0.05) and a decrease in leg pain (p<0.05) occur. Training did not result in a significant improvement in lung function, but maximal inspiratory mouth pressure increased in both groups by 10% (C: p<0.05) and 23% (I: p<0.01). The present study shows a different physiological response pattern to interval or continuous training in chronic obstruction pulmonary disease, which might be a reflection of specific training effects in either oxidative or glycolytic muscle metabolic pathways. Further work is required to determine the role of the different exercise programmes and the particular category of patients for whom this might be beneficial.
Activation of Jun kinase is an early event in hepatic regeneration.
Authors: J K Westwick, C Weitzel, H L Leffert, D A Brenner
Journal: Journal of Clinical Investigation (1995)

Compensatory hepatic regeneration after partial hepatectomy (PH) is dependent upon the extent of resection. This study analyzes the regulation of the AP-1 transcription factor c-Jun during hepatic regeneration. There is a progressive increase in c-jun mRNA levels after sham operation, one-third PH, and two-thirds PH. A concomitant increase in AP-1 binding activity is also observed. The c-Jun protein is a major constituent of the AP-1 complex in quiescent and early regenerating liver. The activity of c-Jun nuclear kinase (JNK), which phosphorylates the activation domain of the c-Jun protein, is markedly stimulated after one-third PH. JNK1 or an immunologically related kinase is a constituent of this stimulated JNK activity after PH. When primary cultures of adult rat hepatocytes are incubated with epidermal growth factor or transforming growth factor-alpha, AP-1 transcriptional activity is increased and the activation domain of the c-Jun protein is further potentiated. Phosphopeptide mapping of the endogenous c-Jun protein in proliferating cultured hepatocytes demonstrates phosphorylation of the c-Jun activation domain. Combining the results of these in vivo and culture studies, we conclude that the minimal stimulation of one-third PH activates JNK, which phosphorylates the c-Jun activation domain in hepatocytes, resulting in enhanced transcription of AP-1-dependent genes.
Allelic forms of gp195, a major blood-stage antigen of Plasmodium falciparum, are expressed in liver stages.
Authors: A Szarfman, D Walliker, J S McBride, J A Lyon, I A Quakyi, R Carter
Journal: The Journal of Experimental Medicine (1988)

Mature exoerythrocytic (EE) forms of two cloned lines (3D7 and HB3) of Plasmodium falciparum were obtained in the livers of splenectomized chimpanzees. Sectioned preparations were examined by immunofluorescence (IFA) using mAbs that distinguished allelic variants of the blood-form antigen gp195 and mAbs that recognized multiple conserved epitopes of gp195. EE forms and blood schizonts exhibited identical IFA reactions for each respective clone, showing that the antigen was expressed identically in liver and blood-stage parasites. A third chimpanzee was infected with sporozoites derived from a mixture of 3D7 and HB3 gametocytes that had undergone cross-fertilization in the mosquitoes. IFAs on the EE forms in this animal showed that segregation of each gp195 allele had occurred earlier in the life cycle, providing evidence that the parasite is haploid for the whole of its mammalian development.
Adenosine 5'-Triphosphate-Sensitive Potassium Channels
Authors: F M Ashcroft
Journal: Annual Review of Neuroscience (1988)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
A critical role for the transcription factor Scl in platelet production during stress thrombopoiesis
Authors: Matthew P. McCormack, Mark A. Hall, Simone M. Schoenwaelder, Quan Zhao, Sarah Ellis, Julia A. Prentice, Ashleigh J. Clarke, Nicholas J. Slater, Jessica M. Salmon, Shaun P. Jackson, Stephen M. Jane, David J. Curtis
Journal: Blood (2006)
Nonmuscle Myosin II Regulates the Morphogenesis of Metanephric Mesenchyme–Derived Immature Nephrons
Authors: Mariam C. Recuenco, Tomoko Ohmori, Shunsuke Tanigawa, Atsuhiro Taguchi, Sayoko Fujimura, Mary Anne Conti, Qize Wei, Hiroshi Kiyonari, Takaya Abe, Robert S. Adelstein, Ryuichi Nishinakamura
Journal: Journal of the American Society of Nephrology (2014)

The kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud. The mesenchyme transforms into epithelia and forms complicated nephron structures, whereas the ureteric bud extends its pre-existing epithelial ducts. Although the roles are well established for extracellular stimuli, such as Wnt and Notch, it is unclear how the intracellular cytoskeleton regulates these morphogenetic processes. Myh9 and Myh10 encode nonmuscle myosin II heavy chains, and Myh9 mutations in humans are implicated in congenital kidney diseases and focal segmental glomerulosclerosis in adults. Here, we analyzed the roles of Myh9 and Myh10 in the developing kidney. Ureteric bud-specific depletion of Myh9 resulted in no apparent phenotypes, whereas mesenchyme-specific Myh9 deletion caused proximal tubule dilations and renal failure. Mesenchyme-specific Myh9/Myh10 mutant mice died shortly after birth and showed a severe defect in nephron formation. The nascent mutant nephrons failed to form a continuous lumen, which likely resulted from impaired apical constriction of the elongating tubules. In addition, nephron progenitors lacking Myh9/Myh10 or the possible interactor Kif26b were less condensed at midgestation and reduced at birth. Taken together, nonmuscle myosin II regulates the morphogenesis of immature nephrons derived from the metanephric mesenchyme and the maintenance of nephron progenitors. Our data also suggest that Myh9 deletion in mice results in failure to maintain renal tubules but not in glomerulosclerosis.
Molecular phylogeny of the hominoids: inferences from multiple independent DNA sequence data sets
Authors: M. Ruvolo
Journal: Molecular Biology and Evolution (1997)

Consensus on the evolutionary relationships of humans, chimpanzees, and gorillas has not been reached, despite the existence of a number of DNA sequence data sets relating to the phylogeny, partly because not all gene trees from these data sets agree. However, given the well-known phenomenon of gene tree-species tree mismatch, agreement among gene trees is not expected. A majority of gene trees from available DNA sequence data support one hypothesis, but is this evidence sufficient for statistical confidence in the majority hypothesis? All available DNA sequence data sets showing phylogenetic resolution among the hominoids are grouped according to genetic linkage of their corresponding genes to form independent data sets. Of the 14 independent data sets defined in this way, 11 support a human-chimpanzee clade, 2 support a chimpanzee-gorilla clade, and one supports a human-gorilla clade. The hypothesis of a trichotomous speciation event leading to Homo; Pan, and Gorilla can be firmly rejected on the basis of this data set distribution. The multiple-locus test (Wu 1991), which evaluates hypotheses using gene tree-species tree mismatch probabilities in a likelihood ratio test, favors the phylogeny with a Homo-Pan clade and rejects the other alternatives with a P value of 0.002. When the probabilities are modified to reflect effective population size differences among different types of genetic loci, the observed data set distribution is even more likely under the Homo-Pan clade hypothesis. Maximum-likelihood estimates for the time between successive hominoid divergences are in the range of 300,000-2,800,000 years, based on a reasonable range of estimates for long-term hominoid effective population size and for generation time. The implication of the multiple-locus test is that existing DNA sequence data sets provide overwhelming and sufficient support for a human-chimpanzee clade: no additional DNA data sets need to be generated for the purpose of estimating hominoid phylogeny. Because DNA hybridization evidence (Caccone and Powell 1989) also supports a Homo-Pan clade, the problem of hominoid phylogeny can be confidently considered solved.
Availability and compliance to basic therapy of bronchial asthma in rural region of Kazakhstan
Authors: Tair Nurpeissov, Temyrlan Nurpeissov, Gulzada Abdushukurova, Temyrzhan Nurpeissov, Aigul Zhaksylykova
Journal: European Respiratory Journal (2013)

Background: Combined inhalers (ICS+LABA) are the unchallengeable part of basic treatment of persistent BA. In Kazakhstan according the national laws patients should be provided with free-of-charge medicines including ICS+LABA.

The aim: To analyze the availability of modern basic therapy and compliance to it of patients in rural region of Kazakhstan.

Methods: State statistical reporting, database of central outpatient clinic of Enbekshi-Kazakh district, randomized screening survey by telephone and special questionnaire (n=75).

Results: Total amount of registered adult patients with BA in this region was 293. 75 patients were randomly selected. All of them have moderate of severe BA and get ICS±LABA. Only 67 patients were available and agreed to take part in the telephone survey.

28.4% patients had no any experience of ICS±LABA usage.

Among the rest 48 patients only 18 (26.9%) strictly followed the prescriptions of their physician. These patients seemed to have controlled or partly controlled asthma. 13 patients combined ICS±LABA with oral or parenteral steroids and methylxanthines. 17 patients used to take ICS±LABA incorrectly (occasionally, during acute bronchial constriction, without deep inspiration, etc.) Last two groups had poorly or non-controlled asthma.

Conclusion: In rural regions of Kazakhstan there are all possibilities to provide antiasthmatic therapy with free newest inhalers and GINA guidelines. But this survey revealed that no more than 26.9% patients with moderate or severe asthma get adequate basis therapy accordingly to modern international guidelines. In 28.4% cases the signs of improper medical tactics were revealed. 44.8% patients use their inhalers improperly.
Involvement of PAF in postallergic propranolol-induced bronchoconstriction in guinea-pigs
Authors: M Fujimura, M Tsujiura, N Songur, S Myou, T Matsuda
Journal: European Respiratory Journal (1996)

Administration of propranolol can provoke bronchoconstriction in asthmatic patients. Recently, we successfully developed a guinea-pig model for propranolol-induced bronchoconstriction (PIB). We hypothesized that such bronchoconstriction may result from the inflammatory mediators released by an allergic reaction. The purpose of this study was to examine the role of platelet-activating factor (PAF) in the development of PIB after allergic reaction. Propranolol, at a concentration of 10 mg.mL-1 was inhaled 20 min after antigen challenge in passively sensitized, anaesthetized and artificially-ventilated guinea-pigs. The animals were treated intravenously with PAF antagonists, E6123 (1 and 10 micrograms.kg-1) or Y-24180 (1 and 10 mg.kg-1), 10 min before or 15 min after antigen challenge. Propranolol inhaled 20 min after antigen challenge caused bronchoconstriction. E6123 and Y-24180 administered 15 min after antigen challenge as well as 10 min before antigen challenge reduced the PIB in a dose-dependent manner. We conclude that platelet-activating factor may contribute to the development of propranolol-induced bronchoconstriction after allergic reaction in our guinea-pig model.
Functional differences in bi-level pressure preset ventilators
Authors: M.P. Highcock, J.M. Shneerson, I.E. Smith
Journal: European Respiratory Journal (2001)

The performance of four bilevel positive pressure preset ventilators was compared. The ventilators tested were; BiPAP ST30 (Respironics); Nippy2 (B+D Electrical); Quantum PSV (Healthdyne); and Sullivan VPAP II ST (Resmed). A patient simulator was used to determine the sensitivity of the triggering mechanisms and the responses to a leak within the patient circuit, and to changes in patient effort. Significant differences (p&lt;0.05) between the devices were seen in the trigger delay time and inspiratory trigger pressure. When a leak was introduced into the patient circuit, the fall in tidal volume ( V T ) was less than ten per cent for each ventilator. The addition of patient effort produced a number of changes in the ventilation delivered. Patient efforts of 0.25 s induced a variable fall in V T . An increase in V T was seen with some ventilators with patient efforts of 1 s but the effect was variable. Trigger failures and subsequent falls in minute volume were seen with the BiPAP and the Nippy2 at the highest respiratory frequency. Differences in the responses of the ventilators are demonstrated that may influence the selection of a ventilator, particularly in the treatment of breathless patients with ventilatory failure.
Nonsynonymous Coding Single-Nucleotide Polymorphisms Spanning the Genome in Relation to Glioblastoma Survival and Age at Diagnosis
Authors: Margaret Wrensch, Alex McMillan, John Wiencke, Joe Wiemels, Karl Kelsey, Joe Patoka, Hywel Jones, Victoria Carlton, Rei Miike, Jennette Sison, Michelle Moghadassi, Michael Prados
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Our aim was to discover possible inherited factors associated with glioblastoma age at diagnosis and survival. Although new genotyping technologies allow greatly expanded exploration of such factors, they pose many challenges. Experimental Design: In this pilot study, we (a) genotyped 112 newly diagnosed glioblastoma patients ascertained through a population-based study (group 1) with the ParAllele assay panel of ∼10,000 nonsynonymous coding single-nucleotide polymorphisms (SNP), (b) used several statistical and bioinformatic techniques to identify 17 SNPs potentially related to either glioblastoma age at diagnosis or survival, and (c) genotyped 16 of these SNPs using conventional PCR methods in an independent group of 195 glioblastoma patients (group 2). Results: In group 2, only one of the 16 SNPs, rs8057643 (located on 16p13.2), was significantly associated with glioblastoma age at diagnosis (nominal P = 0.0017; Bonferroni corrected P = 0.054). Median ages at diagnosis for those with 0, 1, or 2 T alleles were 66, 57, and 59 years in group 1 and 64, 57, and 55 years in group 2 (combined P = 0.001). Furthermore, Cox regression analyses of time to death with number of T alleles adjusted for gender and patient group yielded a hazard ratio of 0.82 (95% confidence interval, 0.68-0.98; P = 0.03). Conclusions: Although limited by a relatively small sample size, this pilot study, using well-characterized, unambiguous disease characteristics, illustrates the necessity of independent replication owing to the likelihood of false positives. Several other challenges are discussed, including attempts to incorporate information on the potential functional importance of SNPs in genome-disease association studies.
Binding and Antigen Presentation of Ceramide-Containing Glycolipids by Soluble Mouse and Human Cd1d Molecules
Authors: Olga V. Naidenko, Juli K. Maher, William A. Ernst, Teruyuki Sakai, Robert L. Modlin, Mitchell Kronenberg
Journal: The Journal of Experimental Medicine (1999)

We have purified soluble mouse and human CD1d molecules to assess the structural requirements for lipid antigen presentation by CD1. Plate-bound CD1d molecules from either species can present the glycolipid α-galactosyl ceramide (α-GalCer) to mouse natural killer T cells, formally demonstrating both the in vitro formation of antigenic complexes, and the presentation of α-GalCer by these two CD1d molecules. Using surface plasmon resonance, we show that at neutral pH, mouse CD1 and human CD1d bind to immobilized α-GalCer, unlike human CD1b, which requires acidic pH for lipid antigen binding. The CD1d molecules can also bind both to the nonantigenic β-GalCer and to phosphatidylethanolamine, indicating that diverse lipids can bind to CD1d. These studies provide the first quantitative analysis of monomeric lipid antigen–CD1 interactions, and they demonstrate that the orientation of the galactose, or even the nature of the polar head group, are likely to be more important for T cell receptor contact than CD1d binding.
Potential Health Impact of Nanoparticles
Authors: Tian Xia, Ning Li, Andre E. Nel
Journal: Annual Review of Public Health (2009)

Although mankind stands to obtain great benefit from nanotechnology, it is important to consider the potential health impacts of nanomaterials (NMs). This consideration has launched the field of nanotoxicology, which is charged with assessing toxicological potential as well as promoting safe design and use of NMs. Although no human ailments have been ascribed to NMs thus far, early experimental studies indicate that NMs could initiate adverse biological responses that can lead to toxicological outcomes. One of the principal mechanisms is the generation of reactive oxygen species and oxidant injury. Because oxidant injury is also a major mechanism by which ambient ultrafine particles can induce adverse health effects, it is useful to consider the lessons learned from studying ambient particles. This review discusses the toxicological potential of NMs by comparing the possible injury mechanisms and adverse health effects of engineered and ambient ultrafine particles.
Understanding the side effects of glucocorticoid therapy: shining a light on a drug everyone thinks they know
Authors: William G Dixon, Nick Bansback
Journal: Annals of the Rheumatic Diseases (2012)

Glucocorticoids are one of the most frequently prescribed therapies in rheumatology, a reflection of their effectiveness as a powerful anti-inflammatory drug. Glucocorticoids are also, however, associated with a wide range of adverse events, particularly at higher doses. To make appropriate decisions, doctors and patients need to weigh these benefits against the potential harms. This article describes the many uncertainties which make informed prescribing difficult. We lack knowledge, for example, on the magnitude of risk, the relationship to dose and duration, and what happens to risk on stopping therapy. Beyond safety, we describe how patients may lack understanding of the nature of the benefits and harms, and how to incorporate value judgements which are crucial to the decision making process. We conclude by exploring how future research might fill these knowledge gaps to enable a better informed decision process.
Very late onset small intestinal B cell lymphoma associated with primary intestinal lymphangiectasia and diffuse cutaneous warts
Authors: Y Bouhnik
Journal: Gut (2000)

As only a handful of lymphoma cases have been reported in conjunction with primary intestinal lymphangiectasia, it is not yet clear if this association is merely fortuitous or related to primary intestinal lymphangiectasia induced immune deficiency. We report on two female patients, 50 and 58 years old, who developed small intestinal high grade B cell lymphoma a long time (45 and 40 years, respectively) after the initial clinical manifestations of primary intestinal lymphangiectasia. They presented with a longstanding history of fluctuating protein losing enteropathy, multiple cutaneous plane warts, and markedly dilated mucosal and submucosal lymphatic channels in duodenal biopsies. One had a large ulcerated tumour of the proximal ileum and the other diffuse ileal infiltration. In both, histological examination showed centroblastic high grade B cell lymphoma associated with duodenojejuno-ileal mucosal and submucosal lymphangiectasia. They were subsequently successfully treated with surgery and postoperative chemotherapy (AVmCP: adriamycin, cyclophosphamide, Vm26, and prednisolone), and chemotherapy alone (PACOB: adriamycin, cyclophosphamide, vincristine, bleomycine, and prednisolone), respectively. A three year follow up in both cases showed persistent diffuse lymphangiectasia without evidence of lymphoma. The present findings support the hypothesis that primary intestinal lymphangiectasia is associated with lymphoma development.