tbuckley/cabot-search huggingface dataset:
<i>BRAF/NRAS</i> Wild-Type Melanomas Have a High Mutation Load Correlating with Histologic and Molecular Signatures of UV Damage
Authors: Victoria J. Mar, Stephen Q. Wong, Jason Li, Richard A. Scolyer, Catriona McLean, Anthony T. Papenfuss, Richard W. Tothill, Hojabr Kakavand, Graham J. Mann, John F. Thompson, Andreas Behren, Jonathan S. Cebon, Rory Wolfe, John W. Kelly, Alexander Dobrovic, Grant A. McArthur
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The mutation load in melanoma is generally high compared with other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinicopathologic features. Experimental Design: DNA was extracted from 34 fresh-frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was conducted and mutation rates were correlated with age, sex, tumor site, and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation, and BRAF/NRAS mutational status were investigated. Results: The average mutation rate was 12 per megabase, similar to published results in metastases. The average mutation rate in severely sun damaged (SSD) skin was 21 per Mb compared with 3.8 per Mb in non-SSD skin (P = 0.001). BRAF/NRAS wild-type (WT) tumors had a higher average mutation rate compared with BRAF/NRAS–mutant tumors (27 vs. 5.6 mutations per Mb; P = 0.0001). Tandem CC&amp;gt;TT/GG&amp;gt;AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin (P = 0.0008) and in BRAF/NRAS WT tumors (P = 0.0007). Targetable and potentially targetable mutations in WT tumors, including NF1, KIT, and NOTCH1, were spread over various signaling pathways. Conclusion: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF- and NRAS-mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients. Clin Cancer Res; 19(17); 4589–98. ©2013 AACR.
Enhancing physical performance in chronic obstructive pulmonary disease
Authors: M C Steiner
Journal: Thorax (2001)

The ambition of all athletes is to outperform competitors in their chosen discipline. To this end, ever more sophisticated training schedules are used to maximise physical performance. In recent years some sportsmen and women have resorted to illegal pharmacological methods to augment their training programmes and so gain an unfair advantage over their rivals.

Patients with chronic obstructive pulmonary disease (COPD) are disabled by their inability to carry out many activities of daily living because of exercise intolerance. This leads to increasing social isolation, depression, and dependence. Improving physical performance is therefore an important therapeutic goal in these patients. It has been thought that exercise limitation in COPD was simply due to a limit to pulmonary ventilation. However, a number of observations have indicated that this is not true for many COPD sufferers. Firstly, the relationship between exercise capacity and lung function impairment is poor1 2and bronchodilator therapy often fails to have a meaningful impact on disability in patients with COPD. Furthermore, patients who have their lung function restored to normal by transplantation may not achieve their predicted exercise capacity following the procedure.3 4 Finally, exercise reconditioning during pulmonary rehabilitation results in impressive improvements in exercise capacity while having no impact on lung function impairment.5-7 

Other factors are clearly involved in exercise limitation and it is now evident that peripheral skeletal muscle dysfunction is one of the primary determinants of disability in chronic lung disease.8 Far from being illegal, pharmacological improvement of peripheral muscle performance could be of therapeutic benefit in these patients.

Observational studies have demonstrated a reduction in muscle strength and bulk in COPD.9-11 These measures have also been shown to predict peak exercise capacity.12 13 A number of techniques have been developed in recent years which have increased our understanding …
Akt Substrate of 160 kD Regulates Na+,K+-ATPase Trafficking in Response to Energy Depletion and Renal Ischemia
Authors: Daiane S. Alves, Gunilla Thulin, Johannes Loffing, Michael Kashgarian, Michael J. Caplan
Journal: Journal of the American Society of Nephrology (2015)

Renal ischemia and reperfusion injury causes loss of renal epithelial cell polarity and perturbations in tubular solute and fluid transport. Na+,K+-ATPase, which is normally found at the basolateral plasma membrane of renal epithelial cells, is internalized and accumulates in intracellular compartments after renal ischemic injury. We previously reported that the subcellular distribution of Na+,K+-ATPase is modulated by direct binding to Akt substrate of 160 kD (AS160), a Rab GTPase-activating protein that regulates the trafficking of glucose transporter 4 in response to insulin and muscle contraction. Here, we investigated the effect of AS160 on Na+,K+-ATPase trafficking in response to energy depletion. We found that AS160 is required for the intracellular accumulation of Na+,K+-ATPase that occurs in response to energy depletion in cultured epithelial cells. Energy depletion led to dephosphorylation of AS160 at S588, which was required for the energy depletion–induced accumulation of Na,K-ATPase in intracellular compartments. In AS160-knockout mice, the effects of renal ischemia on the distribution of Na+,K+-ATPase were substantially reduced in the epithelial cells of distal segments of the renal tubules. These data demonstrate that AS160 has a direct role in linking the trafficking of Na+,K+-ATPase to the energy state of renal epithelial cells.
Epidemiologic Survey of Japanese Patients with Idiopathic Pulmonary Fibrosis and Investigation of Ethnic Differences
Authors: Motoki Natsuizaka, Hirofumi Chiba, Koji Kuronuma, Mitsuo Otsuka, Kazumi Kudo, Mitsuru Mori, Masashi Bando, Yukihiko Sugiyama, Hiroki Takahashi
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Idiopathic pulmonary fibrosis (IPF) has an unknown etiology and poor prognosis. Several large-scale epidemiologic studies have been conducted predominantly in Western countries. There are few studies reported from Asian countries. It remains unclear whether ethnic difference exists in IPF. It is important to determine the current IPF status in Asian populations and compare it with that of Western populations.To provide the epidemiologic status of IPF in Japan and to investigate ethnic differences.We selected Hokkaido prefecture (population, 5.6 million) as the epidemiologic cohort of IPF among Japanese. On the basis of the clinical records of 553 patients with IPF who were accepted based on the application of the Certificate of Medical Benefit between 2003 and 2007, we conducted a retrospective epidemiologic and prognostic analysis.The prevalence and cumulative incidence of IPF was 10.0 and 2.23 per 100,000 population, respectively, with 72.7% predominance of males and an increase in frequency with age. The median survival time was 35 months, and the most common (40%) cause of death was acute exacerbation. The most important factor influencing IPF prognosis was the percent vital capacity.The status of IPF in the Japanese population was clarified for the first time through our study. Our results showed that in men, the incidence of death caused by acute exacerbation was higher and that caused by cardiovascular disease was lower in Japan than in Western countries. These results may suggest ethnic differences in IPF.
Promoter Polymorphisms and Transcript Levels of Nicotinic Receptor CHRNA5
Authors: Felicia S. Falvella, Antonella Galvan, Francesca Colombo, Elisa Frullanti, Ugo Pastorino, Tommaso A. Dragani
Journal: JNCI Journal of the National Cancer Institute (2010)

Chromosomal locus 15q25, implicated in lung cancer risk and nicotine dependence, shows extensive linkage disequilibrium that complicates identification of causal variation. Cholinergic receptor nicotinic alpha5 (CHRNA5) has been identified as a lung cancer risk factor. We identified by sequence analysis three haplotypes (delTTC, insATC, and insTGG) in the 5' promoter region and three at the 3'-untranslated region of CHRNA5. Linkage disequilibrium analysis of the 5' variants showed that the insTGG haplotype is associated with three tightly linked risk alleles (nicotine dependence, lung cancer, and chronic obstructive pulmonary disease). The three CHRNA5 promoter haplotypes were statistically significantly associated with lung CHRNA5 transcript levels, determined by real-time polymerase chain reaction. In nontumor lung parenchyma from 68 patients who underwent lung lobectomy, the delTTC haplotype was associated with the highest CHRNA5 transcript levels (relative quantification units = 1.82), whereas the insTGG haplotype was associated with the lowest (0.88 units, P(diff) < .001, Welch t test; all statistical tests were two-sided). Luciferase reporter assays in human lung cancer cell lines A549, H460, H520, and H596 also showed that the 5' region haplotypes were statistically significantly associated with changes in CHRNA5 promoter activity, whereas the 3'-untranslated region variants were not.
Incomplete Reiter's syndrome: clinical comparisons with classical triad.
Authors: F C Arnett
Journal: Annals of the Rheumatic Diseases (1979)

Recently we described 13 patients who appeared to have the typical articular features of Reiter's syndrome (RS) but who did not have clinically obvious genitourinary tract or ocular disease.18All but one also had HLA-B27.The term'incomplete Reiter's syndrome' was preliminarily applied to these patients.This paper describes a prospective comparative study of the clinical and laboratory features of 69 patients with either 'classical' or 'incomplete' disease. Patients and methodsFrom 1 September 1974 to 31 March 1978 all patients with a clinical diagnosis of RS seen by me and available for HLA antigen determinations were included in the study.Reiter's disease was diagnosed on clinical features previously reported,18'217'284 4 (14%) Race (No. blacks) 6 (27 Y.) 4 (21%) 4 (14%) copyright.
The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells.
Authors: A Imura, T Hori, K Imada, T Ishikawa, Y Tanaka, M Maeda, S Imamura, T Uchiyama
Journal: The Journal of Experimental Medicine (1996)

Fresh leukemic cells from patients with adult T cell leukemia (ATL) and some ATL-derived T cell lines show adhesion to human umbilical vein endothelial cells (HUVECs) mainly through E-selectin, but a proportion of this binding remains unaffected by the addition of combinations of antibodies against known adhesion molecules. By immunizing mice with one of such cell lines, we established monoclonal antibodies (mAbs), termed 131 and 315, that recognize a single cell surface antigen (Ag) and inhibit the remaining pathway of the adhesion. These mAbs did not react with normal resting peripheral blood mononuclear cells (PBMC) or most of the cell lines tested except for two other human T cell leukemia virus type I (HTLV-I)-infected T cell lines. After stimulation with phytohemagglutinin (PHA), PBMC expressed Ag 131/315 transiently, indicating that these mAbs define a T cell activation Ag. Western blotting and immunoprecipitation revealed that Ag 131/315 has an apparent molecular mass of 50 kD. Expression cloning was done by transient expression in COS-7 cells and immunological selection to isolate a cDNA clone encoding Ag 131/315. Sequence analysis of the cDNA indicated that it is identical to human OX40, a member of the tumor necrosis factor/nerve growth factor receptor family. We then found that gp34, the ligand of OX40, was expressed on HUVECs and other types of vascular endothelial cells. Furthermore, it was shown that the adhesion of CD4+ cells of PHA-stimulated PBMC to unstimulated HUVECs was considerably inhibited by either 131 or 315. Finally, OX40 transfectants of Kit 225, a human interleukin 2-dependent T cell line, were bound specifically to gp34 transfectants of MMCE, a mouse epithelial cell line, and this binding was blocked by either 315 or 5A8, an anti-gp34 mAb. These results indicate that the OX40/gp34 system directly mediates adhesion of activated T cells or OX40+-transformed T cells to vascular endothelial cells.
Publish or Perish: A Proposal
Authors: MARCIA ANGELL
Journal: Annals of Internal Medicine (1986)

Because promotion and funding of physicians in academic medicine are closely linked to the number of their publications, investigators feel impelled to publish as frequently as possible. This pressure leads to a number of unfortunate practices in medical publishing, including undertaking trivial studies because they yield rapid results, needlessly reporting the same study in installments, reporting a study more than once, and listing as authors people only marginally involved in the study. It may also be a motivation for fraud. An effective way to reduce these offenses and affirm the supremacy of substance over volume in scientific research would be to place a ceiling on the number of publications that can be considered in evaluating a candidate for promotion or funding. Each publication would then receive commensurately more attention, both from the researcher and from those judging the work.
LEUKOCYTE PROTEIN TYROSINE KINASES:Potential Targets for Drug Discovery
Authors: Joseph B. Bolen, Joan S. Brugge
Journal: Annual Review of Immunology (1997)

▪ Abstract Intracellular signal transduction following the extracellular ligation of a wide variety of different types of surface molecules on leukocytes involves the activation of protein tyrosine kinases. The dependence of successful intracellular signaling on the functions of the nontransmembrane class of protein tyrosine kinases coupled with the cell type–specific expression patterns for several of these enzymes makes them appealing targets for therapeutic intervention. Development of drugs that can interfere with the catalytic functions of the nontransmembrane protein tyrosine kinases or that can disrupt critical interactions with regulatory molecules and/or substrates should find clinical applications in the treatment of allergic diseases, autoimmunity, transplantation rejection, and cancer.
Navitoclax Enhances the Efficacy of Taxanes in Non–Small Cell Lung Cancer Models
Authors: Nguyen Tan, Mehnaz Malek, Jiping Zha, Peng Yue, Robert Kassees, Leanne Berry, Wayne J. Fairbrother, Deepak Sampath, Lisa D. Belmont
Journal: Clinical Cancer Research (2011)

To explore the potential of navitoclax in combination with taxane-based chemotherapy in the treatment of non-small cell lung cancer (NSCLC) by defining mechanism of synergy and identifying correlative biomarkers.We treated a panel of NSCLC lines with a dose matrix of paclitaxel and navitoclax (formerly ABT-263), an inhibitor of Bcl-2, Bcl-x(L), and Bcl-w (1), and evaluated synergy. We next used time-lapse microscopy to explore mechanism of synergy. Finally, we developed an immunohistochemical assay and assessed prevalence of Bcl-x(L) in NSCLC tumor tissues.All cell lines exhibit greater than additive response to the combination of navitoclax and a taxane. These results were extended to mouse xenograft tumor models, in which the combination is more efficacious than either single-agent docetaxel or navitoclax. Addition of navitoclax to paclitaxel decreases the time from mitotic entry to cell death and changes cell fate from mitotic slippage to death during mitotic arrest. The relative levels of Bcl-x(L) and Mcl-1 correlate with the extent of synergy, suggesting that cancers with elevated levels of Bcl-x(L) will be relatively resistant to taxane-based therapy but could benefit from the addition of navitoclax to taxane treatment. Finally, a significant percentage of NSCLC patient samples exhibit relatively high Bcl-x(L) levels.The addition of navitoclax to taxane-based chemotherapy in NSCLC has the potential to increase efficacy, particularly in patients whose tumors express high levels of Bcl-x(L).
Proteases and interleukin-6 gene analysis in 92 giant cell tumorsof bone
Authors: G. Gamberi, M.S. Benassi, P. Ragazzini, L. Pazzaglia, F. Ponticelli, C. Ferrari, A. Balladelli, M. Mercuri, M. Gigli, F. Bertoni, P. Picci
Journal: Annals of Oncology (2004)
Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts
Authors: H. Tateishi, M. Yano, M. Mochizuki, T. Suetomi, M. Ono, X. Xu, H. Uchinoumi, S. Okuda, T. Oda, S. Kobayashi, T. Yamamoto, Y. Ikeda, T. Ohkusa, N. Ikemoto, M. Matsuzaki
Journal: Cardiovascular Research (2008)

AimsA domain peptide (DP) matching the Gly2460–Pro2495 region of the cardiac type-2 ryanodine receptor (RyR2), DPc10, is known to mimic channel dysfunction associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), owing to its interference in a normal interaction of the N-terminal (1–600) and central (2000–2500) domains (viz. domain unzipping). Using DPc10 and two other DPs harboring different mutation sites, we investigated the underlying mechanism of abnormal Ca2+ cycling in failing hearts.
RNA-editing-mediated exon evolution
Authors: Galit Lev-Maor, Rotem Sorek, Erez Y Levanon, Nurit Paz, Eli Eisenberg, Gil Ast
Journal: Genome biology (2007)

Alu retroelements are specific to primates and abundant in the human genome. Through mutations that create functional splice sites within intronic Alus, these elements can become new exons in a process denoted exonization. It was recently shown that Alu elements are also heavily changed by RNA editing in the human genome.Here we show that the human nuclear prelamin A recognition factor contains a primate-specific Alu-exon that exclusively depends on RNA editing for its exonization. We demonstrate that RNA editing regulates the exonization in a tissue-dependent manner, through both the creation of a functional AG 3' splice site, and alteration of functional exonic splicing enhancers within the exon. Furthermore, a premature stop codon within the Alu-exon is eliminated by an exceptionally efficient RNA editing event. The sequence surrounding this editing site is important not only for editing of that site but also for editing in other neighboring sites as well.Our results show that the abundant RNA editing of Alu sequences can be recruited as a mechanism supporting the birth of new exons in the human genome.
What does the antimitochondrial antibody mean?
Authors: D R Triger, C A Charlton, A M Ward
Journal: Gut (1982)

In a prospective survey positive antimitochondrial antibodies have been detected in 69/4200 (1.64%) of all sera submitted to a routine immunology laboratory. Of the 69, only nine patients had uniquivocal primary biliary cirrhosis, six others had chronic active hepatitis, 10 had abnormal liver function tests without evidence of primary biliary cirrhosis, while the remaining 44 had no clinical or biochemical evidence of liver disease. Outside the context of liver disease antimitochondrial antibodies were observed with similar frequency in patients with autoimmune disorders as in other conditions. It was not possible to distinguish primary biliary cirrhosis from patients without liver disease by antibody titre or by immunoglobulin subclass. The positive antimitochondrial antibody patients without liver disease were uniformly distributed throughout the city of Sheffield, in contrast with the marked clustering of cases of primary biliary cirrhosis. We conclude that, in the absence of clinical liver disease, the antimitochondrial antibody test alone (as detected by routine immunofluorescent techniques) does not appear to be a specific screening test for primary biliary cirrhosis. While we cannot exclude the possibility that the autoantibody indicates a predisposition to develop primary biliary cirrhosis, further prospective studies are needed to determine which patients will progress in this manner. The possibility that environmental factors may be implicated cannot be discounted.
Ciliary dyskinesia is an early feature of respiratory syncytial virus infection
Authors: Claire M. Smith, Hemant Kulkarni, Priya Radhakrishnan, Andrew Rutman, Michael J. Bankart, Gwyneth Williams, Robert A. Hirst, Andrew J. Easton, Peter W. Andrew, Chris O’Callaghan
Journal: European Respiratory Journal (2013)

Respiratory syncytial virus is a major cause of respiratory disease. There are conflicting accounts of the response of human epithelial cells to respiratory syncytial virus and a lack of data on its effect on ciliary function. Our aim was to study the early stages of respiratory syncytial virus infection of primary human basal and ciliated cultures. Using high speed videomicroscopy, we found that ciliary beat frequency was unaffected by respiratory syncytial virus infection over 72 h; however, ciliary dyskinesia significantly increased within 24 h of infection (p<0.05). Transmission electron microscopy revealed that ultrastructural abnormalities were confined to ciliated cells, including increased cilia loss and mitochondrial damage. Confocal immunofluorescence microscopy showed that respiratory syncytial virus antigen gradually spread from the cell surface to the ciliary tip of infected cells over 3 days. Interestingly, ciliated cultures secreted fewer viruses than basal (progenitor) cell cultures and produced a chemokine response focused on recruitment of neutrophils. This study highlights differences in infection models and underscores the need to explore further the role of ciliated cells in the establishment of respiratory syncytial virus infection. Increased ciliary dyskinesia combined with ciliary loss and epithelial damage is likely to result in reduced mucociliary clearance early in the infective process.
Serum DNA can define tumor-specific genetic and epigenetic markers in gliomas of various grades
Authors: I. Lavon, M. Refael, B. Zelikovitch, E. Shalom, T. Siegal
Journal: Neuro-Oncology (2010)

We evaluated whether cell-free circulating DNA can be used as a noninvasive approach for detection of genetic/epigenetic alterations in brain tumors during the course of the disease. Paired tumor-serum samples from 70 patients with either high-grade astrocytomas (n = 41) or oligodendrogliomas of various grades were analyzed. The median interval between surgery and serum sampling was 1 month (range 0.5–168 months). DNA was extracted from whole blood, serum, and paraffin-embedded tumor sections. Loss of heterozygosity (LOH) in chromosomes 1p, 19q, and 10q was assessed by polymerase chain reaction (PCR)-based microsatellite analysis. The methylation status of O6-methyl guanine methyltransferase (MGMT) and phosphatase and tensin homolog promoters was studied by methylation-specific PCR. LOH and/or methylation that could identify DNA as tumor-specific was found in 80.5% of astrocytic tumors and in all oligodendrogliomas. The rate of serum detection of these biomarkers was 51% and 55%, respectively, with specificity around 100%. The rate of serum detection did not differ between low- and high-grade oligodendrogliomas. Statistically significant tumor-serum concordance was found for MGMT methylation in both astrocytic tumors (83%; P < .001) and oligodendroglial tumors (72%; P < .003) and for LOH of 10q (79%; P < .002) and 1p (62%; P < .03) in oligodendrogliomas. We conclude that serum DNA in glial tumors is informative for both LOH and aberrant gene promoter methylation analysis during the course of the disease. The sensitivity is moderate and specificity is high for both low- and high-grade tumors. Future studies should identify a panel of biomarkers that bear the highest potential for clinical application.