tbuckley/cabot-search huggingface dataset:
Genetic and Structural Variation in the Gastric Cancer Kinome Revealed through Targeted Deep Sequencing
Authors: Zhi Jiang Zang, Choon Kiat Ong, Ioana Cutcutache, Willie Yu, Shen Li Zhang, Dachuan Huang, Lian Dee Ler, Karl Dykema, Anna Gan, Jiong Tao, Siyu Lim, Yujing Liu, P. Andrew Futreal, Heike Grabsch, Kyle A. Furge, Liang Kee Goh, Steve Rozen, Bin Tean Teh, Patrick Tan
Journal: Cancer Research (2010)

Genetic alterations in kinases have been linked to multiple human pathologies. To explore the landscape of kinase genetic variation in gastric cancer (GC), we used targeted, paired-end deep sequencing to analyze 532 protein and phosphoinositide kinases in 14 GC cell lines. We identified 10,604 single-nucleotide variants (SNV) in kinase exons including greater than 300 novel nonsynonymous SNVs. Family-wise analysis of the nonsynonymous SNVs revealed a significant enrichment in mitogen-activated protein kinase (MAPK)-related genes (P < 0.01), suggesting a preferential involvement of this kinase family in GC. A potential antioncogenic role for MAP2K4, a gene exhibiting recurrent alterations in 2 lines, was functionally supported by siRNA knockdown and overexpression studies in wild-type and MAP2K4 variant lines. The deep sequencing data also revealed novel, large-scale structural rearrangement events involving kinases including gene fusions involving CDK12 and the ERBB2 receptor tyrosine kinase in MKN7 cells. Integrating SNVs and copy number alterations, we identified Hs746T as a cell line exhibiting both splice-site mutations and genomic amplification of MET, resulting in MET protein overexpression. When applied to primary GCs, we identified somatic mutations in 8 kinases, 4 of which were recurrently altered in both primary tumors and cell lines (MAP3K6, STK31, FER, and CDKL5). These results demonstrate that how targeted deep sequencing approaches can deliver unprecedented multilevel characterization of a medically and pharmacologically relevant gene family. The catalog of kinome genetic variants assembled here may broaden our knowledge on kinases and provide useful information on genetic alterations in GC.
Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications
Authors: P. Stratton, K. J. Berkley
Journal: Human Reproduction Update (2010)

Many clinicians and patients believe that endometriosis-associated pain is due to the lesions. Yet causality remains an enigma, because pain symptoms attributed to endometriosis occur in women without endometriosis and because pain symptoms and severity correlate poorly with lesion characteristics. Most research and reviews focus on the lesions, not the pain. This review starts with the recognition that the experience of pain is determined by the central nervous system (CNS) and focuses on the pain symptoms.Comprehensive searches of Pubmed, Medline and Embase were conducted for current basic and clinical research on chronic pelvic pain and endometriosis. The information was mutually interpreted by a basic scientist and a clinical researcher, both in the field of endometriosis. The goal was to develop new ways to conceptualize how endometriosis contributes to pain symptoms in the context of current treatments and the reproductive tract.Endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the CNS. This engagement provides a mechanism by which the dynamic and hormonally responsive nervous system is brought directly into play to produce a variety of individual differences in pain that can, in some women, become independent of the disease itself.Major advances in improving understanding and alleviating pain in endometriosis will likely occur if the focus changes from lesions to pain. In turn, how endometriosis affects the CNS would be best examined in the context of mechanisms underlying other chronic pain conditions.
Alcohol Consumption and the Prevalence of the Metabolic Syndrome in the U.S.
Authors: Matthew S. Freiberg, Howard J. Cabral, Tim C. Heeren, Ramachandran S. Vasan, R. Curtis Ellison
Journal: Diabetes Care (2004)

The aim of this study was to examine the relations of alcohol consumption to the prevalence of the metabolic syndrome and its components in the U.S. population.We performed a cross-sectional analysis on data from 8,125 participants from the Third National Health and Nutrition Examination Survey who were evaluated for each component of the metabolic syndrome, using the National Cholesterol Education Program criteria, fasting insulin, and alcohol consumption. Current alcohol consumption was defined as > or =1 alcoholic drink per month.After adjustment for age, sex, race/ethnicity, education, income, tobacco use, physical activity, and diet, subjects who consumed 1-19 and > or =20 drinks of alcohol per month had odds ratios (ORs) for the prevalence of the metabolic syndrome of 0.65 and 0.34, respectively (P <0.05 for all), compared with current nondrinkers. These findings were particularly noteworthy for beer and wine drinkers. The association of > or =20 alcoholic drinks per month with the prevalence of the metabolic syndrome was consistent across ethnicities but was most striking in white men and women (ORs 0.35 and 0.22, respectively; P <0.05). Alcohol consumption was significantly and inversely associated with the prevalence of the following three components of the metabolic syndrome: low serum HDL cholesterol, elevated serum triglycerides, high waist circumference, as well as hyperinsulinemia (P <0.05 for all).Mild to moderate alcohol consumption is associated with a lower prevalence of the metabolic syndrome, with a favorable influence on lipids, waist circumference, and fasting insulin. This association was strongest among whites and among beer and wine drinkers.
Mental health trust criticised for "undertreatment" of psychiatric patient who went on to kill
Authors: A. O'Dowd
Journal: BMJ (2009)

Clinicians at a mental health trust have been criticised for their inadequate care of a paranoid schizophrenic man who killed a pregnant woman.

In an independent report published this week investigators said that the Humber Mental Health Teaching NHS Trust, East Yorkshire, was guilty of a series of failures in caring for Benjamin Holiday, who had been treated as an outpatient there.

Mr Holiday, aged 25, referred to as B in the report, stabbed Tina Stevenson, aged 31, who was pregnant with twins, near her home in Hull the day after he had missed taking his drugs in January 2005.

The report published by NHS Yorkshire and …
Current Trends in Autologous Stem-Cell Transplantation for Myeloma in the Era of Novel Therapies
Authors: Philippe Moreau, Hervé Avet-Loiseau, Jean-Luc Harousseau, Michel Attal
Journal: Journal of Clinical Oncology (2011)

Since the mid 1990s, high-dose therapy followed by autologous stem-cell transplantation (ASCT) has been considered the standard of care for frontline therapy in younger patients with multiple myeloma (MM). During the past 10 years, thalidomide, bortezomib, and lenalidomide have been widely incorporated to the therapeutic armamentarium for the treatment of this disease. These agents show promise for improving the rate of complete remission both before and after ASCT without increasing toxicity. However, it is not clear whether such therapies are superior if they are used as an alternative to transplantation or whether they may reduce the need for and use of transplantation in patients in whom treatment is indicated. Therefore, the role of ASCT itself is a matter of debate: Should it be used upfront or as salvage treatment at the time of progression in patients initially treated with novel agents? This review presents current trends in ASCT for MM in the era of novel therapies.
Sustained Expression of Early Growth Response Protein-1 Blocks Angiogenesis and Tumor Growth
Authors: Markus Lucerna, Jiri Pomyje, Diana Mechtcheriakova, Alexandra Kadl, Florian Gruber, Martin Bilban, Yuri Sobanov, Gernot Schabbauer, Johannes Breuss, Oswald Wagner, Markus Bischoff, Matthias Clauss, Bernd R. Binder, Erhard Hofer
Journal: Cancer Research (2006)

Abstract Transient induction of the transcription factor early growth response protein-1 (EGR-1) plays a pivotal role in the transcriptional response of endothelial cells to the angiogenic growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which are produced by most tumors and are involved in the angiogenic switch. We report here that sustained expression of EGR-1 by recombinant adenoviruses in endothelial cells, however, leads to the specific induction of potent feedback inhibitory mechanisms, including strong up-regulation of transcriptional repressors, negative cell cycle check point effectors, proteins with established antiangiogenic activity, and several proapoptotic genes. Sustained EGR-1 expression consistently leads to an antiangiogenic state characterized by an altered responsiveness to VEGF and bFGF and a striking inhibition of sprouting and tubule formation in vitro. Furthermore, EGR-1–expressing viruses potently inhibit cell invasion and vessel formation in the murine Matrigel model and repress tumor growth in a murine fibrosarcoma model. We propose that gene therapy involving sustained EGR-1 expression may constitute a novel therapeutic principle in the treatment of cancer due to the simultaneous induction of multiple pathways of antiangiogenesis, growth arrest, and apoptosis induction in proliferating cells leading to preferential inhibition of angiogenesis and tumor growth. (Cancer Res 2006; 66(13): 6708-13)
Kidney Protein Dynamics and Ammoniagenesis in Humans with Chronic Metabolic Acidosis
Authors: Giacomo Garibotto, Antonella Sofia, Cristina Robaudo, Stefano Saffioti, Maria Rita Sala, Daniela Verzola, Monica Vettore, Rodolfo Russo, Vanessa Procopio, Giacomo Deferrari, Paolo Tessari
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. To evaluate the effects of chronic metabolic acidosis on protein dynamics and amino acid oxidation in the human kidney, a combination of organ isotopic (14C-leucine) and mass-balance techniques in 11 subjects with normal renal function undergoing venous catheterizations was used. Five of 11 studies were performed in the presence of metabolic acidosis. In subjects with normal acid-base balance, kidney protein degradation was 35% to 130% higher than protein synthesis, so net protein leucine balance was markedly negative. In acidemic subjects, kidney protein degradation was no different from protein synthesis and was significantly lower (P < 0.05) than in controls. Kidney leucine oxidation was similar in both groups. Urinary ammonia excretion and total ammonia production were 186% and 110% higher, respectively, and more of the ammonia that was produced was shifted into urine (82% versus 65% in acidemic subjects versus controls). In all studies, protein degradation and net protein balance across the kidney were inversely related to urinary ammonia excretion and to the partition of ammonia into urine, but not to total ammonia production, arterial pH, [HCO−3], urinary flow, the uptake of glutamine by the kidney, or the ammonia released into the renal veins. The data show that response of the human kidney to metabolic acidosis includes both changes in amino acid uptake and suppression of protein degradation. The latter effect, which is likely induced by the increase in ammonia excretion and partition into the urine, is potentially responsible for kidney hypertrophy.
Wound healing and inflammation genes revealed by array analysis of 'macrophageless' PU.1 null mice
Authors: Lisa Cooper, Claire Johnson, Frank Burslem, Paul Martin
Journal: Genome biology (2004)

Abstract Background Wound healing is a complex process requiring the collaborative efforts of different tissues and cell lineages, and involving the coordinated interplay of several phases of proliferation, migration, matrix synthesis and contraction. Tissue damage also triggers a robust influx of inflammatory leukocytes to the wound site that play key roles in clearing the wound of invading microbes but also release signals that may be detrimental to repair and lead to fibrosis. Results To better define key cellular events pivotal for tissue repair yet independent of inflammation we have used a microarray approach to determine a portfolio of over 1,000 genes expressed across the repair response in a wild-type neonatal mouse versus its PU.1 null sib. The PU.1 null mouse is genetically incapable of raising the standard inflammatory response, because it lacks macrophages and functioning neutrophils, yet repairs skin wounds rapidly and with reduced fibrosis. Conversely, by subtraction, we have determined genes that are either expressed by leukocytes, or upregulated by fibroblasts, endothelial cells, muscle cells and others at the wound site, as a consequence of inflammation. To determine the spatial expression pattern for several genes in each cluster we have also performed in situ hybridization studies. Conclusions Cluster analysis of genes expressed after wounding wild-type mice versus PU.1 null sibs distinguishes between tissue repair genes and genes associated with inflammation and its consequences. Our data reveal and classify several pools of genes, giving insight into their likely functions during repair and hinting at potential therapeutic targets.
Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis
Authors: T. Takeuchi, N. Miyasaka, Y. Tatsuki, T. Yano, T. Yoshinari, T. Abe, T. Koike
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA). <h3>Methods</h3> Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high). <h3>Results</h3> In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (&lt;0.1 μg/ml) at 3 and 6 mg/kg but were greater than 2 μg/ml at 10 mg/kg, whereas the levels were approximately 1 μg/ml for each dosage group in TNF-low patients. <h3>Conclusion</h3> In patients with RA, baseline-TNF is significantly associated with the clinical response to infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab.
Effects of Exposure to Intermittent Hypoxia on Oxidative Stress and Acute Hypoxic Ventilatory Response in Humans
Authors: Vincent Pialoux, Patrick J. Hanly, Glen E. Foster, Julien V. Brugniaux, Andrew E. Beaudin, Sara E. Hartmann, Matiram Pun, Cailean T. Duggan, Marc J. Poulin
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Periodic occlusion of the upper airway in patients with obstructive sleep apnea leads to chronic intermittent hypoxia, which increases the acute hypoxic ventilatory response (AHVR). Animal studies suggest that oxidative stress may modulate AHVR by increasing carotid body sensitivity to hypoxia. This has not been shown in humans.Objectives: To determine whether 4 days of exposure to chronic intermittent hypoxia increases AHVR and oxidative stress and to determine the strength of the association between oxidative stress and AHVR.Methods: After two normoxic control days (Day −4 and Day 0), 10 young healthy men were exposed awake to 4 days (Days 1–4) of intermittent hypoxia for 6 hours per day.Measurements and Main Results: AHVR, assessed using an isocapnic hypoxia protocol, was determined as the slope of the linear regression between ventilation and oxygen desaturation. Oxidative stress was evaluated by measuring plasma DNA, lipid and protein oxidation, uric acid and antioxidant status by measuring α-tocopherol, total vitamin C, and antioxidant enzymatic activities. Between baseline and Day 4, there were significant increases in AHVR, DNA oxidation, uric acid, and vitamin C, whereas antioxidant enzymatic activities and α-tocopherol were unchanged. There were strong correlations between the changes in AHVR and DNA oxidation (r = 0.88; P = 0.002).Conclusions: Chronic intermittent hypoxia increases oxidative stress by increasing production of reactive oxygen species without a compensatory increase in antioxidant activity. This human study shows that reactive oxygen species overproduction modulates increased AHVR. These mechanisms may be responsible for increased AHVR in patients with obstructive sleep apnea.
Interleukin-13–induced MUC5AC Is Regulated by 15-Lipoxygenase 1 Pathway in Human Bronchial Epithelial Cells
Authors: Jinming Zhao, Ben Maskrey, Silvana Balzar, Kazuyuki Chibana, Anthony Mustovich, Haizhen Hu, John B. Trudeau, Valerie O'Donnell, Sally E. Wenzel
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: 15-Lipoxygenase-1 (15LO1) and MUC5AC are highly expressed in asthmatic epithelial cells. IL-13 is known to induce 15LO1 and MUC5AC in human airway epithelial cells in vitro. Whether 15LO1 and/or its product 15-HETE modulate MUC5AC expression is unknown.Objectives: To determine the expression of 15LO1 in freshly harvested epithelial cells from subjects with asthma and normal control subjects and to determine whether IL-13–induced 15LO1 expression and activation regulate MUC5AC expression in human bronchial epithelial cells in vitro.Methods: Human airway epithelial cells from subjects with asthma and normal subjects were evaluated ex vivo for 15LO1 and MUC5AC expression. The impact of 15LO1 on MUC5AC expression in vitro was analyzed by inhibiting 15LO1 through pharmacologic (PD146176) and siRNA approaches in human bronchial epithelial cells cultured under air–liquid interface. We analyzed 15 hydroxyeicosatetraenoic acid (15-HETE) by liquid chromatography/UV/mass spectrometry. MUC5AC and 15LO1 were analyzed by real-time RT-PCR, immunofluoresence, and Western blot.Measurements and Main Results: Epithelial 15LO1 expression increased with asthma severity (P < 0.0001). 15LO1 significantly correlated with MUC5AC ex vivo and in vitro. IL-13 increased 15LO1 expression and stimulated formation of two molecular species of 15-HETE esterified to phosphotidylethanolamine (15-HETE-PE). Inhibition of 15LO1 suppressed 15-HETE-PE and decreased MUC5AC expression in the presence of IL-13 stimulation. The addition of exogenous 15-HETE partially restored MUC5AC expression.Conclusions: Epithelial 15LO1 expression increases with increasing asthma severity. IL-13 induction of 15-HETE-PE enhances MUC5AC expression in human airway epithelial cells. High levels of 15LO1 activity could contribute to the increases of MUC5AC observed in asthma.
Hypothesis for Induction and Propagation of Chemical Sensitivity Based on Biopsy Studies
Authors: William J. Meggs
Journal: Environmental Health Perspectives (1997)

The reactive airways dysfunction syndrome (RADS), the reactive upper airways dysfunction syndrome (RUDS), the sick building syndrome (SBS), and the multiple chemical sensitivity syndrome (MCS) are overlapping disorders in which there is an intolerance to environmental chemicals.The onset of these illnesses is often associated with an initial acute chemical exposure.To understand the pathophysiology of these conditions, a study of the nasal pathology of individuals experiencing these syndromes was undertaken.Preliminary data indicate that the nasal pathology of these disorders is characterized by defects in tight junctions between cells, desquamation of the respiratory epithelium, glandular hyperplasia, lymphocytic infiltrates, and peripheral nerve fiber proliferation.These findings suggest a model for a relationship between the chronic inflammation seen in these conditions and an individual's sensitivity to chemicals.A positive feedback loop is set up: the inflammatory response to low levels of chemical irritants is enhanced due to the observed changes in the epithelium, and the epithelial changes are propagated by the inflammatory response to the chemicals.This model, combined with the concept of neurogenic switching, has the potential to explain many aspects of RADS, RUDS,
Psychiatric Treatment of a Health Care Worker After Infection With Ebola Virus in Lagos, Nigeria
Authors: Abdulaziz Mohammed, Taiwo Lateef Sheikh, Saheed Gidado, Ismail Adeshina Abdus-salam, Joseph Adeyemi, Adebola Olayinka, Chima Ohuabunwo, Orina Oluwagbemiga Victor, Patrick Nguku, Erinfolami Adebayo Rasheed, Funmi Doherty, Ndadilnasiya Waziri, Faisal Shuaib, Babalola Obafemi Joseph, Idris Mohammed Bomai, Akin Oyemakinde
Journal: American Journal of Psychiatry (2015)
Liver Intestine-Cadherin (<i>CDH17</i>) Haplotype Is Associated with Increased Risk of Hepatocellular Carcinoma
Authors: Xiao Qi Wang, John M. Luk, Mercè Garcia-Barcelo, Xiaoping Miao, Pauline P. Leung, David W. Ho, Siu Tim Cheung, Brian Y. Lam, Cindy K. Cheung, Ashley S. Wong, Silvana S. Lau, Man Ting So, Wan Ching Yu, Qi Cai, Karen S. Liu, Chee Kin Hui, George K. Lau, Ronnie T.P. Poon, John Wong, Sheung Tat Fan
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Hepatocellular carcinoma (HCC), the most common form of liver cancer, is a leading cause of cancer death worldwide. We previously showed that aberrant mRNA splicing of the liver intestine-cadherin gene CDH17 in liver tissues was triggered by the specific constellation of two CDH17 single nucleotide polymorphisms (651T and IVS6+35G). CDH17 aberrant splicing was highly associated with tumor dissemination and shorter survival of HCC patients. Consequently, it is highly relevant to assess whether the presence of these single nucleotide polymorphisms in the general population represents a risk to the development of HCC. Experimental Design: We conducted a case-control study including 164 HCC and 99 cirrhosis patients and 293 healthy controls. Genotyping was done by PCR and direct sequencing. Odds ratio (OR) and χ2 analysis were used to analyze genotypes and haplotypes. Results: Genotypes 651TT [OR, 2.62; 95% confidence interval (95% CI), 1.34-5.03] and IVS6+35 GG (OR, 1.95; 95% CI, 1.04-3.62) were highly associated with HCC disease. The 651T (C&amp;gt;T) and IVS6+35G (A&amp;gt;G) alleles were also overrepresented in HCC patients and, in particular, the T-G haplotype was the most prevalent in HCC patients when compared with healthy controls (OR, 1.57; 95% CI, 1.167-2.109; P = 0.004), which was in agreement with the aberrant splicing observed in tumor tissues. There was no significant difference in genotype and allele frequencies between cirrhosis patients and controls. Conclusion: The functional T-G haplotype of CDH17 (651 C&amp;gt;T and IVS6+35A&amp;gt;G) is a genetic susceptibility factor for the development of HCC in a Chinese population.