tbuckley/cabot-search huggingface dataset:
Genomic acquisition of a capsular polysaccharide virulence cluster by non-pathogenic Burkholderia isolates
Authors: Bernice Meng Qi Sim, Narisara Chantratita, Wen Fong Ooi, Tannistha Nandi, Ryan Tewhey, Vanaporn Wuthiekanun, Janjira Thaipadungpanit, Sarinna Tumapa, Pramila Ariyaratne, Wing-Kin Sung, Xiao Hui Sem, Hui Hoon Chua, Kalpana Ramnarayanan, Chi Ho Lin, Yichun Liu, Edward J Feil, Mindy B Glass, Gladys Tan, Sharon J Peacock, Patrick Tan
Journal: Genome biology (2010)

Burkholderia thailandensis is a non-pathogenic environmental saprophyte closely related to Burkholderia pseudomallei, the causative agent of the often fatal animal and human disease melioidosis. To study B. thailandensis genomic variation, we profiled 50 isolates using a pan-genome microarray comprising genomic elements from 28 Burkholderia strains and species.Of 39 genomic regions variably present across the B. thailandensis strains, 13 regions corresponded to known genomic islands, while 26 regions were novel. Variant B. thailandensis isolates exhibited isolated acquisition of a capsular polysaccharide biosynthesis gene cluster (B. pseudomallei-like capsular polysaccharide) closely resembling a similar cluster in B. pseudomallei that is essential for virulence in mammals; presence of this cluster was confirmed by whole genome sequencing of a representative variant strain (B. thailandensis E555). Both whole-genome microarray and multi-locus sequence typing analysis revealed that the variant strains formed part of a phylogenetic subgroup distinct from the ancestral B. thailandensis population and were associated with atypical isolation sources when compared to the majority of previously described B. thailandensis strains. In functional assays, B. thailandensis E555 exhibited several B. pseudomallei-like phenotypes, including colony wrinkling, resistance to human complement binding, and intracellular macrophage survival. However, in murine infection assays, B. thailandensis E555 did not exhibit enhanced virulence relative to other B. thailandensis strains, suggesting that additional factors are required to successfully colonize and infect mammals.The discovery of such novel variant strains demonstrates how unbiased genomic surveys of non-pathogenic isolates can reveal insights into the development and emergence of new pathogenic species.
Rapid identification of PAX2/5/8 direct downstream targets in the otic vesicle by combinatorial use of bioinformatics tools
Authors: Mirana Ramialison, Baubak Bajoghli, Narges Aghaallaei, Laurence Ettwiller, Sylvain Gaudan, Beate Wittbrodt, Thomas Czerny, Joachim Wittbrodt
Journal: Genome biology (2008)

Abstract Background The pax2 / 5 / 8 genes belonging to the PAX family of transcription factors are key developmental regulators that are involved in the patterning of various embryonic tissues. More particularly, their function in inner ear specification has been widely described. However, little is known about the direct downstream targets and, so far, no global approaches have been performed to identify these target genes in this particular tissue. Results Here we present an original bioinformatics pipeline composed of comparative genomics, database querying and text mining tools, which is designed to rapidly and specifically discover PAX2/5/8 direct downstream targets involved in inner ear development. We provide evidence supported by experimental validation in medaka fish that brain 2 ( POU domain , class 3 , transcription factor 2 ), claudin-7 , secretory pathway component sec31-like and meteorin-like precursor are novel direct downstream targets of PAX2/5/8. Conclusions This study illustrates the power of extensive mining of public data repositories using bioinformatics methods to provide answers for a specific biological question. It furthermore demonstrates how the usage of such a combinatorial approach is advantageous for the biologist in terms of experimentation time and costs.
Non-small cell lung cancer - Advanced disease: Barriers to inclusion in clinical trials and its impact on survival
Authors: Claudia Lares dos Santos, Ligia Fernandes, Ines Sanches, Filipa Cruz e Costa, Fernando Barata
Journal: European Respiratory Journal (2012)

Introduction: Inclusion in clinical trials allows patients to submit to innovative therapies and a meta-analysis showed that this may be associated with increased rates of survival.

Aims: Identify reasons that hindered the inclusion of patients in clinical trials of first-line therapy; Compare overall survival (OS) and progression-free survival (PFS) between groups of included and excluded patients.

Methods: This study was conducted over 36 months in a central hospital. Patients with well defined histology and candidates to chemotherapy were considered eligible for clinical trials. Reasons for non inclusion have been detailed. OS and PFS were compared.

Results: We identified 199 eligible patients, mean age 64.9 +-10.7 years, 75.9% males, 61.8% with non-squamous cell carcinoma. From these 22.1% were included in trials. Among those not included 18.7% had performance status (Zubrod) 2 and 66.5% had other exclusion criteria, mainly heart disease (22.3%), respiratory disease (21.4%), brain metastases (15, 5%) or second malignancy (15.5%). About 15% of patients refused to be involved in trials. Of patients who had performance status 0/1 (N = 170), there was no statistically significant difference in analysis of OS or PFS between those included in trials and the excluded, whether by criteria (Cox Regression: OS p=0.705/ PFS p=0.807) or by refusal (Cox Regression: OS p=0.465; PFS=0.900).

Conclusion: Liberalization of exclusion criteria and recognition of causes that lead to refusal are possible determinants of increased participation in clinical trials.

Bibliography: CA Stiller(1994). Centralised treatment, entry to trials and survival. Br J Cancer.70,352-362.
To evaluate primary default among smear positive pulmonary tuberculosis patients at three chest clinics of Ojha Institute of Chest Diseases, Karachi, Pakistan
Authors: Nisar Rao, Tehzeeb Anwer, Iftikhar Arain, Ismat Ara
Journal: European Respiratory Journal (2011)

Objective:  To evaluate the magnitude & reasons of primary default among smear positive TB cases at 3 chest clinics of Ojha Institute of Chest Diseases.   Method:  Prospective study, conducted from 1st January 2010 to 30th June 2010. The TB suspects were asked for sputum Acid Fast Bacilli smear examination. Then sputum positive cases were checked for registration for treatment. Those who did not report for treatment initiation were labeled as “primary defaulters (PD)”. They were then contacted on phone/ home visit with the request to get registered for treatment. They were also asked about reasons for not reporting.   Results:  Out of 7467 TB suspects 5167 (69.19%) submitted sputum. 1121 (21.69%) were smear positive TB. 947 (84.5%) registered for treatment while 173 (15.5%) did not (PD). 91/173 (53%) were successfully traced and registered for treatment. 15 patients (8.6%) were taking treatment from physicians ouside chest clinic, 7 (4%) were admitted without registration, 7 (4%) were suspected Drug-Resistant TB. 24 (13.87%) were untraceable PD. One patient was reported to have died at home due to unknown cause.Thirty seven out of 173 patients (21.38%) were unaware of their disease.  The major reason for primary default was distance to clinic i.e. 83 (47.97%). 12 (6.93%) defaulted due to loss of wages, 8 defaulted due to the timing of the clinic, 9 were not interested in taking treatment.   Conclusion:  The primary default is high in the chest clinics of Ojha Institute. Proper counseling/default tracing will help to reduce the primary default rate.
Biphasic Insulin Aspart 30/70: Pharmacokinetics and Pharmacodynamics Compared With Once-Daily Biphasic Human Insulin and Basal-Bolus Therapy
Authors: Tim Heise, Lutz Heinemann, Ulrike Hövelmann, Bianca Brauns, Leszek Nosek, Hanne L. Haahr, Klaus J. Olsen
Journal: Diabetes Care (2009)

OBJECTIVE Pharmacological profiles of biphasic insulin aspart 30/70 (BIAsp 30) once daily (OD), twice daily (b.i.d.), and three times daily (t.i.d.) were compared with other insulin regimens in two crossover glucose clamp studies of insulin-treated type 2 diabetic patients. RESEARCH DESIGNS AND METHODS Study 1 consisted of BIAsp 30 OD, b.i.d., and t.i.d. versus biphasic human insulin 30/70 (BHI 30), OD (n = 24). Study 2 examined BIAsp 30 t.i.d. versus basal-bolus therapy (insulin glargine OD plus insulin glulisine t.i.d.) (n = 24). Pharmacokinetics/pharmacodynamics (PK/PD) were investigated over 24 h. RESULTS Study 1: PK and PD were markedly different between BIAsp 30 OD and BHI 30 OD: the maximum insulin concentration and glucose infusion rate (GIR) were higher for BIAsp 30; time to maximum metabolism was 1.7 h sooner for BIAsp 30. Study 2: both regimens showed three distinct prandial-related GIR peaks. GIR 24-h area under the curve for BIAsp t.i.d. was higher than for basal-bolus therapy: 2,585.2 vs. 2,289.2 mg/kg. CONCLUSIONS BIAsp had pharmacological advantages over BHI. BIAsp t.i.d. had a similar PD profile to basal-bolus therapy.
Calmodulin Regulation of Excitation-Contraction Coupling in Cardiac Myocytes
Authors: Dongmei Yang, Long-Sheng Song, Wei-Zhong Zhu, Khalid Chakir, Wei Wang, Caihong Wu, Yibin Wang, Rui-Ping Xiao, S.R. Wayne Chen, Heping Cheng
Journal: Circulation Research (2003)

Calmodulin (CaM) as a ubiquitous Ca2+ sensor interacts with multiple key molecules involved in excitation-contraction (EC) coupling. In the present study, we report that adenoviral expression of a mutant CaM lacking all of its four Ca2+-binding sites, CaM(1-4), at a level 6.5-fold over endogenous CaM markedly increases the amplitude and abbreviates the decay time of Ca2+ transients and contraction in cultured rat ventricular myocytes. To determine the underlying mechanisms, we examined the properties of L-type Ca2+ channels, Ca2+/CaM-dependent protein kinase II (CaMKII), and phospholamban (PLB) in the sarcoplasmic reticulum (SR). We found that CaM(1-4) expression markedly augmented L-type Ca2+ current amplitude and slowed its inactivation. Surprisingly, overexpression of CaM(1-4) increased CaMKII activity and phosphorylation of PLB-Thr-17. Moreover, CaM(1-4) elevated diastolic Ca2+ and caffeine-labile Ca2+ content of the SR. Inhibition of CaMKII by KN-93 or a myristoylated autocamtide-2 related inhibitory peptide prevented the aforementioned PLB phosphorylation and reversed the positive inotropic and relaxant effects, indicating that CaMKII is essential to CaM(1-4) actions. These results demonstrate that CaM modulates Ca2+ influx, SR Ca2+ release, and Ca2+ recycling during cardiac EC coupling. A novel finding of this study is that expression of a Ca2+-insensitive CaM mutant can lead to activation of CaMKII in cardiac myocytes.
Interleukin 7 promotes long-term in vitro growth of antitumor cytotoxic T lymphocytes with immunotherapeutic efficacy in vivo.
Authors: D H Lynch, R E Miller
Journal: The Journal of Experimental Medicine (1994)

A major obstacle to the effective use of adoptive immunotherapeutic treatment of cancer is the difficulty of obtaining tumor-reactive lymphocytes in either sufficient numbers or with appropriate in vivo function to make such an approach feasible. Previous studies have shown that antitumor cytotoxic T lymphocytes (CTL) with in vivo efficacy can be generated in vitro from lymphoid cells obtained from lymph nodes that drain the anatomical site of a tumor. Results presented here demonstrate that inclusion of interleukin 7 (IL-7) into the medium in which such CTL are cultured can support their growth in vitro for prolonged periods of time in the absence of repeated stimulation with either tumor stimulator cells or tumor antigen. More importantly, antitumor CTL propagated in medium containing IL-7 have retained both their antigenic specificity and their ability to reject tumors in vivo subsequent to intravenous injection. Parallel cultures of antitumor CTL similarly cultured in medium containing only IL-2 could only be maintained for 5-6 wk, after which the number and proportion of viable cells that were recoverable from such cultures progressively decreased. Phenotypic analysis of CTL maintained after extended culture (i.e., 22 mo) in medium containing IL-7 demonstrated them to be CD3+4-8+ T cells. These cells were also found to express lymphocyte function associated 1, intercellular adhesion molecule 1, and Mel-14 cell interaction molecules. The data also demonstrate that these CTL do not require the presence of antigen-presenting cell populations to mount a proliferative response to tumor stimulator cells. Cells in these cultures were also demonstrated to produce IL-2 after stimulation with irradiated tumor cells, thereby indicating that these CTL have become independent of the requirement for CD4+ helper cells to survive and function either in vitro or in vivo. Collectively, the findings that IL-7 can beneficially augment the generation, and propagate the long-term growth, of antitumor CTL from lymph nodes draining a tumor site may have profound implications for promoting the immunotherapeutic treatment of cancer in humans.
Phase III Trial of Trimodality Therapy With Cisplatin, Fluorouracil, Radiotherapy, and Surgery Compared With Surgery Alone for Esophageal Cancer: CALGB 9781
Authors: Joel Tepper, Mark J. Krasna, Donna Niedzwiecki, Donna Hollis, Carolyn E. Reed, Richard Goldberg, Krystyna Kiel, Christopher Willett, David Sugarbaker, Robert Mayer
Journal: Journal of Clinical Oncology (2008)

The primary treatment modality for patients with carcinoma of the esophagus or gastroesophageal junction has been surgery, although primary radiation therapy with concurrent chemotherapy produces similar results. As both have curative potential, there has been great interest in the use of trimodality therapy. To this end, we compared survival, response, and patterns of failure of trimodality therapy to esophagectomy alone in patients with nonmetastatic esophageal cancer.Four hundred seventy-five eligible patients were planned for enrollment. Patients were randomly assigned to either esophagectomy with node dissection alone or cisplatin 100 mg/m(2) and fluorouracil 1,000 mg/m(2)/d for 4 days on weeks 1 and 5 concurrent with radiation therapy (50.4 Gy total: 1.8 Gy/fraction over 5.6 weeks) followed by esophagectomy with node dissection.Fifty-six patients were enrolled between October 1997 and March 2000, when the trial was closed due to poor accrual. Thirty patients were randomly assigned to trimodality therapy and 26 were assigned to surgery alone. Patient and tumor characteristics were similar between groups. Treatment was generally well tolerated. Median follow-up was 6 years. An intent-to-treat analysis showed a median survival of 4.48 v 1.79 years in favor of trimodality therapy (exact stratified log-rank, P = .002). Five-year survival was 39% (95% CI, 21% to 57%) v 16% (95% CI, 5% to 33%) in favor of trimodality therapy.The results from this trial reflect a long-term survival advantage with the use of chemoradiotherapy followed by surgery in the treatment of esophageal cancer, and support trimodality therapy as a standard of care for patients with this disease.
Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC
Authors: Cheng Quan, Yun-Qing Ren, Lei-Hong Xiang, Liang-Dan Sun, Ai-E Xu, Xing-Hua Gao, Hong-Duo Chen, Xiong-Ming Pu, Ri-Na Wu, Chao-Zhao Liang, Jia-Bin Li, Tian-Wen Gao, Jian-Zhong Zhang, Xiu-Li Wang, Jun Wang, Rong-Ya Yang, Ling Liang, Jian-Bin Yu, Xian-Bo Zuo, Sheng-Quan Zhang, Shu-Mei Zhang, Gang Chen, Xiao-Dong Zheng, Pan Li, Jun Zhu, Yong-Wei Li, Xiao-Dong Wei, Wei-Song Hong, Ying Ye, Yong Zhang, Wei-Su Wu, Hui Cheng, Pu-Ling Dong, Da-Yan Hu, Yang Li, Min Li, Xin Zhang, Hua-Yang Tang, Xian-Fa Tang, Sheng-Xin Xu, Su-Min He, Yong-Mei Lv, Min Shen, Hong-Quan Jiang, Ying Wang, Kai Li, Xiao-Jing Kang, Yu-Qin Liu, Li Sun, Zhi-Fang Liu, Shao-Qiong Xie, Cheng-Yao Zhu, Qiang Xu, Jin-Ping Gao, Wen-Long Hu, Cheng Ni, Ting-Meng Pan, Yun Li, Sha Yao, Cai-Feng He, Yang-Sheng Liu, Ze-Ying Yu, Xian-Yong Yin, Feng-Yu Zhang, Sen Yang, Youwen Zhou, Xue-Jun Zhang
Journal: Nature Genetics (2010)
Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase
Authors: Annemarieke E. Loot, Judith G. Schreiber, Beate Fisslthaler, Ingrid Fleming
Journal: The Journal of Experimental Medicine (2009)

Proline-rich tyrosine kinase 2 (PYK2) can be activated by angiotensin II (Ang II) and reactive oxygen species. We report that in endothelial cells, Ang II enhances the tyrosine phosphorylation of endothelial NO synthase (eNOS) in an AT(1)-, H(2)O(2)-, and PYK2-dependent manner. Low concentrations (1-100 micromol/liter) of H(2)O(2) stimulated the phosphorylation of eNOS Tyr657 without affecting that of Ser1177, and attenuated basal and agonist-induced NO production. In isolated mouse aortae, 30 micromol/liter H(2)O(2) induced phosphorylation of eNOS on Tyr657 and impaired acetylcholine-induced relaxation. Endothelial overexpression of a dominant-negative PYK2 mutant protected against H(2)O(2)-induced endothelial dysfunction. Correspondingly, carotid arteries from eNOS(-/-) mice overexpressing the nonphosphorylatable eNOS Y657F mutant were also protected against H(2)O(2). In vivo, 3 wk of treatment with Ang II considerably increased levels of Tyr657-phosphorylated eNOS in the aortae of wild-type but not Nox2(y/-) mice, and this was again associated with a clear impairment in endothelium-dependent vasodilatation in the wild-type but not in the Nox2(y/-) mice. Collectively, endothelial PYK2 activation by Ang II and H(2)O(2) causes the phosphorylation of eNOS on Tyr657, attenuating NO production and endothelium-dependent vasodilatation. This mechanism may contribute to the endothelial dysfunction observed in cardiovascular diseases associated with increased activity of the renin-angiotensin system and elevated redox stress.
A glimpse at cardiac ion channel macromolecular complexes
Authors: E. Balse, S. N. Hatem
Journal: Cardiovascular Research (2014)

Normal cardiac electrical activity depends on the proper membrane expression of a number of ion channels in specialized domains of the sarcolemma of cardiac myocytes.A myriad of protein partners, not yet fully identified, are involved in the trafficking of channel subunits from the endoplasmic reticulum (ER) and Golgi export to the cell surface and in their anchoring into macromolecular complexes. 1Nowadays, a very challenging task is to understand how these partners work together to fine tune the functional expression of ion channels and control cardiac excitability.Two recent articles in Cardiovascular Research bring new building blocks to the emerging scheme of molecular cardiac electrophysiology. 2,3he article of Hund et al. 2 reports a new role of the actin-associated protein, b IV -spectrin.In cardiac myocytes, this protein regulates the targeting of ion channels into the intercalated disc by binding to the adapter protein ankyrin-G.The authors found that the expression of a mutant b IV -spectrin allele with a premature stop codon prior to the ankyrinbinding site is associated with the prolongation of cardiac repolarization and the lengthening of the action potential (AP) in mice that also show sinus node pauses.The effect of the mutated b IV -spectrin (qv 4J ) on cardiac repolarization does not involve classical voltage-gated potassium channels, but the two-pore K + channels TREK-1 that activate in response to mechanical stress or arachidonic acid accumulation.In addition to the identification of an unexpected role for TREK-1 in shaping the AP, this study emphasizes the striking complexity of the molecular organization of ion channels in cardiac myocytes.Indeed, this article follows a previous one from the same laboratory, reporting that the deletion of the CaMKII-binding site of b IV -spectrin causes an opposite effect on cardiac repolarization than the one reported in the present article, i.e. a marked shortening of the AP that cannot adapt anymore
NHS clinicians' pay is frozen for two years as government strives to reduce deficit
Authors: A. O'Dowd
Journal: BMJ (2010)

The pay of most NHS staff will be frozen for the next two years, it has been announced in the government’s emergency budget on Tuesday 22 June.

Chancellor George Osborne, in what he called a “progressive budget” that was “tough but fair,” said that public sector workers had to play their part in tackling the £155bn (€190bn; $230bn) deficit in the United Kingdom.

Mr Osborne, who has pledged to balance the nation’s books by 2015, said, “I know there are many dedicated public sector workers who work very hard and did not cause this recession, but they must share the burden as we pay …
Symptoms of Posttraumatic Stress Disorder and Depression Among Children in Tsunami-Affected Areas in Southern Thailand
Authors: Warunee Thienkrua
Journal: JAMA (2006)

On December 26, 2004, an undersea earthquake occurred off the northwestern coast of Sumatra, Indonesia. The tsunami that followed severely impacted all 6 southwestern provinces of Thailand, where approximately 20,000 children were directly affected.To assess trauma experiences and the prevalence of symptoms of posttraumatic stress disorder (PTSD) and depression among children in tsunami-affected provinces in southern Thailand.Population-based mental health surveys were conducted among children aged 7 to 14 years in Phang Nga, Phuket, and Krabi provinces from February 15-22, 2005 (2 months posttsunami), and September 7-12, 2005 (9 months posttsunami).Trauma experiences and symptoms of PTSD and depression as measured by a tsunami-modified version of the PsySTART Rapid Triage System, the UCLA PTSD Reaction Index, and the Birleson Depression Self-Rating Scale.A total of 371 children (167 displaced and living in camps, 99 not displaced from villages affected by the tsunami, and 105 not displaced from unaffected villages) participated in the first survey. The prevalence rates of PTSD symptoms were 13% among children living in camps, 11% among children from affected villages, and 6% among children from unaffected villages (camps vs unaffected villages, P = .25); for depression symptoms, the prevalence rates were 11%, 5%, and 8%, respectively (P = .39). In multivariate analysis of the first assessment, having had a delayed evacuation, having felt one's own or a family member's life to have been in danger, and having felt extreme panic or fear were significantly associated with PTSD symptoms. Older age and having felt that their own or a family member's life had been in danger were significantly associated with depression symptoms. In the follow-up survey, 72% (151/210) of children from Phang Nga participated. Prevalence rates of symptoms of PTSD and depression among these children did not decrease significantly over time.This assessment documents the prevalence of mental health problems among children in tsunami-affected provinces in southern Thailand at 2 and 9 months posttsunami. Traumatic events experienced during the tsunami were significantly associated with symptoms of PTSD and depression. These data may be useful to target mental health services for children and may inform the design of these interventions.
Body-Mass Index and Mortality among Adults with Incident Type 2 Diabetes
Authors: Deirdre K. Tobias, An Pan, Chandra L. Jackson, Eilis J. O'Reilly, Eric L. Ding, Walter C. Willett, JoAnn E. Manson, Frank B. Hu
Journal: New England Journal of Medicine (2014)

The relation between body weight and mortality among persons with type 2 diabetes remains unresolved, with some studies suggesting decreased mortality among overweight or obese persons as compared with normal-weight persons (an "obesity paradox").