tbuckley/cabot-search huggingface dataset:
Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis
Authors: Simone Difilippantonio, Arkady Celeste, Michael J. Kruhlak, Youngsoo Lee, Michael J. Difilippantonio, Lionel Feigenbaum, Stephen P. Jackson, Peter J. McKinnon, André Nussenzweig
Journal: The Journal of Experimental Medicine (2007)

The chromosomal instability syndromes Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT) share many overlapping phenotypes, including cancer predisposition, radiation sensitivity, cell-cycle checkpoint defects, immunodeficiency, and gonadal dysfunction. The NBS protein Nbs1 is not only a downstream target of AT mutated (ATM) kinase but also acts upstream, promoting optimal ATM activation, ATM recruitment to breaks, and ATM accessibility to substrates. By reconstituting Nbs1 knockout mice with bacterial artificial chromosomes, we have assessed the contribution of distinct regions of Nbs1 to the ATM-dependent DNA damage response. We find that T cell and oocyte development, as well as DNA damage-induced G2/M and S phase checkpoint arrest and radiation survival are dependent on the N-terminal forkhead-associated domain, but not on the principal residues phosphorylated by ATM (S278 and S343) or on the evolutionarily conserved C-terminal region of Nbs1. However, the C-terminal region regulates irradiation-induced apoptosis. These studies provide insight into the complex interplay between Nbs1 and ATM in the DNA damage response.
Safety and Immunogenicity of 4 Intramuscular Double Doses and 4 Intradermal Low Doses vs Standard Hepatitis B Vaccine Regimen in Adults With HIV-1
Authors: Odile Launay
Journal: JAMA (2011)

Alternative schedules more immunogenic than the standard hepatitis B vaccine regimen are needed in patients with human immunodeficiency virus 1 (HIV-1) infection.To compare the safety and immunogenicity of 4 intramuscular double-dose and 4 intradermal low-dose regimens vs the standard hepatitis B vaccine regimen.An open-label, multicenter, 1:1:1 parallel-group, randomized trial conducted between June 28, 2007, and October 23, 2008 (date of last patient visit, July 3, 2009) at 33 centers in France with patients enrolled in French National Agency for Research on AIDS and Viral Hepatitis trials in adults with HIV-1 infection who were hepatitis B virus (HBV) seronegative and having CD4 cell counts of more than 200 cells/μL.Patients were randomly assigned to receive 3 intramuscular injections of the standard dose (20 μg) of recombinant HBV vaccine at weeks 0, 4, and 24 (IM20 × 3 group, n = 145); 4 intramuscular double doses (40 μg [2 injections of 20 μg]) of recombinant HBV vaccine at weeks 0, 4, 8, and 24 (IM40 × 4 group, n = 148); or 4 intradermal injections of low doses (4 μg [1/5 of 20 μg]) of recombinant HBV vaccine at weeks 0, 4, 8, and 24 (ID4 × 4 group, n = 144).Percentage of responders at week 28, defined as patients with hepatitis B surface antibody (anti-HBs) of at least 10 mIU/mL in patients who received at least 1 dose of vaccine. Patients with missing anti-HBs titer measurement at the final follow-up visit at week 28 were considered as nonresponders in the primary (efficacy) analysis.A total of 437 patients were randomized to the 3 study groups, of whom 11 did not receive any vaccine. Of these, 396 had available anti-HBs titers at week 28. The percentage of responders at week 28 was 65% (95% confidence interval [CI], 56%-72%) in the IM20 × 3 group (n = 91), 82% (95% CI, 77%-88%) in the IM40 × 4 group (n = 119) (P < .001 vs IM20 × 3 group), and 77% (95% CI, 69%-84%) in the ID4 × 4 group (n = 108) (P = .02 vs IM20 × 3 group). No safety signal and no effect on CD4 cell count or viral load were observed.In adults with HIV-1, both the 4 intramuscular double-dose regimen and the 4 intradermal low-dose regimen improved serological response compared with the standard HBV vaccine regimen.clinicaltrials.gov Identifier: NCT00480792.
Can endobronchial biopsy analysis be recommended to discriminate between asthma and COPD in routine practice?
Authors: A Bourdin
Journal: Thorax (2004)

International guidelines stress the importance of accurately discriminating between asthma and chronic obstructive pulmonary disease (COPD). Although characteristic pathological features have been described for both conditions, their discriminatory power has never been systematically assessed.Endobronchial biopsy (EBB) specimens from patients with a clear clinical diagnosis of asthma and COPD (50 per group) were examined by three pathologists in a double blind manner. They were asked to propose a pathological diagnosis of either asthma or COPD and to analyse qualitatively the most frequent abnormalities reported in the literature.The sensitivity and specificity of EBB ranged from 36% to 48% and from 56% to 79%, respectively. Eosinophils strongly biased the pathological diagnoses in favour of asthma, whereas their estimated prevalence was similar (11-37% in asthma and 13-41% in COPD). Metaplasia (11-39% in COPD, 1-18% in asthma) and epithelial inflammation (28-61% in COPD, 11-38% in asthma) tended to be specific to COPD, whereas epithelial desquamation (80-98% in asthma, 61-88% in COPD) and basement membrane thickening (71-94% in asthma, 53-88% in COPD) tended to be associated with asthma. There was acceptable intra- and inter-observer agreement only for metaplasia and epithelial eosinophils.Specific histopathological features of asthma and COPD probably exist, but current routine analysis procedures to assess EBB specimens are not sufficiently discriminatory. This might be rectified by improving pathological definitions.
Narrow band imaging to differentiate neoplastic and non-neoplastic colorectal polyps in real time: a meta-analysis of diagnostic operating characteristics
Authors: Sarah K McGill, Evangelos Evangelou, John P A Ioannidis, Roy M Soetikno, Tonya Kaltenbach
Journal: Gut (2013)

<h3>Purpose</h3> Many studies have reported on the use of narrow band imaging (NBI) colonoscopy to differentiate neoplastic from non-neoplastic colorectal polyps. It has potential to replace pathological diagnosis of diminutive polyps. We aimed to perform a systematic review and meta-analysis on the real-time diagnostic operating characteristics of NBI colonoscopy. <h3>Methods</h3> We searched PubMed, SCOPUS and Cochrane databases and abstracts. We used a two-level bivariate meta-analysis following a random effects model to summarise the data and fit hierarchical summary receiver-operating characteristic (HSROC) curves. The area under the HSROC curve serves as an indicator of the diagnostic test strength. We calculated summary sensitivity, specificity and negative predictive value (NPV). We assessed agreement of surveillance interval recommendations based on endoscopic diagnosis compared to pathology. <h3>Results</h3> For NBI diagnosis of colorectal polyps, the area under the HSROC curve was 0.92 (95% CI 0.90 to 0.94), based on 28 studies involving 6280 polyps in 4053 patients. The overall sensitivity was 91.0% (95% CI 87.6% to 93.5%) and specificity was 82.6% (95% CI 79.0% to 85.7%). In eight studies (n=2146 polyps) that used high-confidence diagnostic predictions, sensitivity was 93.8% and specificity was 83.3%. The NPVs exceeded 90% when 60% or less of all polyps were neoplastic. Surveillance intervals based on endoscopic diagnosis agreed with those based on pathology in 92.6% of patients (95% CI 87.9% to 96.3%). <h3>Conclusions</h3> NBI diagnosis of colorectal polyps is highly accurate—the area under the HSROC curve exceeds 0.90. High-confidence predictions provide &gt;90% sensitivity and NPV. It shows high potential for real-time endoscopic diagnosis.
A Trial of Intracranial-Pressure Monitoring in Traumatic Brain Injury
Authors: Randall M. Chesnut, Nancy Temkin, Nancy Carney, Sureyya Dikmen, Carlos Rondina, Walter Videtta, Gustavo Petroni, Silvia Lujan, Jim Pridgeon, Jason Barber, Joan Machamer, Kelley Chaddock, Juanita M. Celix, Marianna Cherner, Terence Hendrix
Journal: New England Journal of Medicine (2012)

Intracranial-pressure monitoring is considered the standard of care for severe traumatic brain injury and is used frequently, but the efficacy of treatment based on monitoring in improving the outcome has not been rigorously assessed.
Paraquat lung: a reappraisal
Authors: P. Smith, D. Heath
Journal: Thorax (1974)

A case is reported of complete isolated occlusion of the right pulmonary artery resulting in underperfusion of the right lung; this was confirmed radiographically and at thoracotomy. Bronchospirometry showed that there was a reduction of ventilation to the right lung. When this lung alone was supplied with a carbon dioxide rich mixture there was a shift of ventilation towards the normal pattern with reversion to the initial distribution when air breathing was resumed. Ventilation of the right lung with a low oxygen mixture failed to cause any shift of ventilation. The results confirm that the effects of pulmonary artery occlusion on differential ventilation which have been shown in animals also occur in man and provide further evidence that carbon dioxide can have a bronchodilator action in man.
Stimulation of aortic smooth muscle prostacyclin by serotonin: role of distinct receptors in contractile and synthetic states.
Authors: D Demolle, A Van Coevorden, J M Boeynaems
Journal: Circulation Research (1989)

It has been shown previously that serotonin stimulates the production of prostacyclin by bovine aortic smooth muscle cells in culture, via 5-HT2 receptors (Coughlin SR, Moskowitz MA, Antoniades HN, Levine L. Proc Natl Acad Sci USA 1981;78:7134-7138). These cells express a synthetic phenotype, whereas the majority of the smooth muscle cells in the media from adult arteries are in a contractile state. We have now compared 5-HT stimulated prostacyclin production in bovine aortic media explants, a preparation of contractile smooth muscle, with cultured smooth muscle cells derived from the explants. In the 1-10 microM range, serotonin stimulates the release of prostacyclin from the explants of bovine aortic media, cultured for a short period. In the presence of cocaine (30 microM), 1 microM was sufficient to produce a maximal effect. The stimulatory action of serotonin was sustained with time and did not induce a lasting desensitization. The effect of serotonin on the explants was inhibited only partially (+/- 30%) by ketanserin, a selective and potent 5-HT2 antagonist. It was mimicked by 5-carboxamido-tryptamine, a 5-HT1 agonist, but was only weakly inhibited by methiothepin, a 5-HT1 antagonist. As expected, in cultured smooth muscle cells, 5-carboxamido-tryptamine was only a weak agonist in stimulating prostacyclin production. In conclusion, it appears that the serotonin effect on prostacyclin production is mediated by different receptors in media explants from bovine aortic media and cultured cells obtained by outgrowth from these explants: a 5-HT2 receptor in the smooth muscle cells in culture and a receptor presenting some similarities with 5-HT1 receptors in the explants.
Gene expression profiles in BCL11B-siRNA treated malignant T cells
Authors: Xin Huang, Qi Shen, Si Chen, Shaohua Chen, Lijian Yang, Jianyu Weng, Xin Du, Piotr Grabarczyk, Grzegorz K Przybylski, Christian A Schmidt, Yangqiu Li
Journal: Journal of Hematology & Oncology (2011)

Abstract Background Downregulation of the B-cell chronic lymphocytic leukemia (CLL)/lymphoma11B ( BCL11B) gene by small interfering RNA (siRNA) leads to growth inhibition and apoptosis of the human T-cell acute lymphoblastic leukemia (T-ALL) cell line Molt-4. To further characterize the molecular mechanism, a global gene expression profile of BCL11B -siRNA -treated Molt-4 cells was established. The expression profiles of several genes were further validated in the BCL11B -siRNA -treated Molt-4 cells and primary T-ALL cells. Results 142 genes were found to be upregulated and 109 genes downregulated in the BCL11B -siRNA -treated Molt-4 cells by microarray analysis. Among apoptosis-related genes, three pro-apoptotic genes, TNFSF 10, BIK , BNIP 3, were upregulated and one anti-apoptotic gene, BCL2L 1 was downregulated. Moreover, the expression of SPP 1 and CREBBP genes involved in the transforming growth factor (TGF-β) pathway was down 16-fold. Expression levels of TNFSF 10, BCL2L 1, SPP 1, and CREBBP were also examined by real-time PCR. A similar expression pattern of TNFSF 10, BCL2L 1, and SPP 1 was identified. However, CREBBP was not downregulated in the BLC11B -siRNA -treated Molt-4 cells. Conclusion BCL11B -siRNA treatment altered expression profiles of TNFSF 10, BCL2L 1, and SPP 1 in both Molt-4 T cell line and primary T-ALL cells.
Lung clearance index in CF: a sensitive marker of lung disease severity
Authors: J. C Davies, S. Cunningham, E. W F W Alton, J A Innes
Journal: Thorax (2007)

agents for soft tissue injury have demonstrated parallel findings.Although nonsteroidal anti-inflammatory drugs can reduce a particular marker of inflammation, their overall benefit towards healing of tendon and muscle injury is questionable. 16keletal muscle dysfunction is a major contributor of morbidity and mortality in COPD.Its pathogenesis, although multifactorial, is not clearly defined.The findings of Barreiro and colleagues 7 chal- lenge the prevailing notion that local inflammation contributes to the decline in muscle function.Like any good research, they have made us think outside the box and to approach this growing problem in a new and refreshing way.Only well designed clinical and animal studies in the future can answer the question: is inflammation good, bad or irrelevant for skeletal muscles in COPD?Or perhaps the more pressing question should be: what aspects of the inflammatory response should be adjusted during the various degenerative and regenerative phases of skeletal muscle as this tissue responds to physical activity, exercise and disuse in COPD?Inflammation is a complicated tangled web of intertwining cascades that are carefully controlled by numerous positive and negative feedback and feed-forward mechanisms.Until we develop a better understanding of the influence of inflammation on muscle injury, regeneration and healing in COPD, clinicians should strongly encourage their COPD patients to stop smoking, exercise regularly and engage in pulmonary rehabilitation, which are proven ways to enhance muscle performance in COPD patients.
Social interactions, emotion and sleep: A systematic review and research agenda
Authors: Louise Beattie, Simon D. Kyle, Colin A. Espie, Stephany M. Biello
Journal: Sleep Medicine Reviews (2014)

Sleep and emotion are closely linked, however the effects of sleep on socio-emotional task performance have only recently been investigated. Sleep loss and insomnia have been found to affect emotional reactivity and social functioning, although results, taken together, are somewhat contradictory. Here we review this advancing literature, aiming to 1) systematically review the relevant literature on sleep and socio-emotional functioning, with reference to the extant literature on emotion and social interactions, 2) summarize results and outline ways in which emotion, social interactions, and sleep may interact, and 3) suggest key limitations and future directions for this field. From the reviewed literature, sleep deprivation is associated with diminished emotional expressivity and impaired emotion recognition, and this has particular relevance for social interactions. Sleep deprivation also increases emotional reactivity; results which are most apparent with neuro-imaging studies investigating amygdala activity and its prefrontal regulation. Evidence of emotional dysregulation in insomnia and poor sleep has also been reported. In general, limitations of this literature include how performance measures are linked to self-reports, and how results are linked to socio-emotional functioning. We conclude by suggesting some possible future directions for this field.
Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1α/p300 complex in a preclinical model of prostate cancer
Authors: Kelie M Reece, Emily D Richardson, Kristina M Cook, Tessa J Campbell, Stephen T Pisle, Alesia J Holly, David J Venzon, David J Liewehr, Cindy H Chau, Douglas K Price, William D Figg
Journal: Molecular Cancer (2014)

The downstream targets of hypoxia inducible factor-1 alpha (HIF-1α) play an important role in tumor progression and angiogenesis. Therefore, inhibition of HIF-mediated transcription has potential in the treatment of cancer. One attractive strategy for inhibiting HIF activity is the disruption of the HIF-1α/p300 complex, as p300 is a crucial coactivator of hypoxia-inducible transcription. Several members of the epidithiodiketopiperazine (ETP) family of natural products have been shown to disrupt the HIF-1α/p300 complex in vitro; namely, gliotoxin, chaetocin, and chetomin. Here, we further characterized the molecular mechanisms underlying the antiangiogenic and antitumor effects of these ETPs using a preclinical model of prostate cancer. In the rat aortic ring angiogenesis assay, gliotoxin, chaetocin, and chetomin significantly inhibited microvessel outgrowth at a GI50 of 151, 8, and 20 nM, respectively. In vitro co-immunoprecipitation studies in prostate cancer cell extracts demonstrated that these compounds disrupted the HIF-1α/p300 complex. The downstream effects of inhibiting the HIF-1α/p300 interaction were evaluated by determining HIF-1α target gene expression at the mRNA and protein levels. Dose-dependent decreases in levels of secreted VEGF were detected by ELISA in the culture media of treated cells, and the subsequent downregulation of VEGFA, LDHA, and ENO1 HIF-1α target genes were confirmed by semi-quantitative real-time PCR. Finally, treatment with ETPs in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. These results suggest that directly targeting the HIF-1α/p300 complex with ETPs may be an effective approach for inhibiting angiogenesis and tumor growth.
Impact of routine bedside infectious disease consultation on clinical management and outcome of Staphylococcus aureus bacteraemia in adults
Authors: R.B. Saunderson, T. Gouliouris, E.K. Nickerson, E.J.P. Cartwright, A. Kidney, S.H. Aliyu, N.M. Brown, D. Limmathurotsakul, S.J. Peacock, M.E. Török
Journal: Clinical Microbiology and Infection (2015)

Staphylococcus aureus bacteraemia (SAB) is a common, serious infection that is associated with high rates of morbidity and mortality. Evidence suggests that infectious disease consultation (IDC) improves clinical management in patients with SAB. We examined whether the introduction of a routine bedside IDC service for adults with SAB improved clinical management and outcomes compared to telephone consultation. We conducted an observational cohort study of 571 adults with SAB at a teaching hospital in the United Kingdom between July 2006 and December 2012. A telephone consultation was provided on the day of positive blood culture in all cases, but an additional bedside IDC was provided after November 2009 (routine IDC group). Compared to patients in the pre-IDC group, those in the routine IDC group were more likely to have a removable focus of infection identified, echocardiography performed and follow-up blood cultures performed. They also received longer courses of antimicrobial therapy, were more likely to receive combination antimicrobial therapy and were more likely to have SAB recorded in the hospital discharge summary. There was a trend towards lower mortality at 30 days in the routine IDC group compared to the pre-IDC group (12% vs. 22%, p 0.07). Our findings suggest that routine bedside IDC should become the standard of care for adults with SAB.
Effect of nebulised L- and D-arginine on exhaled nitric oxide in steroid naive asthma
Authors: D C Chambers
Journal: Thorax (2001)

Background-Nitric oxide (NO) is a product of the enzyme nitric oxide synthase (NOS) and is found in normal and asthmatic human airways.The administration of L-arginine results in an increase in airway NO production in asthmatic subjects.This is thought to occur because L-arginine is the substrate for NOS.However, studies in the systemic vasculature suggest that other mechanisms may be responsible.Methods-Eight patients with steroid naive asthma each received 2.5 g L-arginine, 2.5 g D-arginine, and 2.0% saline by ultrasonic nebuliser on separate days in a randomised, single blind manner.Exhaled NO was measured by chemiluminescence and spirometric tests were performed before and for 3 hours after each administration.The mean concentration of NO after exposure was calculated from the area under the curve. Results-L-arginine,D-arginine, and 2.0% saline induced a mean (95% CI) maximal bronchoconstriction of 11.9% (-1.7 to 25.4), 10.0% (2.8 to 17.2), and 8.5% (-2.5 to 19.5) of the starting forced expiratory volume in one second (FEV 1 ), respectively.Exhaled NO declined in proportion to the degree of bronchoconstriction (r=0.60,p<0.01).Bronchoconstriction and the acute reduction in exhaled NO resolved within 15 minutes.The mean postexposure concentration of NO was 15.75 parts per billion (ppb) after L-arginine, 15.16 ppb after D-arginine, and 12.74 ppb after 2.0% saline.The mean (95% CI) difference between L-arginine and placebo was 3.01 (0.32 to 5.7) ppb, between D-arginine and placebo 2.42 (0.10 to 4.74) ppb, and between L-and D-arginine 0.59 (-1.56 to 2.74) ppb.Conclusions-Exhaled NO decreased with acute bronchoconstriction and returned to baseline with the resolution of bronchoconstriction.Exhaled NO increased following the administration of both L-arginine and D-arginine.Since NOS is stereospecific, this finding suggests that the increase in exhaled NO is not entirely mediated through an increase in NOS enzyme activity.We suggest that arginine may react in a non-stereospecific fashion with reactive oxygen species present in asthmatic airways.
Intravital imaging of CTLs killing islet cells in diabetic mice
Authors: Ken Coppieters, Natalie Amirian, Matthias von Herrath
Journal: Journal of Clinical Investigation (2011)

Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing β cells in the pancreatic islets, which are essentially mini-organs embedded in exocrine tissue. CTLs are considered to have a predominant role in the autoimmune destruction underlying T1D. Visualization of CTL-mediated killing of β cells would provide new insight into the pathogenesis of T1D, but has been technically challenging to achieve. Here, we report our use of intravital 2-photon imaging in mice to visualize the dynamic behavior of a virally expanded, diabetogenic CTL population in the pancreas at cellular resolution. Following vascular arrest and extravasation, CTLs adopted a random motility pattern throughout the compact exocrine tissue and displayed unimpeded yet nonlinear migration between anatomically nearby islets. Upon antigen encounter within islets, a confined motility pattern was acquired that allowed the CTLs to scan the target cell surface. A minority of infiltrating CTLs subsequently arrested at the β cell junction, while duration of stable CTL-target cell contact was on the order of hours. Slow-rate killing occurred in the sustained local presence of substantial numbers of effector cells. Collectively, these data portray the kinetics of CTL homing to and between antigenic target sites as a stochastic process at the sub-organ level and argue against a dominant influence of chemotactic gradients.