tbuckley/cabot-search huggingface dataset:
Regional Variations in Health Care Intensity and Physician Perceptions of Quality of Care
Authors: Brenda E. Sirovich, Daniel J. Gottlieb, H. Gilbert Welch, Elliott S. Fisher
Journal: Annals of Internal Medicine (2006)

Background: Research has documented dramatic differences in health care utilization and spending across U.S. regions with similar levels of patient illness. Although patient outcomes and quality of care have been found to be no better in regions of high health care intensity, it is unknown whether physicians in these regions feel more capable of providing good patient care than those in low-intensity regions. Objective: To determine whether physicians in high-intensity regions feel better able to care for patients than physicians in low-intensity regions. Design: Physician telephone survey. Setting: 51 metropolitan and 9 nonmetropolitan areas of the United States and a supplemental national sample. Participants: 10 577 physicians who provided care to adults in 1998 or 1999 were surveyed for the Community Tracking Study (response rate, 61%). Measurements: The End-of-Life Expenditure Index, a measure of spending that reflects differences in the overall quantity of medical services provided rather than differences in illness or price, was used to determine health care intensity in the physicians' community. Outcomes included physicians' perceived availability of clinical services, ability to provide high-quality care to patients, and career satisfaction. Results: Although the highest-intensity regions have substantially more hospital beds and specialists per capita, physicians in these regions reported more difficulty obtaining needed services for their patients. The proportion of physicians who felt able to obtain elective hospital admissions ranged from 50% in high-intensity regions to 64% in the lowest-intensity region (P < 0.001 for the relationship between intensity and perceived ability to obtain hospital admissions); the proportion of physicians who felt able to obtain high-quality specialist referrals ranged from 64% in high-intensity regions to 79% in low-intensity regions (P < 0.001). Compared with low-intensity regions, fewer physicians in high-intensity regions felt able to maintain good ongoing patient relationships (range, 62% to 70%; P < 0.001) or able to provide high-quality care (range, 72% to 77%; P = 0.009). In most cases, differences persisted but were attenuated in magnitude after adjustment for physician attributes, practice characteristics, and local market factors (for example, managed care penetration); the difference in perceived ability to provide high-quality care was no longer statistically significant (P = 0.099). Limitations: The cross-sectional design prevented demonstration of a causal relationship between intensity and physician perceptions of quality. Conclusion: Despite more resources, physicians in regions of high health care intensity did not report greater ease in obtaining needed services or greater ability to provide high-quality care.
HOXB cluster genes are novel potential regulators of Barrett's oesophagus development
Authors: M. Di Pietro, R. C. Fitzgerald
Journal: Gut (2011)

<h3>Introduction</h3> Barrett9s oesophagus (BO) is a preneoplastic condition to oesophageal adenocarcinoma (OAC) where the squamous epithelium is replaced by a columnar epithelium as a consequence of chronic gastro-oesophageal reflux disease. The molecular events driving this metaplastic change are still poorly understood. Analysis of an in-house microarray screening showed activation in BO of three HOXB cluster genes (HOXB5, HOXB6 and HOXB7). Thus, we set out to validate whether these genes are causally linked to the development of BO <h3>Methods</h3> To externally validate microarray data, RNA was extracted from endoscopic biopsies of colon (n = 14), duodenum (n = 13), gastric body (n = 11), normal oesophagus (n = 14), BO without dysplasia (n = 13), BO with low grade dysplasia (n = 9) and high grade dysplasia (n = 6), as well as surgical specimens of OAC (n = 12). Expression of the mid cluster HOXB genes (HOXB5, HOXB6 and HOXB7), as well as neighbouring genes (HOXB4 and HOXB8), were assessed by qPCR. A normal oesophageal cell line (NES) was transiently transfected with vectors coding for HOXB5, HOXB6 and HOXB7 and the intestinal markers villin, cytokeratin 20 (KRT20), sucrase isomaltase (SI) and MUC2 were assessed by qPCR. Chromatin was isolated from surgical specimens of normal oesophagus (n = 5) and OAC (n = 5) and immunoprecipitated with antibodies against methylated histone H3 at Lysine 27 (H3K27me3) and Lysine 4 (H3K4me3) and acetylated histone H3 (AcH3). <h3>Results</h3> HOXB5, HOXB6 and HOXB7 genes were consistently up-regulated in all pathological stages of Barrett9s disease, including OAC, as compared to normal oesophagus (p &lt; 0.0001 for all three genes). HOXB4 and HOXB8 did not show any transcriptional activation in BO and OAC. When compared with other GI segments, expression levels of these five HOXB genes in BO resembled that of the colon rather than other columnar epithelia (stomach and duodenum). Over-expression of mid cluster HOXB genes in NES cells was associated with activation of villin, KRT20 and MUC2 but not SI. In particular HOXB5 induced villin and MUC2 (2- and 4-fold, respectively); HOXB6 activated villin, KRT20 and MUC2 (4-, 3- and 4-fold, respectively) and HOXB7 induced KRT20 and MUC2 (14-fold for both). Chromatin immunoprecipitation showed significant enrichment of the active mark AcH3 and significant loss of the repressive mark H3K27me3 in OAC compared to normal oesophagus for HOXB5, HOXB6 and HOXB7, but not HOXB4 and HOXB8. No change was detected for the active mark H3K4me3. <h3>Conclusion</h3> Mid cluster HOXB genes are novel potential mediators of the preneoplastic intestinal phenotype in the oesophagus and they are regulated through an epigenetic mechanism acting on the histone code. The HOXB gene signature of oesophageal intestinal metaplasia is similar to that of large bowel, rather than small bowel and gastric epithelia.
Class III β-Tubulin Overexpression Is a Marker of Poor Clinical Outcome in Advanced Ovarian Cancer Patients
Authors: Gabriella Ferrandina, Gian Franco Zannoni, Enrica Martinelli, Amelia Paglia, Valerio Gallotta, Simona Mozzetti, Giovanni Scambia, Cristiano Ferlini
Journal: Clinical Cancer Research (2006)

Overexpression of beta III tubulin has been involved in paclitaxel resistance in several experimental models. We investigated the role of beta III tubulin as predictor of clinical outcome in ovarian cancer patients given platinum/paclitaxel treatment. We also investigated whether beta III tubulin expression could be modified after the selective pressure represented by chemotherapy in vivo.The study was designed to include a series of consecutive ovarian cancer patients with unresectable disease at time of first surgery, who underwent interval debulking surgery with pathologic assessment of response to treatment with platinum/paclitaxel chemotherapy. Immunostaining was done on formalin-fixed, paraffin-embedded tissue sections from pretreatment and posttreatment tissue biopsies by using the polyclonal rabbit anti-class III beta-tubulin antibody.beta III Tubulin immunoreaction was observed in 51 of 62 (82.2%) cases. beta III Tubulin positivity was neither associated with clinicopathologic variables nor with pathologic response to chemotherapy. Significantly lower percentages of beta III tubulin positivity were observed in posttreatment (range, 5-80%; median, 20%) versus pretreatment (range 10-100%; median, 40%) tissue biopsies (P = 0.0011). Cases with high beta III tubulin expression showed a worse overall survival with respect to cases with low beta III tubulin expression (median overall survival, 25 versus 46 months; P = 0.002). Multivariate analysis showed that high content of beta III tubulin remains independently associated with a worse prognosis.Assessment of beta III tubulin could be useful to identify poor prognosis ovarian cancer patients candidates to more aggressive and/or targeted therapy.
Negative Regulation of the Hippo Pathway by E3 Ubiquitin Ligase ITCH Is Sufficient to Promote Tumorigenicity
Authors: Zaidoun Salah, Gerry Melino, Rami I. Aqeilan
Journal: Cancer Research (2011)

Abstract The Hippo tumor suppressor pathway, originally defined in fruit flies, regulates cellular proliferation and survival and exerts profound effects on normal mammalian cell fate and tumorigenesis. The present understanding of Hippo pathway components and mechanisms remains incomplete in cancer. WW domain-containing proteins regulate diverse biological processes through interaction with proline-tyrosine (PPxY)-containing targets. In this study, we report that the E3 ubiquitin ligase ITCH regulates stability of LATS1, a serine/threonine kinase in the Hippo pathway, through protein–protein interaction of the PPxY motifs of LATS1 with the WW domains of ITCH. Ubiquitination of LATS1 catalyzed by ITCH stimulated the proteasomal degradation of LATS1. Furthermore, ITCH-mediated degradation of LATS1 was associated with enhanced cell growth, induction of epithelial-mesenchymal transition, and increased tumorigenicity. Conversely, ITCH depletion increased LATS1 levels, enhancing FAS-induced apoptosis and reducing proliferation, survival, and migration. These phenotypes were rescued when both ITCH and LATS1 were depleted. Together, our results reveal a novel functional link between ITCH and the Hippo pathway, deepening their critical roles in tumorigenesis. Cancer Res; 71(5); 2010–20. ©2011 AACR.
IL-2 production in developing Th1 cells is regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508
Authors: Eun Sook Hwang, Jeong-Ho Hong, Laurie H. Glimcher
Journal: The Journal of Experimental Medicine (2005)

Interleukin (IL)-2 is the predominant cytokine that is produced by naive Th cells in a primary response. It is required for proliferation and differentiation of Th precursor cells into effector cells. Initial high-level IL-2 production is followed by its decline, and the concomitant induction of cytokines that are typical of the differentiated state. Although the factors that are responsible for the early induction of IL-2 are well defined, the mechanisms that are responsible for its down-regulation in later stages of Th development have not been studied as much. Previous work from our laboratory revealed a repressor function for the T-box transcription factor, T-bet, in IL-2 gene transcription. Here, we report that T-betS508 is required for the optimal repression of IL-2 production in developing Th1 cells. Phosphorylation of T-betS508 by casein kinase I and glycogen synthase kinase-3 kinases accompanies T-bet's interaction with the RelA nuclear factor–κB transcription factor. Heterodimerization of T-bet and RelA interferes with the binding of RelA to the IL-2 promoter, and hence, transcriptional activation of the IL-2 gene by RelA.
Effects of mechanical ventilation on diaphragmatic contractile properties in rats.
Authors: G Le Bourdelles, N Viires, J Boczkowski, N Seta, D Pavlovic, M Aubier
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

We measured in rats the effects of 48 h of mechanical ventilation on the weight, contractile properties, and enzymatic profile of the diaphragm, the soleus and the extensor digitorium longus (EDL) muscles. Eighteen animals were randomly divided into a mechanically ventilated (MV, n = 9) group or a control (C, n = 9) group. During the 48 h of mechanical ventilation, animals in the MV group were anesthetized with sodium thiopental and enterally fed with a gastric catheter. Group C animals were neither anesthetized nor mechanically ventilated during the 48-h experimental period, and they had access to food and water ad libitum. Muscular contractile properties were measured in vitro by analysis of force-frequency curves and twitch characteristics. The weights of the three muscles were significantly reduced in the MV group compared with those in the C group. This was accompanied in the diaphragm by a reduction in the normalized force generated for all the frequencies of stimulation, except 20 Hz, whereas twitch characteristics were not modified. The forces generated by the soleus and EDL were not significantly reduced in the MV group compared with those in the C group. Diaphragm, soleus, and EDL citrate synthase and lactate dehydrogenase activities were not significantly different in the two groups. We conclude that mechanical ventilation for 48 h in rats produces a selective force reduction in the diaphragm.
The genome and life-stage specific transcriptomes of Globodera pallida elucidate key aspects of plant parasitism by a cyst nematode
Authors: James A Cotton, Catherine J Lilley, Laura M Jones, Taisei Kikuchi, Adam J Reid, Peter Thorpe, Isheng J Tsai, Helen Beasley, Vivian Blok, Peter J A Cock, Sebastian Eves-van den Akker, Nancy Holroyd, Martin Hunt, Sophie Mantelin, Hardeep Naghra, Arnab Pain, Juan E Palomares-Rius, Magdalena Zarowiecki, Matthew Berriman, John T Jones, Peter E Urwin
Journal: Genome biology (2014)

Abstract Background Globodera pallida is a devastating pathogen of potato crops, making it one of the most economically important plant parasitic nematodes. It is also an important model for the biology of cyst nematodes. Cyst nematodes and root-knot nematodes are the two most important plant parasitic nematode groups and together represent a global threat to food security. Results We present the complete genome sequence of G. pallida , together with transcriptomic data from most of the nematode life cycle, particularly focusing on the life cycle stages involved in root invasion and establishment of the biotrophic feeding site. Despite the relatively close phylogenetic relationship with root-knot nematodes, we describe a very different gene family content between the two groups and in particular extensive differences in the repertoire of effectors, including an enormous expansion of the SPRY domain protein family in G. pallida , which includes the SPRYSEC family of effectors. This highlights the distinct biology of cyst nematodes compared to the root-knot nematodes that were, until now, the only sedentary plant parasitic nematodes for which genome information was available. We also present in-depth descriptions of the repertoires of other genes likely to be important in understanding the unique biology of cyst nematodes and of potential drug targets and other targets for their control. Conclusions The data and analyses we present will be central in exploiting post-genomic approaches in the development of much-needed novel strategies for the control of G. pallida and related pathogens.
Comparison of High-Frequency Oscillatory Ventilation and Conventional Mechanical Ventilation in Pediatric Respiratory Failure
Authors: Punkaj Gupta, Jerril W. Green, Xinyu Tang, Christine M. Gall, Jeffrey M. Gossett, Tom B. Rice, Robert M. Kacmarek, Randall C. Wetzel
Journal: JAMA Pediatrics (2014)

Outcomes associated with use of high-frequency oscillatory ventilation (HFOV) in children with acute respiratory failure have not been established.To compare the outcomes of HFOV with those of conventional mechanical ventilation (CMV) in children with acute respiratory failure.We performed a retrospective, observational study using deidentified data obtained from all consecutive patients receiving mechanical ventilation aged 1 month to 18 years in the Virtual PICU System database from January 1, 2009, through December 31, 2011. The study population was divided into 2 groups: HFOV and CMV. The HFOV group was further divided into early and late HFOV. Propensity score matching was performed as a 1-to-1 match of HFOV and CMV patients. A similar matching process was performed for early HFOV and CMV patients.High-frequency oscillatory ventilation.Length of mechanical ventilation, intensive care unit (ICU) length of stay, ICU mortality, and standardized mortality ratio (SMR).A total of 9177 patients from 98 hospitals qualified for inclusion. Of these, 902 (9.8%) received HFOV, whereas 8275 (90.2%) received CMV. A total of 1764 patients were matched to compare HFOV and CMV, whereas 942 patients were matched to compare early HFOV and CMV. Length of mechanical ventilation (CMV vs HFOV: 14.6 vs 20.3 days, P < .001; CMV vs early HFOV: 14.6 vs 15.9 days, P < .001), ICU length of stay (19.1 vs 24.9 days, P < .001; 19.3 vs 19.5 days, P = .03), and mortality (8.4% vs 17.3%, P < .001; 8.3% vs 18.1%, P < .001) were significantly higher in HFOV and early HFOV patients compared with CMV patients. The SMR in the HFOV group was 2.00 (95% CI, 1.71-2.35) compared with an SMR in the CMV group of 0.85 (95% CI, 0.68-1.07). The SMR in the early HFOV group was 1.62 (95% CI, 1.31-2.01) compared with an SMR in the CMV group of 0.76 (95% CI, 0.62-1.16).Application of HFOV and early HFOV compared with CMV in children with acute respiratory failure is associated with worse outcomes. The results of our study are similar to recently published studies in adults comparing these 2 modalities of ventilation for acute respiratory distress syndrome.
Which imaging modalities should be used for biliary strictures of unknown aetiology?
Authors: D. Domagk, J. Wessling, B. Conrad, R. Fischbach, C. Schleicher, W. Bocker, N. Senninger, A. Heinecke, W. Heindel, W. Domschke, T. Kucharzik
Journal: Gut (2007)

Why is it so difficult to determine the nature of isolated biliary strictures? In patients with no history of biliary surgery, most bile duct strictures have to be considered malignant until proven otherwise. This usually leads to extensive usage of diagnostic imaging—in many cases even to explorative laparotomy. Furthermore, we usually have a “luxury problem”: doctors have to choose the appropriate imaging technique out of the wide range of endoscopic and radiological modalities. For this purpose, doctors should have information about each technique. In a multimodal approach, we prospectively analysed sensitivity and specificity for differentiation between malignant and benign strictures, penetration into surrounding tissues, vascular invasiveness and staging of lymph node.

We included patients with jaundice of unknown aetiology and suspected biliary stricture. According to the study protocol, patients underwent diagnostic laparotomy; alternatively, a long follow-up of more than 12 months …
IRF2BP2 Reduces Macrophage Inflammation and Susceptibility to Atherosclerosis
Authors: Hsiao-Huei Chen, Kianoosh Keyhanian, Xun Zhou, Ragnar O. Vilmundarson, Naif A.M. Almontashiri, Shelly A. Cruz, Nihar R. Pandey, Nida Lerma Yap, Tiffany Ho, Chloe A. Stewart, Hua Huang, Aswin Hari, Michele Geoffrion, Ruth McPherson, Katey J. Rayner, Alexandre F.R. Stewart
Journal: Circulation Research (2015)

Inflammation impairs macrophage cholesterol clearance from vascular tissues and promotes atherosclerosis. Inflammatory macrophages suppress expression of the transcription cofactor interferon regulatory factor 2-binding protein 2 (IRF2BP2), and genetic variants near IRF2BP2 associate with ischemic heart disease progression in humans.To test whether IRF2BP2 in macrophages affects atherosclerosis in mice and humans.We generated mice that delete IRF2BP2 in macrophages. IRF2BP2-deficient macrophages worsened atherosclerosis in irradiated low-density lipoprotein receptor null-recipient mice and in apolipoprotein E null mice. IRF2BP2-deficient macrophages were inflammatory and had impaired cholesterol efflux because of their inability to activate the cholesterol transporter ABCA1 in response to cholesterol loading. Their expression of the anti-inflammatory transcription factor Krüppel-like factor 2 was markedly reduced. Promoter studies revealed that IRF2BP2 is required for MEF2-dependent activation of Krüppel-like factor 2. Importantly, restoring Krüppel-like factor 2 in IRF2BP2-deficient macrophages attenuated M1 inflammatory and rescued M2 anti-inflammatory gene activation and improved the cholesterol efflux deficit by restoring ABCA1 activation in response to cholesterol loading. In a cohort of 1066 angiographic cases and 1011 controls, homozygous carriers of a deletion polymorphism (rs3045215) in the 3' untranslated region sequence of human IRF2BP2 mRNA had a higher risk of coronary artery disease (recessive model, odds ratio [95% confidence interval]=1.560 [1.179-2.065], P=1.73E-03) and had lower IRF2BP2 (and Krüppel-like factor 2) protein levels in peripheral blood mononuclear cells. The effect of this deletion polymorphism to suppress protein expression was confirmed in luciferase reporter studies.Ablation of IRF2BP2 in macrophages worsens atherosclerosis in mice, and a deletion variant that lowers IRF2BP2 expression predisposes to coronary artery disease in humans.
Abnormal Mammary Gland Development and Growth Retardation in Female Mice and MCF7 Breast Cancer Cells Lacking Androgen Receptor
Authors: Shuyuan Yeh, Yueh-Chiang Hu, Peng-Hui Wang, Chao Xie, Qingquan Xu, Meng-Yin Tsai, Zhihong Dong, Ruey-Sheng Wang, Ting-Hein Lee, Chawnshang Chang
Journal: The Journal of Experimental Medicine (2003)

Phenotype analysis of female mice lacking androgen receptor (AR) deficient (AR−/−) indicates that the development of mammary glands is retarded with reduced ductal branching in the prepubertal stages, and fewer Cap cells in the terminal end buds, as well as decreased lobuloalveolar development in adult females, and fewer milk-producing alveoli in the lactating glands. The defective development of AR−/− mammary glands involves the defects of insulin-like growth factor I–insulin-like growth factor I receptor and mitogen-activated protein kinase (MAPK) signals as well as estrogen receptor (ER) activity. Similar growth retardation and defects in growth factor–mediated Ras/Raf/MAPK cascade and ER signaling are also found in AR−/− MCF7 breast cancer cells. The restoration assays show that AR NH2-terminal/DNA-binding domain, but not the ligand-binding domain, is essential for normal MAPK function in MCF7 cells, and an AR mutant (R608K), found in male breast cancer, is associated with the excessive activation of MAPK. Together, our data provide the first in vivo evidence showing that AR-mediated MAPK and ER activation may play important roles for mammary gland development and MCF7 breast cancer cell proliferation.
Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study)
Authors: Riccardo Lencioni, Laura Crocetti, Roberto Cioni, Robert Suh, Derek Glenn, Daniele Regge, Thomas Helmberger, Alice R Gillams, Andrea Frilling, Marcello Ambrogi, Carlo Bartolozzi, Alfredo Mussi
Journal: The Lancet Oncology (2008)