tbuckley/cabot-search huggingface dataset:
Stress-Regulated Transcription Factor ATF4 Promotes Neoplastic Transformation by Suppressing Expression of the INK4a/ARF Cell Senescence Factors
Authors: Michiko Horiguchi, Satoru Koyanagi, Akinori Okamoto, Satoshi O. Suzuki, Naoya Matsunaga, Shigehiro Ohdo
Journal: Cancer Research (2011)

Abstract Many cancers overexpress ATF4, a stress-induced transcription factor that promotes cell survival under hypoxic conditions and other stresses of the tumor microenvironment, but the potential contributions of ATF4 to oncogenesis itself have been little explored. Here, we report that ATF4 promotes oncogene-induced neoplastic transformation by suppressing the expression of cellular senescence-associated genes. Strikingly, primary embryo fibroblasts from ATF4-deficient mice were resistant to transformation by coexpression of H-rasV12 and SV40 large T antigen. In wild-type cells these oncogenes induced expression of the murine Atf4 gene along with the cyclin-dependent kinase inhibitor Cdkn2a, which encodes the cell senescence-associated proteins p16INK4 and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these proteins and drive oncogenic transformation. Conversely, genetic ablation of ATF4 led to constitutive expression of p16INK4a and p19ARF, triggering cellular senescence. Our findings define a central function for ATF4 in promoting oncogenic transformation by suppressing a central pathway of cellular senescence. Cancer Res; 72(2); 395–401. ©2011 AACR.
Predictors of Loss of Residual Renal Function among New Dialysis Patients
Authors: Louise M. Moist, Friedrich K. Port, Sean M. Orzol, Eric W. Young, Truls Ostbye, Robert A. Wolfe, Tempie Hulbert-Shearon, Camille A. Jones, Wendy E. Bloembergen
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Residual renal function (RRF) in end-stage renal disease is clinically important as it contributes to adequacy of dialysis, quality of life, and mortality. This study was conducted to determine the predictors of RRF loss in a national random sample of patients initiating hemodialysis and peritoneal dialysis. The study controlled for baseline variables and included major predictors. The end point was loss of RRF, defined as a urine volume &lt;200 ml/24 h at approximately 1 yr of follow-up. The adjusted odds ratios (AOR) and P values associated with each of the demographic, clinical, laboratory, and treatment parameters were estimated using an “adjusted” univariate analysis. Significant variables ( P &lt; 0.05) were included in a multivariate logistic regression model. Predictors of RRF loss were female gender (AOR = 1.45; P &lt; 0.001), non-white race (AOR = 1.57; P = &lt;0.001), prior history of diabetes (AOR = 1.82; P = 0.006), prior history of congestive heart failure (AOR = 1.32; P = 0.03), and time to follow-up (AOR = 1.06 per month; P = 0.03). Patients treated with peritoneal dialysis had a 65% lower risk of RRF loss than those on hemodialysis (AOR = 0.35; P &lt; 0.001). Higher serum calcium (AOR = 0.81 per mg/dl; P = 0.05), use of an angiotensin-converting enzyme inhibitor (AOR = 0.68; P &lt; 0.001), and use of a calcium channel blocker (AOR = 0.77; P = 0.01) were independently associated with decreased risk of RRF loss. The observations of demographic groups at risk and potentially modifiable factors and therapies have generated testable hypotheses regarding therapies that may preserve RRF among end-stage renal disease patients.
Respiratory Failure in Acute Chest Infections
Authors: E. K. Westlake
Journal: BMJ (1954)

The main difference, therefore, between the bacterial flora of the bladder urine before and after prostatectomy was the marked development of Proteus strains after that procedure.Presence or absence of organisms in the bladder urine before retention of an indwelling catheter did not appear materially to affect the nature of the bacterial flora which subsequently developed after retention of the catheter.Comparing the organisms which occur coinicidently in the urethra and the bladder urine in the presence of an indwelling urethral catheter before prostatectomy, it is seen that there is little relationship between the bacterial flora of the two sites.Staph.albus, Staph.aureus, diphtheroids, and Proteus strains predominate in the urethra, whereas Bact. coli and Str.faecalis predominate in the bladder urine in these circumstances.After prostatectomy, however, it is seen that there is a closer relationship.For there is a high incidence of Bact. coli in both the urethra and the bladder urine in these cir- cumstances.Nevertheless, the relationship is not by any means complete, because there is also a high incidence of '~700 males aged 40-65 i Egan anIae bsdnRgsrr500 - -~~~~eea'figre) *Brs MLobsar pneumonia 100 1 1932 '4 'b '8 '40 '2 '4 '6 '8 '50 '2' YEAR FIG.1.-Mortality from lobar pneumonia and bronchitis among males aged 40-65 in England and Wales (based on Registrar- General's figures).
Niacin Lipid Efficacy Is Independent of Both the Niacin Receptor GPR109A and Free Fatty Acid Suppression
Authors: Brett Lauring, Andrew K. P. Taggart, James R. Tata, Richard Dunbar, Luzelena Caro, Kang Cheng, Jayne Chin, Steven L. Colletti, Josee Cote, Sauzanne Khalilieh, Jiajun Liu, Wen-Lin Luo, Alexandra A. MacLean, Laurence B. Peterson, Adam B. Polis, Waheeda Sirah, Tsuei-Ju Wu, Xuan Liu, Lan Jin, Kenneth Wu, P. Douglas Boatman, Graeme Semple, Dominic P. Behan, Daniel T. Connolly, Eseng Lai, John A. Wagner, Samuel D. Wright, Cynthia Cuffie, Yale B. Mitchel, Daniel J. Rader, John F. Paolini, M. Gerard Waters, Andrew Plump
Journal: Science Translational Medicine (2012)

GPR109A is not the target mediating niacin’s lipid efficacy and the free fatty acid hypothesis does not explain niacin’s mechanism of action.
Comparative Analysis of the Value of Allogeneic Hematopoietic Stem-Cell Transplantation in Acute Myeloid Leukemia With Monosomal Karyotype Versus Other Cytogenetic Risk Categories
Authors: Jan J. Cornelissen, Dimitri Breems, Wim L.J. van Putten, Alois A. Gratwohl, Jakob R. Passweg, Thomas Pabst, Johan Maertens, H. Berna Beverloo, Marinus van Marwijk Kooy, Pierre W. Wijermans, Bart J. Biemond, Edo Vellenga, Leo F. Verdonck, Gert J. Ossenkoppele, Bob Löwenberg
Journal: Journal of Clinical Oncology (2012)

To determine to what extent allogeneic hematopoietic stem-cell transplantation (alloHSCT) quantitatively reduces relapse in acute myeloid leukemia with monosomal karyotype (MK-AML) compared with alternative postremission therapy and how it compares with other cytogenetic subcategories.Of 2,560 patients (younger than age 61 years) without core-binding factor abnormalities including 305 patients with MK-AML receiving first-line induction treatment, 1,975 patients (77%) achieved remission, and 1,588 received consolidation in the first complete remission (CR1) after two induction cycles. Consolidation treatment of 107 patients with MK-AML consisted of alloHSCT (n = 45), chemotherapy (n = 48), or autologous HSCT (n = 14).The 5-year overall survival after start of consolidation was 19% for patients with MK-AML who received alloHSCT and 9% for those who received chemotherapy or autoHSCT (P = .02). Relapse-free survival (RFS) at 5 years was 17% versus 7% (P = .003). Cox regression analysis was performed with alloHSCT as a time-dependent covariate. Hazard ratios (HRs) associated with alloHSCT for relapse and RFS were 0.30 (95% CI, 0.24 to 0.37; P < .001), and 0.52 (95% CI, 0.43 to 0.62; P < .001), respectively. HRs were similar in MK-AML and the other cytogenetic subgroups.AlloHSCT, applied as consolidation in CR1, is associated with a significant reduction of relapse and improvement of survival in MK-AML, with the same relative reduction of relapse or death as in other cytogenetic risk categories.
The <i>Scurfy</i> mutation of <i>FoxP3</i> in the thymus stroma leads to defective thymopoiesis
Authors: Xing Chang, Jian Xin Gao, Qi Jiang, Jing Wen, Nick Seifers, Lishan Su, Virginia L. Godfrey, Tao Zuo, Pan Zheng, Yang Liu
Journal: The Journal of Experimental Medicine (2005)

The Scurfy mutation of the FoxP3 gene (FoxP3(sf)) in the mouse and analogous mutations in human result in lethal autoimmunity. The mutation of FoxP3 in the hematopoietic cells impairs the development of regulatory T cells. In addition, development of the Scurfy disease also may require mutation of the gene in nonhematopoietic cells. The T cell-extrinsic function of FoxP3 has not been characterized. Here we show that the FoxP3(sf) mutation leads to defective thymopoiesis, which is caused by inactivation of FoxP3 in the thymic stromal cells. FoxP3 mutation also results in overexpression of ErbB2 in the thymic stroma, which may be involved in defective thymopoiesis. Our data reveal a novel T cell-extrinsic function of FoxP3. In combination, the T cell-intrinsic and -extrinsic defects provide plausible explanation for the severity of the autoimmune diseases in the scurfy mice and in patients who have immunodysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome.
The Clara Cell10 Adenine38Guanine Polymorphism and Sarcoidosis Susceptibility in Dutch and Japanese Subjects
Authors: Rob Janssen, Hiroe Sato, Jan C. Grutters, Henk J. T. Ruven, Ron M. du Bois, Ryosuke Matsuura, Masao Yamazaki, Shigeki Kunimaru, Takateru Izumi, Ken I. Welsh, Sonoko Nagai, Jules M. M. van den Bosch
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

CC10 (CC16, uteroglobin) is a pulmonary protein postulated to play a counter regulatory role in sarcoidosis pathogenesis. The adenine38guanine (A38G) polymorphism of the encoding CC10 gene (SCGB1A1) is functional. Recently, an association between the low CC10 producing 38A allele and sarcoidosis susceptibility has been reported in Japanese patients from Hokkaido. The aim of the present study was to confirm this association in a clinically well characterized population of Dutch white and Kyoto Japanese patients with sarcoidosis and control subjects. No difference in genotype or allele frequency was found between patients with sarcoidosis and control subjects in either ethnic population. Remarkably, however, a significant difference was found between the control subjects from Kyoto and Hokkaido, but not between the Japanese groups of patients with sarcoidosis. Furthermore, review of previously published A38G genotyping results showed a consistent difference in CC10 A38G allele frequencies between whites and Japanese subjects. We conclude that the CC10 A38G polymorphism does not influence sarcoidosis susceptibility in Dutch whites or in Japanese subjects from Kyoto. This stresses the importance of studying the influence of polymorphisms on disease susceptibility in multiple ethnically and geographically distinct disease and control populations before reaching conclusions.
Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4
Authors: Han-Xiang Deng, Christopher J Klein, Jianhua Yan, Yong Shi, Yanhong Wu, Faisal Fecto, Hau-Jie Yau, Yi Yang, Hong Zhai, Nailah Siddique, E Tessa Hedley-Whyte, Robert DeLong, Marco Martina, Peter J Dyck, Teepu Siddique
Journal: Nature Genetics (2009)
Recruitment of Serum Response Factor and Hyperacetylation of Histones at Smooth Muscle–Specific Regulatory Regions During Differentiation of a Novel P19-Derived In Vitro Smooth Muscle Differentiation System
Authors: Ichiro Manabe, Gary K. Owens
Journal: Circulation Research (2001)

Abstract —Little is known regarding transcriptional regulatory mechanisms that control the sequential and coordinate expression of genes during smooth muscle cell (SMC) differentiation. To facilitate mechanistic studies of SMC differentiation, we established a novel P19-derived clonal cell line (designated A404) harboring a smooth muscle (SM) α-actin promoter/intron-driven puromycin resistance gene. Retinoic acid plus puromycin treatment stimulated rapid differentiation of multipotential A404 cells into SMCs that expressed multiple SMC differentiation marker genes, including the definitive SM-lineage marker SM myosin heavy chain. Using this system, we demonstrated that various transcription factors were upregulated coincidentally with the expression of SMC differentiation marker genes. Of interest, the expression of serum response factor (SRF), whose function is critical for SMC-specific transcription, was high in undifferentiated A404 cells, and it did not increase over the course of differentiation. However, chromatin immunoprecipitation analyses showed that SRF did not bind the target sites of endogenous SMC marker genes in chromatin in undifferentiated cells, but it did in differentiated A404 cells, and it was associated with hyperacetylation of histones H3 and H4. The present studies define a novel cell system for studies of transcriptional regulation during the early stages of SMC differentiation, and using this system, we obtained evidence for the involvement of chromatin remodeling and selective recruitment of SRF to CArG elements in the induction of cell-selective marker genes during SMC differentiation.
PMO-187 A multi-centre audit of 16 064 colonoscopies looking at caecal intubation rates, over a 2-year period. Non-GI operators and those doing &lt;100 p.a. need to improve or stop performing colonoscopy
Authors: A M Verma, N McGrath, P Bennett, J de Caestecker, A Dixon, J Eaden, P Wurm, A P Chilton
Journal: Gut (2012)

<h3>Introduction</h3> Colonoscopy is the gold standard assessment for large bowel mucosal pathology, but a complete examination is an essential requirement. The first national colonoscopy audit carried out in 1999 demonstrated caecal intubation rates (CIRs) of 56.9%, which the authors described as "unacceptably low". As a result the Joint Advisory Group on Gastrointestinal endoscopy (JAG) launched a programme of continuous quality improvement by standardising training, peer review and audit. JAG recommends practitioners undertake at least 100 procedures per annum with target CIRs of 90%. This current audit provides an assessment of performance against these quality standards. <h3>Methods</h3> Data were collected from all procedures undertaken in 2008–2009 from six hospitals across three English regions. The data included grade and specialism of operator, number of procedures and CIRs. Caecal intubation was recorded if reports positively documented reaching defined landmarks. <h3>Results</h3> 16 064 colonoscopies performed with a CIR of 90.57% (95% CI 90.11% to 91.01%). Operators doing 100+ procedures per annum. CIR=91.76% (95% CI 91.24% to 92.25%). <b>Operators doing &lt;100 procedures per annum=87.77% (95% CI 86.82% to 88.67%)</b>. Gastroenterologists=91.01% (95% CI 90.32% to 91.70%). Surgeons=91.03% (95% CI 90.27% to 91.79%). <b>Others practitioners=81.51% (95% CI 78.79% to 84.22%)</b>. Bowel cancer screening colonoscopies=97.71% (95% CI 97.07% to 98.34%). Non-screening colonoscopies=88.31% (95% CI 87.68% to 88.94%). <h3>Conclusion</h3> This audit of 16 064 colonoscopies over three regions demonstrates aggregated achievement of the CIR quality standard, which is evidence of the effects of improvements in training and the implementation of standards Introduced by JAG since the 1999 national audit of colonoscopy. There is however a significant performance gap when comparing BCSP colonoscopists with non-screening colonoscopists and the CIR of &gt;90% is supported by the volume of BCS colonoscopy work load (BCSP colonoscopies should be considered the new "gold standard"). Endoscopists performing low volume colonoscopy (&lt;100 procedures per annum) and non-GI practitioners have a CIR (including the 95% CIs) of &lt;90%. Endoscopists and/or non-GI practitioners with low volume practice who does not meet the quality standards should engage in skills augmentation plus further training and increase the numbers of procedures performed with local mentorship, <b>or stop performing colonoscopy</b>. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Bowles CJ</b>, Leicester R, Romaya C, <i>et al.</i> A prospective study of colonoscopy practice in the UK today: are we adequately prepared for national colorectal cancer screening tomorrow? <i>Gut</i> 2004;<b>53</b>:277–83. 2. http://www.thejag.org.uk
MetaMerge: scaling up genome-scale metabolic reconstructions, with application to Mycobacterium tuberculosis
Authors: Leonid Chindelevitch, Sarah Stanley, Deborah Hung, Aviv Regev, Bonnie Berger
Journal: Genome biology (2012)

Reconstructed models of metabolic networks are widely used for studying metabolism in various organisms. Many different reconstructions of the same organism often exist concurrently, forcing researchers to choose one of them at the exclusion of the others. We describe MetaMerge, an algorithm for semi-automatically reconciling a pair of existing metabolic network reconstructions into a single metabolic network model. We use MetaMerge to combine two published metabolic networks for Mycobacterium tuberculosis into a single network, which allows many reactions that could not be active in the individual models to become active, and predicts essential genes with a higher positive predictive value.
Use of induced pluripotent stem cells (IPSC) encoded with anti-grp78 shrna induces apoptosis/type i pcd after a gene-silencing bystander effect for circumvention of vinorelbine-induced angiogenesis, and inhibition of metastatic spread in advanced gist
Authors: J. Giannios, S. Delis, N. Alexandropulos
Journal: Gut (2011)

<h3>Introduction</h3> Vinorelbine in advanced gastro-intestinal stromal tumour (GIST) cells induces tumour relapse with enhanced angiogenesis and metastasis by inducing an innate cancer cellular stress response, which enhances the expression of GRP78 that blocks cell death or apoptosis increasing growth, and spread of GIST due to chemoresistance. We aim to circumvent this with the use of induced pluripotent stem cells encoded with antisense GRP78 shRNA. <h3>Methods</h3> We take induced pluripotent stem cells(iPSCs), which we infected them with a DNA vector that encoded an RNA molecule of 67 nucleotides. The sequence of this small hairpin RNA (shRNA) is designed to suppress the GRP78 gene. GIST cells were obtained from patients, and they were implanted in animal models, which were treated with vinorelbine. After tumour relapse, there was induction of enhanced angiogenesis, and metastasis. These chemoresistant tumour cells were treated with the induced pluripotent stem cells, which were encoded with shRNA against GRP78. <h3>Results</h3> Post-treatment, stem cells encoded with anti-GRP78 shRNA converted dicer into a siRNA molecule generating a long lasting RNAi silencing effect of GRP78, which spreads to adjacent tumour cells inducing a gene silencing bystander effect (GSBE). Capillary growth into the tumours were blocked, while VEGF and bFGF were downregulated. PKG was upregulated inhibiting b-catenin. Integration of endothelial precursor cells and tumour cells was blocked inhibiting growth of mosaic blood vessels. This leads to inhibition of tumour spread or metastasis, while the existing tumours die from lack of nutrients/oxygen, and a waste disposal pathway. TEM exhibited induction of type I PCD or apoptosis in tumour cells leading to a bystander killing effect. Thus, anti-GRP78 induced pluripotent stem cells (iPSCs) circumvented vinorelbine induced angiogenesis, and metastasis eradicating chemoresistant GIST cells. <h3>Conclusion</h3> Vinorelbine induced angiogenesis, and metastatic spread in GIST are circumvented with induced pluripotent stem cells (iPSCs) encoded with anti-GRP78 shRNA, which induces apoptosis after a gene silencing bystander effect (GSBE).
Complaints about adult social care rose by 18% last year
Authors: J. Wise
Journal: BMJ (2015)

Complaints about adult social care increased by 18% in 2014/15 from the previous year, a report from the local government ombudsman has shown.1

The ombudsman received 2803 complaints about adult social care in 2014/15. Of these, 55% were upheld, 4% more than in the previous year. The areas people complained about most were assessment and care planning, residential care, home care, and charging and safeguarding. The report said that poor communication by providers was a frequent cause for complaint, regardless of the care setting.

The ombudsman received 497 …
Heat-shock protein synthesis by human polymorphonuclear cells.
Authors: N S Eid, R E Kravath, K W Lanks
Journal: The Journal of Experimental Medicine (1987)

Mature human neutrophils from peripheral blood are known to be capable of limited protein biosynthetic activity. We now show that these cells are inducible for heat-shock protein synthesis when placed in short-term culture. Synthesis of hsp70 and hsp85 as well as the response to various temperatures and the time course of induction were typical for mammalian cell systems. This heat-shock response was blocked by actinomycin D added before heat exposure. This demonstration that hsp genes can be activated by heat exposure of terminally differentiated neutrophils supports the hypothesis that gene activation can serve a physiological role in these cells and opens up the possibility that synthesis of other gene products is similarly inducible.
STUDIES ON MENINGOCOCCAL INFECTION
Authors: Henry W. Scherp, Geoffrey Rake
Journal: The Journal of Experimental Medicine (1945)

Absorption tests indicated that the protective antibody (Type I) in four antimeningococcal horse sera corresponded closely to one of the components of the polysaccharide preparation previously isolated by the authors from Type I meningococci. This antibody was, however, a minor fraction in the three therapeutic sera tested, being secondary in amount to non-protective antibody corresponding to another component of the polysaccharide preparation, plus antibody corresponding to agar. In one case, removal of the agar-antibody diminished the protective titer by 30 per cent.
Phase I and Pharmacologic Study of Infusional Topotecan and Carboplatin in Relapsed and Refractory Acute Leukemia
Authors: Scott H. Kaufmann, Judith E. Karp, Louis Letendre, Timothy J. Kottke, Stephanie Safgren, Jackie Greer, Ivana Gojo, Pamela Atherton, Phyllis A. Svingen, David A. Loegering, Mark R. Litzow, Jeff A. Sloan, Joel M. Reid, Matthew M. Ames, Alex A. Adjei, Charles Erlichman
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To assess the maximum tolerated dose, toxicities, pharmacokinetics, and antileukemic activity of topotecan and carboplatin in adults with recurrent or refractory acute leukemias. Experimental Design: Patients received topotecan and carboplatin by 5-day continuous infusion at nine dose levels. Patients achieving a complete remission received up to two additional courses for consolidation. Plasma topotecan and ultrafilterable platinum were assayed on days 1 to 5. In addition, pretreatment levels of various polypeptides in leukemic cells were examined by immunoblotting to assess possible correlations with response. Results: Fifty-one patients received a total of 69 courses of therapy. Dose-limiting toxicity consisted of grade 4/5 typhlitis and grade 3/4 mucositis after one course of therapy or grade 4 neutropenia and thrombocytopenia lasting &amp;gt;50 days when a second course was administered on day 21. Among 45 evaluable patients, there were 7 complete remissions, 2 partial remissions, 1 incomplete complete remission, and 1 reversion to chronic-phase chronic myelogenous leukemia. Topotecan steady-state plasma concentrations increased with dose. No accumulation of topotecan or ultrafilterable platinum occurred between days 1 and 5 of therapy. Leukemic cell levels of topoisomerase I, checkpoint kinase 1, checkpoint kinase 2, and Mcl-1 correlated with proliferating cell nuclear antigen but not with response. In contrast, low Bcl-2 expression correlated with response (P = 0.014, Mann-Whitney U test). Conclusions: The maximum tolerated dose was 1.6 mg/m2/d topotecan plus 150 mg/m2/d carboplatin. The complete remission rate in a heavily pretreated population was 16% (33% at the highest three dose levels). Responses seem to correlate with low pretreatment blast cell Bcl-2 expression.