tbuckley/cabot-search huggingface dataset:
Nicotinic Acid Adenine Dinucleotide Phosphate Mediates Ca <sup>2+</sup> Signals and Contraction in Arterial Smooth Muscle via a Two-Pool Mechanism
Authors: François-Xavier Boittin, Antony Galione, A. Mark Evans
Journal: Circulation Research (2002)

Previous studies of arterial smooth muscle have shown that inositol 1,4,5-trisphosphate (IP 3 ) and cyclic ADP-ribose mobilize Ca 2+ from the sarcoplasmic reticulum. In contrast, little is known about Ca 2+ mobilization by nicotinic acid adenine dinucleotide phosphate, a pyridine nucleotide derived from β-NADP + . We show here that intracellular dialysis of nicotinic acid adenine dinucleotide phosphate (NAADP) induces spatially restricted “bursts” of Ca 2+ release that initiate a global Ca 2+ wave and contraction in pulmonary artery smooth muscle cells. Depletion of sarcoplasmic reticulum Ca 2+ stores with thapsigargin and inhibition of ryanodine receptors with ryanodine, respectively, block the global Ca 2+ waves by NAADP. Under these conditions, however, localized Ca 2+ bursts are still observed. In contrast, xestospongin C, an IP 3 receptor antagonist, had no effect on Ca 2+ signals by NAADP. We propose that NAADP mobilizes Ca 2+ via a 2-pool mechanism, and that initial Ca 2+ bursts are amplified by subsequent sarcoplasmic reticulum Ca 2+ release via ryanodine receptors but not via IP 3 receptors.
Appendicectomy and childhood hygiene: different sides of the same coin?
Authors: A EKBOM
Journal: Gut (1998)

See article on page494 

The aetiology of ulcerative colitis and Crohn’s disease remains an enigma. There is, however, a growing consensus that early events/exposure are of importance and constitute a “window of opportunity”. Both analytical and observational studies as well as animal models give credence to this hypothesis. Smoking has, until recently, been the only factor that has been consistently associated with an increased risk of Crohn’s disease and a decreased risk of ulcerative colitis. Appendicectomy has now been added to this very short list as there has been a consistent finding in several studies that this operation is associated with a decreased risk of ulcerative colitis.1 2 Duggan et al ’s study (see page 494) confirms these results. Their findings for childhood hygiene are in accordance with previous studies where the availability of hot running water is associated …
Religiosity and Major Depression in Adults at High Risk: A Ten-Year Prospective Study
Authors: Lisa Miller, Priya Wickramaratne, Marc J. Gameroff, Mia Sage, Craig E. Tenke, Myrna M. Weissman
Journal: American Journal of Psychiatry (2011)

Objective: Previously the authors found that personal importance of religion or spirituality was associated with a lower risk for major depression in a study of adults with and without a history of depression. Here the authors examine the association of personal importance of religion or spirituality with major depression in the adult offspring of the original sample using a 10-year prospective longitudinal design. Method: Participants were 114 adult offspring of depressed and nondepressed parents, followed longitudinally. The analysis covers the period from the 10-year to the 20-year follow-up assessments. Diagnosis was assessed with the Schedule for Affective Disorders and Schizophrenia–Lifetime Version. Religiosity measures included personal importance of religion or spirituality, frequency of attendance at religious services, and denomination (all participants were Catholic or Protestant). In a logistic regression analysis, major depression at 20 years was used as the outcome measure and the three religiosity variables at 10 years as predictors. Results: Offspring who reported at year 10 that religion or spirituality was highly important to them had about one-fourth the risk of experiencing major depression between years 10 and 20 compared with other participants. Religious attendance and denomination did not significantly predict this outcome. The effect was most pronounced among offspring at high risk for depression by virtue of having a depressed parent; in this group, those who reported a high importance of religion or spirituality had about one-tenth the risk of experiencing major depression between years 10 and 20 compared with those who did not. The protective effect was found primarily against recurrence rather than onset of depression. Conclusions: A high self-report rating of the importance of religion or spirituality may have a protective effect against recurrence of depression, particularly in adults with a history of parental depression.
Letter by Choi et al Regarding Article, “Effects of the Selective Estrogen Receptor Modulator Raloxifene on Coronary Outcomes in the Raloxifene Use for the Heart Trial: Results of Subgroup Analyses by Age and Other Factors”
Authors: Brian G. Choi, Gemma Vilahur, Juan J. Badimon
Journal: Circulation (2009)

To the Editor:We read with great interest the subgroup analyses of the Raloxifene use for the Heart (RUTH) trial. 1 Although this post hoc analysis did not show benefit of raloxifene for any prespecified group, we believe that one particular subgroup, not defined in this study, may benefit from raloxifene in the reduction of coronary outcomes.Although RUTH did not show an overall benefit in postmenopausal women with established coronary disease or risk factors, osteoporotic women enrolled in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial who were at high risk for coronary disease had 40% fewer cardiovascular events than those receiving placebo. 2 Why might there have been discrepant results between the hypothesis-generating MORE and the conclusive RUTH?MORE enrolled only postmenopausal women with osteoporosis, whereas RUTH did not use osteoporosis as an enrollment criterion.Might raloxifene be cardioprotective only in osteoporotic women?In both experimental and epidemiological studies, menopause results in the curious phenomenon of skeletal orthotopic bone loss and vascular heterotopic bone formation. 3,4The cytokine-signaling pathways that regulate orthotopic bone remodeling also influence vascular calcification.It came as no surprise when we demonstrated that raloxifene, a bone-active drug, remodels vascular calcification.Via an increase in bone-morphogenetic protein-2, raloxifene influences vascular calcification morphology into a more laminar structure that may enhance plaque stability. 5However, in postmenopausal women without osteoporosis who may not have concomitant calcified vessels, as in RUTH, raloxifene would have benefit neither for osteoporosis nor for plaque stability.The MORE women, who were all osteoporotic, may be more likely to have calcified vessels, and it was in these women that cardiovascular benefit was demonstrated.If the RUTH trial had included prespecified osteoporotic women as a subgroup, a benefit from the remodeling effects of raloxifene on plaque morphology might have been seen.We would encourage a study of raloxifene for the prevention of cardiovascular events in osteoporotic postmenopausal women or, at the very least, an analysis of existing MORE or RUTH data to see whether there is a correlation between the severity of osteoporosis and the degree of cardiovascular benefit.
Broad, Hybrid Capture–Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches
Authors: Alexander Drilon, Lu Wang, Maria E. Arcila, Sohail Balasubramanian, Joel R. Greenbowe, Jeffrey S. Ross, Phil Stephens, Doron Lipson, Vincent A. Miller, Mark G. Kris, Marc Ladanyi, Naiyer A. Rizvi
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Broad, hybrid capture–based next-generation sequencing (NGS), as a clinical test, uses less tissue to identify more clinically relevant genomic alterations compared with profiling with multiple non-NGS tests. We set out to determine the frequency of such genomic alterations via this approach in tumors in which previous extensive non-NGS testing had not yielded a targetable driver alteration. Experimental Design: We enrolled patients with lung adenocarcinoma with a ≤15 pack-year smoking history whose tumors previously tested “negative” for alterations in 11 genes (mutations in EGFR, ERBB2, KRAS, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1 and fusions involving ALK, ROS1, and RET) via multiple non-NGS methods. We performed hybridization capture of the coding exons of 287 cancer-related genes and 47 introns of 19 frequently rearranged genes and sequenced these to deep, uniform coverage. Results: Actionable genomic alterations with a targeted agent based on NCCN guidelines were identified in 26% [8 of 31: EGFR G719A, BRAF V600E, SOCS5-ALK, HIP1-ALK, CD74-ROS1, KIF5B-RET (n = 2), CCDC6-RET]. Seven of these patients either received or are candidates for targeted therapy. Comprehensive genomic profiling using this method also identified a genomic alteration with a targeted agent available on a clinical trial in an additional 39% (12 of 31). Conclusions: Broad, hybrid capture–based NGS identified actionable genomic alterations in 65% [95% confidence interval (CI), 48%–82%] of tumors from never or light smokers with lung cancers deemed without targetable genomic alterations by earlier extensive non-NGS testing. These findings support first-line profiling of lung adenocarcinomas using this approach as a more comprehensive and efficient strategy compared with non-NGS testing. Clin Cancer Res; 21(16); 3631–9. ©2015 AACR. See related commentary by McCutcheon and Giaccone, p. 3584
Human primary and memory cytotoxic T lymphocyte responses are efficiently induced by means of CD40-activated B cells as antigen-presenting cells: potential for clinical application
Authors: Michael S. von Bergwelt-Baildon, Robert H. Vonderheide, Britta Maecker, Naoto Hirano, Karen S. Anderson, Marcus O. Butler, Zhinan Xia, Wan Y. Zeng, Kai W. Wucherpfennig, Lee M. Nadler, Joachim L. Schultze
Journal: Blood (2002)
Prostate Cancer Mortality in Areas With High and Low Prostate Cancer Incidence
Authors: P. Stattin, S. Carlsson, B. Holmstrom, A. Vickers, J. Hugosson, H. Lilja, H. Jonsson
Journal: JNCI Journal of the National Cancer Institute (2014)

The effect of prostate-specific antigen (PSA) screening on prostate cancer mortality remains debated, despite evidence from randomized trials. We investigated the association between prostate cancer incidence, reflecting uptake of PSA testing, and prostate cancer mortality.The study population consisted of all men aged 50 to 74 years residing in eight counties in Sweden with an early increase in prostate cancer incidence and six counties with a late increase during two time periods. Incidence of metastatic prostate cancer was investigated in the period from 2000 to 2009, and prostate cancer-specific mortality and excess mortality were investigated in the period from 1990 to 1999 and the period from 2000 to 2009 by calculating rate ratios for high- vs low-incidence counties and rate ratios for the period from 2000 to 2009 vs the period from 1990 to 1999 within these two groups. All statistical tests were two-sided.There were 4528134 person-years at risk, 1577 deaths from prostate cancer, and 1210 excess deaths in men with prostate cancer in high-incidence counties and 2471373 person-years at risk, 985 prostate cancer deaths, and 878 excess deaths in low-incidence counties in the period from 2000 to 2009. Rate ratios in counties with high vs low incidence adjusted for time period were 0.81 (95% confidence interval [CI] = 0.73 to 0.90) for prostate cancer- specific mortality and 0.74 (95% CI = 0.64 to 0.86) for excess mortality, and the rate ratio of metastatic prostate cancer was 0.85 (95% CI = 0.79 to 0.92).The lower prostate cancer mortality in high-incidence counties reflecting a high PSA uptake suggests that more-intense as compared with less-intense opportunistic PSA screening reduces prostate cancer mortality.
Activation of Placenta-Specific Transcription Factor<i>Distal-less</i>Homeobox 5 Predicts Clinical Outcome in Primary Lung Cancer Patients
Authors: Tatsuya Kato, Nagato Sato, Atsushi Takano, Masaki Miyamoto, Hitoshi Nishimura, Eiju Tsuchiya, Satoshi Kondo, Yusuke Nakamura, Yataro Daigo
Journal: Clinical Cancer Research (2008)

To identify novel biomarkers and therapeutic targets for lung cancers, we screened for genes that were highly transactivated in lung cancers using a cDNA microarray representing 27,648 genes. DLX5 gene, a member of the human distal-less homeobox transcriptional factor family that is expressed during early embryonic development, was found to be overexpressed in the great majority of lung cancers. Tissue microarray consisting of archival non-small cell lung cancer samples from 369 patients was applied to examine the clinicopathologic significance of DLX5 protein. A role of DLX5 in cancer cell growth and/or survival was investigated through small interfering RNA experiments.Northern blot and immunohistochemical analyses detected expression of DLX5 only in placenta among 23 normal tissues examined. Immunohistochemical analysis showed that positive immunostaining of DLX5 was correlated with tumor size (pT classification; P = 0.0053) and poorer prognosis of non-small cell lung cancer patients (P = 0.0045). It was also shown to be an independent prognostic factor (P = 0.0415). Treatment of lung cancer cells with small interfering RNAs for DLX5 effectively knocked down its expression and suppressed cell growth.These data implied that DLX5 is useful as a target for the development of anticancer drugs and cancer vaccines as well as for a prognostic biomarker in clinic.
Functional Analysis of the ATM-p53-p21 Pathway in the LRF CLL4 Trial: Blockade at the Level of p21 Is Associated with Short Response Duration
Authors: Ke Lin, Janet Adamson, Gillian G. Johnson, Anthony Carter, Melanie Oates, Rachel Wade, Sue Richards, David Gonzalez, Estella Matutes, Claire Dearden, David G. Oscier, Daniel Catovsky, Andrew R. Pettitt
Journal: Clinical Cancer Research (2012)

Abstract Purpose: This study sought to establish whether functional analysis of the ATM-p53-p21 pathway adds to the information provided by currently available prognostic factors in patients with chronic lymphocytic leukemia (CLL) requiring frontline chemotherapy. Experimental Design: Cryopreserved blood mononuclear cells from 278 patients entering the LRF CLL4 trial comparing chlorambucil, fludarabine, and fludarabine plus cyclophosphamide were analyzed for ATM-p53-p21 pathway defects using an ex vivo functional assay that uses ionizing radiation to activate ATM and flow cytometry to measure upregulation of p53 and p21 proteins. Clinical endpoints were compared between groups of patients defined by their pathway status. Results: ATM-p53-p21 pathway defects of four different types (A, B, C, and D) were identified in 194 of 278 (70%) samples. The type A defect (high constitutive p53 expression combined with impaired p21 upregulation) and the type C defect (impaired p21 upregulation despite an intact p53 response) were each associated with short progression-free survival. The type A defect was associated with chemoresistance, whereas the type C defect was associated with early relapse. As expected, the type A defect was strongly associated with TP53 deletion/mutation. In contrast, the type C defect was not associated with any of the other prognostic factors examined, including TP53/ATM deletion, TP53 mutation, and IGHV mutational status. Detection of the type C defect added to the prognostic information provided by TP53/ATM deletion, TP53 mutation, and IGHV status. Conclusion: Our findings implicate blockade of the ATM-p53-p21 pathway at the level of p21 as a hitherto unrecognized determinant of early disease recurrence following successful cytoreduction. Clin Cancer Res; 18(15); 4191–200. ©2012 AACR.
DITPA (3,5-Diiodothyropropionic Acid), a Thyroid Hormone Analog to Treat Heart Failure
Authors: Steven Goldman, Madeline McCarren, Eugene Morkin, Paul W. Ladenson, Robert Edson, Stuart Warren, Janet Ohm, Hoang Thai, Lori Churby, Jamie Barnhill, Terrence O'Brien, Inder Anand, Alberta Warner, Brack Hattler, Mark Dunlap, John Erikson, Mei-Chiung Shih, Phil Lavori
Journal: Circulation (2009)

In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects.This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure-specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (-20%), low-density lipoprotein cholesterol (-30%), and body weight (-11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen.DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.
Screening for Depression in Adults: A Summary of the Evidence for the U.S. Preventive Services Task Force
Authors: Michael P. Pignone, Bradley N. Gaynes, Jerry L. Rushton, Catherine Mills Burchell, C. Tracy Orleans, Cynthia D. Mulrow, Kathleen N. Lohr
Journal: Annals of Internal Medicine (2002)

Suicide is the 11th leading cause of death and the seventh leading cause of years of potential life lost in the United States. Although suicide is of great public health significance, its clinical management is complicated.The authors systematically reviewed the literature to determine whether screening for suicide risk in primary care settings decreases morbidity, mortality, or both.MEDLINE (1966 to 17 October 2002), PsycINFO, Cochrane databases, hand-searched bibliographies, and experts.For screening, only English-language studies performed in primary care settings were examined. For treatment, randomized, controlled trials and cohort studies were included if they were performed in any setting where suicide completions, suicide attempts, or suicidal ideation were reported.A primary reviewer abstracted data on key variables of study sample, design, and outcomes; a second reviewer checked information accuracy against the original articles.No study directly addressed whether screening for suicide in primary care reduces morbidity and mortality. The remainder of the review focused on the questions of reliable screening tests for suicide risk and the effectiveness of interventions to decrease depression, suicidal ideation, and suicide attempts or completion. One screening study provided limited evidence for the accuracy of suicide screening in a primary care setting. Intervention studies provided fair and mixed evidence that treating those at risk for suicide reduces the number of suicide attempts or completions. The evidence suggests mild to moderate improvement for interventions addressing intermediate outcomes such as suicidal ideation, decreased depressive severity, decreased hopelessness, or improved level of function.Because of the complexity of studying the risk for suicide and the paucity of well-designed research studies, only limited evidence guides the primary care clinician's assessment and management of suicide risk.
Tolerance Profile of Chemotherapy for Colorectal Cancer in Elderly Patients Aged Over Than 70 Years
Authors: Achraf Chaari, Olfa Gharbi, Hochlef Makram, Imene Chabchoub, Faten Ezzairi, Leila Ben Fatma, Ridha ben hadj Hamida, Mohamed rached Ltaief, Ahlem braham Krifa, Moncef Mokni, Slim Ben Ahmed
Journal: Annals of Oncology (2013)
PTU-181 Optimised response prediction in oesophagogastric adenocarcinomas (OGA) with combination of molecular biomarkers, serum cell death markers and FDG-PET
Authors: G H Bain, E Collie-Duguid, G Murray, F Gilbert, A Denison, F McKiddie, T Ahearn, J Leeds, P Phull, K Park, A Welch, L Schweiger, R D Petty
Journal: Gut (2012)

<h3>Introduction</h3> Predictive biomarkers (BMs) for OGA would optimise treatment selection and avoid ineffective therapy. Metabolic response (MR) defined as &gt;35% decrease in tumour FDG Standardised Uptake Value (SUV) between day 0 and day 14 after starting chemotherapy has a high negative predictive value (95%) for response, but limited positive predictive value (50%). Combining molecular BMs and serum cell death markers with FDG-PET may optimise response prediction. We used global gene expression profiling (GEP) and cell death ELISAs to identify molecular BMs and serum markers that when combined with FDG-PET would improve predictive accuracy. <h3>Methods</h3> 28 patients with locally advanced/metastatic OGA received platinum based chemotherapy (PBC). FDG-PET scans were at day 0 &amp; 14 and GEP (Affymetrix ST1.0 Exon Genechips) on day 0 tumour biopsies. A tissue microarray comprising an independent set of 154 OGA who had surgery +/-neoadjuvant PBC was used with immunohistochemistry (IHC) for qualification of GEP results. Cytokeratin 18 (CK18) M30 (apoptosis) and M65 (apoptosis+necrosis) ELISAs (Pevivia, Sweden) were used to assess cell death from serial serum samples during chemo. Radiological response was assessed after 3/4 cycles of PBC by RECISTv1.1. <h3>Results</h3> We identified a gene expression signature (86 genes) that separated FDG-PET MR patients (&gt;35% fall SUV day 0–14) into those that do and do not have a RECIST response. In cross validation this signature correctly predicted response in 14/14 metabolic responders (MRs). Pathway analysis on GEP data identified potential novel mechanisms of response including the Leptin pathway. Leptin mRNA was higher in FDG MRs who did <b>not</b> have a RECIST response compared to those that did (p=0.026). In the independent set high Leptin protein by IHC was associated with <b>lack</b> of histopathologic response to neoadjuvant PBC (n=64, p=0.007). High Leptin expression also had a therapy independent prognostic effect with longer survival in the absence of histopathologic response or with no neoadjuvant PBC and in low Leptin patients poor survival was mitigated to a degree by neoadjuvant PBC. Serum CK18M30 decreased from day 0–14 in MRs but in metabolic non-responders (MNRs) there was a smaller fall or a rise (p=0.021). Levels in MNRs did not change with subsequent chemo. In MRs levels continued to fall in RECIST responders but increased again in non-responders. <h3>Conclusion</h3> Molecular biomarkers (Leptin in particular) and serum cell death markers combine with FDG-PET to optimise response prediction in OGA. Further investigation of this combined molecular, serum and imaging approach is warranted. <h3>Competing interests</h3> None declared.
Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial
Authors: Stephen D Wiviott, Eugene Braunwald, Carolyn H McCabe, Ivan Horvath, Matyas Keltai, Jean-Paul R Herrman, Frans Van de Werf, William E Downey, Benjamin M Scirica, Sabina A Murphy, Elliott M Antman
Journal: The Lancet (2008)