tbuckley/cabot-search huggingface dataset:
Germline Mutations in the<i>CDKN2B</i>Tumor Suppressor Gene Predispose to Renal Cell Carcinoma
Authors: Mariam Jafri, Naomi C. Wake, David B. Ascher, Douglas E.V. Pires, Dean Gentle, Mark R. Morris, Eleanor Rattenberry, Michael A. Simpson, Richard C. Trembath, Astrid Weber, Emma R. Woodward, Alan Donaldson, Tom L. Blundell, Farida Latif, Eamonn R. Maher
Journal: Cancer Discovery (2015)

Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC.Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease.
1301 BARIATRIC SURGERY CAN BE PROPOSED TO MORBID OBESE HIGHLY SELECTED WITH COMPENSATED CIRRHOSIS
Authors: G. Lassailly, R. Caïazzo, L. Arnalsteen, G. Lebuffe, D. Buob, A. Patrice, A. Louvet, E. Leteurtre, M. Colin, S. Dharancy, V. Canva-Delcambre, P. Deltenre, F. Pattou, P. Mathurin
Journal: Journal of Hepatology (2012)
Dose-Response Relationships of Inhaled Insulin Delivered via the Aerodose Insulin Inhaler and Subcutaneously Injected Insulin in Patients With Type 2 Diabetes
Authors: Dennis Kim, Sunder Mudaliar, Sithipol Chinnapongse, Neelima Chu, Sarah M. Boies, Trent Davis, Ayesh D. Perera, Robert S. Fishman, David A. Shapiro, Robert Henry
Journal: Diabetes Care (2003)

OBJECTIVE—To compare the dose-response relationship following inhalation of regular insulin delivered via the Aerodose insulin inhaler with that following subcutaneously injected regular insulin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—Twenty-four patients with type 2 diabetes (21 nonsmoking men, aged 36–80 years) each received two of three doses of 80, 160, or 240 units inhaled regular insulin, delivered via a clinical Aerodose insulin inhaler, and two of three corresponding doses of 8, 16, or 24 units by subcutaneous injection under isoglycemic clamp conditions on 4 separate study days in an incomplete block design study. Glucose infusion rates (GIRs) and serum insulin concentrations were monitored over the following 8 h. RESULTS—Inhaled insulin exhibited significantly shorter time-to-peak insulin levels (Tmax 77 ± 66 vs. 193 ± 104 min, P &amp;lt; 0.001) and time-to-peak metabolic effects (TGIRmax 240 ± 94 vs. 353 ± 60 min, P &amp;lt; 0.001) compared with subcutaneously injected insulin. Comparison of total insulin absorption (insulin area under the curve [AUC]) versus total metabolic effect (GIR-AUC) from 0 to 8 h (group means) revealed overlapping dose-response relationships for both inhaled and subcutaneous injection treatments. Comparison of slopes revealed no significant differences between the inhaled and subcutaneous injection treatment groups (P = 0.6). No significant differences in either relative bioavailability or relative biopotency were found among doses, indicating a consistent subcutaneous injection-to-inhaled dosing conversion ratio among doses. No serious adverse events or clinically relevant changes in lung function were observed. CONCLUSIONS—The overlapping dose-response curves of inhaled and subcutaneous treatments together with a consistent relative bioavailability and relative biopotency for inhaled insulin across doses suggest that the Aerodose insulin inhaler will deliver a pharmacologically predictable insulin dose to patients with diabetes similar to that observed following subcutaneous injection.
Germline Genetic Contributions to Risk for Esophageal Adenocarcinoma, Barrett's Esophagus, and Gastroesophageal Reflux
Authors: W. E. Ek, D. M. Levine, M. D'Amato, N. L. Pedersen, P. K. E. Magnusson, F. Bresso, L. E. Onstad, P. T. Schmidt, H. Tornblom, H. Nordenstedt, Y. Romero, W.-H. Chow, L. J. Murray, M. D. Gammon, G. Liu, L. Bernstein, A. G. Casson, H. A. Risch, N. J. Shaheen, N. C. Bird, B. J. Reid, D. A. Corley, L. J. Hardie, W. Ye, A. H. Wu, M. Zucchelli, T. D. Spector, P. Hysi, T. L. Vaughan, D. C. Whiteman, S. MacGregor
Journal: JNCI Journal of the National Cancer Institute (2013)

BackgroundEsophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA.
The Influence of the Hypothalamus on Gastric Hydrochloric Acid Secretion
Authors: A. S. Leonard, D. M. Long, F. Thomas, D. M. Nicoloff, O. H. Wangensteen
Journal: JAMA (1963)

ROKITANSKY<sup>1</sup>AND SCHIFF,<sup>2</sup>in the 1840's, demonstrated clinically and experimentally a relationship between central nervous system abnormalities and gastric ulcer formation. In 1932, Cushing's<sup>3</sup>clinical findings confirming these earlier observations lent impetus to renewed interest in the evaluation of the responsible factors. One method of approach has been the assessment of the possible role of the autonomic centers in ulcerogenesis.<sup>4, 5</sup>Controversial results have been reported by investigators regarding hydrochloric acid production following hypothalamic stimulation.<sup>6,7</sup>Among the variable factors which may be responsible for the disparity in results are (1) the intensity of the stimulating current, (2) methods of collecting secretions, (3) short duration of experiments, and (4) the depth of anesthesia, resulting in varying thresholds to stimulation. In an attempt to clarify this problem, an experiment was designed to evaluate hydrochloric acid secretion following chronic hypothalamic stimulation at varying intervals in unanesthetized animals.
Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting
Authors: Jianxing Xiang, Hao Yang, Ting Zhao, Miao Sun, Xingshun Xu, Xin-Fu Zhou, Shi-Hua Li, Xiao-Jiang Li
Journal: Journal of Clinical Investigation (2013)

Defective neurogenesis in the postnatal brain can lead to many neurological and psychiatric disorders, yet the mechanism behind postnatal neurogenesis remains to be investigated. Huntingtin-associated protein 1 (HAP1) participates in intracellular trafficking in neurons, and its absence leads to postnatal death in mice. Here, we used tamoxifen-induced (TM-induced) Cre recombination to deplete HAP1 in mice at different ages. We found that HAP1 reduction selectively affects survival and growth of postnatal mice, but not adults. Neurogenesis, but not gliogenesis, was affected in HAP1-null neurospheres and mouse brain. In the absence of HAP1, postnatal hypothalamic neurons exhibited reduced receptor tropomyosin-related kinase B (TRKB) levels and decreased survival. HAP1 stabilized the association of TRKB with the intracellular sorting protein sortilin, prevented TRKB degradation, and promoted its anterograde transport. Our findings indicate that intracellular sorting of neurotrophin receptors is critical for postnatal neurogenesis and could provide a therapeutic target for defective postnatal neurogenesis.
Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT)
Authors: K. E. Boers, S. M. C. Vijgen, D. Bijlenga, J. A. M. van der Post, D. J. Bekedam, A. Kwee, P. C. M. van der Salm, M. G. van Pampus, M. E. A. Spaanderman, K. de Boer, J. J. Duvekot, H. A. Bremer, T. H. M. Hasaart, F. M. C. Delemarre, K. W. M. Bloemenkamp, C. A. van Meir, C. Willekes, E. J. Wijnen, M. Rijken, S. le Cessie, F. J. M. E. Roumen, J. G. Thornton, J. M. M. van Lith, B. W. J. Mol, S. A. Scherjon
Journal: BMJ (2010)

To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term.
Response to Learned Threat: An fMRI Study in Adolescent and Adult Anxiety
Authors: Jennifer C. Britton, Christian Grillon, Shmuel Lissek, Maxine A. Norcross, Kristin L. Szuhany, Gang Chen, Monique Ernst, Eric E. Nelson, Ellen Leibenluft, Tomer Shechner, Daniel S. Pine
Journal: American Journal of Psychiatry (2013)

Objective Poor threat-safety discrimination reflects prefrontal cortex dysfunction in adult anxiety disorders. While adolescent anxiety disorders are impairing and predict high risk for adult anxiety disorders, the neural correlates of threat-safety discrimination have not been investigated in this population. The authors compared prefrontal cortex function in anxious and healthy adolescents and adults following conditioning and extinction, processes requiring threat-safety learning. Method Anxious and healthy adolescents and adults (N=114) completed fear conditioning and extinction in the clinic. The conditioned stimuli (CS+) were neutral faces, paired with an aversive scream. Physiological and subjective data were acquired. Three weeks later, 82 participants viewed the CS+ and morphed images resembling the CS+ in an MRI scanner. During scanning, participants made difficult threat-safety discriminations while appraising threat and explicit memory of the CS+. Results During conditioning and extinction, the anxious groups reported more fear than the healthy groups, but the anxious adolescent and adult groups did not differ on physiological measures. During imaging, both anxious adolescents and adults exhibited lower activation in the subgenual anterior cingulate cortex than their healthy counterparts, specifically when appraising threat. Compared with their age-matched counterpart groups, anxious adults exhibited reduced activation in the ventromedial prefrontal cortex when appraising threat, whereas anxious adolescents exhibited a U-shaped pattern of activation, with greater activation in response to the most extreme CS+ and CS–. Conclusions Two regions of the prefrontal cortex are involved in anxiety disorders. Reduced subgenual anterior cingulate cortex engagement is a shared feature in adult and adolescent anxiety disorders, but ventromedial prefrontal cortex dysfunction is age-specific. The unique U-shaped pattern of activation in the ventromedial prefrontal cortex in many anxious adolescents may reflect heightened sensitivity to threat and safety conditions. How variations in the pattern relate to later risk for adult illness remains to be determined.
A Pivotal Role of Cyclic AMP-Responsive Element Binding Protein in Tumor Progression
Authors: Rinat Abramovitch, Einat Tavor, Jasmine Jacob-Hirsch, Evelyne Zeira, Ninette Amariglio, Orit Pappo, Gideon Rechavi, Eithan Galun, Alik Honigman
Journal: Cancer Research (2004)

Abstract Tumor microenvironment controls the selection of malignant cells capable of surviving in stressful and hypoxic conditions. The transcription factor, cyclic AMP-responsive element binding (CREB) protein, activated by multiple extracellular signals, modulates cellular response by regulating the expression of a multitude of genes. Previously, we have demonstrated that two cystein residues, at the DNA binding domain of CREB, mediate activation of CREB-dependent gene expression at normoxia and hypoxia. The construction of a dominant-positive CREB mutant, insensitive to hypoxia cue (substitution of two cystein residues at position 300 and 310 with serine in the DNA binding domain) and of a dominant negative CREB mutant (addition of a mutation in serine133), enabled a direct assessment, in vitro and in vivo, of the role of CREB in tumor progression. In this work, we demonstrate both in vitro and in vivo that CREB controls hepatocellular carcinoma growth, supports angiogenesis, and renders resistance to apoptosis. Along with the identification, by DNA microarray, of the CREB-regulated genes in normoxia and hypoxia, this work demonstrates for the first time that in parallel to other hypoxia responsive mechanisms, CREB plays an important role in hepatocellular carcinoma tumor progression.
mAbs and Ad-Vectored IFN-α Therapy Rescue Ebola-Infected Nonhuman Primates When Administered After the Detection of Viremia and Symptoms
Authors: Xiangguo Qiu, Gary Wong, Lisa Fernando, Jonathan Audet, Alexander Bello, Jim Strong, Judie B. Alimonti, Gary P. Kobinger
Journal: Science Translational Medicine (2013)

ZMAb is a promising treatment against Ebola virus (EBOV) disease that has been shown to protect 50% (two of four) of nonhuman primates (NHPs) when administered 2 days post-infection (dpi). To extend the treatment window and improve protection, we combined ZMAb with adenovirus-vectored interferon-α (Ad-IFN) and evaluated efficacy in EBOV-infected NHPs. Seventy-five percent (three of four) and 100% (four of four) of cynomolgus and rhesus macaques survived, respectively, when treatment was initiated after detection of viremia at 3 dpi. Fifty percent (two of four) of the cynomolgus macaques survived when Ad-IFN was given at 1 dpi, followed by ZMAb starting at 4 dpi, after positive diagnosis. The treatment was able to suppress viremia reaching ~10(5) TCID50 (median tissue culture infectious dose) per milliliter, leading to survival and robust specific immune responses. This study describes conditions capable of saving 100% of EBOV-infected NHPs when initiated after the presence of detectable viremia along with symptoms.
Prevalence of Delayed Gastric Emptying in Diabetic Patients and Relationship to Dyspeptic Symptoms
Authors: M. Samsom, J.R. Vermeijden, A.J.P.M. Smout, E. van Doorn, J. Roelofs, P.S. van Dam, E.P. Martens, S.J. Eelkman-Rooda, G.P. van Berge-Henegouwen
Journal: Diabetes Care (2003)

OBJECTIVE—Data on the prevalence of abnormal gastric emptying in diabetic patients are still lacking. The relation between gastric emptying and dyspeptic symptoms assessed during gastric emptying measurement has not yet been investigated. The aim was to investigate the prevalence of delayed gastric emptying in a large cohort of unselected diabetic patients and to investigate the relation between gastric emptying and gastrointestinal sensations experienced in the 2 weeks before and during the test meal, prospectively. RESEARCH DESIGN AND METHODS—Gastric emptying was evaluated in 186 patients (106 with type 1 diabetes, mean duration of diabetes 11.6 ± 11.3 years) using 100 mg 13C-enriched octanoic acid added to a solid meal. RESULTS—Gastric emptying was significantly slower in the diabetic subjects than in the healthy volunteers (T50: 99.5 ± 35.4 vs. 76.8 ± 21.4 min, P &amp;lt; 0.003; Ret120 min: 30.6 ± 17.2 vs. 20.4 ± 9.7%, P &amp;lt; 0.006). Delayed gastric emptying was observed in 51 (28%) diabetic subjects. The sensations experienced in the 2 weeks before the test were weakly correlated with the sensation scored during the gastric emptying test. Sensations assessed during the gastric emptying test did predict gastric emptying to some extent (r = 0.46, P &amp;lt; 0.0001), whereas sensations experienced in the previous 2 weeks did not. CONCLUSIONS—This prospective study shows that delayed gastric emptying can be observed in 28% of unselected patients with diabetes. Upper gastrointestinal sensations scored during the gastric emptying tests do predict the rate of gastric emptying to some extent and sensation experienced during daily life does not.
Randomized Trial of Erlotinib Plus Whole-Brain Radiotherapy for NSCLC Patients With Multiple Brain Metastases
Authors: Siow Ming Lee, Conrad R. Lewanski, Nicholas Counsell, Christian Ottensmeier, Andrew Bates, Nirali Patel, Christina Wadsworth, Yenting Ngai, Allan Hackshaw, Corinne Faivre-Finn
Journal: JNCI Journal of the National Cancer Institute (2014)

Median survival of non-small cell lung cancer (NSCLC) patients with brain metastases is poor. We examined concurrent erlotinib and whole brain radiotherapy (WBRT) followed by maintenance erlotinib in patients with untreated brain metastases, given the potential radiosensitizing properties of erlotinib and its direct effect on brain metastases and systemic activity.
Genomic Deregulation during Metastasis of Renal Cell Carcinoma Implements a Myofibroblast-Like Program of Gene Expression
Authors: Miguel A. López-Lago, Venkata J. Thodima, Asha Guttapalli, Timothy Chan, Adriana Heguy, Ana M. Molina, Victor E. Reuter, Robert J. Motzer, Raju S. K. Chaganti
Journal: Cancer Research (2010)

Abstract Clear cell renal cell carcinoma (RCC) is the most common and invasive adult kidney cancer. The genetic and biological mechanisms that drive metastatic spread of RCC remain largely unknown. We have investigated the molecular signatures and underlying genomic aberrations associated with RCC metastasis, using an approach that combines a human xenograft model; expression profiling of RNA, DNA, and microRNA (miRNA); functional verification; and clinical validation. We show that increased metastatic activity is associated with acquisition of a myofibroblast-like signature in both tumor cell lines and in metastatic tumor biopsies. Our results also show that the mesenchymal trait did not provide an invasive advantage to the metastatic tumor cells. We further show that some of the constituents of the mesenchymal signature, including the expression of the well-characterized myofibroblastic marker S100A4, are functionally relevant. Epigenetic silencing and miRNA-induced expression changes accounted for the change in expression of a significant number of genes, including S100A4, in the myofibroblastic signature; however, DNA copy number variation did not affect the same set of genes. These findings provide evidence that widespread genetic and epigenetic alterations can lead directly to global deregulation of gene expression and contribute to the development or progression of RCC metastasis culminating in a highly malignant myofibroblast-like cell. Cancer Res; 70(23); 9682–92. ©2010 AACR.
Anti-inflammatory properties of ebselen in a model of sephadex-induced lung inflammation
Authors: M.G. Belvisi, E-B. Haddad, C. Battram, M. Birrell, M Foster, S Webber
Journal: European Respiratory Journal (2000)

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), is a seleno-organic compound which protects tissues against oxidative stress. Furthermore, recent data has suggested that this compound possesses a range of anti-inflammatory properties. In this study the authors have investigated the effects of ebselen on Sephadex-induced lung oedema and bronchoalveolar lavage (BAL) tumour necrosis factor (TNF)-alpha and endothelin(ET)-1 levels in rats. Sephadex administration induced lung oedema which was accompanied by an increase in BAL TNF-alpha and ET-1 levels. Ebselen administration (1-30 mg x kg(-1), i.p. at 0, 4 and 12 h post Sephadex) significantly inhibited lung oedema (dose that produced 50% of the maximum inhibition of lung oedema 4.6 mg x kg(-1)) and BAL TNF-alpha levels in a dose-related manner with no effect on ET-1 levels. These data suggest that ebselen may be a useful therapy in lung pathologies in which bronchiolar inflammation is a feature.
Managed Behavioral Health Care Carve-Outs: Past Performance and Future Prospects
Authors: Richard G. Frank, Rachel L. Garfield
Journal: Annual Review of Public Health (2006)

As the managed behavioral health care market has matured, behavioral health carve-outs have solved many problems facing the delivery of behavioral health services; at the same time, they have exacerbated existing difficulties or created new problems. Carve-outs developed to address rising inpatient behavioral health costs and limited insurance coverage. They are based on the economic principles of economies of specialization, economies of scale, price negotiation, and selection. Literature shows that carve-outs have been successful in lowering costs and maintaining or improving access, but results on their impact on quality of care are mixed. In recent years, carve-outs have evolved to take on new roles within the health system, such as coordinating mental and physical health, addressing fragmented public financing systems, and using market power to implement quality improvement. Although not perfect, carve-outs have been instrumental in addressing long-standing challenges in utilization, access, and cost of behavioral health care.
Life Course Trajectories of Systolic Blood Pressure Using Longitudinal Data from Eight UK Cohorts
Authors: Andrew K. Wills, Debbie A. Lawlor, Fiona E. Matthews, Avan Aihie Sayer, Eleni Bakra, Yoav Ben-Shlomo, Michaela Benzeval, Eric Brunner, Rachel Cooper, Mika Kivimaki, Diana Kuh, Graciela Muniz-Terrera, Rebecca Hardy
Journal: PLoS Medicine (2011)

Background Much of our understanding of the age-related progression of systolic blood pressure (SBP) comes from cross-sectional data, which do not directly capture within-individual change. We estimated life course trajectories of SBP using longitudinal data from seven population-based cohorts and one predominantly white collar occupational cohort, each from the United Kingdom and with data covering different but overlapping age periods. Methods and Findings Data are from 30,372 individuals and comprise 102,583 SBP observations spanning from age 7 to 80+y. Multilevel models were fitted to each cohort. Four life course phases were evident in both sexes: a rapid increase in SBP coinciding with peak adolescent growth, a more gentle increase in early adulthood, a midlife acceleration beginning in the fourth decade, and a period of deceleration in late adulthood where increases in SBP slowed and SBP eventually declined. These phases were still present, although at lower levels, after adjusting for increases in body mass index though adulthood. The deceleration and decline in old age was less evident after excluding individuals who had taken antihypertensive medication. Compared to the population-based cohorts, the occupational cohort had a lower mean SBP, a shallower annual increase in midlife, and a later midlife acceleration. The maximum sex difference was found at age 26 (+8.2 mm Hg higher in men, 95% CI: 6.7, 9.8); women then experienced steeper rises and caught up by the seventh decade. Conclusions Our investigation shows a general pattern of SBP progression from childhood in the UK, and suggests possible differences in this pattern during adulthood between a general population and an occupational population. Please see later in the article for the Editors' Summary
Weekly paclitaxel combined with pegylated liposomal doxorubicin (Caelyx™) given every 4 weeks: dose-finding and pharmacokinetic study in patients with advanced solid tumors
Authors: E. Briasoulis, G. Pentheroudakis, V. Karavasilis, E. Tzamakou, D. Rammou, N. Pavlidis
Journal: Annals of Oncology (2004)
Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis.
Authors: D G Harrison, M L Armstrong, P C Freiman, D D Heistad
Journal: Journal of Clinical Investigation (1987)

Atherosclerosis results in impaired relaxation to acetylcholine, thrombin, and the calcium ionophore A23187, all agents that require the presence of endothelium. We now report that dietary treatment of atherosclerosis in monkeys not only produces morphological improvement of the atherosclerotic lesion but restores endothelium-dependent vascular relaxation to normal. Because the intima remains thickened after regression of atherosclerosis, these studies suggest that intimal thickening which is present in both atherosclerotic vessels and after regression of atherosclerosis does not prevent the endothelium-derived relaxing factor from reaching the underlying vascular smooth muscle.