tbuckley/cabot-search huggingface dataset:
Abstract P287: Therapeutic Hypothermia Cardioprotection During Cardiac Arrest Alters Reperfusion-Associated mTORC1 and AMPK Signaling
Authors: Willard W Sharp, David Beiser, Zuo-Hui Shao, Mei Han, Chang-Qing Li, Jing Li, Huashan Wang, Kimm Hamann, Terry Vanden Hoek
Journal: Circulation Research (2011)

Introduction: Therapeutic hypothermia (TH) is highly cardioprotective in cellular and animal models of ischemia/reperfusion (I/R) and cardiac arrest and is dependent upon Akt. The mammalian target of rapamycin complex 1 (mTORC1) is a downstream target of Akt and an important regulator of cellular energy utilization and survival but its relationship to TH is not clear. We hypothesized that TH attenuates mTORC1 activation while simultaneously activating the cell survival kinases AMP activated protein kinase (AMPK) and Stat3. We further hypothesized that inhibitors of mTORC1 or activators of AMPK would replicate and/or enhance TH cardioprotection. Methods: Cardiomyocytes isolated from 1-2-day old C57BL6/J mice, were exposed to simulated I (90 min)/R (3 h). For TH, cells were cooled from 37C to 32C during ischemia and the first hour of reperfusion. Heart samples were also obtained from C57BL/6 mice that underwent an 8-min cardiac arrest. Following 6 min, the mice were randomized to normothermia (NT, 37C) or TH (30C) extended during CPR and for 1 h after resuscitation. Protein lysates were collected at serial time points for Western blot analyses. Results: Cardiomyocyte death during ischemia was minimal, but accelerated during reperfusion (4% vs. 46%,p&lt;.05 n=5). TH attenuated this cell death (24% p&lt;.05 n=5) and attenuated reperfusion-induced mTOR activation seen within 30 min as measured by differential phosphorylation of the mTOR targets 70S6K and eEF2. Compared to NT, TH-treated cardiomyocytes and hearts demonstrated increased p-AMPK after resuscitation, consistent with mTOR inhibition. Stat3 also showed enhanced phosphorylation on tyrosine 705. The mTOR inhibitor rapamycin (100nM) given during I/R similar to TH affected 70S6K and eEF2 and significantly reduced cell death (28% vs. 42%, p&lt;.05 n=5). The AMPK activator metformin (100uM) also significantly reduced cell death (22%, p&lt;.05 n=4). Conclusion: TH cardioprotection is associated with altered signaling events suggesting mTORC1 inhibition and activation of the cell survival kinases AMPK and Stat3. Pharmacologic strategies that mimic these TH effects are available and could be useful as TH adjuncts or mimetics that improve survival after cardiac arrest.
A Comparison Study Between Allogeneic and Autologous Hematopoietic Stem Cell Transplant for High-Risk Peripheral T-Cell Lymphomas (PTCL)
Authors: Haiwen Huang, Qiangli Wang, Zhengming Jin, XiaoWen Tang, Huiying Qiu, Chengcheng Fu, Yue Han, Miao Miao, Huirong Chang, Aining Sun, Depei Wu
Journal: Blood (2016)
Surgery versus optimal medical management of early-stage small cell lung cancer.
Authors: Chi-Fu Jeffrey Yang, Derek Y. Chan, Babatunde Yerokun, Xiaofei F. Wang, Betty Caroline Tong, Thomas A. D'Amico, Mark W. Onaitis, Matthew G. Hartwig, Mark F. Berry, David Harpole
Journal: Journal of Clinical Oncology (2016)

8511 Background: Differences in the use and impact of surgery versus optimal medical management (concurrent chemoradiation) for patients with cT1-2N0M0 SCLC have never been evaluated in population-based studies. Using the National Cancer Data Base (NCDB), we tested the hypothesis that surgery is rarely used but offers a survival advantage over concurrent chemoradiation for patients with cT1-2N0M0 SCLC. Methods: Overall survival (OS) of patients with cT1-2N0M0 SCLC who underwent concurrent chemoradiation versus surgery with adjuvant chemotherapy ± radiation in the NCDB from 2003 to 2011 was assessed using propensity-score-matched analysis. Groups were matched for common prognostic covariates (age, sex, race, year of diagnosis, insurance type, median household income, education, treatment facility type, distance from facility, hospital volume, clinical T status, and Charlson/Deyo comorbidity condition score). Results: Of 4,729 patients who were treated for cT1-2N0M0 SCLC during the study period, 681 (14.4%) patients underwent surgery with adjuvant chemotherapy ± radiation and 1,620 (34.3%) underwent concurrent chemoradiation. After propensity-score matching by surgery with adjuvant chemotherapy with or without radiation versus concurrent chemoradiation, all 12 covariates were well balanced between the surgery (n = 545) and concurrent chemoradiation (n = 545) groups. Surgery was associated with a significantly higher OS than concurrent chemoradiation (5-year OS 48.9% vs 30.0%, log-rank p < .001). To minimize treatment selection bias due to comorbidities, we limited the propensity-matched analysis to 536 patients with no comorbidities; surgery remained significantly associated with a higher OS than concurrent chemoradiation (5-year OS 48.8% vs 30.4%, log-rank p < .01). Conclusions: In a propensity-matched analysis of a national population-based cancer database, surgery with adjuvant chemotherapy ± radiation was found to be used rarely. Patients who underwent surgery with adjuvant chemotherapy ± radiation for node-negative SCLC had improved outcomes when compared to concurrent chemoradiation. These results support an increased role of surgery in multimodality therapy for T1-2N0M0 small cell lung cancer.
Novel molecular targets of resveratrol action in lung cancer
Authors: Fatouma Alimirah, Lorna Whyte, Karen Torres, Rajendra Mehta
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

5459 

Resveratrol, a naturally occurring antibacterial and antifungal compound produced by several plants, has been well documented to modulate cell cycle progression and exert antiproliferative as well as apoptotic effects on multiple cancers including lung. However, reseveratrol’s molecular mechanism of action in human lung cancer has not been fully elucidated. Therefore, we utilized dual protein and gene screening methodologies involving high-throughput immunoblotting (Power Blot) and Microarray gene expression profiling to determine novel molecules and molecular pathways regulated by resveratrol treatment in A549 human lung carcinoma cells. Comparative analysis of protein and gene expressions after resveratrol treatment identified alterations in several canonical pathways including cell cycle checkpoints, apoptosis cell death cascade pathways as well as the pathways regulating nuclear NFκB and the p38 mitogen-activated protein kinase/c-jun-NH2 signaling. Most importantly, these two techniques concomitantly revealed the involvement of the transforming growth factor (TGFβ )/ Smad pathway in mediating resveratrol action in A549 human lung cancer cells. Resveratrol treatment resulted in the up-regulation of smad 7 mRNA expression, a repressor of TGFβ signaling. Conversely, the treatment down-regulated the mRNA expression of TGFβ signaling activators smads 2 and 4. Based on these observations and the fact that TGFβ has been shown to activate the anti-apoptotic PI3K/AKT pathway and induce EGF receptor expression in certain cell types, we investigated the effect of resveratrol treatment on the phosphorylation levels of AKT and its effect on protein expression of the EGF receptor (EGFR). Conventional western blot analysis determined that resveratrol treatment down-regulated the phosphorylation of AKT on threonine 308. Additionally, the results showed that resveratrol had no effect on the expression of EGFR protein levels in A549 cells. Taken together, our findings identify the TGFβ / Smad pathway as a novel molecular target of resveratrol action and imply an interaction with the PI3K/AKT pathway which will help in paving the way for defining resveratrol as an effective chemopreventive or chemotherapeutic agent for human lung cancer. (Supported by Philip Morris USA Inc. and Philip Morris International).
Prokinetic Effect of Indoramin, an Alpha Adrenergic Antagonist, on Gall Bladder Motility in Subjects with Gall Stone Disease
Authors: S Sengupta, P Modak, N McCawley, LJD O'Donnell
Journal: Endoscopy (2004)

Introduction: Alpha adrenergic antagonist has been found in previous studies to have a prokinetic effect on gall bladder motility in normal human subjects. However their effects have not been fully elucidated in subjects with gallstone disease.
Efficacy of a Maternal Depression Prevention Strategy in Head Start
Authors: Michael Silverstein, Yaminette Diaz-Linhart, Howard Cabral, William Beardslee, Mark Hegel, Winta Haile, Jenna Sander, Gregory Patts, Emily Feinberg
Journal: JAMA Psychiatry (2017)

Low-income and minority mothers experience a disproportionate incidence of depression and lack access to treatment services. Development of prevention strategies in accessible community-based venues is a potentially important public health strategy.To determine the efficacy of a depression prevention strategy embedded in Head Start.This randomized clinical trial was performed from February 15, 2011, through May 9, 2016, at 6 Head Start agencies serving families at or below the federal poverty level. Participants included mothers with depressed mood, anhedonia, or depression history but who were not in a current major depressive episode. Participants were followed up for 12 months with masked outcome assessments. Final follow-up was completed on May 9, 2016.Participants were randomized to a problem-solving education (PSE) intervention (n = 111) or usual Head Start services (n = 119).Primary outcomes were problem-solving skills and depressive symptoms. To capture the chronicity and intensity of symptoms, the Quick Inventory of Depressive Symptoms was administered bimonthly, and rates of clinically significant symptom elevations were compared across groups. Secondarily, the presence of a major depressive episode was assessed using the Structured Clinical Interview for DSM-IV Axis I Disorders.Among the 230 participants, 152 (66.1%) were Hispanic, with a mean (SD) age of 31.4 (7.3) years. An intention-to-treat analysis among 223 participants contributing follow-up data found no differences in problem-solving skills across groups. The mean (SD) number of depressive symptom elevations among the PSE participants was 0.84 (1.39) compared with 1.12 (1.47) among the usual service participants (adjusted incident rate ratio [aIRR], 0.60; 95% CI, 0.41-0.90). In analyses stratified according to baseline depressive symptoms, PSE exerted a preventive effect among those with lower-level baseline symptoms, with a mean (SD) of 0.39 (0.84) elevations among PSE participants compared with 0.88 (1.37) among usual service participants (aIRR, 0.39; 95% CI, 0.21-0.75). However, no difference was observed among those with higher-level baseline symptoms (mean [SD] elevations, 2.06 [1.92] for PSE and 2.00 [1.91] for usual service; aIRR, 1.10; 95% CI, 0.67-1.80). Analysis of symptom scores followed the same pattern, with an adjusted mean reduction of 1.33 (95% CI, 0.36-2.29) among participants with lower-level baseline symptoms.The PSE intervention is efficacious in preventing depressive symptom episodes and performs optimally among those with initial low-level symptoms. Additional effectiveness studies in Head Start are necessary to develop meaningful public health programs.clinicaltrials.gov Identifier: NCT01298804.
Rearrangement of Enterocyte Cytoskeletal Proteins in Coeliac Disease
Authors: S Wilson, Y Volkov, C Feighery
Journal: Endoscopy (2004)

Introduction: Coeliac disease is an immune mediated gluten sensitive enteropathy in genetically susceptible individuals resulting in small intestinal inflammation characterized by villous atrophy, crypt hyperplasia and increases in intraepithelial and lamina propria lymphocytes. Although it is well established that immune reactivity to gliadin takes place with the production of proinflammatory cytokines, it is not clear how damage to the small intestinal mucosa ensues.
Hyperglycemia Is the Main Mediator of Prediabetes- and Type 2 Diabetes–Associated Impairment of Microvascular Function: The Maastricht Study
Authors: Ben M. Sörensen, Alfons J.H.M. Houben, Tos T.J.M. Berendschot, Jan S.A.G. Schouten, Abraham A. Kroon, Carla J.H. van der Kallen, Ronald M.A. Henry, Annemarie Koster, Koen D. Reesink, Pieter C. Dagnelie, Nicolaas C. Schaper, Casper G. Schalkwijk, Miranda T. Schram, Coen D.A. Stehouwer
Journal: Diabetes Care (2017)

Prediabetes and type 2 diabetes (T2D) are associated with microvascular dysfunction (1), which may explain their increased risk of microvascular complications. However, mechanisms remain poorly understood. We investigated to what extent prediabetes- and T2D-associated microvascular dysfunction is potentially attributable to (composite indices of) hyperglycemia, insulin resistance, blood pressure, arterial stiffness, lipid profile, and/or low-grade inflammation.

In the Maastricht Study (2), a T2D-enriched population-based cohort study ( n = 1,791, 49% women, aged 60 ± 8 years), we determined flicker light–induced retinal arteriolar %-dilation (1) using the Dynamic Vessel Analyzer, heat-induced skin %-hyperemia (1) using laser Doppler flowmetry, and diabetes status using the oral glucose tolerance test (normal glucose metabolism \[NGM\] \[ n = 1,040\], prediabetes [ n = 276], or T2D [ n = 475]) (Table 1). Mediating effects of composite indices on prediabetes- and T2D-associated microvascular dysfunction were estimated by linear regression.

View this table:

Table 1 
General characteristics and retinal and skin measures for the retinal study population according to glucose metabolism status



Age- and sex-adjusted analyses showed lower retinal arteriolar %-dilation in prediabetes (B = −0.16 [95% CI –0.53; 0.21]), with further deterioration in T2D (B …
Government must lift pay cap to keep staff, says NHS Confederation
Authors: Tom Moberly
Journal: BMJ (2017)

Theresa May’s new government must lift the pay cap on NHS staff wages to help improve staff retention, the membership body for commissioners and providers of NHS services has said.

Speaking at the NHS Confederation’s annual conference in Liverpool on 14 June, Niall Dickson, the confederation’s chief executive, said that securing the workforce to deliver the services that patients need was one of the major challenges facing the NHS. …
<i>PTEN, DICER1, FH</i>, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood
Authors: Kris Ann P. Schultz, Surya P. Rednam, Junne Kamihara, Leslie Doros, Maria Isabel Achatz, Jonathan D. Wasserman, Lisa R. Diller, Laurence Brugières, Harriet Druker, Katherine A. Schneider, Rose B. McGee, William D. Foulkes
Journal: Clinical Cancer Research (2017)

Abstract PTEN hamartoma tumor syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years. DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended. Clin Cancer Res; 23(12); e76–e82. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.
Clinical Characteristics of Hyposecretory Multiple Myeloma (Monoclonal Immunoglobulin &lt; 3 g/dl) in Afro-Caribbean Patients at a Single Urban Institution
Authors: Ashtami Banavali, Elvira Neculiseanu, Padma L. Draksharam, Sireesha Datla, Maushmi Savjani, Jennifer Park, Gurinder Sidhu, Evelyn O. Taiwo
Journal: Blood (2016)
Interaction of Helicobacter Pylori TRX1 with Gastric Epithelial Cells
Authors: E Cummins, S Mitchell, D Kelleher, H Windle
Journal: Endoscopy (2004)

Thioredoxins (Trx) are ubiquitous thiol disulfide reductases that have multifunctional roles in different cell types, including redox regulation of transcription factor activation. Helicobacter pylori contains two thioredoxins (Trx1, Trx2) and, unusually, both species are secreted by the bacterium in vitro. As components of the bacterial secretome these proteins may have a role to play in host-pathogen interactions.
Abstract 252: Dysregulation of β-Adrenergic Signaling in Hearts with Hyperinsulinemia
Authors: Qin Fu, Evan Abel, Y Kevin Xiang
Journal: Circulation Research (2012)

Introduction: Epidemiological studies have demonstrated an increased risk of heart failure in diabetics, but the mechanisms linking diabetes mellitus (DM) to heart failure remain unclear. A uniform metabolic disturbance that characterizes type 2 diabetes is hyperinsulinemia, which accelerates adverse left ventricular (LV) remodeling in pressure overload hypertrophy. Hypothesis: We hypothesize that hyperinsulinemia might affect LV contractility by directly impairing β-adrenergic receptor (βAR) signaling. Methods and Results: Insulin receptor and β 2 AR form a cell surface complex, which dissociates upon insulin stimulation in the heart and cardiomyocytes. Insulin dose-dependent significantly inhibits PKA activities induced by a βAR agonist isoproterenol, and subsequently impairs isoproterenol-induced PKA phosphorylation of phospholamban and contractile responses in myocytes. Mechanistically, insulin action is mediated via IR and β 2 AR dependent manner. Insulin induces both PKA and GRK2-mediated phosphorylation of the β 2 AR, leading to enhanced β 2 AR/Gi coupling that inhibits adenylyl cyclase-mediated cAMP production. Pretreatment with Gi inhibitor pertussis toxin abolishes the insulin-mediated impairment of β-adrenergic stimulation of cAMP signaling. Further studies reveal that chronic insulin stimulation increases phosphodiesterase 4D protein levels in cardiac myocytes, and that the expression of phosphodiesterase 4D is also increased in animal models with high fat feeding or after 2-weeks of transaortic constriction. This leads further attenuation of βAR-induced cAMP activity for contraction response. Inhibition of phosphodiesterase 4 with rolipram rescues cAMP signaling induced by isoproterenol after insulin treatment. Last, PDE4D protein levels are significantly induced in the myocardium in diabetic patients with heart disease compared to those non-diabetic patients with heart disease. Conclusions: This is the first evidence showing that hyperinsulinemia might adversely impact cardiac contractility by inhibiting βAR signaling, which is due to IR-induced β 2 AR/Gi coupling and phosphodiesterase 4 expression in the βAR signaling cascades.
Regulatory landscape fusion in rhabdomyosarcoma through interactions between the PAX3 promoter and FOXO1 regulatory elements
Authors: Cristina Vicente-García, Barbara Villarejo-Balcells, Ibai Irastorza-Azcárate, Silvia Naranjo, Rafael D. Acemel, Juan J. Tena, Peter W. J. Rigby, Damien P. Devos, Jose L. Gómez-Skarmeta, Jaime J. Carvajal
Journal: Genome biology (2017)

The organisation of vertebrate genomes into topologically associating domains (TADs) is believed to facilitate the regulation of the genes located within them. A remaining question is whether TAD organisation is achieved through the interactions of the regulatory elements within them or if these interactions are favoured by the pre-existence of TADs. If the latter is true, the fusion of two independent TADs should result in the rewiring of the transcriptional landscape and the generation of ectopic contacts. We show that interactions within the PAX3 and FOXO1 domains are restricted to their respective TADs in normal conditions, while in a patient-derived alveolar rhabdomyosarcoma cell line, harbouring the diagnostic t(2;13)(q35;q14) translocation that brings together the PAX3 and FOXO1 genes, the PAX3 promoter interacts ectopically with FOXO1 sequences. Using a combination of 4C-seq datasets, we have modelled the three-dimensional organisation of the fused landscape in alveolar rhabdomyosarcoma. The chromosomal translocation that leads to alveolar rhabdomyosarcoma development generates a novel TAD that is likely to favour ectopic PAX3:FOXO1 oncogene activation in non-PAX3 territories. Rhabdomyosarcomas may therefore arise from cells which do not normally express PAX3. The borders of this novel TAD correspond to the original 5'- and 3'- borders of the PAX3 and FOXO1 TADs, respectively, suggesting that TAD organisation precedes the formation of regulatory long-range interactions. Our results demonstrate that, upon translocation, novel regulatory landscapes are formed allowing new intra-TAD interactions between the original loci involved.
Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma
Authors: Steven C. Kao, Yuen Yee Cheng, Marissa Williams, Michaela B. Kirschner, Jason Madore, Trina Lum, Kadir H. Sarun, Anthony Linton, Brian McCaughan, Sonja Klebe, Nico van Zandwijk, Richard A. Scolyer, Michael J. Boyer, Wendy A. Cooper, Glen Reid
Journal: Journal of Thoracic Oncology (2017)
Surgery for patients with ‘lower grade’ glioma: putting assumptions, beliefs and convictions into perspective
Authors: M. Weller
Journal: Annals of Oncology (2017)

Annals of Oncology 2017; 28(8): 1696–1697. doi: 10.1093/annonc/mdx295 An error was introduced to the name of the author during production. This has now been corrected online to M. Weller. The Publisher apologizes for this error. Surgery for patients with ‘lower grade’ glioma: putting assumptions, beliefs and convictions into perspectiveAnnals of OncologyVol. 28Issue 8PreviewFor decades neuro-oncology meetings have benefited from controversial, sometimes heated and emotional debates on the role of surgery for what has traditionally been falsely designated ‘low grade’ glioma; falsely since ‘low grade’ glioma evokes false expectations for often young patients and their caregivers confronted with a disease with a median survival around 7–8 years. Full-Text PDF Open Archive