tbuckley/cabot-search huggingface dataset:
Abstract 31: WEE1 kinase inhibition enhances PI3K inhibitor response in p53 deficient gliomas
Authors: Shaofang Wu, Siyuan Zheng, Shuzhen Wang, W.K.Alfred Yung, Dimpy Koul
Journal: Cancer Research (2015)

Abstract Glioblastoma multiforme (GBM) is an aggressive brain tumor that is resistant to chemotherapy and radiation, and is almost always fatal. Oncogenic activation of the PI3K signaling pathway plays a pivotal role in the development of GBM and is a major molecular target for therapeutic development. However, clinical results of single-agent PI3K inhibitors have been modest to date. PI3K inhibitors have led to tumor stabilization and some disease responses; however, dramatic tumor regressions are not typical. Multiple recent reports have described mechanisms of resistance to PI3K inhibitors. The goal of the present study was to identify ways to improve the efficacy of PI3K inhibitor-based therapy by overcoming adaptive resistance. In this study we show that PI3K inhibitor BKM induces G2/M cell cycle arrest and inhibits GBM cell proliferation. We identified WEE1 as a putative treatment target of resistance to PI3K inhibition based on its potential function as a mitotic gatekeeper and its specific overexpression in GBM. WEE1 kinase is a key molecule in maintaining G2-cell-cycle checkpoint arrest for premitotic DNA repair. We show that that BKM treatment activates WEE1, which in turn phosphorylates CDC2 at Tyr15, inactivates CDC2 and inhibits CDC2 activity, leading to G2/M arrest in glioma initiating cells (GICs). We show that treatment with WEE1 inhibitor MK1775 inhibited BKM-induced Cdc2 Tyr15 phosphorylation, and forced GICs to enter into the mitotic phase of the cell cycle. Using a panel of GICs, we show that MK1775 synergizes with BKM to inhibit GBM cell proliferation. Further, MK1775 and BKM as a single agent alone partially blocks proliferation, however, combination of MK1775 and BKM induces apoptosis as evaluated by Annexin V positive cells, cleaved PARP and caspase 3, and TUNEL staining. This effect was observed specifically in p53 mutant cells. Finally we show that depletion of WEE1 by shRNAs synergizes with BKM to inhibit GBM cell proliferation and induce apoptosis. These results indicate that WEE1 inhibition potentiated the effectiveness of PI3K targeted inhibition in GBM, and suggest a combinational inhibition of WEE1 and PI3K might allow successful targeted therapy in p53 mutant GBM. Citation Format: Shaofang Wu, Siyuan Zheng, Shuzhen Wang, W.K.Alfred Yung, Dimpy Koul. WEE1 kinase inhibition enhances PI3K inhibitor response in p53 deficient gliomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 31. doi:10.1158/1538-7445.AM2015-31
Open defecation is associated with raised risk of preterm birth among Indian women
Authors: Sanjeet Bagcchi
Journal: BMJ (2015)

Open defecation is associated with a substantially increased risk of adverse outcomes of pregnancy among women in rural India, a new study in PLOS Medicine has found.1

Bijaya Padhi of the Asian Institute of Public Health, Bhubaneswar, and colleagues carried out a prospective cohort study of 670 pregnant women in rural parts of Odisha. The women were enrolled in the study during their first trimester and followed, through home visits …
Maintenance therapy for cryptococcosis in patients with AIDS after successful primary therapy: oral fluconazole (300 mg daily) versus oral itraconazole (300 mg daily)
Authors: Fausto de Lalla, Giampietro Pellizzer, Vinicio Manfrin, Paolo Benedetti, Marzia Franzetti, Roberto Nicolin, Alberto Vaglia
Journal: Clinical Microbiology and Infection (1999)
Frequency of T790M substitution in exon 20 of EGFR gene in brain metastases in chemotherapy-naive non-small cell lung cancer patients (NSCLC)
Authors: Radoslaw Mlak, Pawel Krawczyk, Bozena Jarosz, Michal Skronski, Kamila Wojas-Krawczyk, Tomasz Kucharczyk, Marek Sawicki, Barbara Wilczynska, Tomasz Powrozek, Marcin Nicos, Joanna Chorostowska-Wynimko, Tomasz Trojanowski, Janusz Milanowski
Journal: European Respiratory Journal (2012)

Reversible tyrosine kinase inhibitors (TKI) of EGFR (erlotinib, gefitinib) have shown limited efficacy in patients with activating mutations of EGFR gene. The resistance to reversible TKI and the sensitivity to irreversible pan-HER inhibitors (afatinib, neratinib) are related to secondary mutations in EGFR gene, especially T790M mutation (50% of resistance). However, data concerning the frequency of primary T790M substitution in NSCLC metastases is scarce. Our study was aimed to develop a new method for T790M EGFR gene mutation analysis and to estimate the frequency of this mutation in chemotherapy-naive patients with NSCLC brain metastases.  DNA was isolated from 150 paraffin-embedded tissue samples using Qiamp DNA FFPE tissue kit. We used ASP-PCR (allele-specific PCR) technique and fluorescence CY5 labelled primers, which are specific for mutated or wild-type EGFR gene exon 20. The analysis was performed on ALF Fragment Analyzer.  Method proved sufficient and sensitive enough to estimate the presence of T790M mutation in all examined samples. 3 patients (2%) with T790M substitution were detected, one suffering from non-differentiated NSCLC (non-smoker) and two with squamous cell carcinoma (10- and 20-pack-years smokers). Coexistence of T790M and activated EGFR gene mutations was not detected.  The primary T790M substitution of EGFR gene is detectable in chemotherapy- and TKI EGFR-naive patients. It is recommended to perform complete EGFR gene mutation analysis, including exon 20, before treatment.
Abstract 184: The Etiology of Postarrest Mortality Stratified by Location of Arrest
Authors: Tyler A Giberson, Svetlana Bivens, Michael Cocchi, Brandon Giberson, Justin Salciccioli, Michael Donnino
Journal: Circulation (2011)

Introduction: Proposed study and treatment of post-cardiac arrest (CA) patients is often organ-specific. It remains unclear whether post-CA patients routinely expire from neurologic injury, refractory hemodynamic instability, or other reasons. Furthermore, there may be differences related to location of the arrest. Therefore, identifying principal reasons for death (a concept yet to be incorporated into Utstein guidelines) in post-arrest populations is essential. Objective: To develop a classification scheme for post-CA mortality and compare etiologies for death based on location of arrest. Methods: Secondary analysis of a prospective, observational study of CA patients. Inclusion criteria: 1) Age &gt;18 2) CA with ROSC 3) In-hospital death. Traumatic arrests were excluded. Medical records were reviewed independently by 2 MDs and causes of death were classified: 1. Primary neurologic withdrawal of care 2. Presumed neurologic withdrawal of care with other co-morbidities/organ-injury 3. Refractory hypotension 4. Sudden CA. Simple descriptive statistics were used. Results: We evaluated 204 post-CA patients. Mean age was 67 (+/- 17) and 32% were female. Median downtime was 20 (IQR: 10-33) min. Overall in-hospital mortality was 50.5%. Of 103 deaths, 91% fell into 4 broad categories. Main cause of death for out of hospital cardiac arrest (OHCA) patients who had ROSC but did not survive hospitalization was primary neurologic withdrawal of care. Main cause of death for in-hospital cardiac arrests (IHCA) with ROSC which occurred in the ED or ICU was refractory hypotension. Among those with IHCA on the wards, the reasons for death were similar to the OHCA group. Conclusion: These data provide a simple classification scheme of reasons for death in post-arrest patients. There may be differences based on location of arrest but further study is needed. Investigators may need to consider principal reasons for death when matching therapeutic interventions to a given population.
Obesity and bone health in COPD
Authors: Vanessa McDonald, Lisa Wood, Penny Baines, Isabel Higgins, Peter Gibson
Journal: European Respiratory Journal (2013)

Osteoporosis is a well-known comorbidity of COPD; the increased risk in COPD is related to systemic inflammation, reduced physical activity or low lean muscle mass, corticosteroid use, smoking and age. Obesity in COPD is also increasingly common. We hypothesized that in COPD, obesity is protective against osteoporosis. Aim: To determine the association between COPD, body weight and osteoporosis. Methods: People with COPD (>55years) underwent a multidimensional assessment to measure body mass, bone mineral density (BMD), systemic inflammation (CRP), spirometry and symptoms. Participants were stratified into 2 groups; obese (BMI ≥30kg/m) and non-obese (BMI <30kg/m). Results: We recruited 41 participants, 21 (51%) were female with a mean (SD) age of 70.9 (8.7), BMI of 28 (0.7) and FEV1 % predicted of 51.2 (19). There were 24 (58%) who were obese. The total BMD of the obese group was significantly higher than the non-obese group (1.1 (0.14) versus 0.88 (0.22); p=0.0003). Similarly the total body BMD T score was significantly better in the obese group (-0.008 v -2.186; p<0.0001). There were fewer participants in the osteopenic or osteoporotic range in the obese (9 [37.5%]) compared with the non–obese 15 (88.3) group; p=0.001. Using linear regression analysis, appendicular skeletal muscle mass (ASMM), log CRP and BMI were all positively associated with BMD T Score. In a multiple regression model (r2=0.5692; p=0.001) adjusted for age, gender and BMI, ASMM was the only positive predictor of BMD T score. Conclusion: Obesity is protective of poor bone health in COPD; this may be another key to the understanding of the obesity paradox in COPD. Assessing bone health in COPD patients with normal BMI is important.
GOLD BCD or 234 classifications: Which one better reflects COPD patients' functionality?
Authors: Graciane L. Moreira, Nidia A. Hernandes, Thais Paes, Karina C. Furlanetto, Thais Sant'Anna, Leila Donaria, Fabio Pitta
Journal: European Respiratory Journal (2014)

Background:  The association of the new GOLD classification with the functionality of patients with chronic obstructive pulmonary disease (COPD) is unknown.  Objective:  To study which GOLD classification (BCD or 234) better reflects the functionality of patients with COPD.  Methods:  Ninety patients with COPD were classified according to the new and the previous GOLD classifications (BCD and 234, respectively). Functionality was assessed by the 6-minute walk test (6MWT), activities of daily living (ADL) (London Chest Activity of Daily Living Scale, LCADL) and activity/inactivity variables of physical activity in daily life (PADL) assessed by wearing the Sensewear armband monitor for 2 days. Patients were separated in two groups according to their functionality: for the 6MWT and LCADL, the average values were considered as cut-off points to separate the patients with better or worse functionality; and for PADL these cut-off points were the average of inactive time/day and to achieve (or not) more than 30 minutes/day of moderate intensity activities.  Results:  The 6MWT was the only of the 4 outcomes which was associated with the GOLD classifications. Out of the 90 patients, 80% (GOLD B), 85% (GOLD C), 44% (GOLD D) and 81% (GOLD 2), 54% (GOLD 3), 43% (GOLD 4) presented better functionality assessed by the 6MWT. In addition, Cramer´s association coefficient values of 6MWT with GOLD BCD and 234 were V=0.36 and V=0.26, respectively.  Conclusion:  The unidimensional and multidimensional GOLD classifications (234 and BCD) do not reflect well COPD patients9 functionality in a broad sense, although these classifications were better associated with functional exercise capacity (6MWT) than with ADL and PADL.
Abstract 4552: Abnormal Cerebrovascular Development in Hypoplastic Left Heart Syndrome During Fetal Life
Authors: Caroline Kinnear, Megan Thompson, Naila Mahmut, Patrick Shannon, Edgar Jaeggi, David Chitayat, Seema Mital
Journal: Circulation (2008)

Background: Microcephaly is common in newborns with hypoplastic left heart syndrome (HLHS) possibly related to altered cerebral blood flow during fetal life and may lead to neurocognitive deficits. We assessed cerebrovascular growth in fetuses with HLHS. Methods: 27 mid-trimester fetuses with autopsy-confirmed HLHS (gestational age, 23±3 weeks; 11 males) without known chromosomal malformations (2002– 07) were included. Body weight (BW) and head circumference (HC) z scores were calculated. Fetal brain sections were studied in 6 HLHS and 5 normal controls. Brain capillary density (von Willebrand factor, vWf), vascular endothelial growth factor (VEGF), and CD133 (stem cell marker) was measured in germinal matrix, intermediate, subcortical and cortical layers. Results: Mean BW z score was −0.1±1; HC z score was −0.6±1.4. Capillary density (/hpf) was lower in HLHS vs controls in the germinal matrix (4.1±1.4 vs 7.8 ±1.7; p=0.002) (Fig 1 ) and cortex (0.9±0.7 vs 3.5±3.2, p=0.09). Capillaries were larger in the HLHS vs controls (vessel area: 0.059±0.019 vs 0.042±0.016 mm 2 , p=0.005) suggesting reactive dilation to maintain cerebral blood flow. Although VEGF expression was not different between HLHS and controls, the stem cell marker, CD133, was reduced in HLHS (Fig 1 ). Conclusion: This study demonstrates early onset cerebral growth impairment in fetuses with HLHS. This may be related to reduced stem cells and reduced brain capillary density. Whether antenatal interventions that augment antegrade aortic blood flow can improve vascular development and cerebral growth requires further investigation. Figure 1: Brain capillary density (vWF) and CD133 staining was lower in HLHS.
Long-term follow-up results of hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL)
Authors: S. O'Brien, D. Thomas, J. Cortes, S. Faderl, F. Giles, S. Pierce, J. Shan, A. Ferrajoli, M. Keating, H. Kantarjian
Journal: Journal of Clinical Oncology (2004)

6539 Background: The Hyper-CVAD regimen had shown encouraging results with short-term follow up (JCO 18: 547, 2000). This report updates the long-term follow up results with Hyper-CVAD. Methods: Adults with ALL were treated with Hyper-CVAD. There were no restrictions by age, performance, or organ dysfunction. Treatment consisted of 8 dose-intensive cycles of CVAD and high-dose MTX-ara-C with CNS prophylaxis, followed by 2 years of POMP maintenance (detailed in reference). Results: 288 pts were treated; median age 40 yrs (13–92); 59(21%) > 60 yrs; WBC > 30 x 109/L in 73 (25%); Ph+ ALL in 48(17%). Overall CR was 92%; induction death 5%. With a median follow-up of 62 months the 5-year survival rate was 38%, and 5-year CR rate 38%. By multivariate analysis, poor prognostic factors for CR duration were increasing age, Ph+ ALL, and more than one course to CR. Compared with 218 pts receiving prior VAD regimens, Hyper-CVAD was significantly better: CR rate 92% vs 75% (p<0.001); CR post course 1 74% vs 55% (p5% blasts 34% vs 48% (p=0.005); 5-yr survival rate 38% vs 22% (p<0.001); 5-yr CR rate 38% vs 32% (p=0.09). Conclusions: Hyper CVAD long-term results are favorable. Future studies will incorporate longer POMP maintenance + consolidations, rituximab in pre B ALL, and imatinib + Hyper CVAD in Ph+ ALL. No significant financial relationships to disclose.
Effects of patient management guidelines on physician practice patterns: the Community Hospital Oncology Program experience.
Authors: L G Ford, C P Hunter, P Diehr, R W Frelick, J Yates
Journal: Journal of Clinical Oncology (1987)

The Community Hospital Oncology Program (CHOP), funded under contracts by the National Cancer Institute (NCI) from 1981 to 1984, was designed to be a model for delivery of the most up-to-date cancer care in the community setting. Site specific patient management guidelines (PMGs) were developed by physicians who saw a majority of cancer patients in each community and represent a consensus of the most current information on pretreatment evaluation and management for each cancer site. There was the potential for PMGs to have a strong effect on physician practice patterns. A patterns of care study (POC) was conducted in the 17 CHOPs to determine the influence of guidelines on practice patterns. The practice elements examined in this report are clinical staging for breast and small-cell lung cancer, medical oncology consultation for breast cancer patients with positive lymph nodes, and radiation therapy consultation for rectal and small-cell lung cancer. These elements were in all CHOP guidelines. Except for physicians most active in the CHOP, the data provide no evidence of diffusion of guideline principles to the majority of practicing physicians. Although all guidelines contained discussion of the importance of staging before definitive treatment for breast cancer, only 33% of the 1,922 charts examined had a stage recorded. In small-cell lung cancer, 67% of the 388 charts examined had stage recorded. The years in practice of the primary physician had an inverse relationship to practice patterns as defined by the guidelines. Physician specialty was also a determinant of practice patterns for small-cell lung cancer. However, participation in guideline development and their dissemination did not significantly influence the patterns of care elements examined in this study.
Abstract 5570: β-2 Adrenergic Receptors Overexpression Promotes Angiogenesis in the Failing Myocardium through Activation of Vascular Endothelial Growth Factor/Akt Transduction Pathway
Authors: Carmela Zincarelli, Giuseppe Rengo, Fondazione S. Maugeri, Luca Golino, Giovanna G Altobelli, Vincenzo Cimini, Francesca Fortunato, Massimo Marchese, Daniela Femminella, Elena Avallone, Alessandro Rengo, Franco Rengo, Fondazione S. Maugeri, Walter J Koch, Dario Leosco
Journal: Circulation (2008)

β-2 adrenergic receptor (β-2AR) plays a pivotal role in endothelial cell proliferation and promotes angiogenesis in response to hindlimb ischemia. Desensitization/uncoupling of cardiac β-2AR represents a well established phenomenon in heart failure (HF). In this study we aimed to investigate the role of β-2AR in the impairment of angiogenic processes occurring in the failing myocardium. To this purpose, we explored the angiogenic effects of β-2AR in a rat model of post-myocardial infarction (MI) HF. Cardiac adenoviral-mediated β-2AR overexpres-sion has been obtained via direct intramyocardial injection (4 x 10 11 PFU) 4 weeks after MI. We also extended our observation to β-2AR knockout (β2KO) mice developing HF after large anterior MI (infarct size 45 ± 6%). Cardiac β-2AR overexpression in HF rats markedly increased capillary and arteriolar length density, and induced larger left ventricular (LV) hypertrophic responses than that observed in untreated HF animals. Such LV adaptive remodelling was associated to reduced LV diameters and improved cardiac LV fractional shortening (FS) and +dP/dt. At molecular level, cardiac β-2AR gene transfer induced sustained activation of p-Akt and S6 kinase (S6K) phosphorylation and increased p-eNOS and VEGF levels that were instead reduced in untreated HF rats. In β2KO mice, we found a ~25% reduction of cardiac capillary and arteriolar density compared to WT mice. In β2KO mice, MI was associated with a dramatically higher 21-day mortality compared to WT (70% vs 30%, respectively). Survivors β2KO mice showed increased LV end diastolic and systolic diameters, and worse global cardiac contractility compared to controls. Cardiac Akt activation, S6K phosphorylation, p-eNOS, and VEGF-A production were significantly blunted in HF β2KO mice. Conclusions. β-2ARs play an important role in regulating angiogenic responses in post-MI HF hearts. The activation of Akt signal transduction pathway seems to be strongly involved in these mechanisms.
Defining borderline patients: an overview
Authors: J G Gunderson, M T Singer
Journal: American Journal of Psychiatry (1975)

This review of the descriptive literature on borderline patients indicates that accounts of such patients vary depending upon who is describing them, in what context, how the samples are selected, and what data are collected. The authors identify six features that provide a rational means for diagnosing borderline patients during an initial interview: the presence of intense affect, usually depressive or hostile; a history of impulsive behavior; a certain social adaptiveness; brief psychotic experiences; loose thinking in unstructured situations; and relationships that vacillate between transient superficiality and intense dependency. Reliable identification of these patients will permit better treatment planning and clinical research.
Video-assisted modified Weder method for accelerated treatment of postpneumonectomy empyema without bronchopleural fistula
Authors: Danail Petrov, Elyuar Goranov, Svilen Alexov, Yordanka Steneva
Journal: European Respiratory Journal (2011)

Objective:  To introduce a video-assisted modification of Weder method for accelerated treatment of postpneumonectomy empyema (PPE) without bronchopleural fistula.   Methods:  Three men (52, 58, 64 year old) with late PPE were treated by our modification. It follows the principals of original method: pleural cavity radical debridement and packing with wet dressing of povidone-iodine, repeated every second day until the pleural cavity is macroscopically clean and finally obliterated with antibiotic solution. We do not open the former thoracotomy. The debridement is carried out through a muscle-sparing minithoracotomy or in initially drained patients through the totally excised tube port. These 4-5 cm incisions are used for inserting the telescope and the working instruments into the cavity. General anesthesia is used only for the first session, because more extensive surgery might be required. Thoracic epidural via catheter with preserved self-ventilation is the anesthesia for the remaining sessions and for postoperative pain relief. We never put a tube drain into pleural cavity and the last is closed with soft tissues interrupting suturing. Parenteral antibiotics started preoperatively is continued until discharge.   Results:  PPE was successfully treated in all patients after three sessions. The mean hospital stay was 10 days. The long-term functional and cosmetic results were excellent.   Conclusions:  Although our modification is based on a limited clinical experience we believe that it might be a valuable approach for PPE patients without a bronchopleural fistula. It is minimally invasive, well tolerated, anesthesia-sparing and no pleural tube drainage used.