tbuckley/cabot-search huggingface dataset:
COX-2–Derived Prostacyclin Modulates Vascular Remodeling
Authors: R. Daniel Rudic, Derek Brinster, Yan Cheng, Susanne Fries, Wen-Liang Song, Sandra Austin, Thomas M. Coffman, Garret A. FitzGerald
Journal: Circulation Research (2005)

Suppression of prostacyclin (PGI2) biosynthesis may explain the increased incidence of myocardial infarction and stroke which has been observed in placebo controlled trials of cyclooxygenase (COX)-2 inhibitors. Herein, we examine if COX-2-derived PGI2 might condition the response of the vasculature to sustained physiologic stress in experimental models that retain endothelial integrity. Deletion of the PGI2 receptor (IP) or suppression of PGI2 with the selective COX-2 inhibitor, nimesulide, both augment intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow-induced vascular remodeling. Moreover, nimesulide or IP deletion augments the reduction in blood flow caused by common carotid artery ligation in wild-type mice. Generation of both thromboxane (Tx)A2 and the isoprostane, 8, 12 -iso iPF(2alpha)-VI, are increased in the setting of flow reduction and the latter increases further on administration of nimesulide. Deletion of the TxA2 receptor (TP) reduces the hyperplastic response to nimesulide and carotid ligation, despite further augmentation of TP ligand production. Suppression of COX-2-derived PGI2 or deletion of IP profoundly influences the architectural response of the vasculature to hemodynamic stress. Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of COX-2.
A phase I/II study of plevitrexed with nutritional vitamin supplementation in gastric cancer
Authors: A. Thomas, A. Pluzanska, F. Daniel, M. Marples, S. Falk, R. M. Miller, E. F. Evans
Journal: Journal of Clinical Oncology (2005)

4231 Background: Plevitrexed (Px) is a novel thymidylate synthase inhibitor (TSI) that is taken up via the α-folate receptor as well as the reduced folate carrier, but is non-polyglutamated within the cell, resulting pre-clinically in increased tumor targeting, less development of resistance, and less toxicity to normal tissues than other TSIs. Promising activity was observed in a previous Phase II gastric cancer study however hematological toxicity limited day 8 dosing. Methods: This phase I/II study will recruit cohorts of 10 patients with chemonaïve gastric cancer to 65, 130 and 165 mg/sqm of Px given iv on days 1 and 8 of a 3 week cycle, with nutritional supplementation starting 7 days prior to Px with oral folic acid 400-1000μg daily and vitamin B12 1000μg im every 9 weeks. Px doses were selected based on previous safety and efficacy information. The highest tolerable dose will be expanded to 39 patients based on Simon Optimal Design (α 5%, β 80%) for a minimal response rate of 10% assuming a true response rate of 30%. Results: 10 patients (5 male, 5 female, median age 67, range 44 - 74 years) were treated in cohort 1 at 65 mg/sqm. All patients were able to receive days 1 and 8 in the first cycle. Two patients discontinued treatment after the first cycle due to toxicity: one patient due to prolonged neutropenia, and the other patient due to neutropenic sepsis. Two further patients did not receive the cycle 2 day 8 treatment due to disease progression. The most frequent related adverse events were anorexia, asthenia, diarrhea, nausea and vomiting. One confirmed complete response and one unconfirmed partial response were reported; 3 patients had disease stabilization after two cycles. Conclusions: A preliminary comparison of hematological data with prior data suggests that vitamin supplementation may reduce the degree of leukocytopenia allowing consistent day 8 dosing, retaining activity and allowing an increase in dose-intensity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration BTG International, Fulcrum Pharma Developments Ltd. Fulcrum Pharma PLC
Teenage pregnancy and social disadvantage: systematic review integrating controlled trials and qualitative studies
Authors: A. Harden, G. Brunton, A. Fletcher, A. Oakley
Journal: BMJ (2009)

<b>Objectives</b> To determine the impact on teenage pregnancy of interventions that address the social disadvantage associated with early parenthood and to assess the appropriateness of such interventions for young people in the United Kingdom. <b>Design</b> Systematic review, including a statistical meta-analysis of controlled trials on interventions for early parenthood and a thematic synthesis of qualitative studies that investigated the views on early parenthood of young people living in the UK. <b>Data sources</b> 12 electronic bibliographic databases, five key journals, reference lists of relevant studies, study authors, and experts in the field. <b>Review methods</b> Two independent reviewers assessed the methodological quality of studies and abstracted data. <b>Results</b> Ten controlled trials and five qualitative studies were included. Controlled trials evaluated either early childhood interventions or youth development programmes. The overall pooled effect size showed that teenage pregnancy rates were 39% lower among individuals receiving an intervention than in those receiving standard practice or no intervention (relative risk 0.61; 95% confidence interval 0.48 to 0.77). Three main themes associated with early parenthood emerged from the qualitative studies: dislike of school; poor material circumstances and unhappy childhood; and low expectations for the future. Comparison of these factors related to teenage pregnancy with the content of the programmes used in the controlled trials indicated that both early childhood interventions and youth development programmes are appropriate strategies for reducing unintended teenage pregnancies. The programmes aim to promote engagement with school through learning support, ameliorate unhappy childhood through guidance and social support, and raise aspirations through career development and work experience. However, none of these approaches directly tackles all the societal, community, and family level factors that influence young people's routes to early parenthood. <b>Conclusions</b> A small but reliable evidence base supports the effectiveness and appropriateness of early childhood interventions and youth development programmes for reducing unintended teenage pregnancy. Combining the findings from both controlled trials and qualitative studies provides a strong evidence base for informing effective public policy.
CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to Erlotinib via transcriptional regulation of EGFR
Authors: Yunshan Wang, Pengju Zhang, Ziming Liu, Qin Wang, Mingxin Wen, Yuli Wang, Hongtu Yuan, Jian-Hua Mao, Guangwei Wei
Journal: Molecular Cancer (2014)

CUL4A has been proposed as oncogene in several types of human cancer, but its clinical significance and functional role in human non-small cell lung cancer (NSCLC) remain unclear. Expression level of CUL4A was examined by RT-PCR and Western blot. Forced expression of CUL4A was mediated by retroviruses, and CUL4A silencing by shRNAs expressing lentiviruses. Growth capacity of lung cancer cells was measured by MTT in vitro and tumorigenesis in vivo, respectively. We found that CUL4A was highly expressed in human lung cancer tissues and lung cancer cell lines, and this elevated expression positively correlated with disease progression and prognosis. Overexpression of CUL4A in human lung cancer cell lines increased cell proliferation, inhibited apoptosis, and subsequently conferred resistance to chemotherapy. On other hand, silencing CUL4A expression in NSCLC cells reduced proliferation, promoted apoptosis and resulted in tumor growth inhibition in cancer xenograft model. Mechanistically, we revealed CUL4A regulated EGFR transcriptional expression and activation, and subsequently activated AKT. Targeted inhibition of EGFR activity blocked these CUL4A induced oncogenic activities. Our results highlight the significance of CUL4A in NSCLC and suggest that CUL4A could be a promising therapy target and a potential biomarker for prognosis and EGFR target therapy in NSCLC patients.
T-cell co-stimulatory molecules: novel targets for the treatment of allergic airway disease
Authors: K. C. Beier, T. Kallinich, E. Hamelmann
Journal: European Respiratory Journal (2007)

The first two articles in this series discussed the fundamental concept of T-cell co-stimulation as a key event in the induction of any immune response, in addition to reviewing the current data on the role of co-stimulatory molecules for the induction and progression of allergic airway diseases. Based on these considerations, this final edition will delineate and discuss novel strategies for the prevention and/or therapy of allergic diseases based upon the modulation of co-stimulation.
Down-regulation of p57Kip2 Induces Prostate Cancer in the Mouse
Authors: Ren Jie Jin, Yongsoo Lho, Yongqing Wang, Mingfang Ao, Monica Patricia Revelo, Simon W. Hayward, Marcia L. Wills, Susan K. Logan, Pumin Zhang, Robert J. Matusik
Journal: Cancer Research (2008)

p57(Kip2) has been considered a candidate tumor suppressor gene because of its location in the genome, biochemical activities, and imprinting status. However, little is known about the role of p57(Kip2) in tumorigenesis and cancer progression. Here, we show that the expression of p57(Kip2) is significantly decreased in human prostate cancer, and the overexpression of p57(Kip2) in prostate cancer cells significantly suppressed cell proliferation and reduced invasive ability. In addition, overexpression of p57(Kip2) in LNCaP cells inhibited tumor formation in nude mice, resulting in well-differentiated squamous tumors rather than adenocarcinoma. Furthermore, the prostates of p57(Kip2) knockout mice developed prostatic intraepithelial neoplasia and adenocarcinoma. Remarkably, this mouse prostate cancer is pathologically identical to human prostate adenocarcinoma. Therefore, these results strongly suggest that p57(Kip2) is an important gene in prostate cancer tumorigenesis, and the p57(Kip2) pathway may be a potential target for prostate cancer prevention and therapy.
Hypertension and Progression of Chronic Renal Insufficiency in Children
Authors: Mark Mitsnefes, Ping-Leung Ho, Paul T. McEnery
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Hypertension frequently complicates the course of chronic renal insufficiency (CRI) in children. This study sought to define the role of hypertension in progression of CRI in children by using the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) CRI database. The study cohort consisted of 3834 patients aged 2 to 17 yr with an estimated GFR (eGFR) ≤75 ml/min·1.73 m2 enrolled onto NAPRTCS. The time to end point was defined as the time between registry enrollment and progression to renal substitution therapy or a 10 ml/min·1.73 m2 drop in GFR from baseline, whichever was first. Forty-eight percent of the study patients had hypertension at baseline. There was a significant difference in reaching end points between hypertensive and normotensive children (58% versus 49%, respectively, P < 0.001). Significant difference in outcome between hypertensive and nonhypertensive patients was seen in children with eGFR 50 to 75 ml/min·1.73 m2 (P < 0.001). Multivariate Cox regression modeling demonstrated that systolic hypertension was a significant independent predictor of progression of CRI (P = 0.003). Other significant predictors of CRI progression in this model included older age (P = 0.0001), African American ethnicity (P = 0.03), acquired cause of renal disease (P = 0.0001), and baseline eGFR <50 ml/min·1.73 m2 (P = 0.0001). Hypertension is a highly significant and independent predictor for progression of CRI in children. E-mail: [email protected]
Comparative Performance of Private and Public Healthcare Systems in Low- and Middle-Income Countries: A Systematic Review
Authors: Sanjay Basu, Jason Andrews, Sandeep Kishore, Rajesh Panjabi, David Stuckler
Journal: PLoS Medicine (2012)

Introduction Private sector healthcare delivery in low- and middle-income countries is sometimes argued to be more efficient, accountable, and sustainable than public sector delivery. Conversely, the public sector is often regarded as providing more equitable and evidence-based care. We performed a systematic review of research studies investigating the performance of private and public sector delivery in low- and middle-income countries. Methods and Findings Peer-reviewed studies including case studies, meta-analyses, reviews, and case-control analyses, as well as reports published by non-governmental organizations and international agencies, were systematically collected through large database searches, filtered through methodological inclusion criteria, and organized into six World Health Organization health system themes: accessibility and responsiveness; quality; outcomes; accountability, transparency, and regulation; fairness and equity; and efficiency. Of 1,178 potentially relevant unique citations, data were obtained from 102 articles describing studies conducted in low- and middle-income countries. Comparative cohort and cross-sectional studies suggested that providers in the private sector more frequently violated medical standards of practice and had poorer patient outcomes, but had greater reported timeliness and hospitality to patients. Reported efficiency tended to be lower in the private than in the public sector, resulting in part from perverse incentives for unnecessary testing and treatment. Public sector services experienced more limited availability of equipment, medications, and trained healthcare workers. When the definition of “private sector” included unlicensed and uncertified providers such as drug shop owners, most patients appeared to access care in the private sector; however, when unlicensed healthcare providers were excluded from the analysis, the majority of people accessed public sector care. “Competitive dynamics” for funding appeared between the two sectors, such that public funds and personnel were redirected to private sector development, followed by reductions in public sector service budgets and staff. Conclusions Studies evaluated in this systematic review do not support the claim that the private sector is usually more efficient, accountable, or medically effective than the public sector; however, the public sector appears frequently to lack timeliness and hospitality towards patients. Please see later in the article for the Editors' Summary
Early nutritional changes induce sexually dimorphic long-term effects on body weight gain and the response to sucrose intake in adult rats
Authors: Esther Fuente-Martín, Miriam Granado, Cristina García-Cáceres, Miguel A. Sanchez-Garrido, Laura M. Frago, Manuel Tena-Sempere, Jesús Argente, Julie A. Chowen
Journal: Metabolism (2011)
Maternal Posttraumatic Stress Disorder and Depression in Pediatric Primary Care
Authors: Claude M. Chemtob, Omar G. Gudiño, Danielle Laraque
Journal: JAMA Pediatrics (2013)

Maternal posttraumatic stress disorder (PTSD) may be associated with increased risk for child maltreatment and child exposure to traumatic events. Exposure to multiple traumatic events is associated with a wide range of adverse health and social outcomes in children.To examine the association of probable maternal depression, PTSD, and comorbid PTSD and depression with the risk for child maltreatment and parenting stress and with the number of traumatic events to which preschool children are exposed.Cross-sectional observational design. We used analysis of variance to determine whether probable maternal psychopathology groups differed on child maltreatment, parenting stress, and children's exposure to traumatic events. Hierarchical regression analyses were used to examine the unique and interactive effects of depression and PTSD severity scores on these outcomes.Urban pediatric primary care outpatient clinic.Ninety-seven mothers of children aged 3 to 5 years.Pediatric primary care visit.Probable maternal depression and/or PTSD, parenting stress, child exposure to traumatic events, and child maltreatment.Mothers with probable comorbid PTSD and depression reported greater child-directed psychological aggression and physical assault and greater parenting stress. The children of mothers with PTSD (mean number of events the child was exposed to, 5.0) or with comorbid PTSD and depression (3.5 events) experienced more traumatic events than those of mothers with depression (1.2 events) or neither disorder (1.4 events). Severity of depressive symptoms uniquely predicted physical assault and neglect. Symptom scores for PTSD and depression interacted to predict psychological aggression and child exposure to traumatic events. When PTSD symptom severity scores were high, psychological aggression and the number of traumatic events children experienced rose. Depressive symptom severity scores predicted the risk for psychological aggression and exposure to traumatic events only when PTSD symptom severity scores were low.Children of mothers with PTSD are exposed to more traumatic events. Posttraumatic stress disorder is associated with an increased risk for child maltreatment beyond that associated with depression. Screening and intervention for maternal PTSD, in addition to maternal depression, may increase our ability to reduce children's exposure to traumatic stress and maltreatment.
5-Fluorouracil Incorporated into DNA Is Excised by the Smug1 DNA Glycosylase to Reduce Drug Cytotoxicity
Authors: Qian An, Peter Robins, Tomas Lindahl, Deborah E. Barnes
Journal: Cancer Research (2007)

Abstract 5-Fluorouracil (FU) has been widely used for more than four decades in the treatment of a range of common cancers. The fluorine-substituted uracila analogue is converted to several active metabolites but the mechanism of cytotoxicity has remained unclear. In a widely cited but unsubstantiated model, FU is thought to kill cells via the inhibition of thymidylate synthase and increased use of dUTP in place of TTP during DNA replication, with subsequent excision of high levels of uracil causing the fragmentation of newly synthesized DNA. Using gene-targeted cell lines defective in one or both of the two mammalian uracil-DNA glycosylase repair enzymes, we were able to test this model of FU cytotoxicity. Here, we show that incorporation of FU itself into DNA has been previously underestimated and is a predominant cause of cytotoxicity. FU readily becomes incorporated into the DNA of drug-treated cells, and accumulation of FU in the genome, rather than uracil excision, is correlated with FU cytotoxicity in mammalian cells. Furthermore, the Smug1, but not the Ung, uracil-DNA glycosylase excises FU from DNA and protects against cell killing. The data provides a clearer understanding of the action of FU, suggesting predictive biomarkers of drug response and a mechanism for acquired resistance in tumors. [Cancer Res 2007;67(3):940–5]
Body Composition Is Normal in Term Infants Born to Mothers With Well-Controlled Gestational Diabetes Mellitus
Authors: Cheryl P. Au, Camille H. Raynes-Greenow, Robin M. Turner, Angela E. Carberry, Heather E. Jeffery
Journal: Diabetes Care (2012)

This study aims to describe body composition in term infants of mothers with gestational diabetes mellitus (GDM) compared with infants of mothers with normal glucose tolerance (NGT).This cross-sectional study included 599 term babies born at Royal Prince Alfred Hospital, Sydney, Australia. Neonatal body fat percentage (BF%) was measured within 48 h of birth using air-displacement plethysmography. Glycemic control data were based on third-trimester HbA(1c) levels and self-monitoring blood glucose levels. Associations between GDM status and BF% were investigated using linear regression adjusted for relevant maternal and neonatal variables.Of 599 babies, 67 (11%) were born to mothers with GDM. Mean ± SD neonatal BF% was 7.9 ± 4.5% in infants with GDM and 9.3 ± 4.3% in infants with NGT, and this difference was not statistically significant after adjustment. Good glycemic control was achieved in 90% of mothers with GDM.In this study, neonatal BF% did not differ by maternal GDM status, and this may be attributed to good maternal glycemic control.
Does Preventing Obesity Lead to Reduced Health-Care Costs?
Authors: Klim McPherson
Journal: PLoS Medicine (2008)

In a study in this issue of PLoS Medicine, Pieter van Baal and colleagues used data from The Netherlands to simulate the annual and lifetime medical costs attributable to obesity [1]. They also compared these costs to those attributable to smoking as well as to the medical costs associated with healthy, living persons (defined as non-smokers with a body mass index in the range of 18.5 to less than 25 kg/m2). The researchers explored the question of whether reducing obesity would lead to reduced or increased health-care costs
CLINICAL TRIAL OF A NEW ANTIDEPRESSANT (DESIPRAMINE HYDROCHLORIDE) IN A HOSPITAL SETTING
Authors: ANTHONY LAPOLLA
Journal: American Journal of Psychiatry (1965)

Desipramine, the monomethyl metabolite of imipramine, was used as the basic treatment of 20 patients with severe or moderately severe depression. A fixed dose of 50 mg. q.i.d. was given, and drug effects were evaluated in terms of changes in target symptoms, onset of action and side effects. Complete remission or improvement permitting discharge from hospital was obtained in 14 patients (70%). The time to onset of observable response averaged 2 days, while peak antidepressant action occurred after an average of 5.5 days. Side effects were encountered in one patient and consisted of gastro-intestinal upset, dry mouth and drowsiness. Medication was discontinued in this case. No significant effects on blood pressure, peripheral blood picture, urine or liver function were observed. Desipramine appeared to be an effective and well-tolerated antidepressant similar in its activity to imipramine. With the substantial initial dosage used, the relatively prompt onset of action seems to be the prime advantage of the drug in treating serious depressions.
Intracranial myeloid metaplasia: Diagnosis by CT and Fe52 scans and treatment by cranial irradiation
Authors: Dennis B. Cornfield, Paul Shipkin, Abass Alavi, Joseph Becker, Robert Peyster
Journal: American Journal of Hematology (1983)

Abstract A patient with longstanding agnogenic myeloid metaplasia developed a progressive dementia. CT scanning demonstrated multiple intracranial masses, and a Fe 52 bone marrow scan demonstrated erythroid activity within the masses and confirmed the suspicion of extramedullary hematopoiesis. A potentially hazardous biopsy was avoided, and a course of cranial irradiation was administered, resulting in regression of the masses and clearing of the patient's dementia. Fe 52 scintigraphy provides a specific and useful diagnostic approach which may eliminate the need for invasive procedures.