tbuckley/cabot-search huggingface dataset:
Randomized Trial and Pharmacokinetic Study of Pegfilgrastim versus Filgrastim after Dose-Intensive Chemotherapy in Young Adults and Children with Sarcomas
Authors: Elizabeth Fox, Brigitte C. Widemann, Douglas S. Hawkins, Nalini Jayaprakash, Ramzi Dagher, Alberta A. Aikin, Donna Bernstein, Lauren Long, Crystal Mackall, Lee Helman, Seth M. Steinberg, Frank M. Balis
Journal: Clinical Cancer Research (2009)

To compare the effectiveness, tolerance, and pharmacokinetics of a single dose of pegfilgrastim to daily filgrastim in children and young adults with sarcomas treated with dose-intensive combination chemotherapy.Patients were randomized to receive a single dose of 100 mcg/kg of pegfilgrastim s.c. or 5 mcg/kg/day of filgrastim s.c., daily until neutrophil recovery after two treatment cycles with vincristine, doxorubicin, and cyclophosphamide (VDC) and two cycles of etoposide and ifosfamide (IE). The duration of severe neutropenia (absolute neutrophil count, < or =500/mcL) during cycles 1 to 4 and cycle duration for all cycles were compared. Pharmacokinetics of pegfilgrastim and filgrastim and CD34+ stem cell mobilization were studied on cycle 1. Growth factor-related toxicity, transfusions, and episodes of fever and neutropenia and infections were collected for cycles 1 to 4.Thirty-four patients (median age, 20 years; range 3.8-25.8) were enrolled, and 32 completed cycles 1 to 4. The median (range) duration of absolute neutrophil count of <500/mcL was 5.5 (3-8) days for pegfilgrastim and 6 (0-9) days for filgrastim (P = 0.76) after VDC, and 1.5 (0-4) days for pegfilgrastim and 3.75 (0-6.5) days for filgrastim (P = 0.11) after IE. More episodes of febrile neutropenia and documented infections occurred on the filgrastim arm. Serum pegfilgrastim concentrations were highly variable. Pegfilgrastim apparent clearance (11 mL/h/kg) was similar to that reported in adults.A single dose per cycle of pegfilgrastim was well tolerated and may be as effective as daily filgrastim based on the duration of severe neutropenia and number of episodes of febrile neutropenia and documented infections after dose-intensive treatment with VDC and IE.
RNA Interference–Mediated Silencing of the <i>Acetyl-CoA-Carboxylase-α</i> Gene Induces Growth Inhibition and Apoptosis of Prostate Cancer Cells
Authors: Koen Brusselmans, Ellen De Schrijver, Guido Verhoeven, Johannes V. Swinnen
Journal: Cancer Research (2005)

Abstract Overexpression of lipogenic enzymes is a common characteristic of many cancers. Thus far, studies aimed at the exploration of lipogenic enzymes as targets for cancer intervention have focused on fatty acid synthase (FAS), the enzyme catalyzing the terminal steps in fatty acid synthesis. Chemical inhibition or RNA interference (RNAi)–mediated knockdown of FAS consistently inhibits the growth and induces death of cancer cells. Accumulation of the FAS substrate malonyl-CoA has been implicated in the mechanism of cytotoxicity of FAS inhibition. Here, using RNAi technology, we have knocked down the expression of acetyl-CoA carboxylase-α (ACC-α), the enzyme providing the malonyl-CoA substrate. Silencing of the ACC-α gene resulted in a similar inhibition of cell proliferation and induction of caspase-mediated apoptosis of highly lipogenic LNCaP prostate cancer cells as observed after FAS RNAi. In nonmalignant cells with low lipogenic activity, no cytotoxic effects of knockdown of ACC-α or FAS were observed. These findings indicate that accumulation of malonyl-CoA is not a prerequisite for cytotoxicity induced by inhibition of tumor-associated lipogenesis and suggest that in addition to FAS, ACC-α is a potential target for cancer intervention.
The management of abdominal aortic aneurysms
Authors: D. Metcalfe, P. J. E. Holt, M. M. Thompson
Journal: BMJ (2011)

#### Summary points

An abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta greater than 3 cm in diameter (fig 1⇓). The natural course is one of progressive enlargement, and maximum aortic diameter is the strongest predictor of aneurysm rupture.1 w1 w2 The reported incidence of AAA is 4.9-9.9%,2 3 4 and mortality after rupture exceeds 80%, accounting for 8000 deaths annually in the United Kingdom.5 w3 Elective surgical repair has an operative mortality of 1-5% in the best centres,5 6 and several countries have implemented population screening programmes to reduce aneurysm related mortality.



Fig 1 Preoperative computed tomography reconstruction of a 7.4 cm infrarenal abdominal aortic aneurysm 



This review considers the epidemiology and management of AAA using evidence from population studies, randomised controlled trials, meta-analyses, and published guidelines.

#### Sources and selection criteria

We searched PubMed for “abdominal aortic aneurysm” or “AAA” and used reference lists to identify key studies. We also consulted the Cochrane Library and consensus guidelines. The evidence base informing management of abdominal aortic aneurysms is relatively strong and we gave priority to large well designed randomised controlled trials, …
GPs rarely use interventions for weight management in obese and overweight patients, study finds
Authors: S. Mayor
Journal: BMJ (2015)

Most obese and overweight patients are not offered weight management interventions by their GPs, an analysis of electronic patient records from UK practices has shown. The study found that very low rates of advice, referrals, or use of obesity drugs were recorded.

Researchers analysed the anonymised data for 91 413 adult patients with a body mass index of ≥25 kg/m2 recorded between 2005 and 2012.1 They were randomly selected from the Clinical Practice …
Trends in the Aggressiveness of End-of-Life Cancer Care in the Universal Health Care System of Ontario, Canada
Authors: Thi H. Ho, Lisa Barbera, Refik Saskin, Hong Lu, Bridget A. Neville, Craig C. Earle
Journal: Journal of Clinical Oncology (2011)

Purpose To describe trends in the aggressiveness of end-of-life (EOL) cancer care in a universal health care system in Ontario, Canada, between 1993 and 2004, and to compare with findings reported in the United States. Methods A population-based, retrospective, cohort study that used administrative data linked to registry data. Aggressiveness of EOL care was defined as the occurrence of at least one of the following indicators: last dose of chemotherapy received within 14 days of death; more than one emergency department (ED) visit within 30 days of death; more than one hospitalization within 30 days of death; or at least one intensive care unit (ICU) admission within 30 days of death. Results Among 227,161 patients, 22.4% experienced at least one incident of potentially aggressive EOL cancer care. Multivariable analyses showed that with each successive year, patients were significantly more likely to encounter some aggressive intervention (odds ratio, 1.01; 95% CI, 1.01 to 1.02). Multiple emergency department (ED) visits, ICU admissions, and chemotherapy use increased significantly over time, whereas multiple hospital admissions declined (P &lt; .05). Patients were more likely to receive aggressive EOL care if they were men, were younger, lived in rural regions, had a higher level of comorbidity, or had breast, lung, or hematologic malignancies. Chemotherapy and ICU utilization were lower in Ontario than in the United States. Conclusion Aggressiveness of cancer care near the EOL is increasing over time in Ontario, Canada, although overall rates were lower than in the United States. Health system characteristics and patient or physician cultural factors may play a role in the observed differences.
Genome-Wide Association Study in Esophageal Cancer Using GeneChip Mapping 10K Array
Authors: Nan Hu, Chaoyu Wang, Ying Hu, Howard H. Yang, Carol Giffen, Ze-Zhong Tang, Xiao-Yu Han, Alisa M. Goldstein, Michael R. Emmert-Buck, Kenneth H. Buetow, Philip R. Taylor, Maxwell P. Lee
Journal: Cancer Research (2005)

Abstract Whole genome association studies of complex human diseases represent a new paradigm in the postgenomic era. In this study, we report application of the Affymetrix, Inc. (Santa Clara, CA) high-density single nucleotide polymorphism (SNP) array containing 11,555 SNPs in a pilot case-control study of esophageal squamous cell carcinoma (ESCC) that included the analysis of germ line samples from 50 ESCC patients and 50 matched controls. The average genotyping call rate for the 100 samples analyzed was 96%. Using the generalized linear model (GLM) with adjustment for potential confounders and multiple comparisons, we identified 37 SNPs associated with disease, assuming a recessive mode of transmission; similarly, 48 SNPs were identified assuming a dominant mode and 53 SNPs in a continuous mode. When the 37 SNPs identified from the GLM recessive mode were used in a principal components analysis, the first principal component correctly predicted 46 of 50 cases and 47 of 50 controls. Among all the SNPs selected from GLMs for the three modes of transmission, 39 could be mapped to 1 of 33 genes. Many of these genes are involved in various cancers, including GASC1, shown previously to be amplified in ESCCs, and EPHB1 and PIK3C3. In conclusion, we have shown the feasibility of the Affymetrix 10K SNP array in genome-wide association studies of common cancers and identified new candidate loci to study in ESCC.
Continuous positive airway pressure reduces daytime sleepiness in mild to moderate obstructive sleep apnoea: a meta-analysis
Authors: N S Marshall
Journal: Thorax (2006)

<b>Background:</b> Obstructive sleep apnoea syndrome (OSAS) affects an estimated 2–4% of the middle aged population. Meta-analyses of randomised controlled trials have shown that the severe presentation of the syndrome (apnoea hypopnoea index (AHI) &gt;30/hour) is effectively treated with continuous positive airway pressure (CPAP). Until recently there have been insufficient data to determine whether CPAP improves sleepiness in the larger subgroup with mild to moderate OSAS (AHI 5–30/hour). <b>Methods:</b> A systematic search of Medline and a hand search identified seven randomised controlled trials where CPAP was compared with either a placebo or with conservative management in the treatment of mild to moderate OSAS (AHI 5–30/hour). All trials used the Epworth Sleepiness Scale (ESS), four used the Multiple Sleep Latency Test (MSLT), and three used the Maintenance of Wakefulness Test (MWT) to measure sleepiness. <b>Results:</b> Meta-analyses indicated that CPAP significantly reduced subjective daytime sleepiness (ESS) by 1.2 points (95% CI 0.5 to 1.9, p = 0.001), improved objective daytime wakefulness (MWT) by 2.1 minutes (95% CI 0.5 to 3.7, p = 0.011), but did not affect objective daytime sleepiness (MSLT, mean benefit −0.2 minutes, 95% CI −1.0 to 0.6, p = 0.6). The two significant effects were small (effect size &lt;0.30). <b>Conclusions:</b> CPAP elicits small improvements in subjective sleepiness and objective wakefulness in people with mild to moderate OSAS. However, the effects on sleepiness are of limited clinical significance.
Hypertension and Renal Dysfunction
Authors: Camille A. Jones
Journal: Journal of the American Society of Nephrology (2003)

The incidence rate of end-stage renal disease has increased in many countries in the past 20 yr, including the United States and Singapore. The increase in ESRD incidence in the United States is primarily attributable to diabetes and to hypertension. In Singapore the major cause of ESRD is diabetes, however the prevalence of hypertension in the Singapore population is rising rapidly, and renal complications of hypertension may become more common in the future. Information on the association of hypertension with renal dysfunction and ESRD in the United States may be useful in predicting future trends in the incidence of ESRD due to hypertension in Singapore. This paper describes published and unpublished data presented at a conference to assist in developing plans for a comprehensive renal disease prevention program in Singapore. It compares recent data on the reported prevalence of hypertension in the United States and Singapore; and presents information on the association of hypertension with serum creatinine, urinary albumin excretion, and ESRD in the United States.
A decoy receptor 3 analogue reduces localised defects in phagocyte function in pneumococcal pneumonia
Authors: Helen M Marriott, Marc Daigneault, Alfred A R Thompson, Sarah R Walmsley, Sharonjit K Gill, Derrick R Witcher, Victor J Wroblewski, Paul G Hellewell, Moira K B Whyte, David H Dockrell
Journal: Thorax (2012)

<h3>Background</h3> Therapeutic strategies to modulate the host response to bacterial pneumonia are needed to improve outcomes during community-acquired pneumonia. This study used mice with impaired Fas signalling to examine susceptibility to pneumococcal pneumonia and decoy receptor 3 analogue (DcR3-a) to correct factors associated with increased susceptibility. <h3>Methods</h3> Wild-type mice and those with varying degrees of impairment of Fas (<i>lpr</i>) or Fas ligand signalling (<i>gld</i>) were challenged with <i>Streptococcus pneumoniae</i> and microbiological and immunological outcomes measured in the presence or absence of DcR3-a. <h3>Results</h3> During established pneumonia, neutrophils became the predominant cell in the airway and <i>gld</i> mice were less able to clear bacteria from the lungs, demonstrating localised impairment of pulmonary neutrophil function in comparison to <i>lpr</i> or wild-type mice. T-cells from <i>gld</i> mice had enhanced activation and reduced apoptosis in comparison to wild-type and <i>lpr</i> mice during established pneumonia. Treatment with DcR3-a reduced T-cell activation and corrected the defect in pulmonary bacterial clearance in <i>gld</i> mice. <h3>Conclusions</h3> The results suggest that imbalance in tumour necrosis factor superfamily signalling and excessive T-cell activation can impair bacterial clearance in the lung but that DcR3-a treatment can reduce T-cell activation, restore optimal pulmonary neutrophil function and enhance bacterial clearance during <i>S pneumoniae</i> infection.
PI3K–mTORC2 but not PI3K–mTORC1 Regulates Transcription of HIF2A/EPAS1 and Vascularization in Neuroblastoma
Authors: Sofie Mohlin, Arash Hamidian, Kristoffer von Stedingk, Esther Bridges, Caroline Wigerup, Daniel Bexell, Sven Påhlman
Journal: Cancer Research (2015)

Abstract Hypoxia-inducible factor (HIF) is a master regulator of cellular responses to oxygen deprival with a critical role in mediating the angiogenic switch in solid tumors. Differential expression of the HIF subunits HIF1α and HIF2α occurs in many human tumor types, suggesting selective implications to biologic context. For example, high expression of HIF2α that occurs in neuroblastoma is associated with stem cell–like features, disseminated disease, and poor clinical outcomes, suggesting pivotal significance for HIF2 control in neuroblastoma biology. In this study, we provide novel insights into how HIF2α expression is transcriptionally controlled by hypoxia and how this control is abrogated by inhibition of insulin-like growth factor-1R/INSR-driven phosphoinositide 3-kinase (PI3K) signaling. Reducing PI3K activity was sufficient to decrease HIF2α mRNA and protein expression in a manner with smaller and less vascularized tumors in vivo. PI3K-regulated HIF2A mRNA expression was independent of Akt or mTORC1 signaling but relied upon mTORC2 signaling. HIF2A mRNA was induced by hypoxia in neuroblastoma cells isolated from metastatic patient–derived tumor xenografts, where HIF2A levels could be reduced by treatment with PI3K and mTORC2 inhibitors. Our results suggest that targeting PI3K and mTORC2 in aggressive neuroblastomas with an immature phenotype may improve therapeutic efficacy. Cancer Res; 75(21); 4617–28. ©2015 AACR.
A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation
Authors: Prakash C. Viswanathan, D. Woodrow Benson, Jeffrey R. Balser
Journal: Journal of Clinical Investigation (2003)

Our understanding of the genetic basis of disease has expanded with the identification of rare DNA sequence variations (“mutations”) that evoke inherited syndromes such as cystic fibrosis, congenital epilepsy, and cardiac arrhythmias. Common sequence variants (“polymorphisms”) have also been implicated as risk factors in multiple diseases. Mutations in SCN5A, the cardiac Na+ channel gene, that cause a reduction in Na+ current may evoke severe, life-threatening disturbances in cardiac rhythm (i.e., Brugada syndrome), isolated cardiac conduction disease, or combinations of these disorders. Conduction disease is manifest clinically as heart rate slowing (bradycardia), syncope, or “lightheadedness”. Recent electrophysiologic studies reveal that mutations in particular families exhibiting cardiac conduction disease cause marked effects on several competing voltage-dependent gating processes, but nonetheless cause a mild “net” reduction in Na+ current. Here we show that a common SCN5A polymorphism (H558R) in the Na+ channel I-II interdomain cytoplasmic linker, present in 20% of the population, can mitigate the in vitro effects of a nearby mutation (T512I) on Na+ channel function. The mutation and the polymorphism were both found in the same allele of a child with isolated conduction disease, suggesting a direct functional association between a polymorphism and a mutation in the same gene.
Low retinol levels differentially modulate bile salt-induced expression of human and mouse hepatic bile salt transporters
Authors: Martijn O. Hoeke, Jacqueline R.M. Plass, Janette Heegsma, Mariska Geuken, Duncan van Rijsbergen, Julius F.W. Baller, Folkert Kuipers, Han Moshage, Peter L.M. Jansen, Klaas Nico Faber
Journal: Hepatology (2008)

The farnesoid X receptor/retinoid X receptor-alpha (FXR/RXRalpha) complex regulates bile salt homeostasis, in part by modulating transcription of the bile salt export pump (BSEP/ABCB11) and small heterodimer partner (SHP/NR0B2). FXR is activated by bile salts, RXRalpha by the vitamin A derivative 9-cis retinoic acid (9cRA). Cholestasis is associated with vitamin A malabsorption. Therefore, we evaluated the role of vitamin A/9cRA in the expression of human and mouse bile salt export pump (hBSEP/mBsep), small heterodimer partner (hSHP/mShp), and mouse sodium-dependent taurocholate co-transporting polypeptide (mNtcp). HBSEP and hSHP transcription were analyzed in FXR/RXRalpha-transfected HepG2 cells exposed to chenodeoxycholic acid (CDCA) and/or 9cRA. BSEP promoter activity was determined by luciferase reporter assays, DNA-binding of FXR and RXRalpha by pull-down assays. Serum bile salt levels and hepatic expression of Bsep, Shp, and Ntcp were determined in vitamin A-deficient (VAD)/cholic acid (CA)-fed C57BL/6J mice. Results indicated that 9cRA strongly repressed the CDCA-induced BSEP transcription in HepG2 cells, whereas it super-induced SHP transcription; 9cRA reduced DNA-binding of FXR and RXRalpha. The 9cRA repressed the CDCA-induced BSEP promoter activity irrespective of the exact sequence of the FXR-binding site. In vivo, highest Bsep messenger RNA (mRNA), and protein expression was observed in CA-fed VAD mice. Shp transcription was highest in CA-fed vitamin A-sufficient mice. Ntcp protein expression was strongly reduced in CA-fed VAD mice, whereas mRNA levels were normal. CA-fed control and VAD mice had similarly increased serum bile salt levels.We showed that 9cRA has opposite effects on bile salt-activated transcription of FXR/RXRalpha target genes. Vitamin A deficiency in CA-fed mice leads to high BSEP expression. Clearance of serum bile salts may, however, be limited because of post-transcriptional reduction of Ntcp. The molecular effects of vitamin A supplementation during cholestasis need further analysis to predict a therapeutic effect.
PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis
Authors: Xuehui Hong, Ruipeng Song, Huiwen Song, Tongsen Zheng, Jiabei Wang, Yingjian Liang, Shuyi Qi, Zhaoyang Lu, Xuan Song, Hongchi Jiang, Lianxin Liu, Zhiyong Zhang
Journal: Gut (2013)

<h3>Background</h3> Mounting epidemiological evidence supports a role for phosphatase and tensin homologue (PTEN)-T cell leukaemia 1 (Tcl1) signalling deregulation in hepatocarcinogenesis. <h3>Objective</h3> To determine the molecular and biochemical mechanisms by which the PTEN/Tcl1 axis regulates the pentose phosphate pathway (PPP) in hepatocellular carcinoma (HCC). <h3>Methods</h3> We compared levels of PTEN and glucose-6-phosphate dehydrogenase (G6PD) mRNA in human HCC and healthy liver tissue. We measured PPP flux, glucose consumption, lactate production, nicotinamide adenine dinucleotide phosphate (NADPH) levels and lipid accumulation. We investigated the PTEN/Tcl1 axis using molecular biology, biochemistry and mass spectrometry analysis. We assessed proliferation, apoptosis and senescence in cultured cells, and tumour formation in mice. <h3>Results</h3> We showed that PTEN inhibited the PPP pathway in human liver tumours. Through the PPP, PTEN suppressed glucose consumption and biosynthesis. Mechanistically, the PTEN protein bound to G6PD, the first and rate-limiting enzyme of the PPP and prevented the formation of the active G6PD dimer. Tcl1, a coactivator for Akt, reversed the effects of PTEN on biosynthesis. Tcl1 promoted G6PD activity and also increased G6PD pre-mRNA splicing and protein expression in a heterogeneous nuclear ribonucleoprotein (hnRNPK)-dependent manner. PTEN also formed a complex with hnRNPK, which inhibited G6PD pre-mRNA splicing. Moreover, PTEN inactivated Tcl1 via glycogen synthase kinase-3β (GSK3β)-mediated phosphorylation. Importantly, Tcl1 knockdown enhanced the sensitivity of HCC to sorafenib, whereas G6PD knockdown inhibited hepatocarcinogenesis. <h3>Conclusions</h3> These results establish the counteraction between PTEN and Tcl1 as a key mechanism that regulates the PPP and suggest that targeting the PTEN/Tcl1/hnRNPK/G6PD axis could open up possibilities for therapeutic intervention and improve the prognosis of patients with HCC.