tbuckley/cabot-search huggingface dataset:
Sphingosine Kinase-1 as a Chemotherapy Sensor in Prostate Adenocarcinoma Cell and Mouse Models
Authors: Dimitri Pchejetski, Muriel Golzio, Elisabeth Bonhoure, Cyril Calvet, Nicolas Doumerc, Virginie Garcia, Catherine Mazerolles, Pascal Rischmann, Justin Teissié, Bernard Malavaud, Olivier Cuvillier
Journal: Cancer Research (2005)

Abstract Systemic chemotherapy was considered of modest efficacy in prostate cancer until the recent introduction of taxanes. We took advantage of the known differential effect of camptothecin and docetaxel on human PC-3 and LNCaP prostate cancer cells to determine their effect on sphingosine kinase-1 (SphK1) activity and subsequent ceramide/sphingosine 1-phosphate (S1P) balance in relation with cell survival. In vitro, docetaxel and camptothecin induced strong inhibition of SphK1 and elevation of the ceramide/S1P ratio only in cell lines sensitive to these drugs. SphK1 overexpression in both cell lines impaired the efficacy of chemotherapy by decreasing the ceramide/S1P ratio. Alternatively, silencing SphK1 by RNA interference or pharmacologic inhibition induced apoptosis coupled with ceramide elevation and loss of S1P. The differential effect of both chemotherapeutics was confirmed in an orthotopic PC-3/green fluorescent protein model established in nude mice. Docetaxel induced a stronger SphK1 inhibition and ceramide/S1P ratio elevation than camptothecin. This was accompanied by a smaller tumor volume and the reduced occurrence and number of metastases. SphK1-overexpressing PC-3 cells implanted in animals developed remarkably larger tumors and resistance to docetaxel treatment. These results provide the first in vivo demonstration of SphK1 as a sensor of chemotherapy. (Cancer Res 2005; 65(24): 11667-75)
Usefulness of MS-MLPA for detection of MGMT promoter methylation in the evaluation of pseudoprogression in glioblastoma patients
Authors: C.-K. Park, J. Kim, S. Y. Yim, A. R. Lee, J. H. Han, C.-Y. Kim, S.-H. Park, T. M. Kim, S.-H. Lee, S. H. Choi, S.-K. Kim, D. G. Kim, H.-W. Jung
Journal: Neuro-Oncology (2010)

Pseudoprogression is a major diagnostic dilemma in current treatment protocols for malignant gliomas that involve concurrent chemoradiotherapy. We hypothesized that methylation-specific multiplex ligation probe amplification (MS-MLPA), an assay that permits semiquantitative evaluation of promoter methylation, may be used to diagnose pseudoprogression based on the quantification of the methylation status of the O(6)-methylguanine DNA methyltransferase (MGMT) promoter. We examined the methylation ratio of the MGMT promoter with MS-MLPA in 48 samples from glioblastoma patients. The results were compared with those from methylation-specific polymerase chain reaction (MSP), and protein levels were confirmed by immunohistochemical staining. We then evaluated the correlation between those molecular signatures and clinical outcomes. With regard to radiological progression after chemoradiotherapy, the diagnostic accuracy of the MS-MLPA method was 80% (using a cut-off value of 0.2). These results are better than those obtained with MSP (diagnostic accuracy of 68%). Combining the MS-MLPA and MSP methods resulted in a diagnostic accuracy of 93% for the identification of pseudoprogression among patients to whom these results were coherent. These results demonstrate that MS-MLPA is a useful method to predict radiological progression vs pseudoprogression in glioblastoma patients and that the interpretation of these results in combination with MSP results will provide good practical guidelines for clinical decision making in glioblastoma treatment.
Resource implications and health benefits of primary prevention strategies for cardiovascular disease in people aged 30 to 74: mathematical modelling study
Authors: T. Marshall
Journal: BMJ (2002)

To develop a model to determine resource costs and health benefits of implementing guidelines for the prevention of cardiovascular disease in primary care.Modelling of data from six strategies for prevention of cardiovascular disease. Strategies incorporated two ways of identifying patients for assessment: traditional (assessment of all adults) and novel (preselection of patients for assessment using a prior estimate of their risk of cardiovascular disease). Three treatment strategies were modelled in conjunction with each identification strategy.England.Patients aged 30 to 74 eligible for primary prevention strategies for cardiovascular disease who were selected from a hypothetical population of 2000.Resource costs of assessing eligible adults, providing treatment and follow up to those eligible, and number of cardiovascular events this should prevent.Novel strategies prevented more cardiovascular disease, at lower cost, than traditional strategies. Some treatment strategies prevent more cardiovascular disease with fewer resources than others. The findings were robust across a range of different assumptions about workload.Preselecting patients for assessment makes better use of staff time than assessing all adults. Treating many patients with low cost drugs is more efficient than prescribing a few patients intensive antihypertensives and statins. Authors of guidelines should model workload implications and health benefits of following their recommendations.
Clinical Features, Cognitive Biases, and Treatment of Body Dysmorphic Disorder
Authors: Angela Fang, Sabine Wilhelm
Journal: Annual Review of Clinical Psychology (2015)

In the past two decades, research advances have enhanced our understanding of the clinical features, cognitive biases, and treatment of body dysmorphic disorder (BDD). In this review, we critically examine the current state of the evidence on the proposed cognitive and emotional processing mechanisms of BDD. We describe how major findings in these areas made unique contributions to the development of an empirically informed cognitive-behavioral model of BDD, which in turn facilitated the translation of research to treatment strategies. Finally, we outline important areas of future research.
Sports-specific fitness testing in squash.
Authors: K Steininger, R E Wodick
Journal: British Journal of Sports Medicine (1987)

Maximum oxygen uptake and the running speed at the anaerobic threshold were determined during treadmill running. Performance in these laboratory tests and performance on a squash-specific field test were compared and examined with respect to subjective ratings of squash fitness. The field test was performed in a squash court. Six light bulbs were connected to a programming device causing individual bulbs to light up in a given sequence. The players were instructed to react to the flashes by running towards and striking balloons mounted in the vicinity of the bulbs. By altering the interval between the lighting of the bulbs the intensity of exercise could be varied. The test consisted of a series of 3 min periods of exercise at increasing intensities (increased number of runs per unit of time). The results showed a low correlation (r = 0.52) between treadmill ergometry data and a rank-order list based on an independent, partly subjective estimate of fitness. A higher correlation (r = 0.90) was found for the results of the field test and the rank-order list. Maximum oxygen uptake values and anaerobic threshold values derived from laboratory measurements were thus not sufficient for a valid estimate of competition fitness in these players. The results show that a valid estimate of fitness can be derived from measurements involving exercise closely resembling that which is specific for the sports activity in question. Improved training advice and guidance may result from such studies.
2-Deoxy-ATP Enhances Contractility of Rat Cardiac Muscle
Authors: M. Regnier, A. J. Rivera, Y. Chen, P. B. Chase
Journal: Circulation Research (2000)

Abstract —To investigate the kinetic parameters of the crossbridge cycle that regulate force and shortening in cardiac muscle, we compared the mechanical properties of cardiac trabeculae with either ATP or 2-deoxy-ATP (dATP) as the substrate for contraction. Comparisons were made in trabeculae from untreated rats (predominantly V1 myosin) and those treated with propylthiouracil (PTU; V3 myosin). Steady-state hydrolytic activity of cardiac heavy meromyosin (HMM) showed that PTU treatment resulted in &gt;40% reduction of ATPase activity. dATPase activity was &gt;50% elevated above ATPase activity in HMM from both untreated and PTU-treated rats. V max of actin-activated hydrolytic activity was also &gt;50% greater with dATP, whereas the K m for dATP was similar to that for ATP. This indicates that dATP increased the rate of crossbridge cycling in cardiac muscle. Increases in hydrolytic activity were paralleled by increases of 30% to 80% in isometric force (F max ), rate of tension redevelopment ( k tr ), and unloaded shortening velocity ( V u ) in trabeculae from both untreated and PTU-treated rats (at maximal Ca 2+ activation), and F-actin sliding speed in an in vitro motility assay ( V f ). These results contrast with the effect of dATP in rabbit psoas and soleus fibers, where F max is unchanged even though k tr , V u , and V f are increased. The substantial enhancement of mechanical performance with dATP in cardiac muscle suggests that it may be a better substrate for contractility than ATP and warrants exploration of ribonucleotide reductase as a target for therapy in heart failure.
X-ray aspects in treatment of destructive tuberculosis with valve lung volume reduction
Authors: Nikolay Yakushenko, Pavel Gavrilov, Ludmila Archakova, Marina Kondakova, Petr Yablonskiy
Journal: European Respiratory Journal (2013)

Valval lung volume reduction (VLVR) in treatment of destructive lung tuberculosis (DLTB) is rather effective (A. Levin, 2009; Y.Tseimakh, 2010; N.Yakushenko, 2012). The effectiveness hesitates from 67,7% to 90,5%. Now there are no accurate radiological criteria in selection of patients for VLVR.  The aim – development of radiological criteria in selection of patients for VLVR.  Material: 30 patients aged from 18 to 65 with DLTB. Data of lung CT-scans before the valve installation, in 2 and 6 months after is analysed. Location of destructions in lung segments: S1, S2 - 19(63,3%); S3 - 3(10,0%); S6 - 8(26,7%). Pleural adhesions are revealed in 25 (83,3%) cases.  Results: In 2 months full atelectasis of blocked zone was reached in 8 cases, partial – in 4.By 6 months closing of destruction was reached in 19(63,3%) cases. S3-cavities were closed in 100,0% (3) cases, S1, S2 – in 63,2%(12), and in S6 50,0%(4) filling and cavity reduction with tuberculoma forming was noted. Closing of destructive cavities in C6 with formation of a cicatrix wasn’t noted. In the presence of radiological signs of atelectasis (full or partial) in 2 months closing of destructions with formation of a cicatrix was registered in 83,3% (10). Only in 9(50,0%) cases without atelectasis signs closing of cavity is noted, of which 7(77,8%,)with tuberculoma forming. Pleural adhesion and pulmonary tissue fibrosis didn9t influence atelectasis formation.  Conclusions:Radiological signs of atelectasis in 2 months allow to predict high VLVR effectiveness. VLVR of upper lobe processes is significantly more effective than of lower lobe(P
Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease
Authors: Scott Ayton, Peng Lei, Paul A Adlard, Irene Volitakis, Robert A Cherny, Ashley I Bush, David I Finkelstein
Journal: Molecular Neurodegeneration (2014)

The substantia nigra (SN) midbrain nucleus is constitutively iron rich. Iron levels elevate further with age, and pathologically in Parkinson's disease (PD). Iron accumulation in PD SN involves dysfunction of ceruloplasmin (CP), which normally promotes iron export. We previously showed that ceruloplasmin knockout (CP KO) mice exhibit Parkinsonian neurodegeneration (~30% nigral loss) by 6 months, which is prevented by iron chelation. Here, we explored whether known iron-stressors of the SN (1) aging and (2) MPTP, would exaggerate the lesion severity of CP KO mice. We show that while 5 month old CP KO mice exhibited nigral iron elevation and loss of SN neurons, surprisingly, aging CP KO mice to 14 months did not exacerbate iron elevation or SN neuronal loss. Unlike young mice, iron chelation therapy in CP KO mice between 9–14 months did not rescue neuronal loss. MPTP exaggerated iron elevation in young CP KO mice but did not increase cell death when compared to WTs. We conclude that there may exist a proportion of substantia nigra neurons that depend on CP for protection against iron neurotoxicity and could be protected by iron-based therapeutics. Death of the remaining neurons in Parkinson's disease is likely caused by parallel disease mechanisms, which may call for additional therapeutic options.
Collateral damage: the unforeseen effects of emergency outbreak policies
Authors: Sue Lim, Tom Closson, Gillian Howard, Michael Gardam
Journal: The Lancet Infectious Diseases (2004)

SummaryThe 2003 outbreak of severe acute respiratory syndrome took the province of Ontario, Canada, by surprise. A lack of planning and the decentralised nature of the health-care system meant that disruptive control measures had to be put in place to control the outbreak. Several of the control strategies were difficult to implement and resulted in considerable confusion, fear, and costs. We discuss these difficulties and offer suggestions for improving outbreak planning.
Serrated pathway colorectal cancer in the population: genetic consideration
Authors: J. Young, M. Jenkins, S. Parry, B. Young, D. Nancarrow, D. English, G. Giles, J. Jass
Journal: Gut (2007)

A significant proportion of colorectal cancer (CRC) develops through the serrated neoplasia pathway. Such tumours show a distinctive molecular phenotype of somatic <i>BRAF</i> mutations and widespread concordant methylation events in CpG islands (CIMP). These features are also observed in the polyps developing in individuals with hyperplastic polyposis syndrome (HPS). In HPS, multiple serrated polyps develop in the colorectum, and approximately 50% of cases present with at least one CRC. Observations of rare affected sibships including identical twins, suggest a recessive or co-dominant mode of inheritance. In addition, up to 50% of individuals with HPS report a family history of CRC. At a population level, recent work has demonstrated that patients with serrated pathway cancers characterised by <i>BRAF</i> mutation are four times more likely to have a family history of CRC than patients with common CRC. These findings suggest an increased genetic predisposition for serrated pathway CRC in the wider population. We propose that HPS results from the inheritance of two putative co-dominant alleles in approximately 1 in 2000 individuals. Therefore carriers of one co-dominant allele may number up to 1 in 25, and it is likely that these carriers are at increased risk of CRC, accounting for, at least in part, the burden of serrated pathway CRC in the population. This proposition may have important implications for screening and prevention of CRC in individuals who have an increased risk for development of serrated pathway cancers, namely those with multiple, proximal, large or advanced serrated polyps, and their relatives.
Renal Response to Acute Neutral Endopeptidase Inhibition in Mild and Severe Experimental Heart Failure
Authors: Horng H. Chen, John A. Schirger, William L. Chau, Michihisa Jougasaki, Ondrej Lisy, Margaret M. Redfield, Paul T. Barclay, John C. Burnett
Journal: Circulation (1999)

Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is localized in the greatest abundance in the kidney and degrades natriuretic peptides, such as atrial natriuretic peptide (ANP). Mild congestive heart failure (CHF) is characterized by increases in circulating ANP without activation of the renin-angiotensin-aldosterone system (RAAS) or sodium retention. In contrast, severe CHF is characterized by sodium retention and coactivation of both ANP and the RAAS.We defined the acute cardiorenal actions of the NEP inhibitor candoxatrilat (8 microg. kg(-1). min(-1)) in 4 groups of anesthetized dogs (normal, n=8; mild CHF, n=6; severe CHF, n=5; and severe CHF with chronic AT(1) receptor antagonism, n=5). Mild CHF was produced by rapid ventricular pacing at 180 bpm for 10 days and severe CHF at 245 bpm for 10 days. In mild CHF, urinary sodium excretion and glomerular filtration rate were greatest in response to acute NEP inhibition compared with the response in either control animals or those with severe CHF. Furthermore, an increase in glomerular filtration rate was observed only in mild CHF in association with increases in renal blood flow and decreases in renal vascular resistance and distal tubular sodium reabsorption. Urinary ANP and cGMP excretion, markers for renal biological actions of ANP, were greatest in mild CHF. The renal actions observed in mild CHF were attenuated in severe CHF and not restored by chronic AT(1) receptor antagonism.The results of the present study demonstrate that acute NEP inhibition in mild CHF results in marked increases in renal hemodynamics and sodium excretion that exceed that observed in control animals and severe CHF. These studies underscore the potential therapeutic role for NEP inhibition to enhance renal function in mild CHF, an important phase of CHF that is marked by selective activation of endogenous ANP in the absence of an activated RAAS.
Microrna expression signatures predict patient progression and disease outcome in pediatric embryonal central nervous system neoplasms
Authors: Maria Braoudaki, George I Lambrou, Krinio Giannikou, Vasilis Milionis, Kalliopi Stefanaki, Diane K Birks, Neophytos Prodromou, Aggeliki Kolialexi, Antonis Kattamis, Chara A Spiliopoulou, Fotini Tzortzatou-Stathopoulou, Emmanouel Kanavakis
Journal: Journal of Hematology & Oncology (2014)

Although, substantial experimental evidence related to diagnosis and treatment of pediatric central nervous system (CNS) neoplasms have been demonstrated, the understanding of the etiology and pathogenesis of the disease remains scarce. Recent microRNA (miRNA)-based research reveals the involvement of miRNAs in various aspects of CNS development and proposes that they might compose key molecules underlying oncogenesis. The current study evaluated miRNA differential expression detected between pediatric embryonal brain tumors and normal controls to characterize candidate biomarkers related to diagnosis, prognosis and therapy. Overall, 19 embryonal brain tumors; 15 Medulloblastomas (MBs) and 4 Atypical Teratoid/Rabdoid Tumors (AT/RTs) were studied. As controls, 13 samples were used; The First-Choice Human Brain Reference RNA and 12 samples from deceased children who underwent autopsy and were not present with any brain malignancy. RNA extraction was carried out using the Trizol method, whilst miRNA extraction was performed with the mirVANA miRNA isolation kit. The experimental approach included miRNA microarrays covering 1211 miRNAs. Quantitative Real-Time Polymerase Chain Reaction was performed to validate the expression profiles of miR-34a and miR-601 in all 32 samples initially screened with miRNA microarrays and in an additional independent cohort of 30 patients (21MBs and 9 AT/RTs). Moreover, meta-analyses was performed in total 27 embryonal tumor samples; 19 MBs, 8 ATRTs and 121 control samples. Twelve germinomas were also used as an independent validation cohort. All deregulated miRNAs were correlated to patients’ clinical characteristics and pathological measures. In several cases, there was a positive correlation between individual miRNA expression levels and laboratory or clinical characteristics. Based on that, miR-601 could serve as a putative tumor suppressor gene, whilst miR-34a as an oncogene. In general, miR-34a demonstrated oncogenic roles in all pediatric embryonal CNS neoplasms studied. Deeper understanding of the aberrant miRNA expression in pediatric embryonal brain tumors might aid in the development of tumor-specific miRNA signatures, which could potentially afford promising biomarkers related to diagnosis, prognosis and patient targeted therapy.
A case of a laboratory animal feed with high estrogenic activity and its impact on in vivo responses to exogenously administered estrogens.
Authors: H Boettger-Tong, L Murthy, C Chiappetta, J L Kirkland, B Goodwin, H Adlercreutz, G M Stancel, S Mäkelä
Journal: Environmental Health Perspectives (1998)

We recently noted that immature rats failed to exhibit a normal uterine response to exogenously administered estradiol as assessed by both biochemical (induction of gene expression) and morphological (altered uterine and vaginal histology and size) end points. An initial analysis suggested that this was due to a high degree of estrogenization from a dietary source which was producing a near maximal uterotrophic response prior to hormone treatment. Subsequent chemical analysis indicated that the feed in question contained high amounts of two well-known phytoestrogens, genistein (210 mg/kg) and daidzen (14 mg/kg), and the lot of feed in question produced a large uterotrophic effect when fed to immature ovariectomized rats. These findings illustrate that, despite increased awareness of phytoestrogens, some batches of animal feed contain very high amounts of estrogenic components which have marked effects on in vivo end points of hormone action. These observations have important implications for both basic research and screening methods that utilize in vivo approaches.