tbuckley/cabot-search huggingface dataset:
Characteristics of Dasatinib- and Imatinib-Resistant Chronic Myelogenous Leukemia Cells
Authors: Seiichi Okabe, Tetsuzo Tauchi, Kazuma Ohyashiki
Journal: Clinical Cancer Research (2008)

Although dual src-family kinase/BCR/ABL inhibitor, dasatinib (BMS-354825), provides therapeutic advantages to imatinib-resistant cells, the mechanism of dasatinib resistance was not fully known.We used TF-1 BCR/ABL cells, by introducing the BCR/ABL gene into a leukemia cell line, TF-1 and K562, and established dasatinib- (BMS-R) and imatinib-resistant (IM-R) cells. We characterized chronic myelogenous leukemia drug-resistant cells and examined intracellular signaling.The IC(50) of dasatinib was 0.75 nmol/L (TF-1 BCR/ABL), 1 nmol/L (K562), 7.5 nmol/L (TF-1 BCR/ABL IM-R), 10 nmol/L (K562 IM-R), 15 micromol/L (TF-1 BCR/ABL BMS-R), and 25 micromol/L (K562 BMS-R). The number of BCR/ABL copies in resistant cell lines was the same as the parental cell line by fluorescence in situ hybridization analysis. There was no mutation in Abl kinase. We found that protein levels of BCR/ABL were reduced in dasatinib-resistant cell lines. BCR/ABL protein was increased by treatment of an ubiquitin inhibitor. The Src kinase, Lck, as well as mitogen-activated protein kinase and Akt were activated, but p21(WAF), phosphatase and tensin homologue was reduced in K562 BMS-R cells. Removal of dasatinib from the culture medium of K562 BMS-R cells led to apoptosis, and activated caspase 3 and poly (ADP-ribose) polymerase.These results suggest that the expression and protein activation signatures identified in this study provide insight into the mechanism of resistance to dasatinib and imatinib and may be of therapeutic chronic myelogenous leukemia value clinically.
Molecular Staging of Intracranial Ependymoma in Children and Adults
Authors: Andrey Korshunov, Hendrik Witt, Thomas Hielscher, Axel Benner, Marc Remke, Marina Ryzhova, Till Milde, Sebastian Bender, Andrea Wittmann, Anna Schöttler, Andreas E. Kulozik, Olaf Witt, Andreas von Deimling, Peter Lichter, Stefan Pfister
Journal: Journal of Clinical Oncology (2010)

The biologic behavior of intracranial ependymoma is unpredictable on the basis of current staging approaches. We aimed at the identification of recurrent genetic aberrations in ependymoma and evaluated their prognostic significance to develop a molecular staging system that could complement current classification criteria.As a screening cohort, we studied a cohort of 122 patients with ependymoma before standardized therapy by using array-based comparative genomic hybridization. DNA copy-number aberrations identified as possible prognostic markers were validated in an independent cohort of 170 patients with ependymoma by fluorescence in situ hybridization analysis. Copy-number aberrations were correlated with clinical, histopathologic, and survival data.In the screening cohort, age at diagnosis, gain of 1q, and homozygous deletion of CDKN2A comprised the most powerful independent indicators of unfavorable prognosis. In contrast, gains of chromosomes 9, 15q, and 18 and loss of chromosome 6 were associated with excellent survival. On the basis of these findings, we developed a molecular staging system comprised of three genetic risk groups, which was then confirmed in the validation cohort. Likelihood ratio tests and multivariate Cox regression also demonstrated the clear improvement in predictive accuracy after the addition of these novel genetic markers.Genomic aberrations in ependymomas are powerful independent markers of disease progression and survival. By adding genetic markers to established clinical and histopathologic variables, outcome prediction can potentially be improved. Because the analyses can be conducted on routine paraffin-embedded material, it will now be possible to prospectively validate these markers in multicenter clinical trials on population-based cohorts.
Non-African Populations of Drosophila melanogaster Have a Unique Origin
Authors: Emmanuelle Baudry, Barbara Viginier, Michel Veuille
Journal: Molecular Biology and Evolution (2004)

Drosophila melanogaster is widely used as a model in DNA variation studies. Patterns of polymorphism have, however, been affected by the history of this species, which is thought to have recently spread out of Africa to the rest of the world. We analyzed DNA sequence variation in 11 populations, including four continental African and seven non-African samples (including Madagascar), at four independent X-linked loci. Variation patterns at all four loci followed neutral expectations in all African populations, but departed from it in all non-African ones due to a marked haplotype dimorphism at three out of four loci. We also found that all non-African populations show the same major haplotypes, though in various frequencies. A parsimonious explanation for these observations is that all non-African populations are derived from a single ancestral population having undergone a substantial reduction of polymorphism, probably through a bottleneck. Less likely alternatives involve either selection at all four loci simultaneously (including balancing selection at three of them), or admixture between two divergent populations. Small but significant structure was observed among African populations, and there were indications of differentiation across Eurasia for non-African ones. Since population history may result in non-equilibrium variation patterns, our study confirms that the search for footprints of selection in the D. melanogaster genome must include a sufficient understanding of its history.
Agreement between Alternative Classifications of Acute Respiratory Distress Syndrome
Authors: MAUREEN O. MEADE, GORDON H. GUYATT, RICHARD J. COOK, RYAN GROLL, JOHN R. KACHURA, MELANIE WIGG, DEBORAH J. COOK, ARTHUR S. SLUTSKY, THOMAS E. STEWART
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

To examine the agreement between two classifications of acute respiratory distress syndrome (ARDS) that are used interchangeably in clinical practice and clinical research, we classified 118 patients taking part in a randomized trial with respect to the presence of ARDS using the North American–European Consensus Committee (NAECC) and the Lung Injury Severity Score (LISS) criteria. The incidence of ARDS using NAECC criteria was 55.1% (95% confidence interval, 46.1% to 64.1%), and using the LISS criteria 61.9% (95% confidence interval, 53.1% to 70.6%). The p value on the difference between these proportions was 0.07. Raw agreement, chance-corrected agreement (kappa), and chance-independent agreement (phi) on the study occurrence of ARDS using the two classifications were, respectively, 0.73 (95% CI, 0.65 to 0.81), 0.46 (95% CI, 0.32 to 0.61), and 0.63 (95% CI, 0.41 to 0.79). No single component of either index contributed to disagreement to an appreciably greater extent than other components. Baseline characteristics and outcomes were similar among patients who developed ARDS according to either classification. We conclude that NAECC and LISS classifications resulted in similar estimates of the incidence of ARDS in this clinical trial, though patients were frequently classified as having ARDS with only one model. These discordant classifications had no prognostic importance.
Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression.
Authors: J J Letterio, A G Geiser, A B Kulkarni, H Dang, L Kong, T Nakabayashi, C L Mackall, R E Gress, A B Roberts
Journal: Journal of Clinical Investigation (1996)

The progressive inflammatory process found in transforming growth factor beta1 (TGF-beta1)-deficient mice is associated with several manifestations of autoimmunity, including circulating antibodies to nuclear antigens, immune complex deposition, and increased expression of both class I and class II major histocompatibility complex (MHC) antigens. The contribution of MHC class II antigens to the genesis of this phenotype has been determined by crossing the TGF-beta1-null [TGF-beta1(-/-)] genotype into the MHC class II-deficient [MHC-II(-/-)] background. Mice homozygous for both the TGF-beta1 null allele and the class II null allele [TGF-beta1(-/-);MHC-II(-/-)] are without evidence of inflammatory infiltrates, circulating autoantibodies, or glomerular immune complex deposits. Instead, these animals exhibit extensive extramedullary hematopoiesis with progressive splenomegaly and adenopathy, surviving only slightly longer than TGF-beta1(-/-);MHC-II(+/+) mice. The role of CD4+ T cells, which are also absent in MHC class II-deficient mice, is directly demonstrated through the administration of anti-CD4 monoclonal antibodies in class II-positive, TGF-beta1(-/-) mice. The observed reduction in inflammation and improved survival emphasize the significance of CD4+ cells in the pathogenesis of the autoimmune process and suggest that the additional absence of class II antigens in TGF-beta1(-/-);MHC-II(-/-) mice may contribute to their extreme myeloid metaplasia. Thus, MHC class II antigens are essential for the expression of autoimmunity in TGF-beta1-deficient mice, and normally may cooperate with TGF-beta1 to regulate hematopoiesis.
Nutrition, physical activity, and cardiovascular disease: An update
Authors: L IGNARRO, M BALESTRIERI, C NAPOLI
Journal: Cardiovascular Research (2006)

Many epidemiological studies have indicated a protective role for a diet rich in fruits and vegetables against the development and progression of cardiovascular disease (CVD), one of the leading causes of morbidity and mortality worldwide. Physical inactivity and unhealthy eating contribute to these conditions. This article assesses the scientific rationale of benefits of physical activity and good nutrition on CVD, especially on atherosclerosis-related diseases. Compelling evidence has accumulated on the role of oxidative stress in endothelial dysfunction and in the pathogenesis of CVD. Reduced nitric oxide (NO) bioavailability due to oxidative stress seems to be the common molecular disorder comprising stable atherosclerotic narrowing lesions. Energy expenditure of about 1000 kcal (4200 kJ) per week (equivalent to walking 1 h 5 days a week) is associated with significant health benefits. Such benefits can be achieved through structured or nonstructured physical activity, accumulated throughout the day (even through short 10-min bouts) on most days of the week. Some prospective studies showed a direct inverse association between fruit and vegetable intake and the development of CVD incidents such as acute plaque rupture causing unstable angina or myocardial infarction and stroke. Many nutrients and phytochemicals in fruits and vegetables, including fiber, potassium, and folate, could be independently or jointly responsible for the apparent reduction in CVD risk. Novel findings and critical appraisal regarding antioxidants, dietary fibers, omega-3 polyunsaturated fatty acids (n-3 PUFAs), nutraceuticals, vitamins, and minerals, are presented here in support of the current dietary habits together with physical exercise recommendations for prevention and treatment of CVD.
Neonatal Morbidity Among Infants of Diabetic Mothers
Authors: Norman G Soler, Susan M Soler, John M Malins
Journal: Diabetes Care (1978)

While the modern approach to management of diabetic pregnancy has reduced the perinatal mortality significantly, the neonatal morbidity remains high. This study has investigated factors which may account for the persisting high neonatal morbidity when birth trauma has been virtually eliminated and the incidence of respiratory distress syndrome (RDS) considerably reduced. Major congenital malformations emerge not only as the leading cause of perinatal losses but also as an important cause of morbidity. Delivery before 37 weeks increased the incidence of RDS and hypocalcemia, and it is suggested that, when strict metabolic control is used and with the help of facilities to monitor the fetus closely in the last weeks of pregnancy, the number of infants delivered at this early date can be further reduced. The present study also indicates that normoglycemia should also be encouraged on the day of delivery as maternal hyperglycemia at this stage increases the incidence of neonatal hypoglycemia. Jaundice, which very commonly affects newborn infants of diabetic mothers, is influenced by the use of oxytocin for vaginal delivery and by infant overweight (&amp;gt; 90th percentile) at birth, factors which are not beyond control. Finally, route of delivery per se may not be important in relation to neonatal morbidity.
Abstract 3167: Estrogenic regulation of S6 kinase 1 expression creates a positive feed-forward loop in control of breast cancer cell proliferation
Authors: Marina K. Holz, Fannie Seligman, Tirtza Spiegel, Denise Maruani
Journal: Cancer Research (2010)

Abstract The 40S ribosomal S6 kinase 1 (S6K1) acts downstream of the mammalian Target of Rapamycin (mTOR), and is sensitive to inhibition by rapamycin. Chromosomal region 17q23 containing the RPS6KB1 gene is frequently amplified in breast cancer cells, and S6K1 is overexpressed in about 30% of cases. Overexpression of S6K1 correlates with increased rapamycin sensitivity. The role of S6K1 in disease development and progression is supported by the observation that S6K1 overexpression is associated with poor prognosis in breast cancer patients. However, the reason for high-level amplification of the RPS6KB1 gene specifically in breast cancer, and not other cancer types is not well understood. We have previously reported that S6K1 regulates growth of breast cancer cells by phosphorylating Estrogen Receptor α (ERα), and co-expression of S6K1 and ERα in breast cancer cells renders them sensitive to combination therapy with rapamycin and tamoxifen. In this study, we demonstrate that in response to estrogen activation, ERα activates expression of S6K1 by upregulating transcription of the RPS6KB1 gene. Increased levels of S6K1 promote further phosphorylation and activation of ERα, creating a positive feed-forward loop. We hypothesize that this relationship promotes breast cancer cell growth, thus providing a selective advantage to S6K1- and ERα-overexpressing cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3167.
Loading With 600 mg Clopidogrel in Patients With Coronary Artery Disease With and Without Chronic Clopidogrel Therapy
Authors: Adnan Kastrati, Nicolas von Beckerath, Alexander Joost, Gisela Pogatsa-Murray, Olga Gorchakova, Albert Schömig
Journal: Circulation (2004)

Background— It is not known whether further suppression of platelet function can be achieved with clopidogrel beyond that provided by currently recommended loading and maintenance doses. We performed a comparative assessment of the antiplatelet effects of a 600-mg loading dose of clopidogrel given to patients with and without chronic clopidogrel therapy. Methods and Results— Those eligible for this prospective study were aspirin-treated patients with suspected or documented coronary artery disease admitted to hospital for coronary angiography. Two series of 20 consecutive patients each were assessed in this study. The first series included patients who had never received clopidogrel (first-use group); the second series included patients on chronic therapy with a daily dose of 75 mg clopidogrel for ≥1 month (chronic therapy group). Blood samples were drawn before and 6 hours after oral administration of 600 mg clopidogrel for aggregometry and flow cytometry studies. In the first-use group, loading with 600 mg clopidogrel inhibited ADP 5 μmol/L–induced platelet aggregation from 90±9% to 51±19% ( P &lt;0.001). In the chronic therapy group, loading with 600 mg clopidogrel yielded further inhibition of ADP 5 μmol/L–induced platelet aggregation in addition to that achieved by the maintenance dose of 75 mg/d, from 52±14% to 33±12% ( P &lt;0.001). In both groups, 600 mg clopidogrel loading significantly inhibited ADP-induced expression of glycoprotein IIb/IIIa and P-selectin receptors. Conclusions— Further platelet inhibition can be achieved with clopidogrel in addition to that provided by currently recommended loading and maintenance doses. Higher doses may be warranted after assessment of their clinical efficacy and safety.
Transport of sodium and urea in outer medullary descending vasa recta.
Authors: T L Pallone, J Work, R L Myers, R L Jamison
Journal: Journal of Clinical Investigation (1994)

We dissected and perfused outer medullary vasa recta (OMVR) from vascular bundles in the rat. Permeabilities of sodium (PNa) and urea (Pu) were simultaneously determined from the lumen-to-bath efflux of 22Na and [14C]urea. PNa and Pu were also measured by in vivo microperfusion of descending (DVR) and ascending vasa recta (AVR) at the papillary tip of Munich-Wistar rats. In some OMVR PNa was indistinguishable from zero. The mean +/- SE of PNa (x 10(-5), cm/s) in OMVR was 76 +/- 9. Pu in OMVR was always very high (x 10(-5), cm/s), 360 +/- 14. There was no correlation between OMVR PNa and Pu. Inner medullary AVR and DVR had PNa of 115 +/- 10 and 75 +/- 10, respectively, and Pu of 121 +/- 10 and 76 +/- 11, respectively. PNa and Pu in papillary vasa recta were always nearly identical and highly correlated. Transport of [14C] urea in OMVR was reversibly inhibited by addition of unlabeled urea or phloretin to the bath and lumen, providing evidence for carrier-mediated transport. These data suggest that sodium and urea might traverse the wall of inner medullary vasa recta by a paracellular pathway while urea also crosses by a transcellular route in OMVR. Electron microscopic examination of seven in vitro perfused OMVR revealed no fenestrations and exposure of these vessels to 10 microM calcium ionophore A23187 or 1 nM angiotensin II resulted in reversible contraction, suggesting that in vitro perfused OMVR are DVR only.
Percentile Ranking and Citation Impact of a Large Cohort of National Heart, Lung, and Blood Institute–Funded Cardiovascular R01 Grants
Authors: Narasimhan Danthi, Colin O. Wu, Peibei Shi, Michael Lauer
Journal: Circulation Research (2014)

Rationale : Funding decisions for cardiovascular R01 grant applications at the National Heart, Lung, and Blood Institute (NHLBI) largely hinge on percentile rankings. It is not known whether this approach enables the highest impact science. Objective : Our aim was to conduct an observational analysis of percentile rankings and bibliometric outcomes for a contemporary set of funded NHLBI cardiovascular R01 grants. Methods and Results : We identified 1492 investigator-initiated de novo R01 grant applications that were funded between 2001 and 2008 and followed their progress for linked publications and citations to those publications. Our coprimary end points were citations received per million dollars of funding, citations obtained &lt;2 years of publication, and 2-year citations for each grant’s maximally cited paper. In 7654 grant-years of funding that generated $3004 million of total National Institutes of Health awards, the portfolio yielded 16 793 publications that appeared between 2001 and 2012 (median per grant, 8; 25th and 75th percentiles, 4 and 14; range, 0–123), which received 2 224 255 citations (median per grant, 1048; 25th and 75th percentiles, 492 and 1932; range, 0–16 295). We found no association between percentile rankings and citation metrics; the absence of association persisted even after accounting for calendar time, grant duration, number of grants acknowledged per paper, number of authors per paper, early investigator status, human versus nonhuman focus, and institutional funding. An exploratory machine learning analysis suggested that grants with the best percentile rankings did yield more maximally cited papers. Conclusions : In a large cohort of NHLBI-funded cardiovascular R01 grants, we were unable to find a monotonic association between better percentile ranking and higher scientific impact as assessed by citation metrics.
Rectus Transplantation in the Treatment of Ventral Herniae
Authors: H. C. W. Nuttall
Journal: BMJ (1926)

RECTUS TRANSPLANTATION lN VENTRAL HERNIAE.f MAxcU3NAI-.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~s ince the growth arises but rarely when the irritated part is first made anaesthetic.The observations of Sir Lenthal Cheatle4 are more im- portant, since they show the arrest of a malignant process already begun.In some eight of his cases the growth was checked in one direction when the nerve of that part was destroyed by deep malignanrt ulceration.Thus in one case a rodent ulcer, which had invaded the area of the supraorbital nerve, grew no more that way after destruc- tion of the nerve trunk, though growing freely elsewhere.These cases seem decisive.The ulcers were in vigorous growth, their cells proliferating, and their supposed destructive juices in full activity.Yet these juices, whiclh could destroy and digest normal cells, could not, appar- ently, destroy those adjacent cells which differed only in the loss of their nervous connexions.We must, therefore, suppose that malignancy is an attribute, not of the tumour, but of the body excited by the tumour.
Increased levels of osteopontin in sputum supernatant in patients with COPD
Authors: Anastasia Papaporfyriou, Stelios Loukides, Konstantinos Kostikas, Georgios Hillas, Davina Simoes, Elissavet Konstantelou, Spyros Papiris, Nikolaos Koulouris, Petros Bakakos
Journal: European Respiratory Journal (2012)

Background: Osteopontin (OPN) is a glycoprotein that has been associated with inflammation and fibrosis. Recently published data supports that OPN is up-regulated in surgical lung tissue samples of patients with COPD (Schneider F et al FASEB 2010).

Aim: The aim of this study was to determine the levels of OPN in sputum supernatants of patients with COPD, and compare them with healthy subjects and to investigate their possible association with mediators and cells involved in the inflammatory and remodeling process as well as with the extension of emphysema as defined by HRCT.

Methods: Seventy-seven patients with COPD and 40 healthy subjects (20 smokers) were studied. All subjects underwent lung function tests, sputum induction for cell count identification and OPN, TGF-β1, MMP-2, IL-8, LTB4 measurement in sputum supernatants. A HRCT was performed for quantification of emphysema

Measurements and Main results: OPN levels [median (interquartile range) pg/ml] were significantly higher in patients with COPD compared to both healthy smokers and non-smokers [1340 (601-6227) vs 101(77-109) vs 69 (50-89) respectively, p<0.001]. Regression analysis showed a significant association between OPN and sputum neutrophils, IL-8, MMP-2 and the extent of emphysema. The above associations were not observed in healthy subjects.

Conclusions: Our results indicate that OPN levels are higher in patients with COPD compared to both smoking and non-smoking healthy subjects. Moreover, the association of OPN with sputum neutrophils, IL-8 and MMP-2 indicates a role of OPN in neutrophilic inflammation while its association with the extent of emphysema shows a role in the pathogenesis of this particular COPD phenotype.