tbuckley/cabot-search huggingface dataset:
Aurora-A Kinase Regulates Telomerase Activity through c-Myc in Human Ovarian and Breast Epithelial Cells
Authors: Hua Yang, Chien Chen Ou, Richard I. Feldman, Santo V. Nicosia, Patricia A. Kruk, Jin Q. Cheng
Journal: Cancer Research (2004)

Abstract Aurora-A kinase is frequently overexpressed/activated in human ovarian and breast cancers. A rat mammary tumor model study indicates that alterations of Aurora-A are early events during mammary tumor development (T. M. Goepfert et al., Cancer Res., 62: 4115–4122, 2002), suggesting that Aurora-A plays a pivotal role in transformation. However, the molecular mechanism by which Aurora-A induces ovarian and breast cell transformation remains elusive. Here we show that ectopic expression of Aurora-A induces telomerase activity in human ovarian and breast epithelial cell lines HIOSE118 and MCF-10A. The mRNA and promoter activities of human telomerase reverse transcriptase (hTERT) are stimulated by Aurora-A. Furthermore, we have demonstrated that the c-Myc binding sites of hTERT promoter are required for Aurora-A-induced hTERT promoter activity. Ectopic expression of Aurora-A up-regulates c-Myc. Knockdown of c-Myc by RNA interference attenuates Aurora-A-stimulated hTERT expression and telomerase activity. To our knowledge, these findings demonstrate, for the first time, that Aurora-A induces telomerase activity and hTERT by up-regulation of c-Myc and provides an additional mechanism for the role of Aurora-A in malignant transformation in addition to its cell cycle control.
TRAIL sensitize MDR cells to MDR-related drugs by down-regulation of P-glycoprotein through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases
Authors: Suk-Bin Seo, Jung-Gu Hur, Mi-Ju Kim, Jae-Won Lee, Hak-Bong Kim, Jae-Ho Bae, Dong-Wan Kim, Chi-Dug Kang, Sun-Hee Kim
Journal: Molecular Cancer (2010)

Abstract Background The development of new modulator possessing high efficacy, low toxicity and high selectivity is a pivotal approach to overcome P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in cancer treatment. In this study, we suggest a new molecular mechanism that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) down-regulates P-glycoprotein (P-gp) through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases and thereby sensitize MDR cells to MDR-related drugs. Results MDR variants, CEM/VLB 10-2 , CEM/VLB 55-8 and CEM/VLB 100 cells, with gradually increased levels of P-gp derived from human lymphoblastic leukemia CEM cells, were gradually more susceptible to TRAIL-induced apoptosis and cytotoxicity than parental CEM cells. The P-gp level of MDR variants was positively correlated with the levels of DNA-PKcs, pAkt, pGSK-3β and c-Myc as well as DR5 and negatively correlated with the level of c-FLIPs. Hypersensitivity of CEM/VLB 100 cells to TRAIL was accompanied by the activation of mitochondrial apoptotic pathway as well as the activation of initiator caspases. In addition, TRAIL-induced down-regulation of DNA-PKcs/Akt/GSK-3β pathway and c-FLIP and up-regulation of cell surface expression of death receptors were associated with the increased susceptibility to TRAIL of MDR cells. Moreover, TRAIL inhibited P-gp efflux function via caspase-3-dependent degradation of P-gp as well as DNA-PKcs and subsequently sensitized MDR cells to MDR-related drugs such as vinblastine and doxorubicin. We also found that suppression of DNA-PKcs by siRNA enhanced the susceptibility of MDR cells to vincristine as well as TRAIL via down-regulation of c-FLIP and P-gp expression and up-regulation of DR5. Conclusion This study showed for the first time that the MDR variant of CEM cells was hypersensitive to TRAIL due to up-regulation of DR5 and concomitant down-regulation of c-FLIP, and degradation of P-gp and DNA-PKcs by activation of caspase-3 might be important determinants of TRAIL-induced sensitization of MDR cells to MDR-related drugs. Therefore, combination of TRAIL and chemotherapeutic drugs may be a good strategy for treatment of cancer with multidrug resistance.
Colors as explainers?
Authors: Andrew Botterell
Journal: Behavioral and Brain Sciences (2003)

Byrne &amp; Hilbert (B&amp;H) argue that colors are reflectance properties of objects. They also claim that a necessary condition for something's being a color is that it causally explain – or be causally implicated in the explanation of – our perceptions of color. I argue that these two positions are in conflict.
The etiology of severe anemia in a village and a periurban area in Mali
Authors: Alassane Dicko, Amy D. Klion, Mahamadou A. Théra, Issaka Sagara, Daniel Yalcouyé, Mohamed B. Niambele, Moussa Sogoba, Guimogo Dolo, Adama Dao, Dapa A. Diallo, Ogobara K. Doumbo, Louis H. Miller
Journal: Blood (2004)
Estimated Glomerular Filtration Rate and Urinary Albumin Excretion Are Independently Associated with Greater Arterial Stiffness
Authors: Marc M.H. Hermans, Ronald Henry, Jacqueline M. Dekker, Jeroen P. Kooman, Piet J. Kostense, Giel Nijpels, Robert J. Heine, Coen D.A. Stehouwer
Journal: Journal of the American Society of Nephrology (2007)

Mild renal insufficiency is a risk factor for cardiovascular disease (CVD). Both a decline in GFR and (micro)albuminuria are associated with greater cardiovascular mortality. In ESRD, arterial stiffness, an important cause of CVD, is known to be greater, but few data exist in individuals with mild renal insufficiency or microalbuminuria. This study investigated the association of impaired renal function expressed as lower GFR or greater urinary albumin excretion with arterial stiffness. In a population-based study in 806 individuals (402 men), mean age 68 yr (range 50 to 87), peripheral arterial stiffness (by compliance and distensibility of the carotid, brachial, and femoral arteries and by the carotid elastic modulus [E(inc)]) and central arterial stiffness (by total systemic arterial compliance, carotid-femoral transit time, and aortic augmentation index) were measured ultrasonically. GFR was estimated (eGFR) by the Modification of Diet in Renal Disease (MDRD) formula. Urinary albumin excretion was expressed as urinary albumin/creatinine ratio (UACR). eGFR was 60.6 +/- 11.1 ml/min per 1.73 m(2). Median UACR was 0.57 mg/mmol (range 0.1 to 26.6). After adjustment for age, mean arterial pressure (MAP), gender, and glucose tolerance status (GTS), each 5-ml/min per 1.73 m(2) lower eGFR was associated with a lower distensibility coefficient of the carotid (regression coefficient beta -0.20 10(-3)/kPa; 95% confidence interval [CI] -0.34 to -0.07 10(-3)/kPa) and brachial artery (-0.15 10(-3)/kPa; 95% CI -0.28 to -0.03 10(-3)/kPa) and a greater carotid E(inc) (0.02 kPa; 95% CI 0.0004 to 0.04 kPa). No statistically significant association was found of eGFR with other arterial stiffness indices. After adjustment for age, MAP, gender, and GTS, a greater UACR (per quartile) was associated with a greater E(inc) (0.03 kPa; 95% CI 0.001 to 0.07 kPa) and a trend to a lower distensibility coefficient (-0.24 10(-3)/kPa; 95% CI -0.49 to 0.02 10(-3)/kPa) of the carotid artery. After adjustment for age, MAP, gender, and GTS, a greater UACR (per quartile) was in addition associated with a shorter carotid-femoral transit time (-1.67 ms; 95% CI -3.24 to -0.10 ms). These associations were not substantially changed by mutual adjustment for eGFR and UACR. In individuals with mild renal insufficiency, both a lower eGFR and a greater albumin excretion, even below levels that are considered to reflect microalbuminuria, are independently associated with greater arterial stiffness. Moreover, these associations were mutually independent. These findings may explain, in part, why eGFR and microalbuminuria are associated with greater risk for CVD and suggest that amelioration of arterial stiffness could be a target of intervention.
Marrow-Derived Stromal Cells Express Genes Encoding a Broad Spectrum of Arteriogenic Cytokines and Promote In Vitro and In Vivo Arteriogenesis Through Paracrine Mechanisms
Authors: T. Kinnaird, E. Stabile, M.S. Burnett, C.W. Lee, S. Barr, S. Fuchs, S.E. Epstein
Journal: Circulation Research (2004)

We recently demonstrated that marrow stromal cells (MSCs) augment collateral remodeling through release of several cytokines such as VEGF and bFGF rather than via cell incorporation into new or remodeling vessels. The present study was designed to characterize the full spectrum of cytokine genes expressed by MSCs and to further examine the role of paracrine mechanisms that underpin their therapeutic potential. Normal human MSCs were cultured under normoxic or hypoxic conditions for 72 hours. The gene expression profile of the cells was determined using Affymetrix GeneChips representing 12 000 genes. A wide array of arteriogenic cytokine genes were expressed at baseline, and several were induced &gt;1.5-fold by hypoxic stress. The gene array data were confirmed using ELISA assays and immunoblotting of the MSC conditioned media (MSC CM ). MSC CM promoted in vitro proliferation and migration of endothelial cells in a dose-dependent manner; anti-VEGF and anti-FGF antibodies only partially attenuated these effects. Similarly, MSC CM promoted smooth muscle cell proliferation and migration in a dose-dependent manner. Using a murine hindlimb ischemia model, murine MSC CM enhanced collateral flow recovery and remodeling, improved limb function, reduced the incidence of autoamputation, and attenuated muscle atrophy compared with control media. These data indicate that paracrine signaling is an important mediator of bone marrow cell therapy in tissue ischemia, and that cell incorporation into vessels is not a prerequisite for their effects.
Soluble triggering receptor expressed on myeloid cells-1 in acute respiratory infections
Authors: J. Phua, E. S. C. Koay, D. Zhang, L. K. Tai, X. L. Boo, K. C. Lim, T. K. Lim
Journal: European Respiratory Journal (2006)

Levels of the soluble form of the triggering receptor expressed on myeloid cells (sTREM)-1 are elevated in severe sepsis. However, it is not known whether sTREM-1 measurements can distinguish milder bacterial infections from noninfectious inflammation. The present authors studied whether serum sTREM-1 levels differ in community-acquired pneumonia, exacerbations of chronic obstructive pulmonary disease (COPD), asthma and controls, and whether sTREM-1 may be used as a surrogate marker for the need for antibiotics. Serum sTREM-1 levels in 150 patients with pneumonia, COPD and asthma exacerbations and 62 healthy controls were measured. Serum sTREM-1 levels were significantly elevated in pneumonia (median 295.2 ng·mL -1 ), COPD (280.3 ng·mL -1 ) and asthma exacerbations (184.0 ng·mL -1 ) compared with controls (83.1 ng·mL -1 ). Levels were higher in pneumonia and Anthonisen type 1 COPD exacerbations than in type 2 and 3 COPD and asthma exacerbations. The area under the receiver operating characteristics curve for sTREM-1 as a surrogate marker for the need for antibiotics was 0.77. Serum levels of the soluble form of the triggering receptor expressed on myeloid cells-1 were elevated predominantly in pneumonia and Anthonisen type 1 COPD exacerbations versus type 2 and 3 chronic obstructive pulmonary disease exacerbations, asthma and controls. Serum levels of the soluble form of the triggering receptor expressed on myeloid cells-1 has moderate but insufficient accuracy as a surrogate marker for the need for antibiotics in lower respiratory tract infections.
Three-Dimensional Imaging Reveals Ureteric and Mesenchymal Defects in Fgfr2-Mutant Kidneys
Authors: Sunder Sims-Lucas, Christos Argyropoulos, Kayle Kish, Kirk McHugh, John F. Bertram, Raymond Quigley, Carlton M. Bates
Journal: Journal of the American Society of Nephrology (2009)

Current techniques to morphologically characterize the processes of nephrogenesis and ureteric branching during kidney development have many limitations. Here, we used in vivo three-dimensional analysis to study renal development in mice lacking fibroblast growth factor receptor 2 in the ureteric bud (Fgfr2(UB-/-)) and in littermate controls. We found that Fgfr2(UB-/-) mice have more severe defects in ureteric branching morphogenesis than previously reported, including significantly fewer branches and tips than control mice. Furthermore, these mice had decreased ureteric volume and surface area and longer ureteric segments than control mice. We also observed previously unrecognized abnormalities in nephrogenesis, including a gradual increase in volume and surface area during maturation from renal vesicles to mature nephrons, in the mutant mice. Finally, we quantified many events of normal renal development that are either difficult or impossible to measure without this three-dimensional technique. In summary, the three-dimensional approach is a powerful and quantitative means to characterize branching morphogenesis and nephrogenesis.
Adenocarcinoma of The Kidney. IV. Electron Microscopic Study of the Development of Renal Adenocarcinomas Induced in Rats by N-(4′-Fluoro-4-biphenylyl)acetamide234
Authors: Jane H. Dees, Barry M. Heatfield, Benjamin F. Trump
Journal: JNCI Journal of the National Cancer Institute (1980)

Ultrastructural features of various stages in the histogenesis of renal adenocarcinoma induced in F344 rats by the carcinogen N-(4'-fluoro-4-biphenylyl)acetamide (FBPA) are described. FBPA was added to the diet up to 48 weeks; animals were killed at intervals from 4 to 52 weeks. Characterized were foci of cellular alterations followed by foci of proliferation with dysplasia leading to solid and cystic lesions, carcinoma in situ, and finally, carcinoma. Other lesions included foam cell nodules. Alterations also were noted in distal tubules. By electron microscopy, subtle changes in some proximal tubule cells of the pars recta were noted by 4 weeks (foci of cellular alteration). By 12 weeks there was evidence of dedifferentiation and reduction of cell polarity, thickening of basal lamina, alterations in endoplasmic reticulum and mitochondria, and increases in residual bodies. Nuclei of these cells possessed large nucleoli. From 24 to 36 weeks foci of proliferation were seen and consisted of tumor cells arranged in solid and cystic configurations. In solid lesions (less than 3 mm), in addition to the above alterations, cells showed a microvillus brush border in unusual locations, small and irregular mitochondria, multiple Golgi complexes and basal lamina, and loss of cell polarity. From 36 to 52 weeks carcinoma in situ consisted of cells similar to tumor cells described above. In addition, intracellular canaliculi were present. Areas of tumor cell degeneration and necrosis also were seen. Cells of larger carcinomas (greater than 3 mm), also observed at this interval, were identical to those of carcinoma in situ. Calcification of necrotic debris was noted.
Web: The sum of my parts
Authors: C. Weijer
Journal: BMJ (2000)

Charles Weijer reviews the website www.medicineonline.com, where cosmetic surgeons bid for customers

I worry of late that I am not as good looking as I used to be. I stopped exercising about a year ago after a move into the country. The bucolic setting disagrees with me. This week I turn 36 years old. But these aren't the bases for my complaint. The problem is that time has treated me more cruelly than similarly situated others. The rest of my birth cohort seems filled with vim and vigour. I, on the other hand, am fleshy, pallid, and prone to fits of profuse perspiration. This year I vow to do something about it.

My first stop is my general practitioner, the best doctor I have ever had. “Stewart,” I say, “this is the year I do it; tell me where I should start.” He reminds me of visits around this date in the past three years, when he talked me out of trying Prozac (1997), Viagra (1998), and an all-protein diet (1999). “I am …
Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial
Authors: RA Nout, VTHBM Smit, H Putter, IM Jürgenliemk-Schulz, JJ Jobsen, LCHW Lutgens, EM van der Steen-Banasik, JWM Mens, A Slot, MC Stenfert Kroese, BNFM van Bunningen, AC Ansink, WLJ van Putten, CL Creutzberg
Journal: The Lancet (2010)
Clinical guidelines on the management of hepatitis C
Authors: J C L Booth
Journal: Gut (2001)

<h3>Objectives:</h3> The diameters of the vertebral arteries (VAs) are very often unequal. Therefore, this study investigated if unequal VA flow contributes to the development of basilar artery (BA) curvature and if it is a link to the laterality of pontine or cerebellar infarcts occurring around the vertebrobasilar junction. <h3>Methods:</h3> Radiological factors were analysed (infarct laterality, VA dominance, BA curvature and their directional relationships) in 91 patients with acute unilateral pontine or posterior inferior cerebellar artery (PICA) territory infarcts. The “dominant” VA side was defined as either that the VA was larger in diameter or the VA was connected with the BA in more of a straight line, if both VAs looked similar in diameter on CT angiography. Multiple regression analysis was performed to predict moderate to severe BA curvature. <h3>Results:</h3> The dominant VA was more frequent on the left side (p&lt;0.01). Most patients had an opposite directional relationship between the dominant VA and BA curvature (p&lt;0.01). Pontine infarcts were opposite to the side of BA curvature (p&lt;0.01) and PICA infarcts were on the same side as the non-dominant VA side (p&lt;0.01). The difference in VA diameters was the single independent predictor for moderate to severe BA curvature (OR per 1 mm, 2.70; 95% CI 1.22 to 5.98). <h3>Conclusions:</h3> Unequal VA flow is an important haemodynamic contributor of BA curvature and development of peri-vertebrobasilar junctional infarcts.
A Novel, Selective, and Efficacious Nanomolar Pyridopyrazinone Inhibitor of V600EBRAF
Authors: Steven Whittaker, Delphine Ménard, Ruth Kirk, Lesley Ogilvie, Douglas Hedley, Alfonso Zambon, Filipa Lopes, Natasha Preece, Helen Manne, Sareena Rana, Maryou Lambros, Jorge S. Reis-Filho, Richard Marais, Caroline J. Springer
Journal: Cancer Research (2010)

Abstract Oncogenic BRAF is a critical driver of proliferation and survival and is thus a validated therapeutic target in cancer. We have developed a potent inhibitor, termed 1t (CCT239065), of the mutant protein kinase, V600EBRAF. 1t inhibits signaling downstream of V600EBRAF in cancer cells, blocking DNA synthesis, and inhibiting proliferation. Importantly, we show that 1t is considerably more selective for mutated BRAF cancer cell lines compared with wild-type BRAF lines. The inhibitor is well tolerated in mice and exhibits excellent oral bioavailability (F = 71%). Suppression of V600EBRAF-mediated signaling in human tumor xenografts was observed following oral administration of a single dose of 1t. As expected, the growth rate in vivo of a wild-type BRAF human tumor xenograft model is unaffected by inhibitor 1t. In contrast, 1t elicits significant therapeutic responses in mutant BRAF–driven human melanoma xenografts. Cancer Res; 70(20); 8036–44. ©2010 AACR.
Divergent functions of angiotensin II receptor isoforms in the brain
Authors: Robin L. Davisson, Michael I. Oliverio, Thomas M. Coffman, Curt D. Sigmund
Journal: Journal of Clinical Investigation (2000)

The renin-angiotensin system (RAS) plays a critical role in cardiovascular and fluid homeostasis. The major biologically active peptide of the RAS is angiotensin II, which acts through G protein-coupled receptors of two pharmacological classes, AT(1) and AT(2). AT(1) receptors, expressed in brain and peripheral tissues, mediate most classically recognized actions of the RAS, including blood pressure homeostasis and regulation of drinking and water balance. In rodents, two highly homologous AT(1) receptor isoforms, termed AT(1A) and AT(1B) receptors, are expressed at different levels in major forebrain cardiovascular and fluid regulatory centers, with AT(1A) expression generally exceeding AT(1B) expression, but the relative contributions of these receptor subtypes to central angiotensin II responses are not known. We used gene targeting in combination with a unique system for maintaining catheters in the cerebral ventricles of conscious mice to test whether there are differential roles for AT(1A) and AT(1B) receptors in responses elicited by angiotensin II in the brain. Here we show that the blood pressure increase elicited by centrally administered angiotensin II can be selectively ascribed to the AT(1A) receptor. However, the drinking response requires the presence of AT(1B) receptors. To our knowledge, this is the first demonstration of a primary and nonredundant physiological function for AT(1B) receptors.
Coordinated Redistribution of Leukocyte LFA-1 and Endothelial Cell ICAM-1 Accompany Neutrophil Transmigration
Authors: Sunil K. Shaw, Shuo Ma, Michael B. Kim, Ravi M. Rao, Charles U. Hartman, Richard M. Froio, Lin Yang, Todd Jones, Yuan Liu, Asma Nusrat, Charles A. Parkos, F. William Luscinskas
Journal: The Journal of Experimental Medicine (2004)

The leukocyte integrin lymphocyte function-associated antigen 1 (LFA-1) and its endothelial ligand intercellular adhesion molecule (ICAM)-1 play an important role in transmigration as demonstrated by in vivo and in vitro models of inflammation. Despite the prominent role, little is known concerning the distribution and dynamic behavior of these adhesion molecules during leukocyte transmigration. Therefore, we examined the spatial and temporal distribution of LFA-1 on neutrophils actively transmigrating tumor necrosis factor-α–activated human umbilical vein endothelial monolayers under shear flow. Upon neutrophil arrest, LFA-1 was evenly distributed. However, once neutrophils initiated transmigration, LFA-1 rapidly redistributed to form a ringlike cluster at the neutrophil–endothelial junctional interface through which transmigration occurred. As transmigration was completed, LFA-1 redistributed to the neutrophil uropod. Endothelial ICAM-1 and JAM-A both colocalized with the ringlike LFA-1 cluster. Further analysis of PMA-stimulated neutrophils, which increase mobility of LFA-1, showed a rapid redistribution of LFA-1 and ICAM-1, but not endothelial JAM-A. Thus, endothelial JAM-A does not appear to contribute to adhesion or transmigration in this system. This is the first demonstration that neutrophil LFA-1 rapidly redistributes to form a ringlike structure that coclusters with endothelial ICAM-1 as the neutrophil transmigrates.
Our experience in home mechanical ventilation
Authors: Vesna Bukumirovic, Zorica Stevic, Vladimir Zugic, Branka Bulajic-Subotic, Miodrag Vukcevic
Journal: European Respiratory Journal (2012)

Home mechanical ventilation (HMV) increases survival of patients with chronic respiratory failure. National center in Serbia for HMV in neuromuscular patients was established in 2007.   Aim : We aimed to evaluate our practice   Method . We retrospectively analyzed clinical history of patients receiving HMV in our center from 2007-2012.   Results : 126 patients were started on HMV (71 M /55 F) mean age 46±20 years.  Most of the patients were treated with non invasive ventilation. Twelve percent of patients were ventilated invasively via tracheostomy. Three patients were converted from invasive to noninvasive ventilation. Most frequent diagnosis was motor neuron disease (MND) 78, mean FCV% 33±15, followed by Duchenne Muscular dystrophy (DMD) 33, mean FCV% 16,6±8,7 and spinal muscular atrophy (SMA) 15. Overall survival was 59% of patients. In MND group, mean survival was10 months, and all dystrophy patients are still in follow up.   Conclusion:  In our country HMV in last years is increasingly used but its prevalence is still low compared with other countries.