tbuckley/cabot-search huggingface dataset:
To Eat or to Sleep? Orexin in the Regulation of Feeding and Wakefulness
Authors: Jon T. Willie, Richard M. Chemelli, Christopher M. Sinton, Masashi Yanagisawa
Journal: Annual Review of Neuroscience (2001)

▪ Abstract Orexin-A and orexin-B are neuropeptides originally identified as endogenous ligands for two orphan G-protein–coupled receptors. Orexin neuropeptides (also known as hypocretins) are produced by a small group of neurons in the lateral hypothalamic and perifornical areas, a region classically implicated in the control of mammalian feeding behavior. Orexin neurons project throughout the central nervous system (CNS) to nuclei known to be important in the control of feeding, sleep-wakefulness, neuroendocrine homeostasis, and autonomic regulation. orexin mRNA expression is upregulated by fasting and insulin-induced hypoglycemia. C-fos expression in orexin neurons, an indicator of neuronal activation, is positively correlated with wakefulness and negatively correlated with rapid eye movement (REM) and non-REM sleep states. Intracerebroventricular administration of orexins has been shown to significantly increase food consumption, wakefulness, and locomotor activity in rodent models. Conversely, an orexin receptor antagonist inhibits food consumption. Targeted disruption of the orexin gene in mice produces a syndrome remarkably similar to human and canine narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and other pathological manifestations of the intrusion of REM sleep-related features into wakefulness. Furthermore, orexin knockout mice are hypophagic compared with weight and age-matched littermates, suggesting a role in modulating energy metabolism. These findings suggest that the orexin neuropeptide system plays a significant role in feeding and sleep-wakefulness regulation, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions.
Noninvasive Angiography and Assessment of Left Ventricular Function Using Multislice Computed Tomography in Patients With Type 2 Diabetes
Authors: Joanne D. Schuijf, Jeroen J. Bax, J. Wouter Jukema, Hildo J. Lamb, Hubert W. Vliegen, Liesbeth P. Salm, Albert de Roos, Ernst E. van der Wall
Journal: Diabetes Care (2004)

OBJECTIVE—Early identification of coronary artery disease (CAD) in patients with diabetes is important because these patients are at increased risk for CAD and have worse outcome than nondiabetic patients after CAD is diagnosed. Recently, noninvasive coronary angiography and assessment of left ventricular function has been demonstrated with multislice computed tomography (MSCT). The purpose of the present study was to validate this approach in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—MSCT was performed in 30 patients with confirmed type 2 diabetes. From the MSCT images, coronary artery stenoses (≥50% luminal narrowing) and left ventricular function (left ventricular ejection fraction, regional wall motion) were evaluated and compared with results of conventional angiography and two-dimensional echocardiography. RESULTS—Two hundred twenty of 256 coronary artery segments (86%) were interpretable with MSCT. In these segments, sensitivity and specificity for detection of coronary artery stenoses were 95%. Including the uninterpretable segments, sensitivity and specificity were 81 and 82%, respectively. Bland-Altman analysis in the comparison of left ventricular ejection fractions demonstrated a mean difference of −0.48 ± 3.8% for MSCT and echocardiography, which was not significantly different from 0. Agreement between the two modalities for assessment of regional contractile function was excellent (91%, κ statistic 0.81). CONCLUSIONS—Accurate noninvasive evaluation of both the coronary arteries and left ventricular function with MSCT is feasible in patients with type 2 diabetes. This noninvasive approach may allow optimal identification of high-risk patients.
Indicators of homologous recombination deficiency in breast cancer and association with response to neoadjuvant chemotherapy
Authors: E.H. Lips, L. Mulder, J. Hannemann, N. Laddach, M.T.F.D. Vrancken Peeters, M.J. van de Vijver, J. Wesseling, P.M. Nederlof, S. Rodenhuis
Journal: Annals of Oncology (2010)
Assessment of Ki67 in Breast Cancer: Recommendations from the International Ki67 in Breast Cancer Working Group
Authors: M. Dowsett, T. O. Nielsen, R. A'Hern, J. Bartlett, R. C. Coombes, J. Cuzick, M. Ellis, N. L. Henry, J. C. Hugh, T. Lively, L. McShane, S. Paik, F. Penault-Llorca, L. Prudkin, M. Regan, J. Salter, C. Sotiriou, I. E. Smith, G. Viale, J. A. Zujewski, D. F. Hayes
Journal: JNCI Journal of the National Cancer Institute (2011)

Uncontrolled proliferation is a hallmark of cancer. In breast cancer, immunohistochemical assessment of the proportion of cells staining for the nuclear antigen Ki67 has become the most widely used method for comparing proliferation between tumor samples. Potential uses include prognosis, prediction of relative responsiveness or resistance to chemotherapy or endocrine therapy, estimation of residual risk in patients on standard therapy and as a dynamic biomarker of treatment efficacy in samples taken before, during, and after neoadjuvant therapy, particularly neoadjuvant endocrine therapy. Increasingly, Ki67 is measured in these scenarios for clinical research, including as a primary efficacy endpoint for clinical trials, and sometimes for clinical management. At present, the enormous variation in analytical practice markedly limits the value of Ki67 in each of these contexts. On March 12, 2010, an international panel of investigators with substantial expertise in the assessment of Ki67 and in the development of biomarker guidelines was convened in London by the cochairs of the Breast International Group and North American Breast Cancer Group Biomarker Working Party to consider evidence for potential applications. Comprehensive recommendations on preanalytical and analytical assessment, and interpretation and scoring of Ki67 were formulated based on current evidence. These recommendations are geared toward achieving a harmonized methodology, create greater between-laboratory and between-study comparability, and allow earlier valid applications of this marker in clinical practice.
Estimation of contribution of changes in coronary care to improving survival, event rates, and coronary heart disease mortality across the WHO MONICA Project populations
Authors: Hugh Tunstall-Pedoe, Diego Vanuzzo, Michael Hobbs, Markku Mähönen, Zygimantas Cepaitis, Kari Kuulasmaa, Ulrich Keil
Journal: The Lancet (2000)
Characterization and Fate of Telomerase-expressing Epithelia during Kidney Repair
Authors: Jie Song, Suzanne Czerniak, Teresa Wang, Wendy Ying, Diana L. Carlone, David T. Breault, Benjamin D. Humphreys
Journal: Journal of the American Society of Nephrology (2011)

After acute kidney injury, mice with short telomeres develop increased damage with reduced proliferative capacity, which suggests an important role for telomere length in kidney repair. The enzyme telomerase reverse transcriptase (mTert) regulates telomere length; embryonic stem cells and certain adult stem cells express mTert, but whether cells in the adult kidney express mTert and whether these cells play a role in renal repair are unknown. Here, we found that telomerase protein and mRNA were highly enriched in renal papilla, a proposed niche of kidney stem cells. Using mTert-GFP reporter mice, we detected mTert in a subset of papillary epithelial cells comprising the collecting duct predominantly but also the loop of Henle. Approximately 5% of mTert-GFP(+) cells were label retaining, a characteristic of stem cells. mTert mRNA levels increased in renal papilla after ischemia-reperfusion injury, but genetically labeled mTert-expressing papillary cells neither divided nor migrated out of the renal papilla during kidney repair. In summary, these data suggest that cells expressing telomerase reverse transcriptase are not a progenitor-cell population, and they do not play a direct role in kidney repair.
Moment ratio analysis of multiple breath nitrogen washout in infants with lung disease
Authors: A Schibler, M Schneider, U Frey, R Kraemer
Journal: European Respiratory Journal (2000)

Measurement of lung volumes at end expiratory level and assessment of ventilation inhomogeneity is important for respiratory management in infants with lung disease. This study compared multiple breath nitrogen washout was compared with body plethysmography to measure functional residual capacity in infants and assessed ventilation inhomogeneity using mean dilution numbers and alveolar based gas dilution numbers. Measurements were performed in 23 infants with lung disorders, eleven had wheezing bronchitis, four bronchopulmonary disease, and eight cystic fibrosis. Mean age was 11.2+/-5.8 months. Functional residual capacity of nitrogen washout (29.8+/-11.4 mL x kg(-1)) was significantly (p<0.05) lower than the plethysmographically measured functional residual capacity (40.3+/-11.4 mL x kg(-1)). Tidal volumes before nitrogen washout (90.4+/-35.1 mL) were significantly larger than at the end of the washout (72.2+/-26.9 mL). Alveolar based gas dilution numbers (6.7+/-2.3) were significantly lower (p<0.001) than mean dilution numbers (10+/-5.7). Functional residual capacity determination by nitrogen washout and plethysmography in infants with lung disease showed evidence of air trapping and ventilation inhomogeneity. Ventilation inhomogeneities are best described by alveolar based dilution numbers, since rebreathing of 100% oxygen changes ventilation pattern.
Community diabetes: an East London perspective
Authors: S. V Gelding
Journal: Journal of the Royal Society of Medicine (2005)

The rising prevalence of type 2 diabetes in the UK has necessitated a change in the delivery of diabetes care, with a shift of focus from hospital to community. The National Service Framework for Diabetes has enshrined this approach, and the new General Medical Services (GMS2) contract rewards primary healthcare professionals for developing high-quality diabetes care. New approaches cross the primary/secondary care divide and are patient focused. The evolution of diabetes care in the UK is illustrated by service developments in Newham, East London.
THE CURRENT STATUS OF THE IMPLANTABLE CARDIOVERTER DEFIBRILLATOR
Authors: Anne M. Gillis M.D., FRCPC
Journal: Annual Review of Medicine (1996)

▪ Abstract Since its initial application in 1980, the implantable cardioverter defibrillator (ICD) has evolved into a highly sophisticated device that offers programmable tiered therapy (antitachycardia pacing, cardioversion, and defibrillation) for ventricular tachyarrhythmias and backup pacing for bradycardia. It also provides diagnostic information about detected events. Successful implantation of nonthoracotomy systems is now routine. The availability of nonthoracotomy systems has reduced perioperative morbidity and mortality as well as hospital costs. Although the ICD has virtually eliminated sudden cardiac death in recipients, overall cardiac mortality remains considerable in these patients. Several prospective randomized clinical trials comparing ICD therapy to antiarrhythmic drug therapy are under way.
ACCORD and Risk-Factor Control in Type 2 Diabetes
Authors: Peter M. Nilsson
Journal: New England Journal of Medicine (2010)

Patients with type 2 diabetes mellitus without a history of myocardial infarction have the same risk of a coronary event as patients without diabetes who do have a history of myocardial infarction.1 This observation was part of the basis for the recommendation by the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program that diabetes should be considered a "coronary heart disease risk equivalent" and a target for aggressive reduction of risk factors.2 It has also contributed to the rationale for randomized clinical trials to evaluate the effects of risk-factor reduction in such high-risk patients.The Action . . .
Clinical importance of interphase cytogenetics detecting occult chromosome lesions in myelodysplastic syndromes with normal karyotype
Authors: GM Rigolin, R Bigoni, R Milani, F Cavazzini, MG Roberti, A Bardi, P Agostini, M Della Porta, A Tieghi, N Piva, A Cuneo, G Castoldi
Journal: Leukemia (2001)
High levels of RNA-editing site conservation amongst 15 laboratory mouse strains
Authors: Petr Danecek, Christoffer Nellåker, Rebecca E McIntyre, Jorge E Buendia-Buendia, Suzannah Bumpstead, Chris P Ponting, Jonathan Flint, Richard Durbin, Thomas M Keane, David J Adams
Journal: Genome biology (2012)

Abstract Background Adenosine-to-inosine (A-to-I) editing is a site-selective post-transcriptional alteration of double-stranded RNA by ADAR deaminases that is crucial for homeostasis and development. Recently the Mouse Genomes Project generated genome sequences for 17 laboratory mouse strains and rich catalogues of variants. We also generated RNA-seq data from whole brain RNA from 15 of the sequenced strains. Results Here we present a computational approach that takes an initial set of transcriptome/genome mismatch sites and filters these calls taking into account systematic biases in alignment, single nucleotide variant calling, and sequencing depth to identify RNA editing sites with high accuracy. We applied this approach to our panel of mouse strain transcriptomes identifying 7,389 editing sites with an estimated false-discovery rate of between 2.9 and 10.5%. The overwhelming majority of these edits were of the A-to-I type, with less than 2.4% not of this class, and only three of these edits could not be explained as alignment artifacts. We validated 24 novel RNA editing sites in coding sequence, including two non-synonymous edits in the Cacna1d gene that fell into the IQ domain portion of the Cav1.2 voltage-gated calcium channel, indicating a potential role for editing in the generation of transcript diversity. Conclusions We show that despite over two million years of evolutionary divergence, the sites edited and the level of editing at each site is remarkably consistent across the 15 strains. In the Cds2 gene we find evidence for RNA editing acting to preserve the ancestral transcript sequence despite genomic sequence divergence.
Downregulation of Smac/DIABLO Expression in Renal Cell Carcinoma and Its Prognostic Significance
Authors: Yoichi Mizutani, Hiroyuki Nakanishi, Kosuke Yamamoto, Yong Nan Li, Hiroki Matsubara, Kazuya Mikami, Koji Okihara, Akihiro Kawauchi, Benjamin Bonavida, Tsuneharu Miki
Journal: Journal of Clinical Oncology (2004)

Purpose Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) was recently identified as a protein that is released from mitochondria in response to apoptotic stimuli and promotes apoptosis by antagonizing inhibitor of apoptosis proteins. Furthermore, Smac/DIABLO plays an important regulatory role in the sensitization of cancer cells to both immune- and drug-induced apoptosis. However, little is known about the clinical significance of Smac/DIABLO in various cancers, including renal cell carcinoma (RCC). This study examined Smac/DIABLO expression in 78 healthy kidneys and 78 RCCs. Materials and Methods The level of Smac/DIABLO expression was quantified by Western blot analysis using nonfixed fresh frozen tissues. Results The expression of Smac/DIABLO was lower in RCC compared with the autologous normal kidney. Sixty-four (82%) of 78 of RCC expressed Smac/DIABLO, and 18% were negative, whereas 100% of normal kidney tissues were positive. In stage I/II RCC, 96% expressed Smac/DIABLO, whereas only 50% expressed Smac/DIABLO in stage III/IV. Smac/DIABLO expression inversely correlated with the grade of RCC. Patients with RCC expressing Smac/DIABLO had a longer postoperative disease-specific survival than those without Smac/DIABLO expression in the 5-year follow-up. Transfection with Smac/DIABLO cDNA enhanced tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) –mediated and cisplatin-mediated cytotoxicity in RCC. Conclusion The present study demonstrates for the first time that Smac/DIABLO expression was downregulated in RCC and that no Smac/DIABLO expression in RCC predicted a worse prognosis. In addition, transfection with Smac/DIABLO sensitized RCC to TRAIL/cisplatin-induced apoptosis. These results suggest that Smac/DIABLO expression in RCC may be used as a prognostic parameter, and that enhancement of Smac/DIABLO expression in RCC may potentiate immunotherapy and chemotherapy.
Early waning of maternal measles antibodies in era of measles elimination: longitudinal study
Authors: E. Leuridan, N. Hens, V. Hutse, M. Ieven, M. Aerts, P. Van Damme
Journal: BMJ (2010)

To investigate the duration of the presence of maternal antibodies to measles in infants.Prospective study (May 2006 to November 2008).Five hospitals in the Province of Antwerp, Belgium.Of 221 pregnant women recruited, 207 healthy woman-infant pairs were included-divided into a vaccinated group (n=87) and naturally immune group (n=120), according to vaccination documents and history.Measles IgG antibodies measured by enzyme linked immunosorbent assay (ELISA) at seven time points (week 36 of pregnancy, birth (cord), and 1, 6, 9, and 12 months); decay of maternal antibody in infants modelled with linear mixed models.Vaccinated women had significantly fewer IgG antibodies (geometric mean titre 779 (95% confidence interval 581 to 1045) mIU/ml) than did naturally immune women (2687 (2126 to 3373) mIU/ml) (P<0.001). Maternal values were highly correlated with neonatal values (r=0.93 at birth). Infants of vaccinated women had significantly lower antibody concentrations than did infants of naturally immune women (P<0.001 at all ages over the follow-up period). Presence of maternal antibodies endured for a median of 2.61 months-3.78 months for infants of naturally infected women and 0.97 months for infants of vaccinated women. At 6 months of age, more than 99% of infants of vaccinated women and 95% of infants of naturally immune women had lost maternal antibodies according to the model.This study describes a very early susceptibility to measles in infants of both vaccinated women and women with naturally acquired immunity. This finding is important in view of recent outbreaks and is an argument for timeliness of the first dose of a measles vaccine and vaccination of travelling or migrating children under the age of 1 year.
GSK3β Mediates Renal Response to Vasopressin by Modulating Adenylate Cyclase Activity
Authors: Reena Rao, Satish Patel, ChuanMing Hao, James Woodgett, Raymond Harris
Journal: Journal of the American Society of Nephrology (2010)

Glycogen synthase kinase 3beta (GSK3beta), a serine/threonine protein kinase, is a key target of drug discovery in several diseases, including diabetes and Alzheimer disease. Because lithium, a potent inhibitor of GSK3beta, causes nephrogenic diabetes insipidus, GSK3beta may play a crucial role in regulating water homeostasis. We developed renal collecting duct-specific GSK3beta knockout mice to determine whether deletion of GSK3beta affects arginine vasopressin-dependent renal water reabsorption. Although only mildly polyuric under normal conditions, knockout mice exhibited an impaired urinary concentrating ability in response to water deprivation or treatment with a vasopressin analogue. The knockout mice had reduced levels of mRNA, protein, and membrane localization of the vasopressin-responsive water channel aquaporin 2 compared with wild-type mice. The knockout mice also expressed lower levels of pS256-AQP2, a phosphorylated form crucial for membrane trafficking. Levels of cAMP, a major regulator of aquaporin 2 expression and trafficking, were also lower in the knockout mice. Both GSK3beta gene deletion and pharmacologic inhibition of GSK3beta reduced adenylate cyclase activity. In summary, GSK3beta inactivation or deletion reduces aquaporin 2 expression by modulating adenylate cyclase activity and cAMP generation, thereby impairing responses to vasopressin in the renal collecting duct.
Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin's lymphoma patients
Authors: N Germann, S Brienza, M Rotarski, J F Emile, M Di Palma, M Musset, M Reynes, P Soulié, E Cvitkovic, J L Misset
Journal: Annals of Oncology (1999)
Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus
Authors: Tianfu Wu, Xiangmei Qin, Zoran Kurepa, Kirthi Raman Kumar, Kui Liu, Hasna Kanta, Xin J. Zhou, Anne B. Satterthwaite, Laurie S. Davis, Chandra Mohan
Journal: Journal of Clinical Investigation (2007)

Though B cells play key roles in lupus pathogenesis, the molecular circuitry and its dysregulation in these cells as disease evolves remain poorly understood. To address this, a comprehensive scan of multiple signaling axes using multiplexed Western blotting was undertaken in several different murine lupus strains. PI3K/AKT/mTOR (mTOR, mammalian target of rapamycin), MEK1/Erk1/2, p38, NF-κB, multiple Bcl-2 family members, and cell-cycle molecules were observed to be hyperexpressed in lupus B cells in an age-dependent and lupus susceptibility gene–dose–dependent manner. Therapeutic targeting of the AKT/mTOR axis using a rapamycin (sirolimus) derivative ameliorated the serological, cellular, and pathological phenotypes associated with lupus. Surprisingly, the targeting of this axis was associated with the crippling of several other signaling axes. These studies reveal that lupus pathogenesis is contingent upon the activation of an elaborate network of signaling cascades that is shared among genetically distinct mouse models and raise hope that targeting pivotal nodes in these networks may offer therapeutic benefit.
BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival
Authors: Chiara Gorrini, Pegah S. Baniasadi, Isaac S. Harris, Jennifer Silvester, Satoshi Inoue, Bryan Snow, Purna A. Joshi, Andrew Wakeham, Sam D. Molyneux, Bernard Martin, Peter Bouwman, David W. Cescon, Andrew J. Elia, Zoe Winterton-Perks, Jennifer Cruickshank, Dirk Brenner, Alan Tseng, Melinda Musgrave, Hal K. Berman, Rama Khokha, Jos Jonkers, Tak W. Mak, Mona L. Gauthier
Journal: The Journal of Experimental Medicine (2013)

Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.
Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma☆
Authors: Mary-Anne Kedda, Jing Shi, David Duffy, Stephanie Phelps, Ian Yang, Kirrily O'Hara, Kwun Fong, Philip J. Thompson
Journal: Journal of Allergy and Clinical Immunology (2004)