tbuckley/cabot-search huggingface dataset:
Prevalence and Clinical Outcome Associated with Preexisting Malnutrition in Acute Renal Failure
Authors: ENRICO FIACCADORI, MARIA LOMBARDI, SABINA LEONARDI, CARLO FEDERICO ROTELLI, GIOVANNI TORTORELLA, ALBERICO BORGHETTI
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Malnutrition is a frequent finding in hospitalized patients and is associated with an increased risk of subsequent in-hospital morbidity and mortality. Both prevalence and prognostic relevance of preexisting malnutrition in patients referred to nephrology wards for acute renal failure (ARF) are still unknown. This study tests the hypothesis that malnutrition is frequent in such clinical setting, and is associated with excess in-hospital morbidity and mortality. A prospective cohort of 309 patients admitted to a renal intermediate care unit during a 42-mo period with ARF diagnosis was studied. Patients with malnutrition were identified at admission by the Subjective Global Assessment of nutritional status method (SGA); nutritional status was also evaluated by anthropometric, biochemical, and immunologic parameters. Outcome measures included in-hospital mortality and morbidity, and use of health care resources. In-hospital mortality was 39% (120 of 309); renal replacement therapies (hemodialysis or continuous hemofiltration) were performed in 67% of patients (206 of 309); APACHE II score was 23.1 ± 8.2 (range, 10 to 52). Severe malnutrition by SGA was found in 42% of patients with ARF; anthropometric, biochemical, and immunologic nutritional indexes were significantly reduced in this group compared with patients with normal nutritional status. Severely malnourished patients, as compared to patients with normal nutritional status, had significantly increased morbidity for sepsis (odds ratio [OR] 2.88; 95% confidence interval [CI], 1.53 to 5.42, P &lt; 0.001), septic shock (OR 4.05; 95% CI, 1.46 to 11.28, P &lt; 0.01), hemorrhage (OR 2.98; 95% CI, 1.45 to 6.13, P &lt; 0.01), intestinal occlusion (OR 5.57; 95% CI, 1.57 to 19.74, P &lt; 0.01), cardiac dysrhythmia (OR 2.29; 95% CI, 1.36 to 3.85, P &lt; 0.01), cardiogenic shock (OR 4.39; 95% CI, 1.83 to 10.55, P &lt;.001), and acute respiratory failure with mechanical ventilation need (OR 3.35; 95% CI, 3.35 to 8.74, P &lt; 0.0.5). Hospital length of stay was significantly increased ( P &lt; 0.01), and the presence of severe malnutrition was associated with a significant increase of in-hospital mortality (OR 7.21; 95% CI, 4.08 to 12.73, P &lt; 0.001). Preexisting malnutrition was a statistically significant, independent predictor of in-hospital mortality at multivariable logistic regression analysis both with comorbidities (OR 2.02; 95% CI, 1.50 to 2.71, P &lt; 0.001), and with comorbidities and complications (OR 2.12; 95% CI, 1.61 to 2.89, P &lt; 0.001). Malnutrition is highly prevalent among ARF patients and increases the likelihood of in-hospital death, complications, and use of health care resources.
Muscle-specific expression of IGF-1 blocks angiotensin II–induced skeletal muscle wasting
Authors: Yao-Hua Song, Yangxin Li, Jie Du, William E. Mitch, Nadia Rosenthal, Patrick Delafontaine
Journal: Journal of Clinical Investigation (2005)

Advanced congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. We previously showed that angiotensin II infusion in rats produces cachexia secondarily to increased muscle proteolysis and also decreases levels of circulating and skeletal muscle IGF-1. Here we show that angiotensin II markedly downregulates phospho-Akt and activates caspase-3 in skeletal muscle, leading to actin cleavage, an important component of muscle proteolysis, and to increased apoptosis. These changes are blocked by muscle-specific expression of IGF-1, likely via the Akt/mTOR/p70S6K signaling pathway. We also demonstrate that mRNA levels of the ubiquitin ligases atrogin-1 and muscle ring finger–1 are upregulated in angiotensin II–infused WT, but not in IGF-1–transgenic, mice. These findings strongly suggest that angiotensin II downregulation of IGF-1 in skeletal muscle is causally related to angiotensin II–induced wasting. Because the renin-angiotensin system is activated in many catabolic conditions, our findings have broad implications for understanding mechanisms of skeletal muscle wasting and provide a rationale for new therapeutic approaches.
Mutant<i>CHUK</i>and Severe Fetal Encasement Malformation
Authors: Jenni Lahtela, Heidi O. Nousiainen, Vedran Stefanovic, Jonna Tallila, Heli Viskari, Riitta Karikoski, Massimiliano Gentile, Carola Saloranta, Teppo Varilo, Riitta Salonen, Marjo Kestilä
Journal: New England Journal of Medicine (2010)

We report an autosomal recessive lethal syndrome characterized by multiple fetal malformations, the most obvious anomalies being the defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin. We identified the molecular defect that causes this syndrome, using a combined strategy of gene-expression arrays, candidate-gene analysis, clinical studies, and genealogic investigations. A point mutation in two affected fetuses led to the loss of the conserved helix–loop–helix ubiquitous kinase (CHUK), also known as IκB kinase α. CHUK has an essential role in the development of skin epidermis and its derivatives, along with various other morphogenetic events. (Funded by the Academy of Finland and others.).
Taking the trivial doctrine seriously: Functionalism, eliminativism, and materialism
Authors: Maurizio Tirassa
Journal: Behavioral and Brain Sciences (1999)

Gold &amp; Stoljar's (G&amp;S's) characterization of the trivial doctrine and of its relationships with the radical one misses some differences that may be crucial. The radical doctrine can be read as a derivative of the computational version of functionalism that provides the backbone of current cognitive science and is fundamentally uninterested in biology: Both doctrines are fundamentally wrong. The synthesis between neurobiology and psychology requires instead that minds be viewed as ontologically primitive, that is, as material properties of functioning bodies. G&amp;S's characterization of the trivial doctrine should therefore be correspondingly modified.
DNA methylation and gene deletion analysis of brain metastases in melanoma patients identifies mutually exclusive molecular alterations
Authors: D. M. Marzese, R. A. Scolyer, M. Roque, L. M. Vargas-Roig, J. L. Huynh, J. S. Wilmott, R. Murali, M. E. Buckland, G. Barkhoudarian, J. F. Thompson, D. L. Morton, D. F. Kelly, D. S. B. Hoon
Journal: Neuro-Oncology (2014)

The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes.
Monocyte-Mediated Defense Against Microbial Pathogens
Authors: Natalya V. Serbina, Ting Jia, Tobias M. Hohl, Eric G. Pamer
Journal: Annual Review of Immunology (2008)

Circulating blood monocytes supply peripheral tissues with macrophage and dendritic cell (DC) precursors and, in the setting of infection, also contribute directly to immune defense against microbial pathogens. In humans and mice, monocytes are divided into two major subsets that either specifically traffic into inflamed tissues or, in the absence of overt inflammation, constitutively maintain tissue macrophage/DC populations. Inflammatory monocytes respond rapidly to microbial stimuli by secreting cytokines and antimicrobial factors, express the CCR2 chemokine receptor, and traffic to sites of microbial infection in response to monocyte chemoattractant protein (MCP)-1 (CCL2) secretion. In murine models, CCR2-mediated monocyte recruitment is essential for defense against Listeria monocytogenes, Mycobacterium tuberculosis, Toxoplasma gondii, and Cryptococcus neoformans infection, implicating inflammatory monocytes in defense against bacterial, protozoal, and fungal pathogens. Recent studies indicate that inflammatory monocyte recruitment to sites of infection is complex, involving CCR2-mediated emigration of monocytes from the bone marrow into the bloodstream, followed by trafficking into infected tissues. The in vivo mechanisms that promote chemokine secretion, monocyte differentiation and trafficking, and finally monocyte-mediated microbial killing remain active and important areas of investigation.
Intron Size and Genome Size in Plants
Authors: Jonathan F. Wendel, Richard C. Cronn, Ines Alvarez, Bao Liu, Randall L. Small, David S. Senchina
Journal: Molecular Biology and Evolution (2002)

It has long been known that genomes vary over a remarkable range of sizes in both plants (Bennett, Cox, and Leitch 1997) and animals (Gregory 2001). It also has become evident that across the broad phylogenetic sweep, genome size may be correlated with intron size (Deutsch and Long 1999; Vinogradov 1999; McLysaght et al. 2000), suggesting that some component of genome size evolution takes place within genes. Examples include humans and pufferfish (Fugu), where comparisons of 199 introns in 22 orthologous genes showed that introns in Fugu were on average eight times as small as those in humans, consistent with their ratio of genome sizes (McLysaght et al. 2000). Similarly, Deutsch and Long (1999) tabulated intron sizes across a broad phylogenetic spectrum of eukaryotes and noted a general but weak correlation with genome size, with humans having the most and longest introns (mean of 3.4 kbp) among the 10 taxa studied. Intron size is also correlated with genome size in Drosophila (Moriyama, Petrov, and Hartl 1998), showing that the correlation may extend to more recent divergences. At present there is little information on the correlation between genome and intron sizes in plants, although there are suggestions that plants with small genomes have smaller introns (Deutsch and Long 1999; Vinogradov 1999). Whereas broad comparisons across widely divergent taxa are now possible given completed draft sequences for the rice (Goff et al. 2002; Yu et al. 2002) and Arabidopsis (Arabidopsis Genome Initiative 2000) genomes, the divergence time between Poaceae and Brassicaceae is so large that the influence of genome size on intron size may be confounded by numerous other, unstudied covariables. It seems likely that more informative studies will involve closely related taxa that vary significantly in genome size but which share recent evolutionary history and a broad suite of life-history features. An additional advantage of comparing close relatives is that orthology among genes, and hence introns, may be more readily established. This latter point may be especially important, given the relative lability of copy-number for many gene families (Small and Wendel 2000). To exemplify this approach, we studied the relationship between intron size and genome size for or-
Molecular Medicine
Authors: C. Thomas Caskey
Journal: JAMA (1993)

IN THE 40 years that have passed since the publication of the structure of DNA by Watson and Crick,<sup>1</sup>remarkable new DNA technology has emerged that has prompted the Human Genome Initiative at the National Institutes of Health (NIH) and ushered in the era of molecular medicine. Crick made additional contributions to our understanding of the genetic code, which was elucidated in the 1960s,<sup>2</sup>and now devotes attention to the study of developmental biology of the central nervous system at the Salk Institute. Watson continues to make contributions to the field of genetics such as training scientists at Harvard and Cold Spring Harbor Laboratories (developing CSHL to modern preeminence) and serving as a visionary leader of the NIH Human Genome Initiative. The scientific community is fortunate to have the continued leadership of Watson and Crick. In this article, it is my objective to review technological developments in biochemical
Spatial Heterogeneity of Myocardial Blood Flow Presages Salvage Versus Necrosis With Coronary Artery Reperfusion in Conscious Baboons
Authors: Bijan Ghaleh, You-Tang Shen, Stephen F. Vatner
Journal: Circulation (1996)

Background Myocardial blood flow distribution is known to be heterogeneous. It is also known that not all of the area at risk (AAR) infarcts with coronary artery occlusion (CAO) and coronary artery reperfusion (CAR). The goal of the present study was to determine whether the proportion of AAR that is salvaged or infarcted can be predicted by the pre-CAO level of myocardial blood flow, which varies considerably in individual samples as a result of natural heterogeneity. Methods and Results The effects of 90-minute CAO followed by 5- to 7-day CAR were examined in six conscious baboons instrumented with aortic and left atrial catheters and coronary artery occluders. AAR was determined by dual perfusion. Myocardial blood flow was measured by radioactive microspheres before and after CAO and CAR. The AAR was cut into small pieces (0.21±0.01 g) and separated into two categories: salvaged (n=252) or infarcted (n=133). Analysis of myocardial blood flow distribution revealed two distinct populations ( P &lt;.01); infarcted tissues demonstrated higher pre-CAO myocardial blood flow than salvaged tissues. Importantly, 50% of the salvaged tissue samples were characterized by pre-CAO myocardial blood flows of &lt;0.90 mL·min −1 ·g −1 compared with 29% for infarcted samples, whereas 51% of infarcted samples were characterized by pre-CAO myocardial blood flows of &gt;1.12 mL·min −1 ·g −1 compared with 22% of salvaged samples. Endocardial analyses were qualitatively similar to transmural analyses. Conclusions This study suggests that heterogeneity of pre-CAO myocardial blood flows can predict the proportion of myocardium salvaged by CAR and can further explain the spatial heterogeneity of infarction that occurs after CAR, potentially independent of CAR injury.
Medical report from the 2006 FIFA World Cup Germany
Authors: Jiri Dvorak, Astrid Junge, Katharina Grimm, Donald Kirkendall
Journal: British Journal of Sports Medicine (2007)

To continue the injury surveillance of FIFA-sponsored football tournaments and report on other medical aspects of the 2006 FIFA World Cup.Prospective epidemiological injury surveillance and descriptive summary of additional medical aspects.Major international football tournament.National team players, doctors and referees at the 2006 FIFA World Cup Germany.Injury type, location and rate.145 injuries were reported for the 64 matches of the 2006 FIFA World Cup Germany-an overall injury rate of 68.7 per 1000 match hours (95% CI 57.5 to 79.9) or 2.3 injuries per match, in comparison with 2.7 injuries per match in the 2002 FIFA World Cup (p = NS). Physical examinations before participation uncovered no hidden cardiovascular problems. Once the tournament started, no referees were unable to complete their duties. There were no positive doping tests.The injury rate for this World Cup was below that of 2002, but consistent with the overall injury rate per match since data collection began in 1998. There continues to be no evidence of systematic doping in international football.
Treatment of Narcotics Addiction With Narcotic Drugs
Authors: Robert L. DuPont
Journal: JAMA (1976)

WHILE THE use of methadone hydrochloride for both opiate maintenance and detoxification has been well described in the medical literature<sup>1-4</sup>during the past decade, recent legislation has expanded the boundaries of the federal regulatory role in drug-abuse treatment to cover the maintenance and detoxification of drug-dependent persons with all narcotic drugs. The little-known Narcotic Addict Treatment Act of 1974 (Public Law 93-281, May 1974) placed the federal government's control of methadone on a firm legal foundation. This additional control was accomplished by giving to the Drug Enforcement Administration (DEA) of the Department of Justice the responsibility for registering all practitioners who use methadone or other narcotic drugs in the treatment of narcotics addiction. <h3>Registration</h3> The Secretary of Health, Education, and Welfare (HEW), representing the interests of health professionals, must, under this act, publish treatment standards and advise the DEA whether applicants to conduct maintenance or detoxification treatment should be
The pseudokinase SgK223 promotes invasion of pancreatic ductal epithelial cells through JAK1/Stat3 signaling
Authors: Carole M. Tactacan, Yu Wei Phua, Ling Liu, Luxi Zhang, Emily S. Humphrey, Mark Cowley, Mark Pinese, Andrew V. Biankin, Roger J. Daly
Journal: Molecular Cancer (2015)

Characterization of molecular mechanisms underpinning development of pancreatic ductal adenocarcinoma (PDAC) may lead to the identification of novel therapeutic targets and biomarkers. SgK223, also known as Pragmin, is a pseudokinase and scaffolding protein closely related to SgK269/PEAK1. Both proteins are implicated in oncogenic tyrosine kinase signaling, but their mechanisms and function remain poorly characterized. Expression of SgK223 in PDAC and PDAC cell lines was characterized using gene expression microarrays, mass spectrometry (MS)-based phosphoproteomics and Western blotting. SgK223 was overexpressed in human pancreatic ductal epithelial (HPDE) cells via retroviral transduction, and knocked down in PDAC cells using siRNA. Cell proliferation was determined using a colorimetric cell viability assay, and cell migration and invasion using transwells. Expression of markers of epithelial-mesenchyme transition (EMT) was assayed by quantitative PCR. SgK223 and Stat3 signaling was interrogated by immunoprecipitation, Western blot and gene reporter assays. The functional role of specific kinases and Stat3 was determined using selective small molecule inhibitors. Elevated site-selective tyrosine phosphorylation of SgK223 was identified in subsets of PDAC cell lines, and increased expression of SgK223 detected in several PDAC cell lines compared to human pancreatic ductal epithelial (HPDE) cells and in PDACs compared to normal pancreas. Expression of SgK223 in HPDE cells at levels comparable to those in PDAC did not alter cell proliferation but led to a more elongated morphology, enhanced migration and invasion and induced gene expression changes characteristic of a partial EMT. While SgK223 overexpression did not affect activation of Erk or Akt, it led to increased Stat3 Tyr705 phosphorylation and Stat3 transcriptional activity, and SgK223 and Stat3 associated in vivo. SgK223-overexpressing cells exhibited increased JAK1 activation, and use of selective inhibitors determined that the increased Stat3 signaling driven by SgK223 was JAK-dependent. Pharmacological inhibition of Stat3 revealed that Stat3 activation was required for the enhanced motility and invasion of SgK223-overexpressing cells. Increased expression of SgK223 occurs in PDAC, and overexpression of SgK223 in pancreatic ductal epithelial cells promotes acquisition of a migratory and invasive phenotype through enhanced JAK1/Stat3 signaling. This represents the first association of SgK223 with a particular human cancer, and links SgK223 with a major signaling pathway strongly implicated in PDAC progression.
Non–Small-Cell Lung Cancer: Then and Now
Authors: Joan H. Schiller, David R. Gandara, Glenwood D. Goss, Everett E. Vokes
Journal: Journal of Clinical Oncology (2013)

This is only the second Special Series on lung cancer in Journal of Clinical Oncology (JCO) since its inception 30 years ago, and in the interim, the lung cancer world has certainly changed. In 1983, the major interest was in small-cell lung cancer (SCLC), with hopes that it would become a highly curable disease. Of the eight articles on lung cancer published that first year, five were on SCLC and three were on non–small-cell lung cancer (NSCLC). Compare this to 2011, in which 40 original articles and editorials were published—and only seven involved SCLC. This shows that one cannot always predict the direction or outcome of clinical research, or where the biology will take us. It is always interesting to take a step back to appreciate how far we have come and to define areas that are still in need of improvement. In 1983, defining the role of chemotherapy in lung cancer was the name of the game. Of the eight papers that were published in 1983, five involved clinical trials: two in SCLC and three in NSCLC. The two SCLC trials evaluated the role of etoposide, vincristine, doxorubicin, and cyclophosphamide and high-dose chest radiotherapy, 1 and the same drugs with low-dose, total-body irradiation. 2 The three NSCLC trials investigated the combination of cisplatin and vinblastine 3 ; cyclophosphamide, doxorubicin, and etoposide with or without cisplatin 4 ; and methotrexate, cyclophosphamide, hexamethylmelamine, and lomustine 5 for advanced disease. Needless to say, none of these included