tbuckley/cabot-search huggingface dataset:
Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer
Authors: Manickam Janakiraman, Efsevia Vakiani, Zhaoshi Zeng, Christine A. Pratilas, Barry S. Taylor, Dhananjay Chitale, Ensar Halilovic, Manda Wilson, Kety Huberman, Julio Cezar Ricarte Filho, Yogindra Persaud, Douglas A. Levine, James A. Fagin, Suresh C. Jhanwar, John M. Mariadason, Alex Lash, Marc Ladanyi, Leonard B. Saltz, Adriana Heguy, Philip B. Paty, David B. Solit
Journal: Cancer Research (2010)

Mutations in RAS proteins occur widely in human cancer. Prompted by the confirmation of KRAS mutation as a predictive biomarker of response to epidermal growth factor receptor (EGFR)-targeted therapies, limited clinical testing for RAS pathway mutations has recently been adopted. We performed a multiplatform genomic analysis to characterize, in a nonbiased manner, the biological, biochemical, and prognostic significance of Ras pathway alterations in colorectal tumors and other solid tumor malignancies. Mutations in exon 4 of KRAS were found to occur commonly and to predict for a more favorable clinical outcome in patients with colorectal cancer. Exon 4 KRAS mutations, all of which were identified at amino acid residues K117 and A146, were associated with lower levels of GTP-bound RAS in isogenic models. These same mutations were also often accompanied by conversion to homozygosity and increased gene copy number, in human tumors and tumor cell lines. Models harboring exon 4 KRAS mutations exhibited mitogen-activated protein/extracellular signal-regulated kinase kinase dependence and resistance to EGFR-targeted agents. Our findings suggest that RAS mutation is not a binary variable in tumors, and that the diversity in mutant alleles and variability in gene copy number may also contribute to the heterogeneity of clinical outcomes observed in cancer patients. These results also provide a rationale for broader KRAS testing beyond the most common hotspot alleles in exons 2 and 3.
NERVOUS AND MENTAL DISORDERS OF SOLDIERS
Authors: SANGER BROWN
Journal: American Journal of Psychiatry (1920)

April physical and nervous exhaustion, it takes little imagination to understand the state of mind in which many men found themselves.Incidentally it may be said that nothing could more conclusively prove the unity of purpose of these men and their faith in the right of the cause for which they entered the war than the patience, the fortitude and the determination that they displayed throughout.
Association of Family Income Supplements in Adolescence With Development of Psychiatric and Substance Use Disorders in Adulthood Among an American Indian Population
Authors: E. Jane Costello
Journal: JAMA (2010)

In a natural experiment in which some families received income supplements, prevalence of adolescent behavioral symptoms decreased significantly. These adolescents are now young adults.To examine the effects of income supplements in adolescence and adulthood on the prevalence of adult psychiatric disorders.Quasi-experimental, longitudinal.A representative sample of children aged 9, 11, or 13 years in 1993 (349 [25%] of whom are American Indian) were assessed for psychiatric and substance use disorders through age 21 years (1993-2006). Of the 1420 who participated in 1993, 1185 were interviewed as adults. From 1996, when a casino opened on the Indian reservation, every American Indian but no non-Indians received an annual income supplement that increased from $500 to around $9000.Prevalence of adult psychiatric disorders and substance use disorders based on the Diagnostic and Statistical Manual of Mental Disorders in 3 age cohorts, adjusted for age, sex, length of time in the family home, and number of Indian parents.As adults, significantly fewer Indians than non-Indians had a psychiatric disorder (106 Indians [weighted 30.2%] vs 337 non-Indians [weighted 36.0%]; odds ratio [OR], 0.46; 95% confidence interval [CI], 0.30-0.72; P = .001), particularly alcohol and cannabis abuse, dependence, or both. The youngest age-cohort of Indian youth had the longest exposure to the family income. Interactions between race/ethnicity and age cohort were significant. Planned comparisons showed that fewer of the youngest Indian age-cohort had any psychiatric disorder (31.4%) than the Indian middle cohort (41.7%; OR, 0.43; 95% CI, 0.24-0.78; P = .005) or oldest cohort (41.3%; OR, 0.69; 95% CI, 0.51-0.94; P = .01) or the youngest non-Indian cohort (37.1%; OR, 0.66; 95% CI, 0.48-0.90; P = .008). Study hypotheses were not upheld for nicotine or other drugs, or emotional or behavioral disorders. The income supplement received in adulthood had no impact on adult psychopathology.Lower prevalence of psychopathology in American Indian youth following a family income supplement, compared with the nonexposed, non-Indian population, persisted into adulthood.
Molecular mechanisms of peripheral CD25 regulatory T cell (Treg) development
Authors: I Prots, A Skapenko, P E Lipsky, H Schulze-Koops
Journal: Annals of the Rheumatic Diseases (2010)

Compromised development and/or function of CD25 regulatory T cells (Tregs) is of central importance for the development of autoimmune diseases. The mechanisms that regulate the generation of peripheral Tregs are, however, largely unknown. To gain insights into Treg differentiation on a molecular level, the authors investigated gene expression profiles of Tregs at different developmental stages.

Human Tregs were generated in vitro from CD4 CD25-naive T cells in …
Plasma Extravasation in the Rat Trachea Induced by Cold Air is Mediated by Tachykinin Release from Sensory Nerves
Authors: Shigemi Yoshihara, Brendan Chan, Isao Yamawaki, Pierangelo Geppetti, Fabio L. M. Ricciardolo, Pierre P. Massion, Jay A. Nadel
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Cold air was delivered to anesthetized, artificially ventilated, pathogen-free F344 rats via a tracheal cannula. Inhalation of cold air increased Evans blue dye extravasation in the trachea in a time-dependent (1 to 10 min) manner. Plasma extravasation increased after 3 min exposure to cold air and reached a maximum after 10 min exposure. The neutral endopeptidase inhibitor, phosphoramidon (2.5 mg/kg, intravenously), increased by 84% the plasma extravasation induced by inhalation of cold air for 1 min. The plasma extravasation evoked by 5 min exposure to cold air was abolished by the NK1 tachykinin receptor antagonist, CP-99,994 (4 mg/kg, intravenously); was reduced 30% by the B2 bradykinin receptor antagonist, HOE140 (0.1 mumol/kg, intravenously); and was not affected by H1 (pyrilamine, 10 mg/kg, intraperitoneally) or H2 (cimetidine, 10 mg/kg, intraperitoneally) histamine receptor antagonists or the cyclooxygenase inhibitor indomethacin (5 mg/kg, intravenously). In rats infected with Sendai virus, plasma extravasation evoked by inhalation of cold air was greater than in pathogen-free rats. Pretreatment with CP-99,994 (4 mg/kg, intravenously) inhibited completely the plasma extravasation induced by cold air in virus-infected rats. These findings indicate that cold air increases plasma extravasation in the rat trachea by a neurogenic mechanism that involves the release of tachykinins from sensory nerves. Kinin release may also play a role in this neurogenic inflammatory response.
MUTANTS OF NONPRODUCER CELL LINES TRANSFORMED BY MURINE SARCOMA VIRUSES
Authors: M. Hatanaka, R. Klein, R. Toni, J. Walker, R. Gilden
Journal: The Journal of Experimental Medicine (1973)

A variety of cell mutants were obtained by a single 5'-bromodeoxyuridine (BrdU) treatment of an nonproducer (NP) cell line transformed by the Kirsten strain of murine sarcoma virus (Ki-MSV). Isolation procedures of these cell See PDF for Structure mutants are described. The cell mutants obtained were classified by tumorigenic potential and shedding of Type C virus particles. The cell mutants were classified into four groups: (A) tumorigenic, without particles; (B) tumorigenic, with Type C particles; (C) nontumorigenic, without particles; and (D) nontumorigenic, with Type C particles. The tumorigenic cell lines showed variability in morphology with both flat and typical transformed appearing cell lines showing equal transplantability.
RESTORATION OF IMMUNE COMPETENCE IN TOLERANT MICE BY PARABIOSIS TO NORMAL MICE
Authors: Susan Zolla, David Naor
Journal: The Journal of Experimental Medicine (1974)

These studies demonstrate that mice tolerant to human gamma globulin (HGG) regain their ability to make antibody to HGG after parabiosis to normal mice. This can be demonstrated by enumeration of PFC in the spleens of both the normal and tolerant partners. Hemagglutinin titers of normal-tolerant parabionts, however, are exceptionally low; serum antibody appears to be neutralized by circulating HGG present originally in the serum of the tolerant partner. These data support the hypothesis that tolerance to HGG in mice is a "defective" state due to the absence of cells capable of responding to this antigen.
Prostaglandin E2 Activates Mitogen-Activated Protein Kinase/Erk Pathway Signaling and Cell Proliferation in Non–Small Cell Lung Cancer Cells in an Epidermal Growth Factor Receptor–Independent Manner
Authors: Kostyantyn Krysan, Karen L. Reckamp, Harnisha Dalwadi, Sherven Sharma, Enrique Rozengurt, Mariam Dohadwala, Steven M. Dubinett
Journal: Cancer Research (2005)

Abstract Cyclooxygenase 2 (COX-2) overexpression is found in a wide variety of human cancers and is linked to all stages of tumorigenesis. Elevated tumor COX-2 expression is associated with increased angiogenesis, tumor invasion, suppression of host immunity and promotes tumor cell resistance to apoptosis. Previous reports have linked the COX-2 product prostaglandin E2 (PGE2) to the abnormal activation of the mitogen-activated protein kinase/Erk kinase pathway. Here we show that PGE2 is able to rapidly stimulate Erk phosphorylation in a subset of non–small cell lung cancer (NSCLC) cell lines. This effect is not evident in bronchial epithelial cells. In contrast to previous reports in colon cancer, we found that Erk activation as well as cellular proliferation induced by PGE2 was not inhibited by pretreatment of the cells with epidermal growth factor receptor (EGFR) inhibitors. Activation of the Erk pathway by PGE2 was also resistant to src kinase inhibitors but sensitive to the protein kinase C inhibition. PGE2 effects are mediated through four G protein–coupled receptors. Selective inhibition of EP receptors revealed the possible involvement of Ca2+-dependent signaling in PGE2-mediated activation of Erk. Our data indicate the presence of an EGFR-independent activation of the mitogen-activated protein kinase/Erk pathway by PGE2 in NSCLC cells. These findings provide evidence for the possible link between tumor COX-2 overexpression and elevated Erk-mediated cancer cell proliferation and migration. Importantly, these findings suggest that COX-2 overexpression may contribute to EGFR inhibitor resistance in NSCLC.
A mechanistic model for the development and maintenance of portocentral gradients in gene expression in the liver
Authors: Vincent M. Christoffels, Habib Sassi, Jan M. Ruijter, Antoon F. Moorman, Thierry Grange, Wouter H. Lamers
Journal: Hepatology (1999)

In the liver, genes are expressed along a portocentral gradient. Based on their adaptive behavior, a gradient versus compartment type, and a dynamic versus stable type of gradient have been recognized. To understand at least in principle the development and maintenance of these gradients in gene expression in relation to the limited number of signal gradients, we propose a simple and testable model. The model uses portocentral gradients of signal molecules as input, while the output depends on two gene-specific variables, viz., the affinity of the gene for its regulatory factors and the degree of cooperativity that determines the response in the signal-transduction pathways. As a preliminary validity test for its performance, the model was tested on control and hormonally induced expression patterns of phosphoenolpyruvate carboxykinase (PCK), carbamoylphosphate synthetase I (CPS), and glutamine synthetase (GS). Affinity was found to determine the overall steepness of the gradient, whereas cooperativity causes these gradients to steepen locally, as is necessary for a compartment-like expression pattern. Interaction between two or more different signal gradients is necessary to ensure a stable expression pattern under different conditions. The diversity in sequence and arrangement of related DNA-response elements of genes appears to account for the gene-specific shape of the portocentral gradients in expression. The feasibility of testing the function of hepatocyte-specific DNA-response units in vivo is demonstrated by integrating such units into a ubiquitously active promoter/enhancer and analyzing the pattern of expression of these constructs in transgenic mice.
Exploring the Differences in Evolutionary Rates between Monogenic and Polygenic Disease Genes in Human
Authors: S. Podder, T. C. Ghosh
Journal: Molecular Biology and Evolution (2009)

Comparative analyses on disease and nondisease (ND) genes have greatly facilitated the understanding of human diseases. However, most studies have grouped all the disease genes together and have performed comparative analyses with other ND genes. Thus, the molecular mechanism of disease on which disease genes can be separated into monogenic and polygenic diseases (MDs and PDs) has been ignored in earlier studies. Here, we report a comprehensive study of PD and MD genes with respect to ND genes. Our work shows that MD genes are more conserved than PD genes and that ND genes are themselves more conserved than both classes of disease genes. By separating the ND genes into housekeeping and other genes, it was found that housekeeping genes are the most conserved among all categories of genes, whereas other ND genes show an evolutionary rate intermediate between MD and PD genes. Although PD genes have a higher number of interacting partners than MD and ND genes, the reasons for their higher evolutionary rate require explanation. We provide evidences that the faster evolutionary rate of PD genes is influenced by 1) the predominance of date hubs in protein–protein interaction network, 2) the higher number of disorder residues, 3) the lower expression level, and 4) the involvement with more regulatory processes. Logistic regression analysis suggests that the relative importance of the four individual factors in determining the evolutionary rate variation among the four classes of proteins is in the order of mRNA expression level > presence of party/date hubs > disorder > involvement of proteins in core/regulatory processes.
Electrical Potential Difference Across Blood Vessels
Authors: David H. Harshaw, Howard Ziskind, Roger Mazlen, Philip N. Sawyer
Journal: Circulation Research (1962)

A technique for measuring the potential difference across blood vessel wall in vitro is described. It was found that the potential difference across canine blood vessel wall in vitro is roughly 0 ± 50 µv. under the conditions of this experiment.
A novel monoclonal antibody of human stem cell factor inhibits umbilical cord blood stem cell ex vivo expansion
Authors: Jie Fan, Xinxin Ding, Yongping Jiang
Journal: Journal of Hematology & Oncology (2012)

Abstract Stem cell factor (SCF) activates hematopoietic stem cell (HSC) self-renewal and is being used to stimulate the ex vivo expansion of HSCs. The mechanism by which SCF supports expansion of HSCs remains poorly understood. In cord blood ex vivo expansion assays, a newly produced anti-SCF monoclonal antibody (clone 23C8) was found to significantly inhibit the expansion of CD34 + cells. This antibody appears to bind directly to a part of SCF that is critical for biological activity toward expansion of CD34 + cells, which is located in the first 104 amino acids from the NH 2 -terminus.
Leukotriene (LT)C4 aggravate bleomycin-induced pulmonary fibrosis in mice
Authors: Masamitsu Tatewaki, Hirokuni Hirata, Masafumi Arima, Takeshi Fukuda
Journal: European Respiratory Journal (2012)

Background:  Synthesis of cysteinyl leukotrienes (cys-LTs) is thought to cause inflammatory disorders such as bronchial asthma and allergic rhinitis. Recent reports have suggested that LTC 4  is an important regulator of pulmonary fibrosis. This study examined the effect of LTC 4  in LTC 4  synthase-overexpressed transgenic (Tg) mice with bleomycin-induced pulmonary fibrosis. We also focused on the function of lung-derived fibroblasts in the Tg mice.   Methods:  Prior to administration of bleomycin, pranlukast hydrate, a cys-LT1 receptor antagonist, was intragastrically administered to Tg mice daily from the previous day of the administration. Bleomycin was administrated by intratracheal instillation. Concentrations of IL-4, -13, and TGF-β1 in BAL fluid were measured 14 days after the administration of bleomycin. And lung tissue was examined histopathologically. In addition, lung-derived fibroblasts from Tg and wild-type (WT) mice were cultured for 7 days, and LTC 4  secretion and cell viability were assessed by EIA and MTT assay, respectively. And the expression of TGF-β1 mRNA was measured by real time PCR.   Results:  The levels of IL-4, -13, and TGF-β1, and pulmonary fibrosis were greater in Tg than in WT mice. The reduction of LTC 4  function in Tg mice could be decreased both these cytokines and pulmonary fibrosis. Furthermore, continuous LTC 4  secretion from fibroblasts was higher in Tg than in WT mice, while reduction of LTC 4  by pranlukast in fibroblasts from Tg, but not in those from WT mice, decreased cell viability and expression of TGF-β1 mRNA.   Conclusion:  These findings first suggest that overexpression of LTC 4  using transgenic mice is responsible for the development of pulmonary fibrosis.
High <i>EVI1</i> Expression Predicts Outcome in Younger Adult Patients With Acute Myeloid Leukemia and Is Associated With Distinct Cytogenetic Abnormalities
Authors: Stefan Gröschel, Sanne Lugthart, Richard F. Schlenk, Peter J.M. Valk, Karina Eiwen, Chantal Goudswaard, Wim J.L. van Putten, Sabine Kayser, Leo F. Verdonck, Michael Lübbert, Gert-Jan Ossenkoppele, Ulrich Germing, Ingo Schmidt-Wolf, Brigitte Schlegelberger, Jürgen Krauter, Arnold Ganser, Hartmut Döhner, Bob Löwenberg, Konstanze Döhner, Ruud Delwel
Journal: Journal of Clinical Oncology (2010)

PURPOSE The purpose of this study was to investigate frequency and prognostic significance of high EVI1 expression in acute myeloid leukemia (AML). PATIENTS AND METHODS A diagnostic assay detecting multiple EVI1 splice variants was developed to determine the relative EVI1 expression by single real-time quantitative polymerase chain reaction in 1,382 newly diagnosed adult patients with AML younger than 60 years. Patients were treated on four Dutch-Belgian HOVON (n = 458) and two German-Austrian AML Study Group protocols (n = 924). Results The EVI1 assay was tested in the HOVON cohort and validated in the AMLSG cohort. High EVI1 levels (EVI1(+)) were found with similar frequencies in both cohorts combined, with a 10.7% incidence (148 of 1,382). EVI1(+) independently predicted low complete remission (CR) rate (odds ratio, 0.54; P = .002), adverse relapse-free survival (RFS; hazard ratio [HR], 1.32; P = .05), and event-free survival (EFS; HR, 1.46; P < .001). This adverse prognostic impact was more pronounced in the intermediate cytogenetic risk group (EFS; HR, 1.64; P < .001; and RFS; HR, 1.55; P = .02), and was also apparent in cytogenetically normal AML (EFS; HR, 1.67; P = .008). Besides inv(3)/t(3;3), EVI1(+) was significantly associated with chromosome abnormalities monosomy 7 and t(11q23), conferring prognostic impact within these two cytogenetic subsets. EVI1(+) was virtually absent in favorable-risk AML and AML with NPM1 mutations. Patients with EVI1(+) AML (n = 28) who received allogeneic stem cell transplantation in first CR had significantly better 5-year RFS (33% +/- 10% v 0%). CONCLUSION EVI1 expression in AML is unequally distributed in cytogenetic subtypes. It predicts poor outcome, particularly among intermediate cytogenetic risk AML. Patients with EVI1(+) AML may benefit from allogeneic transplantation in first CR. Pretreatment EVI1 screening should be included in risk stratification.
Resistance training among young athletes: safety, efficacy and injury prevention effects
Authors: A D Faigenbaum, G D Myer
Journal: British Journal of Sports Medicine (2009)

A literature review was employed to evaluate the current epidemiology of injury related to the safety and efficacy of youth resistance training. Several case study reports and retrospective questionnaires regarding resistance exercise and the competitive sports of weightlifting and powerlifting reveal that injuries have occurred in young lifters, although a majority can be classified as accidental. Lack of qualified instruction that underlies poor exercise technique and inappropriate training loads could explain, at least partly, some of the reported injuries. Current research indicates that resistance training can be a safe, effective and worthwhile activity for children and adolescents provided that qualified professionals supervise all training sessions and provide age-appropriate instruction on proper lifting procedures and safe training guidelines. Regular participation in a multifaceted resistance training programme that begins during the preseason and includes instruction on movement biomechanics may reduce the risk of sports-related injuries in young athletes. Strategies for enhancing the safety of youth resistance training are discussed.
Insulinemia in Children at Low and High Risk of NIDDM
Authors: David J Pettitt, Patricia P Moll, William C Knowler, David M Mott, Robert G Nelson, Mohammed F Saad, Peter H Bennett, Bruce A Kottke
Journal: Diabetes Care (1993)

Fasting hyperinsulinemia in the presence of normoglycemia usually indicates insulin resistance and is characteristic of populations at high risk for developing NIDDM. Hyperinsulinemia predicts the development of impaired glucose tolerance and NIDDM in Pima Indians, a population with a high incidence of NIDDM. Insulin concentrations in population-based samples of children who have different risks of developing NIDDM later in life have not been reported previously.We compared fasting insulin concentrations in two populations of nondiabetic children, 6-19 yr of age: Pima Indians from southern Arizona and Caucasians from Minnesota.Insulin concentration varied with age, sex, glucose concentration, and relative weight. Mean fasting insulin concentration was 140.3 pM in Pima Indian males, 94.4 pM in Caucasian males, 171.5 pM in Pima Indian females, and 107.1 pM in Caucasian females. For each sex, the mean fasting insulin concentration, controlled for age, glucose, and relative weight, was significantly higher in the Pima Indians than in the Caucasians (P < 0.001).From a young age, Pima Indian children have higher fasting insulin concentrations than Caucasian children. As hyperinsulinemia predicts subsequent NIDDM, these data suggest that the susceptibility to NIDDM is manifest at a young age as fasting hyperinsulinemia.