tbuckley/cabot-search huggingface dataset:
ISG20L1 is a p53 family target gene that modulates genotoxic stress-induced autophagy
Authors: Kathryn G. Eby, Jennifer M. Rosenbluth, Deborah J. Mays, Clayton B. Marshall, Christopher E. Barton, Seema Sinha, Kimberly N. Johnson, Luojia Tang, Jennifer A. Pietenpol
Journal: Molecular Cancer (2010)

Abstract Background Autophagy is characterized by the sequestration of cytoplasm and organelles into multimembrane vesicles and subsequent degradation by the cell's lysosomal system. It is linked to many physiological functions in human cells including stress response, protein degradation, organelle turnover, caspase-independent cell death and tumor suppression. Malignant transformation is frequently associated with deregulation of autophagy and several tumor suppressors can modulate autophagic processes. The tumor suppressor p53 can induce autophagy after metabolic or genotoxic stress through transcriptionally-dependent and -independent mechanisms. In this study we expand on the former mechanism by functionally characterizing a p53 family target gene, ISG20L1 under conditions of genotoxic stress. Results We identified a p53 target gene, ISG20L1, and show that transcription of the gene can be regulated by all three p53 family members (p53, p63, and p73). We generated an antibody to ISG20L1 and found that it localizes to the nucleolar and perinucleolar regions of the nucleus and its protein levels increase in a p53- and p73-dependent manner after various forms of genotoxic stress. When ectopically expressed in epithelial cancer-derived cell lines, ISG20L1 expression decreased clonogenic survival without a concomitant elevation in apoptosis and this effect was partially rescued in cells that were ATG5 deficient. Knockdown of ISG20L1 did not alter 5-FU induced apoptosis as assessed by PARP and caspase-3 cleavage, sub-G 1 content, and DNA laddering. Thus, we investigated the role of ISG20L1 in autophagy, a process commonly associated with type II cell death, and found that ISG20L1 knockdown decreased levels of autophagic vacuoles and LC3-II after genotoxic stress as assessed by electron microscopy, biochemical, and immunohistochemical measurements of LC3-II. Conclusions Our identification of ISG20L1 as a p53 family target and discovery that modulation of this target can regulate autophagic processes further strengthens the connection between p53 signaling and autophagy. Given the keen interest in targeting autophagy as an anticancer therapeutic approach in tumor cells that are defective in apoptosis, investigation of genes and signaling pathways involved in cell death associated with autophagy is critical.
Differential Inhibitor Sensitivity of Anaplastic Lymphoma Kinase Variants Found in Neuroblastoma
Authors: Scott C. Bresler, Andrew C. Wood, Elizabeth A. Haglund, Joshua Courtright, Lili T. Belcastro, Jefferson S. Plegaria, Kristina Cole, Yana Toporovskaya, Huaqing Zhao, Erica L. Carpenter, James G. Christensen, John M. Maris, Mark A. Lemmon, Yaël P. Mossé
Journal: Science Translational Medicine (2011)

Neuroblastoma sensitivity to crizotinib depends on the ATP-binding affinity of ALK variants, suggesting that higher doses may overcome resistance.
Switch from fetal to adult hemoglobin is associated with a change in progenitor cell population.
Authors: R S Weinberg, J D Goldberg, J M Schofield, A L Lenes, R Styczynski, B P Alter
Journal: Journal of Clinical Investigation (1983)

To examine the switch from fetal to adult hemoglobin at the cellular level, erythroid progenitor cells from newborn infants and adults were cultured in methyl cellulose with erythropoietin. Individual erythroid colonies were labeled with [3H]leucine at various times, and globin synthesis patterns examined by gel electrophoresis and fluorography. The percent gamma- or beta-globin synthesis was determined from the total of gamma + beta, and the percent G gamma from the total of G gamma + A gamma. The nonparametric correlation coefficients of percent G gamma with percent gamma or beta were obtained. Each group of colonies at each time point was examined separately. In colonies from adult blood, the proportion of G gamma-synthesis did not correlate with the proportion of gamma-synthesis. Colonies from newborn blood fell into two groups. Those that developed from relatively mature progenitor cells, and were seen on day 14, showed a strong negative correlation of G gamma with beta-globin synthesis. However, those newborn colonies that developed from immature progenitors, and were seen later in culture (days 17 and 21), showed no correlation of G gamma with beta-synthesis. These findings are compatible with a clonal model for hemoglobin switching. Fetal progenitors, in which G gamma- and beta-syntheses are negatively correlated, are gradually replaced during ontogeny by adult progenitors. The adult progenitors produce more beta (less gamma), and the proportions of G gamma- and gamma- or beta-synthesis are not correlated.
Prevention of nosocomial bacterial pneumonia
Authors: J.-L. Vincent
Journal: Thorax (1999)

The term “nosocomial pneumonia” broadly covers all infections occurring 48 hours or more after hospital admission excluding any infection incubating at the time of admission, and has also been called hospital acquired pneumonia. Intensive care unit (ICU) acquired pneumonia (occurring within 48 hours of admission to the ICU) and ventilator associated pneumonia (occurring within 48 hours of starting mechanical ventilation) are also included in the broader term “nosocomial pneumonia”. The development of nosocomial pneumonia remains a major problem in the ICU with most studies reporting an incidence of between 9% and 45%,1-19 depending on the groups of patients being studied, the definition of nosocomial pneumonia, and the criteria used to diagnose it. It has been shown that nosocomial pneumonia acquired in the ICU markedly increases the length of hospital stay12 16 20 21 and the costs of hospital care.21 22 Mortality rates may also be increased,3 5 7 16 17 19 23 although it is not entirely clear whether all deaths from nosocomial pneumonia are directly related to the development of an infection. The so-called “attributable mortality”, defined as the mortality occurring as the direct result of the nosocomial pneumonia, may be especially high when Pseudomonas or Acinetobacter species are involved as pathogens.19 

The diagnosis of nosocomial pneumonia is not straightforward, particularly in patients who are critically ill, as routine parameters do not have a high specificity for pneumonia in these patients.24 For example, infiltrates on chest radiographs consistent with pneumonia may be due to many other processes including oedema, atelectasis, and infarction.25 Positive cultures from tracheal aspirates are also non-specific as the upper respiratory tract of most critically ill patients is colonised by potential pulmonary pathogens.26 Alternative diagnostic techniques such as protected specimen brush biopsies and bronchoalveolar lavage have therefore been …
Skewed X-chromosomal inactivation patterns are present in systemic sclerosis and associated with foxp3 expression
Authors: J Broen, I L M Wolvers-Tettero, L G.-v. Bon, M C Vonk, M J Coenen, R Lafyatis,, T R D J Radstake, A W Langerak
Journal: Annals of the Rheumatic Diseases (2010)

Objective To investigate the possible role of X-chromosomal inactivation (XCI) in systemic sclerosis (SSc) and clinical subtypes.The authors also examined the presence of skewing in on July 22,
Vascular Muscle Series Elastic Element Stiffness during Isometric Contraction
Authors: PHILIP B. DOBRIN
Journal: Circulation Research (1974)

Series elastic element stiffness was studied during isometric muscle contraction in cylindrical segments of dog common carotid artery. These vessel segments were mounted in vitro and restored to in situ length. Vessel diameter was constantly monitored with a linear displacement transducer. The arteries were subjected to isometric contraction by adding norepinephrine to the bath and elevating the transmural pressure enough to maintain constant vessel diameter. Small, rapid quick release-quick stretch cycles were performed repeatedly during isometric contractions to evaluate the stiffness of the undamped series elastic element. After contraction was complete, repeated quick release-quick stretch cycles were also performed during inactivation of the muscle caused by the administration of potassium cyanide. At strains up to the peak in the length-active tension curve, series elastic element stiffness was a linear function of stress thoughout both isometric contraction and isometric relaxation for both quick releases and quick stretches. Vessels excited at strains less than that associated with the peak in the length-tension curve (100 mm Hg) exhibited similar stress-series elastic element stiffness slopes, but vessels excited at larger strains exhibited decreased or negative stress-series elastic stiffness slopes. Studies on potassium cyanide-poisoned vessels failed to indicate any alteration in the quick release properties of the connective tissue at large strains. The concomitant decline in the stress-series elastic element stiffness slope and the active isometric stress at large strains suggests (1) that the series elastic element undergoes mechanical yielding at high stresses or (2) that the series elastic element is an integral part of the force-generating apparatus.
Short Sleep Duration and Poor Sleep Quality Increase the Risk of Diabetes in Japanese Workers With No Family History of Diabetes
Authors: Toshiko Kita, Eiji Yoshioka, Hiroki Satoh, Yasuaki Saijo, Mariko Kawaharada, Eisaku Okada, Reiko Kishi
Journal: Diabetes Care (2011)

OBJECTIVE To investigate whether a difference in the risk for diabetes exists in Japanese workers with regard to sleep duration/quality and the presence or absence of a family history of diabetes (FHD). RESEARCH DESIGN AND METHODS The researchers conducted a prospective, occupational-based study of local government employees in Sapporo, Japan. Between April 2003 and March 2004, 3,570 nondiabetic participants, aged 35–55 years, underwent annual health checkups and completed a self-administered questionnaire that included information on sleep duration/quality and FHD at baseline. Having diabetes was defined as taking medication for diabetes or a fasting plasma glucose level of ≥126 mg/dL at follow-up (2007–2008). RESULTS A total of 121 (3.4%) new cases of diabetes were reported. In multivariate logistic regression models of workers without an FHD, and after adjustment for potential confounding factors, the odds ratio (95% CI) for developing diabetes was 5.37 (1.38–20.91) in those with a sleep duration of ≤5 h compared with those with a sleep duration of &amp;gt;7 h. Other risk factors were awakening during the night (5.03 [1.43–17.64]), self-perceived insufficient sleep duration (6.76 [2.09–21.87]), and unsatisfactory overall quality of sleep (3.71 [1.37–10.07]). In subjects with an FHD, these associations were either absent or weaker. CONCLUSIONS The current study shows that poor sleep is associated with a higher risk of developing diabetes in workers without an FHD. Promoting healthy sleeping habits may be effective for preventing the development of diabetes in people without an FHD.
PEA-15 Inhibits Tumorigenesis in an MDA-MB-468 Triple-Negative Breast Cancer Xenograft Model through Increased Cytoplasmic Localization of Activated Extracellular Signal-Regulated Kinase
Authors: Chandra Bartholomeusz, Ana M. Gonzalez-Angulo, Anna Kazansky, Savitri Krishnamurthy, Ping Liu, Linda X. H. Yuan, Fumiyuki Yamasaki, Shuying Liu, Naoki Hayashi, Dongwei Zhang, Francisco J. Esteva, Gabriel N. Hortobagyi, Naoto T. Ueno
Journal: Clinical Cancer Research (2010)

To determine the role of PEA-15 in breast cancer.A reverse-phase protein array was used to measure PEA-15 expression levels in 320 human breast cancers; these levels were correlated with clinical and tumor characteristics. PEA-15 was overexpressed by an adenovirus vector or by stably expressing PEA-15 in different breast cancer cell lines. The effects on breast cancer cell survival and on the downstream apoptotic signaling pathway were measured in terms of cell proliferation (trypan blue for cell viability, bromodeoxyuridine incorporation for DNA synthesis), anchorage-independent growth (soft agar colony formation), and apoptosis (fluorescence-activated cell sorter analysis). The preclinical efficacy of Ad.PEA-15 given intratumorally was evaluated in nude mice bearing tumors from s.c. implanted human MDA-MB-468 triple-negative breast cancer cells.In human breast cancers, low levels of PEA-15 expression correlated with high nuclear grade (P < 0.0001) and with negative hormone receptor status (P = 0.0004). Overexpression of PEA-15 in breast cancer cells resulted in growth inhibition, reduction in DNA synthesis, and onset of caspase-8-dependent apoptosis. In athymic nude mice bearing MDA-MB-468 xenografts, tumor volumes were significantly smaller in mice treated intratumorally with Ad.PEA-15 than in control mice (P < 0.0001). Tumors from mice treated with Ad.PEA-15 had increased levels of activated (phosphorylated) extracellular signal-regulated kinase and reduced levels of Ki-67 compared with tumors from nontreated or control-adenovirus-treated mice.PEA-15 has therapeutic potential in breast cancer. Further preclinical and clinical exploration of PEA-15 as a druggable target is warranted.
Influence of wild-type MLL on glucocorticoid sensitivity and response to DNA-damage in pediatric acute lymphoblastic leukemia
Authors: Alex H Beesley, Janelle L Rampellini, Misty-Lee Palmer, Jasmin YS Heng, Amy L Samuels, Martin J Firth, Jette Ford, Ursula R Kees
Journal: Molecular Cancer (2010)

Abstract Background Rearrangement of the mixed-lineage leukemia gene ( MLL ) is found in 80% of infant acute lymphoblastic leukemia (ALL) and is associated with poor prognosis and resistance to glucocorticoids (GCs). We have recently observed that GC resistance in T-ALL cell lines is associated with a proliferative metabolism and reduced expression of MLL . In this study we have further explored the relationship between MLL status and GC sensitivity. Results Negative correlation of MLL expression with GC resistance in 15 T-ALL cell lines was confirmed by quantitative RT-PCR. The absence of MLL -rearrangements suggested that this relationship represented expression of wild-type MLL . Analysis of MLL expression patterns revealed a negative relationship with cellular metabolism, proliferation and anti-apoptotic transcriptional networks. In silico analysis of published data demonstrated that reduced levels of MLL mRNA are associated with relapse and prednisolone resistance in T-ALL patients and adverse clinical outcome in children with MLL -rearranged ALL. RNAi knockdown of MLL expression in T-ALL cell lines significantly increased resistance to dexamethasone and gamma irradiation indicating an important role for wild-type MLL in the control of cellular apoptosis. Conclusions The data suggests that reduced expression of wild-type MLL can contribute to GC resistance in ALL patients both with and without MLL -translocations.
Reduced DNA Repair Capacity for Removing Tobacco Carcinogen–Induced DNA Adducts Contributes to Risk of Head and Neck Cancer but not Tumor Characteristics
Authors: Li-E Wang, Zhibin Hu, Erich M. Sturgis, Margaret R. Spitz, Sara S. Strom, Christopher I. Amos, Zhaozheng Guo, Yawei Qiao, Ann Marie Gillenwater, Jeffrey N. Myers, Gary L. Clayman, Randal S. Weber, Adel K. El-Naggar, Li Mao, Scott M. Lippman, Waun Ki Hong, Qingyi Wei
Journal: Clinical Cancer Research (2010)

Although cigarette smoking and alcohol use are known risk factors for squamous cell carcinoma of head and neck (SCCHN), only a few exposed individuals develop this disease, suggesting an individual susceptibility. In this study, we investigated the associations between genetically determined DNA repair capacity (DRC) for removing tobacco-induced DNA adducts and risk of SCCHN and tumor characteristics.
Sexual Selection and Maintenance of Sex: Evidence from Comparisons of Rates of Genomic Accumulation of Mutations and Divergence of Sex-Related Genes in Sexual and Hermaphroditic Species of Caenorhabditis
Authors: C. G. Artieri, W. Haerty, B. P. Gupta, R. S. Singh
Journal: Molecular Biology and Evolution (2008)

Several hypotheses have been proposed to explain the persistence of dioecy despite the reproductive advantages conferred to hermaphrodites, including greater efficiency at purging deleterious mutations in the former. Dioecy can benefit from both mutation purging and accelerated evolution by bringing together beneficial mutations in the same individual via recombination and shuffling of genotypes. In addition, mathematical treatment has shown that sexual selection is also capable of mitigating the cost of maintaining separate sexes by increasing the overall fitness of sexual populations, and genomic comparisons have shown that sexual selection can lead to accelerated evolution. Here, we examine the advantages of dioecy versus hermaphroditism by comparing the rate of evolution in sex-related genes and the rate of accumulation of deleterious mutations using a large number of orthologs (11,493) in the dioecious Caenorhabditis remanei and the hermaphroditic Caenorhabditis briggsae. We have used this data set to estimate the deleterious mutation rate per generation, U, in both species and find that although it is significantly higher in hermaphrodites, both species are at least 2 orders of magnitude lower than the value required to explain the persistence of sex by efficiency at purging deleterious mutations alone. We also find that genes expressed in sperm are evolving rapidly in both species; however, they show a greater increase in their rate of evolution relative to genes expressed in other tissues in C. remanei, suggesting stronger sexual selection pressure acting on these genes in dioecious species. Interestingly, the persistence of a signal of rapid evolution of sperm genes in C. briggsae suggests a recent evolutionary origin of hermaphrodism in this lineage. Our results provide empirical evidence of increased sexual selection pressure in dioecious animals, supporting the possibility that sexual selection may play an important role in the maintenance of sexual reproduction.
Association of peptic ulcer with increased expression of Lewis antigens but not cagA, iceA, and vacA in Helicobacter pylori isolates in an Asian population
Authors: P Y Zheng
Journal: Gut (2000)

<h3>BACKGROUND</h3> Studies in Western populations suggest that <i>cagA, iceA,</i> and <i>vacA</i>gene status in<i> Helicobacter pylori </i>isolates is associated with increased virulence and peptic ulcer disease. <h3>AIM</h3> To investigate the relationship between peptic ulcer and expression of Lewis (Le) antigens as well as <i>cagA, iceA,</i> and <i>vacA</i> in<i>H pylori </i>isolates in Singapore. <h3>METHODS</h3> Expression of Le antigens in<i> H pylori </i>isolates obtained from patients with dyspepsia was measured by enzyme linked immunosorbent assay. The <i>cagA, iceA,</i> and <i>vacA</i>status was determined by polymerase chain reaction. <h3>RESULTS</h3> Of 108<i>H pylori </i>isolates, 103 (95.4%) expressed Le<sup>x</sup> and/or Le<sup>y</sup>, while Le<sup>a</sup> and Le<sup>b</sup> were expressed in 23 (21.3%) and 47 (43.5%) isolates, respectively. Expression of two or more Le antigens (Le<sup>x</sup>, Le<sup>y</sup>, Le<sup>a</sup>, or Le<sup>b</sup>) was significantly higher in <i>H pylori</i> isolated from ulcer patients than in non-ulcer patients (89.6%<i>v</i> 73.2%, p=0.035). There were no significant differences in the prevalence of<i>cagA</i> or <i>iceA</i>1 in<i>H pylori </i>isolates from peptic ulcer and non-ulcer patients (86.6% <i>v</i> 90.2% for<i>cagA</i>; 70.1% <i>v</i>68.3% for <i>iceA</i>1), and no association of peptic ulcer with any specific <i>vacA</i>genotype. <h3>CONCLUSIONS</h3> The present study indicates that peptic ulcer disease is associated with increased expression of Lewis antigens but not<i>cagA, iceA,</i> or<i>vacA</i> genotype in <i>H pylori </i>isolates in our population. This suggests that<i>cagA, iceA,</i> and<i>vacA</i> are not universal virulence markers, and that host-pathogen interactions are important in determining clinical outcome.
Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn
Authors: Batoule H. Majed, Raouf A. Khalil
Journal: Pharmacological Reviews (2012)

Prostacyclin (PGI<sub>2</sub>) is a member of the prostanoid group of eicosanoids that regulate homeostasis, hemostasis, smooth muscle function and inflammation. Prostanoids are derived from arachidonic acid by the sequential actions of phospholipase A<sub>2</sub>, cyclooxygenase (COX), and specific prostaglandin (PG) synthases. There are two major COX enzymes, COX1 and COX2, that differ in structure, tissue distribution, subcellular localization, and function. COX1 is largely constitutively expressed, whereas COX2 is induced at sites of inflammation and vascular injury. PGI<sub>2</sub> is produced by endothelial cells and influences many cardiovascular processes. PGI<sub>2</sub> acts mainly on the prostacyclin (IP) receptor, but because of receptor homology, PGI<sub>2</sub> analogs such as iloprost may act on other prostanoid receptors with variable affinities. PGI<sub>2</sub>/IP interaction stimulates G protein-coupled increase in cAMP and protein kinase A, resulting in decreased [Ca<sup>2+</sup>]<sub>i</sub>, and could also cause inhibition of Rho kinase, leading to vascular smooth muscle relaxation. In addition, PGI<sub>2</sub> intracrine signaling may target nuclear peroxisome proliferator-activated receptors and regulate gene transcription. PGI<sub>2</sub> counteracts the vasoconstrictor and platelet aggregation effects of thromboxane A<sub>2</sub> (TXA<sub>2</sub>), and both prostanoids create an important balance in cardiovascular homeostasis. The PGI<sub>2</sub>/TXA<sub>2</sub> balance is particularly critical in the regulation of maternal and fetal vascular function during pregnancy and in the newborn. A decrease in PGI<sub>2</sub>/TXA<sub>2</sub> ratio in the maternal, fetal, and neonatal circulation may contribute to preeclampsia, intrauterine growth restriction, and persistent pulmonary hypertension of the newborn (PPHN), respectively. On the other hand, increased PGI<sub>2</sub> activity may contribute to patent ductus arteriosus (PDA) and intraventricular hemorrhage in premature newborns. These observations have raised interest in the use of COX inhibitors and PGI<sub>2</sub> analogs in the management of pregnancy-associated and neonatal vascular disorders. The use of aspirin to decrease TXA<sub>2</sub> synthesis has shown little benefit in preeclampsia, whereas indomethacin and ibuprofen are used effectively to close PDA in the premature newborn. PGI<sub>2</sub> analogs have been used effectively in primary pulmonary hypertension in adults and have shown promise in PPHN. Careful examination of PGI<sub>2</sub> metabolism and the complex interplay with other prostanoids will help design specific modulators of the PGI<sub>2</sub>-dependent pathways for the management of pregnancy-related and neonatal vascular disorders.
Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Masahiro Fukuoka, Seiji Yano, Giuseppe Giaccone, Tomohide Tamura, Kazuhiko Nakagawa, Jean-Yves Douillard, Yutaka Nishiwaki, Johan Vansteenkiste, Shinzoh Kudoh, Danny Rischin, Richard Eek, Takeshi Horai, Kazumasa Noda, Ichiro Takata, Egbert Smit, Steven Averbuch, Angela Macleod, Andrea Feyereislova, Rui-Ping Dong, José Baselga
Journal: Journal of Clinical Oncology (2003)

To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC).