Browsing by Subject "Survival"
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Item Open Access Abl Family Kinases Regulate Endothelial Function(2013) Chislock, Elizabeth MarieThe vasculature has a crucial function in normal physiology, enabling the transport of oxygen and nutrients to cells throughout the body. In turn, endothelial cells, which form the inner-most lining of blood vessels, are key regulators of vascular function. In addition to forming a barrier which separates the circulation from underlying tissues, endothelial cells respond to diverse extracellular cues and produce a variety of biologically-active mediators in order to maintain vascular homeostasis. Disruption of normal vascular function is a prominent feature of a variety of pathological conditions. Thus, elucidating the signaling pathways regulating endothelial function is critical for understanding the role of endothelial cells in both normal physiology and pathology, as well as for potential development of therapeutic interventions.
In this dissertation, we use a combination of pharmacological inhibition and knockdown studies, along with generation of endothelial conditional knockout mice, to demonstrate an important role of the Abelson (Abl) family of non-receptor tyrosine kinases (Abl and Arg) in vascular function. Specifically, loss of endothelial expression of the Abl kinases leads to late-stage embryonic and perinatal lethality in conditional knockout mice, indicating a crucial requirement for Abl/Arg kinases in normal vascular development and function. Endothelial Abl/Arg-null embryos display focal regions of vascular loss and tissue damage, as well as increased endothelial cell apoptosis. An important pro-survival function for the Abl kinases is further supported by our finding that either microRNA-mediated Abl/Arg depletion or pharmacological inhibition of the Abl kinases increases endothelial cell susceptibility to stress-induced apoptosis in vitro. The Abl kinases are activated in response to treatment with the pro-angiogenic growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). We show that both VEGF- and bFGF-mediated endothelial cell survival is impaired following Abl kinase inhibition.
These studies have uncovered a previously unappreciated role for the Abl kinases in the regulation of the angiopoietin/Tie2 signaling pathway, which functions to support endothelial cell survival and vascular stability. Loss of Abl/Arg expression leads to reduced mRNA and protein levels of the Tie2 receptor, resulting in impaired activation of intracellular signaling pathways by the Tie2 ligand angiopoietin-1 (Angpt1), as well as decreased Angpt1-mediated endothelial cell survival following serum-deprivation stress. Notably, we found that the Abl kinases are activated following Angpt1 stimulation, suggesting a unique dual role for Abl and Arg in Angpt/Tie2 signaling, potentially modulating Tie2 downstream signaling responses, as well as regulating Tie2 receptor expression.
Further, we show an important contribution of the Abl family kinases to the regulation of endothelial permeability responses both in vitro and in vivo. The Abl kinases are activated in response to a diverse group of permeability-inducing factors, including VEGF and the inflammatory mediators thrombin and histamine. We show that inhibition of Abl kinase activity, using either the ATP-competitive inhibitor imatinib or the allosteric inhibitor GNF-2, protects against disruption of endothelial barrier function by the permeability-inducing factors in vitro. VEGF-induced vascular permeability similarly is decreased in conditional knockout mice lacking endothelial Abl expression, as well as following treatment with Abl kinase inhibitors in vivo. Mechanistically, we show that loss of Abl kinase activity is accompanied by activation of the barrier-stabilizing GTPases (guanosine triphosphatases) Rac1 and Rap1, as well as inhibition of agonist-induced Ca2+ mobilization and generation of acto-myosin contractility.
Taken together, these results demonstrate involvement of the Abl family kinases in the regulation of endothelial cell responses to a broad range of pro-angiogenic and permeability-inducing factors, as well as a critical requirement for the endothelial Abl kinases in normal vascular development and function in vivo. These findings have implications for the clinical use of Abl kinase inhibitors.
Item Open Access Associations between urbanicity and spinal cord astrocytoma management and outcomes.(Cancer epidemiology, 2023-10) Sykes, David AW; Waguia, Romaric; Abu-Bonsrah, Nancy; Price, Mackenzie; Dalton, Tara; Sperber, Jacob; Owolo, Edwin; Hockenberry, Harrison; Bishop, Brandon; Kruchko, Carol; Barnholtz-Sloan, Jill S; Erickson, Melissa; Ostrom, Quinn T; Goodwin, C RoryBackground
The management of spinal cord astrocytomas (SCAs) remains controversial and may include any combination of surgery, radiation, and chemotherapy. Factors such as urbanicity (metropolitan versus non-metropolitan residence) are shown to be associated with patterns of treatment and clinical outcomes in a variety of cancers, but the role urbanicity plays in SCA treatment remains unknown.Methods
The Central Brain Tumor Registry of the United States (CBTRUS) analytic dataset, which combines data from CDC's National Program of Cancer Registries (NPCR) and NCI's Surveillance, Epidemiology, and End Results Programs, was used to identify individuals with SCAs between 2004 and 2019. Individuals' county of residence was classified as metropolitan or non-metropolitan. Multivariable logistic regression models were used to evaluate associations between urbanicity and SCA. Cox proportional hazard models were constructed to assess the effect of urbanicity on survival using the NPCR survival dataset (2004-2018).Results
1697 metropolitan and 268 non-metropolitan SCA cases were identified. The cohorts did not differ in age or gender composition. The populations had different racial/ethnic compositions, with a higher White non-Hispanic population in the non-metropolitan cohort (86 % vs 66 %, p < 0.001) and a greater Black non-Hispanic population in the metropolitan cohort (14 % vs 9.9 %, p < 0.001). There were no significant differences in likelihood of receiving comprehensive treatment (OR=0.99, 95 % CI [0.56, 1.65], p = >0.9), or survival (hazard ratio [HR]=0.92, p = 0.4) when non-metropolitan and metropolitan cases were compared. In the metropolitan cohort, there were statistically significant differences in SCA treatment patterns when stratified by race/ethnicity (p = 0.002).Conclusions
Urbanicity does not significantly impact SCA management or survival. Race/ethnicity may be associated with likelihood of receiving certain SCA treatments in metropolitan communities.Item Open Access Cardiovascular comorbidities and survival of lung cancer patients: Medicare data based analysis.(Lung Cancer, 2017-06-05) Kravchenko, Julia; Berry, Mark; Arbeev, Konstantin; Lyerly, H Kim; Yashin, Anatoly; Akushevich, IgorOBJECTIVES: To evaluate the role of cardiovascular disease (CVD) comorbidity in survival of patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The impact of seven CVDs (at the time of NSCLC diagnosis and during subsequent follow-up) on overall survival was studied for NSCLC patients aged 65+ years using the Surveillance, Epidemiology, and End Results data linked to the U.S. Medicare data, cancer stage- and treatment-specific. Cox regression was applied to evaluate death hazard ratios of CVDs in univariable and multivariable analyses (controlling by age, TNM statuses, and 78 non-CVD comorbidities) and to investigate the effects of 128 different combinations of CVDs on patients' survival. RESULTS: Overall, 95,167 patients with stage I (n=29,836, 31.4%), II (n=5133, 5.4%), IIIA (n=11,884, 12.5%), IIIB (n=18,020, 18.9%), and IV (n=30,294, 31.8%) NSCLC were selected. Most CVDs increased the risk of death for stages I-IIIB patients, but did not significantly impact survival of stage IV patients. The worse survival of patients was associated with comorbid heart failure, myocardial infarction, and cardiac arrhythmias that occurred during a period of follow-up: HRs up to 1.85 (p<0.001), 1.96 (p<0.05), and 1.67 (p<0.001), respectively, varying by stage and treatment. The presence of hyperlipidemia at baseline (HR down to 0.71, p<0.05) was associated with better prognosis. Having multiple co-existing CVDs significantly increased mortality for all treatments, especially for stages I and II patients treated with surgery (HRs up to 2.89, p<0.05) and stages I-IIIB patients treated with chemotherapy (HRs up to 2.59, p<0.001) and chemotherapy and radiotherapy (HRs up to 2.20, p<0.001). CONCLUSION: CVDs impact the survival of NSCLC patients, particularly when multiple co-existing CVDs are present; the impacts vary by stage and treatment. This data should be considered in improving cancer treatment selection process for such potentially challenging patients as the elderly NSCLC patients with CVD comorbidities.Item Open Access Evaluation of genotype-specific survival using joint analysis of genetic and non-genetic subsamples of longitudinal data.(Biogerontology, 2011-04) Arbeev, Konstantin G; Ukraintseva, Svetlana V; Arbeeva, Liubov S; Akushevich, Igor; Kulminski, Alexander M; Yashin, Anatoliy ISmall sample size of genetic data is often a limiting factor for desirable accuracy of estimated genetic effects on age-specific risks and survival. Longitudinal non-genetic data containing information on survival or disease onsets of study participants for whom the genetic data were not collected may provide an additional "reserve" for increasing the accuracy of respective estimates. We present a novel method for joint analyses of "genetic" (covering individuals for whom both genetic information and mortality/morbidity data are available) and "non-genetic" (covering individuals for whom only mortality/morbidity data were collected) subsamples of longitudinal data. Our simulation studies show substantial increase in the accuracy of estimates in such joint analyses compared to analyses based on genetic subsample alone. Application of this method to analysis of the effect of common apolipoprotein E (APOE) polymorphism on survival using combined genetic and non-genetic subsamples of the Framingham Heart Study original cohort data showed that female, but not male, carriers of the APOE e4 allele have significantly worse survival than non-carriers, whereas empirical analyses did not produce any significant results for either sex.Item Open Access Genetic Variants in RUNX3, AMD1 and MSRA in the Methionine Metabolic Pathway and Survival in Non-small Cell Lung Cancer Patients.(International journal of cancer, 2019-01-16) Chen, Ka; Liu, Hongliang; Liu, Zhensheng; Luo, Sheng; Patz, Edward F; Moorman, Patricia G; Su, Li; Shen, Sipeng; Christiani, David C; Wei, QingyiAbnormal methionine dependence in cancer cells has led to methionine restriction as a potential therapeutic strategy. We hypothesized that genetic variants involved in methionine-metabolic genes are associated with survival in non-small cell lung cancer (NSCLC) patients. Therefore, we investigated associations of 16,378 common single-nucleotide polymorphisms (SNPs) in 97 methionine-metabolic pathway genes with overall survival (OS) in NSCLC patients using genotyping data from two published genome-wide association study (GWAS) datasets. In the single-locus analysis, 1,005 SNPs were significantly associated with NSCLC OS (P < 0.05 and false-positive report probability < 0.2) in the discovery dataset. Three SNPs (RUNX3 rs7553295G>T, AMD1 rs1279590G>A and MSRA rs73534533C>A) were replicated in the validation dataset and their meta-analysis showed that adjusted hazards ratio [HR] of 0.82 [95% confidence interval (CI) =0.75-0.89] and Pmeta =2.86 x 10-6 , 0.81 (0.73-0.91) and Pmeta =4.63 x 10-4 , and 0.77 (0.68-0.89) and Pmeta =2.07 x 10-4 , respectively). A genetics score of protective genotypes of these three SNPs revealed an increased OS in a dose-response manner (Ptrend <.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between these genotypes and gene mRNA expression levels. Moreover, differential expression analysis further supported a tumor-suppressive effect of MSRA, with lower mRNA levels in both lung squamous carcinoma and adenocarcinoma (P <.0001 and <.0001, respectively) than in adjacent normal tissues. Additionally, low mutation rates of these three genes indicated the critical roles of these functional SNPs in cancer progression. Taken together, these genetic variants of methionine-metabolic pathway genes may be promising predictors of survival in NSCLC patients. This article is protected by copyright. All rights reserved.Item Open Access Optimism and survival: does an optimistic outlook predict better survival at advanced ages? A twelve-year follow-up of Danish nonagenarians.(Aging Clin Exp Res, 2013-10) Engberg, Henriette; Jeune, Bernard; Andersen-Ranberg, Karen; Martinussen, Torben; Vaupel, James W; Christensen, KaareBACKGROUND AND AIMS: Studies examining predictors of survival among the oldest-old have primarily focused on objective measures, such as physical function and health status. Only a few studies have examined the effect of personality traits on survival, such as optimism. The aim of this study was to examine whether an optimistic outlook predicts survival among the oldest-old. METHODS: The Danish 1905 Cohort Survey is a nationwide, longitudinal survey comprising all individuals born in Denmark in 1905. At baseline in 1998, a total of 2,262 persons aged 92 or 93 agreed to participate in the intake survey. The baseline in-person interview consisted of a comprehensive questionnaire including physical functioning and health, and a question about whether the respondent had an optimistic, neutral or pessimistic outlook on his or her own future. RESULTS: During the follow-up period of 12 years (1998-2010) there were 2,239 deaths (99 %) in the 1905 Cohort Survey. Univariable analyses revealed that optimistic women and men were at lower risk of death compared to their neutral counterparts [HR 0.82, 95 % CI (0.73-0.93) and 0.81, 95 % CI (0.66-0.99), respectively]. When confounding factors such as baseline physical and cognitive functioning and disease were taken into account the association between optimism and survival weakened in both sexes, but the general pattern persisted. Optimistic women were still at lower risk of death compared to neutral women [HR 0.85, 95 % CI (0.74-0.97)]. The risk of death was also decreased for optimistic men compared to their neutral counterparts, but the effect was non-significant [HR 0.91, 95 % CI (0.73-1.13)]. CONCLUSION: An optimistic outlook appears to be a significant predictor of survival among the oldest-old women. It may also be a significant predictor for men but the sample size is small.Item Open Access Potentially functional variants of ERAP1, PSMF1 and NCF2 in the MHC-I-related pathway predict non-small cell lung cancer survival.(Cancer immunology, immunotherapy : CII, 2021-03-02) Yang, Sen; Tang, Dongfang; Zhao, Yu Chen; Liu, Hongliang; Luo, Sheng; Stinchcombe, Thomas E; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Wang, Qiming; Wei, QingyiBackground
Cellular immunity against tumor cells is highly dependent on antigen presentation by major histocompatibility complex class I (MHC-I) molecules. However, few published studies have investigated associations between functional variants of MHC-I-related genes and clinical outcomes of lung cancer patients.Methods
We performed a two-phase Cox proportional hazards regression analysis by using two previously published genome-wide association studies to evaluate associations between genetic variants in the MHC-I-related gene set and the survival of non-small cell lung cancer (NSCLC) patients, followed by expression quantitative trait loci analysis.Results
Of the 7811 single-nucleotide polymorphisms (SNPs) in 89 genes of 1185 NSCLC patients in the discovery dataset of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 24 SNPs remained statistically significant after validation in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. In a multivariate stepwise Cox model, three independent functional SNPs (ERAP1 rs469783 T > C, PSMF1 rs13040574 C > A and NCF2 rs36071574 G > A) remained significant with an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.77-0.89, P = 8.0 × 10-7], 0.86 (0.80-0.93, P = 9.4 × 10-5) and 1.31 (1.11-1.54, P = 0.001) for overall survival (OS), respectively. Further combined genotypes revealed a poor survival in a dose-response manner in association with the number of unfavorable genotypes (Ptrend < 0.0001 and 0.0002 for OS and disease-specific survival, respectively). Also, ERAP1 rs469783C and PSMF1 rs13040574A alleles were associated with higher mRNA expression levels of their genes.Conclusion
These potentially functional SNPs of the MHC-I-related genes may be biomarkers for NSCLC survival, possibly through modulating the expression of corresponding genes.Item Open Access Reduced length of hospital stay in colorectal surgery after implementation of an enhanced recovery protocol.(Anesth Analg, 2014-05) Miller, TE; Thacker, JK; White, WD; Mantyh, C; Migaly, J; Jin, J; Roche, AM; Eisenstein, EL; Edwards, R; Anstrom, KJ; Moon, RE; Gan, TJBACKGROUND: Enhanced recovery after surgery (ERAS) is a multimodal approach to perioperative care that combines a range of interventions to enable early mobilization and feeding after surgery. We investigated the feasibility, clinical effectiveness, and cost savings of an ERAS program at a major U. S. teaching hospital. METHODS: Data were collected from consecutive patients undergoing open or laparoscopic colorectal surgery during 2 time periods, before and after implementation of an ERAS protocol. Data collected included patient demographics, operative, and perioperative surgical and anesthesia data, need for analgesics, complications, inpatient medical costs, and 30-day readmission rates. RESULTS: There were 99 patients in the traditional care group, and 142 in the ERAS group. The median length of stay (LOS) was 5 days in the ERAS group compared with 7 days in the traditional group (P < 0.001). The reduction in LOS was significant for both open procedures (median 6 vs 7 days, P = 0.01), and laparoscopic procedures (4 vs 6 days, P < 0.0001). ERAS patients had fewer urinary tract infections (13% vs 24%, P = 0.03). Readmission rates were lower in ERAS patients (9.8% vs 20.2%, P = 0.02). DISCUSSION: Implementation of an enhanced recovery protocol for colorectal surgery at a tertiary medical center was associated with a significantly reduced LOS and incidence of urinary tract infection. This is consistent with that of other studies in the literature and suggests that enhanced recovery programs could be implemented successfully and should be considered in U.S. hospitals.Item Open Access The H3K27 Histone Demethylase Kdm6b (Jmjd3) is Induced by Neuronal Activity and Contributes to Neuronal Survival and Differentiation(2012) Wijayatunge, RanjulaChanges in gene transcription driven by the activation of intracellular calcium signaling pathways play an important role in neural development and plasticity. A growing body of evidence suggests that stimulus-driven modulation of histone modifications play an important role in the regulation of neuronal activity-regulated gene transcription. However, the histone modifying enzymes that are targets of activity-regulated signaling cascades in neurons remain to be identified. The histone demethylases (HDMs) are a large family of enzymes that have selective catalytic activity against specific sites of histone methylation. To identify HDMs that may be important for activity-regulated gene transcription in neurons, we induced seizures in mice and screened for HDMs whose expression is induced in the hippocampus. Among the few HDMs that changed expression, Kdm6b showed the highest induction. Kdm6B is a histone H3K27-specific HDM whose enzymatic activity leads to transcriptionally permissive chromatin environments. In situ hybridization analysis revealed that Kdm6b is highly induced in post-mitotic neurons of the dentate gyrus region of the hippocampus. We can recapitulate the activity-dependent induction of Kdm6b expression in cultured hippocampal neurons by application of Bicuculline, a GABAA receptor antagonist that leads to synaptic NMDA receptor activation and calcium influx. Kdm6b expression is also induced following application of BDNF, a neurotrophic factor that is upregulated in the seized hippocampus. To investigate possible functions of Kdm6b in neuronal development, we performed in situ hybridization analysis that allows for the identification of regions with high Kdm6b expression that could be sites of potential function in the developing mouse brain. We found high levels of Kdm6b expression in the inner layer of the external granule layer of the cerebellum, a region where pre-migratory immature neurons reside and a site of significant apoptosis. On the basis of this data and the fact that intracellular calcium signaling arising from synaptic firing supports neuronal survival, we explored the necessity for Kdm6b in the survival of cultured cerebellar granule cells. Knock down of Kdm6b by RNAi increases cell death, demonstrating that Kdm6b contributes to neuronal survival. Ongoing experiments are addressing the role of Kdm6b in neuronal differentiation. Overall these data raise the possibility that stimulus-dependent regulation of Kdm6b, and perhaps regulation of H3K27 methylation mediated by Kdm6b, may contribute to the regulation of gene expression in neurons and thus to their proper development and plasticity.
Item Open Access Unfolded protein response genes regulated by CED-1 are required for Caenorhabditis elegans innate immunity.(2008) Haskins, Kylie AnneThe first line of defense against pathogens is the phylogenetically ancient innate immune system. This system consists of physical barriers and conserved signaling pathways are activated upon infection to produce effector molecules that mount a microbicidal response. Recently, C. elegans has been established as a model organism for the study of innate immunity due to C. elegans genetic tractability and origins predating the evolution of adaptive immunity. Conserved defense pathways essential for mammalian innate immunity have been identified in C. elegans. However, most receptors critical for the activation of the defense signaling pathways in C. elegans remain unknown. The goal of this work was to study CED-1 and its potential role as a cell-surface signaling receptor essential for C. elegans immune response. In this study, we performed a full-genome microarray analysis and discovered that CED-1 functions to activate the expression of pqn/abu unfolded protein response (UPR) genes. The unfolded protein response has been implicated in the normal physiology of immune defense and in several disorders including diabetes, cancer, and neurodegenerative disease. Here we show that ced-1 and pqn/abu genes are required for the survival of C. elegans exposed to live S. enterica. We also show that the overexpression of pqn/abu genes confers protection to pathogen-mediated killing. Taken together, these results indicate that the apoptotic receptor CED-1 and a network of PQN/ABU proteins involved in a non-canonical UPR response are required for proper defense to pathogen infection in Caenorhabditis elegans.Item Open Access "We Can Learn To Mother Ourselves": The Queer Survival of Black Feminism(2010) Gumbs, Alexis Pauline"We Can Learn to Mother Ourselves": The Queer Survival of Black Feminism 1968-1996 addresses the questions of mothering and survival from a queer, diasporic literary perspective, arguing that the literary practices of Black feminists Audre Lorde, June Jordan, Alexis De Veaux and Barbara Smith enable a counternarrative to a neoliberal logic that criminalizes Black mothering and the survival of Black people outside and after their utility to capital. Treating Audre Lorde and June Jordan as primary theorists of mothering and survival, and Alexis De Veaux and Barbara Smith as key literary historical figures in the queer manifestation of Black feminist modes of literary production, this dissertation uses previously unavailable archival material, and queer of color critique and critical Black diasporic theoretical approaches to create an intergenerative reading practice. An intergenerative reading practice interrupts the social reproduction of meaning and value across time, and places untimely literary moments and products in poetic relationship to each other in order to reveal the possibility of another meaning of life. Ultimately this dissertation functions as a sample narrative towards the alternate meaning of life that the poetic breaks of Black feminist literary production in the queer spaces of counter-cultural markets, classrooms, autonomous publishing collectives make possible, concluding that mothering is indeed a reflexive and queer way of reading the present in the service of a substantively different future in which our outlawed love survives.