Long survival in a 69,XXX triploid infant in Greece.

PubMed

Iliopoulos, Dimitrios; Vassiliou, Georgia; Sekerli, Eleni; Sidiropoulou, Vasiliki; Tsiga, Alexandra; Dimopoulou, Despina; Voyiatzis, Nikolaos

2005-12-30

The live birth of a triploidy infant is a very rare event and death usually occurs within the first hours of life. Triploid cases with a survival of more than two months are infrequent. We report on an infant with a 69,XXX chromosome constitution who survived 164 days. Chromosomal analysis demonstrated a 69,XXX karyotype with no evidence of mosaicism. This is the longest survival reported for this condition to date in Greece and the fourth longest worldwide. The infant was admitted to our clinic several times due to respiratory problems, and supplementary oxygen was required. The improved survival of our case was possibly due to better management of respiratory illness and prematurity, and these are essential factors that physicians should consider carefully with such rare cases.

Insulin-like growth factor-I receptor activity is essential for Kaposi's sarcoma growth and survival.

PubMed

Catrina, S-B; Lewitt, M; Massambu, C; Dricu, A; Grünler, J; Axelson, M; Biberfeld, P; Brismar, K

2005-04-25

Kaposi's sarcoma (KS) is a highly vascular tumour and is the most common neoplasm associated with human immunodeficiency virus (HIV-1) infection. Growth factors, in particular vascular endothelial growth factor (VEGF), have been shown to play an important role in its development. The role of insulin-like growth factors (IGFs) in the pathophysiology of different tumours led us to evaluate the role of IGF system in KS. The IGF-I receptors (IGF-IR) were identified by immunohistochemistry in biopsies taken from patients with different AIDS/HIV-related KS stages and on KSIMM cells (an established KS-derived cell line). Insulin-like growth factor-I is a growth factor for KSIMM cells with a maximum increase of 3H-thymidine incorporation of 130 +/- 27.6% (P < 0.05) similar to that induced by VEGF and with which it is additive (281 +/- 13%) (P < 0.05). Moreover, specific blockade of the receptor (either by alpha IR3 antibody or by picropodophyllin, a recently described selective IGF-IR tyrosine phosphorylation inhibitor) induced KSIMM apoptosis, suggesting that IGF-IR agonists (IGF-I and -II) mediate antiapoptotic signals for these cells. We were able to identify an autocrine loop essential for KSIMM cell survival in which IGF-II is the IGF-IR agonist secreted by the cells. In conclusion, IGF-I pathway inhibition is a promising therapeutical approach for KS tumours.

An interaction between hepatocyte growth factor and its receptor (c-MET) prolongs the survival of chronic lymphocytic leukemic cells through STAT3 phosphorylation: a potential role of mesenchymal cells in the disease.

PubMed

Giannoni, Paolo; Scaglione, Silvia; Quarto, Rodolfo; Narcisi, Roberto; Parodi, Manuela; Balleari, Enrico; Barbieri, Federica; Pattarozzi, Alessandra; Florio, Tullio; Ferrini, Silvano; Corte, Giorgio; de Totero, Daniela

2011-07-01

Chronic lymphocytic leukemia cells are characterized by an apparent longevity in vivo which is lost when they are cultured in vitro. Cellular interactions and factors provided by the microenvironment appear essential to cell survival and may protect leukemic cells from the cytotoxicity of conventional therapies. Understanding the cross-talk between leukemic cells and stroma is of interest for identifying signals supporting disease progression and for developing novel therapeutic strategies. Different cell types, sharing a common mesenchymal origin and representative of various bone marrow components, were used to challenge the viability of leukemic cells in co-cultures and in contact-free culture systems. Using a bioinformatic approach we searched for genes shared by lineages prolonging leukemic cell survival and further analyzed their biological role in signal transduction experiments. Human bone marrow stromal cells, fibroblasts, trabecular bone-derived cells and an osteoblast-like cell line strongly enhanced survival of leukemic cells, while endothelial cells and chondrocytes did not. Gene expression profile analysis indicated two soluble factors, hepatocyte growth factor and CXCL12, as potentially involved. We demonstrated that hepatocyte growth factor and CXCL12 are produced only by mesenchymal lineages that sustain the survival of leukemic cells. Indeed chronic lymphocytic leukemic cells express a functional hepatocyte growth factor receptor (c-MET) and hepatocyte growth factor enhanced the viability of these cells through STAT3 phosphorylation, which was blocked by a c-MET tyrosine kinase inhibitor. The role of hepatocyte growth factor was confirmed by its short interfering RNA-mediated knock-down in mesenchymal cells. The finding that hepatocyte growth factor prolongs the survival of chronic lymphocytic leukemic cells is novel and we suggest that the interaction between hepatocyte growth factor-producing mesenchymal and neoplastic cells contributes to maintenance of the leukemic clone.

An interaction between hepatocyte growth factor and its receptor (c-MET) prolongs the survival of chronic lymphocytic leukemic cells through STAT3 phosphorylation: a potential role of mesenchymal cells in the disease

PubMed Central

Giannoni, Paolo; Scaglione, Silvia; Quarto, Rodolfo; Narcisi, Roberto; Parodi, Manuela; Balleari, Enrico; Barbieri, Federica; Pattarozzi, Alessandra; Florio, Tullio; Ferrini, Silvano; Corte, Giorgio; de Totero, Daniela

2011-01-01

Background Chronic lymphocytic leukemia cells are characterized by an apparent longevity in vivo which is lost when they are cultured in vitro. Cellular interactions and factors provided by the microenvironment appear essential to cell survival and may protect leukemic cells from the cytotoxicity of conventional therapies. Understanding the cross-talk between leukemic cells and stroma is of interest for identifying signals supporting disease progression and for developing novel therapeutic strategies. Design and Methods Different cell types, sharing a common mesenchymal origin and representative of various bone marrow components, were used to challenge the viability of leukemic cells in co-cultures and in contact-free culture systems. Using a bioinformatic approach we searched for genes shared by lineages prolonging leukemic cell survival and further analyzed their biological role in signal transduction experiments. Results Human bone marrow stromal cells, fibroblasts, trabecular bone-derived cells and an osteoblast-like cell line strongly enhanced survival of leukemic cells, while endothelial cells and chondrocytes did not. Gene expression profile analysis indicated two soluble factors, hepatocyte growth factor and CXCL12, as potentially involved. We demonstrated that hepatocyte growth factor and CXCL12 are produced only by mesenchymal lineages that sustain the survival of leukemic cells. Indeed chronic lymphocytic leukemic cells express a functional hepatocyte growth factor receptor (c-MET) and hepatocyte growth factor enhanced the viability of these cells through STAT3 phosphorylation, which was blocked by a c-MET tyrosine kinase inhibitor. The role of hepatocyte growth factor was confirmed by its short interfering RNA-mediated knock-down in mesenchymal cells. Conclusions The finding that hepatocyte growth factor prolongs the survival of chronic lymphocytic leukemic cells is novel and we suggest that the interaction between hepatocyte growth factor-producing mesenchymal and neoplastic cells contributes to maintenance of the leukemic clone. PMID:21486864

Sex-specific early survival drives adult sex ratio bias in snowy plovers and impacts mating system and population growth

PubMed Central

Küpper, Clemens; Miller, Tom E. X.; Cruz-López, Medardo; Maher, Kathryn H.; dos Remedios, Natalie; Stoffel, Martin A.; Hoffman, Joseph I.; Krüger, Oliver; Székely, Tamás

2017-01-01

Adult sex ratio (ASR) is a central concept in population biology and a key factor in sexual selection, but why do most demographic models ignore sex biases? Vital rates often vary between the sexes and across life history, but their relative contributions to ASR variation remain poorly understood—an essential step to evaluate sex ratio theories in the wild and inform conservation. Here, we combine structured two-sex population models with individual-based mark–recapture data from an intensively monitored polygamous population of snowy plovers. We show that a strongly male-biased ASR (0.63) is primarily driven by sex-specific survival of juveniles rather than adults or dependent offspring. This finding provides empirical support for theories of unbiased sex allocation when sex differences in survival arise after the period of parental investment. Importantly, a conventional model ignoring sex biases significantly overestimated population viability. We suggest that sex-specific population models are essential to understand the population dynamics of sexual organisms: reproduction and population growth are most sensitive to perturbations in survival of the limiting sex. Overall, our study suggests that sex-biased early survival may contribute toward mating system evolution and population persistence, with implications for both sexual selection theory and biodiversity conservation. PMID:28634289

Down-regulation of zinc transporter 8 (SLC30A8) in pancreatic beta-cells promotes cell survival

USDA-ARS?s Scientific Manuscript database

The pancreatic islet contains high levels of zinc in granular vesicles of beta-cells where insulin is matured, crystallized, and stored before secretion. Zinc is an essential co-factor for insulin crystallization forming dense core in secretory granules. In insulin-containing secretory granules, zin...

Down-regulation of zinc transporter 8 (SLC30A8) in pancreatic beta-cells promotes cell survival.

USDA-ARS?s Scientific Manuscript database

The pancreatic islet contains high levels of zinc in granular vesicles of ß-cells where insulin is matured, crystallized, and stored before secretion. Zinc is an essential co-factor for insulin crystallization forming dense cores in secretory granules. In insulin-containing secretory granules, zinc ...

A prosurvival and proangiogenic stem cell delivery system to promote ischemic limb regeneration.

PubMed

Xu, Yanyi; Fu, Minghuan; Li, Zhihong; Fan, Zhaobo; Li, Xiaofei; Liu, Ying; Anderson, Peter M; Xie, Xiaoyun; Liu, Zhenguo; Guan, Jianjun

2016-02-01

Stem cell therapy is one of the most promising strategies to restore blood perfusion and promote muscle regeneration in ischemic limbs. Yet its therapeutic efficacy remains low owing to the inferior cell survival under the low oxygen and nutrient environment of the injured limbs. To increase therapeutic efficacy, high rates of both short- and long-term cell survival are essential, which current approaches do not support. In this work, we hypothesized that a high rate of short-term cell survival can be achieved by introducing a prosurvival environment into the stem cell delivery system to enhance cell survival before vascularization is established; and that a high rate of long-term cell survival can be attained by building a proangiogenic environment in the system to quickly vascularize the limbs. The system was based on a biodegradable and thermosensitive poly(N-Isopropylacrylamide)-based hydrogel, a prosurvival and proangiogenic growth factor bFGF, and bone marrow-derived mesenchymal stem cells (MSCs). bFGF can be continuously released from the system for 4weeks. The released bFGF significantly improved MSC survival and paracrine effects under low nutrient and oxygen conditions (0% FBS and 1% O2) in vitro. The prosurvival effect of the bFGF on MSCs was resulted from activating cell Kruppel-like factor 4 (KLF4) pathway. When transplanted into the ischemic limbs, the system dramatically improved MSC survival. Some of the engrafted cells were differentiated into skeletal muscle and endothelial cells, respectively. The system also promoted the proliferation of host cells. After only 2weeks of implantation, tissue blood perfusion was completely recovered; and after 4weeks, the muscle fiber diameter was restored similarly to that of the normal limbs. These pronounced results demonstrate that the developed stem cell delivery system has a potential for ischemic limb regeneration. Stem cell therapy is a promising strategy to restore blood perfusion and promote muscle regeneration in ischemic limbs. Yet its therapeutic efficacy remains low owing to the inferior cell survival under the ischemic environment of the injured limbs. To increase therapeutic efficacy, high rate of cell survival is essential, which current approaches do not support. In this work, we tested the hypothesis that a stem cell delivery system that can continuously release a prosurvival and proangiogenic growth factor will promote high rates of cell survival in the ischemic limbs. The prosurvival effect could augment cell survival before vascularization is established, while the proangiogenic effect could stimulate quick angiogenesis to achieve long-term cell survival. Meanwhile, the differentiation of stem cells into endothelial and myogenic lineages, and cell paracrine effects will enhance vascularization and muscle regeneration. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Fibroblast growth factor receptor 2 (FGFR2) is required for corneal epithelial cell proliferation and differentiation during embryonic development.

PubMed

Zhang, Jinglin; Upadhya, Dinesh; Lu, Lin; Reneker, Lixing W

2015-01-01

Fibroblast growth factors (FGFs) play important roles in many aspects of embryonic development. During eye development, the lens and corneal epithelium are derived from the same surface ectodermal tissue. FGF receptor (FGFR)-signaling is essential for lens cell differentiation and survival, but its role in corneal development has not been fully investigated. In this study, we examined the corneal defects in Fgfr2 conditional knockout mice in which Cre expression is activated at lens induction stage by Pax6 P0 promoter. The cornea in LeCre, Fgfr2(loxP/loxP) mice (referred as Fgfr2(CKO)) was analyzed to assess changes in cell proliferation, differentiation and survival. We found that Fgfr2(CKO) cornea was much thinner in epithelial and stromal layer when compared to WT cornea. At embryonic day 12.5-13.5 (E12.5-13.5) shortly after the lens vesicle detaches from the overlying surface ectoderm, cell proliferation (judged by labeling indices of Ki-67, BrdU and phospho-histone H3) was significantly reduced in corneal epithelium in Fgfr2(CKO) mice. At later stage, cell differentiation markers for corneal epithelium and underlying stromal mesenchyme, keratin-12 and keratocan respectively, were not expressed in Fgfr2(CKO) cornea. Furthermore, Pax6, a transcription factor essential for eye development, was not present in the Fgfr2(CKO) mutant corneal epithelial at E16.5 but was expressed normally at E12.5, suggesting that FGFR2-signaling is required for maintaining Pax6 expression in this tissue. Interestingly, the role of FGFR2 in corneal epithelial development is independent of ERK1/2-signaling. In contrast to the lens, FGFR2 is not required for cell survival in cornea. This study demonstrates for the first time that FGFR2 plays an essential role in controlling cell proliferation and differentiation, and maintaining Pax6 levels in corneal epithelium via ERK-independent pathways during embryonic development.

Bag1 is essential for differentiation and survival of hematopoietic and neuronal cells.

PubMed

Götz, Rudolf; Wiese, Stefan; Takayama, Shinichi; Camarero, Guadalupe C; Rossoll, Wilfried; Schweizer, Ulrich; Troppmair, Jakob; Jablonka, Sibylle; Holtmann, Bettina; Reed, John C; Rapp, Ulf R; Sendtner, Michael

2005-09-01

Bag1 is a cochaperone for the heat-shock protein Hsp70 that interacts with C-Raf, B-Raf, Akt, Bcl-2, steroid hormone receptors and other proteins. Here we use targeted gene disruption in mice to show that Bag1 has an essential role in the survival of differentiating neurons and hematopoietic cells. Cells of the fetal liver and developing nervous system in Bag1-/- mice underwent massive apoptosis. Lack of Bag1 did not disturb the primary function of Akt or Raf, as phosphorylation of the forkhead transcription factor FKHR and activation of extracellular signal-regulated kinase (Erk)-1/2 were not affected. However, the defect was associated with the disturbance of a tripartite complex formed by Akt, B-Raf and Bag1, in addition to the absence of Bad phosphorylation at Ser136. We also observed reduced expression of members of the inhibitor of apoptosis (IAP) family. Our data show that Bag1 is a physiological mediator of extracellular survival signals linked to the cellular mechanisms that prevent apoptosis in hematopoietic and neuronal progenitor cells.

Factors related to the relative survival of patients with diffuse large B-cell lymphoma in a population-based study in France: does socio-economic status have a role?

PubMed

Le Guyader-Peyrou, Sandra; Orazio, Sébastien; Dejardin, Olivier; Maynadié, Marc; Troussard, Xavier; Monnereau, Alain

2017-03-01

The survival of patients with diffuse large B-cell lymphoma has increased during the last decade as a result of addition of anti-CD20 to anthracycline-based chemotherapy. Although the trend is encouraging, there are persistent differences in survival within and between the USA and European countries suggesting that non-biological factors play a role. Our aim was to investigate the influence of such factors on relative survival of patients with diffuse large B-cell lymphoma. We conducted a retrospective, multicenter, registry-based study in France on 1165 incident cases of diffuse large B-cell lymphoma between 2002 and 2008. Relative survival analyses were performed and missing data were controlled with the multiple imputation method. In a multivariate analysis, adjusted for age, sex and International Prognostic Index, we confirmed that time period was associated with a better 5-year relative survival. The registry area, the medical specialty of the care department (onco-hematology versus other), the time to travel to the nearest teaching hospital, the place of treatment (teaching versus not-teaching hospital -borderline significance), a comorbidity burden and marital status were independently associated with the 5-year relative survival. Adjusted for first-course treatment, inclusion in a clinical trial and treatment discussion in a multidisciplinary meeting were strongly associated with a better survival outcome. In contrast, socio-economic status (determined using the European Deprivation Index) was not associated with outcome. Despite therapeutic advances, various non-biological factors affected the relative survival of patients with diffuse large B-cell lymphoma. The notion of lymphoma-specific expertise seems to be essential to achieve optimal care management and reopens the debate regarding centralization of these patients' care in hematology/oncology departments. Copyright© Ferrata Storti Foundation.

Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients.

PubMed

Alvarez-Larrán, A; Cervantes, F; Bellosillo, B; Giralt, M; Juliá, A; Hernández-Boluda, J C; Bosch, A; Hernández-Nieto, L; Clapés, V; Burgaleta, C; Salvador, C; Arellano-Rodrigo, E; Colomer, D; Besses, C

2007-06-01

The frequency of vascular events and evolution to myelofibrosis (MF) in young individuals with essential thrombocythemia (ET) is not well known. The incidence and predisposing factors to such complications was studied in 126 subjects diagnosed with ET at a median age of 31 years (range: 5-40). Overall survival and probability of survival free of thrombosis, bleeding and MF were analyzed by the Kaplan-Meier method and the presence of the Janus Kinase 2 (JAK2) V617F mutation correlated with the appearance of such complications. The JAK2 mutation (present in 43% of patients) was associated with higher hemoglobin (Hb) (P<0.001) and lower platelets at diagnosis. With a median follow-up of 10 years (range: 4-25), 31 thrombotic events were registered (incidence rate: 2.2 thromboses/100 patients/year). When compared with the general population, young ET patients showed a significant increase in stroke (odds ratio 50, 95% CI: 21.5-115) and venous thromboses (odds ratio 5.3, 95% CI: 3.9-10.6). Thrombosis-free survival was 84% at 10 years, with tobacco use being associated with higher risk of thrombosis. Actuarial freedom from evolution to MF was 97% at 10 years. In conclusion, young ET patients have thrombotic events, especially stroke and venous thrombosis, more frequently than generally considered, whereas they rarely transform to MF.

Seasonal survival of adult female mottled ducks

USGS Publications Warehouse

Moon, Jena A.; Haukos, David A.; Conway, Warren C.

2017-01-01

The mottled duck (Anas fulgivula) is a non-migratory duck dependent on coastal habitats to meet all of its life cycle requirements in the Western Gulf Coast (WGC) of Texas and Louisiana, USA. This population of mottled ducks has experienced a moderate decline during the past 2 decades. Adult survival has been identified as an important factor influencing population demography. Previous work based on band-recovery data has provided only annual estimates of survival. We assessed seasonal patterns of female mottled duck survival from 2009 to 2012 using individuals marked with satellite platform transmitter terminals (PTTs). We used temperature and movement sensors within each PTT to indicate potential mortality events. We estimated cumulative weekly survival and ranked factors influential in patterns of mortality using known-fate modeling in Program MARK. Models included 4 predictors: week; hunting and non-hunting periods; biological periods defined as breeding, brooding, molt, and pairing; and mass at time of capture. Models containing hunt periods, during and outside the mottled duck season, comprised essentially 100% of model weights where both legal and illegal harvest had a negative influence on mottled duck survival. Survival rates were low during 2009–2011 (12–38% annual rate of survival), when compared with the long-term banding average of 53% annual survival. During 2011, survival of female mottled ducks was the lowest annual rate (12%) ever documented and coincided with extreme drought. Management actions maximizing the availability of wetlands and associated upland habitats during hunting seasons and drought conditions may increase adult female mottled duck survival.

Zinc in innate and adaptive tumor immunity

PubMed Central

2010-01-01

Zinc is important. It is the second most abundant trace metal with 2-4 grams in humans. It is an essential trace element, critical for cell growth, development and differentiation, DNA synthesis, RNA transcription, cell division, and cell activation. Zinc deficiency has adverse consequences during embryogenesis and early childhood development, particularly on immune functioning. It is essential in members of all enzyme classes, including over 300 signaling molecules and transcription factors. Free zinc in immune and tumor cells is regulated by 14 distinct zinc importers (ZIP) and transporters (ZNT1-8). Zinc depletion induces cell death via apoptosis (or necrosis if apoptotic pathways are blocked) while sufficient zinc levels allows maintenance of autophagy. Cancer cells have upregulated zinc importers, and frequently increased zinc levels, which allow them to survive. Based on this novel synthesis, approaches which locally regulate zinc levels to promote survival of immune cells and/or induce tumor apoptosis are in order. PMID:21087493

MYB10 and MYB72 are required for growth under iron-limiting conditions.

PubMed

Palmer, Christine M; Hindt, Maria N; Schmidt, Holger; Clemens, Stephan; Guerinot, Mary Lou

2013-11-01

Iron is essential for photosynthesis and is often a limiting nutrient for plant productivity. Plants respond to conditions of iron deficiency by increasing transcript abundance of key genes involved in iron homeostasis, but only a few regulators of these genes have been identified. Using genome-wide expression analysis, we searched for transcription factors that are induced within 24 hours after transferring plants to iron-deficient growth conditions. Out of nearly 100 transcription factors shown to be up-regulated, we identified MYB10 and MYB72 as the most highly induced transcription factors. Here, we show that MYB10 and MYB72 are functionally redundant and are required for plant survival in alkaline soil where iron availability is greatly restricted. myb10myb72 double mutants fail to induce transcript accumulation of the nicotianamine synthase gene NAS4. Both myb10myb72 mutants and nas4-1 mutants have reduced iron concentrations, chlorophyll levels, and shoot mass under iron-limiting conditions, indicating that these genes are essential for proper plant growth. The double myb10myb72 mutant also showed nickel and zinc sensitivity, similar to the nas4 mutant. Ectopic expression of NAS4 rescues myb10myb72 plants, suggesting that loss of NAS4 is the primary defect in these plants and emphasizes the importance of nicotianamine, an iron chelator, in iron homeostasis. Overall, our results provide evidence that MYB10 and MYB72 act early in the iron-deficiency regulatory cascade to drive gene expression of NAS4 and are essential for plant survival under iron deficiency.

Activated ovarian endothelial cells promote early follicular development and survival.

PubMed

Kedem, Alon; Aelion-Brauer, Anate; Guo, Peipei; Wen, Duancheng; Ding, Bi-Sen; Lis, Raphael; Cheng, Du; Sandler, Vladislav M; Rafii, Shahin; Rosenwaks, Zev

2017-09-19

New data suggests that endothelial cells (ECs) elaborate essential "angiocrine factors". The aim of this study is to investigate the role of activated ovarian endothelial cells in early in-vitro follicular development. Mouse ovarian ECs were isolated using magnetic cell sorting or by FACS and cultured in serum free media. After a constitutive activation of the Akt pathway was initiated, early follicles (50-150 um) were mechanically isolated from 8-day-old mice and co-cultured with these activated ovarian endothelial cells (AOEC) (n = 32), gel (n = 24) or within matrigel (n = 27) in serum free media for 14 days. Follicular growth, survival and function were assessed. After 6 passages, flow cytometry showed 93% of cells grown in serum-free culture were VE-cadherin positive, CD-31 positive and CD 45 negative, matching the known EC profile. Beginning on day 4 of culture, we observed significantly higher follicular and oocyte growth rates in follicles co-cultured with AOECs compared with follicles on gel or matrigel. After 14 days of culture, 73% of primary follicles and 83% of secondary follicles co-cultured with AOEC survived, whereas the majority of follicles cultured on gel or matrigel underwent atresia. This is the first report of successful isolation and culture of ovarian ECs. We suggest that co-culture with activated ovarian ECs promotes early follicular development and survival. This model is a novel platform for the in vitro maturation of early follicles and for the future exploration of endothelial-follicular communication. In vitro development of early follicles necessitates a complex interplay of growth factors and signals required for development. Endothelial cells (ECs) may elaborate essential "angiocrine factors" involved in organ regeneration. We demonstrate that co-culture with ovarian ECs enables culture of primary and early secondary mouse ovarian follicles.

Evaluation of an ion adsorption method to estimate intragravel flow velocity in salmonid spawning gravels

Treesearch

James L. Clayton; John G. King; Russell F. Thurow

1996-01-01

Intragravel water exchange provides oxygenated water, removes metabolic waste, and is an essential factor in salmonid embryo survival. Measurements of intragravel flow velocity have been suggested as an index of gravel quality and also as a useful predictor of fry emergence; however, proposed methods for measuring velocity in gravel are problematic. We evaluate an ion...

From Apprentice to Journeyman to Partner: Benjamin Franklin's Workers and the Growth of the Early-American Printing Trade.

ERIC Educational Resources Information Center

Frasca, Ralph

In studying the history of the American press, little attention has been given to printing networks and the apprenticeship system, factors which permitted the press not only to survive but to grow. Essential to press growth was the apprenticeship system, vocational education which replenished and augmented the craft's practitioners. Apprentices…

Apoptosis-Resistant Cardiac Progenitor Cells Modified With Apurinic/Apyrimidinic Endonuclease/Redox Factor 1 Gene Overexpression Regulate Cardiac Repair After Myocardial Infarction.

PubMed

Aonuma, Tatsuya; Takehara, Naofumi; Maruyama, Keisuke; Kabara, Maki; Matsuki, Motoki; Yamauchi, Atsushi; Kawabe, Jun-Ichi; Hasebe, Naoyuki

2016-08-01

: Overcoming the insufficient survival of cell grafts is an essential objective in cell-based therapy. Apurinic/apyrimidinic endonuclease/redox factor 1 (APE1) promotes cell survival and may enhance the therapeutic effect of engrafted cells. The aim of this study is to determine whether APE1 overexpression in cardiac progenitor cells (CPCs) could ameliorate the efficiency of cell-based therapy. CPCs isolated from 8- to 10-week-old C57BL/6 mouse hearts were infected with retrovirus harboring APE1-DsRed (APE1-CPC) or a DsRed control (control-CPC). Oxidative stress-induced apoptosis was then assessed in APE1-CPCs, control-CPCs, and neonatal rat ventricular myocytes (NRVMs) cocultured with these CPCs. This analysis revealed that APE1 overexpression inhibited CPC apoptosis with activation of transforming growth factor β-activated kinase 1 (TAK1) and nuclear factor (NF)-κB. In the coculture model, NRVM apoptosis was inhibited to a greater extent in the presence of APE1-CPCs compared with control-CPCs. Moreover, the number of surviving DsRed-positive CPC grafts was significantly higher 7 days after the transplant of APE1-CPCs into a mouse myocardial infarction model, and the left ventricular ejection fraction showed greater improvement with attenuation of fibrosis 28 days after the transplant of APE1-CPCs compared with control-CPCs. Additionally, fewer inflammatory macrophages and a higher percentage of cardiac α-sarcomeric actinin-positive CPC-grafts were observed in mice injected with APE1-CPCs compared with control-CPCs after 7 days. In conclusion, antiapoptotic APE1-CPC graft, which increased TAK1-NF-κB pathway activation, survived effectively in the ischemic heart, restored cardiac function, and reduced cardiac inflammation and fibrosis. APE1 overexpression in CPCs may serve as a novel strategy to improve cardiac cell therapy. Improving the survival of cell grafts is essential to maximize the efficacy of cell therapy. The authors investigated the role of APE1 in CPCs under ischemic conditions and evaluated the therapeutic efficacy of transplanted APE1-overexpressing CPCs in a mouse model of myocardial infarction. APE1 hindered apoptosis in CPC grafts subjected to oxidative stress caused in part by increased TAK1-NF-κB pathway activation. Furthermore, APE1-CPC grafts that effectively survived in the ischemic heart restored cardiac function and attenuated fibrosis through pleiotropic mechanisms that remain to be characterized. These findings suggest that APE1 overexpression in CPCs may be a novel strategy to reinforce cardiac cell therapy. ©AlphaMed Press.

Crosstalk between Caveolin-1/Extracellular Signal-regulated Kinase (ERK) and β-Catenin Survival Pathways in Osteocyte Mechanotransduction*

PubMed Central

Gortazar, Arancha R.; Martin-Millan, Marta; Bravo, Beatriz; Plotkin, Lilian I.; Bellido, Teresita

2013-01-01

Osteocyte viability is a critical determinant of bone strength and is promoted by both mechanical stimulation and activation of the Wnt signaling pathway. Earlier studies demonstrated that both stimuli promote survival of osteocytes by activating the ERKs. Here, we show that there is interaction between the caveolin-1/ERK and Wnt/β-catenin signaling pathways in the transduction of mechanical cues into osteocyte survival. Thus, ERK nuclear translocation and anti-apoptosis induced by mechanical stimulation are abolished by the Wnt antagonist Dkk1 and the β-catenin degradation stimulator Axin2. Conversely, GSK3β phosphorylation and β-catenin accumulation induced by mechanical stimulation are abolished by either pharmacologic inhibition of ERKs or silencing caveolin-1. In contrast, the canonical Wnt signaling inhibitor dominant-negative T cell factor does not alter ERK nuclear translocation or survival induced by mechanical stimulation. These findings demonstrate that β-catenin accumulation is an essential component of the mechanotransduction machinery in osteocytes, albeit β-catenin/T cell factor-mediated transcription is not required. The simultaneous requirement of β-catenin for ERK activation and of ERK activation for β-catenin accumulation suggests a bidirectional crosstalk between the caveolin-1/ERK and Wnt/β-catenin pathways in mechanotransduction leading to osteocyte survival. PMID:23362257

Pinus Roxburghii essential oil anticancer activity and chemical composition evaluation.

PubMed

Sajid, Arfaa; Manzoor, Qaisar; Iqbal, Munawar; Tyagi, Amit Kumar; Sarfraz, Raja Adil; Sajid, Anam

2018-01-01

The present study was conducted to appraise the anticancer activity of Pinus roxburghii essential oil along with chemical composition evaluation. MTT assay revealed cytotoxicity induction in colon, leukemia, multiple myeloma, pancreatic, head and neck and lung cancer cells exposed to essential oil. Cancer cell death was also observed through live/dead cell viability assay and FACS analysis. Apoptosis induced by essential oil was confirmed by cleavage of PARP and caspase-3 that suppressed the colony-forming ability of tumor cells and 50 % inhibition occurred at a dose of 25 μg/mL. Moreover, essential oil inhibited the activation of inflammatory transcription factor NF-κB and inhibited expression of NF-κB regulated gene products linked to cell survival (survivin, c-FLIP, Bcl-2, Bcl-xL, c-Myc, c-IAP2), proliferation (Cyclin D1) and metastasis (MMP-9). P. roxburghii essential oil has considerable anticancer activity and could be used as anticancer agent, which needs further investigation to identify and purify the bioactive compounds followed by in vivo studies.

Nuclear degradation of Wilms tumor 1-associating protein and survivin splice variant switching underlie IGF-1-mediated survival.

PubMed

Small, Theodore W; Pickering, J Geoffrey

2009-09-11

WTAP (Wilms tumor 1-associating protein) is a recently identified nuclear protein that is essential for mouse embryo development. The Drosophila homolog of WTAP, Fl(2)d, regulates pre-mRNA splicing; however, the role of WTAP in mammalian cells is uncertain. To elucidate a context for WTAP action, we screened growth and survival factors for their effects on WTAP expression in vascular smooth muscle cells (SMCs), a cell type previously found to express WTAP dynamically. This revealed that insulin-like growth factor-1 (IGF-1) uniquely reduced WTAP abundance. This decline in WTAP proved to be necessary for IGF-1 to confer its antiapoptotic properties, which were blocked by transducing the WTAP gene into SMCs. WTAP down-regulation by IGF-1 was mediated by an IGF-1 receptor-phosphatidylinositol 3-kinase-Akt signaling axis that directed WTAP degradation via a nuclear 26 S proteasome. Moreover, by promoting the degradation of WTAP, IGF-1 shifted the pre-mRNA splicing program for the survival factor, survivin, to reduce expression of survivin-2B, which is proapoptotic, and increase expression of survivin, which is antiapoptotic. Knockdown of survivin-2B rescued the ability of IGF-1 to promote survival when WTAP was overexpressed. These data uncover a novel regulatory cascade for human SMC survival based on adjusting the nuclear abundance of WTAP to define the splice variant balance among survivin isoforms.

Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation

PubMed Central

Haldar, Saptarsi M.; Jeyaraj, Darwin; Anand, Priti; Zhu, Han; Lu, Yuan; Prosdocimo, Domenick A.; Eapen, Betty; Kawanami, Daiji; Okutsu, Mitsuharu; Brotto, Leticia; Fujioka, Hisashi; Kerner, Janos; Rosca, Mariana G.; McGuinness, Owen P.; Snow, Rod J.; Russell, Aaron P.; Gerber, Anthony N.; Bai, Xiaodong; Yan, Zhen; Nosek, Thomas M.; Brotto, Marco; Hoppel, Charles L.; Jain, Mukesh K.

2012-01-01

The ability of skeletal muscle to enhance lipid utilization during exercise is a form of metabolic plasticity essential for survival. Conversely, metabolic inflexibility in muscle can cause organ dysfunction and disease. Although the transcription factor Kruppel-like factor 15 (KLF15) is an important regulator of glucose and amino acid metabolism, its endogenous role in lipid homeostasis and muscle physiology is unknown. Here we demonstrate that KLF15 is essential for skeletal muscle lipid utilization and physiologic performance. KLF15 directly regulates a broad transcriptional program spanning all major segments of the lipid-flux pathway in muscle. Consequently, Klf15-deficient mice have abnormal lipid and energy flux, excessive reliance on carbohydrate fuels, exaggerated muscle fatigue, and impaired endurance exercise capacity. Elucidation of this heretofore unrecognized role for KLF15 now implicates this factor as a central component of the transcriptional circuitry that coordinates physiologic flux of all three basic cellular nutrients: glucose, amino acids, and lipids. PMID:22493257

MyD88 But Not TRIF Is Essential for Osteoclastogenesis Induced by Lipopolysaccharide, Diacyl Lipopeptide, and IL-1α

PubMed Central

Sato, Nobuaki; Takahashi, Naoyuki; Suda, Koji; Nakamura, Midori; Yamaki, Mariko; Ninomiya, Tadashi; Kobayashi, Yasuhiro; Takada, Haruhiko; Shibata, Kenichiro; Yamamoto, Masahiro; Takeda, Kiyoshi; Akira, Shizuo; Noguchi, Toshihide; Udagawa, Nobuyuki

2004-01-01

Myeloid differentiation factor 88 (MyD88) plays essential roles in the signaling of the Toll/interleukin (IL)-1 receptor family. Toll–IL-1 receptor domain-containing adaptor inducing interferon-β (TRIF)-mediated signals are involved in lipopolysaccharide (LPS)-induced MyD88-independent pathways. Using MyD88-deficient (MyD88−/−) mice and TRIF-deficient (TRIF−/−) mice, we examined roles of MyD88 and TRIF in osteoclast differentiation and function. LPS, diacyl lipopeptide, and IL-1α stimulated osteoclastogenesis in cocultures of osteoblasts and hemopoietic cells obtained from TRIF−/− mice, but not MyD88−/− mice. These factors stimulated receptor activator of nuclear factor-κB ligand mRNA expression in TRIF−/− osteoblasts, but not MyD88−/− osteoblasts. LPS stimulated IL-6 production in TRIF−/− osteoblasts, but not TRIF−/− macrophages. LPS and IL-1α enhanced the survival of TRIF−/− osteoclasts, but not MyD88−/− osteoclasts. Diacyl lipopeptide did not support the survival of osteoclasts because of the lack of Toll-like receptor (TLR)6 in osteoclasts. Macrophages expressed both TRIF and TRIF-related adaptor molecule (TRAM) mRNA, whereas osteoblasts and osteoclasts expressed only TRIF mRNA. Bone histomorphometry showed that MyD88−/− mice exhibited osteopenia with reduced bone resorption and formation. These results suggest that the MyD88-mediated signal is essential for the osteoclastogenesis and function induced by IL-1 and TLR ligands, and that MyD88 is physiologically involved in bone turnover. PMID:15353553

Kidney transplantation--a 46-year experience from the Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.

PubMed

Friman, S; Nordén, G; Lennerling, A; Fehrman-Ekholm, I; Felldin, M; Hansson, S; Rydberg, L; Holgersson, J; Rizell, M; Kvarnström, N; Gustafsson, B; Gäbel, M; Olausson, M; Mjörnstedt, L

2011-01-01

The limiting factor in organ transplantation is the availability of organs. Ongoing work to improve donation rates both at the public and the organizational level in donating hospitals is essential. We also think that encouragement of live donation is important, and the possibility of ABO incompatible transplantation has increased the number of LD transplantations. The one-year graft survival rate is excellent and focus has shifted towards achieving long-term results to reduce the attrition rate. There is also an increasing interest in studying and working to reduce comorbidities on a long-term basis and thus, improve survival rates and recipient quality of life.

The Selenocysteine tRNA STAF-Binding Region is Essential for Adequate Selenocysteine tRNA Status, Selenoprotein Expression and Early Age Survival of Mice

USDA-ARS?s Scientific Manuscript database

STAF is a transcription activating factor for a number of RNA Pol III-and RNA Pol II-dependent genes including the selenocysteine (Sec) tRNA gene. Here, the role of STAF in regulating expression of Sec tRNA and selenoproteins was examined in an invivo model. Heterozygous inactivation of the Staf gen...

GIV/Girdin Links Vascular Endothelial Growth Factor Signaling to Akt Survival Signaling in Podocytes Independent of Nephrin

PubMed Central

Wang, Honghui; Misaki, Taro; Taupin, Vanessa; Eguchi, Akiko; Ghosh, Pradipta

2015-01-01

Podocytes are critically involved in the maintenance of the glomerular filtration barrier and are key targets of injury in many glomerular diseases. Chronic injury leads to progressive loss of podocytes, glomerulosclerosis, and renal failure. Thus, it is essential to maintain podocyte survival and avoid apoptosis after acute glomerular injury. In normal glomeruli, podocyte survival is mediated via nephrin-dependent Akt signaling. In several glomerular diseases, nephrin expression decreases and podocyte survival correlates with increased vascular endothelial growth factor (VEGF) signaling. How VEGF signaling contributes to podocyte survival and prevents apoptosis remains unknown. We show here that Gα–interacting, vesicle-associated protein (GIV)/girdin mediates VEGF receptor 2 (VEGFR2) signaling and compensates for nephrin loss. In puromycin aminonucleoside nephrosis (PAN), GIV expression increased, GIV was phosphorylated by VEGFR2, and p-GIV bound and activated Gαi3 and enhanced downstream Akt2, mammalian target of rapamycin complex 1 (mTORC1), and mammalian target of rapamycin complex-2 (mTORC2) signaling. In GIV-depleted podocytes, VEGF-induced Akt activation was abolished, apoptosis was triggered, and cell migration was impaired. These effects were reversed by introducing GIV but not a GIV mutant that cannot activate Gαi3. Our data indicate that after PAN injury, VEGF promotes podocyte survival by triggering assembly of an activated VEGFR2/GIV/Gαi3 signaling complex and enhancing downstream PI3K/Akt survival signaling. Because of its important role in promoting podocyte survival, GIV may represent a novel target for therapeutic intervention in the nephrotic syndrome and other proteinuric diseases. PMID:25012178

Clinical Features of 294 Turkish Patients with Chronic Myeloproliferative Neoplasms

PubMed Central

Andıç, Neslihan; Ünübol, Mustafa; Yağcı, Eren; Akay, Olga Meltem; Yavaşoğlu, İrfan; Kadıköylü, Vefki Gürhan; Bolaman, Ali Zahit

2016-01-01

Objective: Myeloproliferative neoplasms (MPNs) share common clonal stem cells but show significant differences in their clinical courses. The aim of this retrospective study was to evaluate thrombotic and hemorrhagic complications, JAK2 status, gastrointestinal and cardiac changes, treatment modalities, and survival in MPNs in Turkish patients. Materials and Methods: Medical files of 294 patients [112 essential thrombocythemia (ET), 117 polycythemia vera (PV), 46 primary myelofibrosis, and 19 unclassified MPN cases] from 2 different universities in Turkey were examined. Results: Older age, higher leukocyte count at diagnosis, and JAK2 mutation positivity were risk factors for thrombosis. Platelet count over 1000x109/L was a risk factor for hemorrhagic episodes. Hydroxyurea treatment was not related to leukemic transformation. Median follow-up time was 50 months (quartiles: 22.2-81.75) in these patients. Patients with primary myelofibrosis had the shortest survival of 137 months when compared with 179 months for ET and 231 months for PV. Leukemic transformation, thromboembolic events, age over 60 years, and anemia were found to be the factors affecting survival. Conclusion: Thromboembolic complications are the most important preventable risk factors for morbidity and mortality in MPNs. Drug management in MPNs is done according to hemoglobin and platelet counts. Based on the current study population our results support the idea that leukocytosis and JAK2 positivity are more important risk factors for thrombosis than hemoglobin and platelet values. PMID:27094255

Cell death and survival signalling in the cardiovascular system.

PubMed

Tucka, Joanna; Bennett, Martin; Littlewood, Trevor

2012-01-01

The loss of cells is an important factor in many diseases, including those of the cardiovascular system. Whereas apoptosis is an essential process in development and tissue homeostasis, its occurrence is often associated with various pathologies. Apoptosis of neurons that fail to make appropriate connections is essential for the selection of correct neural signalling in the developing embryo, but its appearance in adults is often associated with neurodegenerative disease. Similarly, in the cardiovascular system, remodeling of the mammalian outflow tract during the transition from a single to dual series circulation with four chambers is accompanied by a precise pattern of cell death, but apoptosis of cardiomyocytes contributes to ischemia-reperfusion injury in the heart. In many cases, it is unclear whether apoptosis represents a causative association or merely a consequence of the disease itself. There are many excellent reviews on cell death in the cardiovascular system (1-5); in this review we outline the critical signalling pathways that promote the survival of cardiovascular cells, and their relevance to both physiological cell death and disease.

Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response.

PubMed

Tellier, Julie; Shi, Wei; Minnich, Martina; Liao, Yang; Crawford, Simon; Smyth, Gordon K; Kallies, Axel; Busslinger, Meinrad; Nutt, Stephen L

2016-03-01

Plasma cell differentiation requires silencing of B cell transcription, while it establishes antibody-secretory function and long-term survival. The transcription factors Blimp-1 and IRF4 are essential for the generation of plasma cells; however, their function in mature plasma cells has remained elusive. We found that while IRF4 was essential for the survival of plasma cells, Blimp-1 was dispensable for this. Blimp-1-deficient plasma cells retained their transcriptional identity but lost the ability to secrete antibody. Blimp-1 regulated many components of the unfolded protein response (UPR), including XBP-1 and ATF6. The overlap in the functions of Blimp-1 and XBP-1 was restricted to that response, with Blimp-1 uniquely regulating activity of the kinase mTOR and the size of plasma cells. Thus, Blimp-1 was required for the unique physiological ability of plasma cells that enables the secretion of protective antibody.

Cell death in the thymus--it' s all a matter of contacts.

PubMed

Minter, Lisa M; Osborne, Barbara A

2003-06-01

Apoptosis, or programmed cell death, plays a critical role in shaping the T cell repertoire, deleting unproductive as well as potentially autoreactive T cells. Our understanding of how thymocyte apoptosis is regulated is continually evolving, as new essential modulators of this process are discovered. A conundrum that remains, however, is how signaling through essentially the same receptors and cascades evokes distinct biological responses: death by neglect, positive or negative selection. We hypothesize that the immunological synapse (IS) may be critical to transducing survival signals during thymocyte development, and suggest that factors affecting IS assembly may also influence T cell selection.

Msx homeobox gene family and craniofacial development.

PubMed

Alappat, Sylvia; Zhang, Zun Yi; Chen, Yi Ping

2003-12-01

Vertebrate Msx genes are unlinked, homeobox-containing genes that bear homology to the Drosophila muscle segment homeobox gene. These genes are expressed at multiple sites of tissue-tissue interactions during vertebrate embryonic development. Inductive interactions mediated by the Msx genes are essential for normal craniofacial, limb and ectodermal organ morphogenesis, and are also essential to survival in mice, as manifested by the phenotypic abnormalities shown in knockout mice and in humans. This review summarizes studies on the expression, regulation, and functional analysis of Msx genes that bear relevance to craniofacial development in humans and mice. Key words: Msx genes, craniofacial, tooth, cleft palate, suture, development, transcription factor, signaling molecule.

Connecting Metabolic Pathways: Sigma Factors in Streptomyces spp.

PubMed Central

Sun, Di; Liu, Cong; Zhu, Jingrong; Liu, Weijie

2017-01-01

The gram-positive filamentous bacterium Streptomyces is one of the largest resources for bioactive metabolites, particularly antibiotics. Antibiotic production and other metabolic processes are tightly regulated at the transcriptional level. Sigma (σ) factors are components of bacterial RNA polymerases that determine promoter specificity. In Streptomyces, σ factors also play essential roles in signal transduction and in regulatory networks, thereby assisting in their survival in complex environments. However, our current understanding of σ factors in Streptomyces is still limited. In this mini-review, we demonstrate the roles of Streptomyces σ factors, illustrating that these serve as linkers of different metabolic pathways. Further investigations on σ factors may improve our knowledge of Streptomyces physiology and benefit exploitation of Streptomyces resources. PMID:29312231

Control of lens development by Lhx2-regulated neuroretinal FGFs

PubMed Central

Thein, Thuzar; de Melo, Jimmy; Zibetti, Cristina; Clark, Brian S.; Juarez, Felicia

2016-01-01

Fibroblast growth factor (FGF) signaling is an essential regulator of lens epithelial cell proliferation and survival, as well as lens fiber cell differentiation. However, the identities of these FGF factors, their source tissue and the genes that regulate their synthesis are unknown. We have found that Chx10-Cre;Lhx2lox/lox mice, which selectively lack Lhx2 expression in neuroretina from E10.5, showed an early arrest in lens fiber development along with severe microphthalmia. These mutant animals showed reduced expression of multiple neuroretina-expressed FGFs and canonical FGF-regulated genes in neuroretina. When FGF expression was genetically restored in Lhx2-deficient neuroretina of Chx10-Cre;Lhx2lox/lox mice, we observed a partial but nonetheless substantial rescue of the defects in lens cell proliferation, survival and fiber differentiation. These data demonstrate that neuroretinal expression of Lhx2 and neuroretina-derived FGF factors are crucial for lens fiber development in vivo. PMID:27633990

Developing a mentoring program in clinical nutrition.

PubMed

Martindale, Robert G; McClave, Stephen; Heyland, Daren; August, David

2010-01-01

Mentoring programs in nutrition are essential to the survival of clinical nutrition as we know it today. The best method known to maintain an influx of talent to a discipline is by developing an active mentoring program. This paper describes 1 concept for development of a viable mentor program. Mentoring should be flexible and based on mentees' training background. Realistic goals should be set, with written and verbal feedback, to sustain a successful program. Programs should incorporate the Socratic Method whenever possible. Factors that leave doubt about the survival of nutrition as a viable area of focus for physicians include the inability to generate adequate funds to support oneself and limited numbers of mentors available with dedicated time to be a mentor. A healthy, sustainable mentoring program in clinical nutrition will ensure survival of physician-based nutrition programs.

Biochemical and Structural Characterisation of DNA Ligases from Bacteria and Archaea.

PubMed

Pergolizzi, Giulia; Wagner, Gerd K; Bowater, Richard Peter

2016-08-31

DNA ligases are enzymes that seal breaks in the backbones of DNA, leading to them being essential for the survival of all organisms. DNA ligases have been studied from many different types of cells and organisms and shown to have diverse sizes and sequences, with well conserved specific sequences that are required for enzymatic activity. A significant number of DNA ligases have been isolated or prepared in recombinant forms and, here, we review their biochemical and structural characterisation. All DNA ligases contain an essential lysine that transfers an adenylate group from a co-factor to the 5'-phosphate of the DNA end that will ultimately be joined to the 3'-hydroxyl of the neighbouring DNA strand. The essential DNA ligases in bacteria use nicotinamide adenine dinucleotide ( β -NAD + ) as their co-factor whereas those that are essential in other cells use adenosine-5'-triphosphate (ATP) as their co-factor. This observation suggests that the essential bacterial enzyme could be targeted by novel antibiotics and the complex molecular structure of β -NAD + affords multiple opportunities for chemical modification. Several recent studies have synthesised novel derivatives and their biological activity against a range of DNA ligases has been evaluated as inhibitors for drug discovery and/or non-natural substrates for biochemical applications. Here, we review the recent advances that herald new opportunities to alter the biochemical activities of these important enzymes. The recent development of modified derivatives of nucleotides highlights that the continued combination of structural, biochemical and biophysical techniques will be useful in targeting these essential cellular enzymes. ©2016 The Author(s).

Chromatin replication: TRANSmitting the histone code

PubMed Central

Chang, Han-Wen; Studitsky, Vasily M.

2017-01-01

Efficient overcoming of the nucleosomal barrier and accurate maintenance of associated histone marks during chromatin replication are essential for normal functioning of the cell. Recent studies revealed new protein factors and histone modifications contributing to overcoming the nucleosomal barrier, and suggested an important role for DNA looping in survival of the original histones during replication. These studies suggest new possible mechanisms for transmitting the histone code to next generations of cells. PMID:28393112

Support Policies for Business Start-ups and the Role of Training. National Reports from France, Italy, Spain, United Kingdom, and Synthesis Report.

ERIC Educational Resources Information Center

Prieto, Jose Maria; And Others

This publication contains four national studies, conducted in Spain, France, the United Kingdom, and Italy, that collected data on the role of training as an element of support for business start-up and as an essential factor for the survival of newly established businesses. The study of the Spanish situation examines public and private bodies…

A Homolog of Bacillus subtilis Trigger Factor in Listeria monocytogenes Is Involved in Stress Tolerance and Bacterial Virulence

PubMed Central

Bigot, Armelle; Botton, Eleonore; Dubail, Iharilalao; Charbit, Alain

2006-01-01

Molecular chaperones play an essential role in the folding of nascent chain polypeptides, as well as in the refolding and degradation of misfolded or aggregated proteins. They also assist in protein translocation and participate in stress functions. We identified a gene, designated tig, encoding a protein homologous to trigger factor (TF), a cytosolic ribosome-associated chaperone, in the genome of Listeria monocytogenes. We constructed a chromosomal Δtig deletion and evaluated the impact of the mutation on bacterial growth in broth under various stress conditions and on pathogenesis. The Δtig deletion did not affect cell viability but impaired survival in the presence of heat and ethanol stresses. We also identified the ffh gene, encoding a protein homologous to the SRP54 eukaryotic component of the signal recognition particle. However, a Δffh deletion was not tolerated, suggesting that Ffh is essential, as it is in Bacillus subtilis and Escherichia coli. Thus, although dispensable for growth, TF is involved in the stress response of L. monocytogenes. The Δtig mutant showed no or very modest intracellular survival defects in eukaryotic cells. However, in vivo it showed a reduced capacity to persist in the spleens and livers of infected mice, revealing that TF has a role in the pathogenicity of L. monocytogenes. PMID:17021213

Naftidrofuryl affects neurite regeneration by injured adult auditory neurons.

PubMed

Lefebvre, P P; Staecker, H; Moonen, G; van de Water, T R

1993-07-01

Afferent auditory neurons are essential for the transmission of auditory information from Corti's organ to the central auditory pathway. Auditory neurons are very sensitive to acute insult and have a limited ability to regenerate injured neuronal processes. Therefore, these neurons appear to be a limiting factor in restoration of hearing function following an injury to the peripheral auditory receptor. In a previous study nerve growth factor (NGF) was shown to stimulate neurite repair but not survival of injured auditory neurons. In this study, we have demonstrated a neuritogenesis promoting effect of naftidrofuryl in an vitro model for injury to adult auditory neurons, i.e. dissociated cell cultures of adult rat spiral ganglia. Conversely, naftidrofuryl did not have any demonstrable survival promoting effect on these in vitro preparations of injured auditory neurons. The potential uses of this drug as a therapeutic agent in acute diseases of the inner ear are discussed in the light of these observations.

Helicobacter pylori Containing Only Cytoplasmic Urease Is Susceptible to Acid

PubMed Central

Krishnamurthy, Partha; Parlow, Mary; Zitzer, Jason B.; Vakil, Nimish B.; Mobley, Harry L. T.; Levy, Marilyn; Phadnis, Suhas H.; Dunn, Bruce E.

1998-01-01

Helicobacter pylori, an important etiologic agent in a variety of gastroduodenal diseases, produces large amounts of urease as an essential colonization factor. We have demonstrated previously that urease is located within the cytoplasm and on the surface of H. pylori both in vivo and in stationary-phase culture. The purpose of the present study was to assess the relative contributions of cytoplasmic and surface-localized urease to the ability of H. pylori to survive exposure to acid in the presence of urea. Toward this end, we compared the acid resistance in vitro of H. pylori cells which possessed only cytoplasmic urease to that of bacteria which possessed both cytoplasmic and surface-localized or extracellular urease. Bacteria with only cytoplasmic urease activity were generated by using freshly subcultured bacteria or by treating repeatedly subcultured H. pylori with flurofamide (1 μM), a potent, but poorly diffusible urease inhibitor. H. pylori with cytoplasmic and surface-located urease activity survived in an acid environment when 5 mM urea was present. In contrast, H. pylori with only cytoplasmic urease shows significantly reduced survival when exposed to acid in the presence of 5 mM urea. Similarly, Escherichia coli SE5000 expressing H. pylori urease and the Ni2+ transport protein NixA, which expresses cytoplasmic urease activity at levels similar to those in wild-type H. pylori, survived minimally when exposed to acid in the presence of 5 to 50 mM urea. We conclude that cytoplasmic urease activity alone is not sufficient (although cytoplasmic urease activity is likely to be necessary) to allow survival of H. pylori in acid; the activity of surface-localized urease is essential for resistance of H. pylori to acid under the assay conditions used. Therefore, the mechanism whereby urease becomes associated with the surface of H. pylori, which involves release of the enzyme from bacteria due to autolysis followed by adsorption of the enzyme to the surface of intact bacteria (“altruistic autolysis”), is essential for survival of H. pylori in an acid environment. The ability of H. pylori to survive exposure to low pH is likely to depend on a combination of both cytoplasmic and surface-associated urease activities. PMID:9784504

Survival significance of epidermal growth factor receptor tyrosine kinase inhibitors and current staging system for survival after recurrence in patients with completely resected lung adenocarcinoma

PubMed Central

Saji, Hisashi; Sakai, Hiroki; Kimura, Hiroyuki; Miyazawa, Tomoyuki; Marushima, Hideki; Nakamura, Haruhiko

2017-01-01

Objective We previously reported that the staging system and epidermal growth factor receptor (EGFR) mutation status are key factors for treatment strategy and predicting survival. However, the significance of these factors as predictors of overall survival (OS) and postoperative recurrence survival (PRS) has not been sufficiently elucidated. The objective here was to investigate EGFR mutation status and p-stage, which affect PRS and OS in patients with completely resected lung adenocarcinoma, using a different database. Patients and methods We retrospectively reviewed 56 consecutive lung adenocarcinoma patients with disease recurrence in St. Marianna University Hospital between January 2010 and December 2014. Results EGFR mutants (M) were detected in 16/56 patients (29%). The patients with EGFR M had a better OS than those with EGFR wild-type (WT) status (5-year survival: 50.3% vs 43.1, P=0.133). There was no significant difference in the 3-year recurrence-free survival rate between patients with M and WT (6.3% vs 7.7%, P=0.656), and the patients with EGFR M had a significantly better 3-year PRS than those with WT (77.4% vs 51.7%, P=0.033). The 3-year PRS rate for patients with M/pathologic stage (p-stage) I–II (87.5%) was better than that for patients with M/p-stage III (60.0%), WT/p-stage I–II (52.7%), and WT/p-stage III (43.8%). There was a significant difference between patients with M/p-stage I and WT/p-stage I–II or WT/p-stage III (P=0.021 and 0.030, respectively). During the study period, of the 16 patients with mutants, 12 patients (75%) received EGFR-tyrosine kinase inhibitor (TKI) therapy and among the 40 patients with WT, no patient received EGFR-TKI therapy. Multivariate survival analysis showed that patients with EGFR-TKI therapy had a statistically significant association with favorable PRS (hazard ratio 0.271; 95% confidence interval 0.074–1.000; P=0.050). Conclusion EGFR status and p-stage were found to be essential prognostic factors for estimating PRS using this database. The recurrent patients with EGFR M and EGFR-TKI therapy had a statistically significant association with favorable PRS. PMID:28860823

Legionella and Coxiella effectors: strength in diversity and activity.

PubMed

Qiu, Jiazhang; Luo, Zhao-Qing

2017-10-01

Legionella pneumophila and Coxiella burnetii are two evolutionarily related intracellular pathogens that use the Dot/Icm type IV secretion system to translocate effectors into host cells. These effectors are essential for the establishment of membrane-bound compartments known as replication vacuoles, which enable the survival and replication of bacteria inside host cells. The effectors interfere with diverse signalling pathways to co-opt host processes, such as vesicle trafficking, ubiquitylation, gene expression and lipid metabolism, to promote pathogen survival. In this Review, we explore Dot/Icm effectors from L. pneumophila and C. burnetii as key virulence factors, and we examine the biochemical and cell biological functions of these effectors and their roles in our understanding of bacterial virulence.

Pinus Roxburghii essential oil anticancer activity and chemical composition evaluation

PubMed Central

Sajid, Arfaa; Manzoor, Qaisar; Iqbal, Munawar; Tyagi, Amit Kumar; Sarfraz, Raja Adil; Sajid, Anam

2018-01-01

The present study was conducted to appraise the anticancer activity of Pinus roxburghii essential oil along with chemical composition evaluation. MTT assay revealed cytotoxicity induction in colon, leukemia, multiple myeloma, pancreatic, head and neck and lung cancer cells exposed to essential oil. Cancer cell death was also observed through live/dead cell viability assay and FACS analysis. Apoptosis induced by essential oil was confirmed by cleavage of PARP and caspase-3 that suppressed the colony-forming ability of tumor cells and 50 % inhibition occurred at a dose of 25 μg/mL. Moreover, essential oil inhibited the activation of inflammatory transcription factor NF-κB and inhibited expression of NF-κB regulated gene products linked to cell survival (survivin, c-FLIP, Bcl-2, Bcl-xL, c-Myc, c-IAP2), proliferation (Cyclin D1) and metastasis (MMP-9). P. roxburghii essential oil has considerable anticancer activity and could be used as anticancer agent, which needs further investigation to identify and purify the bioactive compounds followed by in vivo studies. PMID:29743861

The Molecular Motor KIF1A Transports the TrkA Neurotrophin Receptor and Is Essential for Sensory Neuron Survival and Function.

PubMed

Tanaka, Yosuke; Niwa, Shinsuke; Dong, Ming; Farkhondeh, Atena; Wang, Li; Zhou, Ruyun; Hirokawa, Nobutaka

2016-06-15

KIF1A is a major axonal transport motor protein, but its functional significance remains elusive. Here we show that KIF1A-haploinsufficient mice developed sensory neuropathy. We found progressive loss of TrkA(+) sensory neurons in Kif1a(+/-) dorsal root ganglia (DRGs). Moreover, axonal transport of TrkA was significantly disrupted in Kif1a(+/-) neurons. Live imaging and immunoprecipitation assays revealed that KIF1A bound to TrkA-containing vesicles through the adaptor GTP-Rab3, suggesting that TrkA is a cargo of the KIF1A motor. Physiological measurements revealed a weaker capsaicin response in Kif1a(+/-) DRG neurons. Moreover, these neurons were hyposensitive to nerve growth factor, which could explain the reduced neuronal survival and the functional deficiency of the pain receptor TRPV1. Because phosphatidylinositol 3-kinase (PI3K) signaling significantly rescued these phenotypes and also increased Kif1a mRNA, we propose that KIF1A is essential for the survival and function of sensory neurons because of the TrkA transport and its synergistic support of the NGF/TrkA/PI3K signaling pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Francisella tularensis type A Strains Cause the Rapid Encystment of Acanthamoeba castellanii and Survive in Amoebal Cysts for Three Weeks post Infection

DOE Office of Scientific and Technical Information (OSTI.GOV)

El-Etr, S H; Margolis, J; Monack, D

2009-07-28

Francisella tularensis, the causative agent of the zoonotic disease tularemia, has recently gained increased attention due to the emergence of tularemia in geographical areas where the disease has been previously unknown, and the organism's potential as a bioterrorism agent. Although F. tularensis has an extremely broad host range, the bacterial reservoir in nature has not been conclusively identified. In this study, the ability of virulent F. tularensis strains to survive and replicate in the amoeba Acanthamoeba castellanii was explored. We observe that A. castellanii trophozoites rapidly encyst in response to F. tularensis infection and that this rapid encystment phenotype (REP)more » is caused by factor(s) secreted by amoebae and/or F. tularensis into the co-culture media. Further, our results indicate that in contrast to LVS, virulent strains of F. tularensis can survive in A. castellanii cysts for at least 3 weeks post infection and that induction of rapid amoeba encystment is essential for survival. In addition, our data indicate that pathogenic F. tularensis strains block lysosomal fusion in A. castellanii. Taken together, these data suggest that the interactions between F. tularensis strains and amoeba may play a role in the environmental persistence of F. tularensis.« less

CRISPR/Cas9-mediated gene knockout screens and target identification via whole-genome sequencing uncover host genes required for picornavirus infection.

PubMed

Kim, Heon Seok; Lee, Kyungjin; Bae, Sangsu; Park, Jeongbin; Lee, Chong-Kyo; Kim, Meehyein; Kim, Eunji; Kim, Minju; Kim, Seokjoong; Kim, Chonsaeng; Kim, Jin-Soo

2017-06-23

Several groups have used genome-wide libraries of lentiviruses encoding small guide RNAs (sgRNAs) for genetic screens. In most cases, sgRNA expression cassettes are integrated into cells by using lentiviruses, and target genes are statistically estimated by the readout of sgRNA sequences after targeted sequencing. We present a new virus-free method for human gene knockout screens using a genome-wide library of CRISPR/Cas9 sgRNAs based on plasmids and target gene identification via whole-genome sequencing (WGS) confirmation of authentic mutations rather than statistical estimation through targeted amplicon sequencing. We used 30,840 pairs of individually synthesized oligonucleotides to construct the genome-scale sgRNA library, collectively targeting 10,280 human genes ( i.e. three sgRNAs per gene). These plasmid libraries were co-transfected with a Cas9-expression plasmid into human cells, which were then treated with cytotoxic drugs or viruses. Only cells lacking key factors essential for cytotoxic drug metabolism or viral infection were able to survive. Genomic DNA isolated from cells that survived these challenges was subjected to WGS to directly identify CRISPR/Cas9-mediated causal mutations essential for cell survival. With this approach, we were able to identify known and novel genes essential for viral infection in human cells. We propose that genome-wide sgRNA screens based on plasmids coupled with WGS are powerful tools for forward genetics studies and drug target discovery. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

An Essential Vocabulary: An Update.

ERIC Educational Resources Information Center

Davis, Anita P.; McDaniel, Thomas R.

1998-01-01

Updates a list (originally published in 1963) of "survival" or essential words--words so important for survival and success in everyday life that everyone should know them. Notes that recognition of these key words and phrases may require non-English-speaking individuals, disabled readers, and adult literacy students to use rote memorization for…

CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production

PubMed Central

Khairnar, Vishal; Duhan, Vikas; Maney, Sathish Kumar; Honke, Nadine; Shaabani, Namir; Pandyra, Aleksandra A.; Seifert, Marc; Pozdeev, Vitaly; Xu, Haifeng C.; Sharma, Piyush; Baldin, Fabian; Marquardsen, Florian; Merches, Katja; Lang, Elisabeth; Kirschning, Carsten; Westendorf, Astrid M.; Häussinger, Dieter; Lang, Florian; Dittmer, Ulf; Küppers, Ralf; Recher, Mike; Hardt, Cornelia; Scheffrahn, Inka; Beauchemin, Nicole; Göthert, Joachim R.; Singer, Bernhard B.; Lang, Philipp A.; Lang, Karl S.

2015-01-01

B cells are essential for antiviral immune defence because they produce neutralizing antibodies, present antigen and maintain the lymphoid architecture. Here we show that intrinsic signalling of CEACAM1 is essential for generating efficient B-cell responses. Although CEACAM1 exerts limited influence on the proliferation of B cells, expression of CEACAM1 induces survival of proliferating B cells via the BTK/Syk/NF-κB-axis. The absence of this signalling cascade in naive Ceacam1−/− mice limits the survival of B cells. During systemic infection with cytopathic vesicular stomatitis virus, Ceacam1−/− mice can barely induce neutralizing antibody responses and die early after infection. We find, therefore, that CEACAM1 is a crucial regulator of B-cell survival, influencing B-cell numbers and protective antiviral antibody responses. PMID:25692415

Atorvastatin Inhibits the HIF1α-PPAR Axis, Which Is Essential for Maintaining the Function of Human Induced Pluripotent Stem Cells.

PubMed

Nakashima, Yoshiki; Miyagi-Shiohira, Chika; Noguchi, Hirofumi; Omasa, Takeshi

2018-06-19

We herein report a novel mechanism of action of statin preparations using a new drug discovery method. Milk fat globule-EGF factor 8 protein (MFG-E8) was identified from the secretory component of mouse embryonic fibroblast (MEF) as a cell adhesion-promoting factor effective for screening active cellular agents of human induced pluripotent stem cells (hiPSCs) in vitro using electrochemical impedance. Our analyses showed that atorvastatin did not cause death in myocardial cells differentiated from hiPSCs but reduced the pluripotent cell survival in vitro when using serum- and albumin-free media, and inhibited the ability to form teratomas in mice. This result could have been already the cytopathic effect of atorvastatin, and complete elimination of hiPSCs was confirmed in the xenotransplantation assay. The administration of atorvastatin to hiPSCs caused the expression of hypoxia inducible factor (HIF)1α mRNA to be unchanged at 6 hr and downregulated at 24 hr. In addition, the inhibition of the survival of hiPSCs was confirmed by HIF1α-peroxisome proliferator-activated receptor (PPAR) axis inhibition. These results suggest that the addition of atorvastatin to hiPSC cultures reduces the survival of pluripotent cells by suppressing the HIF1α-PPAR axis. In summary, the HIF1α-PPAR axis has an important role in maintaining the survival of pluripotent hiPSCs. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Regulation of Ubiquitination-Mediated Protein Degradation by Survival Kinases in Cancer

PubMed Central

Yamaguchi, Hirohito; Hsu, Jennifer L.; Hung, Mien-Chie

2011-01-01

The ubiquitin–proteasome system is essential for multiple physiological processes via selective degradation of target proteins and has been shown to plays a critical role in human cancer. Activation of oncogenic factors and inhibition of tumor suppressors have been shown to be essential for cancer development, and protein ubiquitination has been linked to the regulation of oncogenic factors and tumor suppressors. Three kinases, AKT, extracellular signal-regulated kinase, and IκB kinase, we refer to as oncokinases, are activated in multiple human cancers. We and others have identified several key downstream targets that are commonly regulated by these oncokinases, some of which are regulated directly or indirectly via ubiquitin-mediated proteasome degradation, including FOXO3, β-catenin, myeloid cell leukemia-1, and Snail. In this review, we summarize these findings from our and other groups and discuss potential future studies and applications in the clinic. PMID:22649777

One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling

PubMed Central

Corbin, Joshua M.; Ruiz-Echevarría, Maria J.

2016-01-01

Cancer cell metabolism differs significantly from the metabolism of non-transformed cells. This altered metabolic reprogramming mediates changes in the uptake and use of nutrients that permit high rates of proliferation, growth, and survival. The androgen receptor (AR) plays an essential role in the establishment and progression of prostate cancer (PCa), and in the metabolic adaptation that takes place during this progression. In its role as a transcription factor, the AR directly affects the expression of several effectors and regulators of essential catabolic and biosynthetic pathways. Indirectly, as a modulator of the one-carbon metabolism, the AR can affect epigenetic processes, DNA metabolism, and redox balance, all of which are important factors in tumorigenesis. In this review, we focus on the role of AR-signaling on one-carbon metabolism in tumorigenesis. Clinical implications of one-carbon metabolism and AR-targeted therapies for PCa are discussed in this context. PMID:27472325

A genome-wide screen identifies Salmonella Enteritidis lipopolysaccharide biosynthesis and the HtrA heat shock protein as crucial factors involved in egg white persistence at chicken body temperature.

PubMed

Raspoet, R; Shearer, N; Appia-Ayme, C; Haesebrouck, F; Ducatelle, R; Thompson, A; Van Immerseel, F

2014-05-01

Eggs contaminated with Salmonella Enteritidis are an important source of human foodborne Salmonella infections. Salmonella Enteritidis is able to contaminate egg white during formation of the egg within the chicken oviduct, and it has developed strategies to withstand the antimicrobial properties of egg white to survive in this hostile environment. The mechanisms involved in the persistence of Salmonella Enteritidis in egg white are likely to be complex. To address this issue, a microarray-based transposon library screen was performed to identify genes necessary for survival of Salmonella Enteritidis in egg white at chicken body temperature. The majority of identified genes belonged to the lipopolysaccharide biosynthesis pathway. Additionally, we provide evidence that the serine protease/heat shock protein (HtrA) appears essential for the survival of Salmonella Enteritidis in egg white at chicken body temperature.

PAF53 is essential in mammalian cells: CRISPR/Cas9 fails to eliminate PAF53 expression.

PubMed

Rothblum, Lawrence I; Rothblum, Katrina; Chang, Eugenie

2017-05-15

When mammalian cells are nutrient and/or growth factor deprived, exposed to inhibitors of protein synthesis, stressed by heat shock or grown to confluence, rDNA transcription is essentially shut off. Various mechanisms are available to accomplish this downshift in ribosome biogenesis. Muramatsu's laboratory (Hanada et al., 1996) first demonstrated that mammalian PAF53 was essential for specific rDNA transcription and that PAF53 levels were regulated in response to growth factors. While S. cerevisae A49, the homologue of vertebrate PAF53, is not essential for viability (Liljelund et al., 1992), deletion of yA49 results in colonies that grow at 6% of the wild type rate at 25°C. Experiments described by Wang et al. (2015) identified PAF53 as a gene "essential for optimal proliferation". However, they did not discriminate genes essential for viability. Hence, in order to resolve this question, we designed a series of experiments to determine if PAF53 was essential for cell survival. We set out to delete the gene product from mammalian cells using CRISPR/CAS9 technology. Human 293 cells were transfected with lentiCRISPR v2 carrying genes for various sgRNA that targeted PAF53. In some experiments, the cells were cotransfected in parallel with plasmids encoding FLAG-tagged mouse PAF53. After treating the transfected cells with puromycin (to select for the lentiCRISPR backbone), cells were cloned and analyzed by western blots for PAF53 expression. Genomic DNA was amplified across the "CRISPRd" exon, cloned and sequenced to identify mutated PAF53 genes. We obtained cell lines in which the endogenous PAF53 gene was "knocked out" only when we rescued with FLAG-PAF53. DNA sequencing demonstrated that in the absence of ectopic PAF53 expression, cells demonstrated unique means of surviving; including recombination or the utilization of alternative reading frames. We never observed a clone in which one PAF53 gene is expressed, unless there was also ectopic expression In the absence of ectopic gene expression, the gene products of both endogenous genes were expressed, irrespective of whether they were partially mutant proteins or not. Copyright © 2016 Elsevier B.V. All rights reserved.

Wildlife health and disease investigations

USGS Publications Warehouse

Roffe, T.J.; Work, Thierry M.; Braun, C.E.

2005-01-01

Wildlife population management requires knowledge of factors that affect population sustainability. Mortality is one of the most important of those factors. Without a clear understanding of the causes of mortality, decisions by managers of whether or how to intercede may be inappropriate. Wildlife biologists are usually the first to discover, assess, and respond to wildlife mortality. Biologists who make accurate, complete and timely field investigations, and proper collection and shipment of samples to a diagnostic facility are essential for an accurate diagnosis. In combination with wildlife disease specialists, biologists can identify causes of wildlife mortality, detect long-term patterns in factors that affect the survival of populations, and take appropriate corrective action to minimize the impact of some mortality factors on wildlife populations.

Variola virus F1L is a Bcl-2-like protein that unlike its vaccinia virus counterpart inhibits apoptosis independent of Bim

PubMed Central

Marshall, B; Puthalakath, H; Caria, S; Chugh, S; Doerflinger, M; Colman, P M; Kvansakul, M

2015-01-01

Subversion of host cell apoptosis is an important survival strategy for viruses to ensure their own proliferation and survival. Certain viruses express proteins homologous in sequence, structure and function to mammalian pro-survival B-cell lymphoma 2 (Bcl-2) proteins, which prevent rapid clearance of infected host cells. In vaccinia virus (VV), the virulence factor F1L was shown to be a potent inhibitor of apoptosis that functions primarily be engaging pro-apoptotic Bim. Variola virus (VAR), the causative agent of smallpox, harbors a homolog of F1L of unknown function. We show that VAR F1L is a potent inhibitor of apoptosis, and unlike all other characterized anti-apoptotic Bcl-2 family members lacks affinity for the Bim Bcl-2 homology 3 (BH3) domain. Instead, VAR F1L engages Bid BH3 as well as Bak and Bax BH3 domains. Unlike its VV homolog, variola F1L only protects against Bax-mediated apoptosis in cellular assays. Crystal structures of variola F1L bound to Bid and Bak BH3 domains reveal that variola F1L forms a domain-swapped Bcl-2 fold, which accommodates Bid and Bak BH3 in the canonical Bcl-2-binding groove, in a manner similar to VV F1L. Despite the observed conservation of structure and sequence, variola F1L inhibits apoptosis using a startlingly different mechanism compared with its VV counterpart. Our results suggest that unlike during VV infection, Bim neutralization may not be required during VAR infection. As molecular determinants for the human-specific tropism of VAR remain essentially unknown, identification of a different mechanism of action and utilization of host factors used by a VAR virulence factor compared with its VV homolog suggest that studying VAR directly may be essential to understand its unique tropism. PMID:25766319

Variola virus F1L is a Bcl-2-like protein that unlike its vaccinia virus counterpart inhibits apoptosis independent of Bim.

PubMed

Marshall, B; Puthalakath, H; Caria, S; Chugh, S; Doerflinger, M; Colman, P M; Kvansakul, M

2015-03-12

Subversion of host cell apoptosis is an important survival strategy for viruses to ensure their own proliferation and survival. Certain viruses express proteins homologous in sequence, structure and function to mammalian pro-survival B-cell lymphoma 2 (Bcl-2) proteins, which prevent rapid clearance of infected host cells. In vaccinia virus (VV), the virulence factor F1L was shown to be a potent inhibitor of apoptosis that functions primarily be engaging pro-apoptotic Bim. Variola virus (VAR), the causative agent of smallpox, harbors a homolog of F1L of unknown function. We show that VAR F1L is a potent inhibitor of apoptosis, and unlike all other characterized anti-apoptotic Bcl-2 family members lacks affinity for the Bim Bcl-2 homology 3 (BH3) domain. Instead, VAR F1L engages Bid BH3 as well as Bak and Bax BH3 domains. Unlike its VV homolog, variola F1L only protects against Bax-mediated apoptosis in cellular assays. Crystal structures of variola F1L bound to Bid and Bak BH3 domains reveal that variola F1L forms a domain-swapped Bcl-2 fold, which accommodates Bid and Bak BH3 in the canonical Bcl-2-binding groove, in a manner similar to VV F1L. Despite the observed conservation of structure and sequence, variola F1L inhibits apoptosis using a startlingly different mechanism compared with its VV counterpart. Our results suggest that unlike during VV infection, Bim neutralization may not be required during VAR infection. As molecular determinants for the human-specific tropism of VAR remain essentially unknown, identification of a different mechanism of action and utilization of host factors used by a VAR virulence factor compared with its VV homolog suggest that studying VAR directly may be essential to understand its unique tropism.

Malignant Peritoneal Mesothelioma: Prognostic Factors and Oncologic Outcome Analysis

PubMed Central

Magge, Deepa; Zenati, Mazen S.; Austin, Frances; Mavanur, Arun; Sathaiah, Magesh; Ramalingam, Lekshmi; Jones, Heather; Zureikat, Amer H.; Holtzman, Matthew; Ahrendt, Steven; Pingpank, James; Zeh, Herbert J.; Bartlett, David L.; Choudry, Haroon A.

2014-01-01

Background Most patients with malignant peritoneal mesothelioma (MPM) present with late-stage, unresectable disease that responds poorly to systemic chemotherapy while, at the same time, effective targeted therapies are lacking. We assessed the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) in MPM. Methods We prospectively analyzed 65 patients with MPM undergoing CRS/HIPEC between 2001 and 2010. Kaplan–Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes. Results Adequate CRS was achieved in 56 patients (CC-0 = 35; CC-1 = 21), and median simplified peritoneal cancer index (SPCI) was 12. Pathologic assessment revealed predominantly epithelioid histology (81 %) and biphasic histology (8 %), while lymph node involvement was uncommon (8 %). Major postoperative morbidity (grade III/IV) occurred in 23 patients (35 %), and 60-day mortality rate was 6 %. With median follow-up of 37 months, median overall survival was 46.2 months, with 1-, 2-, and 5-year overall survival probability of 77, 57, and 39 %, respectively. Median progression-free survival was 13.9 months, with 1-, 2-, and 5-year disease failure probability of 47, 68, and 83 %, respectively. In a multivariate Cox-regression model, age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), aggressive histology (epithelioid, biphasic), and postoperative sepsis were joint significant predictors of poor survival (chi square = 42.8; p = 0.00001), while age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), and aggressive histology (epithelioid, biphasic) were joint significant predictors of disease progression (Chi square = 30.6; p = 0.00001). Conclusions Tumor histology, disease burden, and the ability to achieve adequate surgical cytoreduction are essential prognostic factors in MPM patients undergoing CRS/HIPEC. PMID:24322529

Comprehensive functional characterization of cancer–testis antigens defines obligate participation in multiple hallmarks of cancer

PubMed Central

Maxfield, Kimberly E.; Taus, Patrick J.; Corcoran, Kathleen; Wooten, Joshua; Macion, Jennifer; Zhou, Yunyun; Borromeo, Mark; Kollipara, Rahul K.; Yan, Jingsheng; Xie, Yang; Xie, Xian-Jin; Whitehurst, Angelique W.

2015-01-01

Tumours frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer–testis antigens (CTAs). The extent to which CTA expression represents epiphenomena or confers tumorigenic traits is unknown. In this study, to address this, we implemented a multidimensional functional genomics approach that incorporates 7 different phenotypic assays in 11 distinct disease settings. We identify 26 CTAs that are essential for tumor cell viability and/or are pathological drivers of HIF, WNT or TGFβ signalling. In particular, we discover that Foetal and Adult Testis Expressed 1 (FATE1) is a key survival factor in multiple oncogenic backgrounds. FATE1 prevents the accumulation of the stress-sensing BH3-only protein, BCL-2-Interacting Killer (BIK), thereby permitting viability in the presence of toxic stimuli. Furthermore, ZNF165 promotes TGFβ signalling by directly suppressing the expression of negative feedback regulatory pathways. This action is essential for the survival of triple negative breast cancer cells in vitro and in vivo. Thus, CTAs make significant direct contributions to tumour biology. PMID:26567849

Osteopontin Signals through Calcium and Nuclear Factor of Activated T Cells (NFAT) in Osteoclasts

PubMed Central

Tanabe, Natsuko; Wheal, Benjamin D.; Kwon, Jiyun; Chen, Hong H.; Shugg, Ryan P. P.; Sims, Stephen M.; Goldberg, Harvey A.; Dixon, S. Jeffrey

2011-01-01

Osteopontin (OPN), an integrin-binding extracellular matrix glycoprotein, enhances osteoclast activity; however, its mechanisms of action are elusive. The Ca2+-dependent transcription factor NFATc1 is essential for osteoclast differentiation. We assessed the effects of OPN on NFATc1, which translocates to nuclei upon activation. Osteoclasts from neonatal rabbits and rats were plated on coverslips, uncoated or coated with OPN or bovine albumin. OPN enhanced the proportion of osteoclasts exhibiting nuclear NFATc1. An RGD-containing, integrin-blocking peptide prevented the translocation of NFATc1 induced by OPN. Moreover, mutant OPN lacking RGD failed to induce translocation of NFATc1. Thus, activation of NFATc1 is dependent on integrin binding through RGD. Using fluorescence imaging, OPN was found to increase the proportion of osteoclasts exhibiting transient elevations in cytosolic Ca2+ (oscillations). OPN also enhanced osteoclast survival. The intracellular Ca2+ chelator 1,2-bis(O-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) suppressed Ca2+ oscillations and inhibited increases in NFATc1 translocation and survival induced by OPN. Furthermore, a specific, cell-permeable peptide inhibitor of NFAT activation blocked the effects of OPN on NFATc1 translocation and osteoclast survival. This is the first demonstration that OPN activates NFATc1 and enhances osteoclast survival through a Ca2+-NFAT-dependent pathway. Increased NFATc1 activity and enhanced osteoclast survival may account for the stimulatory effects of OPN on osteoclast function in vivo. PMID:21940634

Multifaceted role of lipids in Mycobacterium leprae.

PubMed

Kaur, Gurkamaljit; Kaur, Jagdeep

2017-03-01

Mycobacterium leprae must adopt a metabolic strategy and undergo various metabolic alterations upon infection to survive inside the human body for years in a dormant state. A change in lipid homeostasis upon infection is highly pronounced in Mycobacterium leprae. Lipids play an essential role in the survival and pathogenesis of mycobacteria. Lipids are present in several forms and serve multiple roles from being a source of nutrition, providing rigidity, evading the host immune response to serving as virulence factors, etc. The synthesis and degradation of lipids is a highly regulated process and is the key to future drug designing and diagnosis for mycobacteria. In the current review, an account of the distinct roles served by lipids, the mechanism of their synthesis and degradation has been elucidated.

The Prognostic Roles of Gender and O6-Methylguanine-DNA Methyltransferase Methylation Status in Glioblastoma Patients: The Female Power.

PubMed

Franceschi, Enrico; Tosoni, Alicia; Minichillo, Santino; Depenni, Roberta; Paccapelo, Alexandro; Bartolini, Stefania; Michiara, Maria; Pavesi, Giacomo; Urbini, Benedetta; Crisi, Girolamo; Cavallo, Michele A; Tosatto, Luigino; Dazzi, Claudio; Biasini, Claudia; Pasini, Giuseppe; Balestrini, Damiano; Zanelli, Francesca; Ramponi, Vania; Fioravanti, Antonio; Giombelli, Ermanno; De Biase, Dario; Baruzzi, Agostino; Brandes, Alba A

2018-04-01

Clinical and molecular factors are essential to define the prognosis in patients with glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status, age, Karnofsky Performance Status (KPS), and extent of surgical resection are the most relevant prognostic factors. Our investigation of the role of gender in predicting prognosis shows a slight survival advantage for female patients. We performed a prospective evaluation of the Project of Emilia Romagna on Neuro-Oncology (PERNO) registry to identify prognostic factors in patients with GBM who received standard treatment. A total of 169 patients (99 males [58.6%] and 70 females [41.4%]) were evaluated prospectively. MGMT methylation was evaluable in 140 patients. Among the male patients, 36 were MGMT methylated (25.7%) and 47 were unmethylated (33.6%); among the female patients, 32 were methylated (22.9%) and 25 were unmethylated (17.9%). Survival was longer in the methylated females compared with the methylated males (P = 0.028) but was not significantly different between the unmethylated females and the unmethylated males (P = 0.395). In multivariate analysis, gender and MGMT methylation status considered together (methylated females vs. methylated males; hazard ratio [HR], 0.459; 95% confidence interval [CI], 0.242-0.827; P = 0.017), age (HR, 1.025; 95% CI, 1.002-1.049; P = 0.032), and KPS (HR, 0.965; 95% CI, 0.948-0.982; P < 0.001) were significantly correlated with survival. Survival was consistently longer among MGMT methylated females compared with males. Gender can be considered as a further prognostic factor. Copyright © 2018 Elsevier Inc. All rights reserved.

Novel alternative to antibiotics in shrimp hatchery: effects of the essential oil of Cinnamosma fragrans on survival and bacterial concentration of Penaeus monodon larvae.

PubMed

Randrianarivelo, R; Danthu, P; Benoit, C; Ruez, P; Raherimandimby, M; Sarter, S

2010-08-01

The activity of two essential oils (EOs) of Cinnamosma fragrans, an endemic plant to Madagascar (B8: linalool-type and B143: 1,8-cineole-type), against bacterial isolates from a shrimp hatchery of Penaeus monodon and their effects on the survival and bacterial concentration of larvae were determined. Minimum inhibitory concentrations were determined using a broth dilution technique. The bacterial concentrations of both larvae and water tank were assessed on Marine agar and Thiosulfate Citrate Bile Sucrose agar. The assays took place in OSO Farming's shrimp hatchery in Madagascar. EOs were directly added to the water tank. Regarding the survival, the assays in larval culture (four replicates each of B8, B143, E and control) showed that B8 oil had a similar effect (P > 0.05) as the antibiotic (Erythromycin) and was more active than B143 (P < 0.05). A negative correlation was observed between the bacterial concentration and the survival of larvae for all assays. Both C. fragrans essential oils, as antibiotic, exhibited significantly higher survival rates and lower bacterial concentrations of the larvae than the control (oil and antibiotic free). The potential of C. fragrans essential oil to control the bacterial load in in vivo conditions, thereby enhancing survival rate of P. monodon larvae, makes it a relevant option for developing a novel alternative to antibiotics in shrimp hatchery culture.

Testicular cancer: A narrative review of the role of socioeconomic position from risk to survivorship

PubMed Central

Richardson, Lisa C.; Neri, Antonio J.; Tai, Eric; Glenn, Jeffrey D.

2015-01-01

Background Testicular cancer (TC) is one of the most curable cancers. Given survival rates of close to 100% with appropriate therapy, ensuring proper treatment is essential. We reviewed and summarized the literature on the association of socioeconomic position (SEP) along the cancer control spectrum from risk factors to survivorship. Methods We searched PubMed from 1966 to 2011 using the following terms: testicular cancer, testicular neoplasm, poverty, and socioeconomic factors, retrieving 119 papers. After excluding papers for the non-English (10) language and non-relevance (46), we reviewed 63 papers. We abstracted information on socioeconomic position (SEP), including occupation, education, income, and combinations of the 3. Five areas were examined: risk factors, diagnosis, treatment, survival, and survivorship. Results Most studies examined area-based measures, not individual measures of SEP. The majority of studies found an increased risk of developing TC with high SEP though recent papers have indicated increased risk in low-income populations. Regarding diagnosis, recent papers have indicated that lower levels of education and SEP are risk factors for later-stage TC diagnosis and hence higher TC mortality. For treatment, 1 study that examined the use of radiation therapy (RT) in stage I seminoma reported that living in a county with lower educational attainment led to lower use of RT. For survival (mortality), several studies found that men living in lower SEP geographic areas experience lower survival and higher mortality. Conclusion The strongest evidence for SEP impact on testicular germ cell tumor (TGCT) was found for the risk of developing cancer as well as survival. The association of SEP with TGCT risk appears to have changed over the last decade. Given the highly curable nature of TGCT, more research is needed to understand how SEP impacts diagnosis and treatment for TGCT and to design interventions to address disparities in TGCT outcomes and SEP. Published by Elsevier Inc. PMID:22127018

Survival of the Fittest: How Bacterial Pathogens Utilize Bile To Enhance Infection

PubMed Central

Sistrunk, Jeticia R.; Nickerson, Kourtney P.; Chanin, Rachael B.; Rasko, David A.

2016-01-01

SUMMARY Bacterial pathogens have coevolved with humans in order to efficiently infect, replicate within, and be transmitted to new hosts to ensure survival and a continual infection cycle. For enteric pathogens, the ability to adapt to numerous host factors under the harsh conditions of the gastrointestinal tract is critical for establishing infection. One such host factor readily encountered by enteric bacteria is bile, an innately antimicrobial detergent-like compound essential for digestion and nutrient absorption. Not only have enteric pathogens evolved to resist the bactericidal conditions of bile, but these bacteria also utilize bile as a signal to enhance virulence regulation for efficient infection. This review provides a comprehensive and up-to-date analysis of bile-related research with enteric pathogens. From common responses to the unique expression of specific virulence factors, each pathogen has overcome significant challenges to establish infection in the gastrointestinal tract. Utilization of bile as a signal to modulate virulence factor expression has led to important insights for our understanding of virulence mechanisms for many pathogens. Further research on enteric pathogens exposed to this in vivo signal will benefit therapeutic and vaccine development and ultimately enhance our success at combating such elite pathogens. PMID:27464994

nfi-1 affects behavior and life-span in C. elegans but is not essential for DNA replication or survival

PubMed Central

Lazakovitch, Elena; Kalb, John M; Matsumoto, Reiko; Hirono, Keiko; Kohara, Yuji; Gronostajski, Richard M

2005-01-01

Background The Nuclear Factor I (one) (NFI) family of transcription/replication factors plays essential roles in mammalian gene expression and development and in adenovirus DNA replication. Because of its role in viral DNA replication NFI has long been suspected to function in host DNA synthesis. Determining the requirement for NFI proteins in mammalian DNA replication is complicated by the presence of 4 NFI genes in mice and humans. Loss of individual NFI genes in mice cause defects in brain, lung and tooth development, but the presence of 4 homologous NFI genes raises the issue of redundant roles for NFI genes in DNA replication. No NFI genes are present in bacteria, fungi or plants. However single NFI genes are present in several simple animals including Drosophila and C. elegans, making it possible to test for a requirement for NFI in multicellular eukaryotic DNA replication and development. Here we assess the functions of the single nfi-1 gene in C. elegans. Results C. elegans NFI protein (CeNFI) binds specifically to the same NFI-binding site recognized by vertebrate NFIs. nfi-1 encodes alternatively-spliced, maternally-inherited transcripts that are expressed at the single cell stage, during embryogenesis, and in adult muscles, neurons and gut cells. Worms lacking nfi-1 survive but have defects in movement, pharyngeal pumping and egg-laying and have a reduced life-span. Expression of the muscle gene Ce titin is decreased in nfi-1 mutant worms. Conclusion NFI gene function is not needed for survival in C. elegans and thus NFI is likely not essential for DNA replication in multi-cellular eukaryotes. The multiple defects in motility, egg-laying, pharyngeal pumping, and reduced lifespan indicate that NFI is important for these processes. Reduction in Ce titin expression could affect muscle function in multiple tissues. The phenotype of nfi-1 null worms indicates that NFI functions in multiple developmental and behavioral systems in C. elegans, likely regulating genes that function in motility, egg-laying, pharyngeal pumping and lifespan maintenance. PMID:16242019

CCCTC-binding Factor Mediates Effects of Glucose On Beta Cell Survival

PubMed Central

Tsui, Shanli; Dai, Wei; Lu, Luo

2013-01-01

Objectives Pancreatic islet β-cell survival is important in regulating insulin activities and maintaining glucose homeostasis. Recently, Pax6 has been shown to be essential for many vital functions in β-cells, though the molecular mechanisms of its regulation in β-cells remain unclear. The present study investigates the novel effects of glucose- and insulin-induced CTCF activity on Pax6 gene expression as well as the subsequent effects of insulin-activated signaling pathways on β-cell proliferation. Material and methods Pancreatic β-TC-1-6 cells were cultured in DMEM medium and stimulated with high concentrations of glucose (5 to 125 mM) and cell viability was assessed by MTT assays. The effect of CTCF on Pax6 was evaluated in high glucose-induced and CCCTC-binding Factor (CTCF)/Erk suppressed cells by promoter reporter and Western analyses. Results Increases in glucose and insulin concentrations up-regulated CTCF and consequently down-regulated Pax6 in β-cell survival and proliferation. Knocking-down CTCF directly affected Pax6 transcription through CTCF binding and blocked the response to glucose. Altered Erk activity mediated the effects of CTCF on controlling Pax6 expression, which partially regulates β-cell proliferation. Conclusions CTCF functions as a molecular mediator between insulin-induced upstream Erk signaling and Pax6 expression in pancreatic β-cells. This pathway may contribute to regulation of β-cell survival and proliferation. PMID:24354619

Predicting Essential Genes and Proteins Based on Machine Learning and Network Topological Features: A Comprehensive Review

PubMed Central

Zhang, Xue; Acencio, Marcio Luis; Lemke, Ney

2016-01-01

Essential proteins/genes are indispensable to the survival or reproduction of an organism, and the deletion of such essential proteins will result in lethality or infertility. The identification of essential genes is very important not only for understanding the minimal requirements for survival of an organism, but also for finding human disease genes and new drug targets. Experimental methods for identifying essential genes are costly, time-consuming, and laborious. With the accumulation of sequenced genomes data and high-throughput experimental data, many computational methods for identifying essential proteins are proposed, which are useful complements to experimental methods. In this review, we show the state-of-the-art methods for identifying essential genes and proteins based on machine learning and network topological features, point out the progress and limitations of current methods, and discuss the challenges and directions for further research. PMID:27014079

COACTIVATOR ACTIVATOR (CoAA) PREVENTS THE TRANSCRIPTIONAL ACTIVITY OF RUNT DOMAIN TRANSCRIPTION FACTORS

PubMed Central

Li, Xiaodong; Hoeppner, Luke H.; Jensen, Eric D.; Gopalakrishnan, Rajaram; Westendorf, Jennifer J.

2013-01-01

Runx proteins are essential for a number of developmental processes and are aberrantly expressed in many human cancers. Runx factors bind DNA and co-factors to activate or repress genes crucial for bone formation, hematopoiesis, and neuronal development. Co-activator activator (CoAA) is a nuclear protein that regulates gene expression, RNA splicing and is overexpressed in many human tumors. In this study, we identified CoAA as a Runx2 binding protein. CoAA repressed Runx factor-dependent activation of reporter genes in a histone deacetylase-independent manner. CoAA also blocked Runx2-mediated repression of the Axin2 promoter, a novel Runx target gene. The carboxy-terminus of CoAA is essential for binding the Runt domains of Runx1 and Runx2. In electophoretic mobility shift assays, CoAA inhibited Runx2 interactions with DNA. These data indicate that CoAA is an inhibitor of Runx factors and can negate Runx factor regulation of gene expression. CoAA is expressed at high levels in human fetal osteoblasts and osteosarcoma cell lines. Suppression of CoAA expression by RNA interference reduced osteosarcoma cell viability in vitro, suggesting that it contributes to the proliferation and/or survival of osteoblast lineage cells. PMID:19585539

Transcription factor NFAT5 promotes macrophage survival in rheumatoid arthritis

PubMed Central

Choi, Susanna; Choi, Soo Youn; Kwon, H. Moo; Hwang, Daehee; Park, Yune-Jung; Cho, Chul-Soo

2017-01-01

Defective apoptotic death of activated macrophages has been implicated in the pathogenesis of rheumatoid arthritis (RA). However, the molecular signatures defining apoptotic resistance of RA macrophages are not fully understood. Here, global transcriptome profiling of RA macrophages revealed that the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5) critically regulates diverse pathologic processes in synovial macrophages including the cell cycle, apoptosis, and proliferation. Transcriptomic analysis of NFAT5-deficient macrophages revealed the molecular networks defining cell survival and proliferation. Proinflammatory M1-polarizing stimuli and hypoxic conditions were responsible for enhanced NFAT5 expression in RA macrophages. An in vitro functional study demonstrated that NFAT5-deficient macrophages were more susceptible to apoptotic death. Specifically, CCL2 secretion in an NFAT5-dependent fashion bestowed apoptotic resistance to RA macrophages in vitro. Injection of recombinant CCL2 into one of the affected joints of Nfat5+/– mice increased joint destruction and macrophage infiltration, demonstrating the essential role of the NFAT5/CCL2 axis in arthritis progression in vivo. Moreover, after intra-articular injection, NFAT5-deficient macrophages were more susceptible to apoptosis and less efficient at promoting joint destruction than were NFAT5-sufficient macrophages. Thus, NFAT5 regulates macrophage survival by inducing CCL2 secretion. Our results provide evidence that NFAT5 expression in macrophages enhances chronic arthritis by conferring apoptotic resistance to activated macrophages. PMID:28192374

Fibroblast growth factors and their receptors in cancer.

PubMed

Wesche, Jørgen; Haglund, Kaisa; Haugsten, Ellen Margrethe

2011-07-15

FGFs (fibroblast growth factors) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration and differentiation during development and adult life. Deregulation of FGFR signalling, on the other hand, has been associated with many developmental syndromes, and with human cancer. In cancer, FGFRs have been found to become overactivated by several mechanisms, including gene amplification, chromosomal translocation and mutations. FGFR alterations are detected in a variety of human cancers, such as breast, bladder, prostate, endometrial and lung cancers, as well as haematological malignancies. Accumulating evidence indicates that FGFs and FGFRs may act in an oncogenic fashion to promote multiple steps of cancer progression by inducing mitogenic and survival signals, as well as promoting epithelial-mesenchymal transition, invasion and tumour angiogenesis. Therapeutic strategies targeting FGFs and FGFRs in human cancer are therefore currently being explored. In the present review we will give an overview of FGF signalling, the main FGFR alterations found in human cancer to date, how they may contribute to specific cancer types and strategies for therapeutic intervention.

Strategic targeting of essential host-pathogen interactions in chlamydial disease.

PubMed

Coombes, B K; Johnson, D L; Mahony, J B

2002-09-01

The chlamydiae are obligate intracellular gram-negative bacteria that are exquisitely adapted for exploitation of their hosts and contribute to a wide range of acute and chronic human diseases. Acute infections treated with non-cidal antibiotics can lead to the development of persistent, non-replicating bacteria with the corollary that these persistent (yet viable) chlamydiae can resist eradication by further antimicrobial treatment and cause chronic disease. These findings highlight an urgent need for therapeutics that are effective against persistent infections and call for creative approaches to identify potential drug targets. The C. pneumoniae and C. trachomatis genome projects have greatly expanded our knowledge of chlamydial pathogenesis and have provided an enormous potential for the identification and characterization of unknown genes and potential virulence factors in these bacteria. As intracellular pathogens, chlamydiae rely on host cells for all aspects of their survival, from the initial attachment with host cell membranes, to cellular invasion, acquisition of host cell metabolites and intracellular replication. As such, the molecules participating in interactions with the host could be attractive targets for therapeutic intervention. This review describes recent advances in chlamydial genomics, proteomics and cell biology that have cast light on host-pathogen relations that are essential for chlamydial survival. Using this knowledge, we discuss how strategically interfering with essential interactions between chlamydiae and the host cell could be exploited to develop an innovative, and potentially more relevant arsenal of therapeutic compounds.

The lifelong maintenance of mesencephalic dopaminergic neurons by Nurr1 and engrailed

PubMed Central

2014-01-01

Specific vulnerability and degeneration of the dopaminergic neurons in the substantia nigra pars compacta of the midbrain is the pathological hallmark of Parkinson’s disease. A number of transcription factors regulate the birth and development of this set of neurons and some remain constitutively expressed throughout life. These maintenance transcription factors are closely associated with essential neurophysiological functions and are required ultimately for the long-term survival of the midbrain dopaminergic neurons. The current review describes the role of two such factors, Nurr1 and engrailed, in differentiation, maturation, and in normal physiological functions including acquisition of neurotransmitter identity. The review will also elucidate the relationship of these factors with life, vulnerability, degeneration and death of mesencephalic dopaminergic neurons in the context of Parkinson’s disease. PMID:24685177

[Semiautomatic defibrillation in children].

PubMed

Rodríguez Núñez, A; Iglesias Vázquez, J A

2004-08-01

The main survival factor in cardiac arrest secondary to ventricular fibrillation (VF) is the interval between collapse and defibrillation; consequently, this treatment constitutes one of the most important links in the survival chain in adults. Although VF is a rare cause of out-of-hospital cardiac arrest in children, its detection and treatment is essential because in the pediatric cardiac arrest scenario, VF is the dysrhythmia with the best prognosis. Automated external defibrillators (AED) are simple devices that allow cardiac rhythm to be analyzed; they can also determine whether it is shockable or not with high sensitivity and specificity in adults and children. Currently available evidence has prompted the recommendation of AED use in children older than 1 year without signs of circulation, mainly in the pre-hospital setting and ideally with a dose-limiting device.

Genome-Scale Approaches to Identify Genes Essential for Haemophilus influenzae Pathogenesis

PubMed Central

Wong, Sandy M. S.; Akerley, Brian J.

2012-01-01

Haemophilus influenzae is a Gram-negative bacterium that has no identified natural niche outside of the human host. It primarily colonizes the nasopharyngeal mucosa in an asymptomatic mode, but has the ability to disseminate to other anatomical sites to cause otitis media, upper, and lower respiratory tract infections, septicemia, and meningitis. To persist in diverse environments the bacterium must exploit and utilize the nutrients and other resources available in these sites for optimal growth/survival. Recent evidence suggests that regulatory factors that direct such adaptations also control virulence determinants required to resist and evade immune clearance mechanisms. In this review, we describe the recent application of whole-genome approaches that together provide insight into distinct survival mechanisms of H. influenzae in the context of different sites of pathogenesis. PMID:22919615

Genome-scale approaches to identify genes essential for Haemophilus influenzae pathogenesis.

PubMed

Wong, Sandy M S; Akerley, Brian J

2012-01-01

Haemophilus influenzae is a Gram-negative bacterium that has no identified natural niche outside of the human host. It primarily colonizes the nasopharyngeal mucosa in an asymptomatic mode, but has the ability to disseminate to other anatomical sites to cause otitis media, upper, and lower respiratory tract infections, septicemia, and meningitis. To persist in diverse environments the bacterium must exploit and utilize the nutrients and other resources available in these sites for optimal growth/survival. Recent evidence suggests that regulatory factors that direct such adaptations also control virulence determinants required to resist and evade immune clearance mechanisms. In this review, we describe the recent application of whole-genome approaches that together provide insight into distinct survival mechanisms of H. influenzae in the context of different sites of pathogenesis.

The essential gene set of a photosynthetic organism

DOE PAGES

Rubin, Benjamin E.; Wetmore, Kelly M.; Price, Morgan N.; ...

2015-10-27

Synechococcus elongatus PCC 7942 is a model organism used for studying photosynthesis and the circadian clock, and it is being developed for the production of fuel, industrial chemicals, and pharmaceuticals. To identify a comprehensive set of genes and intergenic regions that impacts fitness in S. elongatus, we created a pooled library of ~250,000 transposon mutants and used sequencing to identify the insertion locations. By analyzing the distribution and survival of these mutants, we identified 718 of the organism's 2,723 genes as essential for survival under laboratory conditions. The validity of the essential gene set is supported by its tight overlapmore » with wellconserved genes and its enrichment for core biological processes. The differences noted between our dataset and these predictors of essentiality, however, have led to surprising biological insights. One such finding is that genes in a large portion of the TCA cycle are dispensable, suggesting that S. elongatus does not require a cyclic TCA process. Furthermore, the density of the transposon mutant library enabled individual and global statements about the essentiality of noncoding RNAs, regulatory elements, and other intergenic regions. In this way, a group I intron located in tRNA Leu , which has been used extensively for phylogenetic studies, was shown here to be essential for the survival of S. elongatus. Our survey of essentiality for every locus in the S. elongatus genome serves as a powerful resource for understanding the organism's physiology and defines the essential gene set required for the growth of a photosynthetic organism.« less

Prediction and analysis of essential genes using the enrichments of gene ontology and KEGG pathways.

PubMed

Chen, Lei; Zhang, Yu-Hang; Wang, ShaoPeng; Zhang, YunHua; Huang, Tao; Cai, Yu-Dong

2017-01-01

Identifying essential genes in a given organism is important for research on their fundamental roles in organism survival. Furthermore, if possible, uncovering the links between core functions or pathways with these essential genes will further help us obtain deep insight into the key roles of these genes. In this study, we investigated the essential and non-essential genes reported in a previous study and extracted gene ontology (GO) terms and biological pathways that are important for the determination of essential genes. Through the enrichment theory of GO and KEGG pathways, we encoded each essential/non-essential gene into a vector in which each component represented the relationship between the gene and one GO term or KEGG pathway. To analyze these relationships, the maximum relevance minimum redundancy (mRMR) was adopted. Then, the incremental feature selection (IFS) and support vector machine (SVM) were employed to extract important GO terms and KEGG pathways. A prediction model was built simultaneously using the extracted GO terms and KEGG pathways, which yielded nearly perfect performance, with a Matthews correlation coefficient of 0.951, for distinguishing essential and non-essential genes. To fully investigate the key factors influencing the fundamental roles of essential genes, the 21 most important GO terms and three KEGG pathways were analyzed in detail. In addition, several genes was provided in this study, which were predicted to be essential genes by our prediction model. We suggest that this study provides more functional and pathway information on the essential genes and provides a new way to investigate related problems.

TACE/ADAM17 is essential for oligodendrocyte development and CNS myelination.

PubMed

Palazuelos, Javier; Crawford, Howard C; Klingener, Michael; Sun, Bingru; Karelis, Jason; Raines, Elaine W; Aguirre, Adan

2014-09-03

Several studies have elucidated the significance of a disintegrin and metalloproteinase proteins (ADAMs) in PNS myelination, but there is no evidence if they also play a role in oligodendrogenesis and CNS myelination. Our study identifies ADAM17, also called tumor necrosis factor-α converting enzyme (TACE), as a novel key modulator of oligodendrocyte (OL) development and CNS myelination. Genetic deletion of TACE in oligodendrocyte progenitor cells (OPs) induces premature cell cycle exit and reduces OL cell survival during postnatal myelination of the subcortical white matter (SCWM). These cellular and molecular changes lead to deficits in SCWM myelination and motor behavior. Mechanistically, TACE regulates oligodendrogenesis by modulating the shedding of EGFR ligands TGFα and HB-EGF and, consequently, EGFR signaling activation in OL lineage cells. Constitutive TACE depletion in OPs in vivo leads to similar alterations in CNS myelination and motor behavior as to what is observed in the EGFR hypofunctional mouse line EgfrWa2. EGFR overexpression in TACE-deficient OPs restores OL survival and development. Our study reveals an essential function of TACE in oligodendrogenesis, and demonstrates how this molecule modulates EGFR signaling activation to regulate postnatal CNS myelination. Copyright © 2014 the authors 0270-6474/14/3411884-13$15.00/0.

The Drosophila T-box transcription factor Midline functions within the Notch–Delta signaling pathway to specify sensory organ precursor cell fates and regulates cell survival within the eye imaginal disc

PubMed Central

Das, Sudeshna; Chen, Q. Brent; Saucier, Joseph D.; Drescher, Brandon; Zong, Yan; Morgan, Sarah; Forstall, John; Meriwether, Andrew; Toranzo, Randy; Leal, Sandra M.

2014-01-01

We report that the T-box transcription factor Midline (Mid), an evolutionary conserved homolog of the vertebrate Tbx20 protein, functions within the Notch–Delta signaling pathway essential for specifying the fates of sensory organ precursor cells. This complements an established history of research showing that Mid regulates the cell-fate specification of diverse cell types within the developing heart, epidermis and central nervous system. Tbx20 has been detected in diverse neuronal and epithelial cells of embryonic eye tissues in both mice and humans. However, the mechanisms by which either Mid or Tbx20 function to regulate cell-fate specification or other critical aspects of eye development including cell survival have not yet been elucidated. We have also gathered preliminary evidence suggesting that Mid may play an indirect, but vital role in selecting SOP cells within the third-instar larval eye disc by regulating the expression of the proneural gene atonal. During subsequent pupal stages, Mid specifies SOP cell fates as a member of the Notch–Delta signaling hierarchy and is essential for maintaining cell viability within by inhibiting apoptotic pathways. We present several new hypotheses that seek to understand the role of Mid in regulating developmental processes downstream of the Notch receptor that are critical for specifying unique cell fates, patterning the adult eye and maintaining cellular homeostasis during eye disc morphogenesis. PMID:23962751

Prognostic significance of NFIA and NFIB in esophageal squamous carcinoma and esophagogastric junction adenocarcinoma.

PubMed

Yang, Bo; Zhou, Zhi-Hang; Chen, Li; Cui, Xiang; Hou, Jun-Yan; Fan, Kai-Jie; Han, Si-Hao; Li, Peng; Yi, Shao-Qiong; Liu, Yang

2018-05-01

The nuclear factor I (NFI) family members, especially NFIA and NFIB, play essential roles in cancers. The roles of NFIA and NFIB in esophageal squamous cell carcinoma (ESCC) and esophagogastric junction adenocarcinoma (EJA) remain poorly known. This study aimed to determine the expression of NFIA and NFIB in ESCC and EJA and elucidate their prognostic significance. The expression of NFIA and NFIB was examined in 163 ESCC samples and 26 EJA samples by immunohistochemistry. The results showed that high NFIA expression correlated significantly with poor differentiation, lymph node metastasis, and advanced TNM stage in patients with ESCC. High NFIB expression only correlated with poor differentiation in patients with ESCC. Survival analysis showed that NFIA but not NFIB associated with short overall survival (OS) and disease-free survival (DFS) of patients with ESCC. On the other hand, high NFIB expression correlated with lymph node metastasis, advanced TNM stage, and short OS and DFS in patients with EJA. Finally, multivariate analysis demonstrated that high NFIA expression was an independent prognostic factor for ESCC. Taken together, these results demonstrated that NFIA and NFIB could serve as prognostic indicators for ESCC and EJA, respectively. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Mondo/ChREBP-Mlx-Regulated Transcriptional Network Is Essential for Dietary Sugar Tolerance in Drosophila

PubMed Central

Havula, Essi; Teesalu, Mari; Hyötyläinen, Tuulia; Seppälä, Heini; Hasygar, Kiran; Auvinen, Petri; Orešič, Matej; Sandmann, Thomas; Hietakangas, Ville

2013-01-01

Sugars are important nutrients for many animals, but are also proposed to contribute to overnutrition-derived metabolic diseases in humans. Understanding the genetic factors governing dietary sugar tolerance therefore has profound biological and medical significance. Paralogous Mondo transcription factors ChREBP and MondoA, with their common binding partner Mlx, are key sensors of intracellular glucose flux in mammals. Here we report analysis of the in vivo function of Drosophila melanogaster Mlx and its binding partner Mondo (ChREBP) in respect to tolerance to dietary sugars. Larvae lacking mlx or having reduced mondo expression show strikingly reduced survival on a diet with moderate or high levels of sucrose, glucose, and fructose. mlx null mutants display widespread changes in lipid and phospholipid profiles, signs of amino acid catabolism, as well as strongly elevated circulating glucose levels. Systematic loss-of-function analysis of Mlx target genes reveals that circulating glucose levels and dietary sugar tolerance can be genetically uncoupled: Krüppel-like transcription factor Cabut and carbonyl detoxifying enzyme Aldehyde dehydrogenase type III are essential for dietary sugar tolerance, but display no influence on circulating glucose levels. On the other hand, Phosphofructokinase 2, a regulator of the glycolysis pathway, is needed for both dietary sugar tolerance and maintenance of circulating glucose homeostasis. Furthermore, we show evidence that fatty acid synthesis, which is a highly conserved Mondo-Mlx-regulated process, does not promote dietary sugar tolerance. In contrast, survival of larvae with reduced fatty acid synthase expression is sugar-dependent. Our data demonstrate that the transcriptional network regulated by Mondo-Mlx is a critical determinant of the healthful dietary spectrum allowing Drosophila to exploit sugar-rich nutrient sources. PMID:23593032

Systematic review of pancreatic cancer epidemiology in Asia-Pacific Region: major patterns in GLOBACON 2012

PubMed Central

Pourhoseingholi, Mohamad Amin; Ashtari, Sara; Hajizadeh, Nastaran; Fazeli, Zeinab; Zali, Mohammad Reza

2017-01-01

Pancreatic cancer is one of the deadliest cancers with short-term survival rates. Trends for pancreatic cancer incidence and mortality varied considerably in the world. To date, the causes of pancreatic cancer are not known sufficiently, although certain risk factors have been identified such as, smoking, obesity, life style, diabetes mellitus, alcohol, dietary factors and chronic pancreatitis. Since there are no current screening recommendations for pancreatic cancer, primary prevention is very important. Therefore, up-to-date statistics on pancreatic cancer occurrence and outcome are essential for the primary prevention of this disease. Due to the lack of information on epidemiology of pancreatic cancer in most Asian countries, and limited of statistics and registration system in this area, we conducted a systematic review study to evaluate the most recent data concerning epidemiology of pancreatic cancer in Asia-Pacific region. In this review we focused on collected recent data on incidence, mortality, survival and risk factors of pancreatic cancer in this region. In addition, we reviewed and used the data of GLOBOCAN 2012 in this paper to complete the information as a source of compiling pancreatic cancer incidence and mortality rate. PMID:29379588

Persistent parental effects on the survival and size, but not burst swimming performance of juvenile sockeye salmon Oncorhynchus nerka.

PubMed

Nadeau, P S; Hinch, S G; Pon, L B; Patterson, D A

2009-08-01

Sockeye salmon Oncorhynchus nerka were used as a model in an artificial fertilization experiment to investigate the relationships between individual adult O. nerka and their offspring. Survival, size and burst swimming ability were assessed in fry of known parentage (adult spawners from the Weaver Creek population, British Columbia, Canada). Maternal identity significantly affected the survival rate of eggs at hatch time, though this effect did not extend to fry life stages. The results were also suggestive of a paternal effect on both egg and fry survival, though this could not be separated from the experimental block design. After 4 months of exogenous feeding, fry mass remained under significant maternal influence, though fork length did not, despite having a high correlation with mass. Burst swimming performance was highly variable among individuals, and was not significantly influenced by maternal identity or individual fry size. Collectively, the findings presented here suggest that maternal, and possibly paternal, effects can be integral components of population dynamics in the early life stages of O. nerka. A good understanding of these factors will be essential for scientists and fisheries managers in developing a more holistic view of population-level spawning success and fry survival.

Desiccation tolerance in the tardigrade Richtersius coronifer relies on muscle mediated structural reorganization.

PubMed

Halberg, Kenneth Agerlin; Jørgensen, Aslak; Møbjerg, Nadja

2013-01-01

Life unfolds within a framework of constraining abiotic factors, yet some organisms are adapted to handle large fluctuations in physical and chemical parameters. Tardigrades are microscopic ecdysozoans well known for their ability to endure hostile conditions, such as complete desiccation--a phenomenon called anhydrobiosis. During dehydration, anhydrobiotic animals undergo a series of anatomical changes. Whether this reorganization is an essential regulated event mediated by active controlled processes, or merely a passive result of the dehydration process, has not been clearly determined. Here, we investigate parameters pivotal to the formation of the so-called "tun", a state that in tardigrades and rotifers marks the entrance into anhydrobiosis. Estimation of body volume in the eutardigrade Richtersius coronifer reveals an 87 % reduction in volume from the hydrated active state to the dehydrated tun state, underlining the structural stress associated with entering anhydrobiosis. Survival experiments with pharmacological inhibitors of mitochondrial energy production and muscle contractions show that i) mitochondrial energy production is a prerequisite for surviving desiccation, ii) uncoupling the mitochondria abolishes tun formation, and iii) inhibiting the musculature impairs the ability to form viable tuns. We moreover provide a comparative analysis of the structural changes involved in tun formation, using a combination of cytochemistry, confocal laser scanning microscopy and 3D reconstructions as well as scanning electron microscopy. Our data reveal that the musculature mediates a structural reorganization vital for anhydrobiotic survival, and furthermore that maintaining structural integrity is essential for resumption of life following rehydration.

Desiccation Tolerance in the Tardigrade Richtersius coronifer Relies on Muscle Mediated Structural Reorganization

PubMed Central

Halberg, Kenneth Agerlin; Jørgensen, Aslak; Møbjerg, Nadja

2013-01-01

Life unfolds within a framework of constraining abiotic factors, yet some organisms are adapted to handle large fluctuations in physical and chemical parameters. Tardigrades are microscopic ecdysozoans well known for their ability to endure hostile conditions, such as complete desiccation – a phenomenon called anhydrobiosis. During dehydration, anhydrobiotic animals undergo a series of anatomical changes. Whether this reorganization is an essential regulated event mediated by active controlled processes, or merely a passive result of the dehydration process, has not been clearly determined. Here, we investigate parameters pivotal to the formation of the so-called "tun", a state that in tardigrades and rotifers marks the entrance into anhydrobiosis. Estimation of body volume in the eutardigrade Richtersius coronifer reveals an 87 % reduction in volume from the hydrated active state to the dehydrated tun state, underlining the structural stress associated with entering anhydrobiosis. Survival experiments with pharmacological inhibitors of mitochondrial energy production and muscle contractions show that i) mitochondrial energy production is a prerequisite for surviving desiccation, ii) uncoupling the mitochondria abolishes tun formation, and iii) inhibiting the musculature impairs the ability to form viable tuns. We moreover provide a comparative analysis of the structural changes involved in tun formation, using a combination of cytochemistry, confocal laser scanning microscopy and 3D reconstructions as well as scanning electron microscopy. Our data reveal that the musculature mediates a structural reorganization vital for anhydrobiotic survival, and furthermore that maintaining structural integrity is essential for resumption of life following rehydration. PMID:24391987

Caprin-1 is a target of the deafness gene Pou4f3 and is recruited to stress granules in cochlear hair cells in response to ototoxic damage

PubMed Central

Towers, Emily R.; Kelly, John J.; Sud, Richa; Gale, Jonathan E.; Dawson, Sally J.

2011-01-01

The POU4 family of transcription factors are required for survival of specific cell types in different sensory systems. Pou4f3 is essential for the survival of auditory sensory hair cells and several mutations in human POU4F3 cause hearing loss. Thus, genes regulated by Pou4f3 are likely to be essential for hair cell survival. We performed a subtractive hybridisation screen in an inner-ear-derived cell line to find genes with differential expression in response to changes in Pou4f3 levels. The screen identified the stress-granule-associated protein Caprin-1 as being downregulated by Pou4f3. We demonstrated that this regulation occurs through the direct interaction of Pou4f3 with binding sites in the Caprin-1 5′ flanking sequence, and describe the expression pattern of Caprin-1 mRNA and protein in the cochlea. Moreover, we found Caprin-1-containing stress granules are induced in cochlear hair cells following aminoglycoside-induced damage. This is the first report of stress granule formation in mammalian hair cells and suggests that the formation of Caprin-1-containing stress granules is a key damage response to a clinically relevant ototoxic agent. Our results have implications for the understanding of aminoglycoside-induced hearing loss and provide further evidence that stress granule formation is a fundamental cellular stress response. PMID:21402877

The reproductive performance of the Mupli beetle, Luprops tristis , in relation to leaf age of the para rubber tree, Hevea brasiliensis

PubMed Central

Sabu, T. K.; Nirdev, P. M.; Aswathi, P.

2014-01-01

Abstract An analysis of host plant leaf age preferences and phenology studies led to the predictions that tender rubber plant leaves are essential for the completion of the life cycle of the Mupli beetle, Luprops tristis Fabricius (Coleoptera: Tenebrionidae) and that low tender leaf availability during the post-dormancy stage will limit the beetle population. Analyses of the effects of feeding the beetles leaves of various ages, nitrogen (N) content, and moisture content on fecundity and the duration of post-dormancy survival were carried out. The results showed that tender leaf availability during the post-dormancy phase of L. tristis is a critical factor that determines the survival of L. tristis adults and the subsequent generation. The control of powdery mildew ( Odium hevea ) disease-mediated premature leaf fall in rubber plantations may regulate the beetle population. A peak in fecundity during the early phase of post-dormancy is proposed as an adaptive mechanism of L. tristis to synchronize egg production and feeding with tender leaf availability in rubber plantations. Variations in nutrient levels and moisture content between deciduous rubber tree leaves of different ages are attributed to the leaf nutrient resorption mechanism of senescing leaves. These results established that tender leaves with high N and moisture levels are essential for post-dormancy survival and that N influences fecundity. The results of the experiments could aid decision making regarding the population management and control of L. tristis in rubber plantations. PMID:25373159

The important role of von Willebrand factor in platelet-derived FVIII gene therapy for murine hemophilia A in the presence of inhibitory antibodies.

PubMed

Shi, Q; Schroeder, J A; Kuether, E L; Montgomery, R R

2015-07-01

Our previous studies have demonstrated that targeting FVIII expression to platelets results in FVIII storage together with von Willebrand factor (VWF) in platelet α-granules and that platelet-derived FVIII (2bF8) corrects the murine hemophilia A phenotype even in the presence of high-titer anti-FVIII inhibitory antibodies (inhibitors). To explore how VWF has an impact on platelet gene therapy for hemophilia A with inhibitors. 2bF8 transgenic mice in the FVIII(-/-) background (2bF8(tg+/-) F8(-/-) ) with varying VWF phenotypes were used in this study. Animals were analyzed by VWF ELISA, FVIII activity assay, Bethesda assay and tail clip survival test. Only 18% of 2bF8(tg+/-) F8(-/-) VWF(-/-) animals, in which VWF was deficient, survived the tail clip challenge with inhibitor titers of 3-8000 BU mL(-1) . In contrast, 82% of 2bF8(tg+/-) F8(-/-) VWF(+/+) mice, which had normal VWF levels, survived tail clipping with inhibitor titers of 10-50,000 BU mL(-1) . All 2bF8(tg+/-) F8(-/-) VWF(-/-) mice without inhibitors survived tail clipping and no VWF(-/-) F8(-/-) mice survived this challenge. Because VWF is synthesized by endothelial cells and megakaryocytes and is distributed in both plasma and platelets in peripheral blood, we further investigated the effect of each compartment of VWF on platelet-FVIII gene therapy for hemophilia A with inhibitors. In the presence of inhibitors, 42% of animals survived tail clipping in the group with plasma-VWF and 50% survived in the platelet-VWF group. VWF is essential for platelet gene therapy for hemophilia A with inhibitors. Both platelet-VWF and plasma-VWF are required for optimal platelet-derived FVIII gene therapy for hemophilia A in the presence of inhibitors. © 2015 International Society on Thrombosis and Haemostasis.

Nuclear factor one B (NFIB) encodes a subtype-specific tumour suppressor in glioblastoma

PubMed Central

Stringer, Brett W.; Bunt, Jens; Day, Bryan W.; Barry, Guy; Jamieson, Paul R.; Ensbey, Kathleen S.; Bruce, Zara C.; Goasdoué, Kate; Vidal, Hélène; Charmsaz, Sara; Smith, Fiona M.; Cooper, Leanne T.; Piper, Michael

2016-01-01

Glioblastoma (GBM) is an essentially incurable and rapidly fatal cancer, with few markers predicting a favourable prognosis. Here we report that the transcription factor NFIB is associated with significantly improved survival in GBM. NFIB expression correlates inversely with astrocytoma grade and is lowest in mesenchymal GBM. Ectopic expression of NFIB in low-passage, patient-derived classical and mesenchymal subtype GBM cells inhibits tumourigenesis. Ectopic NFIB expression activated phospho-STAT3 signalling only in classical and mesenchymal GBM cells, suggesting a mechanism through which NFIB may exert its context-dependent tumour suppressor activity. Finally, NFIB expression can be induced in GBM cells by drug treatment with beneficial effects. PMID:27083054

Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids

PubMed Central

Eoh, Hyungjin; Rhee, Kyu Y.

2014-01-01

Few mutations attenuate Mycobacterium tuberculosis (Mtb) more profoundly than deletion of its isocitrate lyases (ICLs). However, the basis for this attenuation remains incompletely defined. Mtb’s ICLs are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids. Here, we report that Mtb’s ICLs are essential for survival on both acetate and propionate because of its methylisocitrate lyase (MCL) activity. Lack of MCL activity converts Mtb’s methylcitrate cycle into a “dead end” pathway that sequesters tricarboxylic acid (TCA) cycle intermediates into methylcitrate cycle intermediates, depletes gluconeogenic precursors, and results in defects of membrane potential and intrabacterial pH. Activation of an alternative vitamin B12-dependent pathway of propionate metabolism led to selective corrections of TCA cycle activity, membrane potential, and intrabacterial pH that specifically restored survival, but not growth, of ICL-deficient Mtb metabolizing acetate or propionate. These results thus resolve the biochemical basis of essentiality for Mtb’s ICLs and survival on fatty acids. PMID:24639517

Primary intrathoracic liposarcoma: a clinicopathologic study and prognostic analysis of 23 cases

PubMed Central

2014-01-01

Background Primary intrathoracic liposarcoma is an extremely rare malignancy as well as a rare histologic subtype of intrathoracic sarcoma. Relatively few reports appear in the world literatures. We explored the clinicopathologic features and prognostic factors of this tumor in this study. Methods We retrospectively analyzed the clinicopathological data of 23 patients with primary intrathoracic liposarcoma who were treated in Shanghai chest Hospital affiliated to Jiao Tong University, from January 2003 to March 2013. These patients were classified into three groups according to the distinct tumor locations, including mediastinum, pleura and lung liposarcoma. Also, these patients could be divided into four types, including well-differentiated, myxoid, dedifferentiated and pleomorphic liposarcoma. The influences of age, sex, tumor size, tumor location, tumor histologic type and therapy on the prognosis of the patients were analyzed. Results There were no significant difference for survival among distinct liposarcoma locations. However, significant difference for survival among distinct liposarcoma types were observed. Poor disease-free survival (DFS) was observed in the myxoid, pleomorphic and dedifferentiated types as compared to well-differentiated type (P = 0.038). Inferior overall-survival (OS) was observed in dedifferentiated, pleomorphic and myxoid types relative to well-differentiated type (P = 0.027). The radical surgery was a favorable prognostic factor for OS, as demonstrated by the better OS of the radical surgery group as compared to that of the non-radical surgery group ( P = 0.029). Notably, there were no significant differences for DFS and OS in other clinical parameters including tumor size, gender and age. In addition, radiotherapy and/or chemotherapy could not improve the prognosis of the patients receiving non-radical surgery or suffering from relapse. Conclusions The histological type and the radical surgery are the factors that influence the behavior and prognosis of liposarcoma. In general, radiotherapy and chemotherapy are believed to be ineffective therapeutic modalities for survival. So it is essential to completely resect the primary intrathoracic liposarcoma as radical cure of the disease. PMID:24993036

Estrogen receptor quantitation and staging as complementary prognostic indicators in breast cancer: a study of 583 patients.

PubMed

Godolphin, W; Elwood, J M; Spinelli, J J

1981-12-01

Estrogen receptor (ER) quantity was measured at the time of primary diagnosis on 583 patients with breast cancer seen at the major treatment centre in British Columbia between 1975 and 1979. Survival rates (overall, recurrence-free and post-recurrence) were assessed relative to ER concentration, staging, menopausal status, age, differentiation, and therapy. A linear trend in increased survival was demonstrable through variations in ER concentration from less than 1 to greater than 260 fmoles/mg cytosol protein. This trend was highly significant and remained after adjustment for stage, menopausal status, and age, and was seen for all groups of patients except those with metastatic disease. The association of high ER concentration with increased recurrence-free survival was not due to differing responses to adjuvant therapy, but the trend in post-recurrence survival was only significant in patients who had received hormonal therapy. Survival was as strongly associated with receptor concentration as with staging, and these two factors were almost completely independent. A proportional hazards model was fitted to produce predictions of survival, and showed that TNM stage III patients with high ER concentrations have a better survival than stage I or II patients with lower ER concentrations. This suggests that quantitative assessment of ER status is essential to definition of risk in breast cancer patients and that stratification in clinical trials and consideration for adjuvant therapy ought to be guided, in part, by a standardized ER-quantitative determination performed on the primary tumor.

The Biochemistry of O-GlcNAc Transferase: Which Functions Make It Essential in Mammalian Cells?

PubMed

Levine, Zebulon G; Walker, Suzanne

2016-06-02

O-linked N-acetylglucosamine transferase (OGT) is found in all metazoans and plays an important role in development but at the single-cell level is only essential in dividing mammalian cells. Postmitotic mammalian cells and cells of invertebrates such as Caenorhabditis elegans and Drosophila can survive without copies of OGT. Why OGT is required in dividing mammalian cells but not in other cells remains unknown. OGT has multiple biochemical activities. Beyond its well-known role in adding β-O-GlcNAc to serine and threonine residues of nuclear and cytoplasmic proteins, OGT also acts as a protease in the maturation of the cell cycle regulator host cell factor 1 (HCF-1) and serves as an integral member of several protein complexes, many of them linked to gene expression. In this review, we summarize current understanding of the mechanisms underlying OGT's biochemical activities and address whether known functions of OGT could be related to its essential role in dividing mammalian cells.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rubin, Benjamin E.; Wetmore, Kelly M.; Price, Morgan N.

Synechococcus elongatus PCC 7942 is a model organism used for studying photosynthesis and the circadian clock, and it is being developed for the production of fuel, industrial chemicals, and pharmaceuticals. To identify a comprehensive set of genes and intergenic regions that impacts fitness in S. elongatus, we created a pooled library of ~250,000 transposon mutants and used sequencing to identify the insertion locations. By analyzing the distribution and survival of these mutants, we identified 718 of the organism's 2,723 genes as essential for survival under laboratory conditions. The validity of the essential gene set is supported by its tight overlapmore » with wellconserved genes and its enrichment for core biological processes. The differences noted between our dataset and these predictors of essentiality, however, have led to surprising biological insights. One such finding is that genes in a large portion of the TCA cycle are dispensable, suggesting that S. elongatus does not require a cyclic TCA process. Furthermore, the density of the transposon mutant library enabled individual and global statements about the essentiality of noncoding RNAs, regulatory elements, and other intergenic regions. In this way, a group I intron located in tRNA Leu , which has been used extensively for phylogenetic studies, was shown here to be essential for the survival of S. elongatus. Our survey of essentiality for every locus in the S. elongatus genome serves as a powerful resource for understanding the organism's physiology and defines the essential gene set required for the growth of a photosynthetic organism.« less

The reduced-risk insecticide azadirachtin poses a toxicological hazard to stingless bee Partamona helleri (Friese, 1900) queens.

PubMed

Bernardes, Rodrigo Cupertino; Barbosa, Wagner Faria; Martins, Gustavo Ferreira; Lima, Maria Augusta Pereira

2018-06-01

Large-scale pesticide application poses a major threat to bee biodiversity by causing a decline in bee populations that, in turn, compromises ecosystem maintenance and agricultural productivity. Biopesticides are considered an alternative to synthetic pesticides with a focus on reducing potential detrimental effects to beneficial organisms such as bees. The production of healthy queen stingless bees is essential for the survival and reproduction of hives, although it remains unknown whether biopesticides influence stingless bee reproduction. In the present study, we investigated the effects of the biopesticide azadirachtin on the survival, behavior, morphology, development, and reproduction of queens of the stingless bee Partamona helleri (Friese, 1900). The neonicotinoid imidacloprid was used as a toxic reference standard. Queens were orally exposed in vitro to a contaminated diet (containing azadirachtin and imidacloprid) during development. Azadirachtin resulted in reduced survival, similarly to imidacloprid, altered development time, caused deformations, and reduced the size of the queens' reproductive organs. All of these factors could potentially compromise colony survival. Results from the present study showed azadirachtin posed a toxicological hazard to P. helleri queens. Copyright © 2018 Elsevier Ltd. All rights reserved.

From ridge to reef—linking erosion and changing watersheds to impacts on the coral reef ecosystems of Hawai‘i and the Pacific Ocean

USGS Publications Warehouse

Stock, Jonathan D.; Cochran, Susan A.; Field, Michael E.; Jacobi, James D.; Tribble, Gordon

2011-01-01

Coral reef ecosystems are threatened by unprecedented watershed changes in the United States and worldwide. These ecosystems sustain fishing and tourism industries essential to the economic survival of many communities. Sediment, nutrients, and pollutants from watersheds are increasingly transported to coastal waters, where these contaminants damage corals. Although pollution from watersheds is one of many factors threatening coral survival, it is one that local people can have a profound influence on. U.S. Geological Survey scientists are using mapping, monitoring, and computer modeling to better forecast the effects of watershed changes on reef health. Working with communities in Hawai‘i and on other U.S. islands in the Pacific, they are helping to provide the science needed to make informed decisions on watershed and coral reef management.

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells.

PubMed

Sastry, K S R; Al-Muftah, M A; Li, Pu; Al-Kowari, M K; Wang, E; Ismail Chouchane, A; Kizhakayil, D; Kulik, G; Marincola, F M; Haoudi, A; Chouchane, L

2014-12-01

Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44(+)/CD24(-) cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44(+) CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

Nerve growth factor, interoception, and sympathetic neuron: lesson from congenital insensitivity to pain with anhidrosis.

PubMed

Indo, Yasuhiro

2009-05-11

Nerve growth factor (NGF) is a well-known neurotrophic factor essential for the survival and maintenance of sensory and sympathetic neurons. Congenital insensitivity to pain with anhidrosis (CIPA) is a genetic disorder due to loss-of-function mutations in the NTRK1 (also known as TRKA) gene encoding TrkA, a receptor tyrosine kinase for NGF. Patients with CIPA provide us a rare opportunity to explore the developmental and physiological function of the NGF-dependent neurons in behavior, cognitive, and mental activities that are not available in animal studies. Here, I discuss the significance of findings that patients with CIPA lack NGF-dependent neurons, including interoceptive polymodal receptors, sympathetic postganglionic neurons, and probably several types of neurons in the brain. They also exhibit characteristic emotional behavior or problems. Together, the NGF-TrkA system is essential for the establishment of a neural network for interoception and homeostasis that may underlie 'gut feelings'. Thus, NGF-dependent neurons play a crucial role in emotional experiences and decision-making processes. Prospective studies focused on these neurons might provide further insights into the neural basis of human emotion and feeling.

The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance

PubMed Central

Nunn, Alistair VW; Bell, Jimmy; Barter, Philip

2007-01-01

The peroxisomal proliferating-activated receptors (PPARs) are lipid-sensing transcription factors that have a role in embryonic development, but are primarily known for modulating energy metabolism, lipid storage, and transport, as well as inflammation and wound healing. Currently, there is no consensus as to the overall combined function of PPARs and why they evolved. We hypothesize that the PPARs had to evolve to integrate lipid storage and burning with the ability to reduce oxidative stress, as energy storage is essential for survival and resistance to injury/infection, but the latter increases oxidative stress and may reduce median survival (functional longevity). In a sense, PPARs may be an evolutionary solution to something we call the 'hypoxia-lipid' conundrum, where the ability to store and burn fat is essential for survival, but is a 'double-edged sword', as fats are potentially highly toxic. Ways in which PPARs may reduce oxidative stress involve modulation of mitochondrial uncoupling protein (UCP) expression (thus reducing reactive oxygen species, ROS), optimising forkhead box class O factor (FOXO) activity (by improving whole body insulin sensitivity) and suppressing NFkB (at the transcriptional level). In light of this, we therefore postulate that inflammation-induced PPAR downregulation engenders many of the signs and symptoms of the metabolic syndrome, which shares many features with the acute phase response (APR) and is the opposite of the phenotype associated with calorie restriction and high FOXO activity. In genetically susceptible individuals (displaying the naturally mildly insulin resistant 'thrifty genotype'), suboptimal PPAR activity may follow an exaggerated but natural adipose tissue-related inflammatory signal induced by excessive calories and reduced physical activity, which normally couples energy storage with the ability to mount an immune response. This is further worsened when pancreatic decompensation occurs, resulting in gluco-oxidative stress and lipotoxicity, increased inflammatory insulin resistance and oxidative stress. Reactivating PPARs may restore a metabolic balance and help to adapt the phenotype to a modern lifestyle. PMID:17531095

A Comprehensive Analysis of In Vitro and In Vivo Genetic Fitness of Pseudomonas aeruginosa Using High-Throughput Sequencing of Transposon Libraries

PubMed Central

Aschard, Hugues; Cattoir, Vincent; Yoder-Himes, Deborah; Lory, Stephen; Pier, Gerald B.

2013-01-01

High-throughput sequencing of transposon (Tn) libraries created within entire genomes identifies and quantifies the contribution of individual genes and operons to the fitness of organisms in different environments. We used insertion-sequencing (INSeq) to analyze the contribution to fitness of all non-essential genes in the chromosome of Pseudomonas aeruginosa strain PA14 based on a library of ∼300,000 individual Tn insertions. In vitro growth in LB provided a baseline for comparison with the survival of the Tn insertion strains following 6 days of colonization of the murine gastrointestinal tract as well as a comparison with Tn-inserts subsequently able to systemically disseminate to the spleen following induction of neutropenia. Sequencing was performed following DNA extraction from the recovered bacteria, digestion with the MmeI restriction enzyme that hydrolyzes DNA 16 bp away from the end of the Tn insert, and fractionation into oligonucleotides of 1,200–1,500 bp that were prepared for high-throughput sequencing. Changes in frequency of Tn inserts into the P. aeruginosa genome were used to quantify in vivo fitness resulting from loss of a gene. 636 genes had <10 sequencing reads in LB, thus defined as unable to grow in this medium. During in vivo infection there were major losses of strains with Tn inserts in almost all known virulence factors, as well as respiration, energy utilization, ion pumps, nutritional genes and prophages. Many new candidates for virulence factors were also identified. There were consistent changes in the recovery of Tn inserts in genes within most operons and Tn insertions into some genes enhanced in vivo fitness. Strikingly, 90% of the non-essential genes were required for in vivo survival following systemic dissemination during neutropenia. These experiments resulted in the identification of the P. aeruginosa strain PA14 genes necessary for optimal survival in the mucosal and systemic environments of a mammalian host. PMID:24039572

A Generalizable Methodology for Quantifying User Satisfaction

NASA Astrophysics Data System (ADS)

Huang, Te-Yuan; Chen, Kuan-Ta; Huang, Polly; Lei, Chin-Laung

Quantifying user satisfaction is essential, because the results can help service providers deliver better services. In this work, we propose a generalizable methodology, based on survival analysis, to quantify user satisfaction in terms of session times, i. e., the length of time users stay with an application. Unlike subjective human surveys, our methodology is based solely on passive measurement, which is more cost-efficient and better able to capture subconscious reactions. Furthermore, by using session times, rather than a specific performance indicator, such as the level of distortion of voice signals, the effects of other factors like loudness and sidetone, can also be captured by the developed models. Like survival analysis, our methodology is characterized by low complexity and a simple model-developing process. The feasibility of our methodology is demonstrated through case studies of ShenZhou Online, a commercial MMORPG in Taiwan, and the most prevalent VoIP application in the world, namely Skype. Through the model development process, we can also identify the most significant performance factors and their impacts on user satisfaction and discuss how they can be exploited to improve user experience and optimize resource allocation.

Differential stimulation of neurotrophin release by the biocompatible nano-material (carbon nanotube) in primary cultured neurons.

PubMed

Kim, Yun Gi; Kim, Jong Wan; Pyeon, Hee Jang; Hyun, Jung Keun; Hwang, Ji-Young; Choi, Seong-Jun; Lee, Ja-Yeon; Deák, Ferenc; Kim, Hae-Won; Lee, Young Il

2014-01-01

In order to develop novel, effective therapies for central nervous system regeneration, it is essential to better understand the role of neurotrophic factors and to design, accordingly, better artificial scaffolds to support both neurite outgrowth and synapse formation. Both nerve growth factor and brain-derived neurotrophic factor are major factors in neural survival, development, synaptogenesis, and synaptic connectivity of primary cultured neurons. As a prime candidate coating material for such neural cultures, carbon nanotubes offer unique structural, mechanical, and electrical properties. In this study, carbon nanotubes coated glass-coverslips were used as the matrix of a primary neural culture system used to investigate the effects of carbon nanotubes on neurite outgrowth and nerve growth factor/brain-derived neurotrophic factor release and expression. For these purposes, we performed comparative analyses of primary cultured neurons on carbon nanotubes coated, non-coated, and Matrigel-coated coverslips. The morphological findings showed definite carbon nanotubes effects on the neurite outgrowths and synaptogenic figures in both cortical and hippocampal neurons when compared with the non-coated negative control. Although the carbon nanotubes did not change neurotrophin expression levels, it stimulated brain-derived neurotrophic factor release into the media from both types of neurons. Accordingly, we suggest a different mechanism of action between carbon nanotubes and Matrigel in relation to the specific neurotrophic factors. Since carbon nanotubes supply long-term extracellular molecular cues for the survival and neurite outgrowths of cultured neurons, the results from this study will contribute to an understanding of carbon nanotubes biological effects and provide new insight into their role in the secretion of neurotrophic factors.

Nest visits and capture events affect breeding success of Yellow-billed and Pacific loons

USGS Publications Warehouse

Uher-Koch, Brian D.; Schmutz, Joel A.; Wright, Kenneth G.

2015-01-01

Accurate estimates of breeding success are essential for understanding population dynamics and for managing populations. Unfortunately, research activities to collect these data can negatively impact the breeding success of the study species and bias estimates of breeding success. Despite the potential for negative impacts, few studies have documented the effect of capturing incubating adults on nest survival or compared nest survival following different capture methods. In this study we evaluate the impacts of investigator disturbance associated with captures and nest visits on nest survival of Yellow-billed Loons (Gavia adamsii) and Pacific Loons (Gavia pacifica) in the National Petroleum Reserve-Alaska (NPR-A), an area of conservation concern, in 2011–2013. In an effort to reduce capture-related nest failures, we developed a new suspended dive net technique to catch territorial aquatic birds while off their nests. We then compared nest survival following suspended dive net captures to bow-net trap captures of breeding adult loons. Daily nest survival following bow-net trap or suspended dive net capture was about 30% lower than when adults were not captured. The effect of captures on nest survival was similar between bow-net trap and suspended dive net capture methods. Nest visits without captures also negatively impacted nest survival, although less than captures. If not accounted for, nest visitation biased daily survival rates of nests downward 6%. Effects of investigator disturbance did not differ by species or between years. Our results suggest that any source of disturbance that displaces incubating adult loons could potentially reduce nest survival. To maximize breeding success, human disturbance factors should be limited near loon nests.

The introduction of new policies and strategies to reduce inequities and improve child health in Kenya: A country case study on progress in child survival, 2000-2013.

PubMed

Brault, Marie A; Ngure, Kenneth; Haley, Connie A; Kabaka, Stewart; Sergon, Kibet; Desta, Teshome; Mwinga, Kasonde; Vermund, Sten H; Kipp, Aaron M

2017-01-01

As of 2015, only 12 countries in the World Health Organization's AFRO region had met Millennium Development Goal #4 (MDG#4) to reduce under-five mortality by two-thirds by 2015. Given the variability across the African region, a four-country study was undertaken to examine barriers and facilitators of child survival prior to 2015. Kenya was one of the countries selected for an in-depth case study due to its insufficient progress in reducing under-five mortality, with only a 28% reduction between 1990 and 2013. This paper presents indicators, national documents, and qualitative data describing the factors that have both facilitated and hindered Kenya's efforts in reducing child mortality. Key barriers identified in the data were widespread socioeconomic and geographic inequities in access and utilization of maternal, neonatal, and child health (MNCH) care. To reduce these inequities, Kenya implemented three major policies/strategies during the study period: removal of user fees, the Kenya Essential Package for Health, and the Community Health Strategy. This paper uses qualitative data and a policy review to explore the early impacts of these efforts. The removal of user fees has been unevenly implemented as patients still face hidden expenses. The Kenya Essential Package for Health has enabled construction and/or expansion of healthcare facilities in many areas, but facilities struggle to provide Emergency Obstetric and Neonatal Care (EmONC), neonatal care, and many essential medicines and commodities. The Community Health Strategy appears to have had the most impact, improving referrals from the community and provision of immunizations, malaria prevention, and Prevention of Mother-to-Child Transmission of HIV. However, the Community Health Strategy is limited by resources and thus also unevenly implemented in many areas. Although insufficient progress was made pre-2015, with additional resources and further scale-up of new policies and strategies Kenya can make further progress in child survival.

The introduction of new policies and strategies to reduce inequities and improve child health in Kenya: A country case study on progress in child survival, 2000-2013

PubMed Central

Brault, Marie A.; Ngure, Kenneth; Haley, Connie A.; Kabaka, Stewart; Sergon, Kibet; Desta, Teshome; Mwinga, Kasonde; Vermund, Sten H.; Kipp, Aaron M.

2017-01-01

As of 2015, only 12 countries in the World Health Organization’s AFRO region had met Millennium Development Goal #4 (MDG#4) to reduce under-five mortality by two-thirds by 2015. Given the variability across the African region, a four-country study was undertaken to examine barriers and facilitators of child survival prior to 2015. Kenya was one of the countries selected for an in-depth case study due to its insufficient progress in reducing under-five mortality, with only a 28% reduction between 1990 and 2013. This paper presents indicators, national documents, and qualitative data describing the factors that have both facilitated and hindered Kenya’s efforts in reducing child mortality. Key barriers identified in the data were widespread socioeconomic and geographic inequities in access and utilization of maternal, neonatal, and child health (MNCH) care. To reduce these inequities, Kenya implemented three major policies/strategies during the study period: removal of user fees, the Kenya Essential Package for Health, and the Community Health Strategy. This paper uses qualitative data and a policy review to explore the early impacts of these efforts. The removal of user fees has been unevenly implemented as patients still face hidden expenses. The Kenya Essential Package for Health has enabled construction and/or expansion of healthcare facilities in many areas, but facilities struggle to provide Emergency Obstetric and Neonatal Care (EmONC), neonatal care, and many essential medicines and commodities. The Community Health Strategy appears to have had the most impact, improving referrals from the community and provision of immunizations, malaria prevention, and Prevention of Mother-to-Child Transmission of HIV. However, the Community Health Strategy is limited by resources and thus also unevenly implemented in many areas. Although insufficient progress was made pre-2015, with additional resources and further scale-up of new policies and strategies Kenya can make further progress in child survival. PMID:28763454

Prognostic impact of blood and urinary angiogenic factor levels at diagnosis and during treatment in patients with osteosarcoma: a prospective study.

PubMed

Tabone, Marie-Dominique; Brugières, Laurence; Piperno-Neumann, Sophie; Selva, Marie-Ange; Marec-Bérard, Perrine; Pacquement, Hélène; Lervat, Cyril; Corradini, Nadège; Gentet, Jean-Claude; Couderc, Rémy; Chevance, Aurélie; Mahier-Ait Oukhatar, Céline; Entz-Werle, Natacha; Blay, Jean-Yves; Le Deley, Marie-Cecile

2017-06-15

Angiogenesis is essential for the progression and metastatic spread of solid tumours. Expression of vascular endothelial growth factor (VEGF) has been linked to poor survival among osteosarcoma patients but the clinical relevance of monitoring blood and urine angiogenic factors is uncertain. The aim of this study was to determine the prognostic significance of blood VEGF and blood and urinary basic fibroblast growth factor (bFGF) levels in osteosarcoma patients, both at diagnosis and during treatment. Patients with localised or metastatic osteosarcoma enrolled in OS2005 and OS2006 studies between 2005 and 2011 were prospectively included in this study. VEGF and bFGF levels in serum and plasma and bFGF levels in urine were measured by ELISA at diagnosis, before surgery, and at the end of treatment. Endpoints considered for the prognostic analysis were histological response, progression-free and overall survival. Kruskal-Wallis tests were used to compare the distribution of baseline biomarker values across the different subgroups, and paired sample Wilcoxon rank tests were used to analyze changes over time. Association between biomarker levels and outcomes were assessed in multivariable models (logistic regression for histologic response, and Cox models for survival). Samples were available at diagnosis for 269 patients (54% males; age ≤ 18 years: 73%; localised disease in 68%, doubtful lung lesions in 17%, and metastases in 15%). High serum VEGF and bFGF levels were observed in respectively 61% and 51% of patients. Serum and plasma VEGF values were not strongly correlated with one another (r = 0.53). High serum and plasma VEGF levels were significantly more frequent in patients with large tumours (≥10 cm; p = 0.003 and p = 0.02, respectively). VEGF levels fell significantly during pre-operative chemotherapy (p < 0.0001). No significant correlation was found between this variation and either the histological response, progression-free survival or overall survival (p = 0.26, p = 0.67, and p = 0.87, respectively). No significant association was found between blood or urinary bFGF levels and clinical characteristics, histological response, or survival. Levels of VEGF and bFGF angiogenic factors are high in most osteosarcoma patients, but have no significant impact on response to chemotherapy or outcome in this large prospective series. OS 2006 TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT00470223; date of registration: May 3th 2007.

CTCF knockout reveals an essential role for this protein during the zebrafish development.

PubMed

Carmona-Aldana, Francisco; Zampedri, Cecilia; Suaste-Olmos, Fernando; Murillo-de-Ozores, Adrián; Guerrero, Georgina; Arzate-Mejía, Rodrigo; Maldonado, Ernesto; Navarro, Rosa; Chimal-Monroy, Jesús; Recillas-Targa, Félix

2018-05-01

Chromatin regulation and organization are essential processes that regulate gene activity. The CCCTC-binding factor (CTCF) is a protein with different and important molecular functions related with chromatin dynamics. It is conserved since invertebrates to vertebrates, posing it as a factor with an important role in the physiology. In this work, we aimed to understand the distribution and functional relevance of CTCF during the embryonic development of the zebrafish (Danio rerio). We generated a zebrafish specific anti-Ctcf antibody, and found this protein to be ubiquitous, through different stages and tissues. We used the CRISPR-Cas9 system to induce molecular alterations in the locus. This resulted in early lethality. We delayed the lethality performing knockdown morpholino experiments, and found an aberrant embryo morphology involving malformations in structures through all the length of the embryo. These phenotypes were rescued with human CTCF mRNA injections, showing the specificity of the morpholinos and a partial functional conservation between the fish and the human proteins. Lastly, we found that the pro-apoptotic genes p53 and bbc3/PUMA are deregulated in the ctcf morpholino-injected embryos. In conclusion, CTCF is a ubiquitous factor during the zebrafish development, which regulates the correct formation of different structures of the embryo, and its deregulation impacts on essential cell survival genes. Overall, this work provides a basis to look for the particular functions of CTCF in the different developing tissues and organs of the zebrafish. Copyright © 2018. Published by Elsevier B.V.

Tardigrades Use Intrinsically Disordered Proteins to Survive Desiccation.

PubMed

Boothby, Thomas C; Tapia, Hugo; Brozena, Alexandra H; Piszkiewicz, Samantha; Smith, Austin E; Giovannini, Ilaria; Rebecchi, Lorena; Pielak, Gary J; Koshland, Doug; Goldstein, Bob

2017-03-16

Tardigrades are microscopic animals that survive a remarkable array of stresses, including desiccation. How tardigrades survive desiccation has remained a mystery for more than 250 years. Trehalose, a disaccharide essential for several organisms to survive drying, is detected at low levels or not at all in some tardigrade species, indicating that tardigrades possess potentially novel mechanisms for surviving desiccation. Here we show that tardigrade-specific intrinsically disordered proteins (TDPs) are essential for desiccation tolerance. TDP genes are constitutively expressed at high levels or induced during desiccation in multiple tardigrade species. TDPs are required for tardigrade desiccation tolerance, and these genes are sufficient to increase desiccation tolerance when expressed in heterologous systems. TDPs form non-crystalline amorphous solids (vitrify) upon desiccation, and this vitrified state mirrors their protective capabilities. Our study identifies TDPs as functional mediators of tardigrade desiccation tolerance, expanding our knowledge of the roles and diversity of disordered proteins involved in stress tolerance. Copyright © 2017 Elsevier Inc. All rights reserved.

The Exported Chaperone PfHsp70x Is Dispensable for the Plasmodium falciparum Intraerythrocytic Life Cycle.

PubMed

Cobb, David W; Florentin, Anat; Fierro, Manuel A; Krakowiak, Michelle; Moore, Julie M; Muralidharan, Vasant

2017-01-01

Export of parasite proteins into the host erythrocyte is essential for survival of Plasmodium falciparum during its asexual life cycle. While several studies described key factors within the parasite that are involved in protein export, the mechanisms employed to traffic exported proteins within the host cell are currently unknown. Members of the Hsp70 family of chaperones, together with their Hsp40 cochaperones, facilitate protein trafficking in other organisms, and are thus likely used by P. falciparum in the trafficking of its exported proteins. A large group of Hsp40 proteins is encoded by the parasite and exported to the host cell, but only one Hsp70, P. falciparum Hsp70x (PfHsp70x), is exported with them. PfHsp70x is absent in most Plasmodium species and is found only in P. falciparum and closely related species that infect apes. Herein, we have utilized clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 genome editing in P. falciparum to investigate the essentiality of PfHsp70x. We show that parasitic growth was unaffected by knockdown of PfHsp70x using both the dihydrofolate reductase (DHFR)-based destabilization domain and the glmS ribozyme system. Similarly, a complete gene knockout of PfHsp70x did not affect the ability of P. falciparum to proceed through its intraerythrocytic life cycle. The effect of PfHsp70x knockdown/knockout on the export of proteins to the host red blood cell (RBC), including the critical virulence factor P. falciparum erythrocyte membrane protein 1 (PfEMP1), was tested, and we found that this process was unaffected. These data show that although PfHsp70x is the sole exported Hsp70, it is not essential for the asexual development of P. falciparum . IMPORTANCE Half of the world's population lives at risk for malaria. The intraerythrocytic life cycle of Plasmodium spp. is responsible for clinical manifestations of malaria; therefore, knowledge of the parasite's ability to survive within the erythrocyte is needed to combat the deadliest agent of malaria, P. falciparum . An outstanding question in the field is how P. falciparum undertakes the essential process of trafficking its proteins within the host cell. In most organisms, chaperones such as Hsp70 are employed in protein trafficking. Of the Plasmodium species causing human disease, the chaperone PfHsp70x is unique to P. falciparum , and it is the only parasite protein of its kind exported to the host (S. Külzer et al., Cell Microbiol 14:1784-1795, 2012). This has placed PfHsp70x as an ideal target to inhibit protein trafficking and kill the parasite. However, we show that PfHsp70x is not required for export of parasite effectors and it is not essential for parasite survival inside the RBC.

From artificial structures to self-sustaining oyster reefs

NASA Astrophysics Data System (ADS)

Walles, Brenda; Troost, Karin; van den Ende, Douwe; Nieuwhof, Sil; Smaal, Aad C.; Ysebaert, Tom

2016-02-01

Coastal ecosystems are increasingly recognized as essential elements within coastal defence schemes and coastal adaptation. The capacity of coastal ecosystems, like marshes and oyster reefs, to maintain their own habitat and grow with sea-level rise via biophysical feedbacks is seen as an important advantage of such systems compared to man-made hard engineering structures. Providing a suitable substrate for oysters to settle on offers a kick-start for establishment at places where they were lost or are desirable for coastal protection. Accumulation of shell material, through recruitment and growth, is essential to the maintenance of oyster reefs as it provides substrate for new generations (positive feedback loop), forming a self-sustainable structure. Insight in establishment, survival and growth thresholds and knowledge about the population dynamics are necessary to successfully implement oyster reefs in coastal defence schemes. The aim of this paper is to investigate whether artificial Pacific oyster reefs develop into self-sustaining oyster reefs that contribute to coastal protection. Reef development was investigated by studying recruitment, survival and growth rates of oysters on artificial oyster reefs in comparison with nearby natural Pacific oyster reefs. The artificial reef structure successfully offered substrate for settlement of oysters and therefore stimulated reef formation. Reef development, however, was hampered by local sedimentation and increasing tidal emersion. Tidal emersion is an important factor that can be used to predict where artificial oyster reefs have the potential to develop into self-sustaining reefs that could contribute to coastal protection, but it is also a limiting factor in using oyster reefs for coastal protection.

The Drosophila T-box transcription factor Midline functions within the Notch-Delta signaling pathway to specify sensory organ precursor cell fates and regulates cell survival within the eye imaginal disc.

PubMed

Das, Sudeshna; Chen, Q Brent; Saucier, Joseph D; Drescher, Brandon; Zong, Yan; Morgan, Sarah; Forstall, John; Meriwether, Andrew; Toranzo, Randy; Leal, Sandra M

2013-01-01

We report that the T-box transcription factor Midline (Mid), an evolutionary conserved homolog of the vertebrate Tbx20 protein, functions within the Notch-Delta signaling pathway essential for specifying the fates of sensory organ precursor (SOP) cells. These findings complement an established history of research showing that Mid regulates the cell-fate specification of diverse cell types within the developing heart, epidermis and central nervous system. Tbx20 has been detected in unique neuronal and epithelial cells of embryonic eye tissues in both mice and humans. However, the mechanisms by which either Mid or Tbx20 function to regulate cell-fate specification or other critical aspects of eye development including cell survival have not yet been elucidated. We have also gathered preliminary evidence suggesting that Mid may play an indirect, but vital role in selecting SOP cells within the third-instar larval eye disc by regulating the expression of the proneural gene atonal. During subsequent pupal stages, Mid specifies SOP cell fates as a member of the Notch-Delta signaling hierarchy and is essential for maintaining cell viability by inhibiting apoptotic pathways. We present several new hypotheses that seek to understand the role of Mid in regulating developmental processes downstream of the Notch receptor that are critical for specifying unique cell fates, patterning the adult eye and maintaining cellular homeostasis during eye disc morphogenesis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Quantifying landscape linkages among giant panda subpopulations in regional scale conservation.

PubMed

Qi, Dunwu; Hu, Yibo; Gu, Xiaodong; Yang, Xuyi; Yang, Guang; Wei, Fuwen

2012-06-01

Understanding habitat requirements and identifying landscape linkages are essential for the survival of isolated populations of endangered species. Currently, some of the giant panda populations are isolated, which threatens their long-term survival, particularly in the Xiaoxiangling mountains. In the present study, we quantified niche requirements and then identified potential linkages of giant panda subpopulations in the most isolated region, using ecological niche factor analysis and a least-cost path model. Giant pandas preferred habitat with conifer forest and gentle slopes (>20 to ≤30°). Based on spatial distribution of suitable habitat, linkages were identified for the Yele subpopulation to 4 other subpopulations (Liziping, Matou, Xinmin and Wanba). Their lengths ranged from 15 to 54 km. The accumulated cost ranged from 693 to 3166 and conifer forest covered over 31%. However, a variety of features (e.g. major roads, human settlements and large unforested areas) might act as barriers along the linkages for giant panda dispersal. Our analysis quantified giant panda subpopulation connectivity to ensure long-term survival. © 2012 ISZS, Blackwell Publishing and IOZ/CAS.

Uric acid, an important antioxidant contributing to survival in termites

PubMed Central

Tasaki, Eisuke; Sakurai, Hiroki; Nitao, Masaru; Matsuura, Kenji; Iuchi, Yoshihito

2017-01-01

Reactive oxygen species (ROS) are generated spontaneously in all organisms and cause oxidative damage to biomolecules when present in excess. Accumulated oxidative damage accelerates aging; enhanced antioxidant capacity may be a positive factor for longevity. Recently, numerous studies of aging and longevity have been performed using short-lived animals, however, longevity mechanisms remain unknown. Here we show that a termite Reticulitermes speratus that is thought to be long-lived eusocial insect than other solitary insects uses large quantities of uric acid as an antioxidant against ROS. We demonstrated that the accumulation of uric acid considerably increases the free radical-scavenging activity and resistance against ultraviolet-induced oxidative stress in laboratory-maintained termites. In addition, we found that externally administered uric acid aided termite survival under highly oxidative conditions. The present data demonstrates that in addition to nutritional and metabolic roles, uric acid is an essential antioxidant for survival and contributes significantly to longevity. Uric acid also plays important roles in primates but causes gout when present in excess in humans. Further longevity studies of long-lived organisms may provide important breakthroughs with human health applications. PMID:28609463

Oncogenic NRAS, Required for Pathogenesis of Embryonic Rhabdomyosarcoma, Relies upon the HMGA2–IGF2BP2 Pathway

PubMed Central

Li, Zhizhong; Zhang, Yunyu; Ramanujan, Krishnan; Ma, Yan; Kirsch, David G.; Glass, David J.

2013-01-01

Embryonic rhabdomyosarcoma (ERMS) is the most common soft-tissue tumor in children. Here, we report the identification of the minor groove DNA-binding factor high mobility group AT-hook 2 (HMGA2) as a driver of ERMS development. HMGA2 was highly expressed in normal myoblasts and ERMS cells, where its expression was essential to maintain cell proliferation, survival in vitro, and tumor outgrowth in vivo. Mechanistic investigations revealed that upregulation of the insulin–like growth factor (IGF) mRNA-binding protein IGF2BP2 was critical for HMGA2 action. In particular, IGF2BP2 was essential for mRNA and protein stability of NRAS, a frequently mutated gene in ERMS. shRNA-mediated attenuation of NRAS or pharmacologic inhibition of the MAP-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) effector pathway showed that NRAS and NRAS-mediated signaling was required for tumor maintenance. Taken together, these findings implicate the HMGA2–IGFBP2–NRAS signaling pathway as a critical oncogenic driver in ERMS. PMID:23536553

Zinc Interactions With Brain-Derived Neurotrophic Factor and Related Peptide Fragments.

PubMed

Travaglia, A; La Mendola, D

2017-01-01

Brain-derived neurotrophic factor (BDNF) is a neurotrophin essential for neuronal development and survival, synaptic plasticity, and cognitive function. Dysregulation of BDNF signaling is involved in several neurodegenerative disorders, including Alzheimer's disease. Alteration of metal ion homeostasis is observed both in normal aging and in many neurodegenerative diseases. Interestingly, there is a significant overlap between brain areas characterized by metal ion dyshomeostasis and those where BDNF exerts its biological activity. Therefore, it is reasonable to speculate that metal ions, especially zinc, can modulate the activity of BDNF. The synthesis of BDNF peptidomimetic can be helpful both to understand the molecular interaction of BDNF with metal ions and to develop new drugs for neurodegenerative diseases. © 2017 Elsevier Inc. All rights reserved.

High cholesterol level is essential for myelin membrane growth.

PubMed

Saher, Gesine; Brügger, Britta; Lappe-Siefke, Corinna; Möbius, Wiebke; Tozawa, Ryu-ichi; Wehr, Michael C; Wieland, Felix; Ishibashi, Shun; Nave, Klaus-Armin

2005-04-01

Cholesterol in the mammalian brain is a risk factor for certain neurodegenerative diseases, raising the question of its normal function. In the mature brain, the highest cholesterol content is found in myelin. We therefore created mice that lack the ability to synthesize cholesterol in myelin-forming oligodendrocytes. Mutant oligodendrocytes survived, but CNS myelination was severely perturbed, and mutant mice showed ataxia and tremor. CNS myelination continued at a reduced rate for many months, and during this period, the cholesterol-deficient oligodendrocytes actively enriched cholesterol and assembled myelin with >70% of the cholesterol content of wild-type myelin. This shows that cholesterol is an indispensable component of myelin membranes and that cholesterol availability in oligodendrocytes is a rate-limiting factor for brain maturation.

Hepatitis C virus and antiviral innate immunity: who wins at tug-of-war?

PubMed

Yang, Da-Rong; Zhu, Hai-Zhen

2015-04-07

Hepatitis C virus (HCV) is a major human pathogen of chronic hepatitis and related liver diseases. Innate immunity is the first line of defense against invading foreign pathogens, and its activation is dependent on the recognition of these pathogens by several key sensors. The interferon (IFN) system plays an essential role in the restriction of HCV infection via the induction of hundreds of IFN-stimulated genes (ISGs) that inhibit viral replication and spread. However, numerous factors that trigger immune dysregulation, including viral factors and host genetic factors, can help HCV to escape host immune response, facilitating viral persistence. In this review, we aim to summarize recent advances in understanding the innate immune response to HCV infection and the mechanisms of ISGs to suppress viral survival, as well as the immune evasion strategies for chronic HCV infection.

Epidemiology of lung cancer prognosis: quantity and quality of life.

PubMed

Yang, Ping

2009-01-01

Primary lung cancer is very heterogeneous in its clinical presentation, histopathology, and treatment response; and like other diseases, the prognosis consists of two essential facets: survival and quality of life (QOL). Lung cancer survival is mostly determined by disease stage and treatment modality, and the 5-Year survival rate has been in a plateau of 15% for three decades. QOL is focused on life aspects that are affected by health conditions and medical interventions; the balance of physical functioning and suffering from treatment side effects has long been a concern of care providers as well as patients. Obviously needed are easily measurable biologic markers to stratify patients before treatment for optimal results in survival and QOL and to monitor treatment responses and toxicities. Targeted therapies toward the mechanisms of tumor development, growth, and metastasis are promising and actively translated into clinical practice. Long-term lung cancer (LTLC) survivors are people who are alive 5 Years after the diagnosis. Knowledge about the health and QOL in LTLC survivors is limited because outcome research in lung cancer has been focused mainly on short-term survival. The independent or combined effects of lung cancer treatment, aging, smoking and drinking, comorbid conditions, and psychosocial factors likely cause late effects, including organ malfunction, chronic fatigue, pain, or premature death among lung cancer survivors. New knowledge to be gained should help lung cancer survivors, their healthcare providers, and their caregivers by providing evidence for establishing clinical recommendations to enhance their long-term survival and health-related QOL.

Oxidative and Nitrosative Stress in the Metastatic Microenvironment

PubMed Central

Ortega, Ángel L.; Mena, Salvador; Estrela, José M.

2010-01-01

Metastases that are resistant to conventional therapies are the main cause of most cancer-related deaths in humans. Tumor cell heterogeneity, which associates with genomic and phenotypic instability, represents a major problem for cancer therapy. Additional factors, such as the attack of immune cells or organ-specific microenvironments, also influence metastatic cell behavior and the response to therapy. Interaction of cancer and endothelial cells in capillary beds, involving mechanical contact and transient adhesion, is a critical step in the initiation of metastasis. This interaction initiates a cascade of activation pathways that involves cytokines, growth factors, bioactive lipids and reactive oxygen and nitrogen species (ROS and RNS) produced by either the cancer cell or the endothelium. Vascular endothelium-derived NO and H2O2 are cytotoxic for the cancer cells, but also help to identify some critical molecular targets that appear essential for survival of invasive metastatic cell subsets. Surviving cancer cells that extravasate and start colonization of an organ or tissue can still be attacked by macrophages and be influenced by specific intraorgan microenvironment conditions. At all steps; from the primary tumor until colonization of a distant organ; metastatic cells undergo a dynamic process of constant adaptations that may lead to the survival of highly resistant malignant cell subsets. In this sequence of molecular events both ROS and RNS play key roles. PMID:24281071

Copper Trafficking in Plants and Its Implication on Cell Wall Dynamics

PubMed Central

Printz, Bruno; Lutts, Stanley; Hausman, Jean-Francois; Sergeant, Kjell

2016-01-01

In plants, copper (Cu) acts as essential cofactor of numerous proteins. While the definitive number of these so-called cuproproteins is unknown, they perform central functions in plant cells. As micronutrient, a minimal amount of Cu is needed to ensure cellular functions. However, Cu excess may exert in contrast detrimental effects on plant primary production and even survival. Therefore it is essential for a plant to have a strictly controlled Cu homeostasis, an equilibrium that is both tissue and developmentally influenced. In the current review an overview is presented on the different stages of Cu transport from the soil into the plant and throughout the different plant tissues. Special emphasis is on the Cu-dependent responses mediated by the SPL7 transcription factor, and the crosstalk between this transcriptional regulation and microRNA-mediated suppression of translation of seemingly non-essential cuproproteins. Since Cu is an essential player in electron transport, we also review the recent insights into the molecular mechanisms controlling chloroplastic and mitochondrial Cu transport and homeostasis. We finally highlight the involvement of numerous Cu-proteins and Cu-dependent activities in the properties of one of the major Cu-accumulation sites in plants: the cell wall. PMID:27200069

Impact of Moderate Heat, Carvacrol, and Thymol Treatments on the Viability, Injury, and Stress Response of Listeria monocytogenes

PubMed Central

Guevara, L.; Antolinos, V.; Palop, A.; Periago, P. M.

2015-01-01

The microbial safety and stability of minimally processed foods are based on the application of combined preservative factors. Since microorganisms are able to develop adaptive networks to survive under conditions of stress, food safety may be affected, and therefore understanding of stress adaptive mechanisms plays a key role in designing safe food processing conditions. In the present study, the viability and the sublethal injury of Listeria monocytogenes exposed to moderate heat (55°C) and/or essential oil compounds (carvacrol and thymol, 0.3 mM) treatments were studied. Synergistic effects were obtained when combining mild heat (55°C) with one or both essential oil compounds, leading to inactivation kinetics values three to four times lower than when using heat alone. All the treatments applied caused some injury in the population. The injury levels ranged from around 20% of the surviving population under the mildest conditions to more than 99.99% under the most stringent conditions. Protein extracts of cells exposed to these treatments were analysed by two-dimensional gel electrophoresis. The results obtained revealed that stressed cells exhibited differential protein expression to control cells. The proteins upregulated under these stressing conditions were implicated, among other functions, in stress response, metabolism, and protein refolding. PMID:26539510

mTOR up-regulation of PFKFB3 is essential for acute myeloid leukemia cell survival

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feng, Yonghuai; Institute of Hematology, Peking University, Beijing; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing

Although mTOR (mammalian target of rapamycin) activation is frequently observed in acute myeloid leukemia (AML) patients, the precise function and the downstream targets of mTOR are poorly understood. Here we revealed that PFKFB3, but not PFKFB1, PFKFB2 nor PFKFB4 was a novel downstream substrate of mTOR signaling pathway as PFKFB3 level was augmented after knocking down TSC2 in THP1 and OCI-AML3 cells. Importantly, PFKFB3 silencing suppressed glycolysis and cell proliferation of TSC2 silencing OCI-AML3 cells and activated apoptosis pathway. These results suggested that mTOR up-regulation of PFKFB3 was essential for AML cells survival. Mechanistically, Rapamycin treatment or Raptor knockdown reducedmore » the expression of PFKFB3 in TSC2 knockdown cells, while Rictor silencing did not have such effect. Furthermore, we also revealed that mTORC1 up-regulated PFKFB3 was dependent on hypoxia-inducible factor 1α (HIF1α), a positive regulator of glycolysis. Moreover, PFKFB3 inhibitor PFK15 and rapamycin synergistically blunted the AML cell proliferation. Taken together, PFKFB3 was a promising drug target in AML patients harboring mTOR hyper-activation.« less

The importance of mammalian torpor for survival in a post-fire landscape.

PubMed

Stawski, Clare; Körtner, Gerhard; Nowack, Julia; Geiser, Fritz

2015-06-01

Wildfires have increased in frequency and intensity worldwide with climate change as a main driving factor. While a number of studies have focused on population changes in regard to fires, there are essentially no quantitative data on behavioural and physiological adjustments that are vital for the persistence of individuals during and after fires. Here we show that brown antechinus, a small insectivorous marsupial mammal, (i) endured a prescribed fire in situ, (ii) remained in their scorched home range despite unburned areas nearby, and (iii) substantially increased post-fire torpor use and thus reduced foraging requirements and exposure to predators. Hence, torpor is a physiological adaptation that, although not quantified in this context previously, appears to play a key role in post-fire survival for this and other heterothermic species. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

The EPOS-CC Score: An Integration of Independent, Tumor- and Patient-Associated Risk Factors to Predict 5-years Overall Survival Following Colorectal Cancer Surgery.

PubMed

Haga, Yoshio; Ikejiri, Koji; Wada, Yasuo; Ikenaga, Masakazu; Koike, Shoichiro; Nakamura, Seiji; Koseki, Masato

2015-06-01

Surgical audit is an essential task for the estimation of postoperative outcome and comparison of quality of care. Previous studies on surgical audits focused on short-term outcomes, such as postoperative mortality. We propose a surgical audit evaluating long-term outcome following colorectal cancer surgery. The predictive model for this audit is designated as 'Estimation of Postoperative Overall Survival for Colorectal Cancer (EPOS-CC)'. Thirty-one tumor-related and physiological variables were prospectively collected in 889 patients undergoing elective resection for colorectal cancer between April 2005 and April 2007 in 16 Japanese hospitals. Postoperative overall survival was assessed over a 5-years period. The EPOS-CC score was established by selecting significant variables in a uni- and multivariate analysis and allocating a risk-adjusted multiplication factor to each variable using Cox regression analysis. For validation, the EPOS-CC score was compared to the predictive power of UICC stage. Inter-hospital variability of the observed-to-estimated 5-years survival was assessed to estimate quality of care. Among the 889 patients, 804 (90%) completed the 5-years follow-up. Univariate analysis displayed a significant correlation with 5-years survival for 14 physiological and nine tumor-related variables (p < 0.005). Highly significant p-values below 0.0001 were found for age, ASA score, severe pulmonary disease, respiratory history, performance status, hypoalbuminemia, alteration of hemoglobin, serum sodium level, and for all histological variables except tumor location. Age, TNM stage, lymphatic invasion, performance status, and serum sodium level were independent variables in the multivariate analysis and were entered the EPOS-CC model for the prediction of survival. Risk-adjusted multiplication factors between 1.5 (distant metastasis) and 0.16 (serum sodium level) were accorded to the different variables. The predictive power of EPOS-CC was superior to the one of UICC stage; area under the curve 0.87, 95% CI 0.85-0.90 for EPOS-CC, and 0.80, 0.76-0.83 for UICC stage, p < 0.001. Quality of care did not differ between hospitals. The EPOS-CC score including the independent variables age, performance status, serum sodium level, TNM stage, and lymphatic invasion is superior to the UICC stage in the prediction of 5-years overall survival. This higher accuracy might be explained by the inclusion of physiological factors, thus also taking non-tumor-associated deaths into account. Furthermore, EPOS-CC score may compare quality of care among different institutions. Future studies are necessary to further evaluate this score and help improving the prediction of long-term survival following colorectal cancer surgery.

Homeostatic Agent for General Environment

NASA Astrophysics Data System (ADS)

Yoshida, Naoto

2018-03-01

One of the essential aspect in biological agents is dynamic stability. This aspect, called homeostasis, is widely discussed in ethology, neuroscience and during the early stages of artificial intelligence. Ashby's homeostats are general-purpose learning machines for stabilizing essential variables of the agent in the face of general environments. However, despite their generality, the original homeostats couldn't be scaled because they searched their parameters randomly. In this paper, first we re-define the objective of homeostats as the maximization of a multi-step survival probability from the view point of sequential decision theory and probabilistic theory. Then we show that this optimization problem can be treated by using reinforcement learning algorithms with special agent architectures and theoretically-derived intrinsic reward functions. Finally we empirically demonstrate that agents with our architecture automatically learn to survive in a given environment, including environments with visual stimuli. Our survival agents can learn to eat food, avoid poison and stabilize essential variables through theoretically-derived single intrinsic reward formulations.

Ensemble survival tree models to reveal pairwise interactions of variables with time-to-events outcomes in low-dimensional setting

PubMed Central

Dazard, Jean-Eudes; Ishwaran, Hemant; Mehlotra, Rajeev; Weinberg, Aaron; Zimmerman, Peter

2018-01-01

Unraveling interactions among variables such as genetic, clinical, demographic and environmental factors is essential to understand the development of common and complex diseases. To increase the power to detect such variables interactions associated with clinical time-to-events outcomes, we borrowed established concepts from random survival forest (RSF) models. We introduce a novel RSF-based pairwise interaction estimator and derive a randomization method with bootstrap confidence intervals for inferring interaction significance. Using various linear and nonlinear time-to-events survival models in simulation studies, we first show the efficiency of our approach: true pairwise interaction-effects between variables are uncovered, while they may not be accompanied with their corresponding main-effects, and may not be detected by standard semi-parametric regression modeling and test statistics used in survival analysis. Moreover, using a RSF-based cross-validation scheme for generating prediction estimators, we show that informative predictors may be inferred. We applied our approach to an HIV cohort study recording key host gene polymorphisms and their association with HIV change of tropism or AIDS progression. Altogether, this shows how linear or nonlinear pairwise statistical interactions of variables may be efficiently detected with a predictive value in observational studies with time-to-event outcomes. PMID:29453930

Ensemble survival tree models to reveal pairwise interactions of variables with time-to-events outcomes in low-dimensional setting.

PubMed

Dazard, Jean-Eudes; Ishwaran, Hemant; Mehlotra, Rajeev; Weinberg, Aaron; Zimmerman, Peter

2018-02-17

Unraveling interactions among variables such as genetic, clinical, demographic and environmental factors is essential to understand the development of common and complex diseases. To increase the power to detect such variables interactions associated with clinical time-to-events outcomes, we borrowed established concepts from random survival forest (RSF) models. We introduce a novel RSF-based pairwise interaction estimator and derive a randomization method with bootstrap confidence intervals for inferring interaction significance. Using various linear and nonlinear time-to-events survival models in simulation studies, we first show the efficiency of our approach: true pairwise interaction-effects between variables are uncovered, while they may not be accompanied with their corresponding main-effects, and may not be detected by standard semi-parametric regression modeling and test statistics used in survival analysis. Moreover, using a RSF-based cross-validation scheme for generating prediction estimators, we show that informative predictors may be inferred. We applied our approach to an HIV cohort study recording key host gene polymorphisms and their association with HIV change of tropism or AIDS progression. Altogether, this shows how linear or nonlinear pairwise statistical interactions of variables may be efficiently detected with a predictive value in observational studies with time-to-event outcomes.

[Usage of Calendula officinalis in the prevention and treatment of radiodermatitis: a randomized double-blind controlled clinical trial].

PubMed

Schneider, Franciane; Danski, Mitzy Tannia Reichembach; Vayego, Stela Adami

2015-04-01

To evaluate the efficacy of Calendula officinalis in relation to Essential Fatty Acids for the prevention and treatment of radiodermatitis. This is a randomized double-blind controlled clinical trial with 51 patients with head and neck cancer in radiotherapy treatment divided into two groups: control (27) and experimental (24). There is statistically significant evidence (p-value = 0.0120) that the proportion of radiodermatitis grade 2 in Essential Fatty Acids group is higher than Calendula group. Through the Kaplan-Meier survival curve we observed that Essential Fatty Acids group has always remained below the Calendula group survival curve, due to the lower risk of developing radiodermatitis grade 1, which makes the usage of Calendula more effective, with statistical significance (p-value = 0.00402). Calendula showed better therapeutic response than the Essential Fatty Acids in the prevention and treatment of radiodermatitis. Brazilian Registry of Clinical Trials: RBR-237v4b.

Cellular, ultrastructural and molecular analyses of epidermal cell development in the planarian Schmidtea mediterranea.

PubMed

Cheng, Li-Chun; Tu, Kimberly C; Seidel, Chris W; Robb, Sofia M C; Guo, Fengli; Sánchez Alvarado, Alejandro

2018-01-15

The epidermis is essential for animal survival, providing both a protective barrier and cellular sensor to external environments. The generally conserved embryonic origin of the epidermis, but the broad morphological and functional diversity of this organ across animals is puzzling. We define the transcriptional regulators underlying epidermal lineage differentiation in the planarian Schmidtea mediterranea, an invertebrate organism that, unlike fruitflies and nematodes, continuously replaces its epidermal cells. We find that Smed-p53, Sox and Pax transcription factors are essential regulators of epidermal homeostasis, and act cooperatively to regulate genes associated with early epidermal precursor cell differentiation, including a tandemly arrayed novel gene family (prog) of secreted proteins. Additionally, we report on the discovery of distinct and previously undescribed secreted organelles whose production is dependent on the transcriptional activity of soxP-3, and which we term Hyman vesicles. Copyright © 2017 Elsevier Inc. All rights reserved.

Physiology of temperature regulation: comparative aspects.

PubMed

Bicego, Kênia C; Barros, Renata C H; Branco, Luiz G S

2007-07-01

Few environmental factors have a larger influence on animal energetics than temperature, a fact that makes thermoregulation a very important process for survival. In general, endothermic species, i.e., mammals and birds, maintain a constant body temperature (Tb) in fluctuating environmental temperatures using autonomic and behavioural mechanisms. Most of the knowledge on thermoregulatory physiology has emerged from studies using mammalian species, particularly rats. However, studies with all vertebrate groups are essential for a more complete understanding of the mechanisms involved in the regulation of Tb. Ectothermic vertebrates-fish, amphibians and reptiles-thermoregulate essentially by behavioural mechanisms. With few exceptions, both endotherms and ectotherms develop fever (a regulated increase in Tb) in response to exogenous pyrogens, and regulated hypothermia (anapyrexia) in response to hypoxia. This review focuses on the mechanisms, particularly neuromediators and regions in the central nervous system, involved in thermoregulation in vertebrates, in conditions of euthermia, fever and anapyrexia.

Cardiovascular risk factors predictive for survival and morbidity-free survival in the oldest-old Framingham Heart Study participants.

PubMed

Terry, Dellara F; Pencina, Michael J; Vasan, Ramachandran S; Murabito, Joanne M; Wolf, Philip A; Hayes, Margaret Kelly; Levy, Daniel; D'Agostino, Ralph B; Benjamin, Emelia J

2005-11-01

To examine whether midlife cardiovascular risk factors predict survival and survival free of major comorbidities to the age of 85. Prospective community-based cohort study. Framingham Heart Study, Massachusetts. Two thousand five hundred thirty-one individuals (1,422 women) who attended at least two examinations between the ages of 40 and 50. Risk factors were classified at routine examinations performed between the ages of 40 and 50. Stepwise sex-adjusted logistic regression models predicting the outcomes of survival and survival free of morbidity to age 85 were selected from the following risk factors: systolic and diastolic blood pressure, total serum cholesterol, glucose intolerance, cigarette smoking, education, body mass index, physical activity index, pulse pressure, antihypertensive medication, and electrocardiographic left ventricular hypertrophy. More than one-third of the study sample survived to age 85, and 22% of the original study sample survived free of morbidity. Lower midlife blood pressure and total cholesterol levels, absence of glucose intolerance, nonsmoking status, higher educational attainment, and female sex predicted overall and morbidity-free survival. The predicted probability of survival to age 85 fell in the presence of accumulating risk factors: 37% for men with no risk factors to 2% with all five risk factors and 65% for women with no risk factors to 14% with all five risk factors. Lower levels of key cardiovascular risk factors in middle age predicted overall survival and major morbidity-free survival to age 85. Recognizing and modifying these factors may delay, if not prevent, age-related morbidity and mortality.

TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo.

PubMed

Dong, Li-Hua; Li, Liang; Song, Yu; Duan, Zhi-Li; Sun, Shao-Guang; Lin, Yan-Ling; Miao, Sui-Bing; Yin, Ya-Juan; Shu, Ya-Nan; Li, Huan; Chen, Peng; Zhao, Li-Li; Han, Mei

2015-09-25

Vascular smooth muscle cell (VSMC) survival under stressful conditions is integral to promoting vascular repair, but facilitates plaque stability during the development of atherosclerosis. The cytoskeleton-associated smooth muscle (SM) 22α protein is involved in the regulation of VSMC phenotypes, whereas the pentose phosphate pathway plays an essential role in cell proliferation through the production of dihydronicotinamide adenine dinucleotide phosphate. To identify the relationship between dihydronicotinamide adenine dinucleotide phosphate production and SM22α activity in the development and progression of vascular diseases. We showed that the expression and activity of glucose-6-phosphate dehydrogenase (G6PD) are promoted in platelet-derived growth factor (PDGF)-BB-induced proliferative VSMCs. PDGF-BB induced G6PD membrane translocation and activation in an SM22α K21 ubiquitination-dependent manner. Specifically, the ubiquitinated SM22α interacted with G6PD and mediated G6PD membrane translocation. Furthermore, we found that tumor necrosis factor receptor-associated factor (TRAF) 6 mediated SM22α K21 ubiquitination in a K63-linked manner on PDGF-BB stimulation. Knockdown of TRAF6 decreased the membrane translocation and activity of G6PD, in parallel with reduced SM22α K21 ubiquitination. Elevated levels of activated G6PD consequent to PDGF-BB induction led to increased dihydronicotinamide adenine dinucleotide phosphate generation through stimulation of the pentose phosphate pathway, which enhanced VSMC viability and reduced apoptosis in vivo and in vitro via glutathione homeostasis. We provide evidence that TRAF6-induced SM22α ubiquitination maintains VSMC survival through increased G6PD activity and dihydronicotinamide adenine dinucleotide phosphate production. The TRAF6-SM22α-G6PD pathway is a novel mechanism underlying the association between glucose metabolism and VSMC survival, which is beneficial for vascular repair after injury but facilitates atherosclerotic plaque stability. © 2015 American Heart Association, Inc.

Nfib hemizygous mice are protected from hyperoxic lung injury and death.

PubMed

Kumar, Vasantha H S; Chaker El Khoury, Joseph; Gronostajski, Richard; Wang, Huamei; Nielsen, Lori; Ryan, Rita M

2017-08-01

Nuclear Factor I ( Nfi) genes encode transcription factors essential for the development of organ systems including the lung. Nfib null mice die at birth with immature lungs. Nfib hemizygous mice have reduced lung maturation with decreased survival. We therefore hypothesized that these mice would be more sensitive to lung injury and would have lower survival to hyperoxia. Adult Nfib hemizygous mice and their wild-type (Wt) littermates were exposed to 100% O 2 for 89, 80, 72 and 66 h for survival studies with lung outcome measurements at 66 h. Nfib hemizygous and Wt controls were also studied in RA at 66 h. Cell counts and cytokines were measured in bronchoalveolar lavage (BAL); lung sections examined by histopathology; lung angiogenic and oxidative stress gene expression assessed by real-time PCR Unexpectedly, Nfib hemizygous mice (0/14-0%) had significantly lower mortality compared to Wt mice (10/22-45%) at 80 h of hyperoxia ( P  < 0.003). LD 50 was 80 h in the Wt group versus 89 h in the hemizygous group. There were no differences in BAL cell counts between the groups. Among the cytokines studied, MIP-2 was significantly lower in hemizygous mice exposed to hyperoxia. New vessel formation, edema, congestion, and alveolar hemorrhage were noted on histopathology at 72 and 80 h in wild-type mice. Nfib hemizygous lungs had significant downregulation of genes involved in redox signaling and inflammatory pathways. Adult Nfib hemizygous mice are relatively resistant to hyperoxia compared to wild-type littermates. Mechanisms contributing to this resistance are not clear; however, transcription factors such as Nfib may regulate cell survival and play a role in modulating postnatal lung development. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Circuit Design Features of a Stable Two-Cell System.

PubMed

Zhou, Xu; Franklin, Ruth A; Adler, Miri; Jacox, Jeremy B; Bailis, Will; Shyer, Justin A; Flavell, Richard A; Mayo, Avi; Alon, Uri; Medzhitov, Ruslan

2018-02-08

Cell communication within tissues is mediated by multiple paracrine signals including growth factors, which control cell survival and proliferation. Cells and the growth factors they produce and receive constitute a circuit with specific properties that ensure homeostasis. Here, we used computational and experimental approaches to characterize the features of cell circuits based on growth factor exchange between macrophages and fibroblasts, two cell types found in most mammalian tissues. We found that the macrophage-fibroblast cell circuit is stable and robust to perturbations. Analytical screening of all possible two-cell circuit topologies revealed the circuit features sufficient for stability, including environmental constraint and negative-feedback regulation. Moreover, we found that cell-cell contact is essential for the stability of the macrophage-fibroblast circuit. These findings illustrate principles of cell circuit design and provide a quantitative perspective on cell interactions. Copyright © 2018 Elsevier Inc. All rights reserved.

Histopathology and prognosis in human meningiomas.

PubMed

Backer-Grøndahl, Thomas; Moen, Bjørnar H; Sundstrøm, Stein H; Torp, Sverre H

2014-09-01

Histopathological grading of human meningiomas is based on criteria adopted by the World Health Organization (WHO). However, interpretation of the defined histopathological criteria is often subjective. The aim of this study was to investigate the clinical and histopathological features in these tumours associated with patient survival. This enables evaluation of current grading guidelines and practice. In this study, 196 primary, intracranial, and consecutively treated patients from one institution were included. All histological sections were reviewed. Survival data were controlled with the Norwegian Cause of Death Registry. Falcine location, sheet-like growth, frequent mitoses, subtotal resection grade, and absence of psammoma bodies were strong prognostic factors. Of these factors, the latter two were statistically significantly associated with decreased time to recurrence in multivariate analyses. The WHO 2000 and 2007 classifications were associated with decreased time to recurrence. However, the grading criteria suggested by Ho et al. (2002) and in this study achieved stronger prognostic values. Easily recognizable histopathological criteria are essential in tumour grading. We suggest that any two of the following three variables can be used to recognize atypical (grade II) meningiomas: absence of psammoma bodies, presence of necrosis, and/or ≥4 mitoses per 10 high power fields. © 2014 APMIS. Published by John Wiley & Sons Ltd.

Platelets and cancer: a casual or causal relationship: revisited

PubMed Central

Menter, David G.; Tucker, Stephanie C.; Kopetz, Scott; Sood, Anil K.; Crissman, John D.; Honn, Kenneth V.

2014-01-01

Human platelets arise as subcellular fragments of megakaryocytes in bone marrow. The physiologic demand, presence of disease such as cancer, or drug effects can regulate the production circulating platelets. Platelet biology is essential to hemostasis, vascular integrity, angiogenesis, inflammation, innate immunity, wound healing, and cancer biology. The most critical biological platelet response is serving as “First Responders” during the wounding process. The exposure of extracellular matrix proteins and intracellular components occurs after wounding. Numerous platelet receptors recognize matrix proteins that trigger platelet activation, adhesion, aggregation, and stabilization. Once activated, platelets change shape and degranulate to release growth factors and bioactive lipids into the blood stream. This cyclic process recruits and aggregates platelets along with thrombogenesis. This process facilitates wound closure or can recognize circulating pathologic bodies. Cancer cell entry into the blood stream triggers platelet-mediated recognition and is amplified by cell surface receptors, cellular products, extracellular factors, and immune cells. In some cases, these interactions suppress immune recognition and elimination of cancer cells or promote arrest at the endothelium, or entrapment in the microvasculature, and survival. This supports survival and spread of cancer cells and the establishment of secondary lesions to serve as important targets for prevention and therapy. PMID:24696047

Role of the HTLV-1 viral factors in the induction of apoptosis.

PubMed

Karimi, Mohammad; Mohammadi, Hamed; Hemmatzadeh, Maryam; Mohammadi, Asadollah; Rafatpanah, Houshang; Baradaran, Behzad

2017-01-01

Adult T-cell leukemia (ATL) and HTLV-1-associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) are the two main diseases that are caused by the HTLV-1 virus. One of the features of HTLV-1 infection is its resistance against programmed cell death, which maintains the survival of cells to oncogenic transformation and underlies the viruses' therapeutic resistance. Two main genes by which the virus develops cancer are Tax and HBZ; playing an essential role in angiogenesis in regulating viral transcription and modulating multiple host factors as well as apoptosis pathways. Here we have reviewed by prior research how the apoptosis pathways are suppressed by the Tax and HBZ and new drugs which have been designed to deal with this suppression. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The Cell's Sophisticated Army to Defend Against Assaults on DNAThe Cell's Sophisticated Army to Defend Against Assaults on DNA | Center for Cancer Research

Cancer.gov

The maintenance of genome integrity and function is essen-tial for the survival of cells and organisms. Any damage to our genetic material must be immediately sensed and repaired to preserve a cell’s func-tional integrity. Cells are constantly faced with the challenge of protecting their DNA from assaults by damaging chemicals and ultraviolet light. DNA damage that escapes repair can lead to a variety of genetic disorders and diseases, particularly cancer. To avoid this catastrophe, the cell employs an army of DNA repair factors that “rush to the scene” and initiate a cascade of events to repair the damage. Exactly how different repair factors sense DNA damage and orchestrate their concert-ed response is not well understood.

Prognostication in Philadelphia Chromosome Negative Myeloproliferative Neoplasms: a Review of the Recent Literature.

PubMed

Zhou, Amy; Afzal, Amber; Oh, Stephen T

2017-10-01

The prognosis for patients with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is highly variable. All Ph-negative MPNs carry an increased risk for thrombotic complications, bleeding, and leukemic transformation. Several clinical, biological, and molecular prognostic factors have been identified in recent years, which provide important information in guiding management of patients with Ph-negative MPNs. In this review, we critically evaluate the recent published literature and discuss important new developments in clinical and molecular factors that impact survival, disease transformation, and thrombosis in patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Recent studies have identified several clinical factors and non-driver mutations to have prognostic impact on Ph-negative MPNs independent of conventional risk stratification and prognostic models. In polycythemia vera (PV), leukocytosis, abnormal karyotype, phlebotomy requirement on hydroxyurea, increased bone marrow fibrosis, and mutations in ASXL1, SRSF2, and IDH2 were identified as additional adverse prognostic factors. In essential thrombocythemia (ET), JAK2 V617F mutation, splenomegaly, and mutations in SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2 were found to be additional negative prognostic factors. Bone marrow fibrosis and mutations in ASXL1, SRSF2, EZH2, and IDH1/2 have been found to be additional prognostic factors in primary myelofibrosis (PMF). CALR mutations appear to be a favorable prognostic factor in PMF, which has not been clearly demonstrated in ET. The prognosis for patients with PV, ET, and PMF is dependent upon the presence or absence of several clinical, biological, and molecular risk factors. The significance of additional risk factors identified in these recent studies will need further validation in prospective studies to determine how they may be best utilized in the management of these disorders.

The anaplerotic node is essential for the intracellular survival of Mycobacterium tuberculosis

PubMed Central

Basu, Piyali; Sandhu, Noor; Bhatt, Apoorva; Singh, Albel; Balhana, Ricardo; Gobe, Irene; Crowhurst, Nicola A.; Mendum, Tom A.; Gao, Liang; Ward, Jane L.; Beale, Michael H.; McFadden, Johnjoe; Beste, Dany J. V.

2018-01-01

Enzymes at the phosphoenolpyruvate (PEP)–pyruvate–oxaloacetate or anaplerotic (ANA) node control the metabolic flux to glycolysis, gluconeogenesis, and anaplerosis. Here we used genetic, biochemical, and 13C isotopomer analysis to characterize the role of the enzymes at the ANA node in intracellular survival of the world's most successful bacterial pathogen, Mycobacterium tuberculosis (Mtb). We show that each of the four ANA enzymes, pyruvate carboxylase (PCA), PEP carboxykinase (PCK), malic enzyme (MEZ), and pyruvate phosphate dikinase (PPDK), performs a unique and essential metabolic function during the intracellular survival of Mtb. We show that in addition to PCK, intracellular Mtb requires PPDK as an alternative gateway into gluconeogenesis. Propionate and cholesterol detoxification was also identified as an essential function of PPDK revealing an unexpected role for the ANA node in the metabolism of these physiologically important intracellular substrates and highlighting this enzyme as a tuberculosis (TB)-specific drug target. We show that anaplerotic fixation of CO2 through the ANA node is essential for intracellular survival of Mtb and that Mtb possesses three enzymes (PCA, PCK, and MEZ) capable of fulfilling this function. In addition to providing a back-up role in anaplerosis we show that MEZ also has a role in lipid biosynthesis. MEZ knockout strains have an altered cell wall and were deficient in the initial entry into macrophages. This work reveals that the ANA node is a focal point for controlling the intracellular replication of Mtb, which goes beyond canonical gluconeogenesis and represents a promising target for designing novel anti-TB drugs. PMID:29475946

Somatic mutation load of estrogen receptor-positive breast tumors predicts overall survival: an analysis of genome sequence data.

PubMed

Haricharan, Svasti; Bainbridge, Matthew N; Scheet, Paul; Brown, Powel H

2014-07-01

Breast cancer is one of the most commonly diagnosed cancers in women. While there are several effective therapies for breast cancer and important single gene prognostic/predictive markers, more than 40,000 women die from this disease every year. The increasing availability of large-scale genomic datasets provides opportunities for identifying factors that influence breast cancer survival in smaller, well-defined subsets. The purpose of this study was to investigate the genomic landscape of various breast cancer subtypes and its potential associations with clinical outcomes. We used statistical analysis of sequence data generated by the Cancer Genome Atlas initiative including somatic mutation load (SML) analysis, Kaplan-Meier survival curves, gene mutational frequency, and mutational enrichment evaluation to study the genomic landscape of breast cancer. We show that ER(+), but not ER(-), tumors with high SML associate with poor overall survival (HR = 2.02). Further, these high mutation load tumors are enriched for coincident mutations in both DNA damage repair and ER signature genes. While it is known that somatic mutations in specific genes affect breast cancer survival, this study is the first to identify that SML may constitute an important global signature for a subset of ER(+) tumors prone to high mortality. Moreover, although somatic mutations in individual DNA damage genes affect clinical outcome, our results indicate that coincident mutations in DNA damage response and signature ER genes may prove more informative for ER(+) breast cancer survival. Next generation sequencing may prove an essential tool for identifying pathways underlying poor outcomes and for tailoring therapeutic strategies.

beta-catenin mediates insulin-like growth factor-I actions to promote cyclin D1 mRNA expression, cell proliferation and survival in oligodendroglial cultures.

PubMed

Ye, Ping; Hu, Qichen; Liu, Hedi; Yan, Yun; D'ercole, A Joseph

2010-07-01

By promoting cell proliferation, survival and maturation insulin-like growth factor (IGF)-I is essential to the normal growth and development of the central nervous system. It is clear that IGF-I actions are primarily mediated by the type I IGF receptor (IGF1R), and that phosphoinositide 3 (PI3)-Akt kinases and MAP kinases signal many of IGF-I-IGF1R actions in neural cells, including oligodendrocyte lineage cells. The precise downstream targets of these signaling pathways, however, remain to be defined. We studied oligodendroglial cells to determine whether beta-catenin, a molecule that is a downstream target of glycogen synthase kinase-3beta (GSK3beta) and plays a key role in the Wnt canonical signaling pathway, mediates IGF-I actions. We found that IGF-I increases beta-catenin protein abundance within an hour after IGF-I-induced phosphorylation of Akt and GSK3beta. Inhibiting the PI3-Akt pathway suppressed IGF-I-induced increases in beta-catenin and cyclin D1 mRNA, while suppression of GSK3beta activity simulated IGF-I actions. Knocking-down beta-catenin mRNA by RNA interference suppressed IGF-I-stimulated increases in the abundance of cyclin D1 mRNA, cell proliferation, and cell survival. Our data suggest that beta-catenin is an important downstream molecule in the PI3-Akt-GSK3beta pathway, and as such it mediates IGF-I upregulation of cyclin D1 mRNA and promotion of cell proliferation and survival in oligodendroglial cells. Copyright 2010 Wiley-Liss, Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang Meijuan; Jiang Yu; State Key Laboratory of Biotherapy, West China Hospital, Medical School, Sichuan University, Chengdu

Purpose: To investigate the role of early or up-front radiotherapy (RT), the optimal RT dose required to achieve appropriate treatment outcome and prognostic factors for patients with localized extranodal NK/T-cell lymphoma, nasal-type, in the upper aerodigestive tract. Methods and Materials: Eighty-two patients were reviewed. Eight patients were treated with chemotherapy (CT) alone, 9 patients received RT alone, and 65 patients were given combined modality treatment of CT and RT (CMT). Of those 74 patients receiving RT, 31 patients were given up-front RT, whereas CT was the initial therapy for 43 patients and 41 of those 43 patients received early RT.more » Results: Five-year overall survival (OS) and disease-free survival (DFS) were 52.3% and 39.2%, respectively. RT was the only independent prognostic factor for both OS and DFS at both the univariate and multivariate level. The 5-year OS and DFS were better in patients receiving {>=}54 Gy of RT as compared with that of <54 Gy (5-year OS 75.5% vs. 46.1%, p = 0.019; 5-year DFS 60.3% vs. 33.4%, p = 0.004). Up-front RT presented better survival in Stage I patients when compared with that of initial CT followed by early RT (5-year OS 90.0% vs. 48.9%, p = 0.012; 5-year DFS 78.7% vs. 39.9%, p = 0.021). Conclusion: Early or up-front RT had an essential role in improved OS and DFS in patients with localized extranodal NK/T-cell lymphoma, nasal-type, in the upper aerodigestive tract. The recommended tumor dose was at least 54 Gy. Up-front RT may yield more benefits on survival in patients with Stage I disease.« less

Estimating the probability of survival of individual shortleaf pine (Pinus echinata mill.) trees

Treesearch

Sudip Shrestha; Thomas B. Lynch; Difei Zhang; James M. Guldin

2012-01-01

A survival model is needed in a forest growth system which predicts the survival of trees on individual basis or on a stand basis (Gertner, 1989). An individual-tree modeling approach is one of the better methods available for predicting growth and yield as it provides essential information about particular tree species; tree size, tree quality and tree present status...

Late-life factors associated with healthy aging in older men.

PubMed

Bell, Christina L; Chen, Randi; Masaki, Kamal; Yee, Priscilla; He, Qimei; Grove, John; Donlon, Timothy; Curb, J David; Willcox, D Craig; Poon, Leonard W; Willcox, Bradley J

2014-05-01

To identify potentially modifiable late-life biological, lifestyle, and sociodemographic factors associated with overall and healthy survival to age 85. Prospective longitudinal cohort study with 21 years of follow-up (1991-2012). Hawaii Lifespan Study. American men of Japanese ancestry (mean age 75.7, range 71-82) without baseline major clinical morbidity and functional impairments (N = 1,292). Overall survival and healthy survival (free from six major chronic diseases and without physical or cognitive impairment) to age 85. Factors were measured at late-life baseline examinations (1991-1993). Of 1,292 participants, 1,000 (77%) survived to 85 (34% healthy) and 309 (24%) to 95 (<1% healthy). Late-life factors associated with survival and healthy survival included biological (body mass index, ankle-brachial index, cognitive score, blood pressure, inflammatory markers), lifestyle (smoking, alcohol use, physical activity), and sociodemographic factors (education, marital status). Cumulative late-life baseline risk factor models demonstrated that age-standardized (at 70) probability of survival to 95 ranged from 27% (no factors) to 7% (≥ 5 factors); probability of survival to 100 ranged from 4% (no factors) to 0.1% (≥ 5 factors). Age-standardized (at 70) probability of healthy survival to 90 ranged from 4% (no factors) to 0.01% (≥ 5 factors). There were nine healthy survivors at 95 and one healthy survivor at 100. Several potentially modifiable risk factors in men in late life (mean age 75.7) were associated with markedly greater probability of subsequent healthy survival and longevity. © 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.

Donor retention in health care in Iran: a factor analysis

PubMed Central

Aghababa, Sara; Nasiripour, Amir Ashkan; Maleki, Mohammadreza; Gohari, Mahmoodreza

2017-01-01

Background: Long-term financial support is essential for the survival of a charitable organization. Health charities need to identify the effective factors influencing donor retention. Methods: In the present study, the items of a questionnaire were derived from both literature review and semi-structured interviews related to donor retention. Using a purposive sampling, 300 academic and executive practitioners were selected. After the follow- up, a total of 243 usable questionnaires were prepared for factor analysis. The questionnaire was validated based on the face and content validity and reliability through Cronbach’s α-coefficient. Results: The results of exploratory factor analysis extracted 2 factors for retention: donor factor (variance = 33.841%; Cronbach’s α-coefficient = 90.2) and charity factor (variance = 29.038%; Cronbach’s α-coefficient = 82.8), respectively. Subsequently, confirmatory factor analysis was applied to support the overall reasonable fit. Conclusions: In this study, it was found that repeated monetary donations are supplied to the charitable organizations when both aspects of donor factor (retention factor and charity factor) for retention are taken into consideration. This model could provide a perspective for making sustainable donations and charitable giving PMID:28955663

Increased phosphatidylethanolamine N-methyltransferase gene expression in non-small-cell lung cancer tissue predicts shorter patient survival

PubMed Central

ZINRAJH, DAVID; HÖRL, GERD; JÜRGENS, GÜNTHER; MARC, JANJA; SOK, MIHA; CERNE, DARKO

2014-01-01

Lipid mobilization is of great importance for tumor growth and studies have suggested that cancer cells exhibit abnormal choline phospholipid metabolism. In the present study, we hypothesized that phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is increased in non-small-cell lung cancer (NSCLC) tissues and that increased gene expression acts as a predictor of shorter patient survival. Forty-two consecutive patients with resected NSCLC were enrolled in this study. Paired samples of lung cancer tissues and adjacent non-cancer lung tissues were collected from resected specimens for the estimation of PEMT expression. SYBR Green-based real-time polymerase chain reaction was used for quantification of PEMT mRNA in lung cancer tissues. Lipoprotein lipase (LPL) and fatty acid synthase (FASN) activities had already been measured in the same tissues. During a four-year follow-up, 21 patients succumbed to tumor progression. One patient did not survive due to non-cancer reasons and was not included in the analysis. Cox regression analysis was used to assess the prognostic value of PEMT expression. Our findings show that elevated PEMT expression in the cancer tissue, relative to that in the adjacent non-cancer lung tissue, predicts shorter patient survival independently of standard prognostic factors and also independently of increased LPL or FASN activity, the two other lipid-related predictors of shorter patient survival. These findings suggest that active phosphatidylcholine and/or choline metabolism are essential for tumor growth and progression. PMID:24932311

Increased phosphatidylethanolamine N-methyltransferase gene expression in non-small-cell lung cancer tissue predicts shorter patient survival.

PubMed

Zinrajh, David; Hörl, Gerd; Jürgens, Günther; Marc, Janja; Sok, Miha; Cerne, Darko

2014-06-01

Lipid mobilization is of great importance for tumor growth and studies have suggested that cancer cells exhibit abnormal choline phospholipid metabolism. In the present study, we hypothesized that phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is increased in non-small-cell lung cancer (NSCLC) tissues and that increased gene expression acts as a predictor of shorter patient survival. Forty-two consecutive patients with resected NSCLC were enrolled in this study. Paired samples of lung cancer tissues and adjacent non-cancer lung tissues were collected from resected specimens for the estimation of PEMT expression. SYBR Green-based real-time polymerase chain reaction was used for quantification of PEMT mRNA in lung cancer tissues. Lipoprotein lipase (LPL) and fatty acid synthase (FASN) activities had already been measured in the same tissues. During a four-year follow-up, 21 patients succumbed to tumor progression. One patient did not survive due to non-cancer reasons and was not included in the analysis. Cox regression analysis was used to assess the prognostic value of PEMT expression. Our findings show that elevated PEMT expression in the cancer tissue, relative to that in the adjacent non-cancer lung tissue, predicts shorter patient survival independently of standard prognostic factors and also independently of increased LPL or FASN activity, the two other lipid-related predictors of shorter patient survival. These findings suggest that active phosphatidylcholine and/or choline metabolism are essential for tumor growth and progression.

Regulation of Schistosoma mansoni development and reproduction by the mitogen-activated protein kinase signaling pathway.

PubMed

Andrade, Luiza Freire de; Mourão, Marina de Moraes; Geraldo, Juliana Assis; Coelho, Fernanda Sales; Silva, Larissa Lopes; Neves, Renata Heisler; Volpini, Angela; Machado-Silva, José Roberto; Araujo, Neusa; Nacif-Pimenta, Rafael; Caffrey, Conor R; Oliveira, Guilherme

2014-06-01

Protein kinases are proven targets for drug development with an increasing number of eukaryotic Protein Kinase (ePK) inhibitors now approved as drugs. Mitogen-activated protein kinase (MAPK) family members connect cell-surface receptors to regulatory targets within cells and influence a number of tissue-specific biological activities such as cell proliferation, differentiation and survival. However, the contributions of members of the MAPK pathway to schistosome development and survival are unclear. We employed RNA interference (RNAi) to elucidate the functional roles of five S. mansoni genes (SmCaMK2, SmJNK, SmERK1, SmERK2 and SmRas) involved in MAPK signaling pathway. Mice were injected with post-infective larvae (schistosomula) subsequent to RNAi and the development of adult worms observed. The data demonstrate that SmJNK participates in parasite maturation and survival of the parasites, whereas SmERK are involved in egg production as infected mice had significantly lower egg burdens with female worms presenting underdeveloped ovaries. Furthermore, it was shown that the c-fos transcription factor was overexpressed in parasites submitted to RNAi of SmERK1, SmJNK and SmCaMK2 indicating its putative involvement in gene regulation in this parasite's MAPK signaling cascade. We conclude that MAPKs proteins play important roles in the parasite in vivo survival, being essential for normal development and successful survival and reproduction of the schistosome parasite. Moreover SmERK and SmJNK are potential targets for drug development.

Genome-Wide Identification by Transposon Insertion Sequencing of Escherichia coli K1 Genes Essential for In Vitro Growth, Gastrointestinal Colonizing Capacity, and Survival in Serum.

PubMed

McCarthy, Alex J; Stabler, Richard A; Taylor, Peter W

2018-04-01

Escherichia coli K1 strains are major causative agents of invasive disease of newborn infants. The age dependency of infection can be reproduced in neonatal rats. Colonization of the small intestine following oral administration of K1 bacteria leads rapidly to invasion of the blood circulation; bacteria that avoid capture by the mesenteric lymphatic system and evade antibacterial mechanisms in the blood may disseminate to cause organ-specific infections such as meningitis. Some E. coli K1 surface constituents, in particular the polysialic acid capsule, are known to contribute to invasive potential, but a comprehensive picture of the factors that determine the fully virulent phenotype has not emerged so far. We constructed a library and constituent sublibraries of ∼775,000 Tn 5 transposon mutants of E. coli K1 strain A192PP and employed transposon-directed insertion site sequencing (TraDIS) to identify genes required for fitness for infection of 2-day-old rats. Transposon insertions were lacking in 357 genes following recovery on selective agar; these genes were considered essential for growth in nutrient-replete medium. Colonization of the midsection of the small intestine was facilitated by 167 E. coli K1 gene products. Restricted bacterial translocation across epithelial barriers precluded TraDIS analysis of gut-to-blood and blood-to-brain transits; 97 genes were required for survival in human serum. This study revealed that a large number of bacterial genes, many of which were not previously associated with systemic E. coli K1 infection, are required to realize full invasive potential. IMPORTANCE Escherichia coli K1 strains cause life-threatening infections in newborn infants. They are acquired from the mother at birth and colonize the small intestine, from where they invade the blood and central nervous system. It is difficult to obtain information from acutely ill patients that sheds light on physiological and bacterial factors determining invasive disease. Key aspects of naturally occurring age-dependent human infection can be reproduced in neonatal rats. Here, we employ transposon-directed insertion site sequencing to identify genes essential for the in vitro growth of E. coli K1 and genes that contribute to the colonization of susceptible rats. The presence of bottlenecks to invasion of the blood and cerebrospinal compartments precluded insertion site sequencing analysis, but we identified genes for survival in serum. Copyright © 2018 McCarthy et al.

Genome-Wide Identification by Transposon Insertion Sequencing of Escherichia coli K1 Genes Essential for In Vitro Growth, Gastrointestinal Colonizing Capacity, and Survival in Serum

PubMed Central

McCarthy, Alex J.

2018-01-01

ABSTRACT Escherichia coli K1 strains are major causative agents of invasive disease of newborn infants. The age dependency of infection can be reproduced in neonatal rats. Colonization of the small intestine following oral administration of K1 bacteria leads rapidly to invasion of the blood circulation; bacteria that avoid capture by the mesenteric lymphatic system and evade antibacterial mechanisms in the blood may disseminate to cause organ-specific infections such as meningitis. Some E. coli K1 surface constituents, in particular the polysialic acid capsule, are known to contribute to invasive potential, but a comprehensive picture of the factors that determine the fully virulent phenotype has not emerged so far. We constructed a library and constituent sublibraries of ∼775,000 Tn5 transposon mutants of E. coli K1 strain A192PP and employed transposon-directed insertion site sequencing (TraDIS) to identify genes required for fitness for infection of 2-day-old rats. Transposon insertions were lacking in 357 genes following recovery on selective agar; these genes were considered essential for growth in nutrient-replete medium. Colonization of the midsection of the small intestine was facilitated by 167 E. coli K1 gene products. Restricted bacterial translocation across epithelial barriers precluded TraDIS analysis of gut-to-blood and blood-to-brain transits; 97 genes were required for survival in human serum. This study revealed that a large number of bacterial genes, many of which were not previously associated with systemic E. coli K1 infection, are required to realize full invasive potential. IMPORTANCE Escherichia coli K1 strains cause life-threatening infections in newborn infants. They are acquired from the mother at birth and colonize the small intestine, from where they invade the blood and central nervous system. It is difficult to obtain information from acutely ill patients that sheds light on physiological and bacterial factors determining invasive disease. Key aspects of naturally occurring age-dependent human infection can be reproduced in neonatal rats. Here, we employ transposon-directed insertion site sequencing to identify genes essential for the in vitro growth of E. coli K1 and genes that contribute to the colonization of susceptible rats. The presence of bottlenecks to invasion of the blood and cerebrospinal compartments precluded insertion site sequencing analysis, but we identified genes for survival in serum. PMID:29339415

More than just sugar: allocation of nectar amino acids and fatty acids in a Lepidopteran.

PubMed

Levin, Eran; McCue, Marshall D; Davidowitz, Goggy

2017-02-08

The ability to allocate resources, even when limited, is essential for survival and fitness. We examine how nutrients that occur in minute amounts are allocated among reproductive, somatic, and metabolic demands. In addition to sugar, flower nectars contain two macronutrients-amino acids and fatty acids. We created artificial nectars spiked with 13 C-labelled amino acids and fatty acids and fed these to adult moths (Manduca sexta: Sphingidae) to understand how they allocate these nutrients among competing sinks (reproduction, somatic tissue, and metabolic fuel). We found that both essential and non-essential amino acids were allocated to eggs and flight muscles and were still detectable in early-instar larvae. Parental-derived essential amino acids were more conserved in the early-instars than non-essential amino acids. All amino acids were used as metabolic fuel, but the non-essential amino acids were oxidized at higher rates than essential amino acids. Surprisingly, the nectar fatty acids were not vertically transferred to offspring, but were readily used as a metabolic fuel by the moth, minimizing losses of endogenous nutrient stores. We conclude that the non-carbohydrate components of nectar may play important roles in both reproductive success and survival of these nectar-feeding animals. © 2017 The Author(s).

More than just sugar: allocation of nectar amino acids and fatty acids in a Lepidopteran

PubMed Central

McCue, Marshall D.; Davidowitz, Goggy

2017-01-01

The ability to allocate resources, even when limited, is essential for survival and fitness. We examine how nutrients that occur in minute amounts are allocated among reproductive, somatic, and metabolic demands. In addition to sugar, flower nectars contain two macronutrients—amino acids and fatty acids. We created artificial nectars spiked with 13C-labelled amino acids and fatty acids and fed these to adult moths (Manduca sexta: Sphingidae) to understand how they allocate these nutrients among competing sinks (reproduction, somatic tissue, and metabolic fuel). We found that both essential and non-essential amino acids were allocated to eggs and flight muscles and were still detectable in early-instar larvae. Parental-derived essential amino acids were more conserved in the early-instars than non-essential amino acids. All amino acids were used as metabolic fuel, but the non-essential amino acids were oxidized at higher rates than essential amino acids. Surprisingly, the nectar fatty acids were not vertically transferred to offspring, but were readily used as a metabolic fuel by the moth, minimizing losses of endogenous nutrient stores. We conclude that the non-carbohydrate components of nectar may play important roles in both reproductive success and survival of these nectar-feeding animals. PMID:28148746

The Association Between PD-L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma

PubMed Central

Shin, Su-Jin; Jeon, Yoon Kyung; Cho, Yong Mee; Lee, Jae-Lyun; Chung, Doo Hyun; Park, Ji Young

2015-01-01

Background. Vascular endothelial growth factor pathway (VEGF)-tyrosine kinase inhibitors (TKIs) are used as the first-line treatment for patients with metastatic clear cell renal cell carcinoma (mCCRCC). Recently, programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) blockade emerged as promising therapy for renal cell carcinoma. However, the expression pattern and prognostic implication of programmed death-ligands (PD-Ls) in mCCRCC patients receiving VEGF-TKI remain unclear. Patients and Methods. PD-L1 and PD-L2 expression in tumor cells and the quantities of PD-1+ tumor-infiltrating lymphocytes were immunohistochemically evaluated in 91 mCCRCC patients treated with VEGF-TKI, and their associations with VEGF-TKI responsiveness and clinical outcome were analyzed. Results. PD-L1 immunopositivity was observed in 17.6% and significantly associated with a high International Society of Urological Pathology grade (p = .031) and sarcomatoid features (p = .014). PD-L2 immunopositivity was observed in 39.6% and was not associated with any of the assessed clinicopathological variables. PD-L1-positive cases showed poor VEGF-TKI responsiveness (p = .012) compared with PD-L1-negative cases. In univariate survival analysis, PD-L1 immunopositivity was significantly associated with shorter overall survival (OS) (p = .037) and progression-free survival (PFS) (p = .043). Multivariate survival analysis revealed that PD-L1 expression was independently associated with poor OS (p = .038) and PFS (p = .013) in addition to tumor necrosis (p = .006; p = .029, respectively) and Memorial Sloan Kettering Cancer Center score (p = .018; p = .032, respectively). PD-L2 expression was neither associated with VEGF-TKI responsiveness nor patients’ outcome. Conclusion. PD-L1 expression was significantly related to lack of VEGF-TKI responsiveness and independently associated with shorter survival in mCCRCC patients after VEGF-TKI treatment. PD-L1 may have a predictive and prognostic value for determining the value of VEGF-TKI treatment in patients with mCCRCC. Implications for Practice: Vascular endothelial growth factor pathway (VEGF)-tyrosine kinase inhibitors (TKIs) are essential for the treatment of metastatic renal cell carcinoma patients, but the treatment suffers from a lack of predictive markers. This study demonstrates that PD-L1 expression is a predictor for unfavorable response to VEGF-TKI and a prognostic indicator for poor overall survival and progression-free survival in patients with metastatic clear cell renal cell carcinoma receiving VEGF-TKI. PMID:26424759

Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death

PubMed Central

Narayanan, Kannan Badri; Ali, Manaf; Barclay, Barry J.; Cheng, Qiang (Shawn); D’Abronzo, Leandro; Dornetshuber-Fleiss, Rita; Ghosh, Paramita M.; Gonzalez Guzman, Michael J.; Lee, Tae-Jin; Leung, Po Sing; Li, Lin; Luanpitpong, Suidjit; Ratovitski, Edward; Rojanasakul, Yon; Romano, Maria Fiammetta; Romano, Simona; Sinha, Ranjeet K.; Yedjou, Clement; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Brown, Dustin G.; Ryan, Elizabeth P.; Colacci, Anna Maria; Hamid, Roslida A.; Mondello, Chiara; Raju, Jayadev; Salem, Hosni K.; Woodrick, Jordan; Scovassi, A.Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Kim, Seo Yun; Bisson, William H.; Lowe, Leroy; Park, Hyun Ho

2015-01-01

Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis. PMID:26106145

The interactive effects of essential ions and salinity on the survival of Mysidopsis bahia in 96-H acute toxicity tests of effluents discharged to marine and estuarine receiving waters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Douglas, W.S.; Horne, M.T.

1997-10-01

The importance of salinity in whole effluent toxicity tests using marine organisms has been acknowledged in most testing protocols. However, little if any attention has been given to the specific effects of alteration of the ionic composition of seawater solutions to the test organism. The presence of persistent toxicity in effluents with no apparent toxic agents prompted examination of the potential influence of essential ions on the survival of the opossum shrimp, Mysidopsis bahia, a common effluent toxicity indicator organism. Through stepwise additions of ionic salts to deionized water, the minimum complement of salts to maintain survival of M. bahiamore » during 96-h exposures was determined to be Ca, Mg, K, Br, Na, and Cl. The toxicity curves for Ca, Mg, K, and Br were then determined across test salinity ranging from 10 to 35 parts per thousand. These curves for Ca, Mg, and K revealed that there are significant negative effects on survival when the essential ions are present in either low or high concentrations relative to the levels in natural seawater. Although there were no statistically detectable effects of Br on organism survival over the concentration range tested (5--480 mg/L). Br toxicity at concentrations less than 5 mg/L and greater than 700 mg/L have been shown in other studies. In addition, the tolerance ranges for K, Ca, and Mg were shown to shift significantly with changes in salinity, with lower salinity causing an apparent decrease in tolerance to an excess of essential ions. Tests with toxic effluents from five industrial and municipal sources revealed that adjustment of the ionic balance prior to testing reduced or eliminated toxicity in four of the five whole effluents tested. Suggestions for integrating this information into biomonitoring programs and toxicity identification evaluations are presented.« less

[Management abilities of the head surgeon: essential for survival!].

PubMed

Jähne, J

2012-04-01

Due to increased economic challenges in the management of hospitals head surgeons do not only need excellent surgical expertise but also significant management qualities. The personality of head surgeons should include authenticity, sincerity, fairness and the ability to cooperate. Visionary leadership, strategic thinking and strategic management of the personnel are further prerequisites for success. Besides good abilities in communication head surgeons need knowledge of the operating figures for interpretation. To keep up with the own capabilities time and self-management is essential. A survival as head surgeon is likely if these qualities and abilities exist.

Atypical E2f functions are critical for pancreas polyploidization

PubMed Central

Moreno, Eva; Toussaint, Mathilda J. M.; Tooten, Peter C. J.; van Essen, Saskia C.; van Liere, Elsbeth A.; Youssef, Sameh A.; Bongiovanni, Laura; de Bruin, Alain

2018-01-01

The presence of polyploid cells in the endocrine and exocrine pancreas has been reported for four decades. In rodents, pancreatic polyploidization is initiated after weaning and the number of polyploid cells increases with age. Surprisingly the molecular regulators and biological functions of polyploidization in the pancreas are still unknown. We discovered that atypical E2f activity is essential for polyploidization in the pancreas, using an inducible Cre/LoxP approach in new-born mice to delete ubiquitously the atypical E2f transcription factors, E2f7 and E2f8. In contrast to its critical role in embryonic survival, conditional deletion of both of both atypical E2fs in newborn mice had no impact on postnatal survival and mice lived until old age. However, deficiency of E2f7 or E2f8 alone was sufficient to suppress polyploidization in the pancreas and associated with only a minor decrease in blood serum levels of glucose, insulin, amylase and lipase under 4 hours starvation condition compared to wildtype littermates. In mice with fewer pancreatic polyploid cells that were fed ad libitum, no major impact on hormones or enzymes levels was observed. In summary, we identified atypical E2fs to be essential for polyploidization in the pancreas and discovered that postnatal induced loss of both atypical E2fs in many organs is compatible with life until old age. PMID:29329320

Atypical E2f functions are critical for pancreas polyploidization.

PubMed

Matondo, Ramadhan B; Moreno, Eva; Toussaint, Mathilda J M; Tooten, Peter C J; van Essen, Saskia C; van Liere, Elsbeth A; Youssef, Sameh A; Bongiovanni, Laura; de Bruin, Alain

2018-01-01

The presence of polyploid cells in the endocrine and exocrine pancreas has been reported for four decades. In rodents, pancreatic polyploidization is initiated after weaning and the number of polyploid cells increases with age. Surprisingly the molecular regulators and biological functions of polyploidization in the pancreas are still unknown. We discovered that atypical E2f activity is essential for polyploidization in the pancreas, using an inducible Cre/LoxP approach in new-born mice to delete ubiquitously the atypical E2f transcription factors, E2f7 and E2f8. In contrast to its critical role in embryonic survival, conditional deletion of both of both atypical E2fs in newborn mice had no impact on postnatal survival and mice lived until old age. However, deficiency of E2f7 or E2f8 alone was sufficient to suppress polyploidization in the pancreas and associated with only a minor decrease in blood serum levels of glucose, insulin, amylase and lipase under 4 hours starvation condition compared to wildtype littermates. In mice with fewer pancreatic polyploid cells that were fed ad libitum, no major impact on hormones or enzymes levels was observed. In summary, we identified atypical E2fs to be essential for polyploidization in the pancreas and discovered that postnatal induced loss of both atypical E2fs in many organs is compatible with life until old age.

Eosinophils: important players in humoral immunity.

PubMed

Berek, C

2016-01-01

Eosinophils perform numerous tasks. They are involved in inflammatory reactions associated with innate immune defence against parasitic infections and are also involved in pathological processes in response to allergens. Recently, however, it has become clear that eosinophils also play crucial non-inflammatory roles in the generation and maintenance of adaptive immune responses. Eosinophils, being a major source of the plasma cell survival factor APRIL (activation and proliferation-induced ligand), are essential not only for the long-term survival of plasma cells in the bone marrow, but also for the maintenance of these cells in the lamina propria which underlies the gut epithelium. At steady state under non-inflammatory conditions eosinophils are resident cells of the gastrointestinal tract, although only few are present in the major organized lymphoid tissue of the gut - the Peyer's patches (PP). Surprisingly, however, lack of eosinophils abolishes efficient class-switching of B cells to immunoglobulin (Ig)A in the germinal centres of PP. Thus, eosinophils are required to generate and to maintain mucosal IgA plasma cells, and as a consequence their absence leads to a marked reduction of IgA both in serum and in the gut-associated lymphoid tissues (GALT). Eosinophils thus have an essential part in long-term humoral immune protection, as they are crucial for the longevity of antibody-producing plasma cells in the bone marrow and, in addition, for gut immune homeostasis. © 2015 British Society for Immunology.

Usefulness of BCOR gene mutation as a prognostic factor in acute myeloid leukemia with intermediate cytogenetic prognosis.

PubMed

Terada, Kazuki; Yamaguchi, Hiroki; Ueki, Toshimitsu; Usuki, Kensuke; Kobayashi, Yutaka; Tajika, Kenji; Gomi, Seiji; Kurosawa, Saiko; Saito, Riho; Furuta, Yutaka; Miyadera, Keiki; Tokura, Taichiro; Marumo, Atushi; Omori, Ikuko; Sakaguchi, Masahiro; Fujiwara, Yusuke; Yui, Shunsuke; Ryotokuji, Takeshi; Arai, Kunihito; Kitano, Tomoaki; Wakita, Satoshi; Fukuda, Takahiro; Inokuchi, Koiti

2018-04-16

BCOR gene is a transcription regulatory factor that plays an essential role in normal hematopoiesis. The wider introduction of next-generation sequencing technology has led to reports in recent years of mutations in the BCOR gene in acute myeloid leukemia (AML), but the related clinical characteristics and prognosis are not sufficiently understood. We investigated the clinical characteristics and prognosis of 377 de novo AML cases with BCOR or BCORL1 mutation. BCOR or BCORL1 gene mutations were found in 28 cases (7.4%). Among cases aged 65 years or below that were also FLT3-ITD-negative and in the intermediate cytogenetic prognosis group, BCOR or BCORL1 gene mutations were observed in 11% of cases (12 of 111 cases), and this group had significantly lower 5-year overall survival (OS) (13.6% vs. 55.0%, P=0.0021) and relapse-free survival (RFS) (14.3% vs. 44.5%, P=0.0168) compared to cases without BCOR or BCORL1 gene mutations. Multivariate analysis demonstrated that BCOR mutations were an independent unfavorable prognostic factor (P=0.0038, P=0.0463) for both OS and RFS. In cases of AML that are FLT3-ITD-negative, aged 65 years or below, and in the intermediate cytogenetic prognosis group, which are considered to have relatively favorable prognosis, BCOR gene mutations appear to be an important prognostic factor. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Th1 differentiation drives the accumulation of intravascular, non-protective CD4 T cells during tuberculosis

PubMed Central

Sallin, Michelle A.; Sakai, Shunsuke; Kauffman, Keith D.; Young, Howard A.; Zhu, Jinfang; Barber, Daniel L.

2017-01-01

SUMMARY Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1 polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73+CXCR3+T-betdim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL-12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1+KLRG1+ Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69+CD103+ tissue resident phenotype effectors in lung. In contrast, Th1 cell-derived IFNγ inhibits the accumulation of intravascular CX3CR1+KLRG1+ Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating the dual nature of Th1 polarization in tuberculosis. PMID:28355562

Iκb Kinase α Is Essential for Mature B Cell Development and Function

PubMed Central

Kaisho, Tsuneyasu; Takeda, Kiyoshi; Tsujimura, Tohru; Kawai, Taro; Nomura, Fumiko; Terada, Nobuyuki; Akira, Shizuo

2001-01-01

IκB kinase (IKK) α and β phosphorylate IκB proteins and activate the transcription factor, nuclear factor (NF)-κB. Although both are highly homologous kinases, gene targeting experiments revealed their differential roles in vivo. IKKα is involved in skin and limb morphogenesis, whereas IKKβ is essential for cytokine signaling. To elucidate in vivo roles of IKKα in hematopoietic cells, we have generated bone marrow chimeras by transferring control and IKKα-deficient fetal liver cells. The mature B cell population was decreased in IKKα−/− chimeras. IKKα−/− chimeras also exhibited a decrease of serum immunoglobulin basal level and impaired antigen-specific immune responses. Histologically, they also manifested marked disruption of germinal center formation and splenic microarchitectures that depend on mature B cells. IKKα−/− B cells not only showed impairment of survival and mitogenic responses in vitro, accompanied by decreased, although inducible, NF-κB activity, but also increased turnover rate in vivo. In addition, transgene expression of bcl-2 could only partially rescue impaired B cell development in IKKα−/− chimeras. Taken together, these results demonstrate that IKKα is critically involved in the prevention of cell death and functional development of mature B cells. PMID:11181694

Loss of CaMKI function disrupts salt aversive learning in C. elegans.

PubMed

Lim, Jana P; Fehlauer, Holger; Das, Alakananda; Saro, Gabriella; Glauser, Dominique A; Brunet, Anne; Goodman, Miriam B

2018-06-06

The ability to adapt behavior to environmental fluctuations is critical for survival of organisms ranging from invertebrates to mammals. Caenorhabditis elegans can learn to avoid sodium chloride when it is paired with starvation. This behavior may help animals avoid areas without food. While some genes have been implicated in this salt aversive learning behavior, critical genetic components, and the neural circuit in which they act, remain elusive. Here, we show that the sole worm ortholog of mammalian CaMKI/IV, CMK-1, is essential for salt aversive learning behavior in C. elegans hermaphrodites. We find that CMK-1 acts in the primary salt-sensing ASE neurons to regulate this behavior. By characterizing the intracellular calcium dynamics in ASE neurons using microfluidics, we find that loss of cmk-1 has subtle effects on sensory-evoked calcium responses in ASE axons and their modulation by salt conditioning. Our study implicates the expression of the conserved CaMKI/CMK-1 in chemosensory neurons as a regulator of behavioral plasticity to environmental salt in C. elegans SIGNIFICANCE STATEMENT Like other animals, the nematode Caenorhabditis elegans depends on salt for survival and navigates toward high concentrations of this essential mineral. Besides its role as an essential nutrient, salt also causes osmotic stress at high concentrations. A growing body of evidence indicates that C. elegans balances the requirement for salt with the danger it presents through a process called salt aversive learning. We show that this behavior depends on expression of a calcium/calmodulin-dependent kinase, CMK-1, in the ASE salt sensing neurons. Our study identifies CMK-1 and salt-sensitive chemosensory neurons as key factors in this form of behavioral plasticity. Copyright © 2018 the authors.

Games of lives in surviving childhood brain tumors.

PubMed

Chen, Chin-Mi; Chen, Yueh-Chih; Haase, Joan E

2008-06-01

The purpose of this phenomenological study was to describe the commonality of the lived experience of adolescent and young adult survivors (AYAS) of brain tumors in Taiwan from a sociocultural perspective. Seven AYAS aged 13 to 22 years, who had survived 5 to 10 years from the time of diagnosis, participated in this study. In consideration of their emotional duress, each participant was interviewed only once. The data revealed an essential structure: the game of life. The essential structure included six themes as follows: (a) no longer playing well, (b) wandering on the outer edges of social life, (c) helplessly struggling with role obligations, (d) rationally regulating the meaning of surviving, (e) winning a new social face, and (f) mastering the game of life. The findings suggest how nurses might help AYAS to succeed in psychosocial adjustment.

Lemongrass essential oil and citral inhibit Src/Stat3 activity and suppress the proliferation/survival of small-cell lung cancer cells, alone or in combination with chemotherapeutic agents.

PubMed

Maruoka, Takayuki; Kitanaka, Akira; Kubota, Yoshitsugu; Yamaoka, Genji; Kameda, Tomohiro; Imataki, Osamu; Dobashi, Hiroaki; Bandoh, Shuji; Kadowaki, Norimitsu; Tanaka, Terukazu

2018-03-13

Small-cell lung cancer (SCLC) is intractable due to its high propensity for relapse. Novel agents are thus needed for SCLC treatment. Lemongrass essential oil (LG-EO) and its major constituent, citral, have been reported to inhibit the proliferation and survival of several types of cancer cells. However, the precise mechanisms through which LG-EO and citral exert their effects on SCLC cells have not been fully elucidated. SCLC cells express Src and have high levels of Src-tyrosine kinase (Src-TK) activity. In most SCLC cell lines, constitutive phosphorylation of Stat3(Y705), which is essential for its activation, has been detected. Src-TK can phosphorylate Stat3(Y705), and activated Stat3 promotes the expression of the anti-apoptotic factors Bcl-xL and Mcl-1. In the present study, LG-EO and citral prevented Src-TK from phosphorylating Stat3(Y705), resulting in decreased Bcl-xL and Mcl-1 expression, in turn suppressing the proliferation/survival of SCLC cells. To confirm these findings, the wild-type-src gene was transfected into the LU135 SCLC cell line (LU135‑wt-src), in which Src and activated phospho-Stat3(Y705) were overexpressed. The suppression of cell proliferation and the induction of apoptosis by treatment with LG-EO or citral were significantly attenuated in the LU135-wt-src cells compared with the control LU135-mock cells. The signal transducer and activator of transcription 3 (Stat3) signaling pathway is also associated with intrinsic drug resistance. LU135-wt-src cells were significantly resistant to conventional chemotherapeutic agents compared with LU135-mock cells. The combined effects of citral and each conventional chemotherapeutic agent on SCLC cells were also evaluated. The combination treatment exerted additive or more prominent effects on LU135-wt-src, LU165 and MN1112 cells, which are relatively chemoresistant SCLC cells. These findings suggest that either LG-EO or citral, alone or in combination with chemotherapeutic agents, may be a novel therapeutic option for SCLC patients.

44 CFR Appendix 1 to Part 323 - List of Essential Survival Items

Code of Federal Regulations, 2010 CFR

2010-10-01

... of preattack planning to insure the availability of basic essentials for a productive economy in the...: Blood collecting and dispensing containers. Blood donor sets. Blood grouping and typing sera. Blood recipient sets. Blood shipping containers. 3. Biologicals: Diphtheria toxoid. Diphtheria antitoxin...

Vascularization strategies for tissue engineers.

PubMed

Dew, Lindsey; MacNeil, Sheila; Chong, Chuh Khiun

2015-01-01

All tissue-engineered substitutes (with the exception of cornea and cartilage) require a vascular network to provide the nutrient and oxygen supply needed for their survival in vivo. Unfortunately the process of vascular ingrowth into an engineered tissue can take weeks to occur naturally and during this time the tissues become starved of essential nutrients, leading to tissue death. This review initially gives a brief overview of the processes and factors involved in the formation of new vasculature. It then summarizes the different approaches that are being applied or developed to overcome the issue of slow neovascularization in a range of tissue-engineered substitutes. Some potential future strategies are then discussed.

Chromatin assembly: Journey to the CENter of the chromosome

PubMed Central

Chen, Chin-Chi

2016-01-01

All eukaryotic genomes are packaged into basic units of DNA wrapped around histone proteins called nucleosomes. The ability of histones to specify a variety of epigenetic states at defined chromatin domains is essential for cell survival. The most distinctive type of chromatin is found at centromeres, which are marked by the centromere-specific histone H3 variant CENP-A. Many of the factors that regulate CENP-A chromatin have been identified; however, our understanding of the mechanisms of centromeric nucleosome assembly, maintenance, and reorganization remains limited. This review discusses recent insights into these processes and draws parallels between centromeric and noncentromeric chromatin assembly mechanisms. PMID:27377247

Exploring new roles for the rpoS gene in the survival and virulence of the fire blight pathogen Erwinia amylovora.

PubMed

Santander, Ricardo D; Monte-Serrano, Mercedes; Rodríguez-Herva, José J; López-Solanilla, Emilia; Rodríguez-Palenzuela, Pablo; Biosca, Elena G

2014-12-01

Erwinia amylovora causes fire blight in economically important plants of the family Rosaceae. This bacterial pathogen spends part of its life cycle coping with starvation and other fluctuating environmental conditions. In many Gram-negative bacteria, starvation and other stress responses are regulated by the sigma factor RpoS. We obtained an E. amylovora rpoS mutant to explore the role of this gene in starvation responses and its potential implication in other processes not yet studied in this pathogen. Results showed that E. amylovora needs rpoS to develop normal starvation survival and viable but nonculturable (VBNC) responses. Furthermore, this gene contributed to stationary phase cross-protection against oxidative, osmotic, and acid stresses and was essential for cross-protection against heat shock, but nonessential against acid shock. RpoS also mediated regulation of motility, exopolysaccharide synthesis, and virulence in immature loquats, but not in pear plantlets, and contributed to E. amylovora survival in nonhost tissues during incompatible interactions. Our results reveal some unique roles for the rpoS gene in E. amylovora and provide new knowledge on the regulation of different processes related to its ecology, including survival in different environments and virulence in immature fruits. © 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Bacterial invasion potential in water is determined by nutrient availability and the indigenous community.

PubMed

Van Nevel, Sam; De Roy, Karen; Boon, Nico

2013-09-01

In drinking water (DW) and the distribution systems, bacterial growth and biofilm formation have to be controlled both for limiting taste or odour development and preventing clogging or biocorrosion problems. After a contamination with undesired bacteria, factors like nutrient availability and temperature will influence the survival of these invaders. Understanding the conditions enabling invaders to proliferate is essential for a holistic approach towards microbial risk assessment in DW. Pseudomonas putida was used as a model invader because this easy-growing bacterium can use a wide range of substrates. Invasion experiments in oligo- to eutrophic waters showed the requirement of both a carbon and phosphate source for survival of P. putida in DW. Addition of C, N and P enabled P. putida to grow in DW from 5.80 × 10(4) to 1.84 × 10(8) cells mL(-1) and survive for at least 12 days. However, in surface water with similar nutrient concentrations, P. putida did not survive, indicating the concomitant importance of the present indigenous microbial community of the specific water sample. Either extensive carbon or phosphate limitation can be used in water treatment design in order to obtain a DW which is not susceptible for unwanted bacterial growth. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

HTLV-1 Tax Stabilizes MCL-1 via TRAF6-Dependent K63-Linked Polyubiquitination to Promote Cell Survival and Transformation

PubMed Central

Choi, Young Bong; Harhaj, Edward William

2014-01-01

The human T-cell leukemia virus type 1 (HTLV-1) Tax protein hijacks the host ubiquitin machinery to activate IκB kinases (IKKs) and NF-κB and promote cell survival; however, the key ubiquitinated factors downstream of Tax involved in cell transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of Tax or a Tax mutant impaired in IKK activation. Tax induced the ubiquitination of 22 cellular proteins, including the anti-apoptotic BCL-2 family member MCL-1, in an IKK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63)-linked polyubiquitination of MCL-1 that was dependent on the E3 ubiquitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its mitochondrial localization, where it conjugated four carboxyl-terminal lysine residues of MCL-1 with K63-linked polyubiquitin chains, which stabilized and protected MCL-1 from genotoxic stress-induced degradation. TRAF6 and MCL-1 played essential roles in the survival of HTLV-1 transformed cells and the immortalization of primary T cells by HTLV-1. Therefore, K63-linked polyubiquitination represents a novel regulatory mechanism controlling MCL-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation. PMID:25340740

Inhibition of warm ischemic injury to rat liver, pancreas, and heart grafts by controlling the nutritional status of both donor and recipient.

PubMed

Nishihara, V; Sumimoto, R; Fukuda, Y; Southard, J H; Asahara, T; Dohi, K

1997-01-01

In this study, we tested the effect of donor fasting with or without the use of an essential fatty acids deficiency (EFAD) diet in the recipient using rat heart, pancreas, and liver transplant models. We then compared the survivals, tumor necrosis factor alpha (TNF-alpha) response, and white cell accumulation in rats in order to clarify the mechanisms of the beneficial effect of donor fasting and recipient EFAD. It was found that when the grafts were obtained from fasted donors and then transplanted into fed recipients, the survival rate was significantly higher for all three grafts than for those obtained from fed rats and transplanted into fed rats. The best survival was seen for pancreas grafts obtained from fasted donors and then transplanted into EFAD recipients. TNF-alpha secretion was significantly suppressed in both fasted and EFAD rats, and both the total cell count and neutrophil count were suppressed in EFAD rats. These results clearly indicate that in addition to liver grafts, both heart and pancreas grafts obtained from fasted animals are more tolerant to warm ischemic injury. Furthermore, the combination of donor fasting and recipient EFAD acts synergistically to inhibit the post-transplantation inflammatory reaction (through decreased TNF-alpha secretion and white cell accumulation), thus resulting in an improved survival.

M-CSF mediates host defense during bacterial pneumonia by promoting the survival of lung and liver mononuclear phagocytes

PubMed Central

Bettina, Alexandra; Zhang, Zhimin; Michels, Kathryn; Cagnina, R. Elaine; Vincent, Isaah S.; Burdick, Marie D.; Kadl, Alexandra; Mehrad, Borna

2016-01-01

Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. Macrophage-colony stimulating factor (M-CSF) has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, the proliferation of precursors or the recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and anti-microbial functions of both lung and liver mononuclear phagocytes during pneumonia and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and anti-microbial functions of mononuclear phagocytes in the lungs and liver. PMID:27183631

Contested Desires: The Edible Landscape of School

ERIC Educational Resources Information Center

Burke, Catherine

2005-01-01

Food and drink are associated with survival and for children and young people the edible landscape represents an essential part of survival in the modern school. Within any institution that "contains" persons over time, such as schools, hospitals and prisons, the organization and control of eating and drinking takes on a particularly…

The effect of distant metastases sites on survival in de novo stage-IV breast cancer: A SEER database analysis.

PubMed

Wu, San-Gang; Li, Hui; Tang, Li-Ying; Sun, Jia-Yuan; Zhang, Wen-Wen; Li, Feng-Yan; Chen, Yong-Xiong; He, Zhen-Yu

2017-06-01

To investigate the effect of distant metastases sites on survival in patients with de novo stage-IV breast cancer. From 2010 to 2013, patients with a diagnosis of de novo stage-IV breast cancer were identified using the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox regression analyses were performed to analyze the effect of distant metastases sites on breast cancer-specific survival and overall survival. A total of 7575 patients were identified. The most common metastatic sites were bone, followed by lung, liver, and brain. Patients with hormone receptor+/human epidermal growth factor receptor 2- and hormone receptor+/human epidermal growth factor receptor 2+ status were more prone to bone metastases. Lung and brain metastases were common in hormone receptor-/human epidermal growth factor receptor 2+ and hormone receptor-/human epidermal growth factor receptor 2- subtypes, and patients with hormone receptor+/ human epidermal growth factor receptor 2+ and hormone receptor-/human epidermal growth factor receptor 2+ subtypes were more prone to liver metastases. Patients with liver and brain metastases had unfavorable prognosis for breast cancer-specific survival and overall survival, whereas bone and lung metastases had no effect on patient survival in multivariate analyses. The hormone receptor-/human epidermal growth factor receptor 2- subtype conferred a significantly poorer outcome in terms of breast cancer-specific survival and overall survival. hormone receptor+/human epidermal growth factor receptor 2+ disease was associated with the best prognosis in terms of breast cancer-specific survival and overall survival. Patients with liver and brain metastases were more likely to experience poor prognosis for breast cancer-specific survival and overall survival by various breast cancer subtypes. Distant metastases sites have differential impact on clinical outcomes in stage-IV breast cancer. Follow-up screening for brain and liver metastases might be effective in improving breast cancer-specific survival and overall survival.

A Genetic Screen Reveals that Synthesis of 1,4-Dihydroxy-2-Naphthoate (DHNA), but Not Full-Length Menaquinone, Is Required for Listeria monocytogenes Cytosolic Survival.

PubMed

Chen, Grischa Y; McDougal, Courtney E; D'Antonio, Marc A; Portman, Jonathan L; Sauer, John-Demian

2017-03-21

Through unknown mechanisms, the host cytosol restricts bacterial colonization; therefore, only professional cytosolic pathogens are adapted to colonize this host environment. Listeria monocytogenes is a Gram-positive intracellular pathogen that is highly adapted to colonize the cytosol of both phagocytic and nonphagocytic cells. To identify L. monocytogenes determinants of cytosolic survival, we designed and executed a novel screen to isolate L. monocytogenes mutants with cytosolic survival defects. Multiple mutants identified in the screen were defective for synthesis of menaquinone (MK), an essential molecule in the electron transport chain. Analysis of an extensive set of MK biosynthesis and respiratory chain mutants revealed that cellular respiration was not required for cytosolic survival of L. monocytogenes but that, instead, synthesis of 1,4-dihydroxy-2-naphthoate (DHNA), an MK biosynthesis intermediate, was essential. Recent discoveries showed that modulation of the central metabolism of both host and pathogen can influence the outcome of host-pathogen interactions. Our results identify a potentially novel function of the MK biosynthetic intermediate DHNA and specifically highlight how L. monocytogenes metabolic adaptations promote cytosolic survival and evasion of host immunity. IMPORTANCE Cytosolic bacterial pathogens, such as Listeria monocytogenes and Francisella tularensis , are exquisitely evolved to colonize the host cytosol in a variety of cell types. Establishing an intracellular niche shields these pathogens from effectors of humoral immunity, grants access to host nutrients, and is essential for pathogenesis. Through yet-to-be-defined mechanisms, the host cytosol restricts replication of non-cytosol-adapted bacteria, likely through a combination of cell autonomous defenses (CADs) and nutritional immunity. Utilizing a novel genetic screen, we identified determinants of L. monocytogenes cytosolic survival and virulence and identified a role for the synthesis of the menaquinone precursor 1,4-dihydroxy-2-naphthoate (DHNA) in cytosolic survival. Together, these data begin to elucidate adaptations that allow cytosolic pathogens to survive in their intracellular niches. Copyright © 2017 Chen et al.

Silencing of karyopherin α2 inhibits cell growth and survival in human hepatocellular carcinoma

PubMed Central

Yang, Yunfeng; Guo, Jian; Hao, Yuxia; Wang, Fuhua; Li, Fengxia; Shuang, Shaomin; Wang, Junping

2017-01-01

Karyopherin α2 (KPNA2), involved in nucleocytoplasmic transport, has been reported to be upregulated in hepatocellular carcinoma and considered as a biomarker for poor prognosis. However, comprehensive studies of KPNA2 functions in hepatocellular carcinogenesis are still lacking. Our study examine the roles and related molecular mechanisms of KPNA2 in hepatocellular carcinoma development. Results show that KPNA2 knockdown inhibited the proliferation and growth of hepatocellular carcinoma cells in vitro and in vivo. KPNA2 knockdown also inhibited colony formation ability, induced cell cycle arrest and cellular apoptosis in two hepatocellular carcinoma cell lines, HepG2 and SMMC-7721. Furthermore, gene expression microarray analysis in HepG2 cells with KPNA2 knockdown revealed that critical signaling pathways involved in cell proliferation and survival were deregulated. In conclusion, this study provided systematic evidence that KPNA2 was an essential factor promoting hepatocellular carcinoma and unraveled potential molecular pathways and networks underlying KPNA2-induced hepatocellular carcinogenesis. PMID:28422734

Silencing of karyopherin α2 inhibits cell growth and survival in human hepatocellular carcinoma.

PubMed

Yang, Yunfeng; Guo, Jian; Hao, Yuxia; Wang, Fuhua; Li, Fengxia; Shuang, Shaomin; Wang, Junping

2017-05-30

Karyopherin α2 (KPNA2), involved in nucleocytoplasmic transport, has been reported to be upregulated in hepatocellular carcinoma and considered as a biomarker for poor prognosis. However, comprehensive studies of KPNA2 functions in hepatocellular carcinogenesis are still lacking. Our study examine the roles and related molecular mechanisms of KPNA2 in hepatocellular carcinoma development. Results show that KPNA2 knockdown inhibited the proliferation and growth of hepatocellular carcinoma cells in vitro and in vivo. KPNA2 knockdown also inhibited colony formation ability, induced cell cycle arrest and cellular apoptosis in two hepatocellular carcinoma cell lines, HepG2 and SMMC-7721. Furthermore, gene expression microarray analysis in HepG2 cells with KPNA2 knockdown revealed that critical signaling pathways involved in cell proliferation and survival were deregulated. In conclusion, this study provided systematic evidence that KPNA2 was an essential factor promoting hepatocellular carcinoma and unraveled potential molecular pathways and networks underlying KPNA2-induced hepatocellular carcinogenesis.

MEDICI: Mining Essentiality Data to Identify Critical Interactions for Cancer Drug Target Discovery and Development | Office of Cancer Genomics

Cancer.gov

Protein-protein interactions (PPIs) mediate the transmission and regulation of oncogenic signals that are essential to cellular proliferation and survival, and thus represent potential targets for anti-cancer therapeutic discovery. Despite their significance, there is no method to experimentally disrupt and interrogate the essentiality of individual endogenous PPIs. The ability to computationally predict or infer PPI essentiality would help prioritize PPIs for drug discovery and help advance understanding of cancer biology.

Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival.

PubMed

Schipani, E; Ryan, H E; Didrickson, S; Kobayashi, T; Knight, M; Johnson, R S

2001-11-01

Breakdown or absence of vascular oxygen delivery is a hallmark of many common human diseases, including cancer, myocardial infarction, and stroke. The chief mediator of hypoxic response in mammalian tissues is the transcription factor hypoxia-inducible factor 1 (HIF-1), and its oxygen-sensitive component HIF-1alpha. A key question surrounding HIF-1alpha and the hypoxic response is the role of this transcription factor in cells removed from a functional vascular bed; in this regard there is evidence indicating that it can act as either a survival factor or induce growth arrest and apoptosis. To study more closely how HIF-1alpha functions in hypoxia in vivo, we used tissue-specific targeting to delete HIF-1alpha in an avascular tissue: the cartilaginous growth plate of developing bone. We show here the first evidence that the developmental growth plate in mammals is hypoxic, and that this hypoxia occurs in its interior rather than at its periphery. As a result of this developmental hypoxia, cells that lack HIF-1alpha in the interior of the growth plate die. This is coupled to decreased expression of the CDK inhibitor p57, and increased levels of BrdU incorporation in HIF-1alpha null growth plates, indicating defects in HIF-1alpha-regulated growth arrest occurs in these animals. Furthermore, we find that VEGF expression in the growth plate is regulated through both HIF-1alpha-dependent and -independent mechanisms. In particular, we provide evidence that VEGF expression is up-regulated in a HIF-1alpha-independent manner in chondrocytes surrounding areas of cell death, and this in turn induces ectopic angiogenesis. Altogether, our findings have important implications for the role of hypoxic response and HIF-1alpha in development, and in cell survival in tissues challenged by interruption of vascular flow; they also illustrate the complexities of HIF-1alpha response in vivo, and they provide new insights into mechanisms of growth plate development.

Nrf1 CNC-bZIP protein promotes cell survival and nucleotide excision repair through maintaining glutathione homeostasis.

PubMed

Han, Weinong; Ming, Mei; Zhao, Rui; Pi, Jingbo; Wu, Chunli; He, Yu-Ying

2012-05-25

Skin cancer is the most common cancer in the United States. Its major environmental risk factor is UVB radiation in sunlight. In response to UVB damage, epidermal keratinocytes activate a specific repair pathway, i.e. nucleotide excision repair, to remove UVB-induced DNA lesions. However, the regulation of UVB response is not fully understood. Here we show that the long isoform of the nuclear factor erythroid 2-related factor 1 (Nrf1, also called NFE2L1), a cytoprotective transcription factor critical for the expression of multiple antioxidant response element-dependent genes, plays an important role in the response of keratinocytes to UVB. Nrf1 loss sensitized keratinocytes to UVB-induced apoptosis by up-regulating the expression of the proapoptotic Bcl-2 family member Bik through reducing glutathione levels. Knocking down Bik reduced UVB-induced apoptosis in Nrf1-inhibited cells. In UVB-irradiated surviving cells, however, disruption of Nrf1 impaired nucleotide excision repair through suppressing the transcription of xeroderma pigmentosum C (XPC), a factor essential for initiating the global genome nucleotide excision repair by recognizing the DNA lesion and recruiting downstream factors. Nrf1 enhanced XPC expression by increasing glutathione availability but was independent of the transcription repressor of XPC. Adding XPC or glutathione restored the DNA repair capacity in Nrf1-inhibited cells. Finally, we demonstrate that Nrf1 levels are significantly reduced by UVB radiation in mouse skin and are lower in human skin tumors than in normal skin. These results indicate a novel role of Nrf1 in UVB-induced DNA damage repair and suggest Nrf1 as a tumor suppressor in the skin.

Insulin-Like Growth Factor System in Cancer: Novel Targeted Therapies

PubMed Central

Brahmkhatri, Varsha P.; Prasanna, Chinmayi; Atreya, Hanudatta S.

2015-01-01

Insulin-like growth factors (IGFs) are essential for growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis, and metastatic activities in various cancers. The IGFs actions are mediated through the IGF-1 receptor that is involved in cell transformation induced by tumour. These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs). We describe here the role of the IGF system in cancer, proposing new strategies targeting this system. We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions. This review discusses the emerging view that blocking IGF via IGFBP is a better option than blocking IGF receptors. This can lead to the development of novel cancer therapies. PMID:25866791

Reduced SHARPIN and LUBAC Formation May Contribute to CCl₄- or Acetaminophen-Induced Liver Cirrhosis in Mice.

PubMed

Yamamotoya, Takeshi; Nakatsu, Yusuke; Matsunaga, Yasuka; Fukushima, Toshiaki; Yamazaki, Hiroki; Kaneko, Sunao; Fujishiro, Midori; Kikuchi, Takako; Kushiyama, Akifumi; Tokunaga, Fuminori; Asano, Tomoichiro; Sakoda, Hideyuki

2017-02-04

Linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on nuclear factor-κB (NF-κB) essential modulator (NEMO) and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl₄) or acetaminophen (APAP), both of which produced the fulminant hepatitis phenotype. To elucidate its pathological significance, hepatic SHARPIN expression was suppressed in mice by injecting shRNA adenovirus via the tail vein. Seven days after this transduction, without additional inflammatory stimuli, substantial inflammation and fibrosis with enhanced hepatocyte apoptosis occurred in the livers. A similar but more severe phenotype was observed with suppression of HOIP, which is responsible for the E3 ligase activity of LUBAC. Furthermore, in good agreement with these in vivo results, transduction of Hepa1-6 hepatoma cells with SHARPIN, HOIL-1L, or HOIP shRNA adenovirus induced apoptosis of these cells in response to tumor necrosis factor-α (TNFα) stimulation. Thus, LUBAC is essential for the survival of hepatocytes, and it is likely that reduction of LUBAC is a factor promoting hepatocyte death in addition to the direct effect of drug toxicity.

Core-binding factor beta interacts with Runx2 and is required for skeletal development.

PubMed

Yoshida, Carolina A; Furuichi, Tatsuya; Fujita, Takashi; Fukuyama, Ryo; Kanatani, Naoko; Kobayashi, Shinji; Satake, Masanobu; Takada, Kenji; Komori, Toshihisa

2002-12-01

Core-binding factor beta (CBFbeta, also called polyomavirus enhancer binding protein 2beta (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans. CBFbeta forms a heterodimer with RUNX1 (runt-related transcription factor 1), which has a DNA binding domain homologous to the pair-rule protein runt in Drosophila melanogaster. Both RUNX1 and CBFbeta are essential for hematopoiesis. Haploinsufficiency of another runt-related protein, RUNX2 (also called CBFA1), causes cleidocranial dysplasia in humans and is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation. Mice deficient in Cbfb (Cbfb(-/-)) die at midgestation, so the function of Cbfbeta in skeletal development has yet to be ascertained. To investigate this issue, we rescued hematopoiesis of Cbfb(-/-) mice by introducing Cbfb using the Gata1 promoter. The rescued Cbfb(-/-) mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation. Although mesenchymal cells differentiated into immature osteoblasts, intramembranous bones were poorly formed. The maturation of chondrocytes into hypertrophic cells was markedly delayed, and no endochondral bones were formed. Electrophoretic mobility shift assays and reporter assays showed that Cbfbeta was necessary for the efficient DNA binding of Runx2 and for Runx2-dependent transcriptional activation. These findings indicate that Cbfbeta is required for the function of Runx2 in skeletal development.

SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas

PubMed Central

Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong; Adelmant, Guillaume; Swain, Danielle; Song, Wenyu; Fox, Cameron; Francis, Joshua M.; Pedamallu, Chandra Sekhar; DeLuca, David S.; Brooks, Angela N.; Wang, Su; Que, Jianwen; Rustgi, Anil K.; Wong, Kwok-kin; Ligon, Keith L.; Liu, X. Shirley; Marto, Jarrod A.; Meyerson, Matthew; Bass, Adam J.

2014-01-01

The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology. PMID:24590290

SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas.

PubMed

Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong; Adelmant, Guillaume; Swain, Danielle; Song, Wenyu; Fox, Cameron; Francis, Joshua M; Pedamallu, Chandra Sekhar; DeLuca, David S; Brooks, Angela N; Wang, Su; Que, Jianwen; Rustgi, Anil K; Wong, Kwok-kin; Ligon, Keith L; Liu, X Shirley; Marto, Jarrod A; Meyerson, Matthew; Bass, Adam J

2014-04-01

The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.

The CpxRA two-component system contributes to Legionella pneumophila virulence.

PubMed

Tanner, Jennifer R; Li, Laam; Faucher, Sébastien P; Brassinga, Ann Karen C

2016-06-01

The bacterium Legionella pneumophila is capable of intracellular replication within freshwater protozoa as well as human macrophages, the latter of which results in the serious pneumonia Legionnaires' disease. A primary factor involved in these host cell interactions is the Dot/Icm Type IV secretion system responsible for translocating effector proteins needed to establish and maintain the bacterial replicative niche. Several regulatory factors have been identified to control the expression of the Dot/Icm system and effectors, one of which is the CpxRA two-component system, suggesting essentiality for virulence. In this study, we generated cpxR, cpxA and cpxRA in-frame null mutant strains to further delineate the role of the CpxRA system in bacterial survival and virulence. We found that cpxR is essential for intracellular replication within Acanthamoeba castellanii, but not in U937-derived macrophages. Transcriptome analysis revealed that CpxRA regulates a large number of virulence-associated proteins including Dot/Icm effectors as well as Type II secreted substrates. Furthermore, the cpxR and cpxRA mutant strains were more sodium resistant than the parental strain Lp02, and cpxRA expression reaches maximal levels during postexponential phase. Taken together, our findings suggest the CpxRA system is a key contributor to L. pneumophila virulence in protozoa via virulence factor regulation. © 2016 John Wiley & Sons Ltd.

Stress-triggered signaling affecting survival or suicide of Streptococcus pneumoniae.

PubMed

Cortes, Paulo R; Piñas, Germán E; Cian, Melina B; Yandar, Nubia; Echenique, Jose

2015-01-01

Streptococcus pneumoniae is a major human pathogen that can survive to stress conditions, such as the acidic environment of inflammatory foci, and tolerates lethal pH through a mechanism known as the acid tolerance response. We previously described that S. pneumoniae activates acidic-stress induced lysis in response to acidified environments, favoring the release of cell wall compounds, DNA and virulence factors. Here, we demonstrate that F(0)F(1)-ATPase is involved in the response to acidic stress. Chemical inhibitors (DCCD, optochin) of this proton pump repressed the ATR induction, but caused an increased ASIL. Confirming these findings, mutants of the subunit c of this enzyme showed the same phenotypes as inhibitors. Importantly, we demonstrated that F(0)F(1)-ATPase and ATR are necessary for the intracellular survival of the pneumococcus in macrophages. Alternatively, a screening of two-component system (TCS) mutants showed that ATR and survival in pneumocytes were controlled in contrasting ways by ComDE and CiaRH, which had been involved in the ASIL mechanism. Briefly, CiaRH was essential for ATR (ComE represses activation) whereas ComE was necessary for ASIL (CiaRH protects against induction). They did not regulate F0F1-ATPase expression, but control LytA expression on the pneumococcal surface. These results suggest that both TCSs and F(0)F(1)-ATPase control a stress response and decide between a survival or a suicide mechanism by independent pathways, either in vitro or in pneumocyte cultures. This biological model contributes to the current knowledge about bacterial response under stress conditions in host tissues, where pathogens need to survive in order to establish infections. Copyright © 2014 Elsevier GmbH. All rights reserved.

Effects of life-history requirements on the distribution of a threatened reptile.

PubMed

Thompson, Denise M; Ligon, Day B; Patton, Jason C; Papeş, Monica

2017-04-01

Survival and reproduction are the two primary life-history traits essential for species' persistence; however, the environmental conditions that support each of these traits may not be the same. Despite this, reproductive requirements are seldom considered when estimating species' potential distributions. We sought to examine potentially limiting environmental factors influencing the distribution of an oviparous reptile of conservation concern with respect to the species' survival and reproduction and to assess the implications of the species' predicted climatic constraints on current conservation practices. We used ecological niche modeling to predict the probability of environmental suitability for the alligator snapping turtle (Macrochelys temminckii). We built an annual climate model to examine survival and a nesting climate model to examine reproduction. We combined incubation temperature requirements, products of modeled soil temperature data, and our estimated distributions to determine whether embryonic development constrained the northern distribution of the species. Low annual precipitation constrained the western distribution of alligator snapping turtles, whereas the northern distribution was constrained by thermal requirements during embryonic development. Only a portion of the geographic range predicted to have a high probability of suitability for alligator snapping turtle survival was estimated to be capable of supporting successful embryonic development. Historic occurrence records suggest adult alligator snapping turtles can survive in regions with colder climes than those associated with consistent and successful production of offspring. Estimated egg-incubation requirements indicated that current reintroductions at the northern edge of the species' range are within reproductively viable environmental conditions. Our results highlight the importance of considering survival and reproduction when estimating species' ecological niches, implicating conservation plans, and benefits of incorporating physiological data when evaluating species' distributions. © 2016 Society for Conservation Biology.

Development of an HTS-Compatible Assay for Discovery of Melanoma-Related Microphthalmia Transcription Factor Disruptors Using AlphaScreen Technology.

PubMed

Wang, Jing; Fang, Pengfei; Chase, Peter; Tshori, Sagi; Razin, Ehud; Spicer, Timothy P; Scampavia, Louis; Hodder, Peter; Guo, Min

2017-01-01

Microphthalmia transcription factor (MITF) is a master transcription factor expressed in melanocytes, essential for melanocyte survival, differentiation, and pigment formation, and is a key oncogenic factor in melanoma initiation, migration, and treatment resistance. Although identified as an important therapeutic target for melanoma, clinical inhibitors directly targeting the MITF protein are not available. Based on the functional state of MITF, we have designed an MITF dimerization-based AlphaScreen (MIDAS) assay that sensitively and specifically mirrors the dimerization of MITF in vitro. This assay is further exploited for identification of the MITF dimer disruptor for high-throughput screening. A pilot screen against a library of 1280 pharmacologically active compounds indicates that the MIDAS assay performance exhibits exceptional results with a Z' factor of 0.81 and a signal-to-background (S/B) ratio of 3.92 while identifying initial hit compounds that yield an ability to disrupt MITF-DNA interaction. The results presented demonstrate that the MIDAS assay is ready to screen large chemical libraries in order to discover novel modulators of MITF for potential melanoma treatment.

Evaluation of related factors and the outcome in cardiac arrest resuscitation at Thammasat Emergency Department.

PubMed

Amnuaypattanapon, Kumpol; Udomsubpayakul, Umaporn

2010-12-01

In the present study, we aimed to define the factors contributing to patient survival after treatment by cardiopulmonary resuscitation (CPR) following cardiac arrest. Retrospective analysis was performed on cardiac arrest patients (n=138) who had CPR in the emergency department (ED) at Thammasat University hospital from 2007-2009. Logistic regression was used to analyze factors that related to the sustained return of spontaneous circulation (ROSC) for 20 minutes, survival until discharge, and survival up to 1 month post discharge. The sustained ROSC was 22.5%, survival to discharge 5.6%, and survival from discharge to 1 month 3.6%. Significant factors related to sustained ROSC was the location of cardiac arrest, the cause of arrest, shockable rhythm with defibrillation, the time until chest compression, and CPR duration. The factor influencing survival to discharge was chest compression performed within 15 minutes after cardiac arrest (p = 0.048). No factor however could be attributed to survivability up to 1 month following discharge. Our findings attribute six factors associated to ROSC including the location of arrest, the cause of cardiac arrest, initial cardiac rhythm, shockable rhythm with defibrillation, the time until chest compression and CPR duration. Statistically, resuscitation performed within 15 minutes of cardiac arrest increases the survivability of patients until discharge. However no factors could be related to the percentage of patients surviving up to 1 month post discharge.

Inactivation of Salmonella in Organic Soil by Cinnamaldehyde, Eugenol, Ecotrol, and Sporan

USDA-ARS?s Scientific Manuscript database

Salmonella can survive in soil for months to years; consequently, soil can be a preharvest source of contamination of produce. Elimination of Salmonella with natural products and processes such as essential oils is important to prevent infection among consumers. Essential oils have been mainly eval...

Hyperprolinemic larvae of the drosophilid fly, Chymomyza costata, survive cryopreservation in liquid nitrogen

PubMed Central

Koštál, Vladimír; Zahradníčková, Helena; Šimek, Petr

2011-01-01

The larva of the drosophilid fly, Chymomyza costata, is probably the most complex metazoan organism that can survive submergence in liquid nitrogen (-196 °C) in a fully hydrated state. We examined the associations between the physiological and biochemical parameters of differently acclimated larvae and their freeze tolerance. Entering diapause is an essential and sufficient prerequisite for attaining high levels of survival in liquid nitrogen (23% survival to adult stage), although cold acclimation further improves this capacity (62% survival). Profiling of 61 different metabolites identified proline as a prominent compound whose concentration increased from 20 to 147 mM during diapause transition and subsequent cold acclimation. This study provides direct evidence for the essential role of proline in high freeze tolerance. We increased the levels of proline in the larval tissues by feeding larvae proline-augmented diets and found that this simple treatment dramatically improved their freeze tolerance. Cell and tissue survival following exposure to liquid nitrogen was evident in proline-fed nondiapause larvae, and survival to adult stage increased from 0% to 36% in proline-fed diapause-destined larvae. A significant statistical correlation was found between the whole-body concentration of proline, either natural or artificial, and survival to the adult stage in liquid nitrogen for diapause larvae. Differential scanning calorimetry analysis suggested that high proline levels, in combination with a relatively low content of osmotically active water and freeze dehydration, increased the propensity of the remaining unfrozen water to undergo a glass-like transition (vitrification) and thus facilitated the prevention of cryoinjury. PMID:21788482

Hyperprolinemic larvae of the drosophilid fly, Chymomyza costata, survive cryopreservation in liquid nitrogen.

PubMed

Kostál, Vladimír; Zahradnícková, Helena; Šimek, Petr

2011-08-09

The larva of the drosophilid fly, Chymomyza costata, is probably the most complex metazoan organism that can survive submergence in liquid nitrogen (-196 °C) in a fully hydrated state. We examined the associations between the physiological and biochemical parameters of differently acclimated larvae and their freeze tolerance. Entering diapause is an essential and sufficient prerequisite for attaining high levels of survival in liquid nitrogen (23% survival to adult stage), although cold acclimation further improves this capacity (62% survival). Profiling of 61 different metabolites identified proline as a prominent compound whose concentration increased from 20 to 147 mM during diapause transition and subsequent cold acclimation. This study provides direct evidence for the essential role of proline in high freeze tolerance. We increased the levels of proline in the larval tissues by feeding larvae proline-augmented diets and found that this simple treatment dramatically improved their freeze tolerance. Cell and tissue survival following exposure to liquid nitrogen was evident in proline-fed nondiapause larvae, and survival to adult stage increased from 0% to 36% in proline-fed diapause-destined larvae. A significant statistical correlation was found between the whole-body concentration of proline, either natural or artificial, and survival to the adult stage in liquid nitrogen for diapause larvae. Differential scanning calorimetry analysis suggested that high proline levels, in combination with a relatively low content of osmotically active water and freeze dehydration, increased the propensity of the remaining unfrozen water to undergo a glass-like transition (vitrification) and thus facilitated the prevention of cryoinjury.

Aviation occupant survival factors: an empirical study of the SQ006 accident.

PubMed

Chang, Yu-Hern; Yang, Hui-Hua

2010-03-01

We present an empirical study of Singapore Airline (SIA) flight SQ006 to illustrate the critical factors that influence airplane occupant survivability. The Fuzzy Delphi Method was used to identify and rank the survival factors that may reduce injury and fatality in potentially survivable accidents. This is the first attempt by a group from both the public and private sectors in Taiwan to focus on cabin-safety issues related to survival factors. We designed a comprehensive survey based on our discussions with aviation safety experts. We next designed an array of important cabin-safety dimensions and then investigated and selected the critical survival factors for each dimension. Our findings reveal important cabin safety and survivability information that should provide a valuable reference for developing and evaluating aviation safety programs. We also believe that the results will be practical for designing cabin-safety education material for air travelers. Finally, the major contribution of this research is that it has identified 47 critical factors that influence accident survivability; therefore, it may encourage improvements that will promote more successful cabin-safety management. Copyright 2009 Elsevier Ltd. All rights reserved.

Asking, Giving, Receiving: Friendship as Survival Strategy among Accra's Street Children

ERIC Educational Resources Information Center

Mizen, Phillip; Ofosu-Kusi, Yaw

2010-01-01

This article considers friendship among street children in Accra. Drawing upon the findings of a three-year qualitative research project, the article argues that friendship is a neglected element of research yet cooperation, mutuality and exchange between friends are essential to street children's survival. Living within the extremities of the…

Education for Survival: An Historical Perspective

ERIC Educational Resources Information Center

Aldrich, Richard

2010-01-01

At the beginning of the twenty-first century it is essential to review the nature and aims of education, both formal and informal, in the light of the unprecedented situation in which the human race is placed, and to give priority to education for survival. This article begins by identifying that unprecedented situation. We live on an…

TAK1 modulates satellite stem cell homeostasis and skeletal muscle repair

PubMed Central

Ogura, Yuji; Hindi, Sajedah M.; Sato, Shuichi; Xiong, Guangyan; Akira, Shizuo; Kumar, Ashok

2015-01-01

Satellite cells are resident adult stem cells that are required for regeneration of skeletal muscle. However, signalling mechanisms that regulate satellite cell function are less understood. Here we demonstrate that transforming growth factor-β-activated kinase 1 (TAK1) is important in satellite stem cell homeostasis and function. Inactivation of TAK1 in satellite cells inhibits muscle regeneration in adult mice. TAK1 is essential for satellite cell proliferation and its inactivation causes precocious differentiation. Moreover, TAK1-deficient satellite cells exhibit increased oxidative stress and undergo spontaneous cell death, primarily through necroptosis. TAK1 is required for the activation of NF-κB and JNK in satellite cells. Forced activation of NF-κB improves survival and proliferation of TAK1-deficient satellite cells. Furthermore, TAK1-mediated activation of JNK is essential to prevent oxidative stress and precocious differentiation of satellite cells. Collectively, our study suggests that TAK1 is required for maintaining the pool of satellite stem cells and for regenerative myogenesis. PMID:26648529

Putative oncogene Brachyury (T) is essential to specify cell fate but dispensable for notochord progenitor proliferation and EMT.

PubMed

Zhu, Jianjian; Kwan, Kin Ming; Mackem, Susan

2016-04-05

The transcription factor Brachyury (T) gene is expressed throughout primary mesoderm (primitive streak and notochord) during early embryonic development and has been strongly implicated in the genesis of chordoma, a sarcoma of notochord cell origin. Additionally, T expression has been found in and proposed to play a role in promoting epithelial-mesenchymal transition (EMT) in various other types of human tumors. However, the role of T in normal mammalian notochord development and function is still not well-understood. We have generated an inducible knockdown model to efficiently and selectively deplete T from notochord in mouse embryos. In combination with genetic lineage tracing, we show that T function is essential for maintaining notochord cell fate and function. Progenitors adopt predominantly a neural fate in the absence of T, consistent with an origin from a common chordoneural progenitor. However, T function is dispensable for progenitor cell survival, proliferation, and EMT, which has implications for the therapeutic targeting of T in chordoma and other cancers.

Putative oncogene Brachyury (T) is essential to specify cell fate but dispensable for notochord progenitor proliferation and EMT

PubMed Central

Zhu, Jianjian; Kwan, Kin Ming; Mackem, Susan

2016-01-01

The transcription factor Brachyury (T) gene is expressed throughout primary mesoderm (primitive streak and notochord) during early embryonic development and has been strongly implicated in the genesis of chordoma, a sarcoma of notochord cell origin. Additionally, T expression has been found in and proposed to play a role in promoting epithelial–mesenchymal transition (EMT) in various other types of human tumors. However, the role of T in normal mammalian notochord development and function is still not well-understood. We have generated an inducible knockdown model to efficiently and selectively deplete T from notochord in mouse embryos. In combination with genetic lineage tracing, we show that T function is essential for maintaining notochord cell fate and function. Progenitors adopt predominantly a neural fate in the absence of T, consistent with an origin from a common chordoneural progenitor. However, T function is dispensable for progenitor cell survival, proliferation, and EMT, which has implications for the therapeutic targeting of T in chordoma and other cancers. PMID:27006501

[Sudden cardiac death out of the hospital and early defibrillation].

PubMed

Marín-Huerta, E; Peinado, R; Asso, A; Loma, A; Villacastín, J P; Muñiz, J; Brugada, J

2000-06-01

Since most sudden cardiac death victims show neither symptoms before the event nor other signs or risk factors that would have identified them as a high risk population before their cardiac arrest, emergency out-of-hospital medical services must be improved in order to obtain a higher survival in these patients. Early defibrillation is an essential part of the chain of survival that also includes the early identification of the victim, activation of the emergency medical system, immediate arrival of trained personnel who can perform basic cardiopulmonary resuscitation and early initiation of advanced cardiac life support that would raise the survival rate for sudden cardiac arrest victims. Many studies have demonstrated the enormous importance of early defibrillation in patients with a cardiac arrest due to ventricular fibrillation. The most important predictor of survival in these individuals is the time that elapses until electric defibrillation, the longer the time to defbrillation the lower the number of patients who are eventually discharged. Multiple studies have demonstrated that automatic external defibrillation will reduce the time elapsed to defibrillation and thus improve survival. For these reason, public access defibrillation to allow the use of automatic external defibrillators by minimally trained members of the lay public, has received increasing interest on the part of a groving number of companies, cities or countries. The automatic external defibrillaton, as performed by a lay person is being investigated. The liberalization of its application, if is demonstrated to be effective, will need to be accompanied by legal measures to endorse it and appropriate health education, probably during secondary education.

Density-dependent intraspecific aggression regulates survival in northern Yellowstone wolves (Canis lupus).

PubMed

Cubaynes, Sarah; MacNulty, Daniel R; Stahler, Daniel R; Quimby, Kira A; Smith, Douglas W; Coulson, Tim

2014-11-01

Understanding the population dynamics of top-predators is essential to assess their impact on ecosystems and to guide their management. Key to this understanding is identifying the mechanisms regulating vital rates. Determining the influence of density on survival is necessary to understand the extent to which human-caused mortality is compensatory or additive. In wolves (Canis lupus), empirical evidence for density-dependent survival is lacking. Dispersal is considered the principal way in which wolves adjust their numbers to prey supply or compensate for human exploitation. However, studies to date have primarily focused on exploited wolf populations, in which density-dependent mechanisms are likely weak due to artificially low wolf densities. Using 13 years of data on 280 collared wolves in Yellowstone National Park, we assessed the effect of wolf density, prey abundance and population structure, as well as winter severity, on age-specific survival in two areas (prey-rich vs. prey-poor) of the national park. We further analysed cause-specific mortality and explored the factors driving intraspecific aggression in the prey-rich northern area of the park. Overall, survival rates decreased during the study. In northern Yellowstone, density dependence regulated adult survival through an increase in intraspecific aggression, independent of prey availability. In the interior of the park, adult survival was less variable and density-independent, despite reduced prey availability. There was no effect of prey population structure in northern Yellowstone, or of winter severity in either area. Survival was similar among yearlings and adults, but lower for adults older than 6 years. Our results indicate that density-dependent intraspecific aggression is a major driver of adult wolf survival in northern Yellowstone, suggesting intrinsic density-dependent mechanisms have the potential to regulate wolf populations at high ungulate densities. When low prey availability or high removal rates maintain wolves at lower densities, limited inter-pack interactions may prevent density-dependent survival, consistent with our findings in the interior of the park. © 2014 The Authors. Journal of Animal Ecology © 2014 British Ecological Society.

Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality

PubMed Central

McIntyre, Alan; Harris, Adrian L

2015-01-01

Anti-angiogenic therapy has increased the progression-free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6–8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table1). Many mechanisms of resistance to anti-VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti-angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia-inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre-clinical studies combining anti-angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti-angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre-clinical and clinical studies that have potential for producing synthetic lethality in combination with anti-angiogenic therapy as a future therapeutic strategy. PMID:25700172

Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo.

PubMed

Colvin, Stephanie C; Malik, Raleigh E; Showalter, Aaron D; Sloop, Kyle W; Rhodes, Simon J

2011-01-04

The etiology of most pediatric hormone deficiency diseases is poorly understood. Children with combined pituitary hormone deficiency (CPHD) have insufficient levels of multiple anterior pituitary hormones causing short stature, metabolic disease, pubertal failure, and often have associated nervous system symptoms. Mutations in developmental regulatory genes required for the specification of the hormone-secreting cell types of the pituitary gland underlie severe forms of CPHD. To better understand these diseases, we have created a unique mouse model of CPHD with a targeted knockin mutation (Lhx3 W227ter), which is a model for the human LHX3 W224ter disease. The LHX3 gene encodes a LIM-homeodomain transcription factor, which has essential roles in pituitary and nervous system development in mammals. The introduced premature termination codon results in deletion of the carboxyl terminal region of the LHX3 protein, which is critical for pituitary gene activation. Mice that lack all LHX3 function do not survive beyond birth. By contrast, the homozygous Lhx3 W227ter mice survive, but display marked dwarfism, thyroid disease, and female infertility. Importantly, the Lhx3 W227ter mice have no apparent nervous system deficits. The Lhx3 W227ter mouse model provides a unique array of hormone deficits and facilitates experimental approaches that are not feasible with human patients. These experiments demonstrate that the carboxyl terminus of the LHX3 transcription factor is not required for viability. More broadly, this study reveals that the in vivo actions of a transcription factor in different tissues are molecularly separable.

SRF selectively controls tip cell invasive behavior in angiogenesis.

PubMed

Franco, Claudio A; Blanc, Jocelyne; Parlakian, Ara; Blanco, Raquel; Aspalter, Irene M; Kazakova, Natalia; Diguet, Nicolas; Mylonas, Elena; Gao-Li, Jacqueline; Vaahtokari, Anne; Penard-Lacronique, Virgine; Fruttiger, Markus; Rosewell, Ian; Mericskay, Mathias; Gerhardt, Holger; Li, Zhenlin

2013-06-01

Efficient angiogenic sprouting is essential for embryonic, postnatal and tumor development. Serum response factor (SRF) is known to be important for embryonic vascular development. Here, we studied the effect of inducible endothelial-specific deletion of Srf in postnatal and adult mice. We find that endothelial SRF activity is vital for postnatal growth and survival, and is equally required for developmental and pathological angiogenesis, including during tumor growth. Our results demonstrate that SRF is selectively required for endothelial filopodia formation and cell contractility during sprouting angiogenesis, but seems dispensable for vascular remodeling. At the molecular level, we observe that vascular endothelial growth factor A induces nuclear accumulation of myocardin-related transcription factors (MRTFs) and regulates MRTF/SRF-dependent target genes including Myl9, which is important for endothelial cell migration in vitro. We conclude that SRF has a unique function in regulating migratory tip cell behavior during sprouting angiogenesis. We hypothesize that targeting the SRF pathway could provide an opportunity to selectively target tip cell filopodia-driven angiogenesis to restrict tumor growth.

Wound Healing Problems in the Mouth

PubMed Central

Politis, Constantinus; Schoenaers, Joseph; Jacobs, Reinhilde; Agbaje, Jimoh O.

2016-01-01

Wound healing is a primary survival mechanism that is largely taken for granted. The literature includes relatively little information about disturbed wound healing, and there is no acceptable classification describing wound healing process in the oral region. Wound healing comprises a sequence of complex biological processes. All tissues follow an essentially identical pattern to complete the healing process with minimal scar formation. The oral cavity is a remarkable environment in which wound healing occurs in warm oral fluid containing millions of microorganisms. The present review provides a basic overview of the wound healing process and with a discussion of the local and general factors that play roles in achieving efficient would healing. Results of oral cavity wound healing can vary from a clinically healed wound without scar formation and with histologically normal connective tissue under epithelial cells to extreme forms of trismus caused by fibrosis. Many local and general factors affect oral wound healing, and an improved understanding of these factors will help to address issues that lead to poor oral wound healing. PMID:27853435

BMP Signaling in Astrocytes Downregulates EGFR to Modulate Survival and Maturation

PubMed Central

Scholze, Anja R.; Foo, Lynette C.; Mulinyawe, Sara; Barres, Ben A.

2014-01-01

Astrocytes constitute a major cell population in the brain with a myriad of essential functions, yet we know remarkably little about the signaling pathways and mechanisms that direct astrocyte maturation. To explore the signals regulating astrocyte development, we prospectively purified and cultured immature postnatal rodent astrocytes. We identified fibroblast growth factors (FGFs) and bone morphogenetic proteins (BMPs) as robust trophic factors for immature astrocytes. We showed that astrocytes respond directly to BMPs via phosphorylation of the smad1/5/8 pathway. In vitro, BMP signaling promoted immature astrocytes to adopt multiple characteristics of mature astrocytes, including a more process-bearing morphology, aquaporin-4 (AQP4) and S100β immunoreactivity, limited proliferation, and strong downregulation of epidermal growth factor receptor (EGFR). In vivo, activation of the smad1/5/8 pathway in astrocytes was seen during early postnatal development, but inhibition of astrocyte proliferation was not observed. These insights can aid in the further dissection of the mechanisms and pathways controlling astrocyte biology and development. PMID:25330173

From Molecular to Nanotechnology Strategies for Delivery of Neurotrophins: Emphasis on Brain-Derived Neurotrophic Factor (BDNF)

PubMed Central

Géral, Claire; Angelova, Angelina; Lesieur, Sylviane

2013-01-01

Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the mammalian central nervous system (CNS). Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted. PMID:24300402

Selenium as an Essential Micronutrient: Roles in Cell Cycle and Apoptosis

USDA-ARS?s Scientific Manuscript database

Selenium (Se) is an anticancer nutrient, and the essential role of Se in growth of most mammalian cells is well recognized but certain cancer cells appear to have acquired a survival advantage under conditions of Se-deficiency. The objective of the present study is to understand the molecular basis ...

On an algorithmic definition for the components of the minimal cell.

PubMed

Martínez, Octavio; Reyes-Valdés, M Humberto

2018-01-01

Living cells are highly complex systems comprising a multitude of elements that are engaged in the many convoluted processes observed during the cell cycle. However, not all elements and processes are essential for cell survival and reproduction under steady-state environmental conditions. To distinguish between essential from expendable cell components and thus define the 'minimal cell' and the corresponding 'minimal genome', we postulate that the synthesis of all cell elements can be represented as a finite set of binary operators, and within this framework we show that cell elements that depend on their previous existence to be synthesized are those that are essential for cell survival. An algorithm to distinguish essential cell elements is presented and demonstrated within an interactome. Data and functions implementing the algorithm are given as supporting information. We expect that this algorithmic approach will lead to the determination of the complete interactome of the minimal cell, which could then be experimentally validated. The assumptions behind this hypothesis as well as its consequences for experimental and theoretical biology are discussed.

Insufficiency of pro-heparin-binding epidermal growth factor-like growth factor shedding enhances hypoxic cell death in H9c2 cardiomyoblasts via the activation of caspase-3 and c-Jun N-terminal kinase.

PubMed

Uetani, Teruyoshi; Nakayama, Hironao; Okayama, Hideki; Okura, Takafumi; Higaki, Jitsuo; Inoue, Hirofumi; Higashiyama, Shigeki

2009-05-01

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a cardiogenic and cardiohypertrophic growth factor. ProHB-EGF, a product of the Hb-egf gene and the precursor of HB-EGF, is anchored to the plasma membrane. Its ectodomain region is shed by a disintegrin and metalloproteases (ADAMs) when activated by various stimulations. It has been reported that an uncleavable mutant of Hb-egf, uc-Hb-egf, produces uc-proHB-EGF, which is not cleaved by ADAMs and causes dilation of the heart in knock-in mice. This suggests that the shedding of proHB-EGF is essential for the development and survival of cardiomyocytes: however, the molecular mechanism involved has remained unclear. In this study, we investigated the relationship between uc-proHB-EGF expression and cardiomyocyte survival. Human uc-proHB-EGF was adenovirally introduced into the rat cardiomyoblast cell line H9c2, and the cells were cultured under normoxic and hypoxic conditions. Uc-proHB-EGF-expressing H9c2 cells underwent apoptosis under normoxic conditions, which distinctly increased under hypoxic conditions. Furthermore, we observed an increased Caspase-3 activity, reactive oxygen species accumulation, and an increased c-Jun N-terminal kinase (JNK) activity in the uc-proHB-EGF-expressing H9c2 cells. Treatment of the uc-proHB-EGF transfectants with inhibitors of Caspase-3, reactive oxygen species, and JNK, namely, Z-VAD-fmk, N-acetylcysteine, and SP600125, respectively, significantly reduced hypoxic cell death. These data indicate that insufficiency of proHB-EGF shedding under hypoxic stress leads to cardiomyocyte apoptosis via Caspase-3- and JNK-dependent pathways.

The Essential Role of the Deinococcus radiodurans ssb Gene in Cell Survival and Radiation Tolerance

PubMed Central

Lockhart, J. Scott; DeVeaux, Linda C.

2013-01-01

Recent evidence has implicated single-stranded DNA-binding protein (SSB) expression level as an important factor in microbial radiation resistance. The genome of the extremely radiation resistant bacterium Deinococcus radiodurans contains genes for two SSB homologs: the homodimeric, canonical Ssb, encoded by the gene ssb, and a novel pentameric protein encoded by the gene ddrB. ddrB is highly induced upon exposure to radiation, and deletions result in decreased radiation-resistance, suggesting an integral role of the protein in the extreme resistance exhibited by this organism. Although expression of ssb is also induced after irradiation, Ssb is thought to be involved primarily in replication. In this study, we demonstrate that Ssb in D. radiodurans is essential for cell survival. The lethality of an ssb deletion cannot be complemented by providing ddrB in trans. In addition, the radiation-sensitive phenotype conferred by a ddrB deletion is not alleviated by providing ssb in trans. By altering expression of the ssb gene, we also show that lower levels of transcription are required for optimal growth than are necessary for high radiation resistance. When expression is reduced to that of E. coli, ionizing radiation resistance is similarly reduced. UV resistance is also decreased under low ssb transcript levels where growth is unimpaired. These results indicate that the expression of ssb is a key component of both normal cellular metabolism as well as pathways responsible for the high radiation tolerance of D. radiodurans. PMID:23951213

Prognostic factors for survival after salvage total laryngectomy following radiotherapy or chemoradiation failure: a 10-year retrospective longitudinal study in eastern Denmark.

PubMed

Wulff, N B; Andersen, E; Kristensen, C A; Sørensen, C H; Charabi, B; Homøe, P

2017-04-01

The primary aims were to determine the rates of and prognostic factors for overall survival, disease-specific survival and disease-free survival following salvage total laryngectomy. Retrospective longitudinal study. Tertiary medical centres. A total of 142 patients in eastern Denmark undergoing salvage total laryngectomy for squamous cell carcinoma of the larynx or hypopharynx. 5-year overall survival, 5-year disease-specific survival, 5-year disease-free survival and prognostic factors for these outcomes. 5-year overall survival, disease-specific survival and disease-free survival were 37.7%, 54.9% and 55.3%, respectively. N classification at primary diagnosis, lymph node excision and postoperative complications within 1 year after salvage total laryngectomy were prognostic factors for shorter overall survival, disease-specific survival and disease-free survival. Residual tumour/recurrence was negatively associated with overall survival, close or involved resection margins with disease-specific survival, and second primary cancer was associated with longer disease-specific survival and disease-free survival. Nine per cent of all patients had residual tumour and 33.8% developed a recurrence. Our overall survival, disease-specific survival and disease-free survival findings are in accordance with previous studies. With the purpose of identifying recurrent tumour, we suggest extra attention being given to patients with higher N classification and need for lymph node excision during salvage total laryngectomy along with use of frozen sections. The high number of patients with recurrence within 1 year after salvage total laryngectomy occurred although thorough and regular follow-up visits were performed. © 2016 John Wiley & Sons Ltd.

A comparative study of mixture cure models with covariate

NASA Astrophysics Data System (ADS)

Leng, Oh Yit; Khalid, Zarina Mohd

2017-05-01

In survival analysis, the survival time is assumed to follow a non-negative distribution, such as the exponential, Weibull, and log-normal distributions. In some cases, the survival time is influenced by some observed factors. The absence of these observed factors may cause an inaccurate estimation in the survival function. Therefore, a survival model which incorporates the influences of observed factors is more appropriate to be used in such cases. These observed factors are included in the survival model as covariates. Besides that, there are cases where a group of individuals who are cured, that is, not experiencing the event of interest. Ignoring the cure fraction may lead to overestimate in estimating the survival function. Thus, a mixture cure model is more suitable to be employed in modelling survival data with the presence of a cure fraction. In this study, three mixture cure survival models are used to analyse survival data with a covariate and a cure fraction. The first model includes covariate in the parameterization of the susceptible individuals survival function, the second model allows the cure fraction to depend on covariate, and the third model incorporates covariate in both cure fraction and survival function of susceptible individuals. This study aims to compare the performance of these models via a simulation approach. Therefore, in this study, survival data with varying sample sizes and cure fractions are simulated and the survival time is assumed to follow the Weibull distribution. The simulated data are then modelled using the three mixture cure survival models. The results show that the three mixture cure models are more appropriate to be used in modelling survival data with the presence of cure fraction and an observed factor.

HIF-1 and SKN-1 coordinate the transcriptional response to hydrogen sulfide in Caenorhabditis elegans.

PubMed

Miller, Dana L; Budde, Mark W; Roth, Mark B

2011-01-01

Hydrogen sulfide (H₂S) has dramatic physiological effects on animals that are associated with improved survival. C. elegans grown in H₂S are long-lived and thermotolerant. To identify mechanisms by which adaptation to H₂S effects physiological functions, we have measured transcriptional responses to H₂S exposure. Using microarray analysis we observe rapid changes in the abundance of specific mRNAs. The number and magnitude of transcriptional changes increased with the duration of H₂S exposure. Functional annotation suggests that genes associated with protein homeostasis are upregulated upon prolonged exposure to H₂S. Previous work has shown that the hypoxia-inducible transcription factor, HIF-1, is required for survival in H₂S. In fact, we show that hif-1 is required for most, if not all, early transcriptional changes in H₂S. Moreover, our data demonstrate that SKN-1, the C. elegans homologue of NRF2, also contributes to H₂S-dependent changes in transcription. We show that these results are functionally important, as skn-1 is essential to survive exposure to H₂S. Our results suggest a model in which HIF-1 and SKN-1 coordinate a broad transcriptional response to H₂S that culminates in a global reorganization of protein homeostasis networks.

Native kidney function following liver transplantation using calcineurin inhibitors: single-center analysis with 20 years of follow-up.

PubMed

LaMattina, John C; Mezrich, Joshua D; Fernandez, Luis A; D'Alessandro, Anthony M; Djamali, Arjang; Musat, Alexandru I; Pirsch, John D; Foley, David P

2013-01-01

The incidence of chronic kidney disease (CKD) in liver transplant recipients has been estimated to be from 18% to 28% at 10 yr after transplantation. As outcomes from liver transplantation continue to improve, long-term native kidney function in these recipients becomes more critical to patient survival. We analyzed 1151 adult, deceased-donor, single-organ primary liver transplantations performed at our center between 7/17/84 and 12/31/07. Analysis of renal function was performed on 972 patients with liver allograft survival >1 yr. Kaplan-Meier analysis revealed that 3%, 7%, and 18% of liver transplant recipients with allograft survival >1 yr developed end-stage renal disease (ESRD) at five, 10, and 20 yr, respectively. Significant independent risk factors for ESRD included dialysis during the transplant hospitalization, the stage of CKD at one yr, hypercholesterolemia, non-Caucasian race, and hepatitis C as the primary indication for liver transplantation. The initial immunosuppression of essentially all recipients was a calcineurin inhibitor-based regimen. Close, long-term follow-up of liver transplant recipients permits optimal management of liver allograft and native renal function and can lead to excellent long-term outcomes despite a calcineurin inhibitor-based immunosuppressive regimen. © 2013 John Wiley & Sons A/S.

Serum and glucocorticoid-regulated kinase 1 regulates neutrophil clearance during inflammation resolution.

PubMed

Burgon, Joseph; Robertson, Anne L; Sadiku, Pranvera; Wang, Xingang; Hooper-Greenhill, Edward; Prince, Lynne R; Walker, Paul; Hoggett, Emily E; Ward, Jonathan R; Farrow, Stuart N; Zuercher, William J; Jeffrey, Philip; Savage, Caroline O; Ingham, Philip W; Hurlstone, Adam F; Whyte, Moira K B; Renshaw, Stephen A

2014-02-15

The inflammatory response is integral to maintaining health by functioning to resist microbial infection and repair tissue damage. Large numbers of neutrophils are recruited to inflammatory sites to neutralize invading bacteria through phagocytosis and the release of proteases and reactive oxygen species into the extracellular environment. Removal of the original inflammatory stimulus must be accompanied by resolution of the inflammatory response, including neutrophil clearance, to prevent inadvertent tissue damage. Neutrophil apoptosis and its temporary inhibition by survival signals provides a target for anti-inflammatory therapeutics, making it essential to better understand this process. GM-CSF, a neutrophil survival factor, causes a significant increase in mRNA levels for the known anti-apoptotic protein serum and glucocorticoid-regulated kinase 1 (SGK1). We have characterized the expression patterns and regulation of SGK family members in human neutrophils and shown that inhibition of SGK activity completely abrogates the antiapoptotic effect of GM-CSF. Using a transgenic zebrafish model, we have disrupted sgk1 gene function and shown this specifically delays inflammation resolution, without altering neutrophil recruitment to inflammatory sites in vivo. These data suggest SGK1 plays a key role in regulating neutrophil survival signaling and thus may prove a valuable therapeutic target for the treatment of inflammatory disease.

Serum and Glucocorticoid Regulated Kinase 1 (SGK1) Regulates Neutrophil Clearance During Inflammation Resolution

PubMed Central

Burgon, Joseph; Robertson, Anne L.; Sadiku, Pranvera; Wang, Xingang; Hooper-Greenhill, Edward; Prince, Lynne R.; Walker, Paul; Hoggett, Emily E.; Ward, Jonathan R.; Farrow, Stuart N.; Zuercher, William J.; Jeffrey, Philip; Savage, Caroline O.; Ingham, Philip W.; Hurlstone, Adam F.; Whyte, Moira K. B.; Renshaw, Stephen A.

2013-01-01

The inflammatory response is integral to maintaining health, by functioning to resist microbial infection and repair tissue damage. Large numbers of neutrophils are recruited to inflammatory sites to neutralise invading bacteria through phagocytosis and the release of proteases and reactive oxygen species into the extracellular environment. Removal of the original inflammatory stimulus must be accompanied by resolution of the inflammatory response, including neutrophil clearance, to prevent inadvertent tissue damage. Neutrophil apoptosis and its temporary inhibition by survival signals provides a target for anti-inflammatory therapeutics, making it essential to better understand this process. GM-CSF, a neutrophil survival factor, causes a significant increase in mRNA levels for the known anti-apoptotic protein Serum and Glucocorticoid Regulated Kinase 1 (SGK1). We have characterised the expression patterns and regulation of SGK family members in human neutrophils, and shown that inhibition of SGK activity completely abrogates the anti-apoptotic effect of GM-CSF. Using a transgenic zebrafish model, we have disrupted sgk1 gene function and shown this specifically delays inflammation resolution, without altering neutrophil recruitment to inflammatory sites in vivo. These data suggest SGK1 plays a key role in regulating neutrophil survival signalling, and thus may prove a valuable therapeutic target for the treatment of inflammatory disease. PMID:24431232

When to care for, abandon, or eat your offspring: the evolution of parental care and filial cannibalism.

PubMed

Klug, Hope; Bonsall, Michael B

2007-12-01

Parental care and filial cannibalism (the consumption of one's own offspring) co-occur in many animals. While parental care typically increases offspring survival, filial cannibalism involves the killing of one's young. Using an evolutionary ecology approach, we evaluate the importance of a range of factors on the evolution of parental care and filial cannibalism. Parental care, no care/total abandonment, and filial cannibalism evolved and often coexisted over a range of parameter space. While no single benefit was essential for the evolution of filial cannibalism, benefits associated with adult or offspring survival and/or reproduction facilitated the evolution of cannibalism. Our model highlights the plausibility of a range of alternative hypotheses. Specifically, the evolution of filial cannibalism was enhanced if (1) parents could selectively cannibalize lower-quality offspring, (2) filial cannibalism increased egg maturation rate, (3) energetic benefits of eggs existed, or (4) cannibalism increased a parent's reproductive rate (e.g., through mate attractiveness). Density-dependent egg survivorship alone did not favor the evolution of cannibalism. However, when egg survival was density dependent, filial cannibalism invaded more often when the density dependence was relatively more intense. Our results suggest that population-level resource competition potentially plays an important role in the evolution of both parental care and filial cannibalism.

Essential role for cyclic-AMP responsive element binding protein 1 (CREB) in the survival of acute lymphoblastic leukemia.

PubMed

van der Sligte, Naomi E; Kampen, Kim R; ter Elst, Arja; Scherpen, Frank J G; Meeuwsen-de Boer, Tiny G J; Guryev, Victor; van Leeuwen, Frank N; Kornblau, Steven M; de Bont, Eveline S J M

2015-06-20

Acute lymphoblastic leukemia (ALL) relapse remains a leading cause of cancer related death in children, therefore, new therapeutic options are needed. Recently, we showed that a peptide derived from Cyclic-AMP Responsive Element Binding Protein (CREB) was highly phosphorylated in pediatric leukemias. In this study, we determined CREB phosphorylation and mRNA levels showing that CREB expression was significantly higher in ALL compared to normal bone marrow (phosphorylation: P < 0.0001, mRNA: P = 0.004). High CREB and phospho-CREB expression was correlated with a lower median overall survival in a cohort of 140 adult ALL patients. ShRNA mediated knockdown of CREB in ALL cell lines blocked leukemic cell growth by inducing cell cycle arrest and apoptosis. Gene expression array analysis showed downregulation of CREB target genes regulating cell proliferation and glucose metabolism and upregulation of apoptosis inducing genes. Similar to CREB knockdown, the CREB inhibitor KG-501 decreased leukemic cell viability and induced apoptosis in ALL cell lines, as well as primary T-ALL samples, with cases showing high phospho-CREB levels being more sensitive than those with lower phospho-CREB levels. Together, these in vitro findings support an important role for CREB in the survival of ALL cells and identify this transcription factor as a potential target for treatment.

Mastic oil from Pistacia lentiscus var. chia inhibits growth and survival of human K562 leukemia cells and attenuates angiogenesis.

PubMed

Loutrari, Heleni; Magkouta, Sophia; Pyriochou, Anastasia; Koika, Vasiliki; Kolisis, Fragiskos N; Papapetropoulos, Andreas; Roussos, Charis

2006-01-01

Mastic oil from Pistacia lentiscus var. chia, a natural plant extract traditionally used as a food additive, has been extensively studied for its antimicrobial activity attributed to the combination of its bioactive components. One of them, perillyl alcohol (POH), displays tumor chemopreventive, chemotherapeutic, and antiangiogenic properties. We investigated whether mastic oil would also suppress tumor cell growth and angiogenesis. We observed that mastic oil concentration and time dependently exerted an antiproliferative and proapoptotic effect on K562 human leukemia cells and inhibited the release of vascular endothelial growth factor (VEGF) from K562 and B16 mouse melanoma cells. Moreover, mastic oil caused a concentration-dependent inhibition of endothelial cell (EC) proliferation without affecting cell survival and a significant decrease of microvessel formation both in vitro and in vivo. Investigation of underlying mechanism(s) demonstrated that mastic oil reduced 1) in K562 cells the activation of extracellular signal-regulated kinases 1/2 (Erk1/2) known to control leukemia cell proliferation, survival, and VEGF secretion and 2) in EC the activation of RhoA, an essential regulator of neovessel organization. Overall, our results underscore that mastic oil, through its multiple effects on malignant cells and ECs, may be a useful natural dietary supplement for cancer prevention.

Renormalization of Coulomb interactions in s-wave superconductor NaxCoO2

NASA Astrophysics Data System (ADS)

Yada, Keiji; Kontani, Hiroshi

2007-03-01

We study the renormalized Coulomb interactions due to retardation effect in NaxCoO2. Although the Morel Anderson's pseudo-potential for a1g orbital μa1g* is relatively large because the direct Coulomb repulsion U is large, that for interband transition between a1g and eg' orbitals μa1g,eg'* is very small since the renormalization factor for pair hopping J is square of that for U. Therefore, the s-wave superconductivity due to valence-band Suhl-Kondo mechanism will survive against strong Coulomb interactions. The interband hopping of Cooper pairs due to shear phonons is essential to understand the superconductivity in NaxCoO2.

Accurate and reproducible measurements of RhoA activation in small samples of primary cells.

PubMed

Nini, Lylia; Dagnino, Lina

2010-03-01

Rho GTPase activation is essential in a wide variety of cellular processes. Measurement of Rho GTPase activation is difficult with limited material, such as tissues or primary cells that exhibit stringent culture requirements for growth and survival. We defined parameters to accurately and reproducibly measure RhoA activation (i.e., RhoA-GTP) in cultured primary keratinocytes in response to serum and growth factor stimulation using enzyme-linked immunosorbent assay (ELISA)-based G-LISA assays. We also established conditions that minimize RhoA-GTP in unstimulated cells without affecting viability, allowing accurate measurements of RhoA activation on stimulation or induction of exogenous GTPase expression. Copyright 2009 Elsevier Inc. All rights reserved.

Iron and cancer: more ore to be mined

PubMed Central

Torti, Suzy V.; Torti, Frank M.

2014-01-01

Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy. PMID:23594855

Fallowing for Cottonwood Plantations: Benefits Carry to Rotation's End

Treesearch

John K. Francis

1982-01-01

Johnson grass and other weeds are so prolific in old fields on the Mississippi Delta that frequent cultivation is necessary during the first season to obtain acceptable survival of planted cottonwood. A number of site preparation treatments were tested as a means of increasing early survival and growth. Fallowing, essentially five diskings the summer before planting,...

Membrane stability of winter wheat plants exposed to subzero temperatures for variable lengths of time

USDA-ARS?s Scientific Manuscript database

The ability to survive episodes of subfreezing temperature is essential to winter wheat. Fully cold-acclimated plants of six lines of winter wheat were exposed to -12, -14, -16 or -18° C, four 1-5 hours. Electrolyte leakage and plant survival were used to assess damage to the plants. Plants exposed ...

Role of Nurr1 in the Generation and Differentiation of Dopaminergic Neurons from Stem Cells.

PubMed

Rodríguez-Traver, Eva; Solís, Oscar; Díaz-Guerra, Eva; Ortiz, Óscar; Vergaño-Vera, Eva; Méndez-Gómez, Héctor R; García-Sanz, Patricia; Moratalla, Rosario; Vicario-Abejón, Carlos

2016-07-01

NURR1 is an essential transcription factor for the differentiation, maturation, and maintenance of midbrain dopaminergic neurons (DA neurons) as it has been demonstrated using knock-out mice. DA neurons of the substantia nigra pars compacta degenerate in Parkinson's disease (PD) and mutations in the Nurr1 gene have been associated with this human disease. Thus, the study of NURR1 actions in vivo is fundamental to understand the mechanisms of neuron generation and degeneration in the dopaminergic system. Here, we present and discuss findings indicating that NURR1 is a valuable molecular tool for the in vitro generation of DA neurons which could be used for modeling and studying PD in cell culture and in transplantation approaches. Transduction of Nurr1 alone or in combination with other transcription factors such as Foxa2, Ngn2, Ascl1, and Pitx3, induces the generation of DA neurons, which upon transplantation have the capacity to survive and restore motor behavior in animal models of PD. We show that the survival of transplanted neurons is increased when the Nurr1-transduced olfactory bulb stem cells are treated with GDNF. The use of these and other factors with the induced pluripotent stem cell (iPSC)-based technology or the direct reprogramming of astrocytes or fibroblasts into human DA neurons has produced encouraging results for the study of the cellular and molecular mechanisms of neurodegeneration in PD and for the search of new treatments for this disease.

Role of BAFF and APRIL in human B-cell chronic lymphocytic leukaemia

PubMed Central

Haiat, Stéphanie; Billard, Christian; Quiney, Claire; Ajchenbaum-Cymbalista, Florence; Kolb, Jean-Pierre

2006-01-01

B-cell chronic lymphocytic leukaemia (B-CLL) is the most prevalent leukaemia in Western countries and is characterized by the gradual accumulation in patients of small mature B cells. Since the vast majority of tumoral cells are quiescent, the accumulation mostly results from deficient apoptosis rather than from acute proliferation. Although the phenomenon is relevant in vivo, B-CLL cells die rapidly in vitro as a consequence of apoptosis, suggesting a lack of essential growth factors in the culture medium. Indeed, the rate of B-CLL cell death in vitro is modulated by different cytokines, some favouring the apoptotic process, others counteracting it. Two related members of the tumour necrosis factor family, BAFF (B-cell activating factor of the TNF family) and APRIL (a proliferation-inducing ligand), already known for their crucial role in normal B-cell survival, differentiation and apoptosis, were recently shown to be expressed by B-CLL cells. These molecules are able to protect the leukaemic cells against spontaneous and drug-induced apoptosis via autocrine and/or paracrine pathways. This review will focus on the role of BAFF and APRIL in the survival of tumoral cells. It will discuss the expression of these molecules by B-CLL cells, their regulation, transduction pathways and their effects on leukaemic cells. The design of reagents able to counteract the effects of these molecules seems to be a new promising therapeutic approach for B-CLL and is already currently developed in the treatment of autoimmune diseases. PMID:16827889

Dual Delivery of bFGF- and NGF-Binding Coacervate Confers Neuroprotection by Promoting Neuronal Proliferation.

PubMed

Wu, Yanqing; Wang, Zhouguang; Cai, Pingtao; Jiang, Ting; Li, Yiyang; Yuan, Yuan; Li, Rui; Khor, Sinan; Lu, Yingfeng; Wang, Jian; Chen, Daqing; Zeng, Qiqiang; Zhong, Ruisheng; Zhang, Hongyu; Lin, Yuan; Li, Xiaokun; Xiao, Jian

2018-06-12

Basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) are essential for proper development, survival, growth, and maintenance of neurons in the central and peripheral nervous systems. However, because bFGF and NGF have short half-life and rapid diffusion rate, they have limited clinical efficacy. Thus, there is an urgent need to develop an effective delivery system to protect bFGF and NGF from proteolysis while maintaining their normal bioactivities. To more efficiently deliver bFGF and NGF, we used a coacervate (synthesized with heparin and a biodegradable polycation at mass ratio of 500: 100). The maximal package loads of GFs in coacervate were determined by Western Blotting; release efficiency of bFGF and NGF was measured by ELISA. Additionally, we evaluated the effect of bFGF and NGF on the viability, survival, and proliferation of neurons by MTT assay, BrdU cell proliferation, and calcein staining. Our coacervate incorporated bFGF and NGF and continuously released them for at least three weeks. This enhanced the growth and proliferation of PC12 cells and SH-SY5Y cells. Moreover, co-delivery of bFGF and NGF using coacervate was more neuroprotective than free application of both factors or coacervate delivery of each GF separately. Dual delivery of bFGF and NGF binding coacervate was neuroprotective via stimulating the growth and proliferation of neurons. © 2018 The Author(s). Published by S. Karger AG, Basel.

An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma.

PubMed

Lollies, A; Hartmann, S; Schneider, M; Bracht, T; Weiß, A L; Arnolds, J; Klein-Hitpass, L; Sitek, B; Hansmann, M-L; Küppers, R; Weniger, M A

2018-01-01

Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30 + lymphomas, namely cHL (21/30) and primary mediastinal B-cell lymphoma (8/9), but also CD30 + diffuse large B-cell lymphoma (15/20) frequently express BATF3 protein. Mass spectrometry and co-immunoprecipitation established interactions of BATF3 with JUN and JUNB in cHL and ALCL lines. BATF3 knockdown using short hairpin RNAs was toxic for cHL and ALCL lines, reducing their proliferation and survival. We identified MYC as a critical BATF3 target and confirmed binding of BATF3 to the MYC promoter. JAK/STAT signaling regulated BATF3 expression, as chemical JAK2 inhibition reduced and interleukin 13 stimulation induced BATF3 expression in cHL lines. Chromatin immunoprecipitation substantiated a direct regulation of BATF3 by STAT proteins in cHL and ALCL lines. In conclusion, we identified STAT-mediated BATF3 expression that is essential for lymphoma cell survival and promoted MYC activity in cHL and ALCL, hence we recognized a new oncogenic axis in these lymphomas.

Non-metabolic functions of glycolytic enzymes in tumorigenesis.

PubMed

Yu, X; Li, S

2017-05-11

Cancer cells reprogram their metabolism to meet the requirement for survival and rapid growth. One hallmark of cancer metabolism is elevated aerobic glycolysis and reduced oxidative phosphorylation. Emerging evidence showed that most glycolytic enzymes are deregulated in cancer cells and play important roles in tumorigenesis. Recent studies revealed that all essential glycolytic enzymes can be translocated into nucleus where they participate in tumor progression independent of their canonical metabolic roles. These noncanonical functions include anti-apoptosis, regulation of epigenetic modifications, modulation of transcription factors and co-factors, extracellular cytokine, protein kinase activity and mTORC1 signaling pathway, suggesting that these multifaceted glycolytic enzymes not only function in canonical metabolism but also directly link metabolism to epigenetic and transcription programs implicated in tumorigenesis. These findings underscore our understanding about how tumor cells adapt to nutrient and fuel availability in the environment and most importantly, provide insights into development of cancer therapy.

dFOXO Activates Large and Small Heat Shock Protein Genes in Response to Oxidative Stress to Maintain Proteostasis in Drosophila.

PubMed

Donovan, Marissa R; Marr, Michael T

2016-09-02

Maintaining protein homeostasis is critical for survival at the cellular and organismal level (Morimoto, R. I. (2011) Cold Spring Harb. Symp. Quant. Biol. 76, 91-99). Cells express a family of molecular chaperones, the heat shock proteins, during times of oxidative stress to protect against proteotoxicity. We have identified a second stress responsive transcription factor, dFOXO, that works alongside the heat shock transcription factor to activate transcription of both the small heat shock protein and the large heat shock protein genes. This expression likely protects cells from protein misfolding associated with oxidative stress. Here we identify the regions of the Hsp70 promoter essential for FOXO-dependent transcription using in vitro methods and find a physiological role for FOXO-dependent expression of heat shock proteins in vivo. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Palmate-like pentafoliata1 encodes a novel Cys(2)His(2) zinc finger transcription factor essential for compound leaf morphogenesis in Medicago truncatula

PubMed Central

2010-01-01

As the primary site for photosynthetic carbon fixation and the interface between plants and the environment, plant leaves play a key role in plant growth, biomass production and survival, and global carbon and oxygen cycles. Leaves can be simple with a single blade or compound with multiple units of blades known as leaflets. In a palmate-type compound leaf, leaflets are clustered at the tip of the leaf. In a pinnate-type compound leaf, on the other hand, leaflets are placed on a rachis in distance from each other. Higher orders of complexities such as bipinnate compound leaves of the “sensitive” plant, Mimosa pudica, also occur in nature. However, how different leaf morphologies are determined is still poorly understood. Medicago truncatula is a model legume closely related to alfalfa and soybean with trifoliate compound leaves. Recently, we have shown that Palmate-like Pentafoliata1 (PALM1) encodes a putative Cys(2) His(2) zinc finger transcription factor essential for compound leaf morphogenesis in M. truncatula. Here, we present our phylogenetic relationship analysis of PALM1 homologs from different species and demonstrate that PALM1 has transcriptional activity in the transactivation assay in yeast. PMID:20724826

Hormesis is induced in the red flour beetle Tribolium castaneum through ingestion of charred toast.

PubMed

Grünwald, Stefanie; Niedermeier, Janine; Wenzel, Uwe

2015-06-01

Charred foods are generally suspected to exert health threats by providing toxicants, such as acrylamide or polycyclic aromatic hydrocarbons. Using the red flour beetle Tribolium castaneum as a model organism, we tested its survival under heat stress in response to feeding charred toast. Survival of beetles was measured at 42 °C after a pre-feeding phase with flour enriched with increasing concentrations of charred toast. In order to assess the influence of key transcription factors for phase-I and phase-II xenobiotic metabolism, gene homologs for ahr and nrf-2, respectively, were knocked down by the use of RNA interference (RNAi). Beetles fed only charred toast died off much earlier than control beetles fed on flour, whereas beetles fed flour enriched with 5% charred toast survived significantly longer than the control. Both, ahr and nrf-2 proved essential in order to enable the increase in survival by the feeding of 5% charred toast. Moreover, functional loss of ahr and nrf-2 made the beetles hypersensitive versus the feeding of 100% charred toast. Finally, at the transcriptional level, it was shown that RNAi for ahr blocked the inducing activities of charred toast on nrf-2. Our studies suggest a hormetic response of the red flour beetle to feeding of charred toast that causes an increased stress resistance through the activation of ahr and nrf-2. Those adaptations, however, are saturable and accordingly the hormetic effects at increasing concentrations of the toxicants become expended.

Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death.

PubMed

Narayanan, Kannan Badri; Ali, Manaf; Barclay, Barry J; Cheng, Qiang Shawn; D'Abronzo, Leandro; Dornetshuber-Fleiss, Rita; Ghosh, Paramita M; Gonzalez Guzman, Michael J; Lee, Tae-Jin; Leung, Po Sing; Li, Lin; Luanpitpong, Suidjit; Ratovitski, Edward; Rojanasakul, Yon; Romano, Maria Fiammetta; Romano, Simona; Sinha, Ranjeet K; Yedjou, Clement; Al-Mulla, Fahd; Al-Temaimi, Rabeah; Amedei, Amedeo; Brown, Dustin G; Ryan, Elizabeth P; Colacci, Annamaria; Hamid, Roslida A; Mondello, Chiara; Raju, Jayadev; Salem, Hosni K; Woodrick, Jordan; Scovassi, A Ivana; Singh, Neetu; Vaccari, Monica; Roy, Rabindra; Forte, Stefano; Memeo, Lorenzo; Kim, Seo Yun; Bisson, William H; Lowe, Leroy; Park, Hyun Ho

2015-06-01

Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Nerve Growth Factor Expression Is Not Associated with Perineural Invasion in Extrahepatic Cholangiocarcinoma.

PubMed

Urabe, Kazuhide; Murakami, Yoshiaki; Kondo, Naru; Uemura, Kenichiro; Hashimoto, Yasushi; Nakagawa, Naoya; Sasaki, Hayato; Hiyama, Eiso; Takahashi, Shinya; Sueda, Taijiro

2016-03-01

Although the presence of perineural invasion has been recognized as a poor prognostic factor in extrahepatic cholangiocarcinoma, the molecular mechanisms of perineural invasion in extrahepatic cholangiocarcinoma remain unclear. Nerve growth factor has been reported to be a candidate predictive biomarker of perineural invasion in some cancers. To investigate the impact of intratumoral nerve growth factor expression in resected extrahepatic cholangiocarcinoma on survival. Intratumoral nerve growth factor expression was investigated immunohistochemically in 112 patients with resected extrahepatic cholangiocarcinoma. Associations between nerve growth factor expression and clinicopathological factors were statistically evaluated, and risk factors for poor survival were analyzed using univariate and multivariate analyses. High and low nerve growth factor expression was observed in 62 (55%) and 50 (45%) patients, respectively. For all 112 patients, no significant correlation was found between nerve growth factor expression and presence of perineural invasion (P = 0.942). Moreover, nerve growth factor expression was not associated with recurrence-free survival (P = 0.861) and overall survival (P = 0.973). In multivariate analysis, lymph node metastasis (P = 0.004) was identified as an independent risk factor for early recurrence and the presence of perineural invasion (P = 0.002) and lymph node metastasis (P < 0.001) was identified as independent risk factors for poor survival. Intratumoral nerve growth factor expression is not associated with perineural invasion or recurrence-free and overall survival in patients with resected extrahepatic cholangiocarcinoma.

Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group.

PubMed

Kaspers, Gertjan J L; Zimmermann, Martin; Reinhardt, Dirk; Gibson, Brenda E S; Tamminga, Rienk Y J; Aleinikova, Olga; Armendariz, Hortensia; Dworzak, Michael; Ha, Shau-Yin; Hasle, Henrik; Hovi, Liisa; Maschan, Alexei; Bertrand, Yves; Leverger, Guy G; Razzouk, Bassem I; Rizzari, Carmelo; Smisek, Petr; Smith, Owen; Stark, Batia; Creutzig, Ursula

2013-02-10

In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group. Patients with relapsed or primary refractory non-French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years). The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups. DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.

Breast cancers with EGFR and HER2 co-amplification favor distant metastasis and poor clinical outcome

PubMed Central

Guo, Peng; Pu, Tianjie; Chen, Shinan; Qiu, Yan; Zhong, Xiaorong; Zheng, Hong; Chen, Lina; Bu, Hong; Ye, Feng

2017-01-01

ErbB signaling serves essential roles in invasive ductal carcinoma (IDC). The aim of the present study was to assess gene amplification in ErbB family members in IDC with clinical implications. Quantitative polymerase chain reaction and fluorescence in situ hybridization were performed on formalin-fixed paraffin-embedded tumor samples for gene amplification detection. The clinical and histopathological characteristics, as well as the prognostic significance, were analyzed. Among the 119 IDC patients evaluated, epidermal growth factor receptor [EGFR; also known as human epidermal growth factor receptor (HER)1], HER2, HER3 and HER4 gene amplification was observed in 30 (25.2%), 44 (36.9%), 0 (0.0%) and 1 (0.8%) patients, respectively. EGFR amplification was associated with estrogen receptor status (P=0.028) and higher possibilities of recurrence (P=0.015) and distant metastasis (following initial surgery) (P=0.011). In survival analysis, EGFR amplification was also associated with disease-free survival (DFS) (P=0.001) and overall survival (OS) (P=0.003). HER2 amplification was associated with larger tumor size (P=0.006), later clinical stage (P=0.003) and distant metastasis (following initial surgery) (P=0.006). In survival analysis, HER2 amplification was also associated with DFS (P=0.011). Notably, the present study identified a group of patients in whom EGFR and HER2 were co-amplified. This group of patients appeared to have a higher possibility of metastasis (when diagnosed) (P=0.014) and distant metastasis (following initial surgery) (P<0.001). In survival analysis, these patients were noticed to be associated with DFS (P<0.001) and OS (P=0.002). With respect to treatment regimen, this was also true for the DFS association with chemotherapy (P<0.001), radiotherapy (P<0.001) and hormonal therapy (P=0.001). The present results suggest that EGFR and HER2 amplification favor distant metastasis following initial surgery and are significantly associated with poor clinical outcome in breast cancer patients. PMID:29181099

A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis.

PubMed

Passamonti, F; Giorgino, T; Mora, B; Guglielmelli, P; Rumi, E; Maffioli, M; Rambaldi, A; Caramella, M; Komrokji, R; Gotlib, J; Kiladjian, J J; Cervantes, F; Devos, T; Palandri, F; De Stefano, V; Ruggeri, M; Silver, R T; Benevolo, G; Albano, F; Caramazza, D; Merli, M; Pietra, D; Casalone, R; Rotunno, G; Barbui, T; Cazzola, M; Vannucchi, A M

2017-12-01

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms with variable risk of evolution into post-PV and post-ET myelofibrosis, from now on referred to as secondary myelofibrosis (SMF). No specific tools have been defined for risk stratification in SMF. To develop a prognostic model for predicting survival, we studied 685 JAK2, CALR, and MPL annotated patients with SMF. Median survival of the whole cohort was 9.3 years (95% CI: 8-not reached-NR-). Through penalized Cox regressions we identified negative predictors of survival and according to beta risk coefficients we assigned 2 points to hemoglobin level <11 g/dl, to circulating blasts ⩾3%, and to CALR-unmutated genotype, 1 point to platelet count <150 × 10 9 /l and to constitutional symptoms, and 0.15 points to any year of age. Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) allocated SMF patients into four risk categories with different survival (P<0.0001): low (median survival NR; 133 patients), intermediate-1 (9.3 years, 95% CI: 8.1-NR; 245 patients), intermediate-2 (4.4 years, 95% CI: 3.2-7.9; 126 patients), and high risk (2 years, 95% CI: 1.7-3.9; 75 patients). Finally, we found that the MYSEC-PM represents the most appropriate tool for SMF decision-making to be used in clinical and trial settings.

The effects of essential oils on growth performance survival and fillet composition of channel catfish

USDA-ARS?s Scientific Manuscript database

Essential oils (EOs) are highly scented compounds of fragrant grasses, trees, and plants. The word “essential” is derived from the word “quintessence” which can be defined as the “pure and concentrated essence of a substance”. Since EOs contain most of the plant’s active substances, their name is ...

Modeling the survival of Salmonella on slice cooked ham as a function of apple skin polyphenols, acetic acid, oregano essential oil and carvacrol

USDA-ARS?s Scientific Manuscript database

Response surface methodology was applied to investigate the combined effect of apple skin polyphenols (ASP), acetic acid (AA), oregano essential oil (O) and carvacrol (C) on the inactivation of Salmonella on sliced cooked ham. A full factorial experimental design was employed with control variables ...

Chloroplast targeting of FtsHprotease is essential for chloroplast development and thylakoid stability at elevated temperatures in plants

USDA-ARS?s Scientific Manuscript database

AtFtsH11 is a chloroplast and mitochondria dual targeted metalloprotease, identified as essential for Arabidopsis plant to survive at moderate high temperatures at all developmental stages. Our study showed that FtsH11 plays critical roles in both the early stages of chloroplast biogenesis and main...

[Cardiopulmonary resuscitation: the essential of 2015 guidelines].

PubMed

Maudet, Ludovic; Carron, Pierre-Nicolas; Trueb, Lionel

2016-02-10

Cardiopulmonary resuscitation (CPR) guidelines have been updated in October 2015. The 2010 guidelines are reaffirmed: immediate call for help via the local dispatch center, high quality CPR (frequency between 100 and 120/min, compression depth between 5 and 6 cm) and early defibrillation improve patient's survival chances. This article reviews the essential elements of resuscitation and recommended advanced measures.

Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis

PubMed Central

Broseus, Julien; Florensa, Lourdes; Zipperer, Esther; Schnittger, Susanne; Malcovati, Luca; Richebourg, Steven; Lippert, Eric; Cermak, Jaroslav; Evans, Jyoti; Mounier, Morgane; Raya, José Maria; Bailly, François; Gattermann, Norbert; Haferlach, Torsten; Garand, Richard; Allou, Kaoutar; Besses, Carlos; Germing, Ulrich; Haferlach, Claudia; Travaglino, Erica; Luno, Elisa; Pinan, Maria Angeles; Arenillas, Leonor; Rozman, Maria; Perez Sirvent, Maria Luz; Favre, Bernardine; Guy, Julien; Alonso, Esther; Ahwij, Nuhri; Jerez, Andrés; Hermouet, Sylvie; Maynadié, Marc; Cazzola, Mario; Girodon, François

2012-01-01

Background Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. Design and Methods We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases. Results In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600×109/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia (P<0.001) but better survival (P<0.001) and a higher risk of thrombosis (P=0.039) than patients with refractory anemia with ring sideroblasts. Conclusions The clinical course of refractory anemia with ring sideroblasts and marked thrombocytosis is better than that of refractory anemia with ring sideroblasts and worse than that of essential thrombocythemia. The higher risk of thrombotic events in this disorder suggests that anti-platelet therapy might be considered in this subset of patients. From a clinical point of view, it appears to be important to consider refractory anemia with ring sideroblasts and marked thrombocytosis as a distinct entity. PMID:22532522

LIF potentiates the NT-3-mediated survival of spiral ganglia neurones in vitro.

PubMed

Marzella, P L; Clark, G M; Shepherd, R K; Bartlett, P F; Kilpatrick, T J

1997-05-06

The survival of auditory neurones depends on the continued supply of trophic factors. Early postnatal spiral ganglion cells (SGC) in a dissociated cell culture were used as a model of auditory innervation to test the trophic factors leukaemia inhibitory factor (LIF) and neurotrophin-3 (NT-3) for their ability, individually or in combination, to promote neuronal survival. The findings suggest that LIF supports neuronal survival in a concentration-dependent manner. Moreover LIF potentiated NT-3-mediated spiral ganglion neuronal survival in a synergistic fashion.

Essential role of TRPC6 channels in G2/M phase transition and development of human glioma.

PubMed

Ding, Xia; He, Zhuohao; Zhou, Kechun; Cheng, Ju; Yao, Hailan; Lu, Dongliang; Cai, Rong; Jin, Yening; Dong, Bin; Xu, Yinghui; Wang, Yizheng

2010-07-21

Patients with glioblastoma multiforme, the most aggressive form of glioma, have a median survival of approximately 12 months. Calcium (Ca(2+)) signaling plays an important role in cell proliferation, and some members of the Ca(2+)-permeable transient receptor potential canonical (TRPC) family of channel proteins have demonstrated a role in the proliferation of many types of cancer cells. In this study, we investigated the role of TRPC6 in cell cycle progression and in the development of human glioma. TRPC6 protein and mRNA expression were assessed in glioma (n = 33) and normal (n = 17) brain tissues from patients and in human glioma cell lines U251, U87, and T98G. Activation of TRPC6 channels was tested by platelet-derived growth factor-induced Ca(2+) imaging. The effect of inhibiting TRPC6 activity or expression using the dominant-negative mutant TRPC6 (DNC6) or RNA interference, respectively, was tested on cell growth, cell cycle progression, radiosensitization of glioma cells, and development of xenografted human gliomas in a mouse model. The green fluorescent protein (GFP) and wild-type TRPC6 (WTC6) were used as controls. Survival of mice bearing xenografted tumors in the GFP, DNC6, and WTC6 groups (n = 13, 15, and 13, respectively) was compared using Kaplan-Meier analysis. All statistical tests were two-sided. Functional TRPC6 was overexpressed in human glioma cells. Inhibition of TRPC6 activity or expression attenuated the increase in intracellular Ca(2+) by platelet-derived growth factor, suppressed cell growth and clonogenic ability, induced cell cycle arrest at the G2/M phase, and enhanced the antiproliferative effect of ionizing radiation. Cyclin-dependent kinase 1 activation and cell division cycle 25 homolog C expression regulated the cell cycle arrest. Inhibition of TRPC6 activity also reduced tumor volume in a subcutaneous mouse model of xenografted human tumors (P = .014 vs GFP; P < .001 vs WTC6) and increased mean survival in mice in an intracranial model (P < .001 vs GFP or WTC6). In this preclinical model, TRPC6 channels were essential for glioma development via regulation of G2/M phase transition. This study suggests that TRPC6 might be a new target for therapeutic intervention of human glioma.

CD47: A Master Regulator of Stemness | Center for Cancer Research

Cancer.gov

Identifying the pathways cells use to regulate proliferation, differentiation, and survival are essential for designing new treatments to stimulate organ and tissue repair following injury and for diseases as diverse as cancer and diabetes. The thrombospondin-1 receptor CD47 seems to limit cell survival and regeneration after stress. At the same time, CD47 levels are increased

The Design Process in the Art Classroom: Building Problem Solving Skills for Life and Careers

ERIC Educational Resources Information Center

Vande Zande, Robin; Warnock, Lauren; Nikoomanesh, Barbara; Van Dexter, Kurt

2014-01-01

Problem solving is essential to everyone's life. People survive if they are nourished, sheltered, and protected--and they construct ways to obtain nourishment, shelter, and protection through problem solving. Though problems vary in complexity--survival at the one end and the pursuit of comfort at the other--we are reliant on our ability to…

Engineering aids for the design of survivable defense communications transmission capability

NASA Astrophysics Data System (ADS)

Stover, H. A.

1984-01-01

Adequate military communications are essential to the security of the United States, especially in the various stages of major wars. Enough communications must survive to make effective use of our military forces and weaponry, even in the face of a concerted enemy effort to destroy those communications. An evolutionary approach to provide survivability is recommended. It must be provided by the design engineer. Afterthought and modification must be replaced with foresight and design. The engineer must make survivability a criterion in every design decision. The design engineer needs help with the challenges and associated details of successfully accomplishing this. The author discusses and recommends development of convenient-to-use survivability engineering design tools to provide this help.

Production and survival of elk (Cervus elaphus) calves in Michigan

USGS Publications Warehouse

Bender, L.C.; Carlson, E.; Schmitt, S.M.; Haufler, J.B.

2002-01-01

We determined production and survival of elk (Cervus elaphus nelsoni) calves in Michigan using a variety of methods to index herd productivity. Calf production in Michigan was comparable with the highest rates ever recorded for North American elk. Calf survival averaged 0.90 (SD = 0.05), 0.97 (SD = 0.04) and 0.87 (SD = 0.05) for summer, winter and annually, 1987-1991. Calf survival rates in Michigan were higher than in other North American elk populations. Continued high calf production, in combination with high calf survival, indicates that elk condition is excellent in Michigan, as habitat quality allows cow elk to breed and successfully raise a calf, essentially every year, despite the high energetic demands associated with late gestation and lactation.

Disruption of aminergic signalling reveals novel compounds with distinct inhibitory effects on mosquito reproduction, locomotor function and survival

NASA Astrophysics Data System (ADS)

Fuchs, Silke; Rende, Ermelinda; Crisanti, Andrea; Nolan, Tony

2014-07-01

Insecticide resistance amongst disease vectors is a growing problem and novel compounds are needed. Biogenic amines are important for neurotransmission and we have recently shown a potential role for these in mosquito fertility. Here, we dissected the relative contribution of different aminergic signalling pathways to biological processes essential for vectorial capacity such as fertility, locomotion and survival by injecting agonists and antagonists and showed that octopaminergic/tyraminergic signalling is essential for oviposition and hatching rate. We show that egg melanisation is regulated by adrenergic signalling, whose disruption causes premature melanisation specifically through the action of tyramine. In addition to this, co-injection of tyramine with DOPA, the precursor of melanin, had a strong cumulative negative effect on mosquito locomotion and survival. Dopaminergic and serotonergic antagonists such as amitriptyline and citalopram recapitulate this effect. Together these results reveal potential new target sites for the development of future mosquito sterilants and insecticides.

The Ornithine Decarboxylase Gene Is Essential for Cell Survival during Early Murine Development

PubMed Central

Pendeville, Hélène; Carpino, Nick; Marine, Jean-Christophe; Takahashi, Yutaka; Muller, Marc; Martial, Joseph A.; Cleveland, John L.

2001-01-01

Overexpression and inhibitor studies have suggested that the c-Myc target gene for ornithine decarboxylase (ODC), the enzyme which converts ornithine to putrescine, plays an important role in diverse biological processes, including cell growth, differentiation, transformation, and apoptosis. To explore the physiological function of ODC in mammalian development, we generated mice harboring a disrupted ODC gene. ODC-heterozygous mice were viable, normal, and fertile. Although zygotic ODC is expressed throughout the embryo prior to implantation, loss of ODC did not block normal development to the blastocyst stage. Embryonic day E3.5 ODC-deficient embryos were capable of uterine implantation and induced maternal decidualization yet failed to develop substantially thereafter. Surprisingly, analysis of ODC-deficient blastocysts suggests that loss of ODC does not affect cell growth per se but rather is required for survival of the pluripotent cells of the inner cell mass. Therefore, ODC plays an essential role in murine development, and proper homeostasis of polyamine pools appears to be required for cell survival prior to gastrulation. PMID:11533243

Glycogen Synthase Kinase-3β is a pro-survival signal for the maintenance of human mast cell homeostasis

PubMed Central

Rådinger, Madeleine; Smrž, Daniel; Metcalfe, Dean D.; Gilfillan, Alasdair M.

2011-01-01

Homeostasis of mature tissue-resident mast cells is dependent on the relative activation of pro- and anti-apoptotic regulators. In this study we investigated the role of Glycogen Synthase Kinase-3β (GSK3β) in the survival of neoplastic and non-neoplastic human mast cells. GSK3β was observed to be phosphorylated at the Y216 activating residue under resting conditions in both the neoplastic HMC1.2 cell line and in peripheral blood-derived primary human mast cells (HuMCs), suggesting constitutive activation of GSK3β in these cells. Lentiviral-transduced short hairpin RNA (shRNA) knockdown of GSK3β in both the HMC1.2 cells and HuMCs resulted in a significant reduction in cell survival as determined with the MTT assay. The decrease in SCF-mediated survival in the GSK3β knockdown HuMCs was reflected by enhancement of SCF-withdrawal-induced apoptosis, as determined by Annexin V staining and caspase cleavage; and this was associated with a pronounced reduction in SCF-mediated phosphorylation of Src homology 2 domain-containing phosphatase 2 (SHP2) and ERK1/2 and reduced expression of the anti-apoptotic proteins Bcl-xl and Bcl-2. These data show that GSK3β is an essential anti-apoptotic factor in both neopastic and non-transformed primary human mast cells through the regulation of SCF-mediated SHP2 and ERK activation. Our data suggest that targeting of GSK3β with small molecular weight inhibitors such as CHIR 99021 may thus provide a mechanism for limiting mast cell survival and thus subsequently decreasing the intensity of the allergic inflammatory response. PMID:22039301

Metaplastic carcinoma of the breast: A retrospective review

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dave, Giatri; Cosmatos, Harry; Do, Tri

2006-03-01

Purpose: Metaplastic carcinoma of the breast represents a rare and heterogeneous group of malignancies that accounts for less than 1% of all breast cancers. The purpose of this study is to better characterize the clinical management of this disease including the role of radiation therapy after surgery. We compared patients that have been treated with either modified radical mastectomy (MRM) or breast-conserving surgery (BCS). Methods and Materials: We performed a retrospective review of 43 patients with metaplastic breast cancer who were evaluated in our regional radiation oncology department between 1987 and 2002. Twenty-one patients were treated with an MRM andmore » 22 with BCS. Five patients from the MRM group received adjuvant radiation, as did 19 patients from the BCS group. Univariate and multivariate analysis of pathologic and treatment-related factors was performed. Local control, disease-free, and overall survival rates were calculated by the Kaplan-Meier method and compared for the two groups. Results: Mean follow-up for all patients was 44.2 months. Mean tumor size was 3.4 cm. Four patients (9%) had positive estrogen receptors and 20 (25%) had positive nodes. The overall 5-year projected local recurrence-free (88% vs. 85%, p = 0.86), disease-free (55% vs. 84%, p = 0.13), and overall survivals (80% vs. 89%, p = 0.58) were not significantly different for both groups. The only tumor parameter significantly associated with overall survival was nodal status. Conclusion: Our study suggests that breast conservation appears to be a reasonable treatment option for women with metaplastic breast cancer, achieving equal survival to mastectomy. The use of adjuvant radiation seems essential for achieving high local control rates after conservation therapy. Further studies will be needed to determine the impact of chemotherapy on survival outcomes.« less

c-Met and its ligand hepatocyte growth factor/scatter factor regulate mature B cell survival in a pathway induced by CD74.

PubMed

Gordin, Maya; Tesio, Melania; Cohen, Sivan; Gore, Yael; Lantner, Frida; Leng, Lin; Bucala, Richard; Shachar, Idit

2010-08-15

The signals regulating the survival of mature splenic B cells have become a major focus in recent studies of B cell immunology. Durable B cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. In this study, we describe a novel biological mechanism involved in mature B cell homeostasis, the hepatocyte growth factor/scatter factor (HGF)/c-Met pathway. We demonstrate that c-Met activation by HGF leads to a survival cascade, whereas its blockade results in induction of mature B cell death. Our results emphasize a unique and critical function for c-Met signaling in the previously described macrophage migration inhibitory factor/CD74-induced survival pathway. Macrophage migration inhibitory factor recruits c-Met to the CD74/CD44 complex and thereby enables the induction of a signaling cascade within the cell. This signal results in HGF secretion, which stimulates the survival of the mature B cell population in an autocrine manner. Thus, the CD74-HGF/c-Met axis defines a novel physiologic survival pathway in mature B cells, resulting in the control of the humoral immune response.

Destiny in the Pacific: Implications for U.S. Policy of Rising Japanese Nationalism and Economic Power.

DTIC Science & Technology

1986-06-01

the military machine running rampant throughout Asia. Ironically, Japanese economic interests remain essentially the same in the 80’s requiring access...multiple claimants to the throne, today’s emperor has essentially the same blood flowing in his veins as his predecessor 2,000 years ago (albeit somewhat... essential to its survival, only 10% of respondents in a 1983 survey stated that U.S. economic policies and actions were helpful to Japan while 33% believed

Death after discharge: predictors of mortality in older brain-injured patients.

PubMed

Peck, Kimberly A; Calvo, Richard Y; Sise, C Beth; Johnson, Jeffrey; Yen, Jessica W; Sise, Michael J; Dunne, Casey E; Badiee, Jayraan; Shackford, Steven R; Lobatz, Michael A

2014-12-01

Older patients with traumatic brain injury (TBI) may be at high risk of death after hospitalization. The purpose of this study was to characterize long-term mortality of older TBI patients who survived to discharge. We hypothesized that predictors of postdischarge mortality differed from those of inpatient mortality. A retrospective cohort study was performed on TBI patients older than 55 years admitted to our Level I trauma center between July 1, 2006, and December 31, 2011. Postdischarge deaths were identified by matching patient data with local vital records up to December 31, 2011, when data collection was terminated (censoring). Patients were categorized by age, comorbidities, history of preinjury anticoagulant/prescription antiplatelet agent therapy, injury severity indices, initial TBI type, prehospital living status, discharge location, and discharge condition. The effect of risk factors on postdischarge mortality was evaluated by Cox proportional hazards modeling. Of 353 patients, 322 (91.2%) survived to discharge. Postdischarge mortality was 19.8% (n = 63) for the study period. Of the postdischarge deaths, 54.0% died within 6 months of discharge, and 68.3% died within 1 year. Median days to death after discharge or censoring were 149 and 410, respectively. Factors associated with death after discharge included age, preinjury anticoagulant use, higher number of Charlson comorbidities, discharge to a long-term care facility, and severe disability. Factors related to injury severity (i.e., Injury Severity Score [ISS], initial Glasgow Coma Scale [GCS] score) and preinjury prescription antiplatelet agent use, previously found to predict inpatient death, did not predict postdischarge mortality. Older TBI patients who survive to discharge have a significant risk of death within 1 year. Predictors of postdischarge mortality and inpatient death differ. Death after discharge is largely a function of overall health status. Monitoring health status and continued aggressive management of comorbidities after discharge may be essential in determining long-term outcomes. Epidemiologic study, level III.

Differential expression of survival proteins during decreased intracellular oxygen tension in brain endothelial cells of grey mullets.

PubMed

Ekambaram, Padmini; Narayanan, Meenakshi; Parasuraman, Parimala

2017-02-15

The brain requires constant oxygen supply to perform its biological functions essential for survival. Because of low oxygen capacity and poor oxygen diffusibility of water, many fish species have evolved various adaptive mechanisms to cope with depleted oxygen. Endothelial cells (EC) are the primary components responsible for controlled environment of brain. Brain homeostasis largely depends on integrity of the EC. To elucidate their adaptive strategy, EC were isolated from the fish brain of Kovalam-control site and Ennore estuary-test/field hypoxic site and were subjected to low oxygen tension in laboratory. Cell viability, 4-hydroxynonenal (4HNE) and total antioxidant capacity (TAC) were analyzed to ascertain stress. Hypoxic insult, cytoprotective role of HSPs and apoptotic effect were analyzed by assessing hypoxia-inducible-factor-α (HIF1α), heat-shock-protein-70 (HSP70), heme-oxygenase 1 (HO-1), and apoptosis signal regulating kinase-1 (ASK1). This study evidenced that HSP70 and HO-1 are the key stress proteins, confer high tolerance to decreased oxygen tension mediated stress. Copyright © 2016 Elsevier Ltd. All rights reserved.

Egf Signaling Directs Neoblast Repopulation by Regulating Asymmetric Cell Division in Planarians.

PubMed

Lei, Kai; Thi-Kim Vu, Hanh; Mohan, Ryan D; McKinney, Sean A; Seidel, Chris W; Alexander, Richard; Gotting, Kirsten; Workman, Jerry L; Sánchez Alvarado, Alejandro

2016-08-22

A large population of proliferative stem cells (neoblasts) is required for physiological tissue homeostasis and post-injury regeneration in planarians. Recent studies indicate that survival of a few neoblasts after sublethal irradiation results in the clonal expansion of the surviving stem cells and the eventual restoration of tissue homeostasis and regenerative capacity. However, the precise mechanisms regulating the population dynamics of neoblasts remain largely unknown. Here, we uncovered a central role for epidermal growth factor (EGF) signaling during in vivo neoblast expansion mediated by Smed-egfr-3 (egfr-3) and its putative ligand Smed-neuregulin-7 (nrg-7). Furthermore, the EGF receptor-3 protein localizes asymmetrically on the cytoplasmic membrane of neoblasts, and the ratio of asymmetric to symmetric cell divisions decreases significantly in egfr-3(RNAi) worms. Our results not only provide the first molecular evidence of asymmetric stem cell divisions in planarians, but also demonstrate that EGF signaling likely functions as an essential regulator of neoblast clonal expansion. Copyright © 2016 Elsevier Inc. All rights reserved.

Francisella tularensis SchuS4 and SchuS4 lipids inhibit IL-12p40 in primary human dendritic cells by inhibition of IRF1 and IRF8*

PubMed Central

Ireland, Robin; Wang, Rong; Alinger, Joshua B.; Small, Pamela; Bosio, Catharine M.

2013-01-01

Induction of innate immunity is essential for host survival of infection. Evasion and inhibition of innate immunity is a strategy used by pathogens, such as the highly virulent bacterium Francisella tularensis, to ensure their replication and transmission. The mechanism and bacterial components responsible for this suppression of innate immunity by F. tularensis are not defined. Here, we demonstrate that lipids enriched from virulent F. tularensis strain SchuS4, but not attenuated Live Vaccine Strain (LVS), inhibit inflammatory responses in vitro and in vivo. Suppression of inflammatory responses is associated with IκBα independent inhibition of NF-κBp65 activation and selective inhibition of activation of Interferon Regulatory Factors (IRFs). Interference with NF-κBp65 and IRFs is also observed following infection with viable SchuS4. Together these data provide novel insight as to how highly virulent bacteria selectively modulate the host to interfere innate immune responses required for survival of infection. PMID:23817430

Akt-phosphorylated Mitogen-activated Kinase-activating Death Domain Protein (MADD) Inhibits TRAIL-induced Apoptosis by Blocking Fas-associated Death Domain (FADD) Association with Death Receptor 4*

PubMed Central

Li, Peifeng; Jayarama, Shankar; Ganesh, Lakshmy; Mordi, David; Carr, Ryan; Kanteti, Prasad; Hay, Nissim; Prabhakar, Bellur S.

2010-01-01

MADD plays an essential role in cancer cell survival. Abrogation of endogenous MADD expression results in significant spontaneous apoptosis and enhanced susceptibility to tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. However, the regulation of MADD function is largely unknown. Here, we demonstrate that endogenous MADD is phosphorylated at three highly conserved sites by Akt, and only the phosphorylated MADD can directly interact with the TRAIL receptor DR4 thereby preventing Fas-associated death domain recruitment. However, in cells susceptible to TRAIL treatment, TRAIL induces a reduction in MADD phosphorylation levels resulting in MADD dissociation from, and Fas-associated death domain association with DR4, which allows death-inducing signaling complex (DISC) formation leading to apoptosis. Thus, the pro-survival function of MADD is dependent upon its phosphorylation by Akt. Because Akt is active in most cancer cells and phosphorylated MADD confers resistance to TRAIL-induced apoptosis, co-targeting Akt-MADD axis is likely to increase efficacy of TRAIL-based therapies. PMID:20484047

A diffusible signal derived from hematopoietic cells supports the survival and proliferation of regenerative cells during zebrafish fin fold regeneration.

PubMed

Hasegawa, Tomoya; Nakajima, Teruhiro; Ishida, Takashi; Kudo, Akira; Kawakami, Atsushi

2015-03-01

Multicellular organisms maintain body integrity by constantly regenerating tissues throughout their lives; however, the overall mechanism for regulating regeneration remains an open question. Studies of limb and fin regeneration in teleost fish and urodeles have shown the involvement of a number of locally activated signals at the wounded site during regeneration. Here, we demonstrate that a diffusible signal from a distance also play an essential role for regeneration. Among a number of zebrafish mutants, we found that the zebrafish cloche (clo) and tal1 mutants, which lack most hematopoietic tissues, displayed a unique regeneration defect accompanying apoptosis in primed regenerative tissue. Our analyses of the mutants showed that the cells in the primed regenerative tissue are susceptible to apoptosis, but their survival is normally supported by the presence of hematopoietic tissues, mainly the myeloid cells. We further showed that a diffusible factor in the wild-type body fluid mediates this signal. Thus, our study revealed a novel mechanism that the hematopoietic tissues regulate tissue regeneration through a diffusible signal. Copyright © 2014 Elsevier Inc. All rights reserved.

Protein Kinase Cδ Promotes Transitional B Cell-Negative Selection and Limits Proximal B Cell Receptor Signaling To Enforce Tolerance

PubMed Central

Zikherman, Julie; Lau, Tannia; Leitges, Michael; Weiss, Arthur

2014-01-01

Protein kinase Cδ (PKCδ) deficiency causes autoimmune pathology in humans and mice and is crucial for the maintenance of B cell homeostasis. However, the mechanisms underlying autoimmune disease in PKCδ deficiency remain poorly defined. Here, we address the antigen-dependent and -independent roles of PKCδ in B cell development, repertoire selection, and antigen responsiveness. We demonstrate that PKCδ is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell-activating factor (BAFF) receptor. We found that PKCδ is essential for antigen-dependent negative selection of splenic transitional B cells and is required for activation of the proapoptotic Ca2+-Erk pathway that is selectively activated during B cell-negative selection. Unexpectedly, we also identified a previously unrecognized role for PKCδ as a proximal negative regulator of BCR signaling that substantially impacts survival and proliferation of mature follicular B cells. As a consequence of these distinct roles, PKCδ deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation. PMID:24515435

Essential Assembly Factor Rpf2 Forms Novel Interactions within the 5S RNP in Trypanosoma brucei

PubMed Central

Kamina, Anyango D.; Jaremko, Daniel; Christen, Linda

2017-01-01

ABSTRACT Ribosome biogenesis is a highly complex and conserved cellular process that is responsible for making ribosomes. During this process, there are several assembly steps that function as regulators to ensure proper ribosome formation. One of these steps is the assembly of the 5S ribonucleoprotein particle (5S RNP) in the central protuberance of the 60S ribosomal subunit. In eukaryotes, the 5S RNP is composed of 5S rRNA, ribosomal proteins L5 and L11, and assembly factors Rpf2 and Rrs1. Our laboratory previously showed that in Trypanosoma brucei, the 5S RNP is composed of 5S rRNA, L5, and trypanosome-specific RNA binding proteins P34 and P37. In this study, we characterize an additional component of the 5S RNP, the T. brucei homolog of Rpf2. This is the first study to functionally characterize interactions mediated by Rpf2 in an organism other than fungi. T. brucei Rpf2 (TbRpf2) was identified from tandem affinity purification using extracts prepared from protein A-tobacco etch virus (TEV)-protein C (PTP)-tagged L5, P34, and P37 cell lines, followed by mass spectrometry analysis. We characterized the binding interactions between TbRpf2 and the previously characterized members of the T. brucei 5S RNP. Our studies show that TbRpf2 mediates conserved binding interactions with 5S rRNA and L5 and that TbRpf2 also interacts with trypanosome-specific proteins P34 and P37. We performed RNA interference (RNAi) knockdown of TbRpf2 and showed that this protein is essential for the survival of the parasites and is critical for proper ribosome formation. These studies provide new insights into a critical checkpoint in the ribosome biogenesis pathway in T. brucei. IMPORTANCE Trypanosoma brucei is the parasitic protozoan that causes African sleeping sickness. Ribosome assembly is essential for the survival of this parasite through the different host environments it encounters during its life cycle. The assembly of the 5S ribonucleoprotein particle (5S RNP) functions as one of the regulatory checkpoints during ribosome biogenesis. We have previously characterized the 5S RNP in T. brucei and showed that trypanosome-specific proteins P34 and P37 are part of this complex. In this study, we characterize for the first time the interactions of the homolog of the assembly factor Rpf2 with members of the 5S RNP in another organism besides fungi. Our studies show that Rpf2 is essential in T. brucei and that it forms unique interactions within the 5S RNP, particularly with P34 and P37. These studies have identified parasite-specific interactions that can potentially function as new therapeutic targets against sleeping sickness. PMID:29062898

Essential Assembly Factor Rpf2 Forms Novel Interactions within the 5S RNP in Trypanosoma brucei.

PubMed

Kamina, Anyango D; Jaremko, Daniel; Christen, Linda; Williams, Noreen

2017-01-01

Ribosome biogenesis is a highly complex and conserved cellular process that is responsible for making ribosomes. During this process, there are several assembly steps that function as regulators to ensure proper ribosome formation. One of these steps is the assembly of the 5S ribonucleoprotein particle (5S RNP) in the central protuberance of the 60S ribosomal subunit. In eukaryotes, the 5S RNP is composed of 5S rRNA, ribosomal proteins L5 and L11, and assembly factors Rpf2 and Rrs1. Our laboratory previously showed that in Trypanosoma brucei , the 5S RNP is composed of 5S rRNA, L5, and trypanosome-specific RNA binding proteins P34 and P37. In this study, we characterize an additional component of the 5S RNP, the T. brucei homolog of Rpf2. This is the first study to functionally characterize interactions mediated by Rpf2 in an organism other than fungi. T . brucei Rpf2 (TbRpf2) was identified from tandem affinity purification using extracts prepared from protein A-tobacco etch virus (TEV)-protein C (PTP)-tagged L5, P34, and P37 cell lines, followed by mass spectrometry analysis. We characterized the binding interactions between TbRpf2 and the previously characterized members of the T. brucei 5S RNP. Our studies show that TbRpf2 mediates conserved binding interactions with 5S rRNA and L5 and that TbRpf2 also interacts with trypanosome-specific proteins P34 and P37. We performed RNA interference (RNAi) knockdown of TbRpf2 and showed that this protein is essential for the survival of the parasites and is critical for proper ribosome formation. These studies provide new insights into a critical checkpoint in the ribosome biogenesis pathway in T. brucei . IMPORTANCE Trypanosoma brucei is the parasitic protozoan that causes African sleeping sickness. Ribosome assembly is essential for the survival of this parasite through the different host environments it encounters during its life cycle. The assembly of the 5S ribonucleoprotein particle (5S RNP) functions as one of the regulatory checkpoints during ribosome biogenesis. We have previously characterized the 5S RNP in T. brucei and showed that trypanosome-specific proteins P34 and P37 are part of this complex. In this study, we characterize for the first time the interactions of the homolog of the assembly factor Rpf2 with members of the 5S RNP in another organism besides fungi. Our studies show that Rpf2 is essential in T. brucei and that it forms unique interactions within the 5S RNP, particularly with P34 and P37. These studies have identified parasite-specific interactions that can potentially function as new therapeutic targets against sleeping sickness.

Making a case for the socioeconomic determinacy of survival in osteosarcoma.

PubMed

Nathan, Saminathan S; Healey, John H

2013-03-01

The literature on osteosarcoma survival generally focuses on tumor and treatment variables, although it is unclear whether and how ethnic and socioeconomic factors might influence survival. We therefore investigated the relative contribution of socioeconomic influences together with more traditional tumor-specific factors on osteosarcoma survival. We performed survival analyses on two national databases in two countries. Using multivariable analyses, we compared these with corresponding institution-specific survival to determine if socioeconomic factors might impact osteosarcoma survival. East Asian descent, state-specific treatment, female sex, treatment in the 1990s, low-grade disease, intracompartmental disease, small size, wide resections as opposed to forequarter or hindquarter amputations, and single primaries were good prognostic factors. Survival was better in the more affluent states. Males were affected at an older age than females. Blacks tended to have larger tumors, although their overall survival was similar to whites. East Asians were more likely to be treated in the 1990s with wide resections for smaller tumors and were located around states associated with good treatment. East Asians in Singapore and the United States had the same survival. Survival in East Asians in Singapore was similar to that of other races. The provision of health care for osteosarcoma varies greatly across the United States but is uniform in the socialized medical system in Singapore. Hence, the observed differences in the United States were likely the result of socioeconomic factors. Our analysis suggests ethnic and economic bias may influence survival in osteosarcoma and should receive greater attention in the collective literature on survival analyses. Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Impact of triple-negative phenotype on prognosis of patients with breast cancer brain metastases.

PubMed

Xu, Zhiyuan; Schlesinger, David; Toulmin, Sushila; Rich, Tyvin; Sheehan, Jason

2012-11-01

To elucidate survival times and identify potential prognostic factors in patients with triple-negative (TN) phenotype who harbored brain metastases arising from breast cancer and who underwent stereotactic radiosurgery (SRS). A total of 103 breast cancer patients with brain metastases were treated with SRS and then studied retrospectively. Twenty-four patients (23.3%) were TN. Survival times were estimated using the Kaplan-Meier method, with a log-rank test computing the survival time difference between groups. Univariate and multivariate analyses to predict potential prognostic factors were performed using a Cox proportional hazard regression model. The presence of TN phenotype was associated with worse survival times, including overall survival after the diagnosis of primary breast cancer (43 months vs. 82 months), neurologic survival after the diagnosis of intracranial metastases, and radiosurgical survival after SRS, with median survival times being 13 months vs. 25 months and 6 months vs. 16 months, respectively (p < 0.002 in all three comparisons). On multivariate analysis, radiosurgical survival benefit was associated with non-TN status and lower recursive partitioning analysis class at the initial SRS. The TN phenotype represents a significant adverse prognostic factor with respect to overall survival, neurologic survival, and radiosurgical survival in breast cancer patients with intracranial metastasis. Recursive partitioning analysis class also served as an important and independent prognostic factor. Copyright © 2012 Elsevier Inc. All rights reserved.

Survival of a bacterioferritin deletion mutant of Brucella melitensis 16M in human monocyte-derived macrophages.

PubMed Central

Denoel, P A; Crawford, R M; Zygmunt, M S; Tibor, A; Weynants, V E; Godfroid, F; Hoover, D L; Letesson, J J

1997-01-01

A bacterioferritin (BFR) deletion mutant of Brucella melitensis 16M was generated by gene replacement. The deletion was complemented with a broad-host-range vector carrying the wild-type bfr gene, pBBR-bfr. The survival and growth of the mutant, B. melitensis PAD 2-78, were similar to those of its parental strain in human monocyte-derived macrophages (MDM). These results suggest that BFR is not essential for the intracellular survival of B. melitensis in human MDM. PMID:9317046

Polyamines and fatty acids in sucrose precultured banana meristems and correlation with survival rate after cryopreservation.

PubMed

Ramon, Mathew; Geuns, Jan M C; Swennen, Rony; Pannis, Bart

2002-01-01

Polyamines and fatty acids were studied in proliferating meristem cultures of 3 banana cultivars with high (Cachaco), medium (Williams Bronze free) and low (Mbwazirume) survival rates after cryopreservation. A 2-week preculture on medium containing 0.4 M sucrose which is essential to obtain survival after cryopreservation resulted in increased polyamine levels, especially putrescine. This increase in putrescine content was positively correlated with the survival rate after simple freezing or after vitrification. The total fatty acid content also increased after a 0.4 M sucrose pretreatment. However, only the ratio of unsaturated/saturated fatty acids correlated positively with the survival rate after cryopreservation. This is the first report showing a correlation of both putrescine increase and level of unsaturation of membrane lipids after sucrose treatment with survival rate after cryopreservation.

Expression of lactate/H⁺ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses.

PubMed

Kim, Younghye; Choi, Jung-Woo; Lee, Ju-Han; Kim, Young-Sik

2015-01-01

Clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau protein, leading to the accumulation of hypoxia-inducible factor-α (HIF-α). HIF-1α induces aerobic glycolysis, the Warburg effect, whereas HIF-2α functions as an oncoprotein. Lactate transport through monocarboxylate transporters (MCTs) and the chaperone CD147 is essential for high glycolytic cancer cell survival. To elucidate the clinical significance of MCT1, MCT4, and CD147 expression, we investigated their expressions by immunohistochemistry in ccRCC specimens and validated the results by an open-access The Cancer Genome Atlas data analysis. Overexpression of MCT1, MCT4, and CD147 was observed in 49.4% (89/180), 39.4% (71/180), and 79.4% (143/180) of ccRCC patients, respectively. High MCT1 expression was associated with older age (P = .017), larger tumor size (P = .015), and advanced TNM stage (P = .012). However, MCT4 overexpression was not related to any variables. CD147 overexpression correlated with high grade (P = .005), tumor necrosis (P = .016), and larger tumor size (P = .038). In univariate analysis, high expression of MCT1 (P < .001), MCT4 (P = .016), and CD147 (P = .02) was linked to short progression-free survival. In multivariate analysis, high MCT1 expression was associated with worse progression-free survival (P = .001). In conclusion, high expression of MCT1 and CD147 is associated with poor prognostic factors. Overexpression of MCT1, MCT4, and CD147 predicts tumor progression. Reversing the Warburg effect by targeting the lactate transporters may be a useful strategy to prevent ccRCC progression. Copyright © 2014 Elsevier Inc. All rights reserved.

The Cellular State Determines the Effect of Melatonin on the Survival of Mixed Cerebellar Cell Culture

PubMed Central

Franco, Daiane Gil; Markus, Regina P.

2014-01-01

The constitutive activation of nuclear factor-κB (NF-κB), a key transcription factor involved in neuroinflammation, is essential for the survival of neurons in situ and of cerebellar granule cells in culture. Melatonin is known to inhibit the activation of NF-κB and has a cytoprotective function. In this study, we evaluated whether the cytoprotective effect of melatonin depends on the state of activation of a mixed cerebellar culture that is composed predominantly of granule cells; we tested the effect of melatonin on cultured rat cerebellar cells stimulated or not with lipopolysaccharide (LPS). The addition of melatonin (0.1 nM–1 µM) reduced the survival of naïve cells while inhibiting LPS-induced cell death. Melatonin (100 nM) transiently (15 min) inhibited the nuclear translocation of both NF-κB dimers (p50/p50, p50/RelA) and, after 60 min, increased the activation of p50/RelA. Melatonin-induced p50/RelA activity in naïve cells resulted in the transcription of inducible nitric oxide synthase (iNOS) and the production of NO. Otherwise, in cultures treated with LPS, melatonin blocked the LPS-induced activation of p50/RelA and the reduction in p50/p50 levels and inhibited iNOS expression and NO synthesis. Therefore, melatonin in vehicle-treated cells induces cell death, while it protects against LPS-induced cytotoxicity. In summary, we confirmed that melatonin is a neuroprotective drug when cerebellar cells are challenged; however, melatonin can also lead to cell death when the normal balance of the NF-κB pathway is disturbed. Our data provide a mechanistic basis for understanding the influence of cell context on the final output response of melatonin. PMID:25184316

Nrf2 but not autophagy inhibition is associated with the survival of wild-type epidermal growth factor receptor non-small cell lung cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Yan

Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Icotinib and Gefitinib are two epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) that have been used to treat NSCLC. While it is well known that mutations of EGFR can affect the sensitivity of NSCLC to the EGFR-TKI, other mechanisms may also be adopted by lung cancer cells to develop resistance to EGFR-TKI treatment. Cancer cells can use multiple adaptive mechanisms such as activation of autophagy and Nrf2 to protect against various stresses and chemotherapeutic drugs. Whether autophagy or Nrf2 activation contributes to themore » resistance of NSCLC to EGFR-TKI treatment in wild-type EGFR NSCLC cells remains elusive. In the present study, we confirmed that Icotinib and Gefitinib induced apoptosis in EGFR mutant HCC827 but not in EGFR wild-type A549 NSCLC cells. Icotinib and Gefitinib did not induce autophagic flux or inhibit mTOR in A549 cells. Moreover, suppression of autophagy by chloroquine, a lysosomal inhibitor, did not affect Icotinib- or Gefitinib-induced cell death in A549 cells. In contrast, Brusatol, an Nrf2 inhibitor, significantly suppressed the cell survival of A549 cells. However, Brusatol did not further sensitize A549 cells to EGFR TKI-induced cell death. Results from this study suggest that inhibition of Nrf2 can decrease cell vitality of EGFR wild-type A549 cells independent of autophagy. - Highlights: • Cancer cells use adaptive mechanisms against chemotherapy. • Autophagy is not essential for the drug resistance of lung cancer A549 cells. • Inhibition of Nrf2 decreases cell survival of lung cancer A549 cells.« less

Essential oil of Artemisia vestita exhibits potent in vitro and in vivo antibacterial activity: Investigation of the effect of oil on biofilm formation, leakage of potassium ions and survival curve measurement

PubMed Central

YANG, CHANG; HU, DONG-HUI; FENG, YAN

2015-01-01

The aim of the present study was to investigate the chemical composition of the essential oil of Artemisia vestita and to determine the antibacterial activity of the essential oil and its two major components, grandisol and 1,8-cineole, against certain respiratory infection-causing bacterial strains, in vitro and in vivo. The chemical composition of the essential oil was analyzed using gas chromatography-mass spectrometry. A micro-well dilution method was used to determine the minimum inhibition concentration (MIC) values of the essential oil and its major constituents. A model of Streptococcus pyogenes infection in mice was used to determine its in vivo activities. Lung and blood samples were obtained to assess bacterial cell counts. Toxicity evaluation of the essential oil and its components was completed by performing biochemical analysis of the serum, particularly monitoring aspartate transaminase, alanine transaminase, urea and creatinine. The essential oil exhibited potent antibacterial activity, whereas the two major constituents were less potent. The essential oil exhibited MIC values between 20 and 80 μg/ml, while the values of the two constituents were between 130 and 200 μg/ml. Scanning electron microscopy results demonstrated that the essential oil inhibited biofilm formation and altered its architecture. Survival curves indicated that the essential oil led to a reduction in the viability of different bacteria. The essential oil also induced significant leakage of potassium ions from S. pyogenes. The essential oil (100 μg/mouse) and grandisol (135 μg/mouse) significantly reduced the number of viable bacterial cells in the lungs (P<0.01). However, intake of 100 μg/mouse of essential oil or grandisol 135 μg/mouse once or twice each day for 9 days did not produce any toxic effects in the mice. In conclusion, the in vitro and in vivo results suggested that the essential oil of A. vestita and one of its major constituents, grandisol, can significantly inhibit the growth of different bacterial strains. PMID:26259564

Essential oil of Artemisia vestita exhibits potent in vitro and in vivo antibacterial activity: Investigation of the effect of oil on biofilm formation, leakage of potassium ions and survival curve measurement.

PubMed

Yang, Chang; Hu, Dong-Hui; Feng, Yan

2015-10-01

The aim of the present study was to investigate the chemical composition of the essential oil of Artemisia vestita and to determine the antibacterial activity of the essential oil and its two major components, grandisol and 1,8‑cineole, against certain respiratory infection‑causing bacterial strains, in vitro and in vivo. The chemical composition of the essential oil was analyzed using gas chromatography‑mass spectrometry. A micro‑well dilution method was used to determine the minimum inhibition concentration (MIC) values of the essential oil and its major constituents. A model of Streptococcus pyogenes infection in mice was used to determine its in vivo activities. Lung and blood samples were obtained to assess bacterial cell counts. Toxicity evaluation of the essential oil and its components was completed by performing biochemical analysis of the serum, particularly monitoring aspartate transaminase, alanine transaminase, urea and creatinine. The essential oil exhibited potent antibacterial activity, whereas the two major constituents were less potent. The essential oil exhibited MIC values between 20 and 80 µg/ml, while the values of the two constituents were between 130 and 200 µg/ml. Scanning electron microscopy results demonstrated that the essential oil inhibited biofilm formation and altered its architecture. Survival curves indicated that the essential oil led to a reduction in the viability of different bacteria. The essential oil also induced significant leakage of potassium ions from S. pyogenes. The essential oil (100 µg/mouse) and grandisol (135 µg/mouse) significantly reduced the number of viable bacterial cells in the lungs (P<0.01). However, intake of 100 µg/mouse of essential oil or grandisol 135 µg/mouse once or twice each day for 9 days did not produce any toxic effects in the mice. In conclusion, the in vitro and in vivo results suggested that the essential oil of A. vestita and one of its major constituents, grandisol, can significantly inhibit the growth of different bacterial strains.

Report: Study is about the prevalence of the HCV disease and survival of HCV patients with associated factors in the population of district Multan.

PubMed

Tabassum, Hina; Amin, Muhammad; Amanullah, Muhammad; Tabassum, Sana

2015-09-01

To find out the significant factors associated with HCV disease and evaluate the impact of these factors on the survival pattern of HCV patients in district Multan. The study was conducted in Nishter Hospital of Multan district from 1st January 2011 to 1st October 2012. To see a significant difference between the survival rates of patients with associated factors, non-parametric Cox- proportional hazard model with their graphical results were used. All the patients above 11 years old of both sexes were included in the study. All those who were surviving with HCV disease were studied with their associated factors such as age, family history (FH) barber/parlor services, blood group (BG) types weight loss (WL), Gender and drug use were collected from Nishter Hospital Multan. Results indicated that age, blood group types and gender are the most significant factors in the patients who are surviving with HCV disease. It was also observed that survival rate of female patients is high as compare to male patients.

Geographic disparities in colorectal cancer survival

PubMed Central

Henry, Kevin A; Niu, Xiaoling; Boscoe, Francis P

2009-01-01

Background Examining geographic variation in cancer patient survival can help identify important prognostic factors that are linked by geography and generate hypotheses about the underlying causes of survival disparities. In this study, we apply a recently developed spatial scan statistic method, designed for time-to-event data, to determine whether colorectal cancer (CRC) patient survival varies by place of residence after adjusting survival times for several prognostic factors. Methods Using data from a population-based, statewide cancer registry, we examined a cohort of 25,040 men and women from New Jersey who were newly diagnosed with local or regional stage colorectal cancer from 1996 through 2003 and followed to the end of 2006. Survival times were adjusted for significant prognostic factors (sex, age, stage at diagnosis, race/ethnicity and census tract socioeconomic deprivation) and evaluated using a spatial scan statistic to identify places where CRC survival was significantly longer or shorter than the statewide experience. Results Age, sex and stage adjusted survival times revealed several areas in the northern part of the state where CRC survival was significantly different than expected. The shortest and longest survival areas had an adjusted 5-year survival rate of 73.1% (95% CI 71.5, 74.9) and 88.3% (95% CI 85.4, 91.3) respectively, compared with the state average of 80.0% (95% CI 79.4, 80.5). Analysis of survival times adjusted for age, sex and stage as well as race/ethnicity and area socioeconomic deprivation attenuated the risk of death from CRC in several areas, but survival disparities persisted. Conclusion The results suggest that in areas where additional adjustments for race/ethnicity and area socioeconomic deprivation changed the geographic survival patterns and reduced the risk of death from CRC, the adjustment factors may be contributing causes of the disparities. Further studies should focus on specific and modifiable individual and neighborhood factors in the high risk areas that may affect a person's chance of surviving cancer. PMID:19627576

Attention Deficit Disorder--A New Age Yuppie Disorder or an Age Old Human Characteristic Essential for Our Survival?

ERIC Educational Resources Information Center

Orgill, Anna A.

This brief paper suggests that Attention Deficit Disorder (ADD) may result from a specific "novelty seeking" gene which has been associated over the history of man's evolution with a biological advantage in situations where energy, risk taking, and creativity are essentials. It reviews research on the genetics of ADD which suggest that novelty…

An Essential Component in Chloroplast Development and Maintenance at Moderate High Temperature in Higher Plants: Chloroplast-targeted FtsH11 Proteases

USDA-ARS?s Scientific Manuscript database

Among the 12 predicted FtsH proteases in Arabidopsis, AtFtsH11 is the only metalloprotease targeting to both chloroplast and mitochondria and the only one essential for Arabidopsis plant to survive at moderate heat stress at all developmental stages. Under optimal conditions, atftsh11 mutants were...

Prognostic factors and relative risk for survival in N1-3 oral squamous cell carcinoma: a multivariate analysis using Cox's hazard model.

PubMed

Noguchi, M; Kido, Y; Kubota, H; Kinjo, H; Kohama, G

1999-12-01

The records of 136 patients with N1-3 oral squamous cell carcinoma treated by surgery were investigated retrospectively, with the aim of finding out which factors were predictive of survival on multivariate analysis. Four independent factors significantly influenced survival in the following order: pN stage; T stage; histological grade; and N stage. The most significant was pN stage, the five-year survival for patients with pN0 being 91% and for patients with pN1-3 41%. A further study was carried out on the 80 patients with pN1-3 to find out their prognostic factors for survival and the independent factors identified by multivariate analysis were T stage and presence or absence of extracapsular spread to metastatic lymph nodes.

The neurotrophins act synergistically with LIF and members of the TGF-beta superfamily to promote the survival of spiral ganglia neurons in vitro.

PubMed

Marzella, P L; Gillespie, L N; Clark, G M; Bartlett, P F; Kilpatrick, T J

1999-12-01

A number of growth factor families have been implicated in normal inner ear development, auditory neuron survival and protection. Several growth factors, including transforming growth factor-beta5 (TGF-beta5) and TGF-beta3, neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were tested for their ability, individually or in combination, to promote auditory neuron survival in dissociated cell cultures of early rat post-natal spiral ganglion cells (SGCs). The results indicate that at discrete concentrations all growth factors act in an additive fashion and some in synergy when promoting neuronal survival. These findings support the hypothesis that growth factors from different families may be interdependent when sustaining neuronal integrity.

Establishment of a long-term primary culture of striatal neurons.

PubMed

Sebben, M; Gabrion, J; Manzoni, O; Sladeczek, F; Gril, C; Bockaert, J; Dumuis, A

1990-03-01

A new method of obtaining long-term primary cultures (lasting more than 8 weeks) of striatal neurons is described in this paper. The originality of the method consists of: (1) starting the culture for 3 days in a serum-free medium which allows attachment and neurite proliferation of neurons as well as the death of non-neuronal cells (mainly consisting of astrocytes); (2) introducing a limited amount of fetal calf serum (FCS) (2-5%) after 3 days in vitro (3 DIV), which likely provides optimal neuronal survival and attachment factors, and a limited amount of astrocyte proliferating factors. The period of introduction of serum, as well as the amount of serum introduced are critical factors. By phase contrast and transmission electron microscopy, we observed that neurons continued to develop neurite extensions, synaptic vesicles and synapse formations up to 50 DIV. Neuronal membranes, and synaptic contacts were particularly healthy up to 50 DIV. Interestingly, the number of astrocytes was constant between 30-50 DIV and limited to about 10%. We therefore obtained an equilibrium between neuronal and astrocyte differentiation and proliferation. It is likely that the small population of astrocytes, plus the low percentage of FCS added, provide essential factors for neuronal survival and differentiation, whereas a high density of differentiated neurons inhibited astrocyte cell proliferation. The clear-cut stability of these neuronal cultures goes in parallel with the stability of the pharmacological responses studied here: the coupling of carbachol and quisqualate receptors with the inositol phosphate production system. The culture method described here could be of particular interest to pursue biochemical, pharmacological and biological studies on neurons as well as on reciprocal interactions between neurons and astrocytes.

Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo

PubMed Central

Colvin, Stephanie C.; Malik, Raleigh E.; Showalter, Aaron D.; Sloop, Kyle W.; Rhodes, Simon J.

2011-01-01

The etiology of most pediatric hormone deficiency diseases is poorly understood. Children with combined pituitary hormone deficiency (CPHD) have insufficient levels of multiple anterior pituitary hormones causing short stature, metabolic disease, pubertal failure, and often have associated nervous system symptoms. Mutations in developmental regulatory genes required for the specification of the hormone-secreting cell types of the pituitary gland underlie severe forms of CPHD. To better understand these diseases, we have created a unique mouse model of CPHD with a targeted knockin mutation (Lhx3 W227ter), which is a model for the human LHX3 W224ter disease. The LHX3 gene encodes a LIM-homeodomain transcription factor, which has essential roles in pituitary and nervous system development in mammals. The introduced premature termination codon results in deletion of the carboxyl terminal region of the LHX3 protein, which is critical for pituitary gene activation. Mice that lack all LHX3 function do not survive beyond birth. By contrast, the homozygous Lhx3 W227ter mice survive, but display marked dwarfism, thyroid disease, and female infertility. Importantly, the Lhx3 W227ter mice have no apparent nervous system deficits. The Lhx3 W227ter mouse model provides a unique array of hormone deficits and facilitates experimental approaches that are not feasible with human patients. These experiments demonstrate that the carboxyl terminus of the LHX3 transcription factor is not required for viability. More broadly, this study reveals that the in vivo actions of a transcription factor in different tissues are molecularly separable. PMID:21149718

Nuclear receptors and pathogenesis of pancreatic cancer

PubMed Central

Polvani, Simone; Tarocchi, Mirko; Tempesti, Sara; Galli, Andrea

2014-01-01

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease. PMID:25232244

A registry analysis of damage to the deceased donor pancreas during procurement.

PubMed

Ausania, F; Drage, M; Manas, D; Callaghan, C J

2015-11-01

Surgical injury to the pancreas is thought to occur commonly during procurement. The UK Transplant Registry was analyzed to determine the frequency of pancreatic injuries, identify factors associated with damage, and assess the impact of injuries on graft survival. Twelve hundred ninety-six pancreata were procured from donation after brain death donors, with 314 (19.5%) from donation after circulatory death donors. More than 50% of recovered pancreata had at least one injury, most commonly a short portal vein (21.5%). Liver donation, procurement team origin, hepatic artery (HA) arising from the superior mesenteric artery (SMA), and increasing donor BMI were associated with increased rates of pancreas damage on univariate analyses; on multivariate analysis only the presence of an HA from the SMA remained significant (p = 0.02). Six hundred forty solid organ pancreas transplants were performed; 238 had some form of damage. Overall, there was no difference in graft survival between damaged and undamaged organs (p = 0.28); however, graft loss was significantly more frequent in pancreata with arterial damage (p = 0.04) and in those with parenchymal damage (p = 0.05). Damage to the pancreas during organ recovery is more common than other organs, and meticulous surgical technique and awareness of damage risk factors are essential to reduce rates of procurement-related injuries. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Molecular Mechanism for the Control of Eukaryotic Elongation Factor 2 Kinase by pH: Role in Cancer Cell Survival

PubMed Central

Xie, Jianling; Mikolajek, Halina; Pigott, Craig R.; Hooper, Kelly J.; Mellows, Toby; Moore, Claire E.; Mohammed, Hafeez; Werner, Jörn M.; Thomas, Gareth J.

2015-01-01

Acidification of the extracellular and/or intracellular environment is involved in many aspects of cell physiology and pathology. Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmodulin-dependent kinase that regulates translation elongation by phosphorylating and inhibiting eEF2. Here we show that extracellular acidosis elicits activation of eEF2K in vivo, leading to enhanced phosphorylation of eEF2. We identify five histidine residues in eEF2K that are crucial for the activation of eEF2K during acidosis. Three of them (H80, H87, and H94) are in its calmodulin-binding site, and their protonation appears to enhance the ability of calmodulin to activate eEF2K. The other two histidines (H227 and H230) lie in the catalytic domain of eEF2K. We also identify His108 in calmodulin as essential for activation of eEF2K. Acidification of cancer cell microenvironments is a hallmark of malignant solid tumors. Knocking down eEF2K in cancer cells attenuated the decrease in global protein synthesis when cells were cultured at acidic pH. Importantly, activation of eEF2K is linked to cancer cell survival under acidic conditions. Inhibition of eEF2K promotes cancer cell death under acidosis. PMID:25776553

Conditional knockout of N-WASP in mouse fibroblast caused keratinocyte hyper proliferation and enhanced wound closure

PubMed Central

Jain, Neeraj; Kalailingam, Pazhanichamy; Tan, Kai Wei; Tan, Hui Bing; Sng, Ming Keat; Chan, Jeremy Soon Kiat; Tan, Nguan Soon; Thanabalu, Thirumaran

2016-01-01

Neural-Wiskott Aldrich Syndrome Protein (N-WASP) is expressed ubiquitously, regulates actin polymerization and is essential during mouse development. We have previously shown that N-WASP is critical for cell-ECM adhesion in fibroblasts. To characterize the role of N-WASP in fibroblast for skin development, we generated a conditional knockout mouse model in which fibroblast N-WASP was ablated using the Cre recombinase driven by Fibroblast Specific Protein promoter (Fsp-Cre). N-WASPFKO (N-WASPfl/fl; Fsp-cre) were born following Mendelian genetics, survived without any visible abnormalities for more than 1 year and were sexually reproductive, suggesting that expression of N-WASP in fibroblast is not critical for survival under laboratory conditions. Histological sections of N-WASPFKO mice skin (13 weeks old) showed thicker epidermis with higher percentage of cells staining for proliferation marker (PCNA), suggesting that N-WASP deficient fibroblasts promote keratinocyte proliferation. N-WASPFKO mice skin had elevated collagen content, elevated expression of FGF7 (keratinocyte growth factor) and TGFβ signaling proteins. Wound healing was faster in N-WASPFKO mice compared to control mice and N-WASP deficient fibroblasts were found to have enhanced collagen gel contraction properties. These results suggest that N-WASP deficiency in fibroblasts improves wound healing by growth factor-mediated enhancement of keratinocyte proliferation and increased wound contraction in mice. PMID:27909303

Cellular Signaling by Fibroblast Growth Factors (FGFs) and Their Receptors (FGFRs) in Male Reproduction

PubMed Central

Cotton, Leanne M.; O’Bryan, Moira K.; Hinton, Barry T.

2008-01-01

The major function of the reproductive system is to ensure the survival of the species by passing on hereditary traits from one generation to the next. This is accomplished through the production of gametes and the generation of hormones that function in the maturation and regulation of the reproductive system. It is well established that normal development and function of the male reproductive system is mediated by endocrine and paracrine signaling pathways. Fibroblast growth factors (FGFs), their receptors (FGFRs), and signaling cascades have been implicated in a diverse range of cellular processes including: proliferation, apoptosis, cell survival, chemotaxis, cell adhesion, motility, and differentiation. The maintenance and regulation of correct FGF signaling is evident from human and mouse genetic studies which demonstrate that mutations leading to disruption of FGF signaling cause a variety of developmental disorders including dominant skeletal diseases, infertility, and cancer. Over the course of this review, we will provide evidence for differential expression of FGFs/FGFRs in the testis, male germ cells, the epididymis, the seminal vesicle, and the prostate. We will show that this signaling cascade has an important role in sperm development and maturation. Furthermore, we will demonstrate that FGF/FGFR signaling is essential for normal epididymal function and prostate development. To this end, we will provide evidence for the involvement of the FGF signaling system in the regulation and maintenance of the male reproductive system. PMID:18216218

Cellular signaling by fibroblast growth factors (FGFs) and their receptors (FGFRs) in male reproduction.

PubMed

Cotton, Leanne M; O'Bryan, Moira K; Hinton, Barry T

2008-04-01

The major function of the reproductive system is to ensure the survival of the species by passing on hereditary traits from one generation to the next. This is accomplished through the production of gametes and the generation of hormones that function in the maturation and regulation of the reproductive system. It is well established that normal development and function of the male reproductive system is mediated by endocrine and paracrine signaling pathways. Fibroblast growth factors (FGFs), their receptors (FGFRs), and signaling cascades have been implicated in a diverse range of cellular processes including: proliferation, apoptosis, cell survival, chemotaxis, cell adhesion, motility, and differentiation. The maintenance and regulation of correct FGF signaling is evident from human and mouse genetic studies which demonstrate that mutations leading to disruption of FGF signaling cause a variety of developmental disorders including dominant skeletal diseases, infertility, and cancer. Over the course of this review, we will provide evidence for differential expression of FGFs/FGFRs in the testis, male germ cells, the epididymis, the seminal vesicle, and the prostate. We will show that this signaling cascade has an important role in sperm development and maturation. Furthermore, we will demonstrate that FGF/FGFR signaling is essential for normal epididymal function and prostate development. To this end, we will provide evidence for the involvement of the FGF signaling system in the regulation and maintenance of the male reproductive system.

A Large-Scale RNAi Screen Identifies SGK1 as a Key Survival Kinase for GBM Stem Cells.

PubMed

Kulkarni, Shreya; Goel-Bhattacharya, Surbhi; Sengupta, Sejuti; Cochran, Brent H

2018-01-01

Glioblastoma multiforme (GBM) is the most common type of primary malignant brain cancer and has a very poor prognosis. A subpopulation of cells known as GBM stem-like cells (GBM-SC) have the capacity to initiate and sustain tumor growth and possess molecular characteristics similar to the parental tumor. GBM-SCs are known to be enriched in hypoxic niches and may contribute to therapeutic resistance. Therefore, to identify genetic determinants important for the proliferation and survival of GBM stem cells, an unbiased pooled shRNA screen of 10,000 genes was conducted under normoxic as well as hypoxic conditions. A number of essential genes were identified that are required for GBM-SC growth, under either or both oxygen conditions, in two different GBM-SC lines. Interestingly, only about a third of the essential genes were common to both cell lines. The oxygen environment significantly impacts the cellular genetic dependencies as 30% of the genes required under hypoxia were not required under normoxic conditions. In addition to identifying essential genes already implicated in GBM such as CDK4, KIF11 , and RAN , the screen also identified new genes that have not been previously implicated in GBM stem cell biology. The importance of the serum and glucocorticoid-regulated kinase 1 (SGK1) for cellular survival was validated in multiple patient-derived GBM stem cell lines using shRNA, CRISPR, and pharmacologic inhibitors. However, SGK1 depletion and inhibition has little effect on traditional serum grown glioma lines and on differentiated GBM-SCs indicating its specific importance in GBM stem cell survival. Implications: This study identifies genes required for the growth and survival of GBM stem cells under both normoxic and hypoxic conditions and finds SGK1 as a novel potential drug target for GBM. Mol Cancer Res; 16(1); 103-14. ©2017 AACR . ©2017 American Association for Cancer Research.

The canonical nuclear factor-κB pathway regulates cell survival in a developmental model of spinal cord motoneurons.

PubMed

Mincheva, Stefka; Garcera, Ana; Gou-Fabregas, Myriam; Encinas, Mario; Dolcet, Xavier; Soler, Rosa M

2011-04-27

In vivo and in vitro motoneuron survival depends on the support of neurotrophic factors. These factors activate signaling pathways related to cell survival or inactivate proteins involved in neuronal death. In the present work, we analyzed the involvement of the nuclear factor-κB (NF-κB) pathway in mediating mouse spinal cord motoneuron survival promoted by neurotrophic factors. This pathway comprises ubiquitously expressed transcription factors that could be activated by two different routes: the canonical pathway, associated with IKKα/IKKβ kinase phosphorylation and nuclear translocation RelA (p65)/p50 transcription factors; and the noncanonical pathway, related to IKKα kinase homodimer phosphorylation and RelB/p52 transcription factor activation. In our system, we show that neurotrophic factors treatment induced IKKα and IKKβ phosphorylation and RelA nuclear translocation, suggesting NF-κB pathway activation. Protein levels of different members of the canonical or noncanonical pathways were reduced in a primary culture of isolated embryonic motoneurons using an interference RNA approach. Even in the presence of neurotrophic factors, selective reduction of IKKα, IKKβ, or RelA proteins induced cell death. In contrast, RelB protein reduction did not have a negative effect on motoneuron survival. Together these results demonstrated that the canonical NF-κB pathway mediates motoneuron survival induced by neurotrophic factors, and the noncanonical pathway is not related to this survival effect. Canonical NF-κB blockade induced an increase of Bim protein level and apoptotic cell death. Bcl-x(L) overexpression or Bax reduction counteracted this apoptotic effect. Finally, RelA knockdown causes changes of CREB and Smn protein levels.

Evolutionary Ecology of Organs: A Missing Link in Cancer Development?

PubMed

Thomas, Frédéric; Nesse, Randolph M; Gatenby, Robert; Gidoin, Cindy; Renaud, François; Roche, Benjamin; Ujvari, Beata

2016-08-01

There is striking variation in the incidence of cancer in human organs. Malignant tumors are common in the colon and breast but rare in the heart and small bowel. The uterus frequently develops benign fibroid tumors but uterine cancers are relatively rare. The organ-specific difference in cancer prevalence has been explained primarily by the relative roles of intrinsic and extrinsic risk factors. In this opinion article, we propose also considering organs as distinct but connected ecosystems whose different vulnerabilities to malignant transformation may be partially explained by how essential each organ is for survival through the age of reproduction. We present and discuss some of the basic concepts and assumptions of this perspective on evolutionary medicine. Copyright © 2016 Elsevier Inc. All rights reserved.

Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus

PubMed Central

Foster, Timothy J.; Geoghegan, Joan A.; Ganesh, Vannakambadi K.; Höök, Magnus

2014-01-01

Staphylococcus aureus is an important opportunistic pathogen and persistently colonizes about 20% of the human population. Its surface is ‘decorated’ with proteins that are covalently anchored to the cell wall peptidoglycan. Structural and functional analysis has identified four distinct classes of surface proteins, of which microbial surface component recognizing adhesive matrix molecules (MSCRAMMs) are the largest class. These surface proteins have numerous functions, including adhesion to and invasion of host cells and tissues, evasion of immune responses and biofilm formation. Thus, cell wall-anchored proteins are essential virulence factors for the survival of S. aureus in the commensal state and during invasive infections, and targeting them with vaccines could combat S. aureus infections. PMID:24336184

Racial and ethnic disparities in outcomes after heart transplantation: A systematic review of contributing factors and future directions to close the outcomes gap.

PubMed

Morris, Alanna A; Kransdorf, Evan P; Coleman, Bernice L; Colvin, Monica

2016-08-01

The demographics of patients undergoing heart transplantation in the United States have shifted over the last 10 years, with an increasing number of racial and ethnic minorities undergoing heart transplant. Multiple studies have shown that survival of African American patients after heart transplantation is lower compared with other ethnic groups. We review the data supporting the presence of this outcome disparity and examine the multiple mechanisms that contribute. With an increasingly diverse population in the United States, knowledge of these disparities, their mechanisms, and ways to improve outcomes is essential. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

The nursing care of the infant receiving bubble CPAP therapy.

PubMed

Bonner, Krista M; Mainous, Rosalie O

2008-04-01

There are increasing numbers of low birth-weight and premature infants surviving with conditions such as chronic lung disease or bronchopulmonary dysplasia due to complications of assisted mechanical ventilation and other factors. Continuous positive airway pressure (CPAP) has been used as an alternative respiratory treatment to prevent and manage lung disease in preterm infants since the 1970s. Evidence has demonstrated the usefulness of CPAP in the delivery room, as a rescue therapy, as an extubation tool, and a method for managing apnea of prematurity. Bubble CPAP is a unique, simple, inexpensive way of providing continuous positive pressure to infants. Some background and training in the setup, care, and evaluation of the infant on bubble CPAP is essential for positive outcomes.

Detection of vulnerable neurons damaged by environmental insults in utero

PubMed Central

Torii, Masaaki; Chang, Yu-Wen; Ishii, Seiji; Waxman, Stephen G.; Kocsis, Jeffery D.; Rakic, Pasko; Hashimoto-Torii, Kazue

2017-01-01

Development of prognostic biomarkers for the detection of prenatally damaged neurons before manifestations of postnatal disorders is an essential step for prevention and treatment of susceptible individuals. We have developed a versatile fluorescence reporter system in mice enabling detection of Heat Shock Factor 1 activation in response to prenatal cellular damage caused by exposure to various harmful chemical or physical agents. Using an intrautero electroporation-mediated reporter assay and transgenic reporter mice, we are able to identify neurons that survive prenatal exposure to harmful agents but remain vulnerable in postnatal life. This system may provide a powerful tool for exploring the pathogenesis and treatment of multiple disorders caused by exposure to environmental stress before symptoms become manifested, exacerbated, and/or irreversible. PMID:28123061

Factors predicting survival following noninvasive ventilation in amyotrophic lateral sclerosis.

PubMed

Peysson, S; Vandenberghe, N; Philit, F; Vial, C; Petitjean, T; Bouhour, F; Bayle, J Y; Broussolle, E

2008-01-01

The involvement of respiratory muscles is a major predicting factor for survival in amyotrophic lateral sclerosis (ALS). Recent studies show that noninvasive ventilation (NIV) can relieve symptoms of alveolar hypoventilation. However, factors predicting survival in ALS patients when treated with NIV need to be clarified. We conducted a retrospective study of 33 consecutive ALS patients receiving NIV. Ten patients had bulbar onset. We determined the median survivals from onset, diagnosis and initiation of NIV and factors predicting survival. Statistical analysis was performed using the Kaplan-Meier test and Cox proportional hazard models. The median initial and maximal total uses of NIV were 10 and 14 h/24h. The overall median survival from ALS onset was 34.2 months and worsened with increasing age and bulbar onset of the disease. The median survival from initiation of NIV was 8.4 months and was significantly poorer in patients with advanced age or with airway mucus accumulation. Survival from initiation of NIV was not influenced by respiratory parameters or bulbar symptoms. Advanced age at diagnosis and airway mucus accumulation represent poorer prognostic factors of ALS patients treated with NIV. NIV is a helpful treatment of sleep-disordered breathing, including patients with bulbar involvement. Copyright 2008 S. Karger AG, Basel.

Factors Associated with Life Expectancy in Patients with Metastatic Spine Disease from Adenocarcinoma of the Lung

PubMed Central

Goodwin, C. Rory; Khattab, Mohamed H.; Sankey, Eric W.; Elder, Benjamin D.; Kosztowski, Thomas A.; Sarabia-Estrada, Rachel; Bydon, Ali; Witham, Timothy F.; Wolinsky, Jean-Paul; Gokaslan, Ziya L.; Sciubba, Daniel M.

2015-01-01

Study Design Retrospective study. Objective Our objective was to identify preoperative prognostic factors associated with survival in patients with spinal metastasis from lung carcinoma. Methods A retrospective analysis of 26 patients diagnosed with lung carcinoma metastatic to the spinal column was performed to determine factors associated with survival. We used 3 months survival as the clinical cutoff for whether surgical intervention should be performed. We analyzed patients who survived less than 3 months compared with those who survived more than 3 months. Demographic, preoperative, operative, and postoperative factors including functional scores were collected for analysis. Results The median survival for all patients in our study was 3.5 months. We found a statistically significant difference between the group that survived less than 3 months and the group that survived greater than 3 months in terms of extrathoracic metastasis, visceral metastasis, and average postoperative modified Rankin score. Conclusion Determining which patients with lung cancer spinal metastases will benefit from surgical intervention is often dictated by the patient's predicted life expectancy. Factors associated with poorer prognosis include age, functional status, visceral metastases, and extrathoracic metastases. Although the prognosis for patients with lung cancer spinal metastases is poor, some patients may experience long-term benefit from surgical intervention. PMID:26430597

Results of liver transplantation in patients with acute liver failure due to Amanita phalloides and paracetamol (acetaminophen) intoxication

PubMed Central

Grąt, Michał; Hołówko, Wacław; Masior, Łukasz; Wronka, Karolina M.; Grąt, Karolina; Stypułkowski, Jan; Patkowski, Waldemar; Krawczyk, Marek

2015-01-01

Introduction Amanita phalloides and paracetamol intoxications are responsible for the majority of acute liver failures. Aim To assess survival outcomes and to analyse risk factors affecting survival in the studied group. Material and methods Of 1369 liver transplantations performed in the Department of General, Transplant, and Liver Surgery, Medical University of Warsaw before December 2013, 20 (1.46%) patients with Amanita phalloides (n = 13, 0.95%) and paracetamol (n = 7, 0.51%) intoxication were selected for this retrospective study. Overall and graft survival at 5 years were set as primary outcome measures. Results Five-year overall survival after liver transplantation in the studied group was 53.57% and 53.85% in patients with paracetamol and Amanita phalloides poisoning, respectively (p = 0.816). Five-year graft survival was 26.79% for patients with paracetamol and 38.46% with Amanita phalloides intoxication (p = 0.737). Risk factors affecting patient survival were: pre-transplant bilirubin concentration (p = 0.023) and higher number of red blood cells (p = 0.013) and fresh frozen plasma (p = 0.004) transfused intraoperatively. Likewise, higher number of red blood cells (p = 0.012) and fresh frozen plasma (p = 0.007) transfused were risk factors affecting 5-year graft survival. Surprisingly, donor and recipient blood type incompatibility was neither the risk factor for 5-year overall survival (p = 0.939) nor the risk factor for 5-year graft survival (p = 0.189). Conclusions In selected intoxicated patients urgent liver transplantation is the only successful modality of treatment. Risk factors affecting survival are in correspondence with the patient's pre-transplant status (bilirubin level in serum) and intraoperative status (number of red blood cells and fresh frozen plasma transfused). PMID:27350835

Stage is a prognostic factor for surgically treated patients with early-stage lip cancer for whom a 'wait and see' policy in terms of neck status has been implemented.

PubMed

Eskiizmir, G; Ozgur, E; Karaca, G; Temiz, P; Yanar, N Hacioglu; Ozyurt, B Cengiz

2017-10-01

To determine the locoregional control and survival rates (in terms of risk factors) of patients who underwent surgical resection of early-stage lip cancer and for whom a 'wait and see' policy in terms of neck status had been implemented. The sociodemographic data, tumour stage, tumour characteristics and histopathological features of 41 patients with early-stage lip cancer were evaluated. Factors predictive of survival and locoregional recurrence were analysed. The five-year overall survival and disease-free survival rates were determined, and the prognostic risk factors were compared. The mean follow-up period was 60.5 months (range, 4-92 months). Age, sex, tumour stage, tumour thickness and volume, and perineural involvement were not predictive of locoregional recurrence or survival. Pathological tumour stage (T1 vs T2) was a prognostic factor for both five-year overall survival (87.3 vs 65.6 per cent, p = 0.042) and disease-free survival (88.6 vs 65.6 per cent, p = 0.037). Tumour stage was clearly a major factor affecting the prognosis of surgically treated patients with early-stage lip cancer for whom a 'wait and see' policy in terms of neck status had been implemented.

Relevance of both individual risk factors and occupational exposure in cancer survival studies: the example of intestinal type sinonasal adenocarcinoma.

PubMed

Tripodi, Dominique; Ferron, Christophe; Malard, Olivier; de Montreuil, Claude Beauvillain; Planche, Lucie; Sebille-Rivain, Veronique; Roedlich, Claude; Quéméner, Sylvia; Renaudin, Karine; Longuenesse, Claire; Verger, Christian; Meflah, Khaled; Gratas, Catherine; Géraut, Christian

2011-09-01

Wood dust is a well-established risk factor for intestinal type sinonasal adenocarcinoma. The 5-year overall survival has varied from 20% to 80% according T1-T4 stages; 5-year survival according to histologic subtype has varied from 20% to 50%. To date, no study has evaluated whether environmental, occupational, and personal risk factors have any impact on both overall and cancer-specific survival. We aimed to determine whether exposure to carcinogenic risk factors besides wood exposure can influence the survival of patients with sinonasal ethmoid carcinoma. Retrospective cohort study of the association of survival data and occupational and personal carcinogenic risk factors. All patients hospitalized for ethmoid adenocarcinoma at the Nantes University Hospital between 1988 and 2004 were included . Data concerning TNM classification, histology, type and quality of tumor resection at the macro- and microscopic level, and occupational and personal exposure to carcinogens were collected. Statistical analysis was conducted using univariate and multivariate linear regression. A total of 98 patients were included with a response rate of 98%. Data showed 86% of patients had been exposed to wood dust. The 5-year survival was 62%. We first identified four factors that independently influenced overall survival: diplopia (P = .0159), spread to the orbit (P = .0113), bilateral involvement (P = .0134), TNM stage (P < .001). When the analysis included all occupational environmental factors (wood dust, solvent, and metals exposure) as well as personal risk factors, the length of exposure to metals (P = .0307) and tobacco exposure (P = .0031) also were found to influence 5-year overall survival. We identified high prevalence of colon cancer (4%) and double cancer (18%). We showed exposure to both environmental (tobacco) and occupational (metal dust) factors could influence survival in the diagnosis of a cancer. Our study suggests that screening for colon cancer should be offered to wood dust workers. A prospective multicentric study should be necessary to confirm our results. Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.

Long-term disease-free survival in advanced melanomas treated with nitrosoureas: mechanisms and new perspectives.

PubMed

Durando, Xavier; Thivat, Emilie; D'Incan, Michel; Sinsard, Anne; Madelmont, Jean-Claude; Chollet, Philippe

2005-11-15

Median survival of metastatic malignant melanoma is 6.0 to 7.5 months, with a 5-year survival of approximately 6.0%. Although long-term complete remissions are rare, few reports describe cases after chemotherapy. Fifty-three patients with metastatic melanoma were treated with Cystemustine, a chloroethyl nitrosourea (CENU) (60 or 90 mg/m2). We describe 5 cases, presenting with complete response with long-term disease-free survival of long-term remission of 14, 12, 9, 7 and 6 years after Cystemustine therapy alone. Long-term survival has already been described in literature, but in all cases they have been obtained after chemotherapy associated with or followed by surgery. But despite these noteworthy and encouraging but also rare results, it appears essential to increase Cystemustine efficiency.

Analysis of the Salmonella regulatory network suggests involvement of SsrB and H-NS in σ E-regulated SPI-2 gene expression

DOE PAGES

Li, Jie; Overall, Christopher C.; Nakayasu, Ernesto S.; ...

2015-02-10

The extracytoplasmic functioning sigma factor σ E is known to play an essential role for Salmonella enterica serovar Typhimurium to survive and proliferate in macrophages and mice. However, its regulatory network is not well characterized, especially during infection. Here we used microarray to identify genes regulated by σ E in Salmonella grown in three conditions: a nutrient-rich condition and two others that mimic early and late intracellular infection. We found that in each condition σ E regulated different sets of genes, and notably, several global regulators. When comparing nutrient-rich and infection-like conditions, large changes were observed in the expression ofmore » genes involved in Salmonella pathogenesis island (SPI)-1 type-three secretion system (TTSS), SPI-2 TTSS, protein synthesis, and stress responses. In total, the expression of 58% of Salmonella genes was affected by σ E in at least one of the three conditions. An important finding is that σ E up-regulates SPI-2 genes, which are essential for Salmonella intracellular survival, by up-regulating SPI-2 activator ssrB expression at the early stage of infection and down-regulating SPI-2 repressor hns expression at a later stage. Moreover, σ E is capable of countering the silencing of H-NS, releasing the expression of SPI-2 genes. This connection between σ E and SPI-2 genes, combined with the global regulatory effect of σ E, may account for the lethality of rpoE-deficient Salmonella in murine infection.« less

Analysis of the Salmonella regulatory network suggests involvement of SsrB and H-NS in σ E-regulated SPI-2 gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Jie; Overall, Christopher C.; Nakayasu, Ernesto S.

The extracytoplasmic functioning sigma factor σ E is known to play an essential role for Salmonella enterica serovar Typhimurium to survive and proliferate in macrophages and mice. However, its regulatory network is not well characterized, especially during infection. Here we used microarray to identify genes regulated by σ E in Salmonella grown in three conditions: a nutrient-rich condition and two others that mimic early and late intracellular infection. We found that in each condition σ E regulated different sets of genes, and notably, several global regulators. When comparing nutrient-rich and infection-like conditions, large changes were observed in the expression ofmore » genes involved in Salmonella pathogenesis island (SPI)-1 type-three secretion system (TTSS), SPI-2 TTSS, protein synthesis, and stress responses. In total, the expression of 58% of Salmonella genes was affected by σ E in at least one of the three conditions. An important finding is that σ E up-regulates SPI-2 genes, which are essential for Salmonella intracellular survival, by up-regulating SPI-2 activator ssrB expression at the early stage of infection and down-regulating SPI-2 repressor hns expression at a later stage. Moreover, σ E is capable of countering the silencing of H-NS, releasing the expression of SPI-2 genes. This connection between σ E and SPI-2 genes, combined with the global regulatory effect of σ E, may account for the lethality of rpoE-deficient Salmonella in murine infection.« less

Simple ecological trade-offs give rise to emergent cross-ecosystem distributions of a coral reef fish.

PubMed

Grol, Monique G G; Nagelkerken, Ivan; Rypel, Andrew L; Layman, Craig A

2011-01-01

Ecosystems are intricately linked by the flow of organisms across their boundaries, and such connectivity can be essential to the structure and function of the linked ecosystems. For example, many coral reef fish populations are maintained by the movement of individuals from spatially segregated juvenile habitats (i.e., nurseries, such as mangroves and seagrass beds) to areas preferred by adults. It is presumed that nursery habitats provide for faster growth (higher food availability) and/or low predation risk for juveniles, but empirical data supporting this hypothesis is surprisingly lacking for coral reef fishes. Here, we investigate potential mechanisms (growth, predation risk, and reproductive investment) that give rise to the distribution patterns of a common Caribbean reef fish species, Haemulon flavolineatum (French grunt). Adults were primarily found on coral reefs, whereas juvenile fish only occurred in non-reef habitats. Contrary to our initial expectations, analysis of length-at-age revealed that growth rates were highest on coral reefs and not within nursery habitats. Survival rates in tethering trials were 0% for small juvenile fish transplanted to coral reefs and 24-47% in the nurseries. As fish grew, survival rates on coral reefs approached those in non-reef habitats (56 vs. 77-100%, respectively). As such, predation seems to be the primary factor driving across-ecosystem distributions of this fish, and thus the primary reason why mangrove and seagrass habitats function as nursery habitat. Identifying the mechanisms that lead to such distributions is critical to develop appropriate conservation initiatives, identify essential fish habitat, and predict impacts associated with environmental change.

Simple ecological trade-offs give rise to emergent cross-ecosystem distributions of a coral reef fish

PubMed Central

Grol, Monique G. G.; Rypel, Andrew L.; Layman, Craig A.

2010-01-01

Ecosystems are intricately linked by the flow of organisms across their boundaries, and such connectivity can be essential to the structure and function of the linked ecosystems. For example, many coral reef fish populations are maintained by the movement of individuals from spatially segregated juvenile habitats (i.e., nurseries, such as mangroves and seagrass beds) to areas preferred by adults. It is presumed that nursery habitats provide for faster growth (higher food availability) and/or low predation risk for juveniles, but empirical data supporting this hypothesis is surprisingly lacking for coral reef fishes. Here, we investigate potential mechanisms (growth, predation risk, and reproductive investment) that give rise to the distribution patterns of a common Caribbean reef fish species, Haemulon flavolineatum (French grunt). Adults were primarily found on coral reefs, whereas juvenile fish only occurred in non-reef habitats. Contrary to our initial expectations, analysis of length-at-age revealed that growth rates were highest on coral reefs and not within nursery habitats. Survival rates in tethering trials were 0% for small juvenile fish transplanted to coral reefs and 24–47% in the nurseries. As fish grew, survival rates on coral reefs approached those in non-reef habitats (56 vs. 77–100%, respectively). As such, predation seems to be the primary factor driving across-ecosystem distributions of this fish, and thus the primary reason why mangrove and seagrass habitats function as nursery habitat. Identifying the mechanisms that lead to such distributions is critical to develop appropriate conservation initiatives, identify essential fish habitat, and predict impacts associated with environmental change. PMID:21072542

Survival strategies of elderly women in Ngangelizwe Township, Mthatha, South Africa: Livelihoods, social networks and income.

PubMed

Sidloyi, Sinethemba S; Bomela, Nolunkcwe J

2016-01-01

This study seeks to examine the critical issue of how the elderly women of Ngangelizwe, Mthatha, Eastern Cape, South Africa address the challenges they encounter in their attempts to provide for their needs and those of their dependants. These challenges include among others lack of education, access to resources, caring for their sick children suffering from AIDS related diseases as well as their orphaned grandchildren. In-depth interviews were held with 15 retired women above 60 years old who are also heads of households, receiving or not receiving state pension, and/or a child support grant. The study reveals that friendship-based ties, social networks and their impact on the livelihoods, health, survival and social adjustment of the elderly women are essential components of their lives. The study also reports on the strategies they employ to alleviate poverty through their own and school-going age grandchildren's participation in income generating activities. The study indicates that for most women, the inability to attain basic essentials of life leads to loss of self-dignity. Socio-economic factors such as low levels of education, unemployment, little or no income, poor access to resources, many dependants and looking after their children who are ill creates a situation where they operate within the "little opportunities" circle. The evidence in this study suggests that friendship-based ties, social groups, including social capital, pension grants, child support grants and remittances from their employed children help to mitigate some of the poverty experiences of the elderly women. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Disrupting mitochondrial Ca2+ homeostasis causes tumor-selective TRAIL sensitization through mitochondrial network abnormalities.

PubMed

Ohshima, Yohei; Takata, Natsuhiko; Suzuki-Karasaki, Miki; Yoshida, Yukihiro; Tokuhashi, Yasuaki; Suzuki-Karasaki, Yoshihiro

2017-10-01

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent with high tumor-selective cytotoxicity. The congenital and acquired resistance of some cancer types including malignant melanoma and osteosarcoma impede the current TRAIL therapy of these cancers. Since fine tuning of the intracellular Ca2+ level is essential for cell function and survival, Ca2+ dynamics could be a promising target for cancer treatment. Recently, we demonstrated that mitochondrial Ca2+ removal increased TRAIL efficacy toward malignant melanoma and osteosarcoma cells. Here we report that mitochondrial Ca2+ overload leads to tumor-selective sensitization to TRAIL cytotoxicity. Treatment with the mitochondrial Na+/Ca2+ exchanger inhibitor CGP-37157 and oxidative phosphorylation inhibitor antimycin A and FCCP resulted in a rapid and persistent mitochondrial Ca2+ rise. These agents also increased TRAIL sensitivity in a tumor-selective manner with a switching from apoptosis to a nonapoptotic cell death. Moreover, we found that mitochondrial Ca2+ overload led to increased mitochondrial fragmentation, while mitochondrial Ca2+ removal resulted in mitochondrial hyperfusion. Regardless of their reciprocal actions on the mitochondrial dynamics, both interventions commonly exacerbated TRAIL-induced mitochondrial network abnormalities. These results expand our previous study and suggest that an appropriate level of mitochondrial Ca2+ is essential for maintaining the mitochondrial dynamics and the survival of these cells. Thus, disturbing mitochondrial Ca2+ homeostasis may serve as a promising approach to overcome the TRAIL resistance of these cancers with minimally compromising the tumor-selectivity.

Aberrant expression of cancer stem cell markers (CD44, CD90, and CD133) contributes to disease progression and reduced survival in hepatoblastoma patients: 4-year survival data.

PubMed

Bahnassy, Abeer A; Fawzy, Mohamed; El-Wakil, Mohamed; Zekri, Abdel-Rahman N; Abdel-Sayed, Ahmed; Sheta, Marwa

2015-03-01

Hepatoblastoma (HB) is an embryonal tumor of the liver in children. Prognosis and response to treatment in HB are highly variable. Cancer stem cells (CSCs) constitute a population of cells, which contribute to the development and progression of many tumors. However, their role in HB is not well defined yet. We assessed the prognostic and predictive values of some CSC markers in HB patients. Protein and messenger RNA expressions of the CSC markers CD133, CD90, and CD44 were assessed in 43 HB patients and 20 normal hepatic tissues using immunohistochemistry and quantitative real-time polymerase chain reaction. The expression levels of these markers were correlated to standard prognostic factors, patients' response to treatment, overall survival (OS), and disease-free survival (DFS). CD44, CD90, and CD133 proteins were detected in 48.8%, 32.6%, and 48.8% compared with 46.5%, 41.7%, and 58.1% RNA, respectively (concordance, 77.8%-96%). None of the normal tissue samples was positive for any of the markers. Significant correlations were reported between α-fetoprotein and both CD44 and CD133 (P = 0.02) as well as between tumor types CD90 and CD133 (P = 0.009). Reduced OS correlated with CD44, CD90, and CD133 expressions (P < 0.001), advanced stage (P < 0.001), response to treatment (P < 0.001), and total excision of the tumor. Reduced DFS correlated with CD44 and CD133 expressions (P < 0.001) only. In conclusion, CD133, CD44, and CD90 could be used as prognostic and predictive markers in HB. High expression of these markers is significantly associated with poor response to treatment and reduced survival. Moreover, complete surgical resection and systemic chemotherapy are essential to achieve good response and prolonged survival, especially in early stage patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Increased Cdc7 expression is a marker of oral squamous cell carcinoma and overexpression of Cdc7 contributes to the resistance to DNA-damaging agents.

PubMed

Cheng, An Ning; Jiang, Shih Sheng; Fan, Chi-Chen; Lo, Yu-Kang; Kuo, Chan-Yen; Chen, Chung-Hsing; Liu, Ying-Lan; Lee, Chun-Chung; Chen, Wei-Shone; Huang, Tze-Sing; Wang, Tao-Yeuan; Lee, Alan Yueh-Luen

2013-09-01

Cdc7-Dbf4 kinase (Dbf4-dependent kinase, DDK) is an essential factor of DNA replication and DNA damage response (DDR), which is associated with tumorigenesis. However, Cdc7 expression has never been associated to the outcome of oral squamous cell carcinoma (OSCC) patients, and the mechanism underlying cancer cell survival mediated by Cdc7 remains unclear. The Cdc7 protein expression of 105 OSCC tumor and 30 benign tissues was examined by immunohistochemistry assay. Overall survival rates of 80 OSCC patients were measured using Kaplan-Meier estimates and the log-rank tests. Cdc7 overexpression by adenovirus system was used to scrutinize the underlying mechanism contributed to cancer cell survival upon DDR. In silico analysis showed that increased Cdc7 is a common feature of cancer. Cdc7 overexpression was found in 96 of 105 (91.4%) studied cases of OSCC patients. Patients with higher Cdc7 expression, either categorized into two groups: Cdc7 high expression (2+ to 3+) versus Cdc7 low expression (0 to 1+) [hazard ratios (HR)=2.6; 95% confidence interval (CI)=1.28-5.43; P=0.0087] or four groups (0 to 3+) [HR=1.71; 95% CI=1.20-2.44; P=0.0032], exhibited a poorer outcome. Multivariate analysis showed that Cdc7 is an independent marker for survival prediction. Overexpressed Cdc7 inhibits genotoxin-induced apoptosis to increase the survival of cancer cells. In summary, Cdc7 expression, which is universally upregulated in cancer, is an independent prognostic marker of OSCC. Cdc7 inhibits genotoxin-induced apoptosis and increases survival in cancer cells upon DDR, suggesting that high expression of Cdc7 enhances the resistance to chemotherapy. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Essential role of the TFIID subunit TAF4 in murine embryogenesis and embryonic stem cell differentiation

PubMed Central

Langer, Diana; Martianov, Igor; Alpern, Daniel; Rhinn, Muriel; Keime, Céline; Dollé, Pascal; Mengus, Gabrielle; Davidson, Irwin

2016-01-01

TAF4 (TATA-binding protein-associated factor 4) and its paralogue TAF4b are components of the TFIID core module. We inactivated the murine Taf4a gene to address Taf4 function during embryogenesis. Here we show that Taf4a−/− embryos survive until E9.5 where primary germ layers and many embryonic structures are identified showing Taf4 is dispensable for their specification. In contrast, Taf4 is required for correct patterning of the trunk and anterior structures, ventral morphogenesis and proper heart positioning. Overlapping expression of Taf4a and Taf4b during embryogenesis suggests their redundancy at early stages. In agreement with this, Taf4a−/− embryonic stem cells (ESCs) are viable and comprise Taf4b-containing TFIID. Nevertheless, Taf4a−/− ESCs do not complete differentiation into glutamatergic neurons and cardiomyocytes in vitro due to impaired preinitiation complex formation at the promoters of critical differentiation genes. We define an essential role of a core TFIID TAF in differentiation events during mammalian embryogenesis. PMID:27026076

Essential role of the TFIID subunit TAF4 in murine embryogenesis and embryonic stem cell differentiation.

PubMed

Langer, Diana; Martianov, Igor; Alpern, Daniel; Rhinn, Muriel; Keime, Céline; Dollé, Pascal; Mengus, Gabrielle; Davidson, Irwin

2016-03-30

TAF4 (TATA-binding protein-associated factor 4) and its paralogue TAF4b are components of the TFIID core module. We inactivated the murine Taf4a gene to address Taf4 function during embryogenesis. Here we show that Taf4a(-/-) embryos survive until E9.5 where primary germ layers and many embryonic structures are identified showing Taf4 is dispensable for their specification. In contrast, Taf4 is required for correct patterning of the trunk and anterior structures, ventral morphogenesis and proper heart positioning. Overlapping expression of Taf4a and Taf4b during embryogenesis suggests their redundancy at early stages. In agreement with this, Taf4a(-/-) embryonic stem cells (ESCs) are viable and comprise Taf4b-containing TFIID. Nevertheless, Taf4a(-/-) ESCs do not complete differentiation into glutamatergic neurons and cardiomyocytes in vitro due to impaired preinitiation complex formation at the promoters of critical differentiation genes. We define an essential role of a core TFIID TAF in differentiation events during mammalian embryogenesis.

The Gut Microbiome of the Vector Lutzomyia longipalpis Is Essential for Survival of Leishmania infantum

PubMed Central

Kelly, Patrick H.; Bahr, Sarah M.; Serafim, Tiago D.; Ajami, Nadim J.; Petrosino, Joseph F.; Meneses, Claudio; Kirby, John R.; Valenzuela, Jesus G.; Kamhawi, Shaden

2017-01-01

ABSTRACT The vector-borne disease leishmaniasis, caused by Leishmania species protozoa, is transmitted to humans by phlebotomine sand flies. Development of Leishmania to infective metacyclic promastigotes in the insect gut, a process termed metacyclogenesis, is an essential prerequisite for transmission. Based on the hypothesis that vector gut microbiota influence the development of virulent parasites, we sequenced midgut microbiomes in the sand fly Lutzomyia longipalpis with or without Leishmania infantum infection. Sucrose-fed sand flies contained a highly diverse, stable midgut microbiome. Blood feeding caused a decrease in microbial richness that eventually recovered. However, bacterial richness progressively decreased in L. infantum-infected sand flies. Acetobacteraceae spp. became dominant and numbers of Pseudomonadaceae spp. diminished coordinately as the parasite underwent metacyclogenesis and parasite numbers increased. Importantly, antibiotic-mediated perturbation of the midgut microbiome rendered sand flies unable to support parasite growth and metacyclogenesis. Together, these data suggest that the sand fly midgut microbiome is a critical factor for Leishmania growth and differentiation to its infective state prior to disease transmission. PMID:28096483

Factors affecting nest survival of Henslow's Sparrows (Ammodramus henslowii) in southern Indiana

USGS Publications Warehouse

Crimmins, Shawn M.; McKann, Patrick C.; Robb, Joseph R.; Lewis, Jason P.; Vanosdol, Teresa; Walker, Benjamin A.; Williams, Perry J.; Thogmartin, Wayne E.

2016-01-01

Populations of Henslow’s Sparrows have declined dramatically in recent decades, coinciding with widespread loss of native grassland habitat. Prescribed burning is a primary tool for maintaining grassland patches, but its effects on nest survival of Henslow’s Sparrows remains largely unknown, especially in conjunction with other factors. We monitored 135 nests of Henslow’s Sparrows at Big Oaks National Wildlife Refuge in southern Indiana from 1998–2001 in an effort to understand factors influencing nest survival, including prescribed burning of habitat. We used a mixed-effects implementation of the logistic exposure model to predict daily nest survival in an information theoretic framework. We found that daily survival declined near the onset of hatching and increased with the height of standing dead vegetation, although this relationship was weak. We found only nominal support to suggest that time since burn influenced nest survival. Overall, nest age was the most important factor in estimating daily nest survival rates. Our daily survival estimate from our marginal model (0.937) was similar to that derived from the Mayfield method (0.944) suggesting that our results are comparable to previous studies using the Mayfield approach. Our results indicate that frequent burning to limit woody encroachment into grassland habitats might benefit Henslow’s Sparrow, but that a variety of factors ultimately influence daily nest survival. However, we note that burning too frequently can also limit occupancy by Henslow’s Sparrows. We suggest that additional research is needed to determine the population-level consequences of habitat alteration and if other extrinsic factors influence demographics of Henslow’s Sparrows.

A Medium-Throughput Single Cell CRISPR-Cas9 Assay to Assess Gene Essentiality.

PubMed

Grassian, A R; Scales, T M E; Knutson, S K; Kuntz, K W; McCarthy, N J; Lowe, C E; Moore, J D; Copeland, R A; Keilhack, H; Smith, J J; Wickenden, J A; Ribich, S

2015-01-01

Target selection for oncology is a crucial step in the successful development of therapeutics. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of specific loci offers an alternative method to RNA interference and small molecule inhibitors for determining whether a cell line is dependent on a specific gene product for proliferation or survival. In our initial studies using CRISPR-Cas9 to verify the dependence on EZH2 activity for proliferation of a SMARCB1/SNF5/INI1 mutant malignant rhabdoid tumor (MRT) cell line, we noted that the initial reduction in proliferation was lost over time. We hypothesized that in the few cells that retain proliferative capacity, at least one allele of EZH2 remains functional. To verify this, we developed an assay to analyze 10s-100s of clonal cell populations for target gene disruption using restriction digest and fluorescent fragment length analyses. Our results clearly show that in cell lines in which EZH2 is essential for proliferation, at least one potentially functional allele of EZH2 is retained in the clones that survive. This assay clearly indicates whether or not a specific gene is essential for survival and/or proliferation in a given cell line. Such data can aid the development of more robust therapeutics by increasing confidence in target selection.

The Activity of a Hexameric M17 Metallo-Aminopeptidase Is Associated With Survival of Mycobacterium tuberculosis

PubMed Central

Correa, Andre F.; Bastos, Izabela M. D.; Neves, David; Kipnis, Andre; Junqueira-Kipnis, Ana P.; de Santana, Jaime M.

2017-01-01

Mycobacterium tuberculosis is one of the most prevalent human pathogens causing millions of deaths in the last years. Moreover, tuberculosis (TB) treatment has become increasingly challenging owing to the emergence of multidrug resistant M. tuberculosis strains. Thus, there is an immediate need for the development of new anti-TB drugs. Proteases appear to be a promising approach and may lead to shortened and effective treatments for drug-resistant TB. Although the M. tuberculosis genome predicts more than 100 genes encoding proteases, only a few of them have been studied. Aminopeptidases constitute a set of proteases that selectively remove amino acids from the N-terminus of proteins and peptides and may act as virulence factors, essential for survival and maintenance of many microbial pathogens. Here, we characterized a leucine aminopeptidase of M. tuberculosis (MtLAP) as a cytosolic oligomeric metallo-aminopeptidase. Molecular and enzymatic properties lead us to classify MtLAP as a typical member of the peptidase family M17. Furthermore, the aminopeptidase inhibitor bestatin strongly inhibited MtLAP activity, in vitro M. tuberculosis growth and macrophage infection. In murine model of TB, bestatin treatment reduced bacterial burden and lesion in the lungs of infected mice. Thus, our data suggest that MtLAP participates in important metabolic pathways of M. tuberculosis necessary for its survival and virulence and consequently may be a promising target for new anti-TB drugs. PMID:28396657

Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765

PubMed Central

Herman, Sarah E. M.; Gordon, Amber L.; Hertlein, Erin; Ramanunni, Asha; Zhang, Xiaoli; Jaglowski, Samantha; Flynn, Joseph; Jones, Jeffrey; Blum, Kristie A.; Buggy, Joseph J.; Hamdy, Ahmed

2011-01-01

B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell–specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted. PMID:21422473

Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock.

PubMed

Gazit, Salomé L; Mariko, Boubacar; Thérond, Patrice; Decouture, Benoit; Xiong, Yuquan; Couty, Ludovic; Bonnin, Philippe; Baudrie, Véronique; Le Gall, Sylvain M; Dizier, Blandine; Zoghdani, Nesrine; Ransinan, Jessica; Hamilton, Justin R; Gaussem, Pascale; Tharaux, Pierre-Louis; Chun, Jerold; Coughlin, Shaun R; Bachelot-Loza, Christilla; Hla, Timothy; Ho-Tin-Noé, Benoit; Camerer, Eric

2016-09-30

Sphingosine-1-phosphate (S1P) signaling is essential for vascular development and postnatal vascular homeostasis. The relative importance of S1P sources sustaining these processes remains unclear. To address the level of redundancy in bioactive S1P provision to the developing and mature vasculature. S1P production was selectively impaired in mouse platelets, erythrocytes, endothelium, or smooth muscle cells by targeted deletion of genes encoding sphingosine kinases -1 and -2. S1P deficiency impaired aggregation and spreading of washed platelets and profoundly reduced their capacity to promote endothelial barrier function ex vivo. However, and in contrast to recent reports, neither platelets nor any other source of S1P was essential for vascular development, vascular integrity, or hemostasis/thrombosis. Yet rapid and profound depletion of plasma S1P during systemic anaphylaxis rendered both platelet- and erythrocyte-derived S1P essential for survival, with a contribution from blood endothelium observed only in the absence of circulating sources. Recovery was sensitive to aspirin in mice with but not without platelet S1P, suggesting that platelet activation and stimulus-response coupling is needed. S1P deficiency aggravated vasoplegia in this model, arguing a vital role for S1P in maintaining vascular resistance during recovery from circulatory shock. Accordingly, the S1P2 receptor mediated most of the survival benefit of S1P, whereas the endothelial S1P1 receptor was dispensable for survival despite its importance for maintaining vascular integrity. Although source redundancy normally secures essential S1P signaling in developing and mature blood vessels, profound depletion of plasma S1P renders both erythrocyte and platelet S1P pools necessary for recovery and high basal plasma S1P levels protective during anaphylactic shock. © 2016 American Heart Association, Inc.

Genomewide Identification of Essential Genes and Fitness Determinants of Streptococcus mutans UA159

PubMed Central

Zeng, Lin; Culp, David J.

2018-01-01

ABSTRACT Transposon mutagenesis coupled with next-generation DNA sequencing (Tn-seq) is a powerful tool for discovering regions of the genome that are required for the survival of bacteria in different environments. We adapted this technique to the dental caries pathogen Streptococcus mutans UA159 and identified 11% of the genome as essential, with many genes encoding products required for replication, translation, lipid metabolism, and cell wall biogenesis. Comparison of the essential genome of S. mutans UA159 with those of selected other streptococci for which such information is available revealed several metabolic pathways and genes that are required in S. mutans, but not in some Streptococcus spp. We further identified genes that are essential for sustained growth in rich or defined medium, as well as for persistence in vivo in a rodent model of oral infection. Collectively, our results provide a novel and comprehensive view of the genes required for essential processes of S. mutans, many of which could represent potential targets for therapeutics. IMPORTANCE Tooth decay (dental caries) is a common cause of pain, impaired quality of life, and tooth loss in children and adults. It begins because of a compositional change in the microorganisms that colonize the tooth surface driven by repeated and sustained carbohydrate intake. Although several bacterial species are associated with tooth decay, Streptococcus mutans is the most common cause. Therefore, it is important to identify biological processes that contribute to the survival of S. mutans in the human mouth, with the aim of disrupting the processes with antimicrobial agents. We successfully applied Tn-seq to S. mutans, discovering genes that are required for survival, growth, and persistence, both in laboratory environments and in a mouse model of tooth decay. This work highlights new avenues for the control of an important human pathogen. PMID:29435491

[Nerve growth factor and the physiology of pain: the relationships among interoception, sympathetic neurons and the emotional response indicated by the molecular pathophysiology of congenital insensitivity to pain with anhidrosis].

PubMed

Indo, Yasuhiro

2015-05-01

Nerve growth factor (NGF) is a neurotrophic factor essential for the survival and maintenance of neurons. Congenital insensitivity to pain with anhidrosis (CIPA) is caused by loss-of-function mutations in NTRK1, which encodes a receptor tyrosine kinase, TrkA, for NGF. Mutations in NTRK1 cause the selective loss of NGF-dependent neurons, including both NGF-dependent primary afferents and sympathetic postganglionic neurons, in otherwise intact systems. The NGF-dependent primary afferents are thinly myelinated AΔ or unmyelinated C-fibers that are dependent on the NGF-TrkA system during development. NGF-dependent primary afferents are not only nociceptive neurons that transmit pain and temperature sensation, but also are polymodal receptors that play essential roles for interoception by monitoring various changes in the physiological status of all tissues in the body. In addition, they contribute to various inflammatory processes in acute, chronic and allergic inflammation. Together with sympathetic postganglionic neurons, they maintain the homeostasis of the body and emotional responses via interactions with the brain, immune and endocrine systems. Pain is closely related to emotions that accompany physical responses induced by systemic activation of the sympathetic nervous system. In contrast to a negative image of emotions in daily life, Antonio Damasio proposed the 'Somatic Marker Hypothesis', wherein emotions play critical roles in the decision-making and reasoning processes. According to this hypothesis, reciprocal communication between the brain and the body-proper are essential for emotional responses. Using the pathophysiology of CIPA as a foundation, this article suggests that NGF-dependent neurons constitute a part of the neuronal network required for homeostasis and emotional responses, and indicates that this network plays important roles in mediating the reciprocal communication between the brain and the body-proper.

Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells.

PubMed

Lyons, Amy; Coleman, Michael; Riis, Sarah; Favre, Cedric; O'Flanagan, Ciara H; Zhdanov, Alexander V; Papkovsky, Dmitri B; Hursting, Stephen D; O'Connor, Rosemary

2017-10-13

Mitochondrial activity and metabolic reprogramming influence the phenotype of cancer cells and resistance to targeted therapy. We previously established that an insulin-like growth factor 1 (IGF-1)-inducible mitochondrial UTP carrier (PNC1/SLC25A33) promotes cell growth. This prompted us to investigate whether IGF signaling is essential for mitochondrial maintenance in cancer cells and whether this contributes to therapy resistance. Here we show that IGF-1 stimulates mitochondrial biogenesis in a range of cell lines. In MCF-7 and ZR75.1 breast cancer cells, IGF-1 induces peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) and PGC-1α-related coactivator (PRC). Suppression of PGC-1β and PRC with siRNA reverses the effects of IGF-1 and disrupts mitochondrial morphology and membrane potential. IGF-1 also induced expression of the redox regulator nuclear factor-erythroid-derived 2-like 2 (NFE2L2 alias NRF-2). Of note, MCF-7 cells with acquired resistance to an IGF-1 receptor (IGF-1R) tyrosine kinase inhibitor exhibited reduced expression of PGC-1β, PRC, and mitochondrial biogenesis. Interestingly, these cells exhibited mitochondrial dysfunction, indicated by reactive oxygen species expression, reduced expression of the mitophagy mediators BNIP3 and BNIP3L, and impaired mitophagy. In agreement with this, IGF-1 robustly induced BNIP3 accumulation in mitochondria. Other active receptor tyrosine kinases could not compensate for reduced IGF-1R activity in mitochondrial protection, and MCF-7 cells with suppressed IGF-1R activity became highly dependent on glycolysis for survival. We conclude that IGF-1 signaling is essential for sustaining cancer cell viability by stimulating both mitochondrial biogenesis and turnover through BNIP3 induction. This core mitochondrial protective signal is likely to strongly influence responses to therapy and the phenotypic evolution of cancer. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

What's in Your Back Pack? Three Essential Items for Survival in the Tough and Changing World of Campus Construction

ERIC Educational Resources Information Center

del Monte, Rick

2009-01-01

As students know, the tools in their backpacks can influence success. If they are off to math class, a good calculator is essential. When on their way to English class, a laptop is fundamental. Building facility executives too have tools in their backpacks to assure the successful creation of educational buildings. Only their tools are…

Combining Heavy Ion Radiation and Artificial MicroRNAs to Target the Homologous Recombination Repair Gene Efficiently Kills Human Tumor Cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng Zhiming; Department of Radiation Oncology, School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia; Wang Ping

2013-02-01

Purpose: Previously, we demonstrated that heavy ions kill more cells at the same dose than X-rays because DNA-clustered lesions produced by heavy ions affect nonhomologous end-joining (NHEJ) repair but not homologous recombination repair (HRR). We have also shown that our designed artificial microRNAs (amiRs) could efficiently target XRCC4 (an essential factor for NHEJ) or XRCC2 (an essential factor for HRR) and sensitize human tumor cells to X-rays. Based on these data, we were interested in testing the hypothesis that combining heavy ions and amiRs to target HRR but not NHEJ should more efficiently kill human tumor cells. Methods and Materials:more » Human tumor cell lines (U87MG, a brain tumor cell line, and A549, a lung cancer cell line) and their counterparts, overexpressed with amiR to target XRCC2, XRCC4 or both, were used in this study. Survival sensitivities were examined using a clonogenic assay after these cells were exposed to X-rays or heavy ions. In addition, these cell lines were subcutaneously injected into nude mice to form xenografts and the tumor size was compared after the tumor areas were exposed to X-rays or heavy ions. Results: Although targeting either XRCC4 (NHEJ factor) or XRCC2 (HRR factor) sensitized the human tumor cells to X-rays, in vitro and the xenograft animal model, targeting only XRCC2 but not XRCC4 sensitized the human tumor cells to heavy ions in vitro and in the xenograft animal model. Conclusions: Combining heavy ions with targeting the HRR pathway, but not the NHEJ pathway, could significantly improve the efficiency of tumor cell death.« less

Combining heavy ion radiation and artificial microRNAs to target the homologous recombination repair gene efficiently kills human tumor cells.

PubMed

Zheng, Zhiming; Wang, Ping; Wang, Hongyan; Zhang, Xiangming; Wang, Minli; Cucinotta, Francis A; Wang, Ya

2013-02-01

Previously, we demonstrated that heavy ions kill more cells at the same dose than X-rays because DNA-clustered lesions produced by heavy ions affect nonhomologous end-joining (NHEJ) repair but not homologous recombination repair (HRR). We have also shown that our designed artificial microRNAs (amiRs) could efficiently target XRCC4 (an essential factor for NHEJ) or XRCC2 (an essential factor for HRR) and sensitize human tumor cells to X-rays. Based on these data, we were interested in testing the hypothesis that combining heavy ions and amiRs to target HRR but not NHEJ should more efficiently kill human tumor cells. Human tumor cell lines (U87MG, a brain tumor cell line, and A549, a lung cancer cell line) and their counterparts, overexpressed with amiR to target XRCC2, XRCC4 or both, were used in this study. Survival sensitivities were examined using a clonogenic assay after these cells were exposed to X-rays or heavy ions. In addition, these cell lines were subcutaneously injected into nude mice to form xenografts and the tumor size was compared after the tumor areas were exposed to X-rays or heavy ions. Although targeting either XRCC4 (NHEJ factor) or XRCC2 (HRR factor) sensitized the human tumor cells to X-rays, in vitro and the xenograft animal model, targeting only XRCC2 but not XRCC4 sensitized the human tumor cells to heavy ions in vitro and in the xenograft animal model. Combining heavy ions with targeting the HRR pathway, but not the NHEJ pathway, could significantly improve the efficiency of tumor cell death. Copyright © 2013 Elsevier Inc. All rights reserved.

Granulocyte Macrophage-Colony Stimulating Factor-induced Zn Sequestration Enhances Macrophage Superoxide and Limits Intracellular Pathogen Survival

PubMed Central

Vignesh, Kavitha Subramanian; Landero Figueroa, Julio A.; Porollo, Aleksey; Caruso, Joseph A.; Deepe, George S.

2013-01-01

SUMMARY Macrophages possess numerous mechanisms to combat microbial invasion, including sequestration of essential nutrients, like Zn. The pleiotropic cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) enhances antimicrobial defenses against intracellular pathogens such as Histoplasma capsulatum, but its mode of action remains elusive. We have found that GM-CSF activated infected macrophages sequestered labile Zn by inducing binding to metallothioneins (MTs) in a STAT3 and STAT5 transcription factor-dependent manner. GM-CSF upregulated expression of Zn exporters, Slc30a4 and Slc30a7 and the metal was shuttled away from phagosomes and into the Golgi apparatus. This distinctive Zn sequestration strategy elevated phagosomal H+ channel function and triggered reactive oxygen species (ROS) generation by NADPH oxidase. Consequently, H. capsulatum was selectively deprived of Zn, thereby halting replication and fostering fungal clearance. GM-CSF mediated Zn sequestration via MTs in vitro and in vivo in mice and in human macrophages. These findings illuminate a GM-CSF-induced Zn-sequestration network that drives phagocyte antimicrobial effector function. PMID:24138881

Pathogenic Leptospira: Advances in understanding the molecular pathogenesis and virulence

PubMed Central

Ghazaei, Ciamak

2018-01-01

Leptospirosis is a common zoonotic disease has emerged as a major public health problem, with developing countries bearing disproportionate burdens. Although the diverse range of clinical manifestations of the leptospirosis in humans is widely documented, the mechanisms through which the pathogen causes disease remain undetermined. In addition, leptospirosis is a much-neglected life-threatening disease although it is one of the most important zoonoses occurring in a diverse range of epidemiological distribution. Recent advances in molecular profiling of pathogenic species of the genus Leptospira have improved our understanding of the evolutionary factors that determine virulence and mechanisms that the bacteria employ to survive. However, a major impediment to the formulation of intervention strategies has been the limited understanding of the disease determinants. Consequently, the association of the biological mechanisms to the pathogenesis of Leptospira, as well as the functions of numerous essential virulence factors still remain implicit. This review examines recent advances in genetic screening technologies, the underlying microbiological processes, the virulence factors and associated molecular mechanisms driving pathogenesis of Leptospira species. PMID:29445617

The key players of the primary root growth and development also function in lateral roots in Arabidopsis.

PubMed

Tian, Huiyu; Jia, Yuebin; Niu, Tiantian; Yu, Qianqian; Ding, Zhaojun

2014-05-01

The core regulators which are required for primary root growth and development also function in lateral root development or lateral root stem cell niche maintenance. The primary root systems and the lateral root systems are the two important root systems which are vital to the survival of plants. Though the molecular mechanism of the growth and development of both the primary root systems and the lateral root systems have been extensively studied individually in Arabidopsis, there are not so much evidence to show that if both root systems share common regulatory mechanisms. AP2 family transcription factors such as PLT1 (PLETHORA1) and PLT2, GRAS family transcription factors such as SCR (SCARECROW) and SHR (SHORT ROOT) and WUSCHEL-RELATED HOMEOBOX transcription factor WOX5 have been extensively studied and found to be essential for primary root growth and development. In this study, through the expression pattern analysis and mutant examinations, we found that these core regulators also function in lateral root development or lateral root stem cell niche maintenance.

Chemical, Biological, and Radiological (CBR) Contamination Survivability, Small Items of Equipment

DTIC Science & Technology

2012-06-22

thickness (number of coats), paint condition, and surface cleanliness (mud, grease, and other). j. Pretest (baseline) and posttest (30 days after...survivability testing of small items of mission-essential (ME) Army materiel. Small items, for example , include personal gear, small arms, radios...their effects. An example would be the age of the paint on the surface (aged, new, etc.). f. The only current mechanism for converting agent mass

The thrombopoietin/MPL/Bcl-xL pathway is essential for survival and self-renewal in human preleukemia induced by AML1-ETO

PubMed Central

Chou, Fu-Sheng; Griesinger, Andrea; Wunderlich, Mark; Lin, Shan; Link, Kevin A.; Shrestha, Mahesh; Goyama, Susumu; Mizukawa, Benjamin; Shen, Shuhong; Marcucci, Guido

2012-01-01

AML1-ETO (AE) is a fusion product of translocation (8;21) that accounts for 40% of M2 type acute myeloid leukemia (AML). In addition to its role in promoting preleukemic hematopoietic cell self-renewal, AE represses DNA repair genes, which leads to DNA damage and increased mutation frequency. Although this latter function may promote leukemogenesis, concurrent p53 activation also leads to an increased baseline apoptotic rate. It is unclear how AE expression is able to counterbalance this intrinsic apoptotic conditioning by p53 to promote survival and self-renewal. In this report, we show that Bcl-xL is up-regulated in AE cells and plays an essential role in their survival and self-renewal. Further investigation revealed that Bcl-xL expression is regulated by thrombopoietin (THPO)/MPL-signaling induced by AE expression. THPO/MPL-signaling also controls cell cycle reentry and mediates AE-induced self-renewal. Analysis of primary AML patient samples revealed a correlation between MPL and Bcl-xL expression specifically in t(8;21) blasts. Taken together, we propose that survival signaling through Bcl-xL is a critical and intrinsic component of a broader self-renewal signaling pathway downstream of AML1-ETO–induced MPL. PMID:22337712

Potential impact of atelectasis and primary tumor glycolysis on F-18 FDG PET/CT on survival in lung cancer patients.

PubMed

Hasbek, Zekiye; Yucel, Birsen; Salk, Ismail; Turgut, Bulent; Erselcan, Taner; Babacan, Nalan Akgul; Kacan, Turgut

2014-01-01

Atelectasis is an important prognostic factor that can cause pleuritic chest pain, coughing or dyspnea, and even may be a cause of death. In this study, we aimed to investigate the potential impact of atelectasis and PET parameters on survival and the relation between atelectasis and PET parameters. The study consisted of patients with lung cancer with or without atelectasis who underwent (18)F-FDG PET/CT examination before receiving any treatment. (18)F-FDG PET/CT derived parameters including tumor size, SUVmax, SUVmean, MTV, total lesion glycosis (TLG), SUV mean of atelectasis area, atelectasis volume, and histological and TNM stage were considered as potential prognostic factors for overall survival. Fifty consecutive lung cancer patients (22 patients with atelectasis and 28 patients without atelectasis, median age of 65 years) were evaluated in the present study. There was no relationship between tumor size and presence or absence of atelectasis, nor between presence/absence of atelectasis and TLG of primary tumors. The overall one-year survival rate was 83% and median survival was 20 months (n=22) in the presence of atelectasis; the overall one-year survival rate was 65.7% (n=28) and median survival was 16 months (p=0.138) in the absence of atelectasis. With respect to PFS; the one-year survival rate of AT+ patients was 81.8% and median survival was 19 months; the one-year survival rate of AT- patients was 64.3% and median survival was 16 months (p=0.159). According to univariate analysis, MTV, TLG and tumor size were significant risk factors for PFS and OS (p<0.05). However, SUVmax was not a significant factor for PFS and OS (p>0.05). The present study suggested that total lesion glycolysis and metabolic tumor volume were important predictors of survival in lung cancer patients, in contrast to SUVmax. In addition, having a segmental lung atelectasis seems not to be a significant factor on survival.

Contrasting patterns of nest survival and postfledging survival in ovenbirds and Acadian flycatchers in Missouri forest fragments

Treesearch

Julianna M. A. Jenkins; Frank R. Thompson; John Faaborg

2016-01-01

We can improve our ability to assess population viability and forecast population growth under different scenarios by understanding factors that limit population parameters in each stage of the annual cycle. Postfledging mortality rates may be as variable as nest survival across regions and fragmentation gradients, although factors that negatively impact nest survival...

Metabolic Adaptations of Uropathogenic E. coli in the Urinary Tract

PubMed Central

Mann, Riti; Mediati, Daniel G.; Duggin, Iain G.; Harry, Elizabeth J.; Bottomley, Amy L.

2017-01-01

Escherichia coli ordinarily resides in the lower gastrointestinal tract in humans, but some strains, known as Uropathogenic E. coli (UPEC), are also adapted to the relatively harsh environment of the urinary tract. Infections of the urine, bladder and kidneys by UPEC may lead to potentially fatal bloodstream infections. To survive this range of conditions, UPEC strains must have broad and flexible metabolic capabilities and efficiently utilize scarce essential nutrients. Whole-organism (or “omics”) methods have recently provided significant advances in our understanding of the importance of metabolic adaptation in the success of UPECs. Here we describe the nutritional and metabolic requirements for UPEC infection in these environments, and focus on particular metabolic responses and adaptations of UPEC that appear to be essential for survival in the urinary tract. PMID:28642845

Metabolic Adaptations of Uropathogenic E. coli in the Urinary Tract.

PubMed

Mann, Riti; Mediati, Daniel G; Duggin, Iain G; Harry, Elizabeth J; Bottomley, Amy L

2017-01-01

Escherichia coli ordinarily resides in the lower gastrointestinal tract in humans, but some strains, known as Uropathogenic E. coli (UPEC), are also adapted to the relatively harsh environment of the urinary tract. Infections of the urine, bladder and kidneys by UPEC may lead to potentially fatal bloodstream infections. To survive this range of conditions, UPEC strains must have broad and flexible metabolic capabilities and efficiently utilize scarce essential nutrients. Whole-organism (or "omics") methods have recently provided significant advances in our understanding of the importance of metabolic adaptation in the success of UPECs. Here we describe the nutritional and metabolic requirements for UPEC infection in these environments, and focus on particular metabolic responses and adaptations of UPEC that appear to be essential for survival in the urinary tract.

PBP deletion mutants of Escherichia coli exhibit irregular distribution of MreB at the deformed zones.

PubMed

Vijayan, Saptha; Mallick, Sathi; Dutta, Mouparna; Narayani, M; Ghosh, Anindya S

2014-02-01

MreB is a cytoskeletal protein, which is responsible for maintaining proper cellular morphology and is essential for cell survival. Likewise, penicillin-binding protein 5 (PBP5) helps in maintaining cell shape, though non-essential for survival. The contradicting feature of these two proteins paves the way for this study, wherein we attempt to draw a relation on the nature of distribution of MreB in PBP deletion mutants. The study revealed that the uniform MreB helices/patches were destabilized/disturbed at the zone of deformities of the PBP mutants, whereas the helical patterns were retained at the regions maintaining a rod shape. We interpret that MreB remains functional irrespective of its distribution being misguided by the aberrant shapes of PBP mutants.

Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis.

PubMed

Cheng, Feixiong; Murray, James L; Zhao, Junfei; Sheng, Jinsong; Zhao, Zhongming; Rubin, Donald H

2016-09-01

Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap) host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase). Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B) identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline) that may be potential for antiviral indication (e.g. anti-Ebola). In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics.

ArgR is an essential local transcriptional regulator of the arcABC operon in Streptococcus suis and is crucial for biological fitness in an acidic environment.

PubMed

Fulde, Marcus; Willenborg, Joerg; de Greeff, Astrid; Benga, Laurentiu; Smith, Hilde E; Valentin-Weigand, Peter; Goethe, Ralph

2011-02-01

Streptococcus suis is one of the most important pathogens in pigs and can also cause severe infections in humans. Despite its clinical relevance, very little is known about the factors that contribute to its virulence. Recently, we identified a new putative virulence factor in S. suis, the arginine deiminase system (ADS), an arginine catabolic enzyme system encoded by the arcABC operon, which enables S. suis to survive in an acidic environment. In this study, we focused on ArgR, an ADS-associated regulator belonging to the ArgR/AhrC arginine repressor family. Using an argR knockout strain we were able to show that ArgR is essential for arcABC operon expression and necessary for the biological fitness of S. suis. By cDNA expression microarray analyses and quantitative real-time RT-PCR we found that the arcABC operon is the only gene cluster regulated by ArgR, which is in contrast to the situation in many other bacteria. Reporter gene analysis with gfp under the control of the arcABC promoter demonstrated that ArgR is able to activate the arcABC promoter. Electrophoretic mobility shift assays with fragments of the arcABC promoter and recombinant ArgR, and chromatin immunoprecipitation with antibodies directed against ArgR, revealed that ArgR interacts with the arcABC promoter in vitro and in vivo by binding to a region from -147 to -72 bp upstream of the transcriptional start point. Overall, our results show that in S. suis, ArgR is an essential, system-specific transcriptional regulator of the ADS that interacts directly with the arcABC promoter in vivo.

Risk factors for the prognosis of pediatric medulloblastoma: a retrospective analysis of 40 cases.

PubMed

Yu, Jianzhong; Zhao, Rui; Shi, Wei; Li, Hao

2017-05-01

In this study, we evaluated the association of molecular subtypes, clinical characteristics and pathological types with the prognosis of patients with medulloblastoma. We analyzed forty patients with medulloblastoma who underwent surgical resection at our center between January 2004 and June 2014. Risk factors associated with survival, disease progression and recurrence were analyzed with a univariate Cox regression analysis, and the identified significant risk factors were further analyzed by Kaplan-Meier survival curves. Factors associated with overall survival included M stage (p=0.014), calcification (p=0.012), postoperative treatment, postoperative Karnofsky Performance Scale (KPS) score (p=0.015), and molecular subtype (p=0.005 for WNT and p=0.008 for SHH). Number of symptoms (p=0.029), M stage (p<0.001), and postoperative radiotherapy (p=0.033) were associated with disease progression. Patients with the WNT or SHH subtype had better survival outcomes than patients with non-WNT/SHH subtypes. Risk factors for disease progression-free survival were symptoms >2 and ≥M1 stage without postoperative radiotherapy. The risk of recurrence increased with advanced M stage. Protective factors for recurrence included M0 stage and a combination of chemotherapy and radiotherapy. We identified the risk factors associated with survival, disease progression and recurrence of medulloblastoma patients. This information is helpful for understanding the prognostic factors related to medulloblastoma.

[Analysis of histoprognostic factors for the non metastatic rectal cancer in a west Algerian series of 58 cases].

PubMed

Mesli, Smain Nabil; Regagba, Derbali; Tidjane, Anisse; Benkalfat, Mokhtar; Abi-Ayad, Chakib

2016-01-01

The aim of our study was to analyze histoprognostic factors in patients with non-metastatic rectal cancer operated at the division of surgery "A" in Tlemcen, west Algeria, over a period of six years. Retrospective study of 58 patients with rectal adenocarcinoma. Evaluation criterion was survival. Parameters studied were sex, age, tumor stage, tumor recurrence. The average age was 58 years, 52% of men and 48% of women, with sex-ratio (1,08). Tumor seat was: middle rectum 41.37%, lower rectum 34.48% and upper rectum 24.13%. Concerning TNM clinical staging, patients were classified as stage I (17.65%), stage II (18.61%), stage III (53.44%) and stage IV (7.84%). Median overall survival was 40 months ±2,937 months. Survival based on tumor staging: stage III and IV had a lower 3 years survival rate (19%) versus stage I, II which had a survival rate of 75% (P = 0.000) (95%). Patients with tumor recurrences had a lower 3 years survival rate compared to those who had no tumoral recurrences (30.85% vs 64.30% P = 0.043). In this series, univariate analysis of prognostic factors affecting survival allowed to retain only three factors influencing survival: tumor size, stage and tumor recurrences. In multivariate analysis using Cox's model only one factor was retained: tumor recurrence.

Italian regional health system structure and expected cancer survival.

PubMed

Vercelli, Marina; Lillini, Roberto; Quaglia, Alberto; Capocaccia, Riccardo

2014-01-01

Few studies deal with the association of socioeconomic and health system resource variables with cancer survival at the Italian regional level, where the greatest number of decisions about social and health policies and resource allocations are taken. The present study aimed to describe the causal relationships between socioeconomic and health system resource factors and regional cancer survival and to compute the expected cancer survival at provincial, regional and area levels. Age-standardized relative survival at 5 years from diagnosis of cases incident in 1995-1998 and followed up to 2004 were derived by gender for 11 sites from the Italian Association of Cancer Registries data bank. The socioeconomic and health system resource variables, describing at a regional level the macro-economy, demography, labor market, and health resources for 1995-2005, came from the Health for All database. A principal components factor analysis was applied to the socioeconomic and health system resource variables. For every site, linear regression models were computed considering the relative survival at 5 years as a dependent variable and the principal components factor analysis factors as independent variables. The factors described the socioeconomic and health-related features of the regional systems and were causally related to the characteristics of the patient taken in charge. The models built by the factors allowed computation of the expected relative survival at 5 years with very good concordance with those observed at regional, macro-regional and national levels. In the regions without any cancer registry, survival was coherent with that of neighboring regions with similar socioeconomic and health system resources characteristics. The models highlighted the causal correlations between socioeconomic and health system resources and cancer survival, suggesting that they could be good evaluation tools for the efficiency of the resources allocation and use.

skNAC, a Smyd1-interacting transcription factor, is involved in cardiac development and skeletal muscle growth and regeneration.

PubMed

Park, Chong Yon; Pierce, Stephanie A; von Drehle, Morgan; Ivey, Kathryn N; Morgan, Jayson A; Blau, Helen M; Srivastava, Deepak

2010-11-30

Cardiac and skeletal muscle development and maintenance require complex interactions between DNA-binding proteins and chromatin remodeling factors. We previously reported that Smyd1, a muscle-restricted histone methyltransferase, is essential for cardiogenesis and functions with a network of cardiac regulatory proteins. Here we show that the muscle-specific transcription factor skNAC is the major binding partner for Smyd1 in the developing heart. Targeted deletion of skNAC in mice resulted in partial embryonic lethality by embryonic day 12.5, with ventricular hypoplasia and decreased cardiomyocyte proliferation that were similar but less severe than in Smyd1 mutants. Expression of Irx4, a ventricle-specific transcription factor down-regulated in hearts lacking Smyd1, also depended on the presence of skNAC. Viable skNAC(-/-) adult mice had reduced postnatal skeletal muscle growth and impaired regenerative capacity after cardiotoxin-induced injury. Satellite cells isolated from skNAC(-/-) mice had impaired survival compared with wild-type littermate satellite cells. Our results indicate that skNAC plays a critical role in ventricular cardiomyocyte expansion and regulates postnatal skeletal muscle growth and regeneration in mice.

Train crashworthiness design for occupant survivability

DOT National Transportation Integrated Search

1995-11-01

Studies were conducted evaluating the effectiveness of alternative strategies for providing crashworthiness of the vehicle structures. Conventional practice results in cars of essentially uniform : longitudinal strength. The crash energy management a...

Recent advances in recurrent urinary tract infection from pathogenesis and biomarkers to prevention.

PubMed

Jhang, Jia-Fong; Kuo, Hann-Chorng

2017-01-01

Recurrent urinary tract infection (UTI) might be one of the most common problems in urological clinics. Recent research has revealed novel evidence about recurrent UTI and it should be considered a different disease from the first infection. The pathogenesis of recurrent UTI might include two mechanisms, bacterial factors and deficiencies in host defense. Bacterial survival in the urinary bladder after antibiotic treatment and progression to form intracellular bacterial communities might be the most important bacterial factors. In host defense deficiency, a defect in pathogen recognition and urothelial barrier function impairment play the most important roles. Immunodeficiency and urogenital tract anatomical abnormalities have been considered the essential risk factors for recurrent UTI. In healthy women, voiding dysfunction and behavioral factors also increase the risk of recurrent UTI. Sexual intercourse and estrogen deficiency in postmenopausal women might have the strongest association with recurrent UTI. Traditional lifestyle factors such as fluid intake and diet are not considered independent risk factors now. Serum and urine biomarkers to predict recurrent UTI from the first infection have also attracted a wide attention recently. Current clinical evidence suggests that serum macrophage colony-stimulating factor and urinary nerve growth factor have potential predictive value for recurrent UTI. Clinical trials have proven the efficacy of the oral immunoactive agent OM-89 for the prevention of UTI. Vaccines for recurrent UTI are recommended by the latest guidelines and are available on the market.

Long-term disease-free survival in advanced melanomas treated with nitrosoureas: mechanisms and new perspectives

PubMed Central

Durando, Xavier; Thivat, Emilie; D'Incan, Michel; Sinsard, Anne; Madelmont, Jean-Claude; Chollet, Philippe

2005-01-01

Background Median survival of metastatic malignant melanoma is 6.0 to 7.5 months, with a 5-year survival of ~6.0%. Although long-term complete remissions are rare, few reports describe cases after chemotherapy. Fifty-three patients with metastatic melanoma were treated with Cystemustine, a chloroethyl nitrosourea (CENU) (60 or 90 mg/m2). Case presentation We describe 5 cases, presenting with complete response with long-term disease-free survival of long-term remission of 14, 12, 9, 7 and 6 years after Cystemustine therapy alone. Conclusion Long-term survival has already been described in literature, but in all cases they have been obtained after chemotherapy associated with or followed by surgery. But despite these noteworthy and encouraging but also rare results, it appears essential to increase cystemustine efficiency. PMID:16287507

A simple prognostic model for overall survival in metastatic renal cell carcinoma.

PubMed

Assi, Hazem I; Patenaude, Francois; Toumishey, Ethan; Ross, Laura; Abdelsalam, Mahmoud; Reiman, Tony

2016-01-01

The primary purpose of this study was to develop a simpler prognostic model to predict overall survival for patients treated for metastatic renal cell carcinoma (mRCC) by examining variables shown in the literature to be associated with survival. We conducted a retrospective analysis of patients treated for mRCC at two Canadian centres. All patients who started first-line treatment were included in the analysis. A multivariate Cox proportional hazards regression model was constructed using a stepwise procedure. Patients were assigned to risk groups depending on how many of the three risk factors from the final multivariate model they had. There were three risk factors in the final multivariate model: hemoglobin, prior nephrectomy, and time from diagnosis to treatment. Patients in the high-risk group (two or three risk factors) had a median survival of 5.9 months, while those in the intermediate-risk group (one risk factor) had a median survival of 16.2 months, and those in the low-risk group (no risk factors) had a median survival of 50.6 months. In multivariate analysis, shorter survival times were associated with hemoglobin below the lower limit of normal, absence of prior nephrectomy, and initiation of treatment within one year of diagnosis.

A simple prognostic model for overall survival in metastatic renal cell carcinoma

PubMed Central

Assi, Hazem I.; Patenaude, Francois; Toumishey, Ethan; Ross, Laura; Abdelsalam, Mahmoud; Reiman, Tony

2016-01-01

Introduction: The primary purpose of this study was to develop a simpler prognostic model to predict overall survival for patients treated for metastatic renal cell carcinoma (mRCC) by examining variables shown in the literature to be associated with survival. Methods: We conducted a retrospective analysis of patients treated for mRCC at two Canadian centres. All patients who started first-line treatment were included in the analysis. A multivariate Cox proportional hazards regression model was constructed using a stepwise procedure. Patients were assigned to risk groups depending on how many of the three risk factors from the final multivariate model they had. Results: There were three risk factors in the final multivariate model: hemoglobin, prior nephrectomy, and time from diagnosis to treatment. Patients in the high-risk group (two or three risk factors) had a median survival of 5.9 months, while those in the intermediate-risk group (one risk factor) had a median survival of 16.2 months, and those in the low-risk group (no risk factors) had a median survival of 50.6 months. Conclusions: In multivariate analysis, shorter survival times were associated with hemoglobin below the lower limit of normal, absence of prior nephrectomy, and initiation of treatment within one year of diagnosis. PMID:27217858

Fibroblast growth factor 22 is not essential for skin development and repair but plays a role in tumorigenesis.

PubMed

Jarosz, Monika; Robbez-Masson, Luisa; Chioni, Athina-Myrto; Cross, Barbara; Rosewell, Ian; Grose, Richard

2012-01-01

Fibroblast Growth Factors play critical roles during development, tissue homeostasis and repair by controlling cell proliferation, survival, migration and differentiation. Of the 22 mammalian FGFs, FGF22, a member of the FGF7/10/22 subfamily, has been shown to have a clear role in synaptogenesis, but its roles in other tissues have not been studied. We have investigated the in vivo functions of FGF22 in mice. Fgf22 null animals were viable, fertile and did not display any obvious abnormalities. Despite the known expression profile of FGF22 in the skin, no differences in either skin or pelage were observed, demonstrating that FGF22 is dispensable during embryogenesis and in unchallenged adult skin. Mice lacking FGF22 were able to heal acute wounds just as efficiently as wild type mice. However, classical two-step skin carcinogenesis challenge revealed that FGF22 null mice developed fewer papillomas than wild type controls, suggesting a potential pro-oncogenic role for FGF22 in the skin.

Gelidium amansii promotes dendritic spine morphology and synaptogenesis, and modulates NMDA receptor-mediated postsynaptic current.

PubMed

Hannan, Md Abdul; Mohibbullah, Md; Hong, Yong-Ki; Nam, Joo Hyun; Moon, Il Soo

2014-01-01

Neurotrophic factors are essential for the differentiation and maturation of developing neurons as well as providing survival support to the mature neurons. Moreover, therapeutically neurotrophic factors are promising to reconstruct partially damaged neuronal networks in neurodegenerative diseases. In the previous study, we reported that the ethanol extract of an edible marine alga, Gelidium amansii (GAE) had shown promising effects in the development and maturation of both axon and dendrites of hippocampal neurons. Here, we demonstrate that in primary culture of hippocampal neurons (1) GAE promotes a significant increase in the number of filopodia and dendritic spines; (2) promotes synaptogenesis; (3) enhances N-methyl-D-aspartic acid (NMDA) receptor recruitment; and (4) modulates NMDA-receptor-mediated postsynaptic current. Taken together these findings that GAE might be involved in both morphological and functional maturation of neurons suggest the possibility that GAE may constitute a promising candidate for novel compounds for the prevention and treatment of neurodegenerative diseases.

Heterogeneous Family of Cyclomodulins: Smart Weapons That Allow Bacteria to Hijack the Eukaryotic Cell Cycle and Promote Infections

PubMed Central

El-Aouar Filho, Rachid A.; Nicolas, Aurélie; De Paula Castro, Thiago L.; Deplanche, Martine; De Carvalho Azevedo, Vasco A.; Goossens, Pierre L.; Taieb, Frédéric; Lina, Gerard; Le Loir, Yves; Berkova, Nadia

2017-01-01

Some bacterial pathogens modulate signaling pathways of eukaryotic cells in order to subvert the host response for their own benefit, leading to successful colonization and invasion. Pathogenic bacteria produce multiple compounds that generate favorable conditions to their survival and growth during infection in eukaryotic hosts. Many bacterial toxins can alter the cell cycle progression of host cells, impairing essential cellular functions and impeding host cell division. This review summarizes current knowledge regarding cyclomodulins, a heterogeneous family of bacterial effectors that induce eukaryotic cell cycle alterations. We discuss the mechanisms of actions of cyclomodulins according to their biochemical properties, providing examples of various cyclomodulins such as cycle inhibiting factor, γ-glutamyltranspeptidase, cytolethal distending toxins, shiga toxin, subtilase toxin, anthrax toxin, cholera toxin, adenylate cyclase toxins, vacuolating cytotoxin, cytotoxic necrotizing factor, Panton-Valentine leukocidin, phenol soluble modulins, and mycolactone. Special attention is paid to the benefit provided by cyclomodulins to bacteria during colonization of the host. PMID:28589102

Host cell proteins in biotechnology-derived products: A risk assessment framework.

PubMed

de Zafra, Christina L Zuch; Quarmby, Valerie; Francissen, Kathleen; Vanderlaan, Martin; Zhu-Shimoni, Judith

2015-11-01

To manufacture biotechnology products, mammalian or bacterial cells are engineered for the production of recombinant therapeutic human proteins including monoclonal antibodies. Host cells synthesize an entire repertoire of proteins which are essential for their own function and survival. Biotechnology manufacturing processes are designed to produce recombinant therapeutics with a very high degree of purity. While there is typically a low residual level of host cell protein in the final drug product, under some circumstances a host cell protein(s) may copurify with the therapeutic protein and, if it is not detected and removed, it may become an unintended component of the final product. The purpose of this article is to enumerate and discuss factors to be considered in an assessment of risk of residual host cell protein(s) detected and identified in the drug product. The consideration of these factors and their relative ranking will lead to an overall risk assessment that informs decision-making around how to control the levels of host cell proteins. © 2015 Wiley Periodicals, Inc.

Overview of the improvement of the ring-stage survival assay-a novel phenotypic assay for the detection of artemisinin-resistant Plasmodium falciparum.

PubMed

Zhang, Jie; Feng, Guo-Hua; Zou, Chun-Yan; Su, Pin-Can; Liu, Huai-E; Yang, Zhao-Qing

2017-11-18

Artemisinin resistance in Plasmodium falciparum threatens the remarkable efficacy of artemisinin-based combination therapies worldwide. Thus, greater insight into the resistance mechanism using monitoring tools is essential. The ring-stage survival assay is used for phenotyping artemisinin-resistance or decreased artemisinin sensitivity. Here, we review the progress of this measurement assay and explore its limitations and potential applications.

Multivariate analysis of prognostic factors in synovial sarcoma.

PubMed

Koh, Kyoung Hwan; Cho, Eun Yoon; Kim, Dong Wook; Seo, Sung Wook

2009-11-01

Many studies have described the diversity of synovial sarcoma in terms of its biological characteristics and clinical features. Moreover, much effort has been expended on the identification of prognostic factors because of unpredictable behaviors of synovial sarcomas. However, with the exception of tumor size, published results have been inconsistent. We attempted to identify independent risk factors using survival analysis. Forty-one consecutive patients with synovial sarcoma were prospectively followed from January 1997 to March 2008. Overall and progression-free survival for age, sex, tumor size, tumor location, metastasis at presentation, histologic subtype, chemotherapy, radiation therapy, and resection margin were analyzed, and standard multivariate Cox proportional hazard regression analysis was used to evaluate potential prognostic factors. Tumor size (>5 cm), nonlimb-based tumors, metastasis at presentation, and a monophasic subtype were associated with poorer overall survival. Multivariate analysis showed metastasis at presentation and monophasic tumor subtype affected overall survival. For the progression-free survival, monophasic subtype was found to be only 1 prognostic factor. The study confirmed that histologic subtype is the single most important independent prognostic factors of synovial sarcoma regardless of tumor stage.

The Plasmodium falciparum rhoptry protein RhopH3 plays essential roles in host cell invasion and nutrient uptake

PubMed Central

Sherling, Emma S; Knuepfer, Ellen; Brzostowski, Joseph A; Miller, Louis H; Blackman, Michael J; van Ooij, Christiaan

2017-01-01

Merozoites of the protozoan parasite responsible for the most virulent form of malaria, Plasmodium falciparum, invade erythrocytes. Invasion involves discharge of rhoptries, specialized secretory organelles. Once intracellular, parasites induce increased nutrient uptake by generating new permeability pathways (NPP) including a Plasmodium surface anion channel (PSAC). RhopH1/Clag3, one member of the three-protein RhopH complex, is important for PSAC/NPP activity. However, the roles of the other members of the RhopH complex in PSAC/NPP establishment are unknown and it is unclear whether any of the RhopH proteins play a role in invasion. Here we demonstrate that RhopH3, the smallest component of the complex, is essential for parasite survival. Conditional truncation of RhopH3 substantially reduces invasive capacity. Those mutant parasites that do invade are defective in nutrient import and die. Our results identify a dual role for RhopH3 that links erythrocyte invasion to formation of the PSAC/NPP essential for parasite survival within host erythrocytes. DOI: http://dx.doi.org/10.7554/eLife.23239.001 PMID:28252384

Peptide Conjugated Phosphorodiamidate Morpholino Oligomers Increase Survival of Mice Challenged with Ames Bacillus anthracis

PubMed Central

Geller, Bruce L.; Mellbye, Brett; Lane, Douglas; Iversen, Patrick L.; Bavari, Sina

2012-01-01

Targeting bacterial essential genes using antisense phosphorodiamidate morpholino oligomers (PMOs) represents an important strategy in the development of novel antibacterial therapeutics. PMOs are neutral DNA analogues that inhibit gene expression in a sequence-specific manner. In this study, several cationic, membrane-penetrating peptides were conjugated to PMOs (PPMOs) that target 2 bacterial essential genes: acyl carrier protein (acpP) and gyrase A (gyrA). These were tested for their ability to inhibit growth of Bacillus anthracis, a gram-positive spore-forming bacterium and causative agent of anthrax. PPMOs targeted upstream of both target gene start codons and conjugated with the bacterium-permeating peptide (RFF)3R were found to be most effective in inhibiting bacterial growth in vitro. Both of the gene-targeted PPMOs protected macrophages from B. anthracis induced cell death. Subsequent, in vivo testing of the PPMOs resulted in increased survival of mice challenged with the virulent Ames strain of B. anthracis. Together, these studies suggest that PPMOs targeting essential genes have the potential of being used as antisense antibiotics to treat B. anthracis infections. PMID:22978365

Survival rate and prognostic factors of conventional osteosarcoma in Northern Thailand: A series from Chiang Mai University Hospital.

PubMed

Pruksakorn, Dumnoensun; Phanphaisarn, Areerak; Arpornchayanon, Olarn; Uttamo, Nantawat; Leerapun, Taninnit; Settakorn, Jongkolnee

2015-12-01

Osteosarcoma is a common and aggressive primary malignant bone tumor occurring in children and adolescents. It is one of the most aggressive human cancers and the most common cause of cancer-associated limb loss. As treatment in Thailand has produced a lower survival rate than in developed countries; therefore, this study identified survival rate and the poor prognostic factors of osteosarcoma in Northern Thailand. The retrospective cases of osteosarcoma, diagnosis between 1 January 1996 and 31 December 2013, were evaluated. Five and ten year overall survival rates were analyzed using time-to-event analysis. Potential prognostic factors were identified by multivariate regression analysis. There were 208 newly diagnosed osteosarcomas during that period, and 144 cases met the criteria for analysis. The majority of the osteosarcoma cases (78.5%) were aged 0-24 years. The overall 5- and 10-year survival rates were 37.9% and 33.6%, respectively. Presence of metastasis at initial examination, delayed and against treatment co-operation, and axial skeletal location were identified as independent prognostic factors for survival, with hazard ratios of 4.3, 2.5 and 3.8, and 3.1, respectively. This osteosarcoma cohort had a relatively poor overall survival rate. The prognostic factors identified would play a critical role in modifying survival rates of osteosarcoma patients; as rapid disease recognition, a better treatment counselling, as well as improving of chemotherapeutic regimens were found to be important in improving the overall survival rate in Thailand. Copyright © 2015 Elsevier Ltd. All rights reserved.

Diminished survival of human cytotrophoblast cells exposed to hypoxia/reoxygenation injury and associated reduction of heparin-binding epidermal growth factor-like growth factor.

PubMed

Leach, Richard E; Kilburn, Brian A; Petkova, Anelia; Romero, Roberto; Armant, D Randall

2008-04-01

The antiapoptotic action of heparin-binding epidermal growth factor (HBEGF)-like growth factor and its regulation by O(2) constitutes a key factor for trophoblast survival. The hypothesis that cytotrophoblast survival is compromised by exposure to hypoxia-reoxygenation (H/R) injury, which may contribute to preeclampsia and some missed abortions, prompted us to investigate HBEGF regulation and its role as a survival factor during H/R in cytotrophoblast cells. A transformed human first-trimester cytotrophoblast cell line HTR-8/SVneo was exposed to H/R (2% O(2) followed by 20% O(2)) and assessed for HBEGF expression and cell death. Cellular HBEGF declined significantly within 30 minutes of reoxygenation after culture at 2% O(2). H/R significantly reduced proliferation and increased cell death when compared with trophoblast cells cultured continuously at 2% or 20% O(2). Restoration of cell survival also was achieved by adding recombinant HBEGF during reoxygenation. HBEGF inhibited apoptosis through its binding to either human epidermal receptor (HER)-1 or HER4, its cognate receptors. These results provide evidence that cytotrophoblast exposure to H/R induces apoptosis and decreased cell proliferation. HBEGF accumulation is diminished under these conditions, whereas restoration of HBEGF signaling improves trophoblast survival.

Factors predicting survival in amyotrophic lateral sclerosis patients on non-invasive ventilation.

PubMed

Gonzalez Calzada, Nuria; Prats Soro, Enric; Mateu Gomez, Lluis; Giro Bulta, Esther; Cordoba Izquierdo, Ana; Povedano Panades, Monica; Dorca Sargatal, Jordi; Farrero Muñoz, Eva

2016-01-01

Non invasive ventilation (NIV) improves quality of life and extends survival in amyotrophic lateral sclerosis (ALS) patients. However, few data exist about the factors related to survival. We intended to assess the predictive factors that influence survival in patients after NIV initiation. Patients who started NIV from 2000 to 2014 and were tolerant (compliance ≥ 4 hours) were included; demographic, disease related and respiratory variables at NIV initiation were analysed. Statistical analysis was performed using the Kaplan-Meier test and Cox proportional hazard models. 213 patients were included with median survival from NIV initiation of 13.5 months. In univariate analysis, the identified risk factors for mortality were severity of bulbar involvement (HR 2), Forced Vital Capacity (FVC) % (HR 0.99) and ALSFRS-R (HR 0.97). Multivariate analysis showed that bulbar involvement (HR 1.92) and ALSFRS-R (HR 0.97) were independent predictive factors of survival in patients on NIV. In our study, the two prognostic factors in ALS patients following NIV were the severity of bulbar involvement and ALSFRS-R at the time on NIV initiation. A better assessment of bulbar involvement, including evaluation of the upper airway, and a careful titration on NIV are necessary to optimize treatment efficacy.

Curcumin suppresses crosstalk between colon cancer stem cells and stromal fibroblasts in the tumor microenvironment: potential role of EMT.

PubMed

Buhrmann, Constanze; Kraehe, Patricia; Lueders, Cora; Shayan, Parviz; Goel, Ajay; Shakibaei, Mehdi

2014-01-01

Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially on cancer stem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment. Colon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro with/without curcumin and/or 5-FU. Monolayer tumor microenvironment co-cultures supported intensive crosstalk between cancer cells and fibroblasts and enhanced up-regulation of metastatic active adhesion molecules (β1-integrin, ICAM-1), transforming growth factor-β signaling molecules (TGF-β3, p-Smad2), proliferation associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13), TGF-β3, favored CSC survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116 compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but dramatically decreased in the presence of curcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET), thereby sensitizing CSCs to 5-FU treatment. Enrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-β and EMT. Modulation of this synergistic crosstalk by curcumin might be a potential therapy for CRC and suppress metastasis.

Curcumin Suppresses Crosstalk between Colon Cancer Stem Cells and Stromal Fibroblasts in the Tumor Microenvironment: Potential Role of EMT

PubMed Central

Buhrmann, Constanze; Kraehe, Patricia; Lueders, Cora; Shayan, Parviz; Goel, Ajay; Shakibaei, Mehdi

2014-01-01

Objective Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially on cancer stem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment. Methods Colon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro with/without curcumin and/or 5-FU. Results Monolayer tumor microenvironment co-cultures supported intensive crosstalk between cancer cells and fibroblasts and enhanced up-regulation of metastatic active adhesion molecules (β1-integrin, ICAM-1), transforming growth factor-β signaling molecules (TGF-β3, p-Smad2), proliferation associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13), TGF-β3, favored CSC survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116 compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but dramatically decreased in the presence of curcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET), thereby sensitizing CSCs to 5-FU treatment. Conclusion Enrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-β and EMT. Modulation of this synergistic crosstalk by curcumin might be a potential therapy for CRC and suppress metastasis. PMID:25238234

Region 4 of Rhizobium etli Primary Sigma Factor (SigA) Confers Transcriptional Laxity in Escherichia coli.

PubMed

Santillán, Orlando; Ramírez-Romero, Miguel A; Lozano, Luis; Checa, Alberto; Encarnación, Sergio M; Dávila, Guillermo

2016-01-01

Sigma factors are RNA polymerase subunits engaged in promoter recognition and DNA strand separation during transcription initiation in bacteria. Primary sigma factors are responsible for the expression of housekeeping genes and are essential for survival. RpoD, the primary sigma factor of Escherichia coli, a γ-proteobacteria, recognizes consensus promoter sequences highly similar to those of some α-proteobacteria species. Despite this resemblance, RpoD is unable to sustain transcription from most of the α-proteobacterial promoters tested so far. In contrast, we have found that SigA, the primary sigma factor of Rhizobium etli, an α-proteobacteria, is able to transcribe E. coli promoters, although it exhibits only 48% identity (98% coverage) to RpoD. We have called this the transcriptional laxity phenomenon. Here, we show that SigA partially complements the thermo-sensitive deficiency of RpoD285 from E. coli strain UQ285 and that the SigA region σ4 is responsible for this phenotype. Sixteen out of 74 residues (21.6%) within region σ4 are variable between RpoD and SigA. Mutating these residues significantly improves SigA ability to complement E. coli UQ285. Only six of these residues fall into positions already known to interact with promoter DNA and to comprise a helix-turn-helix motif. The remaining variable positions are located on previously unexplored sites inside region σ4, specifically into the first two α-helices of the region. Neither of the variable positions confined to these helices seem to interact directly with promoter sequence; instead, we adduce that these residues participate allosterically by contributing to correct region folding and/or positioning of the HTH motif. We propose that transcriptional laxity is a mechanism for ensuring transcription in spite of naturally occurring mutations from endogenous promoters and/or horizontally transferred DNA sequences, allowing survival and fast environmental adaptation of α-proteobacteria.

Region 4 of Rhizobium etli Primary Sigma Factor (SigA) Confers Transcriptional Laxity in Escherichia coli

PubMed Central

Santillán, Orlando; Ramírez-Romero, Miguel A.; Lozano, Luis; Checa, Alberto; Encarnación, Sergio M.; Dávila, Guillermo

2016-01-01

Sigma factors are RNA polymerase subunits engaged in promoter recognition and DNA strand separation during transcription initiation in bacteria. Primary sigma factors are responsible for the expression of housekeeping genes and are essential for survival. RpoD, the primary sigma factor of Escherichia coli, a γ-proteobacteria, recognizes consensus promoter sequences highly similar to those of some α-proteobacteria species. Despite this resemblance, RpoD is unable to sustain transcription from most of the α-proteobacterial promoters tested so far. In contrast, we have found that SigA, the primary sigma factor of Rhizobium etli, an α-proteobacteria, is able to transcribe E. coli promoters, although it exhibits only 48% identity (98% coverage) to RpoD. We have called this the transcriptional laxity phenomenon. Here, we show that SigA partially complements the thermo-sensitive deficiency of RpoD285 from E. coli strain UQ285 and that the SigA region σ4 is responsible for this phenotype. Sixteen out of 74 residues (21.6%) within region σ4 are variable between RpoD and SigA. Mutating these residues significantly improves SigA ability to complement E. coli UQ285. Only six of these residues fall into positions already known to interact with promoter DNA and to comprise a helix-turn-helix motif. The remaining variable positions are located on previously unexplored sites inside region σ4, specifically into the first two α-helices of the region. Neither of the variable positions confined to these helices seem to interact directly with promoter sequence; instead, we adduce that these residues participate allosterically by contributing to correct region folding and/or positioning of the HTH motif. We propose that transcriptional laxity is a mechanism for ensuring transcription in spite of naturally occurring mutations from endogenous promoters and/or horizontally transferred DNA sequences, allowing survival and fast environmental adaptation of α-proteobacteria. PMID:27468278

Human papilloma virus and survival of oropharyngeal cancer patients treated with surgery and adjuvant radiotherapy.

PubMed

Broglie, Martina A; Soltermann, Alex; Haile, Sarah R; Huber, Gerhard F; Stoeckli, Sandro J

2015-07-01

Impact of p16 protein, a surrogate marker for human papilloma virus induced cancer, p53 and EGFR as well as clinical factors on survival in a patient cohort with oropharyngeal squamous cell carcinoma (OPSCC) treated by surgical resection and adjuvant radiotherapy (RT) ± concomitant chemotherapy (CT). This is a retrospective analysis of patient's charts and tumor tissue. 57 patients were consecutively included and their tumor tissue assembled on a tissue microarray following immunohistochemical analysis. Survival times were estimated by means of Kaplan-Meier analysis. The importance of clinical and immunohistochemical factors for outcome was estimated by cox proportional hazard models. With 88% 5-year overall survival, 91% 5-year disease-specific survival and 91% 5-year disease-free survival, respectively, we found excellent survival rates in this surgically treated patient cohort of mainly advanced OPSCC (93% AJCC stage III or IV). The only factors positively influencing survival were p16 overexpression as well as p53 negativity and even more pronounced the combination of those biomarkers. Survival analysis of patients classified into three risk categories according to an algorithm based on p16, smoking, T- and N-category revealed a low, intermediate and high-risk group with significant survival differences between the low and the high-risk group. Patients with OPSCC can be successfully treated by surgery and adjuvant RT ± CT with a clear survival benefit of p16 positive, p53 negative patients. We recommend considering a combination of immunohistochemical (p16, p53) and clinical factors (smoking, T- and N-category) for risk stratification.

Factors affecting survival outcomes of patients with non-metastatic Ewing's sarcoma family tumors in the spine: a retrospective analysis of 63 patients in a single center.

PubMed

Wan, Wei; Lou, Yan; Hu, Zhiqi; Wang, Ting; Li, Jinsong; Tang, Yu; Wu, Zhipeng; Xu, Leqin; Yang, Xinghai; Song, Dianwen; Xiao, Jianru

2017-01-01

Little information has been published in the literature regarding survival outcomes of patients with Ewing's sarcoma family tumors (ESFTs) of the spine. The purpose of this study is to explore factors that may affect the prognosis of patients with non-metastatic spinal ESFTs. A retrospective analysis of survival outcomes was performed in patients with non-metastatic spinal ESFTs. Univariate and multivariate analyses were employed to identify prognostic factors for recurrence and survival. Recurrence-free survival (RFS) and overall survival (OS) were defined as the date of surgery to the date of local relapse and death. Kaplan-Meier methods were applied to estimate RFS and OS. Log-rank test was used to analyze single factors for RFS and OS. Factors with p values ≤0.1 were subjected to multivariate analysis. A total of 63 patients with non-metastatic spinal ESFTs were included in this study. The mean follow-up period was 35.1 months (range 1-155). Postoperative recurrence was detected in 25 patients, and distant metastasis and death occurred in 22 and 36 patients respectively. The result of multivariate analysis suggested that age older than 25 years and neoadjuvant chemotherapy were favorable independent prognostic factors for RFS and OS. In addition, total en-bloc resection, postoperative chemotherapy, radiotherapy and non-distant metastasis were favorable independent prognostic factors for OS. Age older than 25 years and neoadjuvant chemotherapy are favorable prognostic factors for both RFS and OS. In addition, total en-bloc resection, postoperative chemotherapy, radiotherapy and non-distant metastasis are closely associated with favorable survival.

[Study on factors influencing survival in patients with advanced gastric carcinoma after resection by Cox's proportional hazard model].

PubMed

Wang, S; Sun, Z; Wang, S

1996-11-01

A prospective follow-up study of 539 advanced gastric carcinoma patients after resection was undertaken between 1 January 1980 and 31 December 1989, with a follow-up rate of 95.36%. A multivariate analysis of possible factors influencing survival of these patients was performed, and their predicting models of survival rates was established by Cox proportional hazard model. The results showed that the major significant prognostic factors influencing survival of these patients were rate and station of lymph node metastases, type of operation, hepatic metastases, size of tumor, age and location of tumor. The most important factor was the rate of lymph node metastases. According to their regression coefficients, the predicting value (PV) of each patient was calculated, then all patients were divided into five risk groups according to PV, their predicting models of survival rates after resection were established in groups. The goodness-fit of estimated predicting models of survival rates were checked by fitting curve and residual plot, and the estimated models tallied with the actual situation. The results suggest that the patients with advanced gastric cancer after resection without lymph node metastases and hepatic metastases had a better prognosis, and their survival probability may be predicted according to the predicting model of survival rates.

STAT3 Controls the Long-Term Survival and Phenotype of Repair Schwann Cells during Nerve Regeneration.

PubMed

Benito, Cristina; Davis, Catherine M; Gomez-Sanchez, Jose A; Turmaine, Mark; Meijer, Dies; Poli, Valeria; Mirsky, Rhona; Jessen, Kristjan R

2017-04-19

After nerve injury, Schwann cells convert to a phenotype specialized to promote repair. But during the slow process of axonal regrowth, these repair Schwann cells gradually lose their regeneration-supportive features and eventually die. Although this is a key reason for the frequent regeneration failures in humans, the transcriptional mechanisms that control long-term survival and phenotype of repair cells have not been studied, and the molecular signaling underlying their decline is obscure. We show, in mice, that Schwann cell STAT3 has a dual role. It supports the long-term survival of repair Schwann cells and is required for the maintenance of repair Schwann cell properties. In contrast, STAT3 is less important for the initial generation of repair Schwann cells after injury. In repair Schwann cells, we find that Schwann cell STAT3 activation by Tyr705 phosphorylation is sustained during long-term denervation. STAT3 is required for maintaining autocrine Schwann cell survival signaling, and inactivation of Schwann cell STAT3 results in a striking loss of repair cells from chronically denervated distal stumps. STAT3 inactivation also results in abnormal morphology of repair cells and regeneration tracks, and failure to sustain expression of repair cell markers, including Shh, GDNF, and BDNF. Because Schwann cell development proceeds normally without STAT3, the function of this factor appears restricted to Schwann cells after injury. This identification of transcriptional mechanisms that support long-term survival and differentiation of repair cells will help identify, and eventually correct, the failures that lead to the deterioration of this important cell population. SIGNIFICANCE STATEMENT Although injured peripheral nerves contain repair Schwann cells that provide signals and spatial clues for promoting regeneration, the clinical outcome after nerve damage is frequently poor. A key reason for this is that, during the slow growth of axons through the proximal parts of injured nerves repair, Schwann cells gradually lose regeneration-supporting features and eventually die. Identification of signals that sustain repair cells is therefore an important goal. We have found that in mice the transcription factor STAT3 protects these cells from death and contributes to maintaining the molecular and morphological repair phenotype that promotes axonal regeneration. Defining the molecular mechanisms that maintain repair Schwann cells is an essential step toward developing therapeutic strategies that improve nerve regeneration and functional recovery. Copyright © 2017 Benito, Davis et al.

Stadium IB - IIA cervical cancer patient’s survival rate after receiving definitive radiation and radical operation therapy followed by adjuvant radiation therapy along with analysis of factors affecting the patient’s survival rate

NASA Astrophysics Data System (ADS)

Ruslim, S. K.; Purwoto, G.; Widyahening, I. S.; Ramli, I.

2017-08-01

To evaluate the characteristics and overall survival rates of early stage cervical cancer (FIGO IB-IIA) patients who receive definitive radiation therapy and those who are prescribed adjuvant postoperative radiation and to conduct a factors analysis of the variables that affect the overall survival rates in both groups of therapy. The medical records of 85 patients with cervical cancer FIGO stages IB-IIA who were treated at the Department of Radiotherapy of Cipto Mangunkusumo Hospital were reviewed and analyzed to determine their overall survival and the factors that affected it between a definitive radiation group and an adjuvant postoperative radiation group. There were 25 patients in the definitive radiation and 60 patients in the adjuvant radiation group. The overall survival rates in the adjuvant radiation group at years one, two, and three were 96.7%, 95%, and 93.3%, respectively. Negative lymph node metastasis had an average association with overall survival (p < 0.2). In the definitive radiation group, overall survival at years one, two, and three were 96%, 92%, and 92%, respectively. A hemoglobin (Hb) level >12 g/dl was a factor with an average association with the overall survival (p < 0.2). The differences between both groups of therapy were not statistically significant (92% vs. 93.3%; p = 0.138). This study did not show any statistically significant overall survival for cervical cancer FIGO stage IB-IIA patients who received definitive radiation or adjuvant postoperative radiation. Negative lymph node metastasis had an effect on the overall survival rate in the adjuvant postoperative radiation group, while a preradiation Hb level >12 g/dl tended to affect the overall survival in the definitive radiation group patients.

ETS transcription factor ETV2/ER71/Etsrp in hematopoietic and vascular development, injury, and regeneration.

PubMed

Zhao, Haiyong; Xu, Canxin; Lee, Tae-Jin; Liu, Fang; Choi, Kyunghee

2017-04-01

The major goal in regenerative medicine is to repair and restore injured, diseased or aged tissue function, thereby promoting general health. As such, the field of regenerative medicine has great translational potential in undertaking many of the health concerns and needs that we currently face. In particular, hematopoietic and vascular systems supply oxygen and nutrients and thus play critical roles in tissue development and tissue regeneration. Additionally, tissue vasculature serves as a tissue stem cell niche and thus contributes to tissue homeostasis. Notably, hematopoietic and vascular systems are sensitive to injury and subject to regeneration. As such, successful hematopoietic and vascular regeneration is prerequisite for efficient tissue repair and organismal survival and health. Recent studies have established that the interplay among the ETS transcription factor ETV2, vascular endothelial growth factor, and its receptor VEGFR2/FLK1 is essential for hematopoietic and vascular development. Emerging studies also support the role of these three factors and possible interplay in hematopoietic and vascular regeneration. Comprehensive understanding of the molecular mechanisms involved in the regulation and function of these three factors may lead to more effective approaches in promoting tissue repair and regeneration. Developmental Dynamics 246:318-327, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Delayed innocent bystander cell death following hypoxia in Caenorhabditis elegans

PubMed Central

Sun, C-L; Kim, E; Crowder, C M

2014-01-01

After hypoxia, cells may die immediately or have a protracted course, living or dying depending on an incompletely understood set of cell autonomous and nonautonomous factors. In stroke, for example, some neurons are thought to die from direct hypoxic injury by cell autonomous primary mechanisms, whereas other so called innocent bystander neurons die from factors released from the primarily injured cells. A major limitation in identifying these factors is the inability of current in vivo models to selectively target a set of cells for hypoxic injury so that the primarily injured cells and the innocent bystanders are clearly delineated. In order to develop such a model, we generated transgenic Caenorhabditis elegans strains where 2–3% of somatic cells were made selectively sensitive to hypoxia. This was accomplished by cell type-specific wild-type rescue in either pharyngeal myocytes or GABAergic neurons of a hypoxia resistance-producing translation factor mutation. Surprisingly, hypoxic targeting of these relatively small subsets of non-essential cells produced widespread innocent bystander cell injury, behavioral dysfunction and eventual organismal death. The hypoxic injury phenotypes of the myocyte or neuron sensitized strains were virtually identical. Using this model, we show that the C. elegans insulin receptor/FOXO transcription factor pathway improves survival when activated only after hypoxic injury and blocks innocent bystander death. PMID:24317200

Delayed innocent bystander cell death following hypoxia in Caenorhabditis elegans.

PubMed

Sun, C-L; Kim, E; Crowder, C M

2014-04-01

After hypoxia, cells may die immediately or have a protracted course, living or dying depending on an incompletely understood set of cell autonomous and nonautonomous factors. In stroke, for example, some neurons are thought to die from direct hypoxic injury by cell autonomous primary mechanisms, whereas other so called innocent bystander neurons die from factors released from the primarily injured cells. A major limitation in identifying these factors is the inability of current in vivo models to selectively target a set of cells for hypoxic injury so that the primarily injured cells and the innocent bystanders are clearly delineated. In order to develop such a model, we generated transgenic Caenorhabditis elegans strains where 2-3% of somatic cells were made selectively sensitive to hypoxia. This was accomplished by cell type-specific wild-type rescue in either pharyngeal myocytes or GABAergic neurons of a hypoxia resistance-producing translation factor mutation. Surprisingly, hypoxic targeting of these relatively small subsets of non-essential cells produced widespread innocent bystander cell injury, behavioral dysfunction and eventual organismal death. The hypoxic injury phenotypes of the myocyte or neuron sensitized strains were virtually identical. Using this model, we show that the C. elegans insulin receptor/FOXO transcription factor pathway improves survival when activated only after hypoxic injury and blocks innocent bystander death.

Hemorrhoids screening and treatment prior to LVAD: is it a necessity?

PubMed

Skouri, Hadi; Shurrab, Mohammed; Zahnan, Jad; Deeba, Samer; Sfeir, Pierre; Gharzuddin, Walid; Haj-Yahia, Saleem

2016-04-12

Continuous-flow left ventricle assist devices (CF-LVADs) has become an essential modality in the management of stage D heart failure (HF) with significant improvement in survival and quality of life. Due to the durability of such devices and long term support complications such as bleeding and aortic insufficiency has emerged. Bleeding accounts for more than 20 % with the majority being from the gastrointestinal tract. The increase of bleeding tendency are mainly attributed to the loss of large von Willebrand's Factor (vWF) multimers due to shear stress with the chronic intake of anticoagulants. We are reporting two cases of patients with Stage D HF and history of hemorrhoids presenting for LVAD implantation. Many efforts that decrease bleeding related to CF-LVADs will be discussed with focus on hemorrhoids.

Advances in the Diagnosis and Management of Persistent Pulmonary Hypertension of the Newborn (PPHN)

PubMed Central

Konduri, G. Ganesh; Kim, U. Olivia

2009-01-01

Synopsis Rapid evaluation of a neonate who is cyanotic and in respiratory distress is essential for achieving a good outcome. Persistent pulmonary hypertension of the newborn (PPHN) can be a primary cause or a contributing factor to respiratory failure, particularly in neonates born at ≥34 weeks gestation. PPHN represents a failure of normal postnatal adaptation that occurs at birth in the pulmonary circulation. Rapid advances in therapy in recent years have lead to a remarkable decrease in mortality for the affected infants. However, infants who survive PPHN are at a significant risk for long term hearing and neuro-developmental impairments. This review focuses on the diagnosis, recent advances in management and recommendations for the long term follow-up of infants with PPHN. PMID:19501693

Papillomavirus E6 oncoproteins

PubMed Central

Vande Pol, Scott B.; Klingelhutz, Aloysius J.

2013-01-01

Papillomaviruses induce benign and malignant epithelial tumors, and the viral E6 oncoprotein is essential for full transformation. E6 contributes to transformation by associating with cellular proteins, docking on specific acidic LXXLL peptide motifs found on the associated cellular proteins. This review examines insights from recent studies of human and animal E6 proteins that determine the three-dimensional structure of E6 when bound to acidic LXXLL peptides. The structure of E6 is related to recent advances in the purification and identification of E6 associated protein complexes. These E6 protein-complexes, together with other proteins that bind to E6, alter a broad array of biological outcomes including modulation of cell survival, cellular transcription, host cell differentiation, growth factor dependence, DNA damage responses, and cell cycle progression. PMID:23711382

Impact of Parthenium weeds on earthworms (Eudrilus eugeniae) during vermicomposting.

PubMed

Rajiv, P; Rajeshwari, Sivaraj; Rajendran, Venckatesh

2014-11-01

The aim of this work is to evaluate the effect of Parthenium-mediated compost on Eudrilus eugeniae during the process of vermicomposting. Nine different concentrations of Parthenium hysterophorus and cow dung mixtures were used to assess toxicity. The earthworms' growth, fecundity and antioxidant enzyme levels were analysed every 15 days. The antioxidant activities of enzymes [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)], considered as biomarkers, indicate the biochemical and oxidative stresses due to the toxin from Parthenium weeds. The earthworms' growth, biomass gain, cocoon production and antioxidant enzymes were in a low level in a high concentration of P. hysterophorus (without cow dung). The results clearly indicated that appropriate mixing of P. hysterophorus quantity is an essential factor for the survival of earthworms without causing any harm.

Characterization of essential proteins based on network topology in proteins interaction networks

NASA Astrophysics Data System (ADS)

Bakar, Sakhinah Abu; Taheri, Javid; Zomaya, Albert Y.

2014-06-01

The identification of essential proteins is theoretically and practically important as (1) it is essential to understand the minimal surviving requirements for cellular lives, and (2) it provides fundamental for development of drug. As conducting experimental studies to identify essential proteins are both time and resource consuming, here we present a computational approach in predicting them based on network topology properties from protein-protein interaction networks of Saccharomyces cerevisiae. The proposed method, namely EP3NN (Essential Proteins Prediction using Probabilistic Neural Network) employed a machine learning algorithm called Probabilistic Neural Network as a classifier to identify essential proteins of the organism of interest; it uses degree centrality, closeness centrality, local assortativity and local clustering coefficient of each protein in the network for such predictions. Results show that EP3NN managed to successfully predict essential proteins with an accuracy of 95% for our studied organism. Results also show that most of the essential proteins are close to other proteins, have assortativity behavior and form clusters/sub-graph in the network.

44 CFR Appendix 1 to Part 323 - List of Essential Survival Items

Code of Federal Regulations, 2014 CFR

2014-10-01

.... Laboratory glassware. Microscope and slides. Water purification apparatus. Group B None. ii. food Group A 1...) in drums, cans, ampules. Iodine tablets. Liquid chlorine, including containers. Chlorine compounds...

The high-mobility-group box protein SSRP1/T160 is essential for cell viability in day 3.5 mouse embryos.

PubMed

Cao, Shang; Bendall, Heather; Hicks, Geoffrey G; Nashabi, Abudi; Sakano, Hitoshi; Shinkai, Yoichi; Gariglio, Marisa; Oltz, Eugene M; Ruley, H Earl

2003-08-01

The high-mobility-group (HMG) SSRP1 protein is a member of a conserved chromatin-remodeling complex (FACT/DUF/CP) implicated in DNA replication, basal and regulated transcription, and DNA repair. To assist in the functional analysis of SSRP1, the Ssrp1 gene was targeted in murine embryonic stem cells, and the mutation was introduced into the germ line. Embryos homozygous for the targeted allele die soon after implantation, and preimplantation blastocysts are defective for cell outgrowth and/or survival in vitro. The Ssrp1 mutation was also crossed into a p53 null background without affecting growth and/or survival defects caused by loss of Ssrp1 function. Thus, Ssrp1 appears to encode nonredundant and p53-independent functions that are essential for cell viability.

Pinus densiflora leaf essential oil induces apoptosis via ROS generation and activation of caspases in YD-8 human oral cancer cells

PubMed Central

JO, JEONG-RANG; PARK, JU SUNG; PARK, YU-KYOUNG; CHAE, YOUNG ZOO; LEE, GYU-HEE; PARK, GY-YOUNG; JANG, BYEONG-CHURL

2012-01-01

The leaf of Pinus (P.) densiflora, a pine tree widely distributed in Asian countries, has been used as a traditional medicine. In the present study, we investigated the anticancer activity of essential oil, extracted by steam distillation, from the leaf of P. densiflora in YD-8 human oral squamous cell carcinoma (OSCC) cells. Treatment of YD-8 cells with P. densiflora leaf essential oil (PLEO) at 60 μg/ml for 8 h strongly inhibited proliferation and survival and induced apoptosis. Notably, treatment with PLEO led to generation of ROS, activation of caspase-9, PARP cleavage, down-regulation of Bcl-2, and phosphorylation of ERK-1/2 and JNK-1/2 in YD-8 cells. Treatment with PLEO, however, did not affect the expression of Bax, XIAP and GRP78. Importantly, pharmacological inhibition studies demonstrated that treatment with vitamin E (an anti-oxidant) or z-VAD-fmk (a pan-caspase inhibitor), but not with PD98059 (an ERK-1/2 inhibitor) or SP600125 (a JNK-1/2 inhibitor), strongly suppressed PLEO-induced apoptosis in YD-8 cells and reduction of their survival. Vitamin E treatment further blocked activation of caspase-9 and Bcl-2 down-regulation induced by PLEO. Thus, these results demonstrate firstly that PLEO has anti-proliferative, anti-survival and pro-apoptotic effects on YD-8 cells and the effects are largely due to the ROS-dependent activation of caspases. PMID:22086183

Pinus densiflora leaf essential oil induces apoptosis via ROS generation and activation of caspases in YD-8 human oral cancer cells.

PubMed

Jo, Jeong-Rang; Park, Ju Sung; Park, Yu-Kyoung; Chae, Young Zoo; Lee, Gyu-Hee; Park, Gy-Young; Jang, Byeong-Churl

2012-04-01

The leaf of Pinus (P.) densiflora, a pine tree widely distributed in Asian countries, has been used as a traditional medicine. In the present study, we investigated the anticancer activity of essential oil, extracted by steam distillation, from the leaf of P. densiflora in YD-8 human oral squamous cell carcinoma (OSCC) cells. Treatment of YD-8 cells with P. densiflora leaf essential oil (PLEO) at 60 µg/ml for 8 h strongly inhibited proliferation and survival and induced apoptosis. Notably, treatment with PLEO led to generation of ROS, activation of caspase-9, PARP cleavage, down-regulation of Bcl-2, and phosphorylation of ERK-1/2 and JNK-1/2 in YD-8 cells. Treatment with PLEO, however, did not affect the expression of Bax, XIAP and GRP78. Importantly, pharmaco-logical inhibition studies demonstrated that treatment with vitamin E (an anti-oxidant) or z-VAD-fmk (a pan-caspase inhibitor), but not with PD98059 (an ERK-1/2 inhibitor) or SP600125 (a JNK-1/2 inhibitor), strongly suppressed PLEO-induced apoptosis in YD-8 cells and reduction of their survival. Vitamin E treatment further blocked activation of caspase-9 and Bcl-2 down-regulation induced by PLEO. Thus, these results demonstrate firstly that PLEO has anti-proliferative, anti-survival and pro-apoptotic effects on YD-8 cells and the effects are largely due to the ROS-dependent activation of caspases.

[PROGNOSTIC MODELS IN MODERN MANAGEMENT OF VULVAR CANCER].

PubMed

Tsvetkov, Ch; Gorchev, G; Tomov, S; Nikolova, M; Genchev, G

2016-01-01

The aim of the research was to evaluate and analyse prognosis and prognostic factors in patients with squamous cell vulvar carcinoma after primary surgery with individual approach applied during the course of treatment. In the period between January 2000 and July 2010, 113 patients with squamous cell carcinoma of the vulva were diagnosed and operated on at Gynecologic Oncology Clinic of Medical University, Pleven. All the patients were monitored at the same clinic. Individual approach was applied to each patient and whenever it was possible, more conservative operative techniques were applied. The probable clinicopathological characteristics influencing the overall survival and recurrence free survival were analyzed. Univariate statistical analysis and Cox regression analysis were made in order to evaluate the characteristics, which were statistically significant for overall survival and survival without recurrence. A multivariate logistic regression analysis (Forward Wald procedure) was applied to evaluate the combined influence of the significant factors. While performing the multivariate analysis, the synergic effect of the independent prognostic factors of both kinds of survivals was also evaluated. Approaching individually each patient, we applied the following operative techniques: 1. Deep total radical vulvectomy with separate incisions for lymph dissection (LD) or without dissection--68 (60.18 %) patients. 2. En-bloc vulvectomy with bilateral LD without vulva reconstruction--10 (8.85%) 3. Modified radical vulvactomy (hemivulvectomy, patial vulvactomy)--25 (22.02%). 4. wide-local excision--3 (2.65%). 5. Simple (total /partial) vulvectomy--5 (4.43%) patients. 6. En-bloc resection with reconstruction--2 (1.77%) After a thorough analysis of the overall survival and recurrence free survival, we made the conclusion that the relapse occurrence and clinical stage of FIGO were independent prognostic factors for overall survival and the independent prognostic factors for recurrence free survival were: metastatic inguinal nodes (unilateral or bilateral), tumor size (above or below 3 cm) and lymphovascular space invasion. On the basis of these results we created two prognostic models: 1. A prognostic model of overall survival 2. A prognostic model for survival without recurrence. Following the surgical staging of the disease, were able to gather and analyse important clinicopathological indexes, which gave us the opportunity to form prognostic groups for overall survival and recurrence-free survival.

Survival patterns in squamous cell carcinoma of the head and neck: pain as an independent prognostic factor for survival.

PubMed

Reyes-Gibby, Cielito C; Anderson, Karen O; Merriman, Kelly W; Todd, Knox H; Shete, Sanjay S; Hanna, Ehab Y

2014-10-01

Survival outcomes in patients with squamous cell carcinoma of the head and neck (HNSCC) vary by extent of disease, behavioral factors, and socioeconomic factors. We assessed the extent to which pretreatment pain influences survival in 2,340 newly diagnosed patients with HNSCC, adjusting for disease stage, symptoms, pain medications, comorbidities, smoking, alcohol consumption, age, sex, and race/ethnicity. Patients rated their pain at presentation to the cancer center (0 = "no pain" and 10 = "pain as bad as you can imagine"). Survival time was calculated from the date of diagnosis to the date of death of any cause or last follow-up. Five-year overall survival was calculated for all the variables assessed in the study. Severe pain (≥7) was most prevalent among those with oral cancer (20.4%; pharynx = 18.8%; larynx = 16.1%) and significantly varied by tumor stage, fatigue severity, smoking status, comorbid lung disease, and race (all P < .05) across cancer diagnoses. Overall 5-year survival varied by pain for oral (severe pain = 31% vs nonsevere pain = 52%; P < .001) and pharyngeal cancer (severe pain = 33% vs nonsevere pain = 53%; P < .001). Multivariable analyses showed that pain persisted as an independent prognostic factor for survival. Pain reported prior to treatment should be considered in understanding survival outcomes in HNSCC patients. Pretreatment pain was an independent predictor of survival in a large sample of HNSCC patients even after accounting for tumor node metastasis stage, fatigue, age, race/ethnicity, smoking, and alcohol intake. Therefore, symptoms at presentation and before cancer treatment are important factors to be considered in understanding survival outcomes in HNSCC patients. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

Bone marrow vascular endothelial growth factor level per platelet count might be a significant predictor for the treatment outcomes of patients with diffuse large B-cell lymphomas.

PubMed

Kim, Jung Sun; Gang, Ga Won; Lee, Se Ryun; Sung, Hwa Jung; Park, Young; Kim, Dae Sik; Choi, Chul Won; Kim, Byung Soo

2015-10-01

Developing a parameter to predict bone marrow invasion by non-Hodgkin's lymphoma is an important unmet medical need for treatment decisions. This study aimed to confirm the validity of the hypothesis that bone marrow plasma vascular endothelial growth factor level might be correlated with the risk of bone marrow involvement and the prognosis of patients with diffuse large B-cell non-Hodgkin's lymphoma. Forty-nine diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone regimen were enrolled. Vascular endothelial growth factor level was measured with enzyme-linked immunosorbent assay. The validity of bone marrow plasma vascular endothelial growth factor level and bone marrow vascular endothelial growth factor level per platelet count for predicting treatment response and survival after initial rituximab, cyclophosphamide, daunorubicin, vincristine and prednisolone combined chemotherapy was assessed. Bone marrow plasma vascular endothelial growth factor level per platelet count was significantly associated with old age (≥ 65 years), poor performance score (≥ 2), high International prognosis index (≥ 3) and bone marrow invasion. The patients with high bone marrow plasma vascular endothelial growth factor level per platelet count (≥ 3.01) showed a significantly lower complete response rate than the others. On Kaplan-Meier survival curves, the patients with high bone marrow plasma vascular endothelial growth factor levels (≥ 655 pg/ml) or high bone marrow plasma vascular endothelial growth factor level per platelet count (≥ 3.01) demonstrated a significantly shorter overall survival and progression-free survival than the others. In the patients without bone marrow involvement, bone marrow plasma vascular endothelial growth factor level per platelet count had a significant relationship with overall survival and progression-free survival. Multivariate analysis revealed that the patients without BM invasion showing high level of bone marrow plasma vascular endothelial growth factor per platelet count had significantly shorter progression-free survival and overall survival. Bone marrow plasma vascular endothelial growth factor level per platelet count might be associated with bone marrow invasion by diffuse large B-cell lymphoma and is correlated with clinical outcomes after treatment. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Survival factors of hospitalized out-of-hospital cardiac arrest patients in Taiwan: A retrospective study.

PubMed

Lai, Chung-Yu; Lin, Fu-Huang; Chu, Hsin; Ku, Chih-Hung; Tsai, Shih-Hung; Chung, Chi-Hsiang; Chien, Wu-Chien; Wu, Chun-Hsien; Chu, Chi-Ming; Chang, Chi-Wen

2018-01-01

The chain of survival has been shown to improve the chances of survival for victims of cardiac arrest. Post-cardiac arrest care has been demonstrated to significantly impact the survival of out-of-hospital cardiac arrest (OHCA). How post-cardiac arrest care influences the survival of OHCA patients has been a main concern in recent years. The objective of this study was to assess the survival outcome of hospitalized OHCA patients and determine the factors associated with improved survival in terms of survival to discharge. We conducted a retrospective observational study by analyzing records from the National Health Insurance Research Database of Taiwan from 2007 to 2013. We collected cases with an International Classification of Disease Clinical Modification, 9th revision primary diagnosis codes of 427.41 (ventricular fibrillation, VF) or 427.5 (cardiac arrest) and excluded patients less than 18 years old, as well as cases with an unknown outcome or a combination of traumatic comorbidities. We then calculated the proportion of survival to discharge among hospitalized OHCA patients. Factors associated with the dependent variable were examined by logistic regression. Statistical analysis was conducted using SPSS 22 (IBM, Armonk, NY). Of the 11,000 cases, 2,499 patients (22.7%) survived to hospital discharge. The mean age of subjects who survived to hospital discharge and those who did not was 66.7±16.7 and 71.7±15.2 years, respectively. After adjusting for covariates, neurological failure, cardiac comorbidities, hospital level, intensive care unit beds, transfer to another hospital, and length of hospital stay were independent predictors of improved survival. Cardiac rhythm on admission was a strong factor associated with survival to discharge (VF vs. non-VF: adjusted odds ratio: 3.51; 95% confidence interval: 3.06-4.01). In conclusion, cardiac comorbidities, hospital volume, cardiac rhythm on admission, transfer to another hospital and length of hospital stay had a significant positive association with survival to discharge in hospitalized OHCA patients in Taiwan.

A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

DOE Office of Scientific and Technical Information (OSTI.GOV)

Latham, Antony M.; Odell, Adam F.; Mughal, Nadeem A.

2012-11-01

Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a highmore » VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: Black-Right-Pointing-Pointer Endothelial cells mount a stress response under conditions of low serum. Black-Right-Pointing-Pointer Endothelial VEGFR levels are modulated during this response. Black-Right-Pointing-Pointer The cell regulates VEGF-A bioavailability and cell survival. Black-Right-Pointing-Pointer This may partly underlie endothelial dysfunction seen in many pathologies.« less

Does CMV infection increase the incidence of infective endocarditis following kidney transplantation?

PubMed

Einollahi, Behzad; Lessan-Pezeshki, Mahboob; Pourfarziani, Vahid; Nemati, Eghlim; Nafar, Mohsen; Pour-Reza-Gholi, Fatemeh; Ghadyani, Mohammad Hassan; Farahani, Maryam Moshkani

2009-01-01

Infective endocarditis (IE) is a rare but life threatening infection after renal transplantation. In addition, coinfection of CMV and IE has not been reported. Therefore, the current study was initiated to determine whether CMV infection is a risk factor for developing of IE after kidney transplantation. In a retrospectively study, we analyzed the medical records of 3700 kidney recipients at two transplant centers in Iran, between January 2000 and June 2008 for infective endocarditis. During the study, 15 patients with IE hospitalized in our centers were included. The predominant causative microorganisms (60%) were group D non-enterococcal streptococci and enterococci. Patient survival rate in all recipients was 66% at 6 months. Data analysis showed no significant differences in 6 months patient survival from hospitalization between both groups with and without CMV infection (P=0.2). The presentation time of infective endocarditis in recipients with CMV coinfection was more likely to be early when compared to CMV negative coinfection patients (P=0.03). The present study indicates that CMV infection may lead to predispose to infective endocarditis after kidney transplantation. Rapid diagnosis, effective treatment, and prompt recognition of complications in kidney transplant recipients are essential to good patient outcome.

Adaptation to Chronic Nutritional Stress Leads to Reduced Dependence on Microbiota in Drosophila melanogaster

PubMed Central

Kolly, Sylvain; van der Meer, Jan R.; Kawecki, Tadeusz J.

2017-01-01

ABSTRACT Numerous studies have shown that animal nutrition is tightly linked to gut microbiota, especially under nutritional stress. In Drosophila melanogaster, microbiota are known to promote juvenile growth, development, and survival on poor diets, mainly through enhanced digestion leading to changes in hormonal signaling. Here, we show that this reliance on microbiota is greatly reduced in replicated Drosophila populations that became genetically adapted to a poor larval diet in the course of over 170 generations of experimental evolution. Protein and polysaccharide digestion in these poor-diet-adapted populations became much less dependent on colonization with microbiota. This was accompanied by changes in expression levels of dFOXO transcription factor, a key regulator of cell growth and survival, and many of its targets. These evolutionary changes in the expression of dFOXO targets to a large degree mimic the response of the same genes to microbiota, suggesting that the evolutionary adaptation to poor diet acted on mechanisms that normally mediate the response to microbiota. Our study suggests that some metazoans have retained the evolutionary potential to adapt their physiology such that association with microbiota may become optional rather than essential. PMID:29066546

Polyphosphate is a key factor for cell survival after DNA damage in eukaryotic cells.

PubMed

Bru, Samuel; Samper-Martín, Bàrbara; Quandt, Eva; Hernández-Ortega, Sara; Martínez-Laínez, Joan M; Garí, Eloi; Rafel, Marta; Torres-Torronteras, Javier; Martí, Ramón; Ribeiro, Mariana P C; Jiménez, Javier; Clotet, Josep

2017-09-01

Cells require extra amounts of dNTPs to repair DNA after damage. Polyphosphate (polyP) is an evolutionary conserved linear polymer of up to several hundred inorganic phosphate (Pi) residues that is involved in many functions, including Pi storage. In the present article, we report on findings demonstrating that polyP functions as a source of Pi when required to sustain the dNTP increment essential for DNA repair after damage. We show that mutant yeast cells without polyP produce less dNTPs upon DNA damage and that their survival is compromised. In contrast, when polyP levels are ectopically increased, yeast cells become more resistant to DNA damage. More importantly, we show that when polyP is reduced in HEK293 mammalian cell line cells and in human dermal primary fibroblasts (HDFa), these cells become more sensitive to DNA damage, suggesting that the protective role of polyP against DNA damage is evolutionary conserved. In conclusion, we present polyP as a molecule involved in resistance to DNA damage and suggest that polyP may be a putative target for new approaches in cancer treatment or prevention. Copyright © 2017 Elsevier B.V. All rights reserved.

What Is the Biological and Clinical Relevance of Fibrin?

PubMed

Litvinov, Rustem I; Weisel, John W

2016-06-01

As our knowledge of the structure and functions of fibrinogen and fibrin has increased tremendously, several key findings have given some people a superficial impression that the biological and clinical significance of these clotting proteins may be less than earlier thought. Most strikingly, studies of fibrinogen knockout mice demonstrated that many of these mice survive to weaning and beyond, suggesting that fibrin(ogen) may not be entirely necessary. Humans with afibrinogenemia also survive. Furthermore, in recent years, the major emphasis in the treatment of arterial thrombosis has been on inhibition of platelets, rather than fibrin. In contrast to the initially apparent conclusions from these results, it has become increasingly clear that fibrin is essential for hemostasis; is a key factor in thrombosis; and plays an important biological role in infection, inflammation, immunology, and wound healing. In addition, fibrinogen replacement therapy has become a preferred, major treatment for severe bleeding in trauma and surgery. Finally, fibrin is a unique biomaterial and is used as a sealant or glue, a matrix for cells, a scaffold for tissue engineering, and a carrier and/or a vector for targeted drug delivery. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Proinsulin in development: New roles for an ancient prohormone.

PubMed

Hernández-Sánchez, C; Mansilla, A; de la Rosa, E J; de Pablo, F

2006-06-01

In postnatal organisms, insulin is well known as an essential anabolic hormone responsible for maintaining glucose homeostasis. Its biosynthesis by the pancreatic beta cell has been considered a model of tissue-specific gene expression. However, proinsulin mRNA and protein have been found in embryonic stages before the formation of the pancreatic primordium, and later, in extrapancreatic tissues including the nervous system. Phylogenetic studies have also confirmed that production of insulin-like peptides antecedes the morphogenesis of a pancreas, and that these peptides contribute to normal development. In recent years, other roles for insulin distinct from its metabolic function have emerged also in vertebrates. During embryonic development, insulin acts as a survival factor and is involved in early morphogenesis. These findings are consistent with the observation that, at these stages, the proinsulin gene product remains as the precursor form, proinsulin. Independent of its low metabolic activity, proinsulin stimulates proliferation in developing neuroretina, as well as cell survival and cardiogenesis in early embryos. Insulin/proinsulin levels are finely regulated during development, since an excess of the protein interferes with correct morphogenesis and is deleterious for the embryo. This fine-tuned regulation is achieved by the expression of alternative embryonic proinsulin transcripts that have diminished translational activity.

The Essential Role of Cholesterol Metabolism in the Intracellular Survival of Mycobacterium leprae Is Not Coupled to Central Carbon Metabolism and Energy Production

PubMed Central

Marques, Maria Angela M.; Berrêdo-Pinho, Marcia; Rosa, Thabatta L. S. A.; Pujari, Venugopal; Lemes, Robertha M. R.; Lery, Leticia M. S.; Silva, Carlos Adriano M.; Guimarães, Ana Carolina R.; Atella, Georgia C.; Wheat, William H.; Brennan, Patrick J.; Crick, Dean C.; Belisle, John T.

2015-01-01

ABSTRACT Mycobacterium leprae induces the formation of lipid droplets, which are recruited to pathogen-containing phagosomes in infected macrophages and Schwann cells. Cholesterol is among the lipids with increased abundance in M. leprae-infected cells, and intracellular survival relies on cholesterol accumulation. The present study investigated the capacity of M. leprae to acquire and metabolize cholesterol. In silico analyses showed that oxidation of cholesterol to cholest-4-en-3-one (cholestenone), the first step of cholesterol degradation catalyzed by the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD), is apparently the only portion of the cholesterol catabolic pathway seen in Mycobacterium tuberculosis preserved by M. leprae. Incubation of bacteria with radiolabeled cholesterol confirmed the in silico predictions. Radiorespirometry and lipid analyses performed after incubating M. leprae with [4-14C]cholesterol or [26-14C]cholesterol showed the inability of this pathogen to metabolize the sterol rings or the side chain of cholesterol as a source of energy and carbon. However, the bacteria avidly incorporated cholesterol and, as expected, converted it to cholestenone both in vitro and in vivo. Our data indicate that M. leprae has lost the capacity to degrade and utilize cholesterol as a nutritional source but retains the enzyme responsible for its oxidation to cholestenone. Thus, the essential role of cholesterol metabolism in the intracellular survival of M. leprae is uncoupled from central carbon metabolism and energy production. Further elucidation of cholesterol metabolism in the host cell during M. leprae infection will establish the mechanism by which this lipid supports M. leprae intracellular survival and will open new avenues for novel leprosy therapies. IMPORTANCE Our study focused on the obligate intracellular pathogen Mycobacterium leprae and its capacity to metabolize cholesterol. The data make an important contribution for those interested in understanding the mechanisms of mycobacterial pathogenesis, since they indicate that the essential role of cholesterol for M. leprae intracellular survival does not rely on its utilization as a nutritional source. Our findings reinforce the complexity of cholesterol's role in sustaining M. leprae infection. Further elucidation of cholesterol metabolism in the host cell during M. leprae infection will establish the mechanism by which this lipid supports M. leprae intracellular survival and will open new avenues for novel leprosy therapies. PMID:26391209

The Essential Role of Cholesterol Metabolism in the Intracellular Survival of Mycobacterium leprae Is Not Coupled to Central Carbon Metabolism and Energy Production.

PubMed

Marques, Maria Angela M; Berrêdo-Pinho, Marcia; Rosa, Thabatta L S A; Pujari, Venugopal; Lemes, Robertha M R; Lery, Leticia M S; Silva, Carlos Adriano M; Guimarães, Ana Carolina R; Atella, Georgia C; Wheat, William H; Brennan, Patrick J; Crick, Dean C; Belisle, John T; Pessolani, Maria Cristina V

2015-12-01

Mycobacterium leprae induces the formation of lipid droplets, which are recruited to pathogen-containing phagosomes in infected macrophages and Schwann cells. Cholesterol is among the lipids with increased abundance in M. leprae-infected cells, and intracellular survival relies on cholesterol accumulation. The present study investigated the capacity of M. leprae to acquire and metabolize cholesterol. In silico analyses showed that oxidation of cholesterol to cholest-4-en-3-one (cholestenone), the first step of cholesterol degradation catalyzed by the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD), is apparently the only portion of the cholesterol catabolic pathway seen in Mycobacterium tuberculosis preserved by M. leprae. Incubation of bacteria with radiolabeled cholesterol confirmed the in silico predictions. Radiorespirometry and lipid analyses performed after incubating M. leprae with [4-(14)C]cholesterol or [26-(14)C]cholesterol showed the inability of this pathogen to metabolize the sterol rings or the side chain of cholesterol as a source of energy and carbon. However, the bacteria avidly incorporated cholesterol and, as expected, converted it to cholestenone both in vitro and in vivo. Our data indicate that M. leprae has lost the capacity to degrade and utilize cholesterol as a nutritional source but retains the enzyme responsible for its oxidation to cholestenone. Thus, the essential role of cholesterol metabolism in the intracellular survival of M. leprae is uncoupled from central carbon metabolism and energy production. Further elucidation of cholesterol metabolism in the host cell during M. leprae infection will establish the mechanism by which this lipid supports M. leprae intracellular survival and will open new avenues for novel leprosy therapies. Our study focused on the obligate intracellular pathogen Mycobacterium leprae and its capacity to metabolize cholesterol. The data make an important contribution for those interested in understanding the mechanisms of mycobacterial pathogenesis, since they indicate that the essential role of cholesterol for M. leprae intracellular survival does not rely on its utilization as a nutritional source. Our findings reinforce the complexity of cholesterol's role in sustaining M. leprae infection. Further elucidation of cholesterol metabolism in the host cell during M. leprae infection will establish the mechanism by which this lipid supports M. leprae intracellular survival and will open new avenues for novel leprosy therapies. Copyright © 2015 Marques et al.

Chronic kidney disease in dogs in UK veterinary practices: prevalence, risk factors, and survival.

PubMed

O'Neill, D G; Elliott, J; Church, D B; McGreevy, P D; Thomson, P C; Brodbelt, D C

2013-01-01

The prevalence for chronic kidney disease (CKD) in dogs varies widely (0.05-3.74%). Identified risk factors include advancing age, specific breeds, small body size, and periodontal disease. To estimate the prevalence and identify risk factors associated with CKD diagnosis and survival in dogs. Purebred dogs were hypothesized to have higher CKD risk and poorer survival characteristics than crossbred dogs. A merged clinical database of 107,214 dogs attending 89 UK veterinary practices over a 2-year period (January 2010-December 2011). A longitudinal study design estimated the apparent prevalence (AP) whereas the true prevalence (TP) was estimated using Bayesian analysis. A nested case-control study design evaluated risk factors. Survival analysis used the Kaplan-Meier survival curve method and multivariable Cox proportional hazards regression modeling. The CKD AP was 0.21% (95% CI: 0.19-0.24%) and TP was 0.37% (95% posterior credibility interval 0.02-1.44%). Significant risk factors included increasing age, being insured, and certain breeds (Cocker Spaniel, Cavalier King Charles Spaniel). Cardiac disease was a significant comorbid disorder. Significant clinical signs included halitosis, weight loss, polyuria/polydipsia, urinary incontinence, vomiting, decreased appetite, lethargy, and diarrhea. The median survival time from diagnosis was 226 days (95% CI 112-326 days). International Renal Interest Society stage and blood urea nitrogen concentration at diagnosis were significantly associated with hazard of death due to CKD. Chronic kidney disease compromises dog welfare. Increased awareness of CKD risk factors and association of blood biochemistry results with survival time should facilitate diagnosis and optimize case management to improve animal survival and welfare. Copyright © 2013 by the American College of Veterinary Internal Medicine.

CD47: A Master Regulator of Stemness | Center for Cancer Research

Cancer.gov

Identifying the pathways cells use to regulate proliferation, differentiation, and survival are essential for designing new treatments to stimulate organ and tissue repair following injury and for diseases as diverse as cancer and diabetes. The thrombospondin-1 receptor CD47 seems to limit cell survival and regeneration after stress. At the same time, CD47 levels are increased on the surface of cancer cells, which show enhanced proliferation and survival. To understand this apparent paradox, David Roberts, Ph.D., in CCR’s Laboratory of Pathology and his colleagues decided to investigate CD47’s mechanism of action using CD47- and thrombospondin-1-null mice.

Analysis of the mechanism of nucleosome survival during transcription

PubMed Central

Chang, Han-Wen; Kulaeva, Olga I.; Shaytan, Alexey K.; Kibanov, Mikhail; Kuznedelov, Konstantin; Severinov, Konstantin V.; Kirpichnikov, Mikhail P.; Clark, David J.; Studitsky, Vasily M.

2014-01-01

Maintenance of nucleosomal structure in the cell nuclei is essential for cell viability, regulation of gene expression and normal aging. Our previous data identified a key intermediate (a small intranucleosomal DNA loop, Ø-loop) that is likely required for nucleosome survival during transcription by RNA polymerase II (Pol II) through chromatin, and suggested that strong nucleosomal pausing guarantees efficient nucleosome survival. To evaluate these predictions, we analysed transcription through a nucleosome by different, structurally related RNA polymerases and mutant yeast Pol II having different histone-interacting surfaces that presumably stabilize the Ø-loop. The height of the nucleosomal barrier to transcription and efficiency of nucleosome survival correlate with the net negative charges of the histone-interacting surfaces. Molecular modeling and analysis of Pol II-nucleosome intermediates by DNase I footprinting suggest that efficient Ø-loop formation and nucleosome survival are mediated by electrostatic interactions between the largest subunit of Pol II and core histones. PMID:24234452

Fluoroquinolone-mediated inhibition of cell growth, S-G2/M cell cycle arrest, and apoptosis in canine osteosarcoma cell lines.

PubMed

Seo, Kyoung won; Holt, Roseline; Jung, Yong-Sam; Rodriguez, Carlos O; Chen, Xinbin; Rebhun, Robert B

2012-01-01

Despite significant advancements in osteosarcoma research, the overall survival of canine and human osteosarcoma patients has remained essentially static over the past 2 decades. Post-operative limb-spare infection has been associated with improved survival in both species, yet a mechanism for improved survival has not been clearly established. Given that the majority of canine osteosarcoma patients experiencing post-operative infections were treated with fluoroquinolone antibiotics, we hypothesized that fluoroquinolone antibiotics might directly inhibit the survival and proliferation of canine osteosarcoma cells. Ciprofloxacin or enrofloxacin were found to inhibit p21(WAF1) expression resulting in decreased proliferation and increased S-G(2)/M accumulation. Furthermore, fluoroquinolone exposure induced apoptosis of canine osteosarcoma cells as demonstrated by cleavage of caspase-3 and PARP, and activation of caspase-3/7. These results support further studies examining the potential impact of quinolones on survival and proliferation of osteosarcoma.

Comparison of Cox's Regression Model and Parametric Models in Evaluating the Prognostic Factors for Survival after Liver Transplantation in Shiraz during 2000-2012.

PubMed

Adelian, R; Jamali, J; Zare, N; Ayatollahi, S M T; Pooladfar, G R; Roustaei, N

2015-01-01

Identification of the prognostic factors for survival in patients with liver transplantation is challengeable. Various methods of survival analysis have provided different, sometimes contradictory, results from the same data. To compare Cox's regression model with parametric models for determining the independent factors for predicting adults' and pediatrics' survival after liver transplantation. This study was conducted on 183 pediatric patients and 346 adults underwent liver transplantation in Namazi Hospital, Shiraz, southern Iran. The study population included all patients undergoing liver transplantation from 2000 to 2012. The prognostic factors sex, age, Child class, initial diagnosis of the liver disease, PELD/MELD score, and pre-operative laboratory markers were selected for survival analysis. Among 529 patients, 346 (64.5%) were adult and 183 (34.6%) were pediatric cases. Overall, the lognormal distribution was the best-fitting model for adult and pediatric patients. Age in adults (HR=1.16, p<0.05) and weight (HR=2.68, p<0.01) and Child class B (HR=2.12, p<0.05) in pediatric patients were the most important factors for prediction of survival after liver transplantation. Adult patients younger than the mean age and pediatric patients weighing above the mean and Child class A (compared to those with classes B or C) had better survival. Parametric regression model is a good alternative for the Cox's regression model.

Multimodal imaging of lung cancer and its microenvironment (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hariri, Lida P.; Niederst, Matthew J.; Mulvey, Hillary; Adams, David C.; Hu, Haichuan; Chico Calero, Isabel; Szabari, Margit V.; Vakoc, Benjamin J.; Hasan, Tayyaba; Bouma, Brett E.; Engelman, Jeffrey A.; Suter, Melissa J.

2016-03-01

Despite significant advances in targeted therapies for lung cancer, nearly all patients develop drug resistance within 6-12 months and prognosis remains poor. Developing drug resistance is a progressive process that involves tumor cells and their microenvironment. We hypothesize that microenvironment factors alter tumor growth and response to targeted therapy. We conducted in vitro studies in human EGFR-mutant lung carcinoma cells, and demonstrated that factors secreted from lung fibroblasts results in increased tumor cell survival during targeted therapy with EGFR inhibitor, gefitinib. We also demonstrated that increased environment stiffness results in increased tumor survival during gefitinib therapy. In order to test our hypothesis in vivo, we developed a multimodal optical imaging protocol for preclinical intravital imaging in mouse models to assess tumor and its microenvironment over time. We have successfully conducted multimodal imaging of dorsal skinfold chamber (DSC) window mice implanted with GFP-labeled human EGFR mutant lung carcinoma cells and visualized changes in tumor development and microenvironment facets over time. Multimodal imaging included structural OCT to assess tumor viability and necrosis, polarization-sensitive OCT to measure tissue birefringence for collagen/fibroblast detection, and Doppler OCT to assess tumor vasculature. Confocal imaging was also performed for high-resolution visualization of EGFR-mutant lung cancer cells labeled with GFP, and was coregistered with OCT. Our results demonstrated that stromal support and vascular growth are essential to tumor progression. Multimodal imaging is a useful tool to assess tumor and its microenvironment over time.

Toxicity and utilization of chemical weapons: does toxicity and venom utilization contribute to the formation of species communities?

PubMed

Westermann, Fabian L; McPherson, Iain S; Jones, Tappey H; Milicich, Lesley; Lester, Philip J

2015-08-01

Toxicity and the utilization of venom are essential features in the ecology of many animal species and have been hypothesized to be important factors contributing to the assembly of communities through competitive interactions. Ants of the genus Monomorium utilize a variety of venom compositions, which have been reported to give them a competitive advantage. Here, we investigate two pairs of Monomorium species, which differ in the structural compositions of their venom and their co-occurrence patterns with the invasive Argentine ant. We looked at the effects of Monomorium venom toxicity, venom utilization, and aggressive physical interactions on Monomorium and Argentine ant survival rates during arena trials. The venom toxicity of the two species co-occurring with the invasive Argentine ants was found to be significantly higher than the toxicity of the two species which do not. There was no correlation between venom toxicity and Monomorium survival; however, three of the four Monomorium species displayed significant variability in their venom usage which was associated with the number of Argentine ant workers encountered during trials. Average Monomorium mortality varied significantly between species, and in Monomorium smithii and Monomorium antipodum, aggressive interactions with Argentine ants had a significant negative effect on their mortality. Our study demonstrates that different factors and strategies can contribute to the ability of a species to withstand the pressure of a dominant invader at high abundance, and venom chemistry appears to be only one of several strategies utilized.

Overexpression of Hif-1α in Mesenchymal Stem Cells Affects Cell-Autonomous Angiogenic and Osteogenic Parameters.

PubMed

Lampert, F M; Kütscher, C; Stark, G B; Finkenzeller, G

2016-03-01

Reconstruction of large bone defects still represents a major medical challenge. In recent years tissue engineering has developed techniques based on adult mesenchymal stem cells (MSCs) that could represent an attractive therapeutical option to treat large bone defects in the future. It has been demonstrated in various animal models that ex vivo expanded MSCs are capable of promoting the regeneration of skeletal defects after implantation. However, for the efficient regeneration of bone in tissue engineering applications, a rapid vascularization of implanted grafts is essential to ensure the survival of cells in the early post-implantational phase. A promising strategy to enhance vascularization of MSC-containing implants could consist of overexpression of the angiogenic master transcription factor Hypoxia-inducible factor 1 (Hif-1) in the MSCs in order to induce angiogenesis and support osteogenesis. In the present study, we overexpressed Hif-1α in MSCs by using recombinant adenoviruses and investigated cell-autonomous effects. Overexpression of Hif-1α enhanced proliferation, migration, cell survival and expression of pro-angiogenic genes. Other parameters such as expression of the osteogenic markers BMP-2 and RunX2 were decreased. Hif-1α overexpression had no effect on invasion, senescence and osteogenic differentiation of MSCs. Our experiments revealed multifarious effects of Hif-1α overexpression on cell-autonomous parameters. Therefore, Hif-1α overexpression may represent a therapeutic option to improve cellular functions of MSCs to treat critical sized bone defects. © 2015 Wiley Periodicals, Inc.

The type I BMP receptors, Bmpr1a and Acvr1, activate multiple signaling pathways to regulate lens formation

PubMed Central

Rajagopal, Ramya; Huang, Jie; Dattilo, Lisa K.; Kaartinen, Vesa; Mishina, Yuji; Deng, Chu-Xia; Umans, Lieve; Zwijsen, An; Roberts, Anita B.; Beebe, David C.

2009-01-01

BMPs play multiple roles in development and BMP signaling is essential for lens formation. However, the mechanisms by which BMP receptors function in vertebrate development are incompletely understood. To determine the downstream effectors of BMP signaling and their functions in the ectoderm that will form the lens, we deleted the genes encoding the type I BMP receptors, Bmpr1a and Acvr1, and the canonical transducers of BMP signaling, Smad4, Smad1 and Smad5. Bmpr1a and Acvr1 regulated cell survival and proliferation, respectively. Absence of both receptors interfered with the expression of proteins involved in normal lens development and prevented lens formation, demonstrating that BMPs induce lens formation by acting directly on the prospective lens ectoderm. Remarkably, the canonical Smad signaling pathway was not needed for most of these processes. Lens formation, placode cell proliferation, the expression of FoxE3, a lens-specific transcription factor, and the lens protein, αA-crystallin were regulated by BMP receptors in a Smad-independent manner. Placode cell survival was promoted by R-Smad signaling, but in a manner that did not involve Smad4. Of the responses tested, only maintaining a high level of Sox2 protein, a transcription factor expressed early in placode formation, required the canonical Smad pathway. A key function of Smad-independent BMP receptor signaling may be reorganization of actin cytoskeleton to drive lens invagination. PMID:19733164

High Rab27A expression indicates favorable prognosis in CRC.

PubMed

Shi, Chuanbing; Yang, Xiaojun; Ni, Yijiang; Hou, Ning; Xu, Li; Zhan, Feng; Zhu, Huijun; Xiong, Lin; Chen, Pingsheng

2015-06-13

Rab27A is a peculiar member in Rab family and has been suggested to play essential roles in the development of human cancers. However, the association between Rab27A expression and clinicopathological characteristics of colorectal cancer (CRC) has not been elucidated yet. One-step quantitative real-time polymerase chain reaction (qPCR) test with 18 fresh-frozen CRC samples and immunohistochemistry (IHC) analysis in 112 CRC cases were executed to evaluate the relationship between Rab27A expression and the clinicopathological features of CRC. Cox regression and Kaplan-Meier survival analyses were performed to identify the prognostic factors for 112 CRC patients. The results specified that the expression levels of Rab27A mRNA and protein were significantly higher in CRC tissues than that in matched non-cancerous tissues, in both qPCR test (p = 0.029) and IHC analysis (p = 0.020). The IHC data indicated that the Rab27A protein expression in CRC was statistically correlated with lymph node metastasis (p = 0.022) and TNM stage (p = 0.026). Cox multi-factor analysis and Kaplan-Meier method suggested Rab27A protein expression (p = 0.012) and tumor differentiation (p = 0.004) were significantly associated with the overall survival of CRC patients. The data indicated the differentiate expression of Rab27A in CRC tissues and matched non-cancerous tissues. Rab27A may be used as a valuable prognostic biomarker for CRC patients.

Akt-RSK-S6-kinase Signaling Networks Activated by Oncogenic Receptor Tyrosine Kinases

PubMed Central

Moritz, Albrecht; Li, Yu; Guo, Ailan; Villén, Judit; Wang, Yi; MacNeill, Joan; Kornhauser, Jon; Sprott, Kam; Zhou, Jing; Possemato, Anthony; Ren, Jian Min; Hornbeck, Peter; Cantley, Lewis C.; Gygi, Steven P.; Rush, John; Comb, Michael J.

2011-01-01

Receptor tyrosine kinases (RTKs) activate pathways mediated by serine/threonine (Ser/Thr) kinases such as the PI3K (phosphatidylinositol 3-kinase)-Akt pathway, the Ras-MAPK (mitogen-activated protein kinase)-RSK pathway, and the mTOR (mammalian target of rapamycin)-p70 S6 pathway that control important aspects of cell growth, proliferation, and survival. The Akt, RSK, and p70 S6 family of protein kinases transmit signals by phosphorylating substrates on a RxRxxS/T motif. Here, we developed a large-scale proteomic approach to identify over 200 substrates of this kinase family in cancer cell lines driven by the c-Met, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor a (PDGFRα) RTKs. We identified a subset of proteins with RxRxxS/T sites for which phosphorylation was decreased by RTKIs as well as by inhibitors of the PI3K, mTOR, and MAPK pathways and determined the effects of siRNA directed against these substrates on cell viability. We found that phosphorylation of the protein chaperone SGTA (small glutamine-rich tetratricopeptide repeat-containing protein alpha) at Ser305 is essential for PDGFRα stabilization and cell survival in PDGFRα-dependent cancer cells. Our approach provides a new view of RTK and Akt-RSK-S6 kinase signaling, revealing many previously unidentified Akt-RSK-S6 kinase substrates that merit further consideration as targets for combination therapy with RTKIs. PMID:20736484

Short Implants: New Horizon in Implant Dentistry.

PubMed

Jain, Neha; Gulati, Manisha; Garg, Meenu; Pathak, Chetan

2016-09-01

The choice of implant length is an essential factor in deciding the survival rates of these implants and the overall success of the prosthesis. Placing an implant in the posterior part of the maxilla and mandible has always been very critical due to poor bone quality and quantity. Long implants can be placed in association with complex surgical procedures such as sinus lift and bone augmentation. These techniques are associated with higher cost, increased treatment time and greater morbidity. Hence, there is need for a less invasive treatment option in areas of poor bone quantity and quality. Data related to survival rates of short implants, their design and prosthetic considerations has been compiled and structured in this manuscript with emphasis on the indications, advantages of short implants and critical biomechanical factors to be taken into consideration when choosing to place them. Studies have shown that comparable success rates can be achieved with short implants as those with long implants by decreasing the lateral forces to the prosthesis, eliminating cantilevers, increasing implant surface area and improving implant to abutment connection. Short implants can be considered as an effective treatment alternative in resorbed ridges. Short implants can be considered as a viable treatment option in atrophic ridge cases in order to avoid complex surgical procedures required to place long implants. With improvement in the implant surface geometry and surface texture, there is an increase in the bone implant contact area which provides a good primary stability during osseo-integration.

Association of microRNA-200c expression levels with clinicopathological factors and prognosis in endometrioid endometrial cancer.

PubMed

Wilczynski, Milosz; Danielska, Justyna; Domanska-Senderowska, Daria; Dzieniecka, Monika; Szymanska, Bozena; Malinowski, Andrzej

2018-05-01

MicroRNAs (miRNAs) are regulators of gene expression, which play an important role in many critical cellular processes including apoptosis, proliferation and cell differentiation. Aberrant miRNA expression has been reported in a variety of human malignancies. Therefore, miRNAs may be potentially used as cancer biomarkers. miRNA-200c, which is a member of the miRNA-200 family, might play an essential role in tumor progression. The purpose of this study was to evaluate the prognostic and clinical significance of miRNA-200c in women with endometrioid endometrial cancer. Total RNA extraction from 90 archival formalin-fixed paraffin-embedded tissue samples of endometri-oid endometrial cancer and 10 normal endometrium samples was performed. After cDNA synthesis, real-time polymerase chain reaction was conducted and relative expression of miRNA-200c was assessed. Then, miRNA-200c expression levels were evaluated with regard to clinicopathological characteristics. The expression levels of miRNA-200c were significantly increased in endometrioid endometrial cancer samples. Expression of miRNA-200c maintained at significantly higher levels in the early stage endometrioid endometrial cancer compared with more advanced stages. In the Kaplan-Meier analysis, lower levels of miRNA-200c expression were associated with inferior survival. Expression levels of miRNA-200c might be associated with clinicopathological factors and survival in endometrioid endometrial cancer. © 2018 Nordic Federation of Societies of Obstetrics and Gynecology.

Activation of glial FGFRs is essential in glial migration, proliferation, and survival and in glia-neuron signaling during olfactory system development.

PubMed

Gibson, Nicholas J; Tolbert, Leslie P; Oland, Lynne A

2012-01-01

Development of the adult olfactory system of the moth Manduca sexta depends on reciprocal interactions between olfactory receptor neuron (ORN) axons growing in from the periphery and centrally-derived glial cells. Early-arriving ORN axons induce a subset of glial cells to proliferate and migrate to form an axon-sorting zone, in which later-arriving ORN axons will change their axonal neighbors and change their direction of outgrowth in order to travel with like axons to their target areas in the olfactory (antennal) lobe. These newly fasciculated axon bundles will terminate in protoglomeruli, the formation of which induces other glial cells to migrate to surround them. Glial cells do not migrate unless ORN axons are present, axons fail to fasciculate and target correctly without sufficient glial cells, and protoglomeruli are not maintained without a glial surround. We have shown previously that Epidermal Growth Factor receptors and the IgCAMs Neuroglian and Fasciclin II play a role in the ORN responses to glial cells. In the present work, we present evidence for the importance of glial Fibroblast Growth Factor receptors in glial migration, proliferation, and survival in this developing pathway. We also report changes in growth patterns of ORN axons and of the dendrites of olfactory (antennal lobe) neurons following blockade of glial FGFR activation that suggest that glial FGFR activation is important in reciprocal communication between neurons and glial cells.

Activation of Glial FGFRs Is Essential in Glial Migration, Proliferation, and Survival and in Glia-Neuron Signaling during Olfactory System Development

PubMed Central

Gibson, Nicholas J.; Tolbert, Leslie P.; Oland, Lynne A.

2012-01-01

Development of the adult olfactory system of the moth Manduca sexta depends on reciprocal interactions between olfactory receptor neuron (ORN) axons growing in from the periphery and centrally-derived glial cells. Early-arriving ORN axons induce a subset of glial cells to proliferate and migrate to form an axon-sorting zone, in which later-arriving ORN axons will change their axonal neighbors and change their direction of outgrowth in order to travel with like axons to their target areas in the olfactory (antennal) lobe. These newly fasciculated axon bundles will terminate in protoglomeruli, the formation of which induces other glial cells to migrate to surround them. Glial cells do not migrate unless ORN axons are present, axons fail to fasciculate and target correctly without sufficient glial cells, and protoglomeruli are not maintained without a glial surround. We have shown previously that Epidermal Growth Factor receptors and the IgCAMs Neuroglian and Fasciclin II play a role in the ORN responses to glial cells. In the present work, we present evidence for the importance of glial Fibroblast Growth Factor receptors in glial migration, proliferation, and survival in this developing pathway. We also report changes in growth patterns of ORN axons and of the dendrites of olfactory (antennal lobe) neurons following blockade of glial FGFR activation that suggest that glial FGFR activation is important in reciprocal communication between neurons and glial cells. PMID:22493675

Short Implants: New Horizon in Implant Dentistry

PubMed Central

Gulati, Manisha; Garg, Meenu; Pathak, Chetan

2016-01-01

The choice of implant length is an essential factor in deciding the survival rates of these implants and the overall success of the prosthesis. Placing an implant in the posterior part of the maxilla and mandible has always been very critical due to poor bone quality and quantity. Long implants can be placed in association with complex surgical procedures such as sinus lift and bone augmentation. These techniques are associated with higher cost, increased treatment time and greater morbidity. Hence, there is need for a less invasive treatment option in areas of poor bone quantity and quality. Data related to survival rates of short implants, their design and prosthetic considerations has been compiled and structured in this manuscript with emphasis on the indications, advantages of short implants and critical biomechanical factors to be taken into consideration when choosing to place them. Studies have shown that comparable success rates can be achieved with short implants as those with long implants by decreasing the lateral forces to the prosthesis, eliminating cantilevers, increasing implant surface area and improving implant to abutment connection. Short implants can be considered as an effective treatment alternative in resorbed ridges. Short implants can be considered as a viable treatment option in atrophic ridge cases in order to avoid complex surgical procedures required to place long implants. With improvement in the implant surface geometry and surface texture, there is an increase in the bone implant contact area which provides a good primary stability during osseo-integration. PMID:27790598

Modeling post-fledging survival of lark buntings in response to ecological and biological factors

USGS Publications Warehouse

Yackel Adams, A.A.; Skagen, S.K.; Savidge, J.A.

2006-01-01

We evaluated the influences of several ecological, biological, and methodological factors on post-fledging survival of a shortgrass prairie bird, the Lark Bunting (Calamospiza melanocorys). We estimated daily post-fledging survival (n = 206, 82 broods) using radiotelemetry and color bands to track fledglings. Daily survival probabilities were best explained by drought intensity, time in season (quadratic trend), ages ≤3 d post-fledging, and rank given drought intensity. Drought intensity had a strong negative effect on survival. Rank was an important predictor of fledgling survival only during the severe drought of 2002 when the smallest fledglings had lower survival. Recently fledged young (ages ≤3 d post-fledging) undergoing the transition from nest to surrounding habitat experienced markedly lower survival, demonstrating the vulnerable nature of this time period. Survival was greater in mid and late season than early season, corresponding to our assumptions of food availability. Neither mark type nor sex of attending parent influenced survival. The model-averaged product of the 22-d survival calculated using mean rank and median value of time in season was 0.360 ± 0.08 in 2001 and 0.276 ± 0.08 in 2002. Survival estimates that account for age, condition of young, ecological conditions, and other factors are important for parameterization of realistic population models. Biologists using population growth models to elucidate mechanisms of population declines should attempt to estimate species-specific of post-fledging survival rather than use generalized estimates.

PDGFRα/β and VEGFR2 polymorphisms in colorectal cancer: incidence and implications in clinical outcome

PubMed Central

2012-01-01

Background Angiogenesis plays an essential role in tumor growth and metastasis, and is a major target in cancer therapy. VEGFR and PDGFR are key players involved in this process. The purpose of this study was to assess the incidence of genetic variants in these receptors and its potential clinical implications in colorectal cancer (CRC). Methods VEGFR2, PDGFRα and PDGFRβ mutations were evaluated by sequencing their tyrosine kinase domains in 8 CRC cell lines and in 92 samples of patients with CRC. Correlations with clinicopathological features and survival were analyzed. Results Four SNPs were identified, three in PDGFRα [exon 12 (A12): c.1701A>G; exon 13 (A13): c.1809G>A; and exon 17 (A17): c.2439+58C>A] and one in PDGFRβ [exon 19 (B19): c.2601A>G]. SNP B19, identified in 58% of tumor samples and in 4 cell lines (LS174T, LS180, SW48, COLO205), was associated with higher PDGFR and pPDGFR protein levels. Consistent with this observation, 5-year survival was greater for patients with PDGFR B19 wild type tumors (AA) than for those harboring the G-allele genotype (GA or GG) (51% vs 17%; p=0.073). Multivariate analysis confirmed SNP B19 (p=0.029) was a significant prognostic factor for survival, independent of age (p=0.060) or TNM stage (p<0.001). Conclusions PDGFRβ exon 19 c.2601A>G SNP is commonly encountered in CRC patients and is associated with increased pathway activation and poorer survival. Implications regarding its potential influence in response to PDGFR-targeted agents remain to be elucidated. PMID:23146028

Carbon-Starvation Induces Cross-Resistance to Thermal, Acid, and Oxidative Stress in Serratia marcescens

PubMed Central

Pittman, Joseph R.; Kline, La’Kesha C.; Kenyon, William J.

2015-01-01

The broad host-range pathogen Serratia marcescens survives in diverse host and non-host environments, often enduring conditions in which the concentration of essential nutrients is growth-limiting. In such environments, carbon and energy source starvation (carbon-starvation) is one of the most common forms of stress encountered by S. marcescens. Related members of the family Enterobacteriaceae are known to undergo substantial changes in gene expression and physiology in response to the specific stress of carbon-starvation, enabling non-spore-forming cells to survive periods of prolonged starvation and exposure to other forms of stress (i.e., starvation-induced cross-resistance). To determine if carbon-starvation also results in elevated levels of cross-resistance in S. marcescens, both log-phase and carbon-starved cultures, depleted of glucose before the onset of high cell-density stationary-phase, were grown in minimal media at either 30 °C or 37 °C and were then challenged for resistance to high temperature (50 °C), low pH (pH 2.8), and oxidative stress (15 mM H2O2). In general, carbon-starved cells exhibited a higher level of resistance to thermal stress, acid stress, and oxidative stress compared to log-phase cells. The extent of carbon-starvation-induced cross-resistance was dependent on incubation temperature and on the particular strain of S. marcescens. In addition, strain- and temperature-dependent variations in long-term starvation survival were also observed. The enhanced stress-resistance of starved S. marcescens cells could be an important factor in their survival and persistence in many non-host environments and within certain host microenvironments where the availability of carbon sources is suboptimal for growth. PMID:27682115

The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils.

PubMed

Roberts, Christina A; Al-Tameemi, Hassan M; Mashruwala, Ameya A; Rosario-Cruz, Zuelay; Chauhan, Unnati; Sause, William E; Torres, Victor J; Belden, William J; Boyd, Jeffrey M

2017-06-01

Staphylococcus aureus remains a causative agent for morbidity and mortality worldwide. This is in part a result of antimicrobial resistance, highlighting the need to uncover novel antibiotic targets and to discover new therapeutic agents. In the present study, we explored the possibility that iron-sulfur (Fe-S) cluster synthesis is a viable antimicrobial target. RNA interference studies established that Suf ( su l f ur mobilization)-dependent Fe-S cluster synthesis is essential in S. aureus We found that sufCDSUB were cotranscribed and that suf transcription was positively influenced by sigma factor B. We characterized an S. aureus strain that contained a transposon inserted in the intergenic space between sufC and sufD ( sufD *), resulting in decreased transcription of sufSUB Consistent with the transcriptional data, the sufD * strain had multiple phenotypes associated with impaired Fe-S protein maturation. They included decreased activities of Fe-S cluster-dependent enzymes, decreased growth in media lacking metabolites that require Fe-S proteins for synthesis, and decreased flux through the tricarboxylic acid (TCA) cycle. Decreased Fe-S cluster synthesis resulted in sensitivity to reactive oxygen and reactive nitrogen species, as well as increased DNA damage and impaired DNA repair. The sufD * strain also exhibited perturbed intracellular nonchelated Fe pools. Importantly, the sufD* strain did not exhibit altered exoprotein production or altered biofilm formation, but it was attenuated for survival upon challenge by human polymorphonuclear leukocytes. The results presented are consistent with the hypothesis that Fe-S cluster synthesis is a viable target for antimicrobial development. Copyright © 2017 American Society for Microbiology.

TgTKL1 Is a Unique Plant-Like Nuclear Kinase That Plays an Essential Role in Acute Toxoplasmosis

PubMed Central

Varberg, Joseph M.; Coppens, Isabelle; Arrizabalaga, Gustavo

2018-01-01

ABSTRACT In the protozoan parasite Toxoplasma gondii, protein kinases have been shown to play key roles in regulating parasite motility, invasion, replication, egress, and survival within the host. The tyrosine kinase-like (TKL) family of proteins are an unexplored set of kinases in Toxoplasma. Of the eight annotated TKLs in the Toxoplasma genome, a recent genome-wide loss-of-function screen showed that six are important for tachyzoite fitness. By utilizing an endogenous tagging approach, we showed that these six T. gondii TKLs (TgTKLs) localize to various subcellular compartments, including the nucleus, the cytosol, the inner membrane complex, and the Golgi apparatus. To gain insight into the function of TKLs in Toxoplasma, we first characterized TgTKL1, which contains the plant-like enhanced disease resistance 1 (EDR1) domain and localizes to the nucleus. TgTKL1 knockout parasites displayed significant defects in progression through the lytic cycle; we show that the defects were due to specific impairment of host cell attachment. Transcriptomics analysis identified over 200 genes of diverse functions that were differentially expressed in TgTKL1 knockout parasites. Importantly, numerous genes implicated in host cell attachment and invasion were among those most significantly downregulated, resulting in defects in microneme secretion and processing. Significantly, all of the mice inoculated intraperitoneally with TgTKL1 knockout parasites survived the infection, suggesting that TgTKL1 plays an essential role in acute toxoplasmosis. Together, these findings suggest that TgTKL1 mediates a signaling pathway that regulates the expression of multiple factors required for parasite virulence, underscoring the potential of this kinase as a novel therapeutic target. PMID:29559568

MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice.

PubMed

Sundermeier, Thomas R; Sakami, Sanae; Sahu, Bhubanananda; Howell, Scott J; Gao, Songqi; Dong, Zhiqian; Golczak, Marcin; Maeda, Akiko; Palczewski, Krzysztof

2017-02-24

Age-related macular degeneration (AMD) is a major cause of irreversible vision loss. The neovascular or "wet" form of AMD can be treated to varying degrees with anti-angiogenic drugs, but geographic atrophy (GA) is an advanced stage of the more prevalent "dry" form of AMD for which there is no effective treatment. Development of GA has been linked to loss of the microRNA (miRNA)-processing enzyme DICER1 in the mature retinal pigmented epithelium (RPE). This loss results in the accumulation of toxic transcripts of Alu transposable elements, which activate the NLRP3 inflammasome and additional downstream pathways that compromise the integrity and function of the RPE. However, it remains unclear whether the loss of miRNA processing and subsequent gene regulation in the RPE due to DICER1 deficiency also contributes to RPE cell death. To clarify the role of miRNAs in RPE cells, we used two different mature RPE cell-specific Cre recombinase drivers to inactivate either Dicer1 or DiGeorge syndrome critical region 8 ( Dgcr8 ), thus removing RPE miRNA regulatory activity in mice by disrupting two independent and essential steps of miRNA biogenesis. In contrast with prior studies, we found that the loss of each factor independently led to strikingly similar defects in the survival and function of the RPE and retina. These results suggest that the loss of miRNAs also contributes to RPE cell death and loss of visual function and could affect the pathology of dry AMD. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Effect of different wound dressings on cell viability and proliferation.

PubMed

Paddle-Ledinek, Joanne E; Nasa, Zeyad; Cleland, Heather J

2006-06-01

Many new dressings have been developed since the early 1980s. Wound healing comprises cleansing, granulation/vascularization, and epithelialization phases. An optimum microenvironment and the absence of cytotoxic factors are essential for epithelialization. This study examines the effect of extracts of different wound dressings on keratinocyte survival and proliferation. Keratinocyte cultures were exposed for 40 hours to at least three extracts of each of the following wound dressings, which were tested in octuplicate: Acticoat, Aquacel-Ag, Aquacel, Algisite M, Avance, Comfeel Plus transparent, Contreet-H, Hydrasorb, and SeaSorb. Silicone extract provided the reference material. Controls were included of cells cultured in medium that had been incubated under conditions identical to those used with the extracts. Cell survival (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction) and proliferation (5-bromo-2':-deoxyuridine incorporation) were measured. Extracts of silver-containing dressings (Acticoat, Aquacel-Ag, Contreet-H, and Avance) were most cytotoxic. Extracts of Hydrasorb were less cytotoxic but markedly affected keratinocyte proliferation and morphology. Extracts of alginate-containing dressings (Algisite M, SeaSorb, and Contreet-H) demonstrated high calcium concentrations, markedly reduced keratinocyte proliferation, and affected keratinocyte morphology. Extracts of Aquacel and Comfeel Plus transparent induced small but significant inhibition of keratinocyte proliferation. The principle of minimizing harm should be applied to the choice of wound dressing. Silver-based dressings are cytotoxic and should not be used in the absence of infection. Alginate dressings with high calcium content affect keratinocyte proliferation probably by triggering terminal differentiation of keratinocytes. Such dressings should be used with caution in cases in which keratinocyte proliferation is essential. All dressings should be tested in vitro before clinical application.

The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils

PubMed Central

Roberts, Christina A.; Al-Tameemi, Hassan M.; Mashruwala, Ameya A.; Rosario-Cruz, Zuelay; Chauhan, Unnati; Sause, William E.; Torres, Victor J.; Belden, William J.

2017-01-01

ABSTRACT Staphylococcus aureus remains a causative agent for morbidity and mortality worldwide. This is in part a result of antimicrobial resistance, highlighting the need to uncover novel antibiotic targets and to discover new therapeutic agents. In the present study, we explored the possibility that iron-sulfur (Fe-S) cluster synthesis is a viable antimicrobial target. RNA interference studies established that Suf (sulfur mobilization)-dependent Fe-S cluster synthesis is essential in S. aureus. We found that sufCDSUB were cotranscribed and that suf transcription was positively influenced by sigma factor B. We characterized an S. aureus strain that contained a transposon inserted in the intergenic space between sufC and sufD (sufD*), resulting in decreased transcription of sufSUB. Consistent with the transcriptional data, the sufD* strain had multiple phenotypes associated with impaired Fe-S protein maturation. They included decreased activities of Fe-S cluster-dependent enzymes, decreased growth in media lacking metabolites that require Fe-S proteins for synthesis, and decreased flux through the tricarboxylic acid (TCA) cycle. Decreased Fe-S cluster synthesis resulted in sensitivity to reactive oxygen and reactive nitrogen species, as well as increased DNA damage and impaired DNA repair. The sufD* strain also exhibited perturbed intracellular nonchelated Fe pools. Importantly, the sufD* strain did not exhibit altered exoprotein production or altered biofilm formation, but it was attenuated for survival upon challenge by human polymorphonuclear leukocytes. The results presented are consistent with the hypothesis that Fe-S cluster synthesis is a viable target for antimicrobial development. PMID:28320837

A Conserved UDP-Glucose Dehydrogenase Encoded outside the hasABC Operon Contributes to Capsule Biogenesis in Group A Streptococcus

PubMed Central

Cole, Jason N.; Aziz, Ramy K.; Kuipers, Kirsten; Timmer, Anjuli M.; Nizet, Victor

2012-01-01

Group A Streptococcus (GAS) is a human-specific bacterial pathogen responsible for serious morbidity and mortality worldwide. The hyaluronic acid (HA) capsule of GAS is a major virulence factor, contributing to bloodstream survival through resistance to neutrophil and antimicrobial peptide killing and to in vivo pathogenicity. Capsule biosynthesis has been exclusively attributed to the ubiquitous hasABC hyaluronan synthase operon, which is highly conserved across GAS serotypes. Previous reports indicate that hasA, encoding hyaluronan synthase, and hasB, encoding UDP-glucose 6-dehydrogenase, are essential for capsule production in GAS. Here, we report that precise allelic exchange mutagenesis of hasB in GAS strain 5448, a representative of the globally disseminated M1T1 serotype, did not abolish HA capsule synthesis. In silico whole-genome screening identified a putative HasB paralog, designated HasB2, with 45% amino acid identity to HasB at a distant location in the GAS chromosome. In vitro enzymatic assays demonstrated that recombinant HasB2 is a functional UDP-glucose 6-dehydrogenase enzyme. Mutagenesis of hasB2 alone slightly decreased capsule abundance; however, a ΔhasB ΔhasB2 double mutant became completely acapsular. We conclude that HasB is not essential for M1T1 GAS capsule biogenesis due to the presence of a newly identified HasB paralog, HasB2, which most likely resulted from gene duplication. The identification of redundant UDP-glucose 6-dehydrogenases underscores the importance of HA capsule expression for M1T1 GAS pathogenicity and survival in the human host. PMID:22961854

Evidence for Lack of Acquisition of Tolerance in Salmonella enterica Serovar Typhimurium ATCC 14028 after Exposure to Subinhibitory Amounts of Origanum vulgare L. Essential Oil and Carvacrol

PubMed Central

Luz, Isabelle da Silva; Gomes Neto, Nelson Justino; Tavares, Adassa Gama; Nunes, Pollyana Campos; Magnani, Marciane

2012-01-01

Overnight exposure of Salmonella enterica serovar Typhimurium to sublethal amounts of Origanum vulgare essential oil (OV) and carvacrol (CAR) did not result in direct and cross-bacterial protection. Cells subcultured with increasing amounts of OV or CAR survived up to the MIC of either compound, revealing few significant changes in bacterial susceptibility. PMID:22544235

Japan’s Foreign Policy: Metamorphosis in Asia

DTIC Science & Technology

1976-03-01

States. Since, from the viewpoint of the United States, Japan has traditionally been considered essential to the defense of American interests in East Asia...to her effcrts to improve her people’s standard of living, but a sharp and stinging blow to her ecnomic viability — her very survival. It is not out...Security Treaty remains in force essentially as it appeared under initial ratification.) Some Japanese maintain that the initial intent of both

A Nurse's Survival Guide to the Ward - Third edition Richards Ann Edwards Sharon A Nurse's Survival Guide to the Ward - Third edition 500pp £19.99 Elsevier 978 0 7020 4603 2 0702046035 [Formula: see text].

PubMed

2013-05-08

This guide is a useful 'friend and companion' to keep close at hand. It is an essential reference for nurses, not only on the ward but in every field of practice where patient care is given. In fact, it makes an accessible guide for all healthcare practitioners.

An Enzyme-Coated Metal-Organic Framework Shell for Synthetically Adaptive Cell Survival.

PubMed

Liang, Kang; Richardson, Joseph J; Doonan, Christian J; Mulet, Xavier; Ju, Yi; Cui, Jiwei; Caruso, Frank; Falcaro, Paolo

2017-07-10

A bioactive synthetic porous shell was engineered to enable cells to survive in an oligotrophic environment. Eukaryotic cells (yeast) were firstly coated with a β-galactosidase (β-gal), before crystallization of a metal-organic framework (MOF) film on the enzyme coating; thereby producing a bioactive porous synthetic shell. The β-gal was an essential component of the bioactive shell as it generated nutrients (that is, glucose and galactose) required for cell viability in nutrient-deficient media (lactose-based). Additionally, the porous MOF coating carried out other vital functions, such as 1) shielding the cells from cytotoxic compounds and radiation, 2) protecting the non-native enzymes (β-gal in this instance) from degradation and internalization, and 3) allowing for the diffusion of molecules essential for the survival of the cells. Indeed, this bioactive porous shell enabled the survival of cells in simulated extreme oligotrophic environments for more than 7 days, leading to a decrease in cell viability less than 30 %, versus a 99 % decrease for naked yeast. When returned to optimal growth conditions the bioactive porous exoskeleton could be removed and the cells regained full growth immediately. The construction of bioactive coatings represents a conceptually new and promising approach for the next-generation of cell-based research and application, and is an alternative to synthetic biology or genetic modification. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Risk factors affecting survival in heart transplant patients.

PubMed

Almenar, L; Cardo, M L; Martínez-Dolz, L; García-Palomar, C; Rueda, J; Zorio, E; Arnau, M A; Osa, A; Palencia, M

2005-11-01

Certain cardiovascular risk factors have been linked to morbidity and mortality in heart transplant (HT) patients. The sum of various risk factors may have a large cumulative negative effect, leading to a substantially worse prognosis and the need to consider whether HT is contraindicated. The objective of this study was to determine whether the risk factors usually available prior to HT result in an excess mortality in our setting that contraindicates transplantation. Consecutive patients who underwent heart transplantation from November 1987 to January 2004 were included. Heart-lung transplants, retransplants, and pediatric transplants were excluded. Of the 384 patients, 89% were men. Mean age was 52 years (range, 12 to 67). Underlying disease included ischemic heart disease (52%), idiopathic dilated cardiomyopathy (36%), valvular disease (8%), and other (4%). Variables considered risk factors were obesity (BMI >25), dyslipidemia, hypertension, prior thoracic surgery, diabetes, and history of ischemic heart disease. Survival curves by number of risk factors using Kaplan-Meier and log-rank for comparison of curves. Overall patient survival at 1, 5, 10, and 13 years was 76%, 68%, 54%, and 47%, respectively. Survival at 10 years, if fewer than two risk factors were present, was 69%; 59% if two or three factors were present; and 37% if more than three associated risk factors were present (P = .04). The presence of certain risk factors in patients undergoing HT resulted in lower survival rates. The combination of various risk factors clearly worsened outcomes. However, we do not believe this should be an absolute contraindication for transplantation.

Localized primary gastrointestinal diffuse large B cell lymphoma received a surgical approach: an analysis of prognostic factors and comparison of staging systems in 101 patients from a single institution.

PubMed

Zhang, Shengting; Wang, Li; Yu, Dong; Shen, Yang; Cheng, Shu; Zhang, Li; Qian, Ying; Shen, Zhixiang; Li, Qinyu; Zhao, Weili

2015-08-15

Diffuse large B cell lymphoma (DLBCL) represents the most common histological subtype of primary gastrointestinal lymphoma and is a heterogeneous group of disease. Prognostic characterization of individual patients is an essential prerequisite for a proper risk-based therapeutic choice. Clinical and pathological prognostic factors were identified, and predictive value of four previously described prognostic systems were assessed in 101 primary gastrointestinal DLBCL (PG-DLBCL) patients with localized disease, including Ann Arbor staging with Musshoff modification, International Prognostic Index (IPI), Lugano classification, and Paris staging system. Univariate factors correlated with inferior survival time were clinical parameters [age>60 years old, multiple extranodal/gastrointestinal involvement, elevated serum lactate dehydrogenase and β2-microglobulin, and decreased serum albumin], as well as pathological parameters (invasion depth beyond serosa, involvement of regional lymph node or adjacent tissue, Ki-67 index, and Bcl-2 expression). Major independent variables of adverse outcome indicated by multivariate analysis were multiple gastrointestinal involvement. In patients unfit for Rituximab but received surgery, radical surgery significantly prolonged the survival time, comparing with alleviative surgery. Addition of Rituximab could overcome the negative prognostic effect of alleviative surgery. Among the four prognostic systems, IPI and Lugano classification clearly separated patients into different risk groups. IPI was able to further stratify the early-stage patients of Lugano classification into groups with distinct prognosis. Radical surgery might be proposed for the patients unfit for Rituximab treatment, and a combination of clinical and pathological staging systems was more helpful to predict the disease outcome of PG-DLBCL patients.

Fibroblasts Influence Survival and Therapeutic Response in a 3D Co-Culture Model

PubMed Central

Majety, Meher; Pradel, Leon P.; Gies, Manuela; Ries, Carola H.

2015-01-01

In recent years, evidence has indicated that the tumor microenvironment (TME) plays a significant role in tumor progression. Fibroblasts represent an abundant cell population in the TME and produce several growth factors and cytokines. Fibroblasts generate a suitable niche for tumor cell survival and metastasis under the influence of interactions between fibroblasts and tumor cells. Investigating these interactions requires suitable experimental systems to understand the cross-talk involved. Most in vitro experimental systems use 2D cell culture and trans-well assays to study these interactions even though these paradigms poorly represent the tumor, in which direct cell-cell contacts in 3D spaces naturally occur. Investigating these interactions in vivo is of limited value due to problems regarding the challenges caused by the species-specificity of many molecules. Thus, it is essential to use in vitro models in which human fibroblasts are co-cultured with tumor cells to understand their interactions. Here, we developed a 3D co-culture model that enables direct cell-cell contacts between pancreatic, breast and or lung tumor cells and human fibroblasts/ or tumor-associated fibroblasts (TAFs). We found that co-culturing with fibroblasts/TAFs increases the proliferation in of several types of cancer cells. We also observed that co-culture induces differential expression of soluble factors in a cancer type-specific manner. Treatment with blocking antibodies against selected factors or their receptors resulted in the inhibition of cancer cell proliferation in the co-cultures. Using our co-culture model, we further revealed that TAFs can influence the response to therapeutic agents in vitro. We suggest that this model can be reliably used as a tool to investigate the interactions between a tumor and the TME. PMID:26053043

Suppressors of cytokine-signaling proteins induce insulin resistance in the retina and promote survival of retinal cells.

PubMed

Liu, Xuebin; Mameza, Marie G; Lee, Yun Sang; Eseonu, Chikezie I; Yu, Cheng-Rong; Kang Derwent, Jennifer J; Egwuagu, Charles E

2008-06-01

Suppressors of cytokine signaling (SOCS) are implicated in the etiology of diabetes, obesity, and metabolic syndrome. Here, we show that some SOCS members are induced, while others are constitutively expressed, in retina and examine whether persistent elevation of SOCS levels in retina by chronic inflammation or cellular stress predisposes to developing insulin resistance in retina, a condition implicated in diabetic retinopathy. SOCS-mediated insulin resistance and neuroprotection in retina were investigated in 1) an experimental uveitis model, 2) SOCS1 transgenic rats, 3) insulin-deficient diabetic rats, 4) retinal cells depleted of SOCS6 or overexpressing SOCS1/SOCS3, and 5) oxidative stress and light-induced retinal degeneration models. We show that constitutive expression of SOCS6 protein in retinal neurons may improve glucose metabolism, while elevated SOCS1/SOCS3 expression during uveitis induces insulin resistance in neuroretina. SOCS-mediated insulin resistance, as indicated by its inhibition of basally active phosphoinositide 3-kinase/AKT signaling in retina, is validated in retina-specific SOCS1 transgenic rats and retinal cells overexpressing SOCS1/SOCS3. We further show that the SOCS3 level is elevated in retina by oxidative stress, metabolic stress of insulin-deficient diabetes, or light-induced retinal damage and protects ganglion cells from apoptosis, suggesting that upregulation of SOCS3 may be a common physiologic response of neuroretinal cells to cellular stress. Our data suggest two-sided roles of SOCS proteins in retina. Whereas SOCS proteins may improve glucose metabolism, mitigate deleterious effects of inflammation, and promote neuroprotection, persistent SOCS3 expression caused by chronic inflammation or cellular stress can induce insulin resistance and inhibit neurotrophic factors, such as ciliary neurotrophic factor, leukemia inhibitory factor, and insulin, that are essential for retinal cell survival.

A review of the factors influencing spawning, early life stage survival and recruitment variability in the common cuttlefish (Sepia officinalis).

PubMed

Bloor, Isobel S M; Attrill, Martin J; Jackson, Emma L

2013-01-01

Global landings of cephalopods (cuttlefish, squid and octopus) have increased dramatically over the past 50 years and now constitute almost 5% of the total world's fisheries production. At a time when landings of many traditional fin-fish stocks are continuing to experience a global decline as a result of over-exploitation, it is expected that fishing pressure on cephalopod stocks will continue to rise as the fishing industry switch their focus onto these non-quota species. However, long-term trends indicate that landings may have begun to plateau or even decrease. In European waters, cuttlefish are among the most important commercial cephalopod resource and are currently the highest yielding cephalopod group harvested in the north-east Atlantic, with the English Channel supporting the main fishery for this species. Recruitment variability in this short-lived species drives large fluctuations in landings. In order to provide sustainable management for Sepia officinalis populations, it is essential that we first have a thorough understanding of the ecology and life history of this species, in particular, the factors affecting spawning, early life stage (ELS) survival and recruitment variability. This review explores how and why such variability exists, starting with the impact of maternal effects (e.g. navigation, migration and egg laying), moving onto the direct impact of environmental variation on embryonic and ELSs and culminating on the impacts that these variations (maternal and environmental) have at a population level on annual recruitment success. Understanding these factors is critical to the effective management of expanding fisheries for this species. Copyright © 2013 Elsevier Ltd. All rights reserved.

Concentration Dependent Actions of Glucocorticoids on Neuronal Viability and Survival

PubMed Central

Ábrahám, István M; Meerlo, Peter; Luiten, Paul GM

2006-01-01

A growing body of evidence based on experimental data demonstrates that glucocorticoids (GCs) can play a potent role in the survival and death of neurons. However, these observations reflect paradoxical features of GCs, since these adrenal stress hormones are heavily involved in both neurodegenerative and neuroprotective processes. The actual level of GCs appears to have an essential impact in this bimodal action. In the present short review we aim to show the importance of concentration dependent action of GCs on neuronal cell viability and cell survival in the brain. Additionally, we will summarize the possible GC-induced cellular mechanisms at different GC concentrations providing a background for their effect on the fate of nerve cells in conditions that are a challenge to their survival. PMID:18648635

A model for cultural change.

PubMed

Andrews, M M

1998-10-01

Using transcultural nursing administration concepts is essential for survival, growth, satisfaction, and achieving goals in the multicultural workplace. Here, a model for cultural change in diverse health care settings assesses strengths, community resources, and readiness for change.

Clinical outcome after pulmonary metastasectomy from primary hepatocellular carcinoma: Analysis of prognostic factors

PubMed Central

Kwon, Jong-Bum; Park, Khun; Kim, Young-Du; Seo, Jong-Hee; Moon, Seok-Whan; Cho, Deog-Gon; Kim, Yong-Whan; Kim, Dong-Goo; Yoon, Seung-Kew; Lim, Hyeon-Woo

2008-01-01

AIM: To review the surgical outcomes in terms of the surgical indications and relevant prognostic factors. METHODS: Sixteen patients underwent therapeutic lung surgery between March 1999 and May 2006. The observation period was terminated on May 31, 2007. The surgical outcomes and the clinicopathological factors were compared. RESULTS: There was no mortality or major morbidity encountered in this study. The mean follow-up period after metastasectomy was 26.7 ± 28.2 (range: 1-99 mo), and the median survival time was 20 mo. The 1- and 5-year survival rates were 56% and 26%, respectively. At the end of the follow-up, 1 patient died from hepatic failure without recurrence, 6 died from hepatic failure with a recurrent hepatocellular carcinoma (HCC), and 4 died from recurrent HCC with cachexia. Among several clinical factors, Kaplan-Meier analysis revealed that liver transplantation as a treatment for the primary lesion, grade of cell differentiation, and negative evidence HBV infection were independent predictive factors. On Cox’s proportional hazard model, there were no significant factors affecting survival after pulmonary metastasectomy in patients with HCC. CONCLUSION: A metastasectomy should be performed before other treatments in selected patients. Although not significant, patients with liver transplantation of a primary HCC survived longer. Liver transplantation might be the most beneficial modality that can offer patients better survival. A multi-institutional and collaborative study would be needed for identifying clinical prognostic factors predicting survival in patients with HCC and lung metastasis. PMID:18837090

Basal tolerance to heat and cold exposure of the spotted wing drosophila, Drosophila suzukii

PubMed Central

Enriquez, Thomas

2017-01-01

The spotted wing Drosophila, Drosophila suzukii, is a new pest in Europe and America which causes severe damages, mostly to stone fruit crops. Temperature and humidity are among the most important abiotic factors governing insect development and fitness. In many situations, temperature can become stressful thus compromising survival. The ability to cope with thermal stress depends on basal level of thermal tolerance. Basic knowledge on temperature-dependent mortality of D. suzukii is essential to facilitate management of this pest. The objective of the present study was to investigate D. suzukii basal cold and heat tolerance. Adults and pupae were subjected to six low temperatures (−5–7.5 °C) and seven high temperatures (30–37 °C) for various durations, and survival-time-temperature relationships were investigated. Data showed that males were globally more cold tolerant than females. At temperature above 5 °C, adult cold mortality became minor even after prolonged exposures (e.g., only 20% mortality after one month at 7.5 °C). Heat tolerance of males was lower than that of females at the highest tested temperatures (34, 35 and 37 °C). Pupae appeared much less cold tolerant than adults at all temperatures (e.g., Lt50 at 5° C: 4–5 d for adults vs. 21 h for pupae). Pupae were more heat tolerant than adults at the most extreme high temperatures (e.g., Lt50 at 37 °C: 30 min for adults vs. 4 h for pupae). The pupal thermal tolerance was further investigated under low vs. high humidity. Low relative humidity did not affect pupal cold survival, but it reduced survival under heat stress. Overall, this study shows that survival of D. suzukii under heat and cold conditions can vary with stress intensity, duration, humidity, sex and stage, and the methodological approach used here, which was based on thermal tolerance landscapes, provides a comprehensive description of D. suzukiithermal tolerance and limits. PMID:28348931

Protecting and rescuing the effectors: roles of differentiation and survival in the control of memory T cell development

PubMed Central

Kurtulus, Sema; Tripathi, Pulak; Hildeman, David A.

2013-01-01

Vaccines, arguably the single most important intervention in improving human health, have exploited the phenomenon of immunological memory. The elicitation of memory T cells is often an essential part of successful long-lived protective immunity. Our understanding of T cell memory has been greatly aided by the development of TCR Tg mice and MHC tetrameric staining reagents that have allowed the precise tracking of antigen-specific T cell responses. Indeed, following acute infection or immunization, naïve T cells undergo a massive expansion culminating in the generation of a robust effector T cell population. This peak effector response is relatively short-lived and, while most effector T cells die by apoptosis, some remain and develop into memory cells. Although the molecular mechanisms underlying this cell fate decision remain incompletely defined, substantial progress has been made, particularly with regards to CD8+ T cells. For example, the effector CD8+ T cells generated during a response are heterogeneous, consisting of cells with more or less potential to develop into full-fledged memory cells. Development of CD8+ T cell memory is regulated by the transcriptional programs that control the differentiation and survival of effector T cells. While the type of antigenic stimulation and level of inflammation control effector CD8+ T cell differentiation, availability of cytokines and their ability to control expression and function of Bcl-2 family members governs their survival. These distinct differentiation and survival programs may allow for finer therapeutic intervention to control both the quality and quantity of CD8+ T cell memory. Effector to memory transition of CD4+ T cells is less well characterized than CD8+ T cells, emerging details will be discussed. This review will focus on the recent progress made in our understanding of the mechanisms underlying the development of T cell memory with an emphasis on factors controlling survival of effector T cells. PMID:23346085

Protein phosphatase 2A (PP2A) inhibitor CIP2A indicates resistance to radiotherapy in rectal cancer.

PubMed

Birkman, Eva-Maria; Elzagheid, Adam; Jokilehto, Terhi; Avoranta, Tuulia; Korkeila, Eija; Kulmala, Jarmo; Syrjänen, Kari; Westermarck, Jukka; Sundström, Jari

2018-03-01

Preoperative (chemo)radiotherapy, (C)RT, is an essential part of the treatment of rectal cancer patients, but tumor response to this therapy among patients is variable. Thus far, there are no clinical biomarkers that could be used to predict response to (C)RT or to stratify patients into different preoperative treatment groups according to their prognosis. Overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) has been demonstrated in several cancers and is frequently associated with reduced survival. Recently, high CIP2A expression has also been indicated to contribute to radioresistance in head and neck squamous cell carcinoma, but few studies have examined the connection between CIP2A and radiation response regarding other malignancies. We have evaluated CIP2A protein expression levels in relation to tumor regression after preoperative (C)RT and survival of rectal adenocarcinoma patients. The effects of CIP2A knockdown by siRNA on cell survival were further investigated in colorectal cancer cells exposed to radiation. Patients with low-CIP2A-expressing tumors had more frequently moderate or excellent response to long-course (C)RT than patients with high-CIP2A-expressing tumors. They also had higher 36-month disease-specific survival (DSS) rate in categorical analysis. In the multivariate analysis, low CIP2A expression level remained as an independent predictive factor for increased DSS. Suppression of CIP2A transcription by siRNA was found to sensitize colorectal cancer cells to irradiation and decrease their survival in vitro. In conclusion, these results suggest that by contributing to radiosensitivity of cancer cells, low CIP2A protein expression level associates with a favorable response to long-course (C)RT in rectal cancer patients. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Comparison of ORSAT and SCARAB Reentry Analysis Tools for a Generic Satellite Test Case

NASA Technical Reports Server (NTRS)

Kelley, Robert L.; Hill, Nicole M.; Rochelle, W. C.; Johnson, Nicholas L.; Lips, T.

2010-01-01

Reentry analysis is essential to understanding the consequences of the full life cycle of a spacecraft. Since reentry is a key factor in spacecraft development, NASA and ESA have separately developed tools to assess the survivability of objects during reentry. Criteria such as debris casualty area and impact energy are particularly important to understanding the risks posed to people on Earth. Therefore, NASA and ESA have undertaken a series of comparison studies of their respective reentry codes for verification and improvements in accuracy. The NASA Object Reentry Survival Analysis Tool (ORSAT) and the ESA Spacecraft Atmospheric Reentry and Aerothermal Breakup (SCARAB) reentry analysis tools serve as standard codes for reentry survivability assessment of satellites. These programs predict whether an object will demise during reentry and calculate the debris casualty area of objects determined to survive, establishing the reentry risk posed to the Earth's population by surviving debris. A series of test cases have been studied for comparison and the most recent uses "Testsat," a conceptual satellite composed of generic parts, defined to use numerous simple shapes and various materials for a better comparison of the predictions of these two codes. This study is an improvement on the others in this series because of increased consistency in modeling techniques and variables. The overall comparison demonstrated that the two codes arrive at similar results. Either most objects modeled resulted in close agreement between the two codes, or if the difference was significant, the variance could be explained as a case of semantics in the model definitions. This paper presents the main results of ORSAT and SCARAB for the Testsat case and discusses the sources of any discovered differences. Discussion of the results of previous comparisons is made for a summary of differences between the codes and lessons learned from this series of tests.

Optimised selenium enrichment of Artemia sp. feed to improve red drum (Sciaenops ocellatus) larvae rearing.

PubMed

Juhász, Péter; Lengyel, Szvetlana; Udvari, Zsolt; Sándor, Alex Nagy; Stündl, László

2017-09-01

Selenium is an essential microelement for the normal functioning of life processes. Moreover, it is a component of enzymes with antioxidant effects. However, it has the smallest window of any micronutrient between requirement and toxicity. Selenium is a regularly used element in fish feeds; moreover, enriching zooplankton with selenium to rear larvae is also a well-known technology. It is accepted that the most common starter foods of fish larvae, natural rotifers contain the smallest dosage of selenium, but providing selenium enriched Artemia sp. instead could increase survival and growth rate of fish. However, no such references are available for the red drum (Sciaenops ocellatus) larvae. Therefore, in this study, Artemia sp. was enriched with nano-selenium of verified low toxicity and easy availability in 5 treatments (1, 5, 10, 50, 100 mg/l Se), and then, fish larvae were fed with four of these enriched Artemia stocks (1, 5, 10, 50 mg/l Se) and a control group. At the end of the 9-day-long experiment, survival rate (S) and growth parameters (SL, W, K-factor, SGR) of fish larvae were calculated as well as their selenium retention and glutathione peroxidase enzyme activity were analysed. It was revealed that a moderate level of selenium enrichment (~4 mg/kg dry matter) of Artemia sp. positively influences the rearing efficiency (i.e. survival and growth) of fish larvae, but higher dosages of selenium could cause adverse effects.

The p75 neurotrophin receptor localization in blood-CSF barrier: expression in choroid plexus epithelium.

PubMed

Spuch, Carlos; Carro, Eva

2011-05-11

The presence of neurotrophins and their receptors Trk family has been reported in the choroid plexus. High levels of Nerve Growth Factor (NGF), Neurotrophin-4 (NT-4) and TrkB receptor were detected, while nothing was know about p75 neurotrophin receptor (p75NTR) in the choroid plexus epithelial cells. In neurons, p75NTR receptor has a dual function: promoting survival together with TrkA in response to NGF, and inducing apoptotic signaling through p75NTR. We postulated that p75NTR may also affect the survival pathways in the choroid plexus and also undergoes regulated proteolysis with metalloproteases. Here, we demonstrated the presence of p75NTR receptor in the choroid plexus epithelial cells. The p75NTR receptor would be involved in cell death mechanisms and in the damaged induced by amyloid beta (Aβ) in the choroid plexus and finally, we propose an essential role of p75NTR in the Aβ transcytosis through out choroid plexus barrier. The presence analysis reveals the new localization of p75NTR in the choroid plexus and, the distribution mainly in the cytoplasm and cerebrospinal fluid (CSF) side of the epithelial cells. We propose that p75NTR receptor plays a role in the survival pathways and Aβ-induced cell death. These data suggest that p75NTR dysfunction play an important role in the pathogenesis of brain diseases. The importance and novelty of this expression expands a new role of p75NTR.

Thrombopoietin/MPL signaling confers growth and survival capacity to CD41-positive cells in a mouse model of Evi1 leukemia.

PubMed

Nishikawa, Satoshi; Arai, Shunya; Masamoto, Yosuke; Kagoya, Yuki; Toya, Takashi; Watanabe-Okochi, Naoko; Kurokawa, Mineo

2014-12-04

Ecotropic viral integration site 1 (Evi1) is a transcription factor that is highly expressed in hematopoietic stem cells and is crucial for their self-renewal capacity. Aberrant expression of Evi1 is observed in 5% to 10% of de novo acute myeloid leukemia (AML) patients and predicts poor prognosis, reflecting multiple leukemogenic properties of Evi1. Here, we show that thrombopoietin (THPO) signaling is implicated in growth and survival of Evi1-expressing cells using a mouse model of Evi1 leukemia. We first identified that the expression of megakaryocytic surface molecules such as ITGA2B (CD41) and the THPO receptor, MPL, positively correlates with EVI1 expression in AML patients. In agreement with this finding, a subpopulation of bone marrow and spleen cells derived from Evi1 leukemia mice expressed both CD41 and Mpl. CD41(+) Evi1 leukemia cells induced secondary leukemia more efficiently than CD41(-) cells in a serial bone marrow transplantation assay. Importantly, the CD41(+) cells predominantly expressing Mpl effectively proliferated and survived on OP9 stromal cells in the presence of THPO via upregulating BCL-xL expression, suggesting an essential role of the THPO/MPL/BCL-xL cascade in enhancing the progression of Evi1 leukemia. These observations provide a novel aspect of the diverse functions of Evi1 in leukemogenesis. © 2014 by The American Society of Hematology.

Impact of food supplementation and methionine on high densities of cotton rats: Support of the amino-acid-quality hypothesis?

USGS Publications Warehouse

Webb, R.E.; Leslie, David M.; Lochmiller, R.L.; Masters, R.E.

2005-01-01

Considerable research supports the tenet that quantity and quality of food limit vertebrate populations. We evaluated predictions that increased availabilities of food and the essential amino acid methionine were related to population limitation of the hispid cotton rat (Sigmodon hispidus). Effects of supplemental food and methionine on density, survival, and reproductive parameters of wild cotton rats were assessed in north-central Oklahoma in 1998-1999. Twelve enclosed groups of 16 adult cotton rats each (8 male, 8 female) were randomly assigned to either no supplementation (control), supplementation with a mixed ration that had methionine at slightly below maintenance levels (0.20%), or a methionine-enhanced mixed ration (1.20%). In general, densities of cotton rats were twice as high and were sustained longer with dietary supplementation, and methionine-supplemented populations maintained the highest densities. Treatment effects on survival depended on time of year, with higher survival in supplemented enclosures in October and November. Per capita recruitment was highest with methionine-enhanced food. Treatment effects on proportions of overall and female cotton rats in reproductive condition depended on sampling date, but males were most reproductively active with methionine supplementation. Methionine supplementation resulted in an earlier and longer reproductive season. Density-dependent and density-independent factors no doubt interplay to determine population dynamics of cotton rats, but our results suggest that methionine plays a role in the population dynamics of wild cotton rats, apparently by enhancing overall density, recruitment, and reproductive activity of males.

Farnesoid X receptor is essential for the survival of renal medullary collecting duct cells under hypertonic stress.

PubMed

Xu, Sujuan; Huang, Shizheng; Luan, Zhilin; Chen, Tingyue; Wei, Yuanyi; Xing, Miaomiao; Li, Yaqing; Du, Chunxiu; Wang, Bing; Zheng, Feng; Wang, Nanping; Guan, Youfei; Gustafsson, Jan-Åke; Zhang, Xiaoyan

2018-05-22

Hypertonicity in renal medulla is critical for the kidney to produce concentrated urine. Renal medullary cells have to survive high medullary osmolarity during antidiuresis. Previous study reported that farnesoid X receptor (FXR), a nuclear receptor transcription factor activated by endogenous bile acids, increases urine concentrating ability by up-regulating aquaporin 2 expression in medullary collecting duct cells (MCDs). However, whether FXR is also involved in the maintenance of cell survival of MCDs under dehydration condition and hypertonic stress remains largely unknown. In the present study, we demonstrate that 24-hours water restriction selectively up-regulated renal medullary expression of FXR with little MCD apoptosis in wild-type mice. In contrast, water deprivation caused a massive apoptosis of MCDs in both global FXR gene-deficient mice and collecting duct-specific FXR knockout mice. In vitro studies showed that hypertonicity significantly increased FXR and tonicity response enhancer binding protein (TonEBP) expression in mIMCD3 cell line and primary cultured MCDs. Activation and overexpression of FXR markedly increased cell viability and decreased cell apoptosis under hyperosmotic conditions. In addition, FXR can increase gene expression and nuclear translocation of TonEBP. We conclude that FXR protects MCDs from hypertonicity-induced cell injury very likely via increasing TonEBP expression and nuclear translocation. This study provides insights into the molecular mechanism by which FXR enhances urine concentration via maintaining cell viability of MCDs under hyperosmotic condition.

The Mycobacterium tuberculosis MmpL11 Cell Wall Lipid Transporter Is Important for Biofilm Formation, Intracellular Growth, and Nonreplicating Persistence

PubMed Central

Wright, Catherine C.; Hsu, Fong Fu; Arnett, Eusondia; Dunaj, Jennifer L.; Davidson, Patrick M.; Pacheco, Sophia A.; Harriff, Melanie J.; Lewinsohn, David M.; Schlesinger, Larry S.

2017-01-01

ABSTRACT The mycobacterial cell wall is crucial to the host-pathogen interface, because it provides a barrier against antibiotics and the host immune response. In addition, cell wall lipids are mycobacterial virulence factors. The mycobacterial membrane protein large (MmpL) proteins are cell wall lipid transporters that are important for basic mycobacterial physiology and Mycobacterium tuberculosis pathogenesis. MmpL3 and MmpL11 are conserved across pathogenic and nonpathogenic mycobacteria, a feature consistent with an important role in the basic physiology of the bacterium. MmpL3 is essential and transports trehalose monomycolate to the mycobacterial surface. In this report, we characterize the role of MmpL11 in M. tuberculosis. M. tuberculosis mmpL11 mutants have altered biofilms associated with lower levels of mycolic acid wax ester and long-chain triacylglycerols than those for wild-type bacteria. While the growth rate of the mmpL11 mutant is similar to that of wild-type M. tuberculosis in macrophages, the mutant exhibits impaired survival in an in vitro granuloma model. Finally, we show that the survival or recovery of the mmpL11 mutant is impaired when it is incubated under conditions of nutrient and oxygen starvation. Our results suggest that MmpL11 and its cell wall lipid substrates are important for survival in the context of adaptive immune pressure and for nonreplicating persistence, both of which are critically important aspects of M. tuberculosis pathogenicity. PMID:28507063

Do the conventional clinicopathologic parameters predict for response and survival in head and neck cancer patients undergoing neoadjuvant chemotherapy?

PubMed

Fonseca, E; Cruz, J J; Dueñas, A; Gómez, A; Sánchez, P; Martín, G; Nieto, A; Soria, P; Muñoz, A; Gómez, J L; Pardal, J L

1996-01-01

Neoadjuvant chemotherapy for head and neck carcinoma is still an important treatment modality. The prognostic value of patient and tumor parameters has been extensively evaluated in several trials, yielding mixed results. We report the prognostic factors emerging from a group of patients undergoing neoadjuvant chemotherapy. From April 1986 to June 1992, 149 consecutive patients received cisplatin-5-fluorouracil-based neoadjuvant chemotherapy. After four courses of chemotherapy, patients underwent local-regional treatment with surgery, radiation or both. A variety of patient and tumor characteristics were evaluated as predictors for response to chemotherapy and survival. The complete response, partial response and no response rates to NAC were 52%, 33% and 15%, respectively. No parameters predicted response to chemotherapy. At a maximum follow-up of 87 months, overall survival was 39% and disease-free survival was 49%. Variables shown to be predictors of survival in univariate analyses were age, performance status, histology, site, T, N, stage, and response to chemotherapy. Using the Cox regression analysis, only complete response to induction chemotherapy (P = 0.0006), performance status (P = 0.03), stage (P = 0.01), age (P = 0.03) and primary tumor site (P = 0.04) emerged as independent prognostic factors for survival. Complete response to chemotherapy was confirmed as the strongest prognostic factor influencing survival. However, conventional clinicopathologic factors did not predict response, hence, potential prognostic biologic and molecular factors for response must be sought. At present, much effort must be made for the improvement of the complete response rate, which seems to be a requisite to prolong survival.

Plasticity in neurons synthesizing wake/arousal promoting hormone hypocretin/orexin.

PubMed

Gao, Xiao-Bing

2012-01-01

The hypothalamus is a critical brain structure regulating physiological functions essential to the survival of individuals and species. One of the striking characteristics of this brain region is the abundance of nerve cells (neurons) expressing a great numbers of neurotransmitters and neuromodulators, among which are hormones released into the blood stream through brain neuroendocrinological routes. The neurons in the lateral hypothalamus take part in intra- and extrahypothalamic circuits controlling basic physiological functions essential for the well being of animal bodies (such as cardiovascular function, respiratory function, immune responses, etc.), animal behaviors required for the maintenance of the survival of individuals (food foraging, flight, fight, etc.) and species (reproductive function), and higher brain functions (learning and memory, mental state, etc.). Hypocretin (also called orexin) comprises of two neuropeptides exclusively synthesized by neurons in the perifornical/lateral hypothalamus. Although hypocretin/orexin was initially found to enhance food intake, it is now clear that the functions mediated by hypocretin/orexin are well beyond what were originally proposed. Specifically, hypocretin/orexin is a crucial promoter of wakefulness; deficiency in the hypocretin/orexin system leads to diseases and disorders such as narcolepsy. It is clear that neurons synthesizing hypocretin/orexin are consistently under regulation originating from various parts of the brain and that the status of activity in hypocretin/orexin neurons is closely related with the nutritional and behavioral state of animals. Therefore, the demand to make adaptive changes in hypocretin/orexin neurons to accommodate the changes in the external environment and behavioral state of animals is expected. The latest developments in the studies of plasticity in hypocretin/orexin neurons under the challenges from environmental and behavioral factors have dramatically shaped the understanding of the roles of hypocretin/orexin neurons in the maintenance of the survival of animals. More importantly, the studies of plasticity in hypocretin/orexin neurons as the consequence of physiological, behavioral, and environmental challenges may shed new insight on the understanding and treatment of sleep disorders (such as insomnia). Copyright © 2012 Elsevier Inc. All rights reserved.

Cancer Survival Estimates Due to Non-Uniform Loss to Follow-Up and Non-Proportional Hazards

PubMed

K M, Jagathnath Krishna; Mathew, Aleyamma; Sara George, Preethi

2017-06-25

Background: Cancer survival depends on loss to follow-up (LFU) and non-proportional hazards (non-PH). If LFU is high, survival will be over-estimated. If hazard is non-PH, rank tests will provide biased inference and Cox-model will provide biased hazard-ratio. We assessed the bias due to LFU and non-PH factor in cancer survival and provided alternate methods for unbiased inference and hazard-ratio. Materials and Methods: Kaplan-Meier survival were plotted using a realistic breast cancer (BC) data-set, with >40%, 5-year LFU and compared it using another BC data-set with <15%, 5-year LFU to assess the bias in survival due to high LFU. Age at diagnosis of the latter data set was used to illustrate the bias due to a non-PH factor. Log-rank test was employed to assess the bias in p-value and Cox-model was used to assess the bias in hazard-ratio for the non-PH factor. Schoenfeld statistic was used to test the non-PH of age. For the non-PH factor, we employed Renyi statistic for inference and time dependent Cox-model for hazard-ratio. Results: Five-year BC survival was 69% (SE: 1.1%) vs. 90% (SE: 0.7%) for data with low vs. high LFU respectively. Age (<45, 46-54 & >54 years) was a non-PH factor (p-value: 0.036). However, survival by age was significant (log-rank p-value: 0.026), but not significant using Renyi statistic (p=0.067). Hazard ratio (HR) for age using Cox-model was 1.012 (95%CI: 1.004 -1.019) and the same using time-dependent Cox-model was in the other direction (HR: 0.997; 95% CI: 0.997- 0.998). Conclusion: Over-estimated survival was observed for cancer with high LFU. Log-rank statistic and Cox-model provided biased results for non-PH factor. For data with non-PH factors, Renyi statistic and time dependent Cox-model can be used as alternate methods to obtain unbiased inference and estimates. Creative Commons Attribution License

Two-year survival of severe chronic obstructive pulmonary disease subjects requiring invasive mechanical ventilation and the factors affecting survival.

PubMed

Asker, Selvi; Ozbay, Bulent; Ekin, Selami; Yildiz, Hanifi; Sertogullarindan, Bunyamin

2016-05-01

To investigate two-year survival rates and the factors affecting survival in patients of severe chronic obstructive pulmonary disease requiring invasive mechanical ventilation. The retrospective study was conducted at Yuzuncuy?l University, Van, Turkey, and comprised record of in-patients with moderate to severe chronic obstructive pulmonary disease who required invasive mechanical ventilation in the intensive care unit of the Pulmonary Diseases Department between January 2007 and December 2010. Correlation between survival and parameters such as age, gender, duration of illness, history of smoking, arterial blood gas values, pulmonary artery pressure, left ventricular ejection fraction, body mass index and laboratory findings were investigated. SPSS 19 was used for statistical analysis. Of the 69 severe COPD subjects available, 20 (29%) were excluded as they did not meet the inclusion criteria. Overall in-hospital mortality rate was 42% (n:29). Of the remaining 20 (29%) who comprised the study group, 14(70%) were men and 6(30%) were women. The mortality rates at the end of 3rd, 6th, 12th and 24th months were 61%, 76%, 84% and 85.5% respectively. There was no correlation between gender and survival in time point (p>0.05). The only factor that affected the rate of mortality at the end of the 3rd month was age (p<0.05). Mortality was high in subjects with advanced ages (p<0.05). Duration of illness affected the survival at the end of the six month (p<0.05). Survival rates were high in subjects with longer illness durations (p<0.05). Haematocrit level was the only factor that affected mortality rates at the end of 12th and 24th months (p<0.05). Subjects with higher haematocrit levels had higher survival rates (p<0.05). Age, duration of illness and haematocrit levels were the most important factors that affected survival in chronic obstructive pulmonary disease patients requiring mechanical ventilation.

Common themes and unique proteins for the uptake and trafficking of nickel, a metal essential for the virulence of Helicobacter pylori

PubMed Central

de Reuse, Hilde; Vinella, Daniel; Cavazza, Christine

2013-01-01

Nickel is a virulence determinant for the human gastric pathogen Helicobacter pylori. Indeed, H. pylori possesses two nickel-enzymes that are essential for in vivo colonization, [NiFe] hydrogenase and urease, an abundant virulence factor that contains 24 nickel ions per active complex. Because of these two enzymes, survival of H. pylori relies on an important supply of nickel, implying a tight control of its distribution and storage. In this review, we will present the pathways of activation of the nickel enzymes as well as original mechanisms found in H. pylori for the uptake, trafficking and distribution of nickel between the two enzymes. These include (i) an outer-membrane nickel uptake system, the FrpB4 TonB-dependent transporter, (ii) overlapping protein complexes and interaction networks involved in nickel trafficking and distribution between urease and hydrogenase and, (iii) Helicobacter specific nickel-binding proteins that are involved in nickel storage and can play the role of metallo-chaperones. Finally, we will discuss the implication of the nickel trafficking partners in virulence and propose them as novel therapeutic targets for treatments against H. pylori infection. PMID:24367767

Cryptic out-of-frame translational initiation of TBCE rescues tubulin formation in compound heterozygous HRD.

PubMed

Tian, Guoling; Huang, Melissa C; Parvari, Ruti; Diaz, George A; Cowan, Nicholas J

2006-09-05

Microtubules are indispensable dynamic structures that contribute to many essential biological functions. Assembly of the native alpha/beta tubulin heterodimer, the subunit that polymerizes to form microtubules, requires the participation of several molecular chaperones, namely prefoldin, the cytosolic chaperonin CCT, and a series of five tubulin-specific chaperones termed cofactors A-E (TBCA-E). Among these, TBCC, TBCD, and TBCE are essential in higher eukaryotes; they function together as a multimolecular machine that assembles quasinative CCT-generated alpha- and beta-tubulin polypeptides into new heterodimers. Deletion and truncation mutations in the gene encoding TBCE have been shown to cause the rare autosomal recessive syndrome known as HRD, a devastating disorder characterized by congenital hypoparathyroidism, mental retardation, facial dysmorphism, and extreme growth failure. Here we identify cryptic translational initiation at each of three out-of-frame AUG codons upstream of the genetic lesion as a unique mechanism that rescues a mutant HRD allele by producing a functional TBCE protein. Our data explain how afflicted individuals, who would otherwise lack the capacity to make functional TBCE, can survive and point to a limiting capacity to fold tubulin heterodimers de novo as a contributing factor to disease pathogenesis.

Cryptic out-of-frame translational initiation of TBCE rescues tubulin formation in compound heterozygous HRD

PubMed Central

Tian, Guoling; Huang, Melissa C.; Parvari, Ruti; Diaz, George A.; Cowan, Nicholas J.

2006-01-01

Microtubules are indispensable dynamic structures that contribute to many essential biological functions. Assembly of the native α/β tubulin heterodimer, the subunit that polymerizes to form microtubules, requires the participation of several molecular chaperones, namely prefoldin, the cytosolic chaperonin CCT, and a series of five tubulin-specific chaperones termed cofactors A–E (TBCA–E). Among these, TBCC, TBCD, and TBCE are essential in higher eukaryotes; they function together as a multimolecular machine that assembles quasinative CCT-generated α- and β-tubulin polypeptides into new heterodimers. Deletion and truncation mutations in the gene encoding TBCE have been shown to cause the rare autosomal recessive syndrome known as HRD, a devastating disorder characterized by congenital hypoparathyroidism, mental retardation, facial dysmorphism, and extreme growth failure. Here we identify cryptic translational initiation at each of three out-of-frame AUG codons upstream of the genetic lesion as a unique mechanism that rescues a mutant HRD allele by producing a functional TBCE protein. Our data explain how afflicted individuals, who would otherwise lack the capacity to make functional TBCE, can survive and point to a limiting capacity to fold tubulin heterodimers de novo as a contributing factor to disease pathogenesis. PMID:16938882

A novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and development

PubMed Central

Lu, Gang; Ren, Shuxun; Korge, Paavo; Choi, Jayoung; Dong, Yuan; Weiss, James; Koehler, Carla; Chen, Jau-nian; Wang, Yibin

2007-01-01

Mitochondria play a central role in the regulation of programmed cell death signaling. Here, we report the finding of a mitochondrial matrix-targeted protein phosphatase 2C family member (PP2Cm) that regulates mitochondrial membrane permeability transition pore (MPTP) opening and is essential for cell survival, embryonic development, and cardiac function. PP2Cm is highly conserved among vertebrates, with the highest expression levels detected in the heart and brain. Small hairpin RNA (shRNA)-mediated knockdown of PP2Cm resulted in cell death associated with loss of mitochondrial membrane potential in cultured cardiac mycoytes and an induction of hepatocyte apoptosis in vivo. PP2Cm-deficient mitochondria showed elevated susceptibility to calcium-induced MPTP opening, whereas mitochondrial oxidative phosphorylation activities were not affected. Finally, inactivation of PP2Cm in developing zebrafish embryos caused abnormal cardiac and neural development as well as heart failure associated with induced apoptosis. These data suggest that PP2Cm is a novel mitochondrial protein phosphatase that has a critical function in cell death and survival, and may play a role in regulating the MPTP opening. PMID:17374715

Alanine racemase is essential for the growth and interspecies competitiveness of Streptococcus mutans.

PubMed

Wei, Yuan; Qiu, Wei; Zhou, Xue-Dong; Zheng, Xin; Zhang, Ke-Ke; Wang, Shi-Da; Li, Yu-Qing; Cheng, Lei; Li, Ji-Yao; Xu, Xin; Li, Ming-Yun

2016-12-16

D-alanine (D-Ala) is an essential amino acid that has a key role in bacterial cell wall synthesis. Alanine racemase (Alr) is a unique enzyme that interconverts L-alanine and D-alanine in most bacteria, making this enzyme a potential target for antimicrobial drug development. Streptococcus mutans is a major causative factor of dental caries. The factors involved in the survival, virulence and interspecies interactions of S. mutans could be exploited as potential targets for caries control. The current study aimed to investigate the physiological role of Alr in S. mutans. We constructed alr mutant strain of S. mutans and evaluated its phenotypic traits and interspecies competitiveness compared with the wild-type strain. We found that alr deletion was lethal to S. mutans. A minimal supplement of D-Ala (150 μg·mL -1 ) was required for the optimal growth of the alr mutant. The depletion of D-alanine in the growth medium resulted in cell wall perforation and cell lysis in the alr mutant strain. We also determined the compromised competitiveness of the alr mutant strain relative to the wild-type S. mutans against other oral streptococci (S. sanguinis or S. gordonii), demonstrated using either conditioned medium assays or dual-species fluorescent in situ hybridization analysis. Given the importance and necessity of alr to the growth and competitiveness of S. mutans, Alr may represent a promising target to modulate the cariogenicity of oral biofilms and to benefit the management of dental caries.

Notch/Delta signaling constrains reengineering of pro-T cells by PU.1

PubMed Central

Franco, Christopher B.; Scripture-Adams, Deirdre D.; Proekt, Irina; Taghon, Tom; Weiss, Angela H.; Yui, Mary A.; Adams, Stephanie L.; Diamond, Rochelle A.; Rothenberg, Ellen V.

2006-01-01

PU.1 is essential for early stages of mouse T cell development but antagonizes it if expressed constitutively. Two separable mechanisms are involved: attenuation and diversion. Dysregulated PU.1 expression inhibits pro-T cell survival, proliferation, and passage through β-selection by blocking essential T cell transcription factors, signaling molecules, and Rag gene expression, which expression of a rearranged T cell antigen receptor transgene cannot rescue. However, Bcl2 transgenic cells are protected from this attenuation and may even undergo β-selection, as shown by PU.1 transduction of defined subsets of Bcl2 transgenic fetal thymocytes with differentiation in OP9-DL1 and OP9 control cultures. The outcome of PU.1 expression in these cells depends on Notch/Delta signaling. PU.1 can efficiently divert thymocytes toward a myeloid-like state with multigene regulatory changes, but Notch/Delta signaling vetoes diversion. Gene expression analysis distinguishes sets of critical T lineage regulatory genes with different combinatorial responses to PU.1 and Notch/Delta signals, suggesting particular importance for inhibition of E proteins, Myb, and/or Gfi1 (growth factor independence 1) in diversion. However, Notch signaling only protects against diversion of cells that have undergone T lineage specification after Thy-1 and CD25 up-regulation. The results imply that in T cell precursors, Notch/Delta signaling normally acts to modulate and channel PU.1 transcriptional activities during the stages from T lineage specification until commitment. PMID:16880393

Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1–PUMA pathway

PubMed Central

Lee, S-H; Jung, Y-S; Chung, J-Y; Oh, A Y; Lee, S-J; Choi, D H; Jang, S M; Jang, K-S; Paik, S S; Ha, N-C; Park, B-J

2011-01-01

DPC4 (deleted in pancreatic cancer 4)/Smad4 is an essential factor in transforming growth factor (TGF)-β signaling and is also known as a frequently mutated tumor suppressor gene in human pancreatic and colon cancer. However, considering the fact that TGF-β can contribute to cancer progression through transcriptional target genes, such as Snail, MMPs, and epithelial–mesenchymal transition (EMT)-related genes, loss of Smad4 in human cancer would be required for obtaining the TGF-β signaling-independent advantage, which should be essential for cancer cell survival. Here, we provide the evidences about novel role of Smad4, serum-deprivation-induced apoptosis. Elimination of serum can obviously increase the Smad4 expression and induces the cell death by p53-independent PUMA induction. Instead, Smad4-deficient cells show the resistance to serum starvation. Induced Smad4 suppresses the PAK1, which promotes the PUMA destabilization. We also found that Siah-1 and pVHL are involved in PAK1 destabilization and PUMA stabilization. In fact, Smad4-expressed cancer tissues not only show the elevated expression of PAK1, but also support our hypothesis that Smad4 induces PUMA-mediated cell death through PAK1 suppression. Our results strongly suggest that loss of Smad4 renders the resistance to serum-deprivation-induced cell death, which is the TGF-β-independent tumor suppressive role of Smad4. PMID:22130069

Cancer survival in Eastern and Western Germany after the fall of the iron curtain.

PubMed

Jansen, Lina; Gondos, Adam; Eberle, Andrea; Emrich, Katharina; Holleczek, Bernd; Katalinic, Alexander; Brenner, Hermann

2012-09-01

Prior to the German reunification, cancer survival was much lower in East than in West Germany. We compare cancer survival between Eastern and Western Germany in the early twenty-first century, i.e. the second decade after the German reunification. Using data from 11 population-based cancer registries covering a population of 33 million people, 5-year age-standardized relative survival for the time period 2002-2006 was estimated for the 25 most common cancers using model-based period analysis. In 2002-2006, 5-year relative survival was very similar for most cancers, with differences below 3% units for 20 of 25 cancer sites. Larger, statistically significant survival advantages were seen for oral cavity, oesophagus, and gallbladder cancer and skin melanoma in the West and for leukemia in the East. Our study shows that within two decades after the assimilation of political and health care systems, the former major survival gap of cancer patients in Eastern Germany has been essentially overcome. This result is encouraging as it suggests that, even though economic conditions have remained difficult in Eastern Germany, comparable health care provision may nevertheless enable comparable levels of cancer survival within a relatively short period of time.

Physician leadership is essential to the survival of teaching hospitals.

PubMed

Schwartz, R W; Pogge, C

2000-06-01

Academic medical centers (AMCs) face severe financial constraints because they must now compete directly with private providers that focus exclusively on cost-effective healthcare delivery. Educational and research capacities developed at AMCs have been supported by government and third party payers, but government support is diminishing. Physicians are ill-equipped to respond to market pressures. Analyses of cultural change and restructuring in corporate giants such as Greyhound, IBM and FedEx are relevant to teaching hospitals. To succeed, organizations must flatten hierarchy, empower staff, train leaders, and mobilize intellectual capital. Effective leadership is essential. Physicians must educate themselves on forces impacting the AMC, understand changes needed in the structure and processes of AMC governance and acquire competencies for leadership and management if AMCs are to survive and thrive. Surgeons should acquire competencies that will enable them to become leaders in the process of AMC transformation.

Comparison of Cox’s Regression Model and Parametric Models in Evaluating the Prognostic Factors for Survival after Liver Transplantation in Shiraz during 2000–2012

PubMed Central

Adelian, R.; Jamali, J.; Zare, N.; Ayatollahi, S. M. T.; Pooladfar, G. R.; Roustaei, N.

2015-01-01

Background: Identification of the prognostic factors for survival in patients with liver transplantation is challengeable. Various methods of survival analysis have provided different, sometimes contradictory, results from the same data. Objective: To compare Cox’s regression model with parametric models for determining the independent factors for predicting adults’ and pediatrics’ survival after liver transplantation. Method: This study was conducted on 183 pediatric patients and 346 adults underwent liver transplantation in Namazi Hospital, Shiraz, southern Iran. The study population included all patients undergoing liver transplantation from 2000 to 2012. The prognostic factors sex, age, Child class, initial diagnosis of the liver disease, PELD/MELD score, and pre-operative laboratory markers were selected for survival analysis. Result: Among 529 patients, 346 (64.5%) were adult and 183 (34.6%) were pediatric cases. Overall, the lognormal distribution was the best-fitting model for adult and pediatric patients. Age in adults (HR=1.16, p<0.05) and weight (HR=2.68, p<0.01) and Child class B (HR=2.12, p<0.05) in pediatric patients were the most important factors for prediction of survival after liver transplantation. Adult patients younger than the mean age and pediatric patients weighing above the mean and Child class A (compared to those with classes B or C) had better survival. Conclusion: Parametric regression model is a good alternative for the Cox’s regression model. PMID:26306158

Outcome and prognostic factors in metastatic urothelial carcinoma patients receiving second-line chemotherapy: an analysis of real-world clinical practice data in Japan.

PubMed

Matsumoto, Ryuji; Abe, Takashige; Ishizaki, Junji; Kikuchi, Hiroshi; Harabayashi, Toru; Minami, Keita; Sazawa, Ataru; Mochizuki, Tango; Akino, Tomoshige; Murakumo, Masashi; Osawa, Takahiro; Maruyama, Satoru; Murai, Sachiyo; Shinohara, Nobuo

2018-06-25

The objective of the present study was to investigate the survival outcome and prognostic factors of metastatic urothelial carcinoma patients treated with second-line systemic chemotherapy in real-world clinical practice. Overall, 114 patients with metastatic urothelial carcinoma undergoing second-line systemic chemotherapy were included in this retrospective analysis. The dominant second-line chemotherapy was a paclitaxel-based combination regimen (60%, 68/114). We assessed the progression-free survival and overall survival times using the Kaplan-Meier method. The Cox proportional hazards model was applied to identify the factors affecting overall survival. The median progression-free survival and overall survival times were 4 and 9 months, respectively. In the multivariate analysis, an Eastern Cooperative Oncology Group performance status score greater than 0 at presentation, C-reactive protein level ≧1 mg/dl and poor response to prior chemotherapy were adverse prognostic indicators. Patients with 0, 1, 2 and 3 of those risk factors had a median overall survival of 17, 12, 7 and 3 months, respectively. The Eastern Cooperative Oncology Group performance status at presentation, C-reactive protein level and response to prior chemotherapy were prognostic factors for metastatic urothelial carcinoma patients undergoing second-line chemotherapy. In the future, this information might help guide the choice of salvage treatment, such as second-line chemotherapy or immune checkpoint inhibitors, after the failure of first-line chemotherapy.

Repeated pulse exposures to lambda-cyhalothrin affect the behavior, physiology, and survival of the damselfly larvae Ischnura graellsii (Insecta; Odonata).

PubMed

Finotello, Simone; Feckler, Alexander; Bundschuh, Mirco; Johansson, Frank

2017-10-01

Damselflies form an essential part of the aquatic and terrestrial food web. Pesticides may, however, negatively affect their behavior, physiology, and survival. To assess this, a 42-day-lasting bioassay was conducted, during which damselfly larvae (Ischnura graellsii; n = 20) were repeatedly exposed to lambda-cyhalothrin (3 days at; 0, 10, 50, 250, 1250, and 6250ng LCH L -1 ), followed by recovery phases (4 days) in pesticide-free medium for six weeks. This exposure design was used to simulate frequent runoff events in the field. Variables related to the behavior (strikes against prey and capture success), growth, physiology (lipid content and fatty acid composition), as well as mortality were assessed throughout the experiment. The two highest LCH concentrations induced 100% mortality within the first 48h, whereas 85% of the test organisms survived 28 days under control conditions. The number of strikes against prey was not affected by LCH. In contrast, prey capture success decreased significantly (up to ~50% at 250ng LCH L -1 , for instance, after the third pulse exposure) following LCH-exposures compared to the control. This difference was not observed after recovery phases, however, which did not counteract the enhanced energy demand for detoxification and defense mechanisms indicated by a lower growth rate (up to ~20%) and lipid content (up to ~30%) of damselflies at 50 and 250ng LCH L -1 . In addition, two essential fatty acids (eicosapentaenoic acid and arachidonic acid) and two precursors (linolenic acid and α-linolenic acid) decreased in their concentrations upon exposure towards 250ng LCH L -1 . Thus the results of this study indicate that long-term exposure towards LCH pulses can affect damselfly behavior, physiology and survival. Given the essential role of damselflies in food web dynamics, these effects may potentially translate into local population impairments with subsequent bottom-up directed effects within and across ecosystem boundaries. Copyright © 2017 Elsevier Inc. All rights reserved.

Two cation transporters Ena1 and Nha1 cooperatively modulate ion homeostasis, antifungal drug resistance, and virulence of Cryptococcus neoformans via the HOG pathway

PubMed Central

Jung, Kwang-Woo; Strain, Anna K; Nielsen, Kirsten; Jung, Kwang-Hwan; Bahn, Yong-Sun

2012-01-01

Maintenance of cation homeostasis is essential for survival of all living organisms in their biological niches. It is also important for the survival of human pathogenic fungi in the host, where cation concentrations and pH will vary depending on different anatomical sites. However, the exact role of diverse cation transporters and ion channels in virulence of fungal pathogens remains elusive. In this study we functionally characterized ENA1 and NHA1, encoding a putative Na+/ATPase and Na+/H+ antiporter, respectively, in Cryptococcus neoformans, a basidiomycete fungal pathogen which causes fatal meningoencephalitis. Expression of NHA1 and ENA1 is induced in response to salt and osmotic shock mainly in a Hog1-dependent manner. Phenotypic analysis of the ena1, nha1, and ena1 nha1 mutants revealed that Ena1 controls cellular levels of toxic cations, such as Na+ and Li+ whereas both Ena1 and Nha1 are important for controlling less toxic K+ ions. Under alkaline conditions, Ena1 was highly induced and required for growth in the presence of low levels of Na+ or K+ salt and Nha1 played a role in survival under K+ stress. In contrast, Nha1, but not Ena1, was essential for survival at acidic conditions (pH 4.5) under high K+ stress. In addition, Ena1 and Nha1 were required for maintenance of plasma membrane potential and stability, which appeared to modulate antifungal drug susceptibility. Perturbation of ENA1 and NHA1 enhanced capsule production and melanin synthesis. However, Nha1 was dispensable for virulence of C. neoformans although Ena1 was essential. In conclusion, Ena1 and Nha1 play redundant and discrete roles in cation homeostasis, pH regulation, membrane potential, and virulence in C. neoformans, suggesting that these transporters could be novel antifungal drug targets for treatment of cryptococcosis. PMID:22343280

Red blood cells release factors with growth and survival bioactivities for normal and leukemic T cells.

PubMed

Antunes, Ricardo F; Brandão, Cláudia; Maia, Margarida; Arosa, Fernando A

2011-01-01

Human red blood cells are emerging as a cell type capable to regulate biological processes of neighboring cells. Hereby, we show that human red blood cell conditioned media contains bioactive factors that favor proliferation of normal activated T cells and leukemic Jurkat T cells, and therefore called erythrocyte-derived growth and survival factors. Flow cytometry and electron microscopy in parallel with bioactivity assays revealed that the erythrocyte factors are present in the vesicle-free supernatant, which contains up to 20 different proteins. The erythrocyte factors are thermosensitive and do not contain lipids. Native polyacrylamide gel electrophoresis followed by passive elution and mass spectrometry identification reduced the potential erythrocyte factors to hemoglobin and peroxiredoxin II. Two-dimensional differential gel electrophoresis of the erythrocyte factors revealed the presence of multiple hemoglobin oxy-deoxy states and peroxiredoxin II isoforms differing in their isoelectric point akin to the presence of β-globin chains. Our results show that red blood cells release protein factors with the capacity to sustain T-cell growth and survival. These factors may have an unforeseen role in sustaining malignant cell growth and survival in vivo.

Recent advances in recurrent urinary tract infection from pathogenesis and biomarkers to prevention

PubMed Central

Jhang, Jia-Fong; Kuo, Hann-Chorng

2017-01-01

Recurrent urinary tract infection (UTI) might be one of the most common problems in urological clinics. Recent research has revealed novel evidence about recurrent UTI and it should be considered a different disease from the first infection. The pathogenesis of recurrent UTI might include two mechanisms, bacterial factors and deficiencies in host defense. Bacterial survival in the urinary bladder after antibiotic treatment and progression to form intracellular bacterial communities might be the most important bacterial factors. In host defense deficiency, a defect in pathogen recognition and urothelial barrier function impairment play the most important roles. Immunodeficiency and urogenital tract anatomical abnormalities have been considered the essential risk factors for recurrent UTI. In healthy women, voiding dysfunction and behavioral factors also increase the risk of recurrent UTI. Sexual intercourse and estrogen deficiency in postmenopausal women might have the strongest association with recurrent UTI. Traditional lifestyle factors such as fluid intake and diet are not considered independent risk factors now. Serum and urine biomarkers to predict recurrent UTI from the first infection have also attracted a wide attention recently. Current clinical evidence suggests that serum macrophage colony-stimulating factor and urinary nerve growth factor have potential predictive value for recurrent UTI. Clinical trials have proven the efficacy of the oral immunoactive agent OM-89 for the prevention of UTI. Vaccines for recurrent UTI are recommended by the latest guidelines and are available on the market. PMID:28974905

Local-scale drivers of tree survival in a temperate forest.

PubMed

Wang, Xugao; Comita, Liza S; Hao, Zhanqing; Davies, Stuart J; Ye, Ji; Lin, Fei; Yuan, Zuoqiang

2012-01-01

Tree survival plays a central role in forest ecosystems. Although many factors such as tree size, abiotic and biotic neighborhoods have been proposed as being important in explaining patterns of tree survival, their contributions are still subject to debate. We used generalized linear mixed models to examine the relative importance of tree size, local abiotic conditions and the density and identity of neighbors on tree survival in an old-growth temperate forest in northeastern China at three levels (community, guild and species). Tree size and both abiotic and biotic neighborhood variables influenced tree survival under current forest conditions, but their relative importance varied dramatically within and among the community, guild and species levels. Of the variables tested, tree size was typically the most important predictor of tree survival, followed by biotic and then abiotic variables. The effect of tree size on survival varied from strongly positive for small trees (1-20 cm dbh) and medium trees (20-40 cm dbh), to slightly negative for large trees (>40 cm dbh). Among the biotic factors, we found strong evidence for negative density and frequency dependence in this temperate forest, as indicated by negative effects of both total basal area of neighbors and the frequency of conspecific neighbors. Among the abiotic factors tested, soil nutrients tended to be more important in affecting tree survival than topographic variables. Abiotic factors generally influenced survival for species with relatively high abundance, for individuals in smaller size classes and for shade-tolerant species. Our study demonstrates that the relative importance of variables driving patterns of tree survival differs greatly among size classes, species guilds and abundance classes in temperate forest, which can further understanding of forest dynamics and offer important insights into forest management.

Local-Scale Drivers of Tree Survival in a Temperate Forest

PubMed Central

Wang, Xugao; Comita, Liza S.; Hao, Zhanqing; Davies, Stuart J.; Ye, Ji; Lin, Fei; Yuan, Zuoqiang

2012-01-01

Tree survival plays a central role in forest ecosystems. Although many factors such as tree size, abiotic and biotic neighborhoods have been proposed as being important in explaining patterns of tree survival, their contributions are still subject to debate. We used generalized linear mixed models to examine the relative importance of tree size, local abiotic conditions and the density and identity of neighbors on tree survival in an old-growth temperate forest in northeastern China at three levels (community, guild and species). Tree size and both abiotic and biotic neighborhood variables influenced tree survival under current forest conditions, but their relative importance varied dramatically within and among the community, guild and species levels. Of the variables tested, tree size was typically the most important predictor of tree survival, followed by biotic and then abiotic variables. The effect of tree size on survival varied from strongly positive for small trees (1–20 cm dbh) and medium trees (20–40 cm dbh), to slightly negative for large trees (>40 cm dbh). Among the biotic factors, we found strong evidence for negative density and frequency dependence in this temperate forest, as indicated by negative effects of both total basal area of neighbors and the frequency of conspecific neighbors. Among the abiotic factors tested, soil nutrients tended to be more important in affecting tree survival than topographic variables. Abiotic factors generally influenced survival for species with relatively high abundance, for individuals in smaller size classes and for shade-tolerant species. Our study demonstrates that the relative importance of variables driving patterns of tree survival differs greatly among size classes, species guilds and abundance classes in temperate forest, which can further understanding of forest dynamics and offer important insights into forest management. PMID:22347996

Factors associated with survival of epiploic foramen entrapment colic: a multicentre, international study.

PubMed

Archer, D C; Pinchbeck, G L; Proudman, C J

2011-08-01

Epiploic foramen entrapment (EFE) has been associated with reduced post operative survival compared to other types of colic but specific factors associated with reduced long-term survival of these cases have not been evaluated in a large number of horses using survival analysis. To describe post operative survival of EFE cases and to identify factors associated with long-term survival. A prospective, multicentre, international study was conducted using clinical data and long-term follow-up information for 126 horses diagnosed with EFE during exploratory laparotomy at 15 clinics in the UK, Ireland and USA. Descriptive data were generated and survival analysis performed to identify factors associated with reduced post operative survival. For the EFE cohort that recovered following anaesthesia, survival to hospital discharge was 78.5%. Survival to 1 and 2 years post operatively was 50.6 and 34.3%, respectively. The median survival time of EFE cases undergoing surgery was 397 days. Increased packed cell volume (PCV) and increased length of small intestine (SI) resected were significantly associated with increased likelihood of mortality when multivariable analysis of pre- and intraoperative variables were analysed. When all pre-, intra- and post operative variables were analysed separately, only horses that developed post operative ileus (POI) were shown to be at increased likelihood of mortality. Increased PCV, increased length of SI resected and POI are all associated with increased likelihood of mortality of EFE cases. This emphasises the importance of early diagnosis and treatment and the need for improved strategies in the management of POI in order to reduce post operative mortality in these cases. The present study provides evidence-based information to clinicians and owners of horses undergoing surgery for EFE about long-term survival. These results are applicable to university and large private clinics over a wide geographical area. © 2011 EVJ Ltd.

Insulin-like Growth Factor 1 Rescues R28 Retinal Neurons from Apoptotic Death through ERK-mediated BimEL Phosphorylation Independent of Akt

PubMed Central

Kong, Dejuan; Gong, Lijie; Arnold, Edith; Shanmugam, Sumathi; Fort, Patrice E.; Gardner, Thomas W.; Abcouwer, Steven F.

2016-01-01

Insulin-like growth factor 1 (IGF-1) can provide long-term neurotrophic support by activation of Akt, inhibition of FoxO nuclear localization and suppression of Bim gene transcription in multiple neuronal systems. However, MEK/ERK activation can also promote neuron survival through phosphorylation of BimEL. We explored the contribution of the PI3K/Akt/FoxO and MEK/ERK/BimEL pathways in IGF-1 stimulated survival after serum deprivation (SD) of R28 cells differentiated to model retinal neurons. IGF-1 caused rapid activation of Akt leading to FoxO1/3-T32/T24 phosphorylation, and prevented FoxO1/3 nuclear translocation and Bim mRNA upregulation in response to SD. IGF-1 also caused MAPK/MEK pathway activation as indicated by ERK1/2-T202/Y204 and Bim-S65 phosphorylation. Overexpression of FoxO1 increased Bim mRNA expression and amplified the apoptotic response to SD without shifting the serum response curve. Inhibition of Akt activation with LY294002 or by Rictor knockdown did not block the protective effect of IGF-1, while inhibition of MEK activity with PD98059 prevented Bim phosphorylation and blocked IGF-1 protection. In addition, knockdown of Bim expression was protective during SD, while co-silencing of FoxO1 and Fox03 expression had little effect. Thus, the PI3K/Akt/FoxO pathway was not essential for protection from SD-induced apoptosis by IGF-1 in R28 cells. Instead, IGF-1 protection was dependent on activation of the MEK/ERK pathway leading to BimEL phosphorylation, which is known to prevent Bax/Bak oligomerization and activation of the intrinsic mitochondrial apoptosis pathway. These studies demonstrate the requirement of the MEK/ERK pathway in a model of retinal neuron cell survival and highlight the cell specificity for IGF-1 signaling in this response. PMID:27511131

Head and neck adenoid cystic carcinoma: A prospective multicenter REFCOR study of 95 cases.

PubMed

Meyers, M; Granger, B; Herman, P; Janot, F; Garrel, R; Fakhry, N; Poissonnet, G; Baujat, B

2016-02-01

To describe the clinical, histological and therapeutic characteristics of a prospective multicenter series of 95 head and neck adenoid cystic carcinoma patients, and to determine any prognostic factors for disease-free survival. Ninety-five patients with adenoid cystic carcinoma were included in the Réseau d'Expertise Français Des Cancers ORL Rares (REFCOR, French Rare Head and Neck Cancer Expert Network) database between 2009 and 2012. The primary site was the salivary glands in 39 cases, sinus cavities (including hard palate) in 36 cases, pharynx-larynx-trachea in 14 cases, and lips and oral cavity in 4 cases. The tumor was stage I in 15% of cases, stage II in 23%, stage III in 26% and stage IV in 36%. Nine patients had cervical lymph node involvement and 5 had metastases at diagnosis. Fifty-six percent of patients were managed by surgery with postoperative radiation therapy. During follow-up, 3 patients died, 9 developed metastases and 12 showed recurrence or local progression. Mean follow-up was 18 months. On univariate analysis, disease-free survival correlated with T stage (P=0.05), N stage (P=0.003), resection margins (P=0.04), lymph node involvement on histology (P=0.01), and absence of chemotherapy (P=0.03). On multivariate analysis, disease-free survival correlated with T stage (P=0.01), N stage (P=0.09) and surgery (P=0.005). The essential issue in adenoid cystic carcinoma is long-term control. The present results confirm that the reference attitude is radical surgical resection for optimal local control. Adjuvant radiation therapy did not emerge as a prognostic factor. This study also provides a starting-point for translational studies in pathology and genetics. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Prognostic Factors and Expression of MDM2 in Patients with Primary Extremity Liposarcoma

PubMed Central

Júnior, Rosalvo Zósimo Bispo; de Camargo, Olavo Pires; de Oliveira, Cláudia Regina G. C. M.; Filippi, Renée Zon; Baptista, André Mathias; Caiero, Marcelo Tadeu

2008-01-01

OBJECTIVE The objective of this study was to investigate MDM2 (murine double minute 2) protein expression and evaluate its relationship with some anatomical and pathological aspects, aiming also to identify prognostic factors concerning local recurrence-free survival, metastasis-free survival and overall survival in patients with primary liposarcomas of the extremities. MATERIALS AND METHODS Of 50 patients with primary liposarcomas of the extremities admitted to a Reference Service, between 1968 and 2004, 25 were enrolled in the study, following eligibility and exclusion criteria. RESULTS The adverse factors that influenced the risk for local recurrence in the univariant analysis included male sex (P = 0.023), pleomorphic histological subtype (P = 0.027), and high histological grade (P = 0.007). Concerning metastasis-free survival, age less than 50 years (P = 0.040), male sex (P = 0.040), pleomorphic subtype (P < 0.001), and high histological grade (P = 0.003) had a worse prognosis. Adverse factors for overall survival were age under 50 years (P = 0.040), male sex (P = 0.040), pleomorphic subtype (P < 0.001), and high histological grade (P = 0.003). CONCLUSIONS There was no correlation between immunohistochemically observed MDM2 protein expressions and the anatomical and pathological variables studied. The immunohistochemical expression of MDM2 protein was not considered to have a prognostic value for any of the surviving patients in this study (local recurrence-free survival, metastasis-free survival, or overall survival). The immunoexpression of MDM2 protein was a frequent event in the different subtypes of liposarcomas. PMID:18438568

Queen Quality and the Impact of Honey Bee Diseases on Queen Health: Potential for Interactions between Two Major Threats to Colony Health.

PubMed

Amiri, Esmaeil; Strand, Micheline K; Rueppell, Olav; Tarpy, David R

2017-05-08

Western honey bees, Apis mellifera , live in highly eusocial colonies that are each typically headed by a single queen. The queen is the sole reproductive female in a healthy colony, and because long-term colony survival depends on her ability to produce a large number of offspring, queen health is essential for colony success. Honey bees have recently been experiencing considerable declines in colony health. Among a number of biotic and abiotic factors known to impact colony health, disease and queen failure are repeatedly reported as important factors underlying colony losses. Surprisingly, there are relatively few studies on the relationship and interaction between honey bee diseases and queen quality. It is critical to understand the negative impacts of pests and pathogens on queen health, how queen problems might enable disease, and how both factors influence colony health. Here, we review the current literature on queen reproductive potential and the impacts of honey bee parasites and pathogens on queens. We conclude by highlighting gaps in our knowledge on the combination of disease and queen failure to provide a perspective and prioritize further research to mitigate disease, improve queen quality, and ensure colony health.

Leveraging Epidemiology and Clinical Studies of Cancer Outcomes: Recommendations and Opportunities for Translational Research

PubMed Central

2013-01-01

As the number of cancer survivors continues to grow, research investigating the factors that affect cancer outcomes, such as disease recurrence, risk of second malignant neoplasms, and the late effects of cancer treatments, becomes ever more important. Numerous epidemiologic studies have investigated factors that affect cancer risk, but far fewer have addressed the extent to which demographic, lifestyle, genomic, clinical, and psychosocial factors influence cancer outcomes. To identify research priorities as well as resources and infrastructure needed to advance the field of cancer outcomes and survivorship research, the National Cancer Institute sponsored a workshop titled “Utilizing Data from Cancer Survivor Cohorts: Understanding the Current State of Knowledge and Developing Future Research Priorities” on November 3, 2011, in Washington, DC. This commentary highlights recent findings presented at the workshop, opportunities to leverage existing data, and recommendations for future research, data, and infrastructure needed to address high priority clinical and research questions. Multidisciplinary teams that include epidemiologists, clinicians, biostatisticians, and bioinformaticists will be essential to facilitate future cancer outcome studies focused on improving clinical care of cancer patients, identifying those at high risk of poor outcomes, and implementing effective interventions to ultimately improve the quality and duration of survival. PMID:23197494

[Survival pronostic factors in Mexican patients with multiforme glioblastoma].

PubMed

Hernández-Reyna, Ricardo; Medellín-Sánchez, Roberto; Cerda-Flores, Ricardo M; Calderón-Garcidueñas, Ana Laura

2010-01-01

To study the pre- and transoperative factors that influence patients' survival with GM. Clinical and pathological records of all confirmed cases of GM diagnosed between 2000 and 2006 were included. Postoperative survival was divided in less or more than 8 months. χ2 test was used. One hundred and twenty patients (45 women and 75 men) were studied. Age range was from 7 to 85 years, 3.3% were 16 years old or younger and 12.5% were 70 years old or older. Headache was the most frequent complain, 40 patients developed hemiparesia and 6 had parestesias. Predominance of white matter hemispheric lesions was observed: right hemispheric tumors 65 (54%), left lesions 30 (25%) and bilateral tumors 7%. Histologically, 1.6% of GM had a sarcomatous component; 35% of patients survived less than 8 months. A difference between patients survival was the preoperative Karnofsky Performance Scale Score and the degree of cerebral edema during the surgical procedure. Pre-operative Karnofsky evaluation and edema during the surgical procedure were significant prognostic factors for survival.

Impact of socioeconomic status on survival of colorectal cancer patients.

PubMed

Zhang, Qian; Wang, Yufu; Hu, Hanqing; Huang, Rui; Xie, Lei; Liu, Enrui; Chen, Ying-Gang; Wang, Guiyu; Wang, Xishan

2017-12-01

Socioeconomic status (SES) has an impact on the survival of various cancers, but it has not been fully understood in colorectal cancer (CRC). The Surveillance, Epidemiology and End Results database was adopted to detect the role of SES in the survival outcomes of CRC. A total of 184,322 eligible patients were included and SES status was analyzed. The multivariable analysis showed that Non-Hispanic Black (HR, 1.20; 95% CI, 1.15-1.24), being widowed (HR, 1.04; 95% CI, 1.01-1.07), any Medicaid (HR, 1.36; 95% CI, 1.33-1.39) and the lowest education level group patients had relative poorer prognosis. Besides, sex, tumor location, age, differentiation level and American Joint Committee on Cancer stage also had significant effects on overall survival of CRC. The individuals were further divided into five groups according to the number of survival-adverse factors. All of the four groups containing adverse factors showed impaired survival outcomes compared with the group containing no adverse factor.

A New Predictive Tool for Optimization of the Treatment of Brain Metastases from Colorectal Cancer After Stereotactic Radiosurgery.

PubMed

Rades, Dirk; Dahlke, Markus; Gebauer, Niklas; Bartscht, Tobias; Hornung, Dagmar; Trang, Ngo Thuy; Phuong, Pham Cam; Khoa, Mai Trong; Gliemroth, Jan

2015-10-01

To develop a predictive tool for survival after stereotactic radiosurgery of brain metastases from colorectal cancer. Out of nine factors analyzed for survival, those showing significance (p<0.05) or a trend (p≤0.06) were included. For each factor, 0 (worse survival) or 1 (better survival) point was assigned. Total scores represented the sum of the factor scores. Performance status (p=0.010) and interval from diagnosis of colorectal cancer until radiosurgery (p=0.026) achieved significance, extracranial metastases showed a trend (p=0.06). These factors were included in the tool. Total scores were 0-3 points. Six-month survival rates were 17% for patients with 0, 25% for those with 1, 67% for those with 2 and 100% for those with 3 points; 12-month rates were 0%, 0%, 33% and 67%, respectively. Two groups were created: 0-1 and 2-3 points. Six- and 12-month survival rates were 20% vs. 78% and 0% vs. 44% (p=0.002), respectively. This tool helps optimize the treatment of patients after stereotactic radiosurgery for brain metastases from colorectal cancer. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Important risk factors of allograft survival in cadaveric renal transplantation. A study of 426 patients.

PubMed Central

Diethelm, A G; Blackstone, E H; Naftel, D C; Hudson, S L; Barber, W H; Deierhoi, M H; Barger, B O; Curtis, J J; Luke, R G

1988-01-01

Multiple risk factors contribute to the allograft survival of patients who have cadaveric renal transplantation. A retrospective review of 19 such factors in 426 patients identified race, DR match, B + DR match, number of transplants, and preservation time to have a significant influence. The parametric analysis confirmed the effect to be primarily in the early phase, i.e., first 6 months. All patients received cyclosporine with other methods of immunosuppression resulting in an overall 1-year graft survival rate of 66%. The overall 1-year graft survival rate in the white race was 73% and in the black race was 57% (p = 0.002). Allograft survival and DR match showed white recipients with a 1 DR match to have 75% survival at 1 year compared with 57% in the black patient (p = 0.009). If HLA B + DR match was considered, the white recipient allograft survival increased to 76%, 84%, and 88% for 1, 2, and 3 match kidneys by parametric analysis. Patients receiving first grafts had better graft survival (68%) than those undergoing retransplantation (58%) (p = 0.05). Organ preservation less than 12 hours influenced allograft survival with a 78% 1-year survival rate compared with 63% for kidneys with 12-18 hours of preservation. Despite the benefits of B + DR typing, short preservation time, and first transplants to the white recipient, the allograft survival in the black recipient remained uninfluenced by these parameters. PMID:3288138

Factors impacting short and long-term kidney graft survival: modification by single intra-operative -high-dose induction with ATG-Fresenius.

PubMed

Kaden, Jürgen; May, Gottfried; Völp, Andreas; Wesslau, Claus

2011-01-01

A majority of recipients benefited from the intra-operative single high-dose induction (HDI) with ATG-Fresenius (ATG-F) still leaving a group of recipients who did not profit from this kind of induction. Therefore the aim of this retrospective analysis was 1st to identify the risk factors impacting short and long-term graft survival, and 2nd to assess the efficacy of this type of induction in kidney graft recipients with or without these risk factors. A total of 606 recipients receiving two different immunosuppressive treatment regimens (1st: Triple drug therapy [TDT, n=196] consisting mainly of steroids, azathioprine and cyclosporine; 2nd: TDT + 9 mg/kg ATG-F intra-operatively [HDI, n=410]) were included in this analysis and grouped according to their kidney graft survival time (short GST: ≤1 yr, n=100 and long GST: >5 yrs, n=506). The main risk factors associated with a shortened graft survival were pre-transplant sensitization, re-transplantation, rejections (in particular vascular or mixed ones) and the necessity of a long-term anti-rejection therapy. Adding ATG-F single high dose induction to TDT was more efficient in prolonging kidney graft survival than TDT alone not only in recipients without any risk factors (p<0.005) but also in recipients with at least one risk factor (p<0.021). Only in 4.6% of recipients having two or more risk factors this effect could not be demonstrated. The intra-operative single high-dose induction with ATG-F significantly improves the kidney graft survival in recipients with or without risk factors and can therefore be recommended.

Underlying mechanisms for syntrophic metabolism of essential enzyme cofactors in microbial communities

PubMed Central

Romine, Margaret F; Rodionov, Dmitry A; Maezato, Yukari; Osterman, Andrei L; Nelson, William C

2017-01-01

Many microorganisms are unable to synthesize essential B vitamin-related enzyme cofactors de novo. The underlying mechanisms by which such microbes survive in multi-species communities are largely unknown. We previously reported the near-complete genome sequence of two ~18-member unicyanobacterial microbial consortia that maintain stable membership on defined medium lacking vitamins. Here we have used genome analysis and growth studies on isolates derived from the consortia to reconstruct pathways for biogenesis of eight essential cofactors and predict cofactor usage and precursor exchange in these communities. Our analyses revealed that all but the two Halomonas and cyanobacterial community members were auxotrophic for at least one cofactor. We also observed a mosaic distribution of salvage routes for a variety of cofactor precursors, including those produced by photolysis. Potentially bidirectional transporters were observed to be preferentially in prototrophs, suggesting a mechanism for controlled precursor release. Furthermore, we found that Halomonas sp. do not require cobalamin nor control its synthesis, supporting the hypothesis that they overproduce and export vitamins. Collectively, these observations suggest that the consortia rely on syntrophic metabolism of cofactors as a survival strategy for optimization of metabolic exchange within a shared pool of micronutrients. PMID:28186498

Molecular Genetic Analysis of Orf Virus: A Poxvirus That Has Adapted to Skin

PubMed Central

Fleming, Stephen B.; Wise, Lyn M.; Mercer, Andrew A.

2015-01-01

Orf virus is the type species of the Parapoxvirus genus of the family Poxviridae. It induces acute pustular skin lesions in sheep and goats and is transmissible to humans. The genome is G+C rich, 138 kbp and encodes 132 genes. It shares many essential genes with vaccinia virus that are required for survival but encodes a number of unique factors that allow it to replicate in the highly specific immune environment of skin. Phylogenetic analysis suggests that both viral interleukin-10 and vascular endothelial growth factor genes have been “captured” from their host during the evolution of the parapoxviruses. Genes such as a chemokine binding protein and a protein that binds granulocyte-macrophage colony-stimulating factor and interleukin-2 appear to have evolved from a common poxvirus ancestral gene while three parapoxvirus nuclear factor (NF)-κB signalling pathway inhibitors have no homology to other known NF-κB inhibitors. A homologue of an anaphase-promoting complex subunit that is believed to manipulate the cell cycle and enhance viral DNA synthesis appears to be a specific adaptation for viral-replication in keratinocytes. The review focuses on the unique genes of orf virus, discusses their evolutionary origins and their role in allowing viral-replication in the skin epidermis. PMID:25807056

Role of neurotrophic factors in attention deficit hyperactivity disorder.

PubMed

Tsai, Shih-Jen

2017-04-01

Neurotrophins (NTs), a family of proteins including nerve growth factor, brain-derived neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4, are essential for neural growth, survival, and differentiation, and are therefore crucial for brain development. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by problems of inattention and/or hyperactivity-impulsivity. ADHD is one of the most common childhood onset psychiatric disorders. Studies have suggested that both genetic and environmental factors influence the development of the disorder, although the precise causes of ADHD have not yet been identified. In this review, we assess the role of NTs in the pathophysiology of ADHD. Preclinical evidence indicates that BDNF knockout mice are hyperactive, and an ADHD rodent model exhibited decreased cerebral BDNF levels. Several lines of evidence from clinical studies, including blood level and genetic studies, have suggested that NTs are involved in the pathogenesis of ADHD and in the mechanism of biological treatments for ADHD. Future directions for research are proposed, such as using blood NTs as ADHD biomarkers, optimizing NT genetic studies in ADHD, considering NTs as a link between ADHD and other comorbid mental disorders, and investigating methods for optimally modulating NT signaling to discover novel therapeutics for treating ADHD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Factors affecting survival of women diagnosed with breast cancer in El-Minia Governorate, Egypt.

PubMed

Seedhom, Amany Edward; Kamal, Nashwa Nabil

2011-07-01

This study was conducted to determine breast cancer survival time and the association between breast cancer survival and socio-demographic and pathologic factors among women, in El-Minia, Egypt. While there has been much researches regarding prognostic factors for breast cancer but the majority of these studies were from developed countries. El-Minia has a population of approximately 4 million. To date, no research has been performed to determine breast cancer survival and the factors affecting it in El-minia. This retrospective study used data obtained from the cancer registry in the National Institute of Oncology in El-Minia and included 1207 women diagnosed with first primary breast cancer between 1(st) January 2005 and 31(st) December 2009 and followed to 30(th) June 2010. The association between survival and sociodemographic and pathological factors and distant metastasis at diagnosis, and treatment options was investigated using unifactorial chi-square test and multi-factorial (Cox regression) analyses. Kaplan-Meier analysis was used to compare survival time among different groups. Median survival time was 83.8 ± 3.2. Cox regression showed that high vs low educational level (Hazard ratio (HR)= 0.35, 95% CI; 0.27-0.46), metastases to bone (HR = 3.22, 95% CI: 1.71-6.05), metastases to lung (HR= 2.314, 95% CI: 1.225-4.373), tumor size (≤ 2 cm vs ≥ 5 cm: HR = 1.4, 95% CI: 1.1-1.8) and number of involved nodes (1 vs > 10 HR = 5.21, 95%CI: 3.1-9.01) were significantly related to survival. The results showed the need to develop screening programs and standardized treatment regimens in a tax-funded health care system.

Steroid Hormone Signaling Is Essential to Regulate Innate Immune Cells and Fight Bacterial Infection in Drosophila

PubMed Central

Regan, Jennifer C.; Brandão, Ana S.; Leitão, Alexandre B.; Mantas Dias, Ângela Raquel; Sucena, Élio; Jacinto, António; Zaidman-Rémy, Anna

2013-01-01

Coupling immunity and development is essential to ensure survival despite changing internal conditions in the organism. Drosophila metamorphosis represents a striking example of drastic and systemic physiological changes that need to be integrated with the innate immune system. However, nothing is known about the mechanisms that coordinate development and immune cell activity in the transition from larva to adult. Here, we reveal that regulation of macrophage-like cells (hemocytes) by the steroid hormone ecdysone is essential for an effective innate immune response over metamorphosis. Although it is generally accepted that steroid hormones impact immunity in mammals, their action on monocytes (e.g. macrophages and neutrophils) is still not well understood. Here in a simpler model system, we used an approach that allows in vivo, cell autonomous analysis of hormonal regulation of innate immune cells, by combining genetic manipulation with flow cytometry, high-resolution time-lapse imaging and tissue-specific transcriptomic analysis. We show that in response to ecdysone, hemocytes rapidly upregulate actin dynamics, motility and phagocytosis of apoptotic corpses, and acquire the ability to chemotax to damaged epithelia. Most importantly, individuals lacking ecdysone-activated hemocytes are defective in bacterial phagocytosis and are fatally susceptible to infection by bacteria ingested at larval stages, despite the normal systemic and local production of antimicrobial peptides. This decrease in survival is comparable to the one observed in pupae lacking immune cells altogether, indicating that ecdysone-regulation is essential for hemocyte immune functions and survival after infection. Microarray analysis of hemocytes revealed a large set of genes regulated at metamorphosis by EcR signaling, among which many are known to function in cell motility, cell shape or phagocytosis. This study demonstrates an important role for steroid hormone regulation of immunity in vivo in Drosophila, and paves the way for genetic dissection of the mechanisms at work behind steroid regulation of innate immune cells. PMID:24204269

Survival and Associated Risk Factors for Mortality Among Infants with Critical Congenital Heart Disease in a Developing Country.

PubMed

Mat Bah, Mohd Nizam; Sapian, Mohd Hanafi; Jamil, Mohammad Tamim; Alias, Amelia; Zahari, Norazah

2018-05-14

Critical congenital heart disease (CCHD) is associated with significant morbidity and mortality. However, data on survival of CCHD and the risk factors associated with its mortality are limited. This study examined CCHD survival and the risk factors for CCHD mortality. Using a retrospective cohort study of infants born with CCHD from 2006 to 2015, survival over 10 years was estimated using Kaplan-Meier analysis, and the risk factors for mortality were analyzed using multivariate Cox proportional hazards regression. A total of 491 CCHD cases were included in the study, with an overall mortality rate of 34.8% (95% confidence interval [CI] 30.6-39.2). The intervention/surgical mortality rate was 9.8% ≤ 30 days and 11.5% > 30 days after surgery, and 17% died before surgery or intervention. The median age at death was 2.7 months [first quartile: 1 month, third quartile: 7.3 months]. The CCHD survival rate was 90.4% (95% CI 89-91.8%) at 1 month, 69.3% (95% CI 67.2-71.4%) at 1 year, 63.4% (95% CI 61.1-65.7%) at 5 years, and 61.4% (95% CI 58.9-63.9%) at 10 years. Weight of < 2 kg at diagnosis, associated syndromes, poor pre-operative condition, and non-duct-dependent CCHD were independent risk factors for poor survival, with hazard ratios of 2.61, 2.10, 2.22, and 1.70, respectively. CCHD is associated with a high mortality rate. Low weight, poor pre-operative condition, associated syndromes, and non-duct-dependent CCHD are significant risk factors affecting the survival of infants with CCHD.

Serum albumin predicts survival in patients with hilar cholangiocarcinoma

PubMed Central

Waghray, Abhijeet; Sobotka, Anastasia; Marrero, Carlos Romero; Estfan, Bassam; Aucejo, Federico

2017-01-01

Background and aims: Hilar cholangiocarcinoma is a devastating malignancy with incidence varying by geography and other risk factors. Rapid progression of disease and delays in diagnosis restrict the number of patients eligible for curative therapy. The objective of this study was to determine prognostic factors of overall survival in all patients presenting with hilar cholangiocarcinoma. Methods: All adult patients with histologically confirmed hilar cholangiocarcinoma from 2003 to 2013 were evaluated for predictors of survival using demographic factors, laboratory data, symptoms and radiological characteristics at presentation. Results: A total of 116 patients were identified to have pathological diagnosis of hilar cholangiocarcinoma and were included in the analysis. Patients with a serum albumin level >3.0 g/dL (P < 0.01), cancer antigen 19‐9 ≤200 U/mL (P = 0.03), carcinoembryonic antigen ≤10 ìg/L (P < 0.01) or patients without a history of cirrhosis (P < 0.01) or diabetes (P = 0.02) were associated with a greater length of overall survival. A serum albumin level >3.0 g/dL was identified as an independent predictor of overall survival (hazard ratio 0.31; 95% confidence interval 0.14–0.70) with a survival benefit of 44 weeks. Conclusion: This study was the largest analysis to date of prognostic factors in patients with hilar cholangiocarcinoma. A serum albumin level >3.0 g/dL conferred an independent survival advantage with a significantly greater length of survival. PMID:27389416

Essential protein discovery based on a combination of modularity and conservatism.

PubMed

Zhao, Bihai; Wang, Jianxin; Li, Xueyong; Wu, Fang-Xiang

2016-11-01

Essential proteins are indispensable for the survival of a living organism and play important roles in the emerging field of synthetic biology. Many computational methods have been proposed to identify essential proteins by using the topological features of interactome networks. However, most of these methods ignored intrinsic biological meaning of proteins. Researches show that essentiality is tied not only to the protein or gene itself, but also to the molecular modules to which that protein belongs. The results of this study reveal the modularity of essential proteins. On the other hand, essential proteins are more evolutionarily conserved than nonessential proteins and frequently bind each other. That is to say, conservatism is another important feature of essential proteins. Multiple networks are constructed by integrating protein-protein interaction (PPI) networks, time course gene expression data and protein domain information. Based on these networks, a new essential protein identification method is proposed based on a combination of modularity and conservatism of proteins. Experimental results show that the proposed method outperforms other essential protein identification methods in terms of a number essential protein out of top ranked candidates. Copyright © 2016. Published by Elsevier Inc.

Overview on platelet preservation: better controls over storage lesion.

PubMed

Ohto, Hitoshi; Nollet, Kenneth E

2011-06-01

Platelet storage lesion (PSL), correlating with reduced in vivo recovery/survival and hemostatic capacity after transfusion, is characterized essentially by morphological and molecular evidence of platelet activation and energy consumption in the medium. Processes that limit shelf-life are multifactorial, and include both necrosis and apoptosis. PSL is greatly influenced by factors including duration of storage, temperature, ratio of platelet number to media volume, solution composition with respect to energy content and buffering capacity, and gas permeability of the container. Recent progress for slowing PSL has been made with storage media that more effectively fuel ATP production and buffer the inevitable effects of metabolism. Improved oxygen-permeability of containers also helps to maintain aerobic-dominant glycolysis. Patients stand to benefit from platelet products of higher intrinsic quality that store well until the moment of transfusion. Copyright © 2011. Published by Elsevier Ltd.

Hypervitaminosis D and premature aging: lessons learned from Fgf23 and Klotho mutant mice.

PubMed

Razzaque, Mohammed S; Lanske, Beate

2006-07-01

The essential role of low levels of vitamin D during aging is well documented. However, possible effects of high levels of vitamin D on the aging process are not yet clear. Recent in vivo genetic-manipulation studies have shown increased serum level of vitamin D and altered mineral-ion homeostasis in mice that lack either fibroblast growth factor 23 (Fgf23) or klotho (Kl) genes. These mice develop identical phenotypes consistent with premature aging. Elimination or reduction of vitamin-D activity from Fgf23 and Kl mutant mice, either by dietary restriction or genetic manipulation could rescue premature aging-like features and ectopic calcifications, resulting in prolonged survival of both mutants. Such in vivo experimental studies indicated that excessive vitamin-D activity and altered mineral-ion homeostasis could accelerate the aging process.

Gallbladder Cancer in the 21st Century

PubMed Central

Kanthan, Rani; Senger, Jenna-Lynn; Ahmed, Shahid; Kanthan, Selliah Chandra

2015-01-01

Gallbladder cancer (GBC) is an uncommon disease in the majority of the world despite being the most common and aggressive malignancy of the biliary tree. Early diagnosis is essential for improved prognosis; however, indolent and nonspecific clinical presentations with a paucity of pathognomonic/predictive radiological features often preclude accurate identification of GBC at an early stage. As such, GBC remains a highly lethal disease, with only 10% of all patients presenting at a stage amenable to surgical resection. Among this select population, continued improvements in survival during the 21st century are attributable to aggressive radical surgery with improved surgical techniques. This paper reviews the current available literature of the 21st century on PubMed and Medline to provide a detailed summary of the epidemiology and risk factors, pathogenesis, clinical presentation, radiology, pathology, management, and prognosis of GBC. PMID:26421012