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Sample records for disease receiving ras

  1. Urine RAS components in mice and people with type 1 diabetes and chronic kidney disease.

    Science.gov (United States)

    Wysocki, Jan; Goodling, Anne; Burgaya, Mar; Whitlock, Kathryn; Ruzinski, John; Batlle, Daniel; Afkarian, Maryam

    2017-08-01

    The pathways implicated in diabetic kidney disease (DKD) are largely derived from animal models. To examine if alterations in renin-angiotensin system (RAS) in humans are concordant with those in rodent models, we measured concentration of angiotensinogen (AOG), cathepsin D (CTSD), angiotensin-converting enzyme (ACE), and ACE2 and enzymatic activities of ACE, ACE2, and aminopeptidase-A in FVB mice 13-20 wk after treatment with streptozotocin ( n = 9) or vehicle ( n = 15) and people with long-standing type 1 diabetes, with ( n = 37) or without ( n = 81) DKD. In streptozotocin-treated mice, urine AOG and CTSD were 10.4- and 3.0-fold higher than in controls, respectively ( P animals ( P animals ( P = 0.017). Compared with people without DKD, those with DKD had higher urine AOG (170 vs. 15 μg/g) and CTSD (147 vs. 31 μg/g). In people with DKD, urine ACE concentration was 1.8-fold higher (1.4 vs. 0.8 μg/g in those without DKD), while its enzymatic activity was 0.6-fold lower (1.0 vs. 1.6 × 10 9 RFU/g in those without DKD). Lower ACE activity, but not ACE protein concentration, was associated with ACE inhibitor (ACEI) treatment. After adjustment for clinical covariates, AOG, CTSD, ACE concentration, and ACE activity remained associated with DKD. In conclusion, in mice with streptozotocin-induced diabetes and in humans with DKD, urine concentrations and enzymatic activities of several RAS components are concordantly increased, consistent with enhanced RAS activity and greater angiotensin II formation. ACEI use was associated with a specific reduction in urine ACE activity, not ACE protein concentration, suggesting that it may be a marker of exposure to this widely-used therapy. Copyright © 2017 the American Physiological Society.

  2. RAS Insight

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    David Heimbrook, now CEO of the Frederick National Laboratory for Cancer Research, played a major role in a large pharma as it tried to develop an anti-RAS drug. Lessons from that failure inform the RAS Initiative today.

  3. Impact of tumour RAS/BRAF status in a first-line study of panitumumab + FOLFIRI in patients with metastatic colorectal cancer

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    Karthaus, Meinolf; Hofheinz, Ralf-Dieter; Mineur, Laurent; Letocha, Henry; Greil, Richard; Thaler, Josef; Fernebro, Eva; Oliner, Kelly S; Boedigheimer, Michael; Twomey, Brian; Zhang, Ying; Demonty, Gaston; Köhne, Claus-Henning

    2016-01-01

    Background: To investigate tumour biomarker status and efficacy of first-line panitumumab+FOLFIRI for metastatic colorectal carcinoma (mCRC). Methods: 154 patients received first-line panitumumab + FOLFIRI every 14 days. Primary end point was objective response rate (ORR). Data were analysed by tumour RAS (KRAS/NRAS) and BRAF status, and baseline amphiregulin (AREG) expression. Results: Objective responses occurred more frequently in RAS wild type (WT) (59%) vs RAS mutant (MT) (41%) mCRC and in RAS WT/BRAF WT (68%) vs RAS or BRAF MT (37%) disease. Median response duration was longer in RAS WT (13.0 months) vs RAS MT (5.8 months) (hazard ratio (HR): 0.16). Median progression-free survival was longer in RAS WT vs MT (11.2 vs 7.3 months; HR, 0.37) and was also longer in RAS WT/BRAF WT vs RAS or BRAF MT (13.2 vs 6.9 months; HR, 0.25). Incidence of adverse events was similar regardless of RAS/BRAF status, and no new safety signals were noted. Among patients with RAS WT tumours, ORR was 67% with high AREG expression and 38% with low AREG expression. Conclusions: First-line panitumumab+FOLFIRI was associated with favourable efficacy in patients with RAS WT and RAS WT/BRAF WT vs MT mCRC tumours and was well tolerated. PMID:27764839

  4. The prognostic impact of K-RAS mutations in adult acute myeloid leukemia patients treated with high-dose cytarabine

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    Ahmad EI

    2011-07-01

    Full Text Available Ebtesam I Ahmad, Heba H Gawish, Nashwa MA Al Azizi, Ashraf M ElhefniClinical Pathology Department, Hematology and Oncology Unit of Internal Medicine Department, Faculty of Medicine, Zagazig University, Sharkia, EgyptBackground: Activating point mutation of the RAS gene has been generally accepted as an oncogenic event in a variety of malignancies. It represents one of the most common genetic alterations in acute myeloid leukemia (AML. However, little is known about its clinical relevance in the treatment outcome for this leukemia.Objective: This study aimed to clarify the biologic and prognostic impact of K-RAS mutations in relation to the dose of cytarabine (ara-C used in postinduction consolidation chemotherapy in adult AML patients.Patients and methods: The study comprised of 71 de novo AML patients with male/female ratio 1.4:1; their ages ranged from 21–59 years with a median of 37 years. They were subjected to full clinical evaluation, routine laboratory investigations, cytogenetic studies by G-banding (Giemsa staining, and K-RAS mutation detection using real-time polymerase chain reaction. The patients were randomized into two groups according to the ara-C dose used in consolidation treatment, the high the dose ara-C (HDAC group receiving 400 mg ara-C and-low-dose ara-C (LDAC group receiving 100 mg ara-C; they were followed over a period of five years.Results: Mutations in the K-RAS gene (mutRAS were detected in 23 patients (32% with the remaining 48 patients (68% having wild-type RAS (wtRAS. The percent of blast cells was significantly lower in mutRAS compared to wtRAS patients (P ≤ 0.001 while M4 subtype of AML and Inv(16 frequencies were significantly higher in mutRAS compared to wtRAS patients (P = 0.015 and (P = 0.003, respectively. The patients were followed up for a median of 43 months (range 11–57 months. There was no significant difference in overall survival (OS between mutRAS and wtRAS (P = 0.326. Within the mutRAS

  5. RAP/RAS workshop.

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    2013-01-01

    : RAP & RAS increases mix stiffness : : Most WMA additives decrease stiffness : : Tear-Off shingles are stiffer than Man-waste shingles : : Using multiple recycled bins improves consistency : : Finer RAS material improves consiste...

  6. RAS Initiative - Events

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    The NCI RAS Initiative has organized multiple events with outside experts to discuss how the latest scientific and technological breakthroughs can be applied to discover vulnerabilities in RAS-driven cancers.

  7. RAS - Target Identification - Informatics

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    The RAS Informatics lab group develops tools to track and analyze “big data” from the RAS Initiative, as well as analyzes data from external projects. By integrating internal and external data, this group helps improve understanding of RAS-driven cancers.

  8. The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab.

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    Demurtas, Laura; Puzzoni, Marco; Giampieri, Riccardo; Ziranu, Pina; Pusceddu, Valeria; Mandolesi, Alessandra; Cremolini, Chiara; Masi, Gianluca; Gelsomino, Fabio; Antoniotti, Carlotta; Loretelli, Cristian; Meriggi, Fausto; Zaniboni, Alberto; Falcone, Alfredo; Cascinu, Stefano; Scartozzi, Mario

    2017-07-25

    The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting. We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild-type (WT) metastatic CRC patients treated with second-third-line irinotecan/cetuximab were analysed for EGFR gene copy number (GCN) and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Median follow-up duration was 14.3 months. Eighty-eight patients were included in the study, 27.3% had right-sided CRC, 72.7% had left-sided CRC; 36.4% had EGFR GCNpromoter-methylated tumour. Right-sided colorectal cancer (RSCRC) were associated with reduced overall response rate (ORR) (4.2% for RSCRC vs 35.9% for left sided colorectal cancer (LSCRC), P=0.0030), shorter progression-free survival (PFS) (3.0 vs 6.75 months, Ppromoter methylation maintained their independent role for ORR (respectively P=0.0082 and 0.0025), PFS (respectively P=0.0048 andpromoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy. However, these data need to be validated with future prospective and translational studies.

  9. Comparison of the antialbuminuric effects of benidipine and hydrochlorothiazide in Renin-Angiotensin System (RAS) inhibitor-treated hypertensive patients with albuminuria: the COSMO-CKD (COmbination Strategy on Renal Function of Benidipine or Diuretics TreatMent with RAS inhibitOrs in a Chronic Kidney Disease Hypertensive Population) study.

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    Ando, Katsuyuki; Nitta, Kosaku; Rakugi, Hiromi; Nishizawa, Yoshiki; Yokoyama, Hitoshi; Nakanishi, Takeshi; Kashihara, Naoki; Tomita, Kimio; Nangaku, Masaomi; Takahashi, Katsutoshi; Isshiki, Masashi; Shimosawa, Tatsuo; Fujita, Toshiro

    2014-01-01

    This study evaluated the non-inferiority of renoprotection afforded by benidipine versus hydrochlorothiazide in hypertensive patients with chronic kidney disease (CKD). In this prospective, multicenter, open-labeled, randomized trial, the antialbuminuric effects of benidipine and hydrochlorothiazide were examined in renin-angiotensin system (RAS) inhibitor-treated patients with blood pressure (BP) readings of ≥ 130/80 mmHg and ≤ 180/110 mmHg, a urinary albumin to creatinine ratio (UACR) of ≥ 300 mg/g, and an estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73m(2). Patients received benidipine (n = 176, final dose: 4.8 mg/day) or hydrochlorothiazide (n = 170, 8.2 mg/day) for 12 months. Benidipine and hydrochlorothiazide exerted similar BP- and eGFR-decreasing actions. The UACR values for benidipine and hydrochlorothiazide were 930.8 (95% confidence interval: 826.1, 1048.7) and 883.1 (781.7, 997.7) mg/g at baseline, respectively. These values were reduced to 790.0 (668.1, 934.2) and 448.5 (372.9, 539.4) mg/g at last observation carried forward (LOCF) visits. The non-inferiority of benidipine versus hydrochlorothiazide was not demonstrated (benidipine/hydrochlorothiazide ratio of LOCF value adjusted for baseline: 1.67 (1.40, 1.99)). The present study failed to demonstrate the non-inferiority of the antialbuminuric effect of benidipine relative to that of hydrochlorothiazide in RAS inhibitor-treated hypertensive patients with macroalbuminuria.

  10. Periodontal disease in a patient receiving Bevacizumab: a case report

    Directory of Open Access Journals (Sweden)

    Gujral Dorothy M

    2008-02-01

    Full Text Available Abstract Introduction Bevacizumab is a monoclonal antibody that inhibits the action of vascular endothelial growth factor (VEGF thereby acting as an angiogenesis inhibitor. As a result, supply of oxygen and nutrients to tissues is impaired and tumour cell growth is reduced. Reported side effects due to bevacizumab are hypertension and increased risk of bleeding. Bowel perforation has also been reported. Periodontal disease in patients on bevacizumab therapy has not been reported before. Case Presentation We report a case of a forty-three year old woman who developed periodontitis whilst receiving bevacizumab for lung cancer. The periodontal disease remained stable on discontinuation of the drug. Conclusion Further investigations are needed to determine the mechanism for bevacizumab-induced periodontal disease.

  11. Inhibition of RAS in diabetic nephropathy

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    Yacoub R

    2015-04-01

    Full Text Available Rabi Yacoub, Kirk N Campbell Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Abstract: Diabetic kidney disease (DKD is a progressive proteinuric renal disorder in patients with type 1 or type 2 diabetes mellitus. It is a common cause of end-stage kidney disease worldwide, particularly in developed countries. Therapeutic targeting of the renin–angiotensin system (RAS is the most validated clinical strategy for slowing disease progression. DKD is paradoxically a low systematic renin state with an increased intrarenal RAS activity implicated in its pathogenesis. Angiotensin II (AngII, the main peptide of RAS, is not only a vasoactive peptide but functions as a growth factor, activating interstitial fibroblasts and mesangial and tubular cells, while promoting the synthesis of extracellular matrix proteins. AngII also promotes podocyte injury through increased calcium influx and the generation of reactive oxygen species. Blockade of the RAS using either angiotensin converting enzyme inhibitors, or angiotensin receptor blockers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in humans with DKD. In this review, we summarize the role of intrarenal RAS activation in the pathogenesis and progression of DKD and the rationale for RAS inhibition in this population. Keywords: renin–angiotensin system, diabetic kidney disease, angiotensin II, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers

  12. [Cognitive plasticity in Alzheimer's disease patients receiving cognitive stimulation programs].

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    Zamarrón Cassinello, Ma Dolores; Tárraga Mestre, Luis; Fernández-Ballesteros, Rocío

    2008-08-01

    The main purpose of this article is to examine whether cognitive plasticity increases after cognitive training in Alzheimer's disease patients. Twenty six patients participated in this study, all of them diagnosed with mild Alzheimer's disease, 17 of them received a cognitive training program during 6 months, and the other 9 were assigned to the control group. Participants were assigned to experimental or control conditions for clinical reasons. In order to assess cognitive plasticity, all patients were assessed before and after treatment with three subtests from the "Bateria de Evaluación de Potencial de Aprendizaje en Demencias" [Assessment Battery of Learning Potential in Dementia] (BEPAD). After treatment, Alzheimer's disease patients improved their performance in all the tasks assessing cognitive plasticity: viso-spatial memory, audio-verbal memory and verbal fluency. However, the cognitive plasticity scores of the patients in the control group decreased. In conclusion, this study showed that cognitive stimulation programs can improve cognitive functioning in mildly demented patients, and patients who do not receive any cognitive interventions may reduce their cognitive functioning.

  13. [Chronic kidney disease in 5 708 people receiving physical examination].

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    Xu, Guo; Chen, Zhiheng; Zhang, Hao; Gong, Ni; Wang, Yan

    2014-04-01

    To investigate chronic kidney disease (CKD) and its risk factors in people receiving physical examination. This retrospective study included people over 20 years old who had physical examination in the Health Management Center of Third Xiangya Hospital from Janurary 2008 to June 2011. CKD and its risk factors as well as questionnaire were recorded. The risk factors were analyzed by multivariate logistic analysis. CKD was defined by kidney damage (microalbuminuria≥30 mg/L) and/or hematuria and/or reduced kidney function [evaluate glomerular filtration rate (eGFR)physical examination reports were included. The detection rate of albuminuria, reduced renal function and hematuria was 25.0%, 1.7% and 1.1%. The detection rate of CKD was 25.6%, and detection rate of CKD stage 1-5 was 17.8%, 6.7%, 1.1%, 0 and 0, respectively. Multivariate logistic analysis indicated that diabetes mellitus, hypertension, hypercholesterolemia, male, age, and smoking were the risk factors for CKD. Increasing physical activity was the protective factor against CKD. High prevalence of CKD in people receiving physical examination is found in Changsha, especially stage 1 and 2 CKD. Physical examination is important to screen CKD. Stopping smoking, control of blood glucose, blood pressure, blood lipids and increasing physical activity may help reduce the prevalence of CKD.

  14. Ras activation by SOS

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    Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen

    2014-01-01

    SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS...... by Ras-guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather......Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual...

  15. Ras pathway activation in malignant mesothelioma.

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    Patel, Manish R; Jacobson, Blake A; De, Arpita; Frizelle, Sandra P; Janne, Pasi; Thumma, Saritha C; Whitson, Brian A; Farassati, Faris; Kratzke, Robert A

    2007-09-01

    Mutations in Ras family genes are rare in malignant mesothelioma. The role of activation of the Ras signaling pathway in the pathogenesis of mesothelioma is not clear. We studied the activation status of the Ras pathway and the status of other Ras-associated kinases in a panel of human mesothelioma cell lines. In addition, we tested the effect of inhibition of several kinase pathways on mesothelioma cell proliferation. The potential role of kinase signaling on the regulation of cap-dependent translation was also studied. In general, Ras-guanosine triphosphate (GTP) was higher in mesothelioma cell lines when compared with a nontransformed mesothelial cell line (LP9). Furthermore, known Ras effectors such as extracellular-regulated kinase 1/2, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase were found to be active in most of the mesothelioma cell lines tested. Exposure to specific inhibitors of extracellular-regulated kinase 1/2 (U0126) and c-Jun N-terminal kinase (SP600125) significantly decreased the proliferation of H2596 and H2373 cells compared with mock-treated cells. SP600125-mediated c-Jun N-terminal kinase inhibition, but not extracellular-regulated kinase 1/2 inhibition, resulted in a decrease in phosphorylation of 4E-BP1, consequently decreasing cap-dependent activation. These experiments provide a rationale for targeting Ras and associated signaling pathways in mesothelioma and also suggest cap-dependent translation as one mechanism by which Ras induces proliferation in this disease.

  16. [Correlation analysis between abundance of K-ras mutation in plasma free DNA and its correlation with clinical outcome and prognosis in patients with metastatic colorectal cancer].

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    Bai, Yan-qing; Liu, Xiao-jing; Wang, Yan; Ge, Fei-jiao; Zhao, Chuan-hua; Fu, Ya-li; Lin, Li; Xu, Jian-ming

    2013-09-01

    To detect K-ras gene mutations in plasma free DNA by peptide nucleic acid clamp PCR assay (PNA-PCR) and nested primer PCR, and to analyze the correlation between K-ras mutations and prognosis in patients with metastatic colorectal cancer (mCRC). Peripheral blood was collected and free DNA was extracted from plasma in 106 patients with mCRC. Nested primer PCR and PNA-PCR were used to detect K-ras gene mutation in the plasma free DNA. The patients were divided into three groups by K-ras status: wild-type group (wild-type determined by both methods), low mutation group (mutation by PNA-PCR method, wild-type by nested primer PCR method) and high mutation group (mutation by two methods). The correlation between K-ras mutations and prognosis was analyzed. The mutation rate of K-ras in tumor tissues of the 106 patients was 40.6%. The Mutation rate of K-ras in plasma free DNA detected by PNA-PCR was 31.1%, significantly higher than that of 15.1% detected by nested primer PCR (P = 0.006). The consistent rate of the K-ras status in plasma free DNA detected by PNA-PCR and that in tumor tissue detected by traditional method was up to 83.0%. The median overall survival (OS) of patients of the wild type, low mutation and high mutation groups was 23.5 months, 17.3 months and 13.9 months, respectively (P = 0.002). The median progression-free survival (PFS) of the K-ras wild-type, low mutation and high mutation groups with first-line chemotherapy was 6.8 months, 6.1 months and 3.2 months, respectively (P = 0.002), and the median OS of them were 23.0 months, 15.5 months and 13.9 months, respectively (P = 0.036). The overall response rate (ORR) was improved in the K-ras wide-type patients who received cetuximab combined with chemotherapy as first-line therapy (75.0% vs. 23.4%, P = 0.058). Cetuximab combined with in second-line therapy chemotherapy led to a significant improvement in disease control rate (DCR) ( 100% vs. 35.7%, P mutation in plasma free DNA can be used to substitute

  17. H-RAS, K-RAS, and N-RAS gene activation in human bladder cancers.

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    Przybojewska, B; Jagiello, A; Jalmuzna, P

    2000-08-01

    Bladder cancer is one of the leading causes of cancer death in most developed countries. In this work, 19 bladder cancer specimens, along with their infiltrations of the urinary bladder wall from the same patients, were examined for the presence of H-RAS, K-RAS, and N-RAS activation using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The H-RAS activation was found in 15 (about 84%) of the 19 bladder cancers studied. The same results were obtained in the infiltrating urinary bladder wall samples. N-RAS gene mutations were observed in all cases (except 1) in which H-RAS gene mutations were detected. The results suggest a strong relationship between H-RAS and N-RAS gene activation in bladder cancer. Changes in the K-RAS gene in bladder cancers seem to be a rare event; this is in agreement with findings of other authors. We found activation of the gene in one specimen of bladder cancer and its infiltration of the urinary bladder wall in the same patient.

  18. Peptic ulcer disease and other complications in patients receiving dexamethasone palliation for brain metastasis

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    Penzner, R.D.; Lipsett, J.A.

    1982-01-01

    A retrospective analysis was done of 106 patients who received radiation therapy for brain metastasis. Dexamethasone therapy was instituted in 97 patients. Peptic ulcer disease developed in 5 of 89 patients (5.6 percent) who received a dosage of at least 12 mg a day, but did not occur in patients who received a lower dose or in those who did not receive steroids. The interval between institution of dexamethasone therapy and the development of peptic ulcer disease ranged from three to nine weeks. Two patients had perforated ulcers, one of whom required surgical resection. Peptic ulcer disease contributed to the general deterioration and death of three of the five patients. Overall, in 14 of the 89 patients (15.7 percent) a complication of steroid therapy developed in the form of peptic ulcer disease, steroid myopathy or diabetes mellitus (or a combination of these)

  19. Peptic ulcer disease and other complications in patients receiving dexamethasone palliation for brain metastasis

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    Penzner, R.D.; Lipsett, J.A.

    1982-11-01

    A retrospective analysis was done of 106 patients who received radiation therapy for brain metastasis. Dexamethasone therapy was instituted in 97 patients. Peptic ulcer disease developed in 5 of 89 patients (5.6 percent) who received a dosage of at least 12 mg a day, but did not occur in patients who received a lower dose or in those who did not receive steroids. The interval between institution of dexamethasone therapy and the development of peptic ulcer disease ranged from three to nine weeks. Two patients had perforated ulcers, one of whom required surgical resection. Peptic ulcer disease contributed to the general deterioration and death of three of the five patients. Overall, in 14 of the 89 patients (15.7 percent) a complication of steroid therapy developed in the form of peptic ulcer disease, steroid myopathy or diabetes mellitus (or a combination of these).

  20. Intentions to receive a potentially available Lyme disease vaccine in an urban sample.

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    Fogel, Joshua; Kusz, Martin

    2016-01-01

    The only human Lyme disease vaccine of LYMErix was voluntarily removed from the market in the United States in 2002 for a number of reasons. A new human Lyme disease vaccine is currently being developed. We would like any future approved human Lyme disease vaccine to be of interest and marketable to consumers. We surveyed 714 participants to determine variables associated with intentions to receive a Lyme disease vaccine. Predictor variables included demographics, protection motivational theory, Lyme disease knowledge, Lyme disease preventive behaviors, beliefs and perceived health. We found in multivariate linear regression analyses that Asian/Asian American race/ethnicity (p marketers need to address and use approaches to interest those from other race/ethnicities. Also, marketers need to address the erroneous belief that vaccines are typically not safe in order to interest those with such beliefs to use a Lyme disease vaccine.

  1. Prevalence of anemia in patients with type II diabetes and mild to moderate chronic kidney disease and the impact of anti-RAS medications.

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    Dousdampanis, Periklis; Trigka, Konstantina; Fourtounas, Costas

    2014-05-01

    Anemia is a common feature of diabetes and chronic kidney disease (CKD) mainly due to erythropoietin (EPO) deficiency and uremic toxicity. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been established as first-choice medications for the treatment of diabetic nephropathy. However, there are conflicting data regarding their impact on hemoglobin levels in patients with diabetic nephropathy. We evaluated the prevalence of anemia in 101 patients with diabetes mellitus type II and CKD at stage III-IV (group A) compared with 101 non-diabetic patients with similar renal function (group B). Moreover, we evaluated the impact of ACE inhibitors and ARBs on patients' anemia. Anemia was observed in 60 patients in group A and in 47 patients in group B (P patients in group A and 19 patients in group B were receiving exogenous EPO for correction of renal anemia (P patients in group A and 52 patients in group B were receiving ACE inhibitors and/or ARBs (P medications. Anemia is more common in diabetic patients with CKD stage III-IV than in non-diabetic patients with similar renal function. Our results indicate that ACE inhibitors and ARBs are not a significant cause of anemia for both populations.

  2. Renal function in patients with non-dialysis chronic kidney disease receiving intravenous ferric carboxymaltose

    DEFF Research Database (Denmark)

    Macdougall, Iain C; Bock, Andreas H; Carrera, Fernando

    2017-01-01

    with non-dialysis dependent chronic kidney disease (ND-CKD), anemia and iron deficiency without erythropoiesis-stimulating agent therapy received intravenous ferric carboxymaltose (FCM), targeting either higher (400-600 μg/L) or lower (100-200 μg/L) ferritin values, or oral iron. RESULTS: Mean (SD) e...

  3. Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF.

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    Farnsworth, C L; Freshney, N W; Rosen, L B; Ghosh, A; Greenberg, M E; Feig, L A

    1995-08-10

    Tyrosine kinase receptors stimulate the Ras signalling pathway by enhancing the activity of the SOS nucleotide-exchange factor. This occurs, at least in part, by the recruitment of an SOS-GRB2 complex to Ras in the plasma membrane. Here we describe a different signalling pathway to Ras that involves activation of the Ras-GRF exchange factor in response to Ca2+ influx. In particular, we show that the ability of Ras-GRF to activate Ras in vivo is markedly enhanced by raised Ca2+ concentrations. Activation is mediated by calmodulin binding to an IQ motif in Ras-GRF, because substitutions in conserved amino acids in this motif prevent both calmodulin binding to Ras-GRF and Ras-GRF activation in vivo. So far, full-length Ras-GRF has been detected only in brain neurons. Our findings implicate Ras-GRF in the regulation of neuronal functions that are influenced by Ca2+ signals.

  4. Ras acylation, compartmentalization and signaling nanoclusters (Review)

    OpenAIRE

    HENIS, YOAV I.; HANCOCK, JOHN F.; PRIOR, IAN A.

    2008-01-01

    Ras proteins have become paradigms for isoform- and compartment-specific signaling. Recent work has shown that Ras isoforms are differentially distributed within cell surface signaling nanoclusters and on endomembranous compartments. The critical feature regulating Ras protein localization and isoform-specific functions is the C-terminal hypervariable region (HVR). In this review we discuss the differential post-translational modifications and reversible targeting functions of Ras isoform HVR...

  5. 05 Inkanyiso Ras 2.fm

    African Journals Online (AJOL)

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    and follow good moral values like in the Bible. Research approach .... teachings of John the Baptist and his advice to follow Jesus, the Christ (the Messiah) (John 1: 19, 23-26, 29-34; Ras, 1987). In other words, according to ..... A Greek-English Lexicon of the New Testament and other Early Christian Literature. Eighteenth.

  6. Higher nocturnal and awake oxygen saturations in children with sickle cell disease receiving hydroxyurea therapy.

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    Narang, Indra; Kadmon, Gili; Lai, Dennison; Dhanju, Simranpal; Kirby-Allen, Melanie; Odame, Isaac; Amin, Reshma; Lu, Zihang; Al-Saleh, Suhail

    2015-07-01

    Obstructive sleep apnea and intermittent nocturnal oxygen desaturations are highly prevalent in children with sickle cell disease and have been reported to contribute to associated morbidity, including vasoocclusive disease. Hydroxyurea (HU) is increasingly used to treat children with sickle cell disease and has been shown to decrease the number and severity of vasoocclusive crises. Although there has been an increase in the use of HU, the impact of HU on the prevalence of obstructive sleep apnea and nocturnal hypoxia are not well documented. To evaluate whether the use of HU is associated with a decreased frequency of obstructive sleep apnea and higher nocturnal and awake oxygen saturations (SaO2) in children with sickle cell disease. This was a retrospective, cross-sectional review of children with sickle cell disease referred to the sleep laboratory at the Hospital for Sick Children, Toronto, Canada. Polysomnogram data in children with sickle cell disease receiving HU therapy were compared with those not prescribed HU. Children with sickle cell disease receiving HU therapy (HU group, n = 37) were matched with children not receiving HU (no-HU group, n = 104). Obstructive sleep apnea was diagnosed in 14 of 37 (38%) and 54 of 104 (52%) in the HU group and no-HU groups, respectively (P = 0.14). The median obstructive apnea-hypopnea index was 0.9 and 1.9 events/h in the HU group and the no-HU group, respectively (P = 0.28). The HU group compared with the no-HU group had a significantly higher median awake SaO2 (98.6 and 96.2%, respectively; P children with sickle cell disease, the use of HU was associated with an increase in awake and nocturnal SaO2, despite there being no difference in the frequency of obstructive sleep apnea and the severity of the obstructive apnea-hypopnea index. Improving nocturnal SaO2 may be an important mechanism of action of HU therapy. The use of HU to improve nocturnal saturations across the severity spectrum of sickle

  7. [Clinical relevance of the K-ras oncogene in colorectal cancer: experience in a Mexican population].

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    Cabrera-Mendoza, F; Gainza-Lagunes, S; Castañeda-Andrade, I; Castro-Zárate, A

    2014-01-01

    Colorectal cancer is frequent in the developed countries, with a cancer-specific mortality rate of 33%. Different biomarkers are associated with overall survival and the prediction of monoclonal treatment effectiveness. The presence of mutations in the K-ras oncogene alters the response to target therapy with cetuximab and could be an independent prognostic factor. To analyze the difference in survival between patients with mutated K-ras and those with K-ras wild-type status. Thirty-one clinical records were retrospectively analyzed of patients presenting with colorectal cancer that underwent K-ras sequencing through real-time polymerase chain reaction within the time frame of 2009 to 2012 at the Hospital de Alta Especialidad de Veracruz of the Instituto para la Salud y Seguridad Social de los Trabajadores del Estado (HAEV-ISSSTE). Survival analysis for patients with and without K-ras mutation was performed using the Kaplan Meier method. Contrast of covariates was performed using logarithmic transformations. No statistically significant difference was found in relation to survival in the patients with mutated K-ras vs. those with K-ras wild-type (P=.416), nor were significant differences found when analyzing the covariants and survival in the patients with mutated K-ras: ECOG scale (P=.221); age (less than, equal to or greater than 65years, P=.441); clinical stage according to the AJCC (P=.057), and primary lesion site (P=.614). No relation was found between the K-ras oncogene mutation and reduced survival, in contrast to what has been established in the international medical literature. Further studies that include both a larger number of patients and those receiving monoclonal treatment, need to be conducted. There were only 5 patients in the present study that received cetuximab, resulting in a misleading analysis. Copyright © 2013 Asociación Mexicana de Gastroenterología. Published by Masson Doyma México S.A. All rights reserved.

  8. Identification of Differentially Expressed K-Ras Transcript Variants in Patients With Leiomyoma.

    Science.gov (United States)

    Zolfaghari, Nooshin; Shahbazi, Shirin; Torfeh, Mahnaz; Khorasani, Maryam; Hashemi, Mehrdad; Mahdian, Reza

    2017-10-01

    Molecular studies have demonstrated a wide range of gene expression variations in uterine leiomyoma. The rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase (RAS/RAF/MAPK) is the crucial cellular pathway in transmitting external signals into nucleus. Deregulation of this pathway contributes to excessive cell proliferation and tumorigenesis. The present study aims to investigate the expression profile of the K-Ras transcripts in tissue samples from patients with leiomyoma. The patients were leiomyoma cases who had no mutation in mediator complex subunit 12 ( MED12) gene. A quantitative approach has been applied to determine the difference in the expression of the 2 main K-Ras messenger RNA (mRNA) variants. The comparison between gene expression levels in leiomyoma and normal myometrium group was performed using relative expression software tool. The expression of K-Ras4B gene was upregulated in leiomyoma group ( P = .016), suggesting the involvement of K-Ras4B in the disease pathogenesis. Pairwise comparison of the K-Ras4B expression between each leiomyoma tissue and its matched adjacent normal myometrium revealed gene upregulation in 68% of the cases. The expression of K-Ras4A mRNA was relatively upregulated in leiomyoma group ( P = .030). In addition, the mean expression of K-Ras4A gene in leiomyoma tissues relative to normal samples was 4.475 (95% confidence interval: 0.10-20.42; standard error: 0.53-12.67). In total, 58% of the cases showed more than 2-fold increase in K-Ras4A gene expression. Our results demonstrated increased expression of both K-Ras mRNA splicing variants in leiomyoma tissue. However, the ultimate result of KRAS expression on leiomyoma development depends on the overall KRAS isoform balance and, consequently, on activated signaling pathways.

  9. Receiver operating characteristic analysis of regional cerebral blood flow in Alzheimer's disease

    International Nuclear Information System (INIS)

    Zemcov, A.; Barclay, L.L.; Sansone, J.; Metz, C.E.

    1985-01-01

    Receiver operating characteristic (ROC) curves were used to quantitatively assess the ability of individual detectors in a 32-detector 133 Xe inhalation system to discriminate between two populations over the range of regional cerebral blood flow (rCBF) values. These populations were clinically evaluated as normal (age 63.1 +/- 13.1, n = 23) and presumed Alzheimer's disease (age 72.7 +/- 7.0, n = 82). Summary statistics showed that for homologous detectors the average value of blood flow in the normal group was greater than the flow value in the group of subjects with Alzheimer's disease. Conclusions drawn from single values of flow or mean hemispheric flow can lead to erroneous conclusions about hemisphere asymmetries. However, the dynamic relationship between the correct identifications (true positives) compared with incorrect identifications (false positives) of Alzheimer's disease at each detector varies over the range of blood flow values, and quantitative characterization of this relationship in terms of an ROC curve provides more insight into the structure of the data. Detectors approximating the speech, auditory and association cortex were most effective in discriminating between groups. Frontal detectors were marginally useful diagnostically

  10. K-RAS mutations indicating primary resistance to crizotinib in ALK-rearranged adenocarcinomas of the lung: Report of two cases and review of the literature.

    Science.gov (United States)

    Mengoli, Maria Cecilia; Barbieri, Fausto; Bertolini, Federica; Tiseo, Marcello; Rossi, Giulio

    2016-03-01

    The paradigm of mutually exclusive alterations among oncogenic drivers in non-small-cell lung cancer (NSCLC) is challenged by the increasing evidence of detection of two or more driver alterations in the same tumor using highly-sensitive molecular assays. We report here two cases of ALK-rearranged adenocarcinomas harboring concomitant exon 2 K-RAS mutations (G13D and Q61H). The patients, a 49-year-old smoker man and a 59-year-old non-smoking woman, experienced a rapid disease progression and primary resistance to crizotinib. Search for similar cases in the literature reveals that concomitant K-RAS mutations and ALK rearrangement occur in a subset of NSCLC and seems to lead to resistance to crizotinib. Among 8 similar cases receiving crizotinib previously reported (4 in first line and 4 in second line), 1 had a partial response, 1 stable disease and 6 disease progression. One patient still had progression disease when switching to ceritinib. At the end, K-RAS mutations seem to represent a negative predictive marker in ALK-rearranged adenocarcinomas treated with ALK inhibitor. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Potential Risk Factors Associated With Vascular Diseases in Patients Receiving Treatment for Hypertension.

    Science.gov (United States)

    Kim, Hyunjung; Park, Joonhong; Chae, Hyojin; Lee, Gun Dong; Lee, Sang Yoon; Lee, Jong Min; Oh, Yong Seog; Kim, Myungshin; Kim, Yonggoo

    2016-05-01

    Currently, the hypertension (HTN) patients undergo appropriate medical treatment, and traditional risk factors are highly controlled. Therefore, potential risk factors of atherosclerotic vascular diseases (AVD) and venous thromboembolisms (VTE) in HTN should be reconsidered. We investigated thrombophilic genetic mutations and existing biomarkers for AVD or VTE in HTN patients receiving treatment. A total of 183 patients were enrolled: AVD with HTN (group A, n=45), VTE with HTN (group B, n=62), and HTN patients without any vascular diseases (group C, n=76). The lipid profile, homocysteine (Hcy) levels, D-dimers, fibrinogen, antithrombin, lupus anticoagulant, and anti-cardiolipin antibody (aCL) were evaluated. Prothrombin G20210A, Factor V G1691A, and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C were analyzed. All patients revealed wild type prothrombin G20210A and Factor V G1691A polymorphisms. The frequency of MTHFR polymorphisms was 677CT (n=84, 45.9%); 677TT (n=46, 25.1%); 1298AC (n=46, 25.1%); and 1298CC (n=2, 1.1%). The MTHFR 677TT genotype tended to increase the odds ratio (OR) to AVD events in HTN patients (OR 2.648, confidence interval 0.982-7.143, P=0.05). The group A demonstrated significantly higher Hcy levels (P=0.009), fibrinogen (P=0.004), and platelet counts (P=0.04) than group C. Group B had significantly higher levels of D-dimers (P=0.0001), platelet count (P=0.0002), and aCL (P=0.02) frequency than group C. The MTHFR 677TT genotype and Hcy level could be potential risk factors associated with development of AVD in HTN patients receiving treatment. D-dimer and aCL might be useful to estimate the occurrence of VTE in them.

  12. Determining the Incidence of Pneumocystis Pneumonia in Patients With Autoimmune Blistering Diseases Not Receiving Routine Prophylaxis.

    Science.gov (United States)

    Amber, Kyle T; Lamberts, Aniek; Solimani, Farzan; Agnoletti, Arianna F; Didona, Dario; Euverman, Ilona; Cozzani, Emanuele; Yueh, Lee Haur; Di Zenzo, Giovanni; Leshem, Yael Anne; Mimouni, Daniel; Hertl, Michael; Horvath, Barbara

    2017-11-01

    Pneumocystis pneumonia (PCP) is a potentially lethal opportunistic infection that primary prophylaxis can help prevent. The risk of prophylactic therapy must be weighed against the incidence of PCP in the patient population. Prophylaxis most frequently involves trimethoprim-sulfamethoxazole, with second-line therapies, including atovaquone, dapsone, and pentamide. The indication for prophylaxis in immunocompromised patients without HIV is less well defined. Previously, an incidence of at least 3.5% has been proposed as a cutoff to justify prophylaxis. To assess the incidence of PCP in patients with autoimmune blistering diseases receiving no routine prophylaxis. This was a retrospective analysis of patient medical records to determine the incidence of PCP infections. The multicenter study was performed at tertiary care centers that provide care for patients with autoimmune blistering disease in Germany, Italy, Singapore, Israel, and the Netherlands. Patients had a confirmed diagnosis of pemphigus vulgaris/foliaceus, bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid/cicatricial pemphigoid, or anti-p200 pemphigoid. To determine the incidence of PCP defined as patients with the International Classification of Diseases, Ninth Revision (ICD-9), code 136.3, for PCP, or free text documentation of PCP occurring based on characteristic radiographic findings with elevated lactate dehydrogenase, or hospitalization for pneumonia with bronchioalveolar lavage demonstrating Pneumocystis jiroveci on confirmatory stains. A total of 801 patients with autoimmune blistering diseases were included in this study; their mean (SD) age was 66.5 (17.6) years, and a total of 465 (58%) were female. Only 1 patient developed PCP, resulting in an incidence rate of 0.1%. This incidence significantly fell below the recommended threshold of 3.5% (0.1% vs 3.5%, χ21 = 27.0; P autoimmune blistering diseases does not seem to be warranted. Patients with autoimmune

  13. Measuring diagnostic and predictive accuracy in disease management: an introduction to receiver operating characteristic (ROC) analysis.

    Science.gov (United States)

    Linden, Ariel

    2006-04-01

    Diagnostic or predictive accuracy concerns are common in all phases of a disease management (DM) programme, and ultimately play an influential role in the assessment of programme effectiveness. Areas, such as the identification of diseased patients, predictive modelling of future health status and costs and risk stratification, are just a few of the domains in which assessment of accuracy is beneficial, if not critical. The most commonly used analytical model for this purpose is the standard 2 x 2 table method in which sensitivity and specificity are calculated. However, there are several limitations to this approach, including the reliance on a single defined criterion or cut-off for determining a true-positive result, use of non-standardized measurement instruments and sensitivity to outcome prevalence. This paper introduces the receiver operator characteristic (ROC) analysis as a more appropriate and useful technique for assessing diagnostic and predictive accuracy in DM. Its advantages include; testing accuracy across the entire range of scores and thereby not requiring a predetermined cut-off point, easily examined visual and statistical comparisons across tests or scores, and independence from outcome prevalence. Therefore the implementation of ROC as an evaluation tool should be strongly considered in the various phases of a DM programme.

  14. Molecular interaction between K-Ras and H-REV107 in the Ras signaling pathway.

    Science.gov (United States)

    Han, Chang Woo; Jeong, Mi Suk; Jang, Se Bok

    2017-09-16

    Ras proteins are small GTPases that serve as master moderators of a large number of signaling pathways involved in various cellular processes. Activating mutations in Ras are found in about one-third of cancers. H-REV107, a K-Ras binding protein, plays an important role in determining K-Ras function. H-REV107 is a member of the HREV107 family of class II tumor suppressor genes and a growth inhibitory Ras target gene that suppresses cellular growth, differentiation, and apoptosis. Expression of H-REV107 was strongly reduced in about 50% of human carcinoma cell lines. However, the specific molecular mechanism by which H-REV107 inhibits Ras is still unknown. In the present study, we suggest that H-REV107 forms a strong complex with activating oncogenic mutation Q61H K-Ras from various biochemical binding assays and modeled structures. In addition, the interaction sites between K-Ras and H-REV107 were predicted based on homology modeling. Here, we found that some structure-based mutants of the K-Ras disrupted the complex formation with H-REV107. Finally, a novel molecular mechanism describing K-Ras and H-REV107 binding is suggested and insights into new K-Ras effector target drugs are provided. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Infectious diseases and migrant worker health in Singapore: a receiving country's perspective.

    Science.gov (United States)

    Sadarangani, Sapna P; Lim, Poh Lian; Vasoo, Shawn

    2017-07-01

    Approximately 1.4 million migrant workers reside in Singapore, presenting unique infectious disease challenges to both migrants and Singapore. A Pubmed, MEDLINE (Ovid), EBSCO Host (Global Health) and Google Scholar search was performed for both peer, non-peer reviewed articles and reports relevant to migrant health in Singapore, published between 1 January 1989 and 1 September 2016. Additional studies were identified from citations within searched articles. We also reviewed published data and policy documents from the Ministries of Health and Manpower, Singapore. A significant proportion of malaria, enteric fevers, hepatitis A and E and tuberculosis diagnosed in Singapore involve migrant workers. From the 1990-2000 through 2009-11, while malaria and hepatitis A cases have decreased and remain sporadic, enteric fevers and tuberculosis cases have increased, possibly due to greater influx of migrant workers. Hepatitis E numbers remain low but migrant workers account for half of diagnosed cases. In an interplay of immune naivete, work and living conditions, migrants in the construction industry are at higher risk of arboviral infections such as dengue, Zika and chikungunya. Infections such as chikungunya were likely introduced into Singapore by travellers including migrant workers from the Indian subcontinent but autochthonous transmission continued due to the presence of competent mosquito vectors. There is less data regarding sexual health, networks and infections amongst migrant workers, an area which merits further attention. Migrant workers appear to be at higher risk than Singaporeans for specific infectious diseases, probably due to a complex interplay of several factors, including higher disease prevalence in their countries of origin, socio-economic factors, their living conditions in Singapore and financial, language and cultural barriers to healthcare access. Receiving countries need improved surveillance, expansion of preventive measures and decreased

  16. The Ras superfamily G-proteins.

    Science.gov (United States)

    Tetlow, Ashley L; Tamanoi, Fuyuhiko

    2013-01-01

    The Ras superfamily G-proteins are monomeric proteins of approximately 21kDa that act as a molecular switch to regulate a variety of cellular processes. The structure of the Ras superfamily G-proteins, their regulators as well as posttranslational modification of these proteins leading to their membrane association have been elucidated. The Ras superfamily G-proteins interact at their effector domains with their downstream effectors via protein-protein interactions. Mutational activation or overexpression of the Ras superfamily G-proteins has been observed in a number of human cancer cases. Over the years, a variety of approaches to inhibit the Ras superfamily G-proteins have been developed. These different approaches are discussed in this volume. © 2013 Elsevier Inc. All rights reserved.

  17. Norrie disease pedigree carrying the novel mutation C65Y, predicted to disrupt the cystine knot growth factor motif, analyzed by RasI restriction digestion

    Energy Technology Data Exchange (ETDEWEB)

    Strasberg, P.M.; Liede, H.A.; Stein, T. [Univ. of Toronto, Ontario (Canada)] [and others

    1994-09-01

    Norrie disease (MIM 310600; ND) is an X-linked (Xp11.2-11.3) neurodevelopmental disorder characterized by congenital blindness, retinal dysplasia with pseudoglioma formation, and often associated with progressive mental retardation and deafness. The ND gene, comprised of 3 exons, codes for an evolutionarily conserved protein of 133 amino acids. We have analyzed 8 pedigrees segregating Norrie disease. Although microdeletions have been detected in several typical ND patients, Southern blot analysis with probes L1.28, MAO-A, MAO-B, TIMP-3.9X, pTak8, and M27{beta} failed to detect such deletions in these 8 ND pedigrees. With the cloning of the ND gene, PCR analysis of all 3 exons likewise did not reveal any insertions or deletions. SSCP analysis ({sup 35}S-dNTP PCR) on PCR products of exon 3 showed a band shift for 1 patient. Repeat `cold` SSCP on minigels (3 inches x 4 inches) followed by liver staining was confirmatory. Direct sequencing revealed a G{r_arrow}A transition at nucleotide 610 corresponding to amino acid 65, changing Cys to Tyr. The mutation created an RsaI site, such that the uncut, normal, and mutant PCR products (using the same PCR primers) were 297 bp, 243 and 54 bp, and 177, 72 and 54 bp respectively. Affected males in the relevant pedigree had restricted PCR products of 177, 72 and 54 bp, carrier mothers 243, 177, 72, and 54 bp, and normals, including 30 unrelated individuals, 243 and 54 bp. Recent evidence indicates that the ND gene has a C-terminal domain homologous to that of TGF{beta}, thus identifying it as putative peptide growth factor, providing a monogenic disease model for the family of cystine knot growth factors. This is the first report of a mutation in Cys 2, critical for crosslinking to Cys 5 forming a disulphide bridge which holds the cystine knot growth factor tertiary structure together.

  18. Monitoring the effect of first line treatment in RAS/RAF mutated metastatic colorectal cancer by serial analysis of tumor specific DNA in plasma

    DEFF Research Database (Denmark)

    Brenner Thomsen, Caroline Emilie; Hansen, T F; Andersen, R F

    2018-01-01

    BACKGROUND: Precision medicine calls for an early indicator of treatment efficiency. Circulating tumor DNA (ctDNA) is a promising marker in this setting. Our prospective study explored the association between disease development and change of ctDNA during first line chemotherapy in patients...... with RAS/RAF mutated metastatic colorectal cancer (mCRC). METHODS: The study included 138 patients with mCRC receiving standard first line treatment. In patients with RAS/RAF mutated tumor DNA the same mutation was quantified in the plasma using droplet digital PCR. The fractional abundance of ct...... on continuous treatment. The first increase in ctDNA level occurred at a median of 51 days before radiologically confirmed progression. CONCLUSIONS: The results indicate that the ctDNA level holds potential as a clinically valuable marker in first line treatment of mCRC. A rapid decrease was associated...

  19. Workforce participation and activities in Parkinson's disease patients receiving device-aided therapy.

    Science.gov (United States)

    Sahlström, T; Eklund, M; Timpka, J; Henriksen, T; Nyholm, D; Odin, P

    2018-03-22

    Many countries have an aging population, and it is thus likely that Parkinson's disease (PD) will become an increasing health problem. It is important to ensure this group can use their resources in the best way possible, including remaining in the work market. This study aimed to investigate workforce participation and daily activities among patients with PD receiving device-aided therapy to provide new knowledge that may be used to inform decisions about these therapy options. This was a retrospective, descriptive quantitative pilot study, including 67 patients with PD from 3 centers in Sweden and Denmark. Included patients were younger than 67 years at the time of introduction of device-aided therapy. Eligible patients were identified by the Swedish national Parkinson patient registry or by the treating neurologist. Quantitative interviews were made by telephone. A majority of the patients could perform the same, or more, amount of activities approximately 5 years after the introduction of device-aided therapy. A small number of patients receiving deep brain stimulation (DBS) and levodopa-carbidopa intestinal gel (LCIG) were able to increase their work capacity within 1 year of initiating device-aided therapy and a remarkably high share could still work at the end-point of this study, approximately 15 years since the diagnosis of PD. Device-aided therapy may sustain or increase daily activities and workforce participation in patients with PD who have not yet reached retirement age. There is need for prospective studies, both quantitative and qualitative, to confirm these results. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Cardiovascular Disease Among Transgender Adults Receiving Hormone Therapy: A Narrative Review.

    Science.gov (United States)

    Streed, Carl G; Harfouch, Omar; Marvel, Francoise; Blumenthal, Roger S; Martin, Seth S; Mukherjee, Monica

    2017-08-15

    Recent reports estimate that 0.6% of adults in the United States, or approximately 1.4 million persons, identify as transgender. Despite gains in rights and media attention, the reality is that transgender persons experience health disparities, and a dearth of research and evidence-based guidelines remains regarding their specific health needs. The lack of research to characterize cardiovascular disease (CVD) and CVD risk factors in transgender populations receiving cross-sex hormone therapy (CSHT) limits appropriate primary and specialty care. As with hormone therapy in cisgender persons (that is, those whose sex assigned at birth aligns with their gender identity), existing research in transgender populations suggests that CVD risk factors are altered by CSHT. Currently, systemic hormone replacement for cisgender adults requires a nuanced discussion based on baseline risk factors and age of administration of exogenous hormones because of concern regarding an increased risk for myocardial infarction and stroke. For transgender adults, CSHT has been associated with the potential for worsening CVD risk factors (such as blood pressure elevation, insulin resistance, and lipid derangements), although these changes have not been associated with increases in morbidity or mortality in transgender men receiving CSHT. For transgender women, CSHT has known thromboembolic risk, and lower-dose transdermal estrogen formulations are preferred over high-dose oral formulations. In addition, many studies of transgender adults focus predominantly on younger persons, limiting the generalizability of CSHT in older transgender adults. The lack of randomized controlled trials comparing various routes and formulations of CSHT, as well as the paucity of prospective cohort studies, limits knowledge of any associations between CSHT and CVD.

  1. Prevalence of peri-implant inflammatory disease in patients with a history of periodontal disease who receive supportive periodontal therapy.

    Science.gov (United States)

    Aguirre-Zorzano, Luis Antonio; Estefanía-Fresco, Ruth; Telletxea, Olatz; Bravo, Manuel

    2015-11-01

    To describe the status of implants in periodontally compromised patients who regularly receive supportive periodontal therapy (SPT) and to determine the factors associated to peri-implant inflammatory disease in those patients. Clinical and radiographic data of implants in periodontal patients who, after being treated and included in a SPT programme, wore implant prostheses for at least 6 months were recorded. The implants were classified according to the criteria of the 6th European Workshop on Periodontology in health, mucositis and peri-implantitis. Logistic regression analysis was performed to analyse the individual and adjusted effects of each study variable on mucositis or peri-implantitis, using SUDAAN to account for clustering (multiple implants within the patient). A total of 786 implants were placed in 239 patients. At patient level, 60.3%, 24.7% and 15.1% were classified as healthy, mucositis and peri-implantitis patients, respectively. At implant level, the respective percentages were 77.4%, 12.8% and 9.8%. For mucositis, at implant level, the adjusted ORs indicate a significant association with plaque index (P = 0.050), type of periodontitis (P = 0.030) and location (P = 0.045). For peri-implantitis, the adjusted ORs indicate a significant association with plaque index (P implant inflammatory disease in periodontal patients who regularly undergo SPT is clinically significant. The factors associated with peri-implant inflammatory disease were plaque index and implant location, and mucositis was also affected by the type of periodontitis the patient had. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Parallel imaging of Drosophila embryos for quantitative analysis of genetic perturbations of the Ras pathway

    Directory of Open Access Journals (Sweden)

    Yogesh Goyal

    2017-07-01

    Full Text Available The Ras pathway patterns the poles of the Drosophila embryo by downregulating the levels and activity of a DNA-binding transcriptional repressor Capicua (Cic. We demonstrate that the spatiotemporal pattern of Cic during this signaling event can be harnessed for functional studies of mutations in the Ras pathway in human diseases. Our approach relies on a new microfluidic device that enables parallel imaging of Cic dynamics in dozens of live embryos. We found that although the pattern of Cic in early embryos is complex, it can be accurately approximated by a product of one spatial profile and one time-dependent amplitude. Analysis of these functions of space and time alone reveals the differential effects of mutations within the Ras pathway. Given the highly conserved nature of Ras-dependent control of Cic, our approach provides new opportunities for functional analysis of multiple sequence variants from developmental abnormalities and cancers.

  3. Pre-travel advice concerning vector-borne diseases received by travelers prior to visiting Cuzco, Peru.

    Science.gov (United States)

    Mejia, Christian R; Centeno, Emperatriz; Cruz, Briggitte; Cvetkovic-Vega, Aleksandar; Delgado, Edison; Rodriguez-Morales, Alfonso J

    2016-01-01

    Peru is an increasingly popular tourist destination that poses a risk to travelers due to endemic vector-borne diseases (VBDs). The objective of our study was to determine which factors are associated with receiving pre-travel advice (PTA) for VBDs among travelers visiting Cuzco, Peru. A cross-sectional secondary analysis based on data from a survey among travelers departing Cuzco at Alejandro Velazco Astete International Airport during the period January-March 2012 was conducted. From the 1819 travelers included in the original study, 1717 were included in secondary data analysis. Of these participants, 42.2% received PTA and 2.9% were informed about vector-borne diseases, including yellow fever (1.8%), malaria (1.6%) and dengue fever (0.1%). Receiving information on VBDs was associated with visiting areas endemic to yellow fever and dengue fever in Peru. The only disease travelers received specific recommendations for before visiting an endemic area for was yellow fever. Only 1 in 30 tourists received information on VBD prevention; few of those who traveled to an endemic area were warned about specific risks for infectious diseases prior to their trip. These important findings show that most tourists who travel to Peru do not receive PTA for the prevention of infectious and VBD, which can affect not only the travelers but their countries of origin as well. Copyright © 2015 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

  4. Fewer acute respiratory infection episodes among patients receiving treatment for gastroesophageal reflux disease.

    Directory of Open Access Journals (Sweden)

    Herng-Ching Lin

    Full Text Available Patients with gastroesophageal reflux disease (GERD present with comorbid complications with implications for healthcare utilization. To date, little is known about the effects of GERD treatment with a proton-pump inhibitor (PPI on patients' subsequent healthcare utilization for acute respiratory infections (ARIs. This population-based study compared ARI episodes captured through outpatient visits, one year before and one year after GERD patients received PPI treatment. We used retrospective data from the Longitudinal Health Insurance Database 2005 in Taiwan, comparing 21,486 patients diagnosed with GERD from 2010 to 2012 with 21,486 age-sex matched comparison patients without GERD. Annual ARI episodes represented by ambulatory care visits for ARI (visits during a 7-day period bundled into one episode, were compared between the patient groups during the 1-year period before and after the index date (date of GERD diagnosis for study patients, first ambulatory visit in the same year for their matched comparison counterpart. Multiple regression analysis using a difference-in-difference approach was performed to estimate the adjusted association between GERD treatment and the subsequent annual ARI rate. We found that the mean annual ARI episode rate among GERD patients reduced by 11.4%, from 4.39 before PPI treatment, to 3.89 following treatment (mean change = -0.5 visit, 95% confidence interval (CI = (-0.64, -0.36. In Poisson regression analysis, GERD treatment showed an independent association with the annual ARI rate, showing a negative estimate (with p<0.001. The study suggests that GERD treatment with PPIs may help reduce healthcare visits for ARIs, highlighting the importance of treatment-seeking by GERD patients and compliance with treatment.

  5. Comparison of survival in patients with end-stage renal disease receiving hemodialysis versus peritoneal dialysis.

    Science.gov (United States)

    Beladi Mousavi, Seyed Seifollah; Hayati, Fatemeh; Valavi, Ehsan; Rekabi, Fazlollah; Mousavi, Marzieh Beladi

    2015-03-01

    Although the life expectancy of patients with end-stage renal disease (ESRD) has improved in recent years, it is still far below that of the general population. In this retrospective study, we compared the survival of patients with ESRD receiving hemodialysis (HD) versus those on peritoneal dialysis (PD). The study was conducted on patients referred to the HD and PD centers of the Emam Khomini Hospital and the Aboozar Children's Hospital from January 2007 to May 2012 in Ahvaz, Iran. All ESRD patients on maintenance HD or PD for more than two months were included in the study. The survival was estimated by the Kaplan-Meier method and the differences between HD and PD patients were tested by the log-rank test. Overall, 239 patients, 148 patients on HD (61.92%) and 91 patients on continuous ambulatory PD (CAPD) (38.55%) with mean age of 54.1 ± 17 years were enrolled in the study. Regardless of the causes of ESRD and type of renal replacement therapy (RRT), one-, two- and three-year survival of patients was 65%, 51% and 35%, respectively. There was no significant difference between type of RRT in one- (P-value = 0.737), two- (P-value = 0.534) and three- (P-value = 0.867) year survival. There was also no significant difference between diabetic and non-diabetic patients under HD and CAPD in the one-, two- and three-year survival. Although the three-year survival of diabetic patients under CAPD was lower than that of non-diabetic patients (13% vs. 34%), it was not statistically significant (P-value = 0.50). According to the results of the current study, there is no survival advantage of PD during the first years of initiation of dialysis, and the one-, two- and three-year survival of HD and PD patients is also similar.

  6. Educational approaches focusing on the quality of life of people with chronic kidney disease receiving hemodialysis: an integrative review

    OpenAIRE

    Beraldo, Pedro Cezar; Moysés, Simone Tetu; Werneck, Renata Iani; Araujo, Eduardo Santana de; Moysés, Samuel Jorge

    2017-01-01

    Abstract Introduction: The impact of chronic kidney disease (CKD) on the quality of life of patients receiving hemodialysis is widely studied. Despite the vast amount of literature on the topic, it is still important to investigate the educational approaches related to this population’s quality of life, evolution, and treatment. Objective: To systematically review the literature on educational approaches focusing on people with CKD receiving hemodialysis. Methods: An integrative systema...

  7. Renal Artery Stenosis (RAS) Case study

    International Nuclear Information System (INIS)

    Zaater, M.K.

    2012-01-01

    Renal Artery Stenosis (RAS), is one of the causes of secondary hypertension; there are many causes of renal artery stenosis, as atherosclerosis of the renal artery which account for 90% of cases of RAS; fibromuscular dysplasia accounts for 10% of RAS. Various causes of thrombophilia either due congenital causes or acquired causes and can lead to RAS. Our patient was presented by acute attack of epistaxis and hypertension. Angiography of the Renal Arteries,are showed no sign of renal artery stenosis. However, the right kidney showed upper pole infarction, and the left kidney showed evidence of functional lower pole renal artery stenosis, although there is no anatomical stenosis detected in angiography. Work up for the cause of thrombophilia did not help in the diagnosis, which may be due to an undiscovered cause of thrombophilia

  8. Exploiting the bad eating habits of Ras-driven cancers.

    Science.gov (United States)

    White, Eileen

    2013-10-01

    Oncogenic Ras promotes glucose fermentation and glutamine use to supply central carbon metabolism, but how and why have only emerged recently. Ras-mediated metabolic reprogramming generates building blocks for growth and promotes antioxidant defense. To fuel metabolic pathways, Ras scavenges extracellular proteins and lipids. To bolster metabolism and mitigate stress, Ras activates cellular self-cannibalization and recycling of proteins and organelles by autophagy. Targeting these distinct features of Ras-driven cancers provides novel approaches to cancer therapy.

  9. Quality of life and chronic disease in patients receiving primary health care

    OpenAIRE

    Preto, Olinda; Amaral, Odete; Duarte, João; Chaves, Cláudia; Coutinho, Emília; Nelas, Paula

    2016-01-01

    Problem Statement: Chronic disease entails physical, psychological and social issues with a decrease in the quality of life. The assessment of QoL has been applied as indicator in patients with chronic diseases. Research Questions: What is the quality of life in patients with chronic disease? What are the socio-demographic variables that influence the quality of life in patients? Purpose: To assess the quality of life in patients suffering from chronic disease and identify socio-demographic v...

  10. Systemic and localized infection by Candida species in patients with rheumatic diseases receiving anti-TNF therapy

    OpenAIRE

    Aikawa, Nadia E.; Rosa, Daniela T.A.; Del Negro, Gilda M.B.; Moraes, Julio C.B.; Ribeiro, Ana C.M.; Saad, Carla Gonçalves; Silva, Clovis A.; Bonfá, Eloisa

    2016-01-01

    ABSTRACT Objective: To evaluate the prevalence of systemic and localized infection by Candida species and its possible association with demographic, clinical and laboratory manifestations and therapy in patients with rheumatic diseases taking TNF blockers. Methods: Consecutive patients with rheumatic diseases receiving anti-TNF agents were included. The following risk factors up to four weeks prior to the study were analyzed: use of antibiotics, immunosuppressant drugs, hospitalization and ...

  11. RASOnD - A comprehensive resource and search tool for RAS superfamily oncogenes from various species

    Directory of Open Access Journals (Sweden)

    Singh Tej P

    2011-07-01

    Full Text Available Abstract Background The Ras superfamily plays an important role in the control of cell signalling and division. Mutations in the Ras genes convert them into active oncogenes. The Ras oncogenes form a major thrust of global cancer research as they are involved in the development and progression of tumors. This has resulted in the exponential growth of data on Ras superfamily across different public databases and in literature. However, no dedicated public resource is currently available for data mining and analysis on this family. The present database was developed to facilitate straightforward accession, retrieval and analysis of information available on Ras oncogenes from one particular site. Description We have developed the RAS Oncogene Database (RASOnD as a comprehensive knowledgebase that provides integrated and curated information on a single platform for oncogenes of Ras superfamily. RASOnD encompasses exhaustive genomics and proteomics data existing across diverse publicly accessible databases. This resource presently includes overall 199,046 entries from 101 different species. It provides a search tool to generate information about their nucleotide and amino acid sequences, single nucleotide polymorphisms, chromosome positions, orthologies, motifs, structures, related pathways and associated diseases. We have implemented a number of user-friendly search interfaces and sequence analysis tools. At present the user can (i browse the data (ii search any field through a simple or advance search interface and (iii perform a BLAST search and subsequently CLUSTALW multiple sequence alignment by selecting sequences of Ras oncogenes. The Generic gene browser, GBrowse, JMOL for structural visualization and TREEVIEW for phylograms have been integrated for clear perception of retrieved data. External links to related databases have been included in RASOnD. Conclusions This database is a resource and search tool dedicated to Ras oncogenes. It has

  12. Examining the Likelihood of Experiencing Productivity Loss and Receiving Social Security Disability Income Following the Onset of Chronic Disease.

    Science.gov (United States)

    Besen, Elyssa; Jetha, Arif; Gaines, Brittany

    2018-01-01

    The aim of the study was to examine the likelihood of reporting productivity loss and receiving social security disability (SSD) income following a chronic health condition diagnosis using a longitudinal panel design. Using the Panel Study of Income Dynamics, logistic regression analyses were conducted to estimate the likelihood of reporting productivity loss or receiving SSD following the diagnosis of arthritis, cancer, psychological problems, or heart conditions. Respondents reporting a new diagnosis of a condition were matched with five similarly aged respondents not reporting a diagnosis. For all conditions except cancer, the odds of reporting productivity loss and receiving SSD increased at both the wave where the condition was first reported and 2 years after for respondents reporting a condition compared with those not reporting a condition. The onset of chronic disease increases the likelihood of experiencing productivity loss and receiving SSD.

  13. Chronological changes in baseline disease activity of patients with rheumatoid arthritis who received biologic DMARDs between 2003 and 2012.

    Science.gov (United States)

    Sato, Eri; Tanaka, Eiichi; Ochiai, Moeko; Shimizu, Yoko; Kobayashi, Akiko; Shidara, Kumi; Hoshi, Daisuke; Sugimoto, Naoki; Inoue, Eisuke; Seto, Yohei; Nakajima, Ayako; Taniguchi, Atsuo; Momohara, Shigeki; Yamanaka, Hisashi

    2015-05-01

    The use of biologic disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) has been increasing since 2003. In this study, we evaluated changes in the characteristics of patients receiving biologic DMARDs daily, in Japan. The characteristics of all RA patients who received any biologic DMARD at the Institute of Rheumatology, Tokyo Women's Medical University, within 1 year after its approval in Japan, were retrospectively evaluated. The periods of patient enrollment for each biologic agent were: infliximab (IFX), 2003-2004; etanercept (ETN), 2005-2006; tocilizumab (TCZ), 2008-2009; adalimumab (ADA), 2008-2009; abatacept (ABT), 2010-2011; and golimumab (GLM), 2011-2012. We retrospectively collected individual patient characteristics, concomitant medication usage, and disease activity assessed by disease activity score 28 (DAS28) at the time of administration, from the medical records. The retention rate for each agent at 6 months after treatment initiation was also assessed. The numbers of patients who received each biologic DMARD at our institute within 1 year after its approval were: IFX, 49; ETN, 50; TCZ, 62; ADA, 52; ABT, 40; and GLM, 77. From 2003 to 2012, the proportion of patients with prior use of any biologic DMARD increased, as did concomitant use and dose of methotrexate (MTX); however, corticosteroid use and doses decreased. DAS28, at the time of treatment initiation, gradually decreased. At the time of IFX administration, 75% and 25% of patients had high and moderate disease activity respectively, compared to 25% and 58% respectively, of patients who received GLM. No significant difference was observed in the retention rate of biologic DMARDs at 6 months (range, 75.0% to 89.6%). Baseline disease activity of RA patients who received biologic DMARDs between 2003 and 2012 has changed from high to moderate in daily practice in Japan.

  14. H- ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Iβ pathway activation.

    Science.gov (United States)

    Martín-Sánchez, Paloma; Luengo, Alicia; Griera, Mercedes; Orea, María Jesús; López-Olañeta, Marina; Chiloeches, Antonio; Lara-Pezzi, Enrique; de Frutos, Sergio; Rodríguez-Puyol, Manuel; Calleros, Laura; Rodríguez-Puyol, Diego

    2018-02-01

    Ras proteins regulate cell survival, growth, differentiation, blood pressure, and fibrosis in some organs. We have demonstrated that H- ras gene deletion produces mice hypotension via a soluble guanylate cyclase-protein kinase G (PKG)-dependent mechanism. In this study, we analyzed the consequences of H- ras deletion on cardiac remodeling induced by continuous angiotensin II (AngII) infusion and the molecular mechanisms implied. Left ventricular posterior wall thickness and mass and cardiomyocyte cross-sectional area were similar between AngII-treated H-Ras knockout (H -ras -/- ) and control wild-type (H -ras +/+ ) mice, as were extracellular matrix protein expression. Increased cardiac PKG-Iβ protein expression in H -ras -/- mice suggests the involvement of this protein in heart protection. Ex vivo experiments on cardiac explants could support this mechanism, as PKG blockade blunted protection against AngII-induced cardiac hypertrophy and fibrosis markers in H -ras -/- mice. Genetic modulation studies in cardiomyocytes and cardiac and embryonic fibroblasts revealed that the lack of H-Ras down-regulates the B-RAF/MEK/ERK pathway, which induces the glycogen synthase kinase-3β-dependent activation of the transcription factor, cAMP response element-binding protein, which is responsible for PKG-Iβ overexpression in H -ras -/- mouse embryonic fibroblasts. This study demonstrates that H- ras deletion protects against AngII-induced cardiac remodeling, possibly via a mechanism in which PKG-Iβ overexpression could play a partial role, and points to H-Ras and/or downstream proteins as potential therapeutic targets in cardiovascular disease.-Martín-Sánchez, P., Luengo, A., Griera, M., Orea, M. J., López-Olañeta, M., Chiloeches, A., Lara-Pezzi, E., de Frutos, S., Rodríguez-Puyol, M., Calleros, L., Rodríguez-Puyol, D. H- ras deletion protects against angiotensin II-induced arterial hypertension and cardiac remodeling through protein kinase G-Iβ pathway activation.

  15. Anterior cruciate ligament reconstruction in a patient who has received systemic steroids for autoimmune disease

    Directory of Open Access Journals (Sweden)

    Tetsuro Ushio

    2018-01-01

    Conclusion: The patient who had received systemic steroids for a long time recovered satisfactorily after the operation, with achievement of knee stability and possibility to prevent degenerative change in the knee joint. ACL reconstruction should be considered even in patients with such medication.

  16. Radial artery spasm associated with transradial cardiovascular procedures: results from the RAS registry.

    Science.gov (United States)

    Goldsmit, Alejandro; Kiemeneij, Ferdinand; Gilchrist, Ian C; Kantor, Pablo; Kedev, Sasko; Kwan, Tak; Dharma, Surya; Valdivieso, Leon; Wenstemberg, Bernard; Patel, Tejas

    2014-01-01

    To report the incidence and predictors of moderate/severe radial artery spasm (RAS) in patients undergoing cardiovascular percutaneous procedures through a transradial approach (TRA) in centers with TRA expertise. Data regarding the actual rate of clinically meaningful RAS are limited due to difference in study designs and operator expertise. The RAS registry, an international (14 centers from Argentina, Chile, India, Indonesia, Macedonia, The Netherlands and United States of America) registry that included 1,868 patients undergoing TRA cardiovascular procedures (63.5% diagnostic and 56.5% therapeutic).All selected centers used TRA as default strategy in the cardiac catheterization laboratory. Throughout 2012, each center included all consecutive TRA cases (during a 2-month period) into a dedicated database covering clinical characteristics as well as procedural topics related to TRA patterns and RAS occurrence. The incidence of moderate/severe RAS was 2.7%. Only 0.7% of patients required crossover (8 to transfemoral and 5 to contralateral TRA). Patients with moderately/severe spasm were more frequently females, had a history of dyslipidemia, received more often a 7F sheath and more puncture attempts than patients without spasm. By multivariate analysis, the need for more than one attempt and the use of a 7 F sheath were independent predictors of the development of moderate/severe RAS. The incidence of moderate/severe RAS is low in centers with a default TRA. Its development appears to be strongly related to the numbers of puncture attempts and the use of large sheaths. Copyright © 2013 Wiley Periodicals, Inc.

  17. Calprotectin more accurately discriminates the disease status of rheumatoid arthritis patients receiving tocilizumab than acute phase reactants.

    Science.gov (United States)

    Inciarte-Mundo, José; Ruiz-Esquide, Virginia; Hernández, Maria Victoria; Cañete, Juan D; Cabrera-Villalba, Sonia Raquel; Ramirez, Julio; Yagüe, Jordi; Sanmarti, Raimon

    2015-12-01

    To compare the accuracy of serum calprotectin levels, CRP and ESR in stratifying disease activity in RA patients receiving tocilizumab (TCZ). Cross-sectional study of 33 RA patients receiving TCZ. DAS28, Simplified Disease Activity Index, Clinical Disease Activity Index, joint counts and serum levels of CRP, ESR, calprotectin and TCZ were measured. Associations between calprotectin, ESR and CRP and articular indices were analysed by correlation and linear regression. The accuracy and discriminatory capacity of calprotectin was assessed by receiver operating characteristic curves (area under the curve). Calprotectin levels, but not CRP or ESR, were strongly correlated with all composite indices (all r coefficients over 0.50). Calprotectin, but not CRP or ESR, was significantly lower in patients in remission compared with those with low disease activity [1.57 μg/ml (s.d. 1) vs 3.35 μg/ml (s.d. 1), P = 0.001]. In a fully adjusted model (R(2) = 0.82), DAS28-ESR increased 0.48 units per μg/ml calprotectin increase (P 3.2 as the reference variable, calprotectin showed an area under the curve of 0.922, and the best cut-off was 5.19 μg/ml (odds ratio 11.5). CRP levels, but not calprotectin, were dependent on detectable TCZ trough serum levels. Calprotectin serum levels seem to be an accurate biomarker for assessing disease activity in RA patients receiving TCZ. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Induction of Autoantibodies and Autoimmune Diseases in Patients with Psoriasis Receiving Tumor Necrosis Factor Inhibitors.

    Science.gov (United States)

    Oter-López, B; Llamas-Velasco, M; Sánchez-Pérez, J; Dauden, E

    2017-06-01

    The induction of antinuclear antibodies (ANA) and the onset of autoimmune diseases have been reported after treatment with tumor necrosis factor (TNF) inhibitors, though controversy persists. To determine the frequency of onset of autoimmune diseases and of the appearance of autoantibodies in psoriasis patients administered TNF inhibitors (adalimumab and etanercept) subcutaneously and to correlate this with the effectiveness of treatment, adverse effects, and the order of use of TNF inhibitors. We also tried to identify any factors that might predict the appearance of ANA and autimmune diseases. We performed a retrospective study of a cohort of 121 patients monitored over an 11-year period. ANA were measured at baseline and at 3, 6, and 12 months; positive results were followed up by study of antibodies to double-stranded DNA. Extractable nuclear antigen (ENA) antibodies were also studied at baseline and at 3, 6, and 12 months. Patients with a baseline assay of ANA and ENA at least one more assay during the first year were included in the study, and these antibodies were measured annually thereafter. Psoriasis area severity index was calculated and adverse effects were recorded at each visit. A significant increase in ANA positivity was observed during treatment of moderate-to-severe psoriasis with adalimumab and etanercept, but this was not associated with the onset of autoimmune diseases. No correlation was observed with treatment efficacy, the order of use of TNF inhibitors, or the appearance of adverse effects. No predictive factors for the appearance of ANA were identified, except for the body mass index. We recommend ANA measurement and screening for autoimmune diseases prior to treatment with TNF inhibitors, but not routine serial measurements of ANA during follow-up except in patients with signs or symptoms suggestive of autoimmune disease. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  19. Management of coccidioidomycosis in patients receiving biologic response modifiers or disease-modifying antirheumatic drugs.

    Science.gov (United States)

    Taroumian, Sara; Knowles, Susan L; Lisse, Jeffrey R; Yanes, James; Ampel, Neil M; Vaz, Austin; Galgiani, John N; Hoover, Susan E

    2012-12-01

    Coccidioidomycosis (valley fever) is an endemic fungal infection of the American Southwest, an area with a large population of patients with rheumatic diseases. There are currently no guidelines for management of patients who develop coccidioidomycosis while under treatment with biologic response modifiers (BRMs) or disease-modifying antirheumatic drugs (DMARDs). We conducted a retrospective study of how both concurrent diseases were managed and the patient outcomes at 2 centers in Tucson, Arizona. A retrospective chart review identified patients who developed coccidioidomycosis during treatment with DMARDs or BRMs. Patients were seen at least once in a university-affiliated or Veterans Affairs outpatient rheumatology clinic in Tucson, Arizona, between 2007 and 2009. Forty-four patients were identified. Rheumatologic treatment included a BRM alone (n = 11), a DMARD alone (n = 8), or combination therapy (n = 25). Manifestations of coccidioidomycosis included pulmonary infection (n = 29), disseminated disease (n = 9), and asymptomatic positive coccidioidal serologies (n = 6). After the diagnosis of coccidioidomycosis, 26 patients had BRMs and DMARDs stopped, 8 patients had BRMs stopped but DMARD therapy continued, and 10 patients had no change in their immunosuppressive therapy. Forty-one patients had antifungal therapy initiated for 1 month or longer. Followup data were available for 38 patients. BRM and/or DMARD therapy was continued or resumed in 33 patients, only 16 of whom continued concurrent antifungal therapy. None of the patients have had subsequent dissemination or complications of coccidioidomycosis. Re-treating rheumatic disease patients with a BRM and/or a DMARD after coccidioidomycosis appears to be safe in some patients. We propose a management strategy based on coccidioidomycosis disease activity. Copyright © 2012 by the American College of Rheumatology.

  20. Byzantine seals from the Ras fortress

    Directory of Open Access Journals (Sweden)

    Ivanišević Vujadin

    2013-01-01

    Full Text Available In this paper, seals found at the location of the Ras fortress (Tvrđava Ras have been published. Inscriptions on these seals show that they used to belong to persons which could be identified with certain military commanders who served under Alexios I Komnenos. The seals in question are: the seals of protonobelissimos Eustathios Kamytzes, Constantine Dalassenos Doukas, protoproedros and doux Constantine Kekaumenos and a certain person called Alexios. [Projekat Ministarstva nauke Republike Srbije, br. 177021 i br. 177032

  1. Quantitative Assays for RAS Pathway Proteins and Phosphorylation States

    Science.gov (United States)

    The NCI CPTAC program is applying its expertise in quantitative proteomics to develop assays for RAS pathway proteins. Targets include key phosphopeptides that should increase our understanding of how the RAS pathway is regulated.

  2. Genetic and Molecular Analysis of Suppressors of Ras Mutations

    National Research Council Canada - National Science Library

    Eastburn, Dennis

    2000-01-01

    .... The study of Caenorhabditis elegans and other model systems has demonstrated that Ras is part of a conserved Ras/MAPK signaling pathway involved in many aspects of development and cell regulation. The C...

  3. Status of neutron complex of INR RAS

    International Nuclear Information System (INIS)

    Grachev, M.I.; Koptelov, E.A.; Kravchuk, L.V.; Matveev, V.A.; Perekrestenko, A.D.; Sidorkin, S.F.; Stavissky, Y.Y.

    2001-01-01

    The neutron complex of INR RAS consists of two sources of neutrons, beam stop, lead slowing down spectrometer and solid state spectrometers. The description of objects and their condition, the program of planned researches, co-operation with other institutes of the Moscow Region, progress reached for last two years are introduced in the article. (author)

  4. Is het flevolanderschaap een zeldzaam ras?

    NARCIS (Netherlands)

    Oldenbroek, J.K.

    2012-01-01

    In 2011 heeft een internationale werkgroep bepaald dat een ras inheems is als het 40 jaar en 6 generaties in een land aanwezig is. De vraag is dan hoe je om moet gaan met recent gevormde rassen die bedreigd worden in hun voortbestaan. Die vraag wordt in dit artikel, met als voorbeeld het

  5. Second RAS Symposium Brings Together World’s Leading RAS Scientists | Poster

    Science.gov (United States)

    From December 6–8, the Advanced Technology Research Facility of the Frederick National Laboratory for Cancer Research was abuzz with conversation and collaboration as nearly 450 scientists, academics, and industry partners gathered for the Second RAS Initiative Symposium. Attendees hailed from 14 nations, dozens of institutions, and diverse scientific backgrounds, but they shared a common purpose: to present and discuss their research on RAS genes and cancer.

  6. Effect of low-dose proton pump inhibitor on preventing upper gastrointestinal bleeding in chronic kidney disease patients receiving aspirin.

    Science.gov (United States)

    Lim, Hyun; Kim, Jong Hyeok; Baik, Gwang Ho; Park, Ji Won; Kang, Ho Suk; Moon, Sung Hoon; Park, Choong Kee

    2015-03-01

    Upper gastrointestinal bleeding (UGIB) leads to significant morbidity and mortality in chronic kidney disease (CKD) patients. This study determined the efficacy of using a low-dose proton pump inhibitor (PPI) to reduce the risk of non-variceal UGIB in CKD patients receiving aspirin. We retrospectively reviewed the medical records of 500 CKD patients who received aspirin between January 2008 and March 2013. Cumulative incidence analysis using the Kaplan-Meier method was performed to analyze the rate of non-variceal UGIB and association with the administration of low-dose PPI. Of the 500 patients, 191 received low-dose PPI. Over the follow-up period, which lasted 1067 person-years, three patients in the low-dose PPI group (8.9 per 1000 person-years) and 19 patients in the non-PPI group (25.9 per 1000 person-years) developed non-variceal UGIB, respectively (P = 0.113). Low-dose PPI use did not decrease the risk of UGIB in CKD patients, including patients who did not receive dialysis (P = 0.127). However, according to the subgroup analysis of 230 patients who received dialysis, the low-dose PPI group (14.4 per 1000 person-years) demonstrated significantly reduced incidence and risk of non-variceal UGIB in comparison with the non-PPI group (53.8 per 1000 person-years) (P = 0.032). Prophylactic low-dose PPI can reduce the risk of non-variceal UGIB in dialysis patients receiving aspirin. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  7. YKL-40 in patients with end-stage renal disease receiving haemodialysis

    DEFF Research Database (Denmark)

    Nielsen, Ture Lange; Plesner, Louis Lind; Warming, Peder Emil

    2018-01-01

    PURPOSE: This study aimed to determine serum YKL-40 in patients with end-stage renal disease (ESRD) on haemodialysis (HD) and to evaluate the prognostic value of serum YKL-40. METHODS: Patients >18 years on maintenance HD were included. Serum YKL-40 was measured using ELISA before and after...... a single HD treatment. RESULTS: A total of 306 patients were included. Median serum YKL-40 concentration was 238 µgL-1(IQR: 193-291 µgL-1) before HD treatment and 198 µgL-1(IQR: 147-258 µgL-1) after HD treatment, which corresponded to age-corrected 93th percentile in healthy subjects. All-cause mortality...

  8. Inflammatory bowel disease patient's satisfaction with healthcare services received. Physicians' and nurses' perceptions.

    Science.gov (United States)

    Casellas, Francesc; Vera, Isabel; Ginard, Daniel; Torrejón, Antonio

    2013-08-01

    patient satisfaction with healthcare services provided for inflammatory bowel diseases (IBD) is essential due to high resources use. the study aimed to describe patient satisfaction with healthcare services using the CACHE questionnaire and to assess gastroenterologist and nurse perception on patients' satisfaction. observational multicentric prospective study in 35 Spanish hospitals. Patients included had Crohn's disease or ulcerative colitis. The study was approved by the Hospital Universitari Vall d'Hebron Ethics Committee. Scheduled study visits: baseline (patient sociodemographics and clinical data were collected), 2-4 and 6-months. Patient satisfaction with healthcare was assessed by CACHE questionnaire at each visit; it scores from 0-least satisfaction to 100-highest satisfaction.Gastroenterologists and nurses answered once an adapted questionnaire. participating 290 patients (54.2 % males, 41.3 years old), 62 gastroenterologists and 47 nurses. At baseline mean (SD) CACHE score was 81.7 (10.9); satisfaction with clinician care was the highest, patient information the lowest. Scores did not change across study. Gastroenterologist global score was 72.5 (9.8); Staff Care satisfaction was the highest, patient information the lowest. All scores were significantly lower than patients'. Nurses' global score was 82.2 (8.5), clinician care satisfaction was the highest, centre facilities the lowest. Scores on satisfaction with clinician care, centre facilities, and patient information scored statistically lower than patients'. No relationship was found between patients' satisfaction and patients characteristics. conclusions: IBD patients are satisfied with healthcare services provided, even though the information may be improved. Nurses' perception is similar to that of patients, physicians have a lower perception.

  9. Efficacy and safety of Cinacalcet on secondary hyperparathyroidism in Chinese chronic kidney disease patients receiving hemodialysis.

    Science.gov (United States)

    Mei, Changlin; Chen, Nan; Ding, Xiaoqiang; Yu, Xueqing; Wang, Li; Qian, Jiaqi; Wang, Mei; Jiang, Gengru; Li, Xuemei; Hou, Fanfan; Zuo, Li; Wang, Niansong; Liu, Hong

    2016-10-01

    Introduction Secondary hyperparathyroidism (SHPT) develops in patients with chronic renal failure. Cinacalcet hydrochloride has been used successfully in U.S., Europe, and Japan in the treatment of SHPT, while maintaining serum levels of calcium and phosphorus. The efficacy and safety profile of Cinacalcet treatment vs. conventional treatments has been of great interest in clinical practice. In this recent phase III study conducted in China, efficacy and safety of a calcimimetic agent, Cinacalcet (Kyowa Hakko Kirin Co., Ltd.), were assessed for SHPT treatment in stable chronic renal disease patients on hemodialysis. Methods In this double-blind, multicenter, placebo-controlled, randomized phase III study, 238 subjects were enrolled in 12 centers and randomly divided into a Cinacalcet group and a placebo group. The percentage of patients achieving a serum parathyroid hormone (PTH) level ≤250 pg/mL was the primary efficacy end point. Serum calcium and phosphorus levels were measured. Adverse events and serious adverse events were recorded, and causal analysis performed. Findings In primary analysis, 25.4% of the Cinacalcet group and 3.5% of the placebo group achieved the primary end point (PTH ≤250 pg/mL). Calcium and phosphorus levels and calcium-phosphorus product were lower in the Cinacalcet group compared with the placebo group. Eleven serious adverse events were reported and considered to be not related to study drugs. Mild to moderate hypocalcemia and reduced calcium levels were reported and considered to be Cinacalcet related. Discussion This phase III study demonstrated that Cinacalcet is effective and well tolerated in treating SHPT in Chinese chronic kidney disease patients on hemodialysis, and in a patient population with much higher baseline PTH levels. © 2016 International Society for Hemodialysis.

  10. Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21ras

    NARCIS (Netherlands)

    Medema, R.H.; Vries-Smits, A.M. de; Zon, G.C.M. van der; Maassen, J.A.; Bos, J.L.

    1993-01-01

    A number of growth factors, including insulin and epidermal growth factor (EGF), induce accumulation of the GTP-bound form of p21ras. This accumulation could be caused either by an increase in guanine nucleotide exchange on p21ras or by a decrease in the GTPase activity of p21ras. To investigate

  11. Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening

    NARCIS (Netherlands)

    Verissimo, Carla S; Overmeer, René M; Ponsioen, Bas; Drost, Jarno; Mertens, Sander; Verlaan-Klink, Ingrid; Gerwen, Bastiaan van; van der Ven, Marieke; Wetering, Marc van de; Egan, David A; Bernards, René; Clevers, Hans; Bos, Johannes L; Snippert, Hugo J

    2016-01-01

    Colorectal cancer (CRC) organoids can be derived from almost all CRC patients and therefore capture the genetic diversity of this disease. We assembled a panel of CRC organoids carrying either wild-type or mutant RAS, as well as normal organoids and tumor organoids with a CRISPR-introduced oncogenic

  12. [Systemic and localized infection by Candida species in patients with rheumatic diseases receiving anti-TNF therapy].

    Science.gov (United States)

    Aikawa, Nadia E; Rosa, Daniela T A; Del Negro, Gilda M B; Moraes, Julio C B; Ribeiro, Ana C M; Saad, Carla Gonçalves; Silva, Clovis A; Bonfá, Eloisa

    2015-08-01

    To evaluate the prevalence of systemic and localized infection by Candida species and its possible association with demographic, clinical and laboratory manifestations and therapy in patients with rheumatic diseases taking TNF blockers. Consecutive patients with rheumatic diseases receiving anti-TNF agents were included. The following risk factors up to four weeks prior to the study were analyzed: use of antibiotics, immunosuppressant drugs, hospitalization and invasive procedures. All subjects were evaluated for clinical complaints, specific blood cultures were obtained for fungi and blood samples were collected for Candida spp. detection by polymerase chain reaction. 194 patients [67 with rheumatoid arthritis (RA), 47 with ankylosing spondylitis (AS), 36 with juvenile idiopathic arthritis (JIA), 28 with psoriatic arthritis and 16 with other conditions] were included. The average age of patients was 42±16 years, with 68 (35%) male and mean disease duration of 15±10 years. Sixty-four (33%) patients were receiving adalimumab, 59 (30%) etanercept and 71 (36%) infliximab. Eighty-one percent of patients were concomitantly taking immunosuppressants drugs. At the time of the study, only one (0.5%) patient had localized fungal infection (vaginal candidiasis). None of the patients included had systemic candidiasis with positive blood cultures for fungi or PCR positive for Candida spp. in peripheral blood sample. This was the first study to assess the prevalence of invasive and localized fungal disease by candida in a significant number of patients with rheumatic diseases on anti-TNF therapy, and demonstrated low risk of candidiasis, despite the high prevalence of immunosuppressive drug use. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

  13. Systemic and localized infection by Candida species in patients with rheumatic diseases receiving anti-TNF therapy

    Directory of Open Access Journals (Sweden)

    Nadia E. Aikawa

    Full Text Available ABSTRACT Objective: To evaluate the prevalence of systemic and localized infection by Candida species and its possible association with demographic, clinical and laboratory manifestations and therapy in patients with rheumatic diseases taking TNF blockers. Methods: Consecutive patients with rheumatic diseases receiving anti-TNF agents were included. The following risk factors up to four weeks prior to the study were analyzed: use of antibiotics, immunosuppressant drugs, hospitalization and invasive procedures. All subjects were evaluated for clinical complaints; specific blood cultures were obtained for fungi and blood samples were collected for Candida spp. detection by polymerase chain reaction. Results: 194 patients [67 with rheumatoid arthritis (RA, 47 with ankylosing spondylitis (AS, 36 with juvenile idiopathic arthritis (JIA, 28 with psoriatic arthritis and 16 with other conditions] were included. The average age of patients was 42 ± 16 years, with 68 (35% male and mean disease duration of 15 ± 10 years. Sixty-four (33% patients were receiving adalimumab, 59 (30% etanercept and 71 (36% infliximab. Eighty-one percent of patients were concomitantly taking immunosuppressant drugs. At the time of the study, only one (0.5% patient had localized fungal infection (vaginal candidiasis. None of the patients included had systemic candidiasis with positive blood cultures for fungi or PCR positive for Candida spp. in peripheral blood sample. Conclusions: This was the first study to assess the prevalence of invasive and localized fungal disease by Candida in a significant number of patients with rheumatic diseases on anti-TNF therapy, and demonstrated low risk of candidiasis, despite the high prevalence of immunosuppressive drug use.

  14. Systemic and localized infection by Candida species in patients with rheumatic diseases receiving anti-TNF therapy.

    Science.gov (United States)

    Aikawa, Nadia E; Rosa, Daniela T A; Del Negro, Gilda M B; Moraes, Julio C B; Ribeiro, Ana C M; Saad, Carla Gonçalves; Silva, Clovis A; Bonfá, Eloisa

    To evaluate the prevalence of systemic and localized infection by Candida species and its possible association with demographic, clinical and laboratory manifestations and therapy in patients with rheumatic diseases taking TNF blockers. Consecutive patients with rheumatic diseases receiving anti-TNF agents were included. The following risk factors up to four weeks prior to the study were analyzed: use of antibiotics, immunosuppressant drugs, hospitalization and invasive procedures. All subjects were evaluated for clinical complaints; specific blood cultures were obtained for fungi and blood samples were collected for Candida spp. detection by polymerase chain reaction. 194 patients [67 with rheumatoid arthritis (RA), 47 with ankylosing spondylitis (AS), 36 with juvenile idiopathic arthritis (JIA), 28 with psoriatic arthritis and 16 with other conditions] were included. The average age of patients was 42±16 years, with 68 (35%) male and mean disease duration of 15±10 years. Sixty-four (33%) patients were receiving adalimumab, 59 (30%) etanercept and 71 (36%) infliximab. Eighty-one percent of patients were concomitantly taking immunosuppressant drugs. At the time of the study, only one (0.5%) patient had localized fungal infection (vaginal candidiasis). None of the patients included had systemic candidiasis with positive blood cultures for fungi or PCR positive for Candida spp. in peripheral blood sample. This was the first study to assess the prevalence of invasive and localized fungal disease by Candida in a significant number of patients with rheumatic diseases on anti-TNF therapy, and demonstrated low risk of candidiasis, despite the high prevalence of immunosuppressive drug use. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

  15. YKL-40 in patients with end-stage renal disease receiving haemodialysis.

    Science.gov (United States)

    Nielsen, Ture Lange; Plesner, Louis Lind; Warming, Peder Emil; Pallisgaard, Jannik Langtved; Dalsgaard, Morten; Schou, Morten; Høst, Ulla; Rydahl, Casper; Brandi, Lisbet; Køber, Lars; Johansen, Julia Sidenius; Kastrup, Jens; Iversen, Kasper Karmark

    2018-03-08

    This study aimed to determine serum YKL-40 in patients with end-stage renal disease (ESRD) on haemodialysis (HD) and to evaluate the prognostic value of serum YKL-40. Patients >18 years on maintenance HD were included. Serum YKL-40 was measured using ELISA before and after a single HD treatment. A total of 306 patients were included. Median serum YKL-40 concentration was 238 µgL -1 (IQR: 193-291 µgL -1 ) before HD treatment and 198 µgL -1 (IQR: 147-258 µgL -1 ) after HD treatment, which corresponded to age-corrected 93th percentile in healthy subjects. All-cause mortality after 2.8 years was 35.9%. Patients with serum YKL-40 in the highest quartile compared with the lowest quartile had a univariate HR of 4.0 (95% CI: 2.2-7.3, p 40 after HD treatment had significant higher area under the curves from 90 d (p = 0.004) and throughout the rest of the follow-up period when compared to serum YKL-40 before HD treatment. YKL-40 was highly elevated in patients with ESRD on HD, and dialysis reduced serum YKL-40 concentrations approximately one-sixth. YKL-40 measured after dialysis was independently associated with mortality in HD patients.

  16. Role of depression in secondary prevention of Chinese coronary heart disease patients receiving percutaneous coronary intervention.

    Directory of Open Access Journals (Sweden)

    Can Feng

    Full Text Available Coronary heart disease (CHD patients who have undergone percutaneous coronary intervention (PCI have higher rates of depression than the general population. However, few researchers have assessed the impact of depression on the secondary prevention of CHD in China.The main purpose of this investigation was to explore the relationship between depression and secondary prevention of CHD in Chinese patients after PCI.This descriptive, cross-sectional one-site study recruited both elective and emergency PCI patients one year after discharge. Data from 1934 patients were collected in the clinic using questionnaires and medical history records between August 2013 and September 2015. Depression was evaluated by the 9-item Patient Health Questionnaire. Secondary prevention of CHD was compared between depression and non-depression groups.We found that depression affected secondary prevention of CHD in the following aspects: lipid levels, blood glucose levels, smoking status, physical activity, BMI, and rates of medication use.Depressive patients with CHD are at increased risk of not achieving the lifestyle and risk factor control goals recommended in the 2006 AHA guidelines. Screening should focus on patients after PCI because treating depression can improve outcomes by improving secondary prevention of CHD.

  17. Skin tumorigenesis and Ki-ras and Ha-ras mutations in tumors from adult mice exposed in utero to 3'-azido-2',3'-dideoxythymidine.

    Science.gov (United States)

    Zhang, Z; Diwan, B A; Anderson, L M; Logsdon, D; Olivero, O A; Haines, D C; Rice, J M; Yuspa, S H; Poirier, M C

    1998-09-01

    This study was designed to evaluate the potential initiating effects of transplacental 3'-azido-2',3'-dideoxythymine (AZT) and the role of ras mutational activation in skin tumors induced in a two-stage mouse skin model. In addition, mouse liver and lung tumors from a transplacental AZT tumorigenicity study reported elsewhere (Olivero et al., J Natl Cancer Inst 89:1602-1608, 1997) were examined for evidence of ras activation. For both tumor studies, pregnant CD-1 mice were given either vehicle or 25 mg of AZT daily on days 12-18 of gestation. In the 1997 study, the offspring were given no further exposure and were killed at 1 yr of age. For the skin tumor study, all mice received twice-weekly topical 12-O-tetradecanoyl-phorbol-13-acetate (TPA) treatment from weeks 5-35; half of the mice had been exposed to AZT in utero. At weeks 16-18, 30, 31, and 34-41, the skin tumor incidences in mice given AZT and TPA were significantly higher than in mice given TPA alone (P A transition in the second base, and the major mutation in codon 13 (six in seven tumors examined) was a G-->T transversion in the second base. In skin tumors, AZT exposure did not increase the number of Ha-ras codon 61 mutations, and no Ki-ras mutations were observed. Analysis of ras mutations in liver and lung tumors from mice exposed to AZT in utero (Olivero et al., J Natl Cancer Inst 89:16021608, 1997) with no TPA promotion showed no significant AZT-related increases.

  18. Dynamics of Ras Complexes Observed in Living Cells

    Directory of Open Access Journals (Sweden)

    Xiangyong Li

    2012-07-01

    Full Text Available K-Ras works as a switch in many important intracellular signaling pathways and plays important roles in cell growth, proliferation, differentiation and carcinogenesis. For signal transduction from K-Ras to Raf1, the best-characterized effector of K-Ras, the general view is that Ras recruits Raf1 from the cytoplasm to the cell membrane. To elucidate this process, we constructed a series of fusion proteins (including Raf1 and K-Ras fused with either fluorescent proteins or fluorescent protein fragments to compare subcellular localizations of these proteins. Bimolecular fluorescence complementation (BiFC and a co-transfection system were used. In the BiFC system, the K-Ras/Raf1 complexes were mainly located in the cell membrane, while the Raf1 control was uniformly distributed in the cytoplasm. However, the complexes of Raf1 and K-RasC185S, a K-Ras mutant which loses membrane-localization, were also able to accumulate in the cell membrane. In contrast, an apparent cytosolic distribution pattern was observed in cells co-transfected with mcerulean-Raf1 and EGFP-K-RasC185S, suggesting that the membrane localization of K-Ras/Raf1 complexes is not entirely dependent on K-Ras, and that other factors, such as the irreversible conformation formed between K-Ras and Raf1 may play a role. This study sheds light on the interaction between K-Ras and Raf1 and provides a practical method to elucidate the mechanism underlying K-Ras and Raf1 binding to the cell membrane.

  19. Detection of K-ras gene mutations in feces by magnetic nanoprobe in patients with pancreatic cancer: A preliminary study.

    Science.gov (United States)

    Wang, Xiaoguang; Wang, Jingshuai; Chen, Fei; Zhong, Zhengxiang; Qi, Lifeng

    2018-01-01

    The present study aimed to investigate the feasibility and effectiveness of detecting K-ras mutation by using magnetic nanoparticles in fecal samples of patients with pancreatic cancer at different stages. The novel methodology of K-ras mutation detection was compared to the existing methodology of cancer antigen (CA)19-9 examination. Patients with pancreatic cancer (n=88), pancreatic benign diseases who displayed chronic pancreatitis (n=35), pancreatic mucinous cyst neoplasms (n=10) and pancreatic serous cyst (n=9) admitted to the Department of Surgery, Jiaxing Second Hospital were enrolled in the present study. Fecal samples were collected from all patients, DNA was extracted and magnetic nanoprobe was then used to detect K-ras mutation. The results obtained using the novel magnetic nanoprobe detection technique showed a K-ras mutation rate of 81.8% (72/88) in the patients with pancreatic cancer and 18.5% (10/54) in patients with pancreatic benign diseases. In patients with pancreatic cancer, the K-ras mutation rate was comparable in stages I + IIA and IIB + III + IV (78.9 vs. 84.0%; P>0.05). The sensitivity and specificity of K-ras mutation for detection of pancreatic cancer was 81.8 and 81.5%, respectively. Sixty-eight pancreatic cancer patients had >37 U/ml CA99 with a sensitivity and specificity for pancreatic cancer detection of 77.3 and 77.8%, which was not significantly lower than detection by the fecal K-ras mutations (P>0.05). Combinational detection of fecal K-ras mutations and serum CA19-9 significantly increased the sensitivity regarding pancreatic cancer detection to 97.7% (P0.05) compared with fecal K-ras mutations or CA19-9 alone. The findings showed that the magnetic nanoprobe is able to detect fecal K-ras mutations in different stages of pancreatic cancer, with comparable sensitivity and specificity to CA19-9 examination for differentiating pancreatic cancer. Furthermore, combined detection of CA19-9 and K-ras mutations has enhanced sensitivity

  20. Efficacy of low molecular weight heparin in patients with acute exacerbation of chronic obstructive pulmonary disease receiving ventilatory support.

    Science.gov (United States)

    Qian, Yongbing; Xie, Hui; Tian, Rui; Yu, Kanglong; Wang, Ruilan

    2014-04-01

    Severe and acute exacerbation of chronic obstructive pulmonary disease (COPD) is associated with a high mortality. Since COPD is an airway inflammatory disease, and heparin has shown anti-inflammatory effects in previous studies, we evaluated the clinical effect of low molecular weight heparin (LMWH; nadroparin) in COPD patients admitted into the hospital due to acute exacerbations. Sixty-six patients admitted to the intensive care unit (ICU) were randomly divided into control group (n = 33) and LMWH group (n = 33). The control group received conventional treatment, including oxygen therapy (non-invasive or conventional mechanical ventilation), anti-infection, atomization expectorant, spasmolysis, anti-asthmatics, and nutritional support. The LMWH group received the same treatment plus LMWH for 1 week. The levels of plasma C-reactive protein, interleukin-6, and fibrinogen were measured. The main outcomes were duration of mechanical ventilation, length of ICU stay, and hospital stay. There were no significant differences between the groups with respect to demographics, severity of illness, and gas exchange variables. The levels of plasma C-reactive protein, interleukin-6, and fibrinogen were significantly decreased in the LMWH group. LMWH significantly reduced the mean duration of mechanical ventilation (6.6 days vs. 3.8 days; p benefits COPD patients with acute exacerbation.

  1. Nuclear Ras2-GTP controls invasive growth in Saccharomyces cerevisiae.

    Science.gov (United States)

    Broggi, Serena; Martegani, Enzo; Colombo, Sonia

    2013-01-01

    Using an eGFP-RBD3 probe, which specifically binds Ras-GTP, we recently showed that the fluorescent probe was localized to the plasma membrane and to the nucleus in wild type cells growing exponentially on glucose medium, indicating the presence of active Ras in these cellular compartments. To investigate the nuclear function of Ras-GTP, we generated a strain where Ras2 is fused to the nuclear export signal (NES) from the HIV virus, in order to exclude this protein from the nucleus. Our results show that nuclear active Ras2 is required for invasive growth development in haploid yeast, while the expression of the NES-Ras2 protein does not cause growth defects either on fermentable or non-fermentable carbon sources and does not influence protein kinase A (PKA) activity related phenotypes analysed. Moreover, we show that the cAMP/PKA pathway controls invasive growth influencing the localization of active Ras. In particular, we show that PKA activity plays a role in the localization of active Ras and influences the ability of the cells to invade the agar: high PKA activity leads to a predominant nuclear accumulation of active Ras and induces invasive growth, while low PKA activity leads to plasma membrane localization of active Ras and to a defective invasive growth phenotype.

  2. Sinusoidal obstruction syndrome (veno-occlusive disease in a patient receiving bevacizumab for metastatic colorectal cancer: a case report

    Directory of Open Access Journals (Sweden)

    Agarwal Vijay

    2008-07-01

    Full Text Available Abstract Introduction We present the case of a patient with colon cancer who, while receiving bevacizumab, developed sinusoidal obstruction syndrome (veno-occlusive disease (SOSVOD. Certain antitumour agents such as 6-mercaptopurine and 6-thioguanine have also been reported to initiate hepatic SOSVOD in isolated cases. There have been no reports so far correlating bevacizumab with SOSVOD. Case presentation A 77-year-old man was being treated with oxaliplatin and a modified de Gramont regimen of 5-fluorouracil for metastatic colon cancer. Bevacizumab (7.5 mg/kg was added from the seventh cycle onwards. Protracted neutropenia and thrombocytopenia led to discontinuation of oxaliplatin after the ninth cycle. A computed tomography scan showed complete response and bevacizumab was continued for another 3 months, after which time the patient developed right hypochondrial pain, transudative ascites, splenomegaly and abnormal liver function tests. Upper gastrointestinal endoscopy showed oesophageal varices. Liver biopsy showed features considered to be consistent with SOSVOD. Bevacizumab was stopped and a policy of watchful waiting was adopted. He tolerated the acute damage to his liver and subsequently the ascites resolved and liver function tests normalised. Conclusion We need to be aware that bevacizumab can cause sinusoidal obstruction syndrome (veno-occlusive disease and that the occurrence of ascites should not be attributed to progressive disease without appropriate evaluation.

  3. Studying the Immunomodulatory Effects of Small Molecule Ras-Inhibitors in Animal Models of Rheumatoid Arthritis

    Science.gov (United States)

    2017-10-01

    pre-clinical animal models of autoimmune. For example, FTS can attenuate disease manifestations in experimental autoimmune encephalo- myelitis (34...the clinical score of the disease; however, the biology behind the effect of FTS was not comprehensively elucidated. AIA is an experimental animal ...AWARD NUMBER: W81XWH-14-1-0609 TITLE: Studying the Immunomodulatory Effects of Small Molecule Ras-Inhibitors in Animal Models of Rheumatoid

  4. An exploration of the relationship between fatigue and physical functioning in patients with end stage renal disease receiving haemodialysis.

    Science.gov (United States)

    O'Sullivan, Dawn; McCarthy, Geraldine

    2007-11-01

    To measure fatigue and physical functioning in patients with end stage renal disease (ESRD) receiving haemodialysis and to investigate the relationships between fatigue and physical functioning. Fatigue and reduced physical functioning are among the most bothersome symptoms experienced by individuals receiving haemodialysis for ESRD. Research has shown that increasing activity levels has resulted in decreased fatigue levels and improved physical functioning in individuals with cancer. Establishing whether or not a relationship exists between both concepts in haemodialysis patients is a preliminary step in identifying potential fatigue reducing strategies necessary for improved wellbeing. A quantitative exploratory correlational design was used with 46 individuals completing the Multi-dimensional Fatigue Inventory, the Medical Outcomes Study Short-Form 36-item questionnaire and a Demographic Questionnaire. Results indicated fatigue was prevalent with highest scores achieved for physical fatigue; reduced activity and general fatigue. Substantial limitations in physical functioning were found. A significant moderate negative relationship between general fatigue and physical functioning indicated that, as physical functioning levels increased, fatigue levels decreased. A significant difference was also found between general fatigue scores for males and females. Significant relationships were found between overall physical functioning, older age and employment status. The research indicates the prevalence of fatigue and limitations in physical functioning in individuals with ESRD. However, as physical functioning increased fatigue decreased; a finding relevant to clinical nursing. Understanding the levels of fatigue and the value of exercise is of relevance to clinical practice thus assessment of fatigue and physical functioning ability in the clinical setting is necessary.

  5. A meta-analysis of mortality in end-stage renal disease patients receiving implantable cardioverter defibrillators (ICDs.

    Directory of Open Access Journals (Sweden)

    Tien-Hsing Chen

    Full Text Available Data on the effectiveness of implantable implantable cardioverter defibrillators (ICDs with respect to reducing mortality in patients with chronic kidney disease (CKD and end-stage renal disease (ESRD are lacking. The purpose of this meta-analysis was to compare the mortality of patients with ESRD who have received and not received an ICD. A search was conducted on January 31, 2013 of Medline, Cochrane, EMBASE, and Google Scholar. Studies were selected for inclusion based on the following criteria. 1 Randomized controlled trial. 2 ESRD patients with heart failure. 3 Device therapy (ICD, CRT-defibrillator [CRT-D] used to treat heart failure. 4 Primary outcome is survival analysis. 5 Retrospective study if survival analysis was performed. The primary outcome was overall survival (OS, and the secondary outcome was 2-year survival. Odds ratios (ORs with 95% confidence intervals (CI were calculated, and a χ2-based test of homogeneity was performed. Three studies were included in the analysis. The combined OR for OS was 2.245 (95% CI 1.871 to 2.685, P<0.001, indicating that patients with an ICD had a significantly higher OS than those without an ICD. The combined OR for 2-year survival was 2.312 (95% CI 1.921 to 2.784, P<0.001, indicating that patients with an ICD had a significantly higher 2-year survival rate than those without an ICD. The use of ICD in patients with ESRD is associated with an increase in the OS and the 2-year survival rate.

  6. Quality of life in patients receiving telemedicine enhanced chronic heart failure disease management: A meta-analysis.

    Science.gov (United States)

    Knox, Liam; Rahman, Rachel J; Beedie, Chris

    2017-08-01

    Background Previous reviews have investigated the effectiveness of telemedicine in the treatment of heart failure (HF). Dependent variables have included hospitalisations, mortality rates, disease knowledge and health costs. Few reviews, however, have examined the variable of health-related quality of life (QoL). Methods Randomised controlled trials comparing the delivery methods of any form of telemedicine with usual care for the provision of HF disease-management were identified via searches of all relevant databases and reference lists. Studies had to report a quantitative measure for mental, physical or overall QoL in order to be included. Results A total of 33 studies were identified. However, poor reporting of data resulted in the exclusion of seven, leaving 26 studies with 7066 participants. Three separate, random effects meta-analyses were conducted for mental, physical and overall QoL. Telemedicine was not significantly more effective than usual care on mental and physical QoL (standardised mean difference (SMD) 0.03, (95% confidence interval (CI) -0.05-0.12), p = 0.45 and SMD 0.24, (95% CI -0.08-0.56), p = 0.14, respectively). However, when compared to usual care, telemedicine was associated with a small significant increase in overall QoL (SMD 0.23, (95% CI 0.09-0.37), p = 0.001). Moderator analyses indicated that telemedicine delivered over a long-duration (≥52 weeks) and via telemonitoring was most beneficial. Conclusion Compared to usual care, telemedicine significantly increases overall QoL in patients receiving HF disease management. Statistically non-significant but nonetheless positive trends were also observed for physical QoL. These findings provide preliminary support for the use of telemedicine in the management of heart failure without jeopardising patient well-being.

  7. RAS III - concept and operating experience

    International Nuclear Information System (INIS)

    Kunze, U.; Wander, J.

    1990-01-01

    A new noise analysis system RAS III is being employed at the Greifswald NPP 'Bruno Leuschner' units 5 and 6 which differs from its forerunner types by an extended number of measuring points and a higher degree of automation. Substantial prerequisite of the system's full efficiency is implementation of efficient signal monitoring techniques that free the power plant engineer from routine work as well. The system has therefore been completed by algorithms established for automatic noise signal spectra control and for monitoring the pressure vessel vibrations. Moreover, a number of special techniques have been developed, such as for recording velocity-time plots during control element drop experiments. (author)

  8. Nitrification in moving bed and fixed bed biofilters treating effluent water from a large commercial outdoor rainbow trout RAS

    DEFF Research Database (Denmark)

    Suhr, Karin; Pedersen, Per Bovbjerg

    2010-01-01

    The nitrification performance of two fixed bed (FB) biofilters and two moving bed (MB) biofilters was evaluated. They received the same cold (8 degrees C) influent water from a commercial outdoor RAS facility producing rainbow trout (average density 32 kg m(-3)). The filters were constructed as f...

  9. Ras-dva1 small GTPase regulates telencephalon development in Xenopus laevis embryos by controlling Fgf8 and Agr signaling at the anterior border of the neural plate

    Directory of Open Access Journals (Sweden)

    Maria B. Tereshina

    2014-07-01

    Full Text Available We previously found that the small GTPase Ras-dva1 is essential for the telencephalic development in Xenopus laevis because Ras-dva1 controls the Fgf8-mediated induction of FoxG1 expression, a key telencephalic regulator. In this report, we show, however, that Ras-dva1 and FoxG1 are expressed in different groups of cells; whereas Ras-dva1 is expressed in the outer layer of the anterior neural fold, FoxG1 and Fgf8 are activated in the inner layer from which the telencephalon is derived. We resolve this paradox by demonstrating that Ras-dva1 is involved in the transduction of Fgf8 signal received by cells in the outer layer, which in turn send a feedback signal that stimulates FoxG1 expression in the inner layer. We show that this feedback signal is transmitted by secreted Agr proteins, the expression of which is activated in the outer layer by mediation of Ras-dva1 and the homeodomain transcription factor Otx2. In turn, Agrs are essential for maintaining Fgf8 and FoxG1 expression in cells at the anterior neural plate border. Our finding reveals a novel feedback loop mechanism based on the exchange of Fgf8 and Agr signaling between neural and non-neural compartments at the anterior margin of the neural plate and demonstrates a key role of Ras-dva1 in this mechanism.

  10. Ras and Rheb Signaling in Survival and Cell Death

    Energy Technology Data Exchange (ETDEWEB)

    Ehrkamp, Anja [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany); Herrmann, Christian [Department of Physical Chemistry1, Protein Interaction, Ruhr University of Bochum, 44780 Bochum (Germany); Stoll, Raphael [Biomolecular NMR, Ruhr University of Bochum, 44780 Bochum (Germany); Heumann, Rolf, E-mail: rolf.heumann@rub.de [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany)

    2013-05-28

    One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively.

  11. Ras and Rheb Signaling in Survival and Cell Death

    International Nuclear Information System (INIS)

    Ehrkamp, Anja; Herrmann, Christian; Stoll, Raphael; Heumann, Rolf

    2013-01-01

    One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively

  12. Books Received

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education. Books Received. Articles in Resonance – Journal of Science Education. Volume 1 Issue 1 January 1996 pp 118-118 Books Received. Books Received · More Details Fulltext PDF. Volume 1 Issue 2 February 1996 pp 120-120 Books Received. Books Received.

  13. Risk of Subsequent Infection Among Patients Receiving Tumor Necrosis Factor Inhibitors and Other Disease-Modifying Antirheumatic Drugs.

    Science.gov (United States)

    Accortt, Neil A; Bonafede, Machaon M; Collier, David H; Iles, Jan; Curtis, Jeffrey R

    2016-01-01

    To describe the incidence of subsequent serious infections in patients who received systemic drug therapy after an initial serious infection. Patients with rheumatic conditions (rheumatoid arthritis [RA], psoriatic arthritis, ankylosing spondylitis) or psoriasis who experienced a serious infection between January 1, 2006 and December 31, 2011 were identified in a claims database. Patients were required to be continuously enrolled in the Truven Health Analytics MarketScan Research Database for 12 months prior to and at least 60 days after the date of discharge or the end of intravenous antibiotic therapy for the index serious infection. Subsequent serious infection incidence rates per 100 patient-years with 95% confidence intervals (95% CIs) were calculated for up to 18 months post-index, starting 60 days post-index. Cox proportional hazards models were used to adjust for baseline demographic and clinical characteristics, treatment duration, and changes during followup. Among the 21,699 patients who met the inclusion criteria, the majority (84.3%) had RA. Patients who received tumor necrosis factor (TNF) inhibitor therapy after their index infection had a lower rate of subsequent serious infections (18.1 per 100 patient-years for those treated with a TNF inhibitor alone and 17.3 per 100 patient-years for those treated with a TNF inhibitor plus a nonbiologic disease-modifying antirheumatic drug [DMARD]) compared with those treated with a nonbiologic DMARD alone (21.4 per 100 patient-years). Etanercept, either alone (adjusted hazard ratio [HR] 0.87, 95% CI 0.77-0.99) or in combination with a nonbiologic DMARD (adjusted HR 0.76, 95% CI 0.66-0.88), and infliximab (only in combination with a nonbiologic DMARD) (adjusted HR 0.80, 95% CI 0.67-0.95) were associated with a significantly lower risk of subsequent serious infections compared with a nonbiologic DMARD alone. We did not observe an increased risk of subsequent infection in patients who received TNF inhibitor

  14. Receiver Operating Characteristic Curve-Based Prediction Model for Periodontal Disease Updated With the Calibrated Community Periodontal Index.

    Science.gov (United States)

    Su, Chiu-Wen; Yen, Amy Ming-Fang; Lai, Hongmin; Chen, Hsiu-Hsi; Chen, Sam Li-Sheng

    2017-12-01

    The accuracy of a prediction model for periodontal disease using the community periodontal index (CPI) has been undertaken by using an area under a receiver operating characteristics (AUROC) curve. How the uncalibrated CPI, as measured by general dentists trained by periodontists in a large epidemiologic study, and affects the performance in a prediction model, has not been researched yet. A two-stage design was conducted by first proposing a validation study to calibrate CPI between a senior periodontal specialist and trained general dentists who measured CPIs in the main study of a nationwide survey. A Bayesian hierarchical logistic regression model was applied to estimate the non-updated and updated clinical weights used for building up risk scores. How the calibrated CPI affected performance of the updated prediction model was quantified by comparing AUROC curves between the original and updated models. Estimates regarding calibration of CPI obtained from the validation study were 66% and 85% for sensitivity and specificity, respectively. After updating, clinical weights of each predictor were inflated, and the risk score for the highest risk category was elevated from 434 to 630. Such an update improved the AUROC performance of the two corresponding prediction models from 62.6% (95% confidence interval [CI]: 61.7% to 63.6%) for the non-updated model to 68.9% (95% CI: 68.0% to 69.6%) for the updated one, reaching a statistically significant difference (P prediction model was demonstrated for periodontal disease as measured by the calibrated CPI derived from a large epidemiologic survey.

  15. Exacerbations in patients with chronic obstructive pulmonary disease receiving physical therapy: a cohort-nested randomised controlled trial

    Science.gov (United States)

    2014-01-01

    Background Physical exercise training aims at reducing disease-specific impairments and improving quality of life in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations in particular negatively impact COPD progression. Physical therapy intervention seems indicated to influence exacerbations and their consequences. However, information on the effect of physical therapy on exacerbation occurrence is scarce. This study aims to investigate the potential of a protocol-directed physical therapy programme as a means to prevent or postpone exacerbations, to shorten the duration or to decrease the severity of exacerbations in patients with COPD who have recently experienced an exacerbation. Besides, this study focuses on the effect of protocol-directed physical therapy on health status and quality of life and on cost-effectiveness and cost-utility in patients with COPD who have recently experienced an exacerbation. Methods/Design A prospective cohort of 300 COPD patients in all GOLD stages will be constructed. Patients will receive usual multidisciplinary COPD care including guideline-directed physical therapy. Patients in this cohort who have GOLD stage 2 to 4 (post-bronchodilator FEV1/FVC exercise training (ST). An economic evaluation will be embedded in the RCT. Anthropometric measurements, comorbidities, smoking, functional exercise capacity, peripheral muscle strength, physical activity level, health related quality of life, patients’ perceived benefit, physical therapy compliance, motivation level, level of effective mucus clearance, exacerbation symptoms and health care contacts due to COPD will be recorded. Follow-up measurements are scheduled at 3 and 6 weeks, 3, 6, 12 and 24 months after inclusion. Discussion Ways to minimise potential problems regarding the execution of this study will be discussed. Trial registration The Netherlands National Trial Register NTR1972. PMID:24767519

  16. Effects of Gingko biloba supplementation in Alzheimer's disease patients receiving cholinesterase inhibitors: data from the ICTUS study.

    Science.gov (United States)

    Canevelli, Marco; Adali, Nawal; Kelaiditi, Eirini; Cantet, Christelle; Ousset, Pierre-Jean; Cesari, Matteo

    2014-05-15

    Ginkgo biloba (Gb) is currently the most investigated and adopted herbal remedy for cognitive disorders and Alzheimer's disease (AD). Nevertheless, its efficacy in the prevention and treatment of dementia still remains controversial. Specifically, the added effects of Gb in subjects already receiving "conventional" anti-dementia treatments have been to date very scarcely investigated. We evaluated whether the use of Gb is associated with additional cognitive and functional benefit in AD patients already in treatment with cholinesterase inhibitors (ChEIs). Data are from mild to moderate AD patients under ChEI treatment recruited in the Impact of Cholinergic Treatment USe (ICTUS) study. Mixed model analyses were performed to measure six-monthly modifications in the Mini Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score, and the Activities of Daily Living (ADL) scale over a follow-up of 1 year according to the additional Gb supplementation. A total of 828 subjects were considered for the present analyses. Significantly different modifications at the MMSE score over the 12-month follow-up were reported between patients on combined therapy compared to those only taking ChEIs. On the contrary, the modification of the ADAS-Cog score between the two groups did not show statistically significant differences, although similar trends were noticed. No significant modifications of the two adopted outcome measures were observed at the mid-term 6-month evaluation. The modifications over time of the ADL score did not show statistically significant differences between the two groups of interest. Our findings suggest that Gb may provide some added cognitive benefits in AD patients already under ChEIs treatment. The clinical meaningfulness of such effects remains to be confirmed and clarified. Copyright © 2014 Elsevier GmbH. All rights reserved.

  17. Pregnancy and associated events in women receiving enzyme replacement therapy for late-onset glycogen storage disease type II (Pompe disease).

    Science.gov (United States)

    Rohman, Philippa J; Scott, Elaine; Richfield, Linda; Ramaswami, Uma; Hughes, Derralynn A

    2016-10-01

    Glycogen storage disease type II (GSD II or Pompe disease; OMIM; 232 300) is a rare autosomal recessive lysosomal storage disorder resulting from deficiency of α-glucosidase and accumulation of glycogen in muscle. Clinical symptoms include weakness of skeletal and respiratory muscles and, in infants, cardiomyopathy. Patients with GSD II receive infusions of recombinant α-glucosidase (enzyme replacement therapy; ERT), which slow the progression of the disease. ERT is given to male and female patients of all ages but as yet little is documented on the effects of continuing ERT during pregnancy. The aim of this case series was therefore to ascertain the pregnancy outcomes of women with GSD II on ERT and to describe adverse events associated with pregnancy, delivery and therapy. The medical records of eight women attending the Royal Free Hospital Lysosomal Storage Disorders Unit were reviewed. Four of the eight women had seven pregnancies over a period of 8 years. In this series GSD II was associated with interventional deliveries but normal neonates. Cessation of ERT in early pregnancy resulted in deterioration of maternal symptoms and emergence of allergic reactions on restarting ERT. Individualized care plans are required to ensure the best neonatal and maternal outcomes. Consideration should be given to the potential benefits to mother and fetus of continuing ERT during pregnancy. © 2016 Japan Society of Obstetrics and Gynecology.

  18. Overexploitation and cumulative drought trend effect on Ras El Ain ...

    Indian Academy of Sciences (India)

    Boulos Abou Zakhem

    2017-10-06

    Oct 6, 2017 ... The effects of climate change and overexploitation are being strongly perceived in the studied area and the springs discharge is obviously affected. In this paper, Ras El Ain spring discharge and precipitation were analyzed by normalized methods on an yearly timescale. The deficit of Ras El Ain spring ...

  19. Associations between primary tumor RAS, BRAF and PIK3CA mutation status and metastatic site in patients with chemo-resistant metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Christensen, Troels Dreier; Palshof, Jesper Andreas; Larsen, Finn Ole

    2018-01-01

    , after fluoropyrimidine, oxaliplatin and irinotecan treatment failure. The database contained information regarding tumor mutation status of KRAS, NRAS, BRAF and PIK3CA genes. RESULTS: Totally, 448 patients were included. On multivariate analyses, RAS mutations were significantly associated...... investigated the association between RAS (KRAS or NRAS), BRAF, PIK3CA mutations and metastatic pattern in patients with metastatic (m) CRC. MATERIAL AND METHODS: This study reviewed Danish biobank and database of patients with mCRC who received cetuximab and irinotecan, independent of RAS mutation status...... = 1.86-25.02) and PIK3CA mutations with decreased hazard of peritoneal metastases (HR = 0.31; 95%CI = 0.11-0.86). CONCLUSIONS: This study indicated that in patients with mCRC, RAS mutations are associated with increased risk of lung and ovary metastases. BRAF V600E is associated with increased risk...

  20. Oncogenic N-Ras Stimulates SRF-Mediated Transactivation via H3 Acetylation at Lysine 9

    Directory of Open Access Journals (Sweden)

    Sun-Ju Yi

    2018-01-01

    Full Text Available Signal transduction pathways regulate the gene expression by altering chromatin dynamics in response to mitogens. Ras proteins are key regulators linking extracellular stimuli to a diverse range of biological responses associated with gene regulation. In mammals, the three ras genes encode four Ras protein isoforms: H-Ras, K-Ras4A, K-Ras4B, and N-Ras. Although emerging evidence suggests that Ras isoforms differentially regulate gene expressions and are functionally nonredundant, the mechanisms underlying Ras specificity and Ras signaling effects on gene expression remain unclear. Here, we show that oncogenic N-Ras acts as the most potent regulator of SRF-, NF-κB-, and AP-1-dependent transcription. N-Ras-RGL2 axis is a distinct signaling pathway for SRF target gene expression such as Egr1 and JunB, as RGL2 Ras binding domain (RBD significantly impaired oncogenic N-Ras-induced SRE activation. By monitoring the effect of Ras isoforms upon the change of global histone modifications in oncogenic Ras-overexpressed cells, we discovered that oncogenic N-Ras elevates H3K9ac/H3K23ac levels globally in the chromatin context. Importantly, chromatin immunoprecipitation (ChIP assays revealed that H3K9ac is significantly enriched at the promoter and coding regions of Egr1 and JunB. Collectively, our findings define an undocumented role of N-Ras in modulating of H3 acetylation and in gene regulation.

  1. Ras activation and symmetry breaking during Dictyostelium chemotaxis.

    Science.gov (United States)

    Kortholt, Arjan; Keizer-Gunnink, Ineke; Kataria, Rama; Van Haastert, Peter J M

    2013-10-01

    Central to chemotaxis is the molecular mechanism by which a shallow spatial gradient of chemoattractant induces symmetry breaking of activated signaling molecules. Previously, we have used Dictyostelium mutants to investigate the minimal requirements for chemotaxis, and identified a basal signaling module providing activation of Ras and F-actin at the leading edge. Here, we show that Ras activation after application of a pipette releasing the chemoattractant cAMP has three phases, each depending on specific guanine-nucleotide-exchange factors (GEFs). Initially a transient activation of Ras occurs at the entire cell boundary, which is proportional to the local cAMP concentrations and therefore slightly stronger at the front than in the rear of the cell. This transient Ras activation is present in gα2 (gpbB)-null cells but not in gβ (gpbA)-null cells, suggesting that Gβγ mediates the initial activation of Ras. The second phase is symmetry breaking: Ras is activated only at the side of the cell closest to the pipette. Symmetry breaking absolutely requires Gα2 and Gβγ, but not the cytoskeleton or four cAMP-induced signaling pathways, those dependent on phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3], cGMP, TorC2 and PLA2. As cells move in the gradient, the crescent of activated Ras in the front half of the cell becomes confined to a small area at the utmost front of the cell. Confinement of Ras activation leads to cell polarization, and depends on cGMP formation, myosin and F-actin. The experiments show that activation, symmetry breaking and confinement of Ras during Dictyostelium chemotaxis uses different G-protein subunits and a multitude of Ras GEFs and GTPase-activating proteins (GAPs).

  2. Oncogenic RAS enables DNA damage- and p53-dependent differentiation of acute myeloid leukemia cells in response to chemotherapy.

    Directory of Open Access Journals (Sweden)

    Mona Meyer

    Full Text Available Acute myeloid leukemia (AML is a clonal disease originating from myeloid progenitor cells with a heterogeneous genetic background. High-dose cytarabine is used as the standard consolidation chemotherapy. Oncogenic RAS mutations are frequently observed in AML, and are associated with beneficial response to cytarabine. Why AML-patients with oncogenic RAS benefit most from high-dose cytarabine post-remission therapy is not well understood. Here we used bone marrow cells expressing a conditional MLL-ENL-ER oncogene to investigate the interaction of oncogenic RAS and chemotherapeutic agents. We show that oncogenic RAS synergizes with cytotoxic agents such as cytarabine in activation of DNA damage checkpoints, resulting in a p53-dependent genetic program that reduces clonogenicity and increases myeloid differentiation. Our data can explain the beneficial effects observed for AML patients with oncogenic RAS treated with higher dosages of cytarabine and suggest that induction of p53-dependent differentiation, e.g. by interfering with Mdm2-mediated degradation, may be a rational approach to increase cure rate in response to chemotherapy. The data also support the notion that the therapeutic success of cytotoxic drugs may depend on their ability to promote the differentiation of tumor-initiating cells.

  3. RASAL3, a novel hematopoietic RasGAP protein, regulates the number and functions of NKT cells.

    Science.gov (United States)

    Saito, Suguru; Kawamura, Toshihiko; Higuchi, Masaya; Kobayashi, Takahiro; Yoshita-Takahashi, Manami; Yamazaki, Maya; Abe, Manabu; Sakimura, Kenji; Kanda, Yasuhiro; Kawamura, Hiroki; Jiang, Shuying; Naito, Makoto; Yoshizaki, Takumi; Takahashi, Masahiko; Fujii, Masahiro

    2015-05-01

    Ras GTPase-activating proteins negatively regulate the Ras/Erk signaling pathway, thereby playing crucial roles in the proliferation, function, and development of various types of cells. In this study, we identified a novel Ras GTPase-activating proteins protein, RASAL3, which is predominantly expressed in cells of hematopoietic lineages, including NKT, B, and T cells. We established systemic RASAL3-deficient mice, and the mice exhibited a severe decrease in NKT cells in the liver at 8 weeks of age. The treatment of RASAL3-deficient mice with α-GalCer, a specific agonist for NKT cells, induced liver damage, but the level was less severe than that in RASAL3-competent mice, and the attenuated liver damage was accompanied by a reduced production of interleukin-4 and interferon-γ from NKT cells. RASAL3-deficient NKT cells treated with α-GalCer in vitro presented augmented Erk phosphorylation, suggesting that there is dysregulated Ras signaling in the NKT cells of RASAL3-deficient mice. Taken together, these results suggest that RASAL3 plays an important role in the expansion and functions of NKT cells in the liver by negatively regulating Ras/Erk signaling, and might be a therapeutic target for NKT-associated diseases. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. General practice variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease in Denmark

    DEFF Research Database (Denmark)

    Koefoed, Mette M; Søndergaard, Jens; Christensen, René dePont

    2013-01-01

    Spirometry testing is essential to confirm an obstructive lung disease, but studies have reported that a large proportion of patients diagnosed with COPD or asthma have no history of spirometry testing. Also, it has been shown that many patients are prescribed medication for obstructive lung...... disease without a relevant diagnosis or spirometry test registered. General practice characteristics have been reported to influence diagnosis and management of several chronic diseases. However, these findings are inconsistent, and it is uncertain whether practice characteristics influence spirometry...... testing among patients receiving medication for obstructive lung disease. The aim of this study was therefore to examine if practice characteristics are associated with spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease....

  5. Current treatments of Alzheimer disease: are main caregivers satisfied with the drug treatments received by their patients?

    Science.gov (United States)

    Sevilla, C; Jiménez Caballero, P E; Alfonso, V; González-Adalid, M

    2009-01-01

    A full comparison of the satisfaction with treatment using the current Alzheimer's disease (AD) therapies from the perspective of caregivers has not yet been done. The aim of this study was thus to find out the degree of satisfaction with the main available drug treatments in monotherapy for AD from this point of view. A cross-sectional, multicentre study of patients with possible/probable AD according to DSM-IV/NINCDS-ADRDA criteria, on monotherapy with donepezil, galantamine, rivastigmine or memantine, was carried out. Treatment satisfaction was measured by a caregiver proxy-administration of the generic SATMED-Q questionnaire [range: 0 (not satisfied at all) to 100 (totally satisfied)], overall and in 6 domains: tolerability, efficacy, medical care, ease and convenience, impact on daily activities and overall satisfaction. A total of 829 patients were included: 63.3% women, aged 78.2 +/- 6.8 years; 546 (67.3%) on donepezil, 106 (13.1%) on rivastigmine, 99 (12.2%) on galantamine and 60 (7.4%) on memantine. SATMED-Q scores p values were adjusted by MMSE and treatment duration. Caregivers of patients on donepezil showed significantly higher SATMED-Q total (71.8 +/- 12.3; p caregivers of donepezil-treated patients, 76.7% were satisfied with treatment versus 68.7, 61.4 and 46.7% of those caregivers whose patients were treated with galantamine, rivastigmine and memantine, respectively (p = 0.0002). Caregivers of AD patients undergoing donepezil monotherapy seem to be more satisfied with treatment than those of patients receiving the other usual AD treatments in this study, particularly due to the ease and convenience of use of this drug. The higher level of satisfaction of these caregivers could be explained by the fact that, within the donepezil group, a high percentage of patients were treated with orally disintegrating tablets, which are easier for the patient to swallow. Copyright 2009 S. Karger AG, Basel.

  6. Oncogenic K-Ras Signals through Epidermal Growth Factor Receptor and Wild-Type H-Ras to Promote Radiation Survival in Pancreatic and Colorectal Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Keith A. Cengel

    2007-04-01

    Full Text Available Pancreatic and colorectal carcinomas frequently express oncogenic/mutant K-Ras that contributes to both tumorigenesis and clinically observed resistance to radiation treatment. We have previously shown that farnesyltransferase inhibitors (FTI radiosensitize many pancreatic and colorectal cancer cell lines that express oncogenic K-ras at doses that inhibit the prenylation and activation of H-Ras but not K-Ras. In the present study, we have examined the mechanism of FTI-mediated radiosensitization in cell lines that express oncogenic K-Ras and found that wild-type H-Ras is a contributor to radiation survival in tumor cells that express oncogenic K-Ras. In these experiments, inhibiting the expression of oncogenic K-Ras, wild-type H-Ras, or epidermal growth factor receptor (EGFR led to similar levels of radiosensitization as treatment with the FTI tipifarnib. Treatment with the EGFR inhibitor gefitinib led to similar levels of radiosensitization, and the combinations of tipifarnib or gefitinib plus inhibition of K-Ras, H-Ras, or EGFR expression did not provide additional radiosensitization compared with tipifarnib or gefitinib alone. Finally, supplementing culture medium with the EGFR ligand transforming growth factor o was able to reverse the radiosensitizing effect of inhibiting K-ras expression. Taken together, these findings suggest that EGFRactivated H-Ras signaling is initiated by oncogenic K-Ras to promote radiation survival in pancreatic and colorectal cancers.

  7. Simvastatin attenuates acrolein-induced mucin production in rats: involvement of the Ras/extracellular signal-regulated kinase pathway.

    Science.gov (United States)

    Chen, Ya-Juan; Chen, Peng; Wang, Hai-Xia; Wang, Tao; Chen, Lei; Wang, Xun; Sun, Bei-Bei; Liu, Dai-Shun; Xu, Dan; An, Jing; Wen, Fu-Qiang

    2010-06-01

    Airway mucus overproduction is a cardinal feature of airway inflammatory diseases, such as chronic obstructive pulmonary disease and cystic fibrosis. Since the small G-protein Ras is known to modulate cellular functions in the lung, we sought to investigate whether the Ras inhibitor simvastatin could attenuate acrolein-induced mucin production in rat airways. Rats were exposed to acrolein for 12 days, after first being pretreated intragastrically for 24 h with either simvastatin alone or simvastatin in combination with mevalonate, which prevents the isoprenylation needed for Ras activation. Lung tissue was analyzed for extracellular signal-regulated kinase (ERK) activity, goblet cell metaplasia and mucin production. To analyze the effect of simvastatin on mucin production in more detail, acrolein-exposed human airway epithelial NCI-H292 cells were pretreated with simvastatin alone or together with mevalonate. Culture medium was collected to detect mucin secretion, and cell lysates were examined for Ras-GTPase activity and epidermal growth factor receptor (EGFR)/ERK phosphorylation. In vivo, simvastatin treatment dose-dependently suppressed acrolein-induced goblet cell hyperplasia and metaplasia in bronchial epithelium and inhibited ERK phosphorylation in rat lung homogenates. Moreover, simvastatin inhibited Muc5AC mucin synthesis at both the mRNA and protein levels in the lung. In vitro, simvastatin pretreatment attenuated the acrolein-induced significant increase in MUC5AC mucin expression, Ras-GTPase activity and EGFR/ERK phosphorylation. These inhibitory effects of simvastatin were neutralized by mevalonate administration both in vitro and in vivo. Our results suggest that simvastatin may attenuate acrolein-induced mucin protein synthesis in the airway and airway inflammation, possibly by blocking ERK activation mediated by Ras protein isoprenylation. Thus, the evidence from the experiment suggests that human trials are warranted to determine the potential

  8. Early renin-angiotensin system intervention is more beneficial than late intervention in delaying end-stage renal disease in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Schievink, B; Kröpelin, T; Mulder, S

    2016-01-01

    AIMS: To develop and validate a model to simulate progression of diabetic kidney disease (DKD) from early onset until end-stage renal disease (ESRD), and to assess the effect of renin-angiotensin system (RAS) intervention in early, intermediate and advanced stages of DKD. METHODS: We used data from......, intermediate and advanced stage of disease, whose mean age was 60 years and who received placebo, the median time to ESRD was 21.4, 10.8 and 4.7 years, respectively. RAS intervention delayed the predicted time to ESRD by 4.2, 3.6 and 1.4 years, respectively. The benefit of early RAS intervention was more...... pronounced in younger patients; for example, for patients with a mean age of 45 years, RAS intervention at early, intermediate or advanced stage delayed ESRD by 5.9, 4.0 and 1.1 years versus placebo. CONCLUSIONS: RAS intervention early in the course of proteinuric DKD is more beneficial than late...

  9. Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes

    Directory of Open Access Journals (Sweden)

    Olschwang Sylviane

    2008-10-01

    Full Text Available Abstract Background Chronic myelomonocytic leukemia (CMML is a hematological disease close to, but separate from both myeloproliferative disorders (MPD and myelodysplastic syndromes and may show either myeloproliferative (MP-CMML or myelodysplastic (MD-CMML features. Not much is known about the molecular biology of this disease. Methods We studied a series of 30 CMML samples (13 MP- and 11 MD-CMMLs, and 6 acutely transformed cases from 29 patients by using Agilent high density array-comparative genomic hybridization (aCGH and sequencing of 12 candidate genes. Results Two-thirds of samples did not show any obvious alteration of aCGH profiles. In one-third we observed chromosome abnormalities (e.g. trisomy 8, del20q and gain or loss of genes (e.g. NF1, RB1 and CDK6. RAS mutations were detected in 4 cases (including an uncommon codon 146 mutation in KRAS and PTPN11 mutations in 3 cases. We detected 11 RUNX1 alterations (9 mutations and 2 rearrangements. The rearrangements were a new, cryptic inversion of chromosomal region 21q21-22 leading to break and fusion of RUNX1 to USP16. RAS and RUNX1 alterations were not mutually exclusive. RAS pathway mutations occurred in MP-CMMLs (~46% but not in MD-CMMLs. RUNX1 alterations (mutations and cryptic rearrangement occurred in both MP and MD classes (~38%. Conclusion We detected RAS pathway mutations and RUNX1 alterations. The latter included a new cryptic USP16-RUNX1 fusion. In some samples, two alterations coexisted already at this early chronic stage.

  10. Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1 genes

    International Nuclear Information System (INIS)

    Gelsi-Boyer, Véronique; Bentires-Alj, Mohamed; Olschwang, Sylviane; Vey, Norbert; Mozziconacci, Marie-Joëlle; Birnbaum, Daniel; Chaffanet, Max; Trouplin, Virginie; Adélaïde, José; Aceto, Nicola; Remy, Virginie; Pinson, Stephane; Houdayer, Claude; Arnoulet, Christine; Sainty, Danielle

    2008-01-01

    Chronic myelomonocytic leukemia (CMML) is a hematological disease close to, but separate from both myeloproliferative disorders (MPD) and myelodysplastic syndromes and may show either myeloproliferative (MP-CMML) or myelodysplastic (MD-CMML) features. Not much is known about the molecular biology of this disease. We studied a series of 30 CMML samples (13 MP- and 11 MD-CMMLs, and 6 acutely transformed cases) from 29 patients by using Agilent high density array-comparative genomic hybridization (aCGH) and sequencing of 12 candidate genes. Two-thirds of samples did not show any obvious alteration of aCGH profiles. In one-third we observed chromosome abnormalities (e.g. trisomy 8, del20q) and gain or loss of genes (e.g. NF1, RB1 and CDK6). RAS mutations were detected in 4 cases (including an uncommon codon 146 mutation in KRAS) and PTPN11 mutations in 3 cases. We detected 11 RUNX1 alterations (9 mutations and 2 rearrangements). The rearrangements were a new, cryptic inversion of chromosomal region 21q21-22 leading to break and fusion of RUNX1 to USP16. RAS and RUNX1 alterations were not mutually exclusive. RAS pathway mutations occurred in MP-CMMLs (~46%) but not in MD-CMMLs. RUNX1 alterations (mutations and cryptic rearrangement) occurred in both MP and MD classes (~38%). We detected RAS pathway mutations and RUNX1 alterations. The latter included a new cryptic USP16-RUNX1 fusion. In some samples, two alterations coexisted already at this early chronic stage

  11. Diet, Lifestyle and risk of K-ras mutation-positive and -negative colorectal adenomas

    NARCIS (Netherlands)

    Wark, P.A.; Kuil, van der W.; Ploemacher, J.; Muijen, van G.N.P.; Mulder, Ch.J.J.; Weijenberg, M.P.; Kok, F.J.; Kampman, E.

    2006-01-01

    K-ras mutation-positive (K-ras+) and -negative (K-ras-) colorectal adenomas may differ clinically and pathologically. As environmental compounds may cause mutations in the growth-related K-ras oncogene or affect clonal selection depending on mutational status, we evaluated whether the aetiology of

  12. Diet, lifestyle and risk of K-ras mutation-positive and -negative colorectal adenomas.

    NARCIS (Netherlands)

    Wark, P.A.; Kuil, W. van der; Ploemacher, J.; Muijen, G.N.P. van; Mulder, C.J.J.; Weijenberg, M.P.; Kok, F.J.; Kampman, E.

    2006-01-01

    K-ras mutation-positive (K-ras+) and -negative (K-ras-) colorectal adenomas may differ clinically and pathologically. As environmental compounds may cause mutations in the growth-related K-ras oncogene or affect clonal selection depending on mutational status, we evaluated whether the aetiology of

  13. Management of Renovascular Disease | Elamin | Arab Journal of ...

    African Journals Online (AJOL)

    Introduction: Renal artery stenosis (RAS) is not rare, but is often asymptomatic. In older individuals, atherosclerosis is the most common cause of RAS. Atherosclerotic RAS is usually one manifestation of wide spread atherosclerotic disease, and its presence increases the morbidity and mortality of other manifestations of ...

  14. Prognostic implications of c-Ki-ras2 mutations in patients with advanced colorectal cancer treated with 5-fluorouracil and interferon: a study of the eastern cooperative oncology group (EST 2292)

    Science.gov (United States)

    Wadler, S; Bajaj, R; Neuberg, D; Agarwal, V; Haynes, H; Benson, A B

    1997-01-01

    Mutations in c-Ki-ras2 (ras) occur in about 40% of patients with colorectal cancers and occur early in the pathogenesis of this disease. To evaluate the prognostic value of mutations in ras, the Eastern Cooperative Oncology Group (ECOG) conducted a retrospective study (EST 2292) to determine the frequency of mutations in patients with advanced colorectal cancer, and to determine whether ras mutations were associated with altered response to therapy and survival. Patients were enrolled from four studies: P-Z289, an ECOG phase II trial of 5-fluorouracil (5-FU) and interferon (IFN) in patients with advanced colorectal cancer; P-Z991, an ECOG phase I trial of 5-FU and IFN in patients with advanced malignancies; and two trials from the Albert Einstein College of Medicine in patients with advanced colorectal cancer treated with 5-FU and either IFN-alpha or IFN-beta. All patients had advanced colorectal carcinoma and had sufficient histologic material available for analysis for the presence and type of ras, using polymerase chain reaction and dot-blot analysis with sets of probes sufficient to detect all the common mutations of ras at codons 12, 13, and 61. Seventy-two patients were enrolled in this trial. Mutations in ras were detected in 25 (35%), including 17 (23%) in codon 12, four (6%) in codon 13, and four (6%) in codon 61. There was no correlation between the presence of a ras mutation and age, sex, Dukes' stage, histology, or tumor markers. Thirty-one of 72 patients (43%) responded to therapy with 5-FU and IFN, and 10 of 31 responders (32%) and 15 of 41 nonresponders (37%) had mutations in ras. There was no difference in response rates or overall survival between the groups with and without ras mutations. It is unlikely that ras mutations will have significant prognostic value for either response to therapy or survival in patients with colorectal carcinomas treated with 5-FU and IFN.

  15. Genetic and Molecular Analysis of Suppressors of Ras Mutations

    National Research Council Canada - National Science Library

    Sieburth, Derek

    1998-01-01

    .... elegans vulval development. We describe the identification and characterization of a novel gene, sur-8, that functions to regulate a receptor tyrosine kinase-Ras-MAP kinase-mediated signal transduction pathway during C...

  16. Genetic and Molecular Analysis of Suppressors of Ras Mutations

    National Research Council Canada - National Science Library

    Sieburth, Derek

    1999-01-01

    .... elegans vulvaZ development. We describe the identification and characterization of a novel gene, sur-8, that functions to regulate a receptor tyrosine kinase-Ras-MAp kinase- mediated signal transduction pathway during C...

  17. Ras- ERK signaling in behavior: old questions and new perspectives

    Directory of Open Access Journals (Sweden)

    Stefania eFasano

    2011-11-01

    Full Text Available The role of Ras-ERK signaling in behavioral plasticity is well established. Inhibition studies using the blood-brain barrier permeable drug SL327 have conclusively demonstrated that this neuronal cell signaling cascade is a crucial component of the synaptic machinery implicated in the formation of various forms of long-term memory, from spatial learning to fear and operant conditioning. However, abnormal Ras-ERK signaling has also been linked to a number of neuropsychiatric conditions, including mental retardation syndromes (RASopathies, drug addiction and L-DOPA induced Dyskinesia (LID. The work recently done on these brain disorders has pointed to previously underappreciated roles of Ras-ERK in specific subsets of neurons, like GABAergic interneurons of the hippocampus or the cortex, as well as in the medium spiny neurons of the striatum. Here we will highlight the open questions related to Ras-ERK signaling in these behavioral manifestations and propose crucial experiments for the future.

  18. Latest Advances Towards Ras Inhibition: A Medicinal Chemistry Perspective.

    Science.gov (United States)

    Sautier, Brice; Nising, Carl F; Wortmann, Lars

    2016-12-23

    Owing to their high occurrence rate across many human cancers and their lack of druggability so far, mutant forms of the signaling protein Ras are currently among the most attractive (and elusive) oncology targets. This strong appeal explains the sustained effort in the field, and the ensuing progress has rekindled optimism regarding the discovery of Ras inhibitors. In this Minireview, we discuss the most recent advances towards irreversible inhibitors, and highlight approaches to inhibitors of Ras-effector interactions that have been overshadowed by the current focus on direct Ras inhibition. At the same time, we provide a critical assessment from a medicinal chemistry perspective. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. General practice variation in spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease in Denmark: a population-based observational study.

    Science.gov (United States)

    Koefoed, Mette M; Søndergaard, Jens; Christensen, René dePont; Jarbøl, Dorte E

    2013-08-07

    Spirometry testing is essential to confirm an obstructive lung disease, but studies have reported that a large proportion of patients diagnosed with COPD or asthma have no history of spirometry testing. Also, it has been shown that many patients are prescribed medication for obstructive lung disease without a relevant diagnosis or spirometry test registered. General practice characteristics have been reported to influence diagnosis and management of several chronic diseases. However, these findings are inconsistent, and it is uncertain whether practice characteristics influence spirometry testing among patients receiving medication for obstructive lung disease. The aim of this study was therefore to examine if practice characteristics are associated with spirometry testing among patients receiving first-time prescriptions for medication targeting obstructive lung disease. A national register-based cohort study was performed. All patients over 18 years receiving first-time prescriptions for medication targeting obstructive lung disease in 2008 were identified and detailed patient-specific data on sociodemographic status and spirometry tests were extracted. Information on practice characteristics like number of doctors, number of patients per doctor, training practice status, as well as age and gender of the general practitioners was linked to each medication user. Partnership practices had a higher odds ratio (OR) of performing spirometry compared with single-handed practices (OR 1.24, CI 1.09-1.40). We found a significant association between increasing general practitioner age and decreasing spirometry testing. This tendency was most pronounced among partnership practices, where doctors over 65 years had the lowest odds of spirometry testing (OR 0.25, CI 0.10-0.61). Training practice status was significantly associated with spirometry testing among single-handed practices (OR 1.40, CI 1.10-1.79). Some of the variation in spirometry testing among patients receiving

  20. Live birth and adverse birth outcomes in women with ulcerative colitis and Crohn's disease receiving assisted reproduction

    DEFF Research Database (Denmark)

    Nørgård, Bente Mertz; Larsen, P V; Fedder, J

    2016-01-01

    OBJECTIVE: To examine the chance of live births and adverse birth outcomes in women with ulcerative colitis (UC) and Crohn's disease (CD) compared with women without inflammatory bowel disease (IBD) who have undergone assisted reproductive technology (ART) treatments. METHODS: This was a nationwide...

  1. Coordinating ERK signaling via the molecular scaffold Kinase Suppressor of Ras [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Danielle Frodyma

    2017-08-01

    Full Text Available Many cancers, including those of the colon, lung, and pancreas, depend upon the signaling pathways induced by mutated and constitutively active Ras. The molecular scaffolds Kinase Suppressor of Ras 1 and 2 (KSR1 and KSR2 play potent roles in promoting Ras-mediated signaling through the Raf/MEK/ERK kinase cascade. Here we summarize the canonical role of KSR in cells, including its central role as a scaffold protein for the Raf/MEK/ERK kinase cascade, its regulation of various cellular pathways mediated through different binding partners, and the phenotypic consequences of KSR1 or KSR2 genetic inactivation. Mammalian KSR proteins have a demonstrated role in cellular and organismal energy balance with implications for cancer and obesity. Targeting KSR1 in cancer using small molecule inhibitors has potential for therapy with reduced toxicity to the patient. RNAi and small molecule screens using KSR1 as a reference standard have the potential to expose and target vulnerabilities in cancer. Interestingly, although KSR1 and KSR2 are similar in structure, KSR2 has a distinct physiological role in regulating energy balance. Although KSR proteins have been studied for two decades, additional analysis is required to elucidate both the regulation of these molecular scaffolds and their potent effect on the spatial and temporal control of ERK activation in health and disease.

  2. High-Affinity Interaction of the K-Ras4B Hypervariable Region with the Ras Active Site

    Science.gov (United States)

    Chavan, Tanmay S.; Jang, Hyunbum; Khavrutskii, Lyuba; Abraham, Sherwin J.; Banerjee, Avik; Freed, Benjamin C.; Johannessen, Liv; Tarasov, Sergey G.; Gaponenko, Vadim; Nussinov, Ruth; Tarasova, Nadya I.

    2015-01-01

    Ras proteins are small GTPases that act as signal transducers between cell surface receptors and several intracellular signaling cascades. They contain highly homologous catalytic domains and flexible C-terminal hypervariable regions (HVRs) that differ across Ras isoforms. KRAS is among the most frequently mutated oncogenes in human tumors. Surprisingly, we found that the C-terminal HVR of K-Ras4B, thought to minimally impact the catalytic domain, directly interacts with the active site of the protein. The interaction is almost 100-fold tighter with the GDP-bound than the GTP-bound protein. HVR binding interferes with Ras-Raf interaction, modulates binding to phospholipids, and slightly slows down nucleotide exchange. The data indicate that contrary to previously suggested models of K-Ras4B signaling, HVR plays essential roles in regulation of signaling. High affinity binding of short peptide analogs of HVR to K-Ras active site suggests that targeting this surface with inhibitory synthetic molecules for the therapy of KRAS-dependent tumors is feasible. PMID:26682817

  3. Serum Calprotectin Versus Acute-Phase Reactants in the Discrimination of Inflammatory Disease Activity in Rheumatoid Arthritis Patients Receiving Tumor Necrosis Factor Inhibitors.

    Science.gov (United States)

    Inciarte-Mundo, José; Victoria Hernández, Maria; Ruiz-Esquide, Virginia; Raquel Cabrera-Villalba, Sonia; Ramirez, Julio; Cuervo, Andrea; Pascal, Mariona; Yagüe, Jordi; Cañete, Juan D; Sanmarti, Raimon

    2016-07-01

    To compare the accuracy of serum calprotectin and acute-phase reactants (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) in stratifying disease activity in rheumatoid arthritis (RA) patients receiving tumor necrosis factor inhibitors (TNFi), and to correlate calprotectin levels with TNFi trough serum levels. We conducted a cross-sectional study of 87 RA patients receiving adalimumab, etanercept (ETN), or infliximab (IFX); 56 psoriatic arthritis (PsA) patients and 40 healthy blood donors were included as controls. Associations between calprotectin, CRP, and ESR and composite articular indices (Disease Activity Score in 28 joints [DAS28], Simplified Disease Activity Index [SDAI], and Clinical Disease Activity Index) were analyzed by correlation and linear regression and the accuracy and discriminatory capacity of calprotectin by receiver operator characteristic curves (area under the curve [AUC]). Calprotectin levels correlated better with all composite activity indices than CRP and ESR (all r coefficients >0.70). Calprotectin levels were significantly lower in RA and PsA patients in clinical remission compared with those with low disease activity for all articular indices. In RA, ESR discriminated between remission and low disease activity only when using DAS28, and CRP only with SDAI. In RA patients in remission/low disease activity, calprotectin but not CRP or ESR distinguished between patients with no swollen joints and those with ≥1 swollen joint (1.74 μg/ml versus 3.04 μg/ml; P = 0.010). Using DAS28 ≥2.6 as the reference variable, calprotectin showed an AUC of 0.92; the best cutoff was ≥2.47 μg/ml with a likelihood ratio of 6.3 (95% confidence interval 2.5-15.8). Calprotectin serum levels inversely correlated with trough serum drug levels of ETN (ρ = -0.671, P acute-phase reactants, even in patients with low inflammatory activity. © 2016, American College of Rheumatology.

  4. Five-year disease-free survival among stage II-IV breast cancer patients receiving FAC and AC chemotherapy in phase II clinical trials of Panagen.

    Science.gov (United States)

    Proskurina, Anastasia S; Gvozdeva, Tatiana S; Potter, Ekaterina A; Dolgova, Evgenia V; Orishchenko, Konstantin E; Nikolin, Valeriy P; Popova, Nelly A; Sidorov, Sergey V; Chernykh, Elena R; Ostanin, Alexandr A; Leplina, Olga Y; Dvornichenko, Victoria V; Ponomarenko, Dmitriy M; Soldatova, Galina S; Varaksin, Nikolay A; Ryabicheva, Tatiana G; Uchakin, Peter N; Rogachev, Vladimir A; Shurdov, Mikhail A; Bogachev, Sergey S

    2016-08-18

    We report on the results of a phase II clinical trial of Panagen (tablet form of fragmented human DNA preparation) in breast cancer patients (placebo group n = 23, Panagen n = 57). Panagen was administered as an adjuvant leukoprotective agent in FAC and AC chemotherapy regimens. Pre-clinical studies clearly indicate that Panagen acts by activating dendritic cells and induces the development of adaptive anticancer immune response. We analyzed 5-year disease-free survival of patients recruited into the trial. Five-year disease-free survival in the placebo group was 40 % (n = 15), compared with the Panagen arm - 53 % (n = 51). Among stage III patients, disease-free survival was 25 and 52 % for placebo (n = 8) and Panagen (n = 25) groups, respectively. Disease-free survival of patients with IIIB + C stage was as follows: placebo (n = 6)-17 % vs Panagen (n = 18)-50 %. Disease-free survival rate (17 %) of patients with IIIB + C stage breast cancer receiving standard of care therapy is within the global range. Patients who additionally received Panagen demonstrate a significantly improved disease-free survival rate of 50 %. This confirms anticancer activity of Panagen. ClinicalTrials.gov NCT02115984 from 04/07/2014.

  5. Progressive fatal dementia (Creutzfeldt-Jakob disease) in a patient who received homograft tissue for tympanic membrane closure

    NARCIS (Netherlands)

    Tange, R. A.; Troost, D.; Limburg, M.

    1990-01-01

    We report the case history of a 54-year-old man who developed a fatal neurological disorder 4 years after a successful tympanoplasty with homograft pericardium. The final diagnosis of this case was Creutzfeldt-Jakob disease. This infectious spongiform encephalopathy is probably caused by a slow

  6. Demographics, Resource Utilization, and Outcomes of Elderly Patients With Chronic Liver Disease Receiving Hospice Care in the United States.

    Science.gov (United States)

    Fukui, Natsu; Golabi, Pegah; Otgonsuren, Munkhzul; Mishra, Alita; Venkatesan, Chapy; Younossi, Zobair M

    2017-11-01

    Hospice offers non-curative symptomatic management to improve patients' quality of life, satisfaction, and resource utilization. Hospice enrollment among patients with chronic liver disease (CLD) is not well studied. The aim of tis tudy is to examine the characteristics of Medicare enrollees with CLD, who were discharged to hospice. Medicare patients discharged to hospice between 2010 and 2014 were identified in Medicare Inpatient and Hospice Files. CLDs and other co-morbidities were identified by International Classification of Diseases-ninth revision codes. Generalized linear model was used to estimate regression coefficients with P-values. Logistic regression was used to calculate odds ratios and 95% confidence intervals. A total of 2,179 CLD patients and 34,986 controls without CLD met the inclusion criteria. Non-alcoholic fatty liver disease, alcoholic liver disease, and hepatitis C virus (HCV) were the most frequent cause of CLD. CLD patients were younger (70 vs. 83 years), more likely to be male (57.7 vs. 39.3%), had longer hospital stay (length of stay, LOS) (19.4 vs. 13.0 days), higher annual charges ($175,000 vs. $109,000), higher 30-day re-hospitalization rates (51.6 vs. 34.2%), and shorter hospice LOS (13.7 vs. 17.7 days) than controls (all Phospice enrollment as compared with patients without CLD. It was highly likely that these patients were enrolled relatively late, which could potentially lead to less benefit from hospice.

  7. Expression patterns of genes encoding small GTPases Ras-dva-1 and Ras-dva-2 in the Xenopus laevis tadpoles.

    Science.gov (United States)

    Tereshina, Maria B; Bayramov, Andrey V; Zaraisky, Andrey G

    2011-01-01

    Small GTPases of the recently discovered Ras-dva family are specific to the Vertebrate phylum. In Xenopus laevis, Ras-dva-1 is expressed during gastrulation and neurulation in the anterior ectoderm where it regulates the early development of the forebrain and cranial placodes (Tereshina et al., 2006). In the present work, we studied the expression of Ras-dva-1 at later developmental stages. As a result, the Ras-dva-1 expression was revealed in the eye retina, epiphysis (pineal gland), hypophysis (pituitary), branchial arches, pharynx, oesophagus, stomach and gall bladder of swimming tadpoles. Additionally, we investigated for the first time the expression pattern of Ras-dva-2. This gene encodes a protein belonging to a novel sub-group of Ras-dva GTPases that we identified by phylogenetic analysis within Ras-dva family. In contrast to Ras-dva-1, Ras-dva-2 is not expressed before the swimming tadpole stage. At the swimming tadpole stage, however, Ras-dva-2 transcripts can be detected in the eye retina and brain. Later in development, the expression of Ras-dva-2 can also be revealed in the mesonephros and stomach. Copyright © 2010 Elsevier B.V. All rights reserved.

  8. Plasma Nitration of High-Density and Low-Density Lipoproteins in Chronic Kidney Disease Patients Receiving Kidney Transplants

    Directory of Open Access Journals (Sweden)

    Ahmed Bakillah

    2015-01-01

    Full Text Available Background. Functional abnormalities of high-density lipoprotein (HDL could contribute to cardiovascular disease in chronic kidney disease patients. We measured a validated marker of HDL dysfunction, nitrated apolipoprotein A-I, in kidney transplant recipients to test the hypothesis that a functioning kidney transplant reduces serum nitrated apoA-I concentrations. Methods. Concentrations of nitrated apoA-I and apoB were measured using indirect sandwich ELISA assays on sera collected from each transplant subject before transplantation and at 1, 3, and 12 months after transplantation. Patients were excluded if they have history of diabetes, treatment with lipid-lowering medications or HIV protease inhibitors, prednisone dose > 15 mg/day, nephrotic range proteinuria, serum creatinine > 1.5 mg/dL, or active inflammatory disease. Sera from 18 transplanted patients were analyzed. Four subjects were excluded due to insufficient data. Twelve and eight patients had creatinine < 1.5 mg/dL at 3 and 12 months after transplantation, respectively. Results. Nitrated apoA-I was significantly reduced at 12 months after transplantation (p=0.039. The decrease in apoA-I nitration was associated with significant reduction in myeloperoxidase (MPO activity (p=0.047. In contrast to apoA-I, nitrated apoB was not affected after kidney transplantation. Conclusions. Patients with well-functioning grafts had significant reduction in nitrated apoA-I 12 months after kidney transplantation. Further studies are needed in a large cohort to determine if nitrated apoA-I can be used as a valuable marker for cardiovascular risk stratification in chronic kidney disease.

  9. Books Received

    Indian Academy of Sciences (India)

    Books Received. Challenge and Thrill of Pre-College. Mathematics. V Krishnamurthy et al. New Age International. 1996, Rs.220. Mathematics for Science. S M Uppal and H M Humphreys. New Age International. 1996, Rs.17S. Physics for Engineers. M R Srinivasan. New Age Publications. 1996. Statement about ownership ...

  10. A case of nonarteritic anterior ischemic optic neuropathy of a male with family history of the disease after receiving sildenafil

    Directory of Open Access Journals (Sweden)

    Felekis T

    2011-10-01

    Full Text Available T Felekis1, I Asproudis1, K Katsanos2, EV Tsianos21University Eye Clinic of Ioannina, Ioannina, Greece; 2First Department of Internal Medicine, University Hospital of Ioannina, Ioannina, GreeceAbstract: A 51-year-old male was referred to the University Eye Clinic of Ioannina with nonarteritic anterior ischemic optic neuropathy (NAION 12 hours after receiving sildenafil citrate (Viagra®. Examination for possible risk factors revealed mild hypercholesterolemia. Family history showed that his father had suffered from bilateral NAION. Although a cause-and-effect relationship is difficult to prove, there are reports indicating an association between the use of erectile dysfunction agents and the development of NAION. Physicians might need to investigate the presence of family history of NAION among systemic or vascular predisposing risk factors before prescribing erectile dysfunction drugs.Keywords: sildenafil, nonarteritic anterior ischemic optic neuropathy, erectile dysfunction drugs, family history

  11. The bovine papillomavirus E5 oncogene can cooperate with ras: identification of p21 amino acids critical for transformation by c-rasH but not v-rasH

    DEFF Research Database (Denmark)

    Willumsen, B M; Vass, W C; Velu, T J

    1991-01-01

    , and D. R. Lowy, Mol. Cell. Biol. 6:2646-2654, 1986). To determine if some of these amino acids are more important for the biological activity of c-rasH, we have now tested many of the same insertion-deletion mutants in the c-rasH form for their ability to transform NIH 3T3 cells. Since the transforming...... in their v-rasH forms. We conclude that a region including amino acids 102 and 103 encodes a function that is more critical to c-rasH than to v-rasH. Guanine nucleotide exchange is one function that is compatible with such a phenotype....... importance, in c-rasH, of codons 93 to 108, 123 to 130, and 166 to 183, which were nonessential for v-rasH transformation. Relative to the respective transforming activity of wild-type c-rasH and v-rasH, mutants with lesions in codons 102 and 103 were significantly less active in their c-rasH forms than...

  12. RAS testing of liquid biopsy correlates with the outcome of metastatic colorectal cancer patients treated with first-line FOLFIRI plus cetuximab in the CAPRI-GOIM trial.

    Science.gov (United States)

    Normanno, N; Esposito Abate, R; Lambiase, M; Forgione, L; Cardone, C; Iannaccone, A; Sacco, A; Rachiglio, A M; Martinelli, E; Rizzi, D; Pisconti, S; Biglietto, M; Bordonaro, R; Troiani, T; Latiano, T P; Giuliani, F; Leo, S; Rinaldi, A; Maiello, E; Ciardiello, F

    2018-01-01

    Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in patients treated with first-line anti-EGFR monoclonal antibody-based therapy. In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by next generation sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using beads, emulsion, amplification, and magnetics digital PCR (BEAMing). Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing. A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression-free survival of RAS mutant and wild-type patients according to tissue (7.9 versus 12.6 months; P = 0.004) and liquid biopsy testing (7.8 versus 13.8 moths; P < 0.001) were comparable. Similar findings were observed for the median overall survival of RAS mutant and wild-type patients based on tissue (22.1 versus 35.8 months; P = 0.016) and plasma (19.9 versus 35.8 months; P = 0.013) analysis. This study indicates that RAS testing of liquid biopsy results in a similar outcome when compared with tissue testing in mCRC patients

  13. The Protective Arm of the Renin Angiotensin System (RAS)

    DEFF Research Database (Denmark)

    will become of major medical importance in the near future. Focusing on recent research, The Protective Arm of the Renin Angiotensin System presents a host of new experimental studies on specific components of the RAS, namely angiotensin AT2 receptors (AT2R), the angiotensin (1-7) peptide with its receptor...... understanding of the protective side of the Renin Angiotensin System (RAS) involving angiotensin AT2 receptor, ACE2, and Ang(1-7)/Mas receptor Combines the knowledge of editors who pioneered research on the protective renin angiotensin system including; Dr. Thomas Unger, one of the founders of AT2 receptor...... research; Dr. Ulrike M. Steckelings, who contributed significantly to first preclinical studies with a novel specific AT2-agonist, and Dr. Robson Santos who pioneered research on angiotensin-(1-7) and its receptor Mas. Shows that the protective RAS axes are able to ameliorate the course of several...

  14. Characterizing Adults Receiving Primary Medical Care in New York City: Implications for Using Electronic Health Records for Chronic Disease Surveillance.

    Science.gov (United States)

    Romo, Matthew L; Chan, Pui Ying; Lurie-Moroni, Elizabeth; Perlman, Sharon E; Newton-Dame, Remle; Thorpe, Lorna E; McVeigh, Katharine H

    2016-04-28

    Electronic health records (EHRs) from primary care providers can be used for chronic disease surveillance; however, EHR-based prevalence estimates may be biased toward people who seek care. This study sought to describe the characteristics of an in-care population and compare them with those of a not-in-care population to inform interpretation of EHR data. We used data from the 2013-2014 New York City Health and Nutrition Examination Survey (NYC HANES), considered the gold standard for estimating disease prevalence, and the 2013 Community Health Survey, and classified participants as in care or not in care, on the basis of their report of seeing a health care provider in the previous year. We used χ(2) tests to compare the distribution of demographic characteristics, health care coverage and access, and chronic conditions between the 2 populations. According to the Community Health Survey, approximately 4.1 million (71.7%) adults aged 20 or older had seen a health care provider in the previous year; according to NYC HANES, approximately 4.7 million (75.1%) had. In both surveys, the in-care population was more likely to be older, female, non-Hispanic, and insured compared with the not-in-care population. The in-care population from the NYC HANES also had a higher prevalence of diabetes (16.7% vs 6.9%; P care population. Systematic differences between in-care and not-in-care populations warrant caution in using primary care data to generalize to the population at large. Future efforts to use primary care data for chronic disease surveillance need to consider the intended purpose of data collected in these systems as well as the characteristics of the population using primary care.

  15. Intramembrane protease RasP boosts protein production in Bacillus.

    Science.gov (United States)

    Neef, Jolanda; Bongiorni, Cristina; Goosens, Vivianne J; Schmidt, Brian; van Dijl, Jan Maarten

    2017-04-04

    The microbial cell factory Bacillus subtilis is a popular industrial platform for high-level production of secreted technical enzymes. Nonetheless, the effective secretion of particular heterologous enzymes remains challenging. Over the past decades various studies have tackled this problem, and major improvements were achieved by optimizing signal peptides or removing proteases involved in product degradation. On the other hand, serious bottlenecks in the protein export process per se remained enigmatic, especially for protein secretion at commercially significant levels by cells grown to high density. The aim of our present study was to assess the relevance of the intramembrane protease RasP for high-level protein production in B. subtilis. Deletion of the rasP gene resulted in reduced precursor processing and extracellular levels of the overproduced α-amylases AmyE from B. subtilis and AmyL from Bacillus licheniformis. Further, secretion of the overproduced serine protease BPN' from Bacillus amyloliquefaciens was severely impaired in the absence of RasP. Importantly, overexpression of rasP resulted in threefold increased production of a serine protease from Bacillus clausii, and 2.5- to 10-fold increased production of an AmyAc α-amylase from Paenibacillus curdlanolyticus, depending on the culture conditions. Of note, growth defects due to overproduction of the two latter enzymes were suppressed by rasP-overexpression. Here we show that an intramembrane protease, RasP, sets a limit to high-level production of two secreted heterologous enzymes that are difficult to produce in the B. subtilis cell factory. This finding was unexpected and suggests that proteolytic membrane sanitation is key to effective enzyme production in Bacillus.

  16. The non-invasive and automated detection of bovine respiratory disease onset in receiver calves using infrared thermography.

    Science.gov (United States)

    Schaefer, A L; Cook, N J; Bench, C; Chabot, J B; Colyn, J; Liu, T; Okine, E K; Stewart, M; Webster, J R

    2012-10-01

    Bovine respiratory disease complex (BRD) causes considerable economic loss and biosecurity cost to the beef industry globally and also results in significant degradation to the welfare of affected animals. The successful treatment of this disease depends on the early, timely and cost effective identification of affected animals. The objective of the present study was to investigate the use of an automated, RFID driven, noninvasive infrared thermography technology to determine BRD in cattle. Sixty-five calves averaging 220 kg were exposed to standard industry practices of transport and auction. The animals were monitored for BRD using conventional biometric signs for clinical scores, core temperatures, haematology, serum cortisol and infrared thermal values over 3 weeks. The data collected demonstrated that true positive animals for BRD based on a gold standard including core temperature, clinical score, white blood cell number and neutrophil/lymphocyte ratio displayed higher peak infrared thermal values of 35.7±0.35 °C compared to true negative animals 34.9±0.22 °C (P<0.01). The study also demonstrated that such biometric data can be non-invasively and automatically collected based on a system developed around the animal's water station. It is concluded that the deployment of such systems in the cattle industry would aid animal managers and practitioners in the identification and management of BRD in cattle populations. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. [Comparison of LCD and CRT monitors for detection of pulmonary nodules and interstitial lung diseases on digital chest radiographs by using receiver operating characteristic analysis].

    Science.gov (United States)

    Ikeda, Ryuji; Katsuragawa, Shigehiko; Shimonobou, Toshiaki; Hiai, Yasuhiro; Hashida, Masahiro; Awai, Kazuo; Yamashita, Yasuyuki; Doi, Kunio

    2006-05-20

    Soft copy reading of digital images has been practiced commonly in the PACS environment. In this study, we compared liquid-crystal display (LCD) and cathode-ray tube (CRT) monitors for detection of pulmonary nodules and interstitial lung diseases on digital chest radiographs by using receiver operating characteristic (ROC) analysis. Digital chest images with a 1000x1000 matrix size and a 8 bit grayscale were displayed on LCD/CRT monitor with 2M pixels in each observer test. Eight and ten radiologists participated in the observer tests for detection of nodules and interstitial diseases, respectively. In each observer test, radiologists marked their confidence levels for diagnosis of pulmonary nodules or interstitial diseases. The detection performance of radiologists was evaluated by ROC analyses. The average Az values (area under the ROC curve) in detecting pulmonary nodules with LCD and CRT monitors were 0.792 and 0.814, respectively. In addition, the average Az values in detecting interstitial diseases with LCD and CRT monitors were 0.951 and 0.953, respectively. There was no statistically significant difference between LCD and CRT for both detection of pulmonary nodules (P=0.522) and interstitial lung diseases (P=0.869). Therefore, we believe that the LCD monitor instead of the CRT monitor can be used for the diagnosis of pulmonary nodules and interstitial lung diseases in digital chest images.

  18. Genetic polymorphisms associated with fatty liver disease and fibrosis in HIV positive patients receiving combined antiretroviral therapy (cART.

    Directory of Open Access Journals (Sweden)

    Leona Dold

    Full Text Available Hepatic steatosis can occur with any antiretroviral therapy (cART. Although single nucleotide polymorphisms (SNPs have been identified to predispose to alcoholic and non-alcoholic fatty liver disease, their role for treatment-associated steatosis in HIV-positive patients remains unclear. We determined the frequency of PNPLA3 (rs738409, CSPG3/NCAN (rs2228603, GCKR (rs780094, PPP1R3B (rs4240624, TM6SF (rs8542926, LYPLAL1 (rs12137855 and MBOAT7 (rs626283 by RT-PCR in 117 HIV-positive patients on cART and stratified participants based on their "controlled attenuation parameter" (CAP into probable (CAP: 215-300 dB/m and definite (CAP >300 dB/m hepatic steatosis. We analyzed CAP values and routine metabolic parameters according to the allele frequencies. Sixty-five (55.6% and 13 (11.1% patients were allocated to probable and definite steatosis. CAP values (p = 0.012 and serum triglycerides (p = 0.043 were increased in carriers of the GCKR (rs780094 A allele. Cox logistic regression identified triglycerides (p = 0.006, bilirubin (p = 0.021 and BMI (p = 0.068, but not the genetic parameters as risk factors for the occurrence of hepatic steatosis. Taken together, according to the limited sample size, this exploratory study generates the hypothesis that genetic polymorphisms seem to exert minor effects on the risk for fatty liver disease in HIV-positive patients on cART. Nevertheless, SNPs may modify metabolic complications once metabolic abnormalities have developed. Hence, subsequent analysis of a larger cohort is needed.

  19. Genetic polymorphisms associated with fatty liver disease and fibrosis in HIV positive patients receiving combined antiretroviral therapy (cART)

    Science.gov (United States)

    Luda, Carolin; Schwarze-Zander, Carolynne; Boesecke, Christoph; Hansel, Cordula; Nischalke, Hans-Dieter; Lutz, Philipp; Mohr, Raphael; Wasmuth, Jan-Christian; Strassburg, Christian P.; Trebicka, Jonel; Rockstroh, Jürgen Kurt; Spengler, Ulrich

    2017-01-01

    Hepatic steatosis can occur with any antiretroviral therapy (cART). Although single nucleotide polymorphisms (SNPs) have been identified to predispose to alcoholic and non-alcoholic fatty liver disease, their role for treatment-associated steatosis in HIV-positive patients remains unclear. We determined the frequency of PNPLA3 (rs738409), CSPG3/NCAN (rs2228603), GCKR (rs780094), PPP1R3B (rs4240624), TM6SF (rs8542926), LYPLAL1 (rs12137855) and MBOAT7 (rs626283) by RT-PCR in 117 HIV-positive patients on cART and stratified participants based on their “controlled attenuation parameter” (CAP) into probable (CAP: 215–300 dB/m) and definite (CAP >300 dB/m) hepatic steatosis. We analyzed CAP values and routine metabolic parameters according to the allele frequencies. Sixty-five (55.6%) and 13 (11.1%) patients were allocated to probable and definite steatosis. CAP values (p = 0.012) and serum triglycerides (p = 0.043) were increased in carriers of the GCKR (rs780094) A allele. Cox logistic regression identified triglycerides (p = 0.006), bilirubin (p = 0.021) and BMI (p = 0.068), but not the genetic parameters as risk factors for the occurrence of hepatic steatosis. Taken together, according to the limited sample size, this exploratory study generates the hypothesis that genetic polymorphisms seem to exert minor effects on the risk for fatty liver disease in HIV-positive patients on cART. Nevertheless, SNPs may modify metabolic complications once metabolic abnormalities have developed. Hence, subsequent analysis of a larger cohort is needed. PMID:28594920

  20. The bovine papillomavirus E5 oncogene can cooperate with ras: identification of p21 amino acids critical for transformation by c-rasH but not v-rasH

    DEFF Research Database (Denmark)

    Willumsen, B M; Vass, W C; Velu, T J

    1991-01-01

    by cooperation between the BPV E5 gene and ras. E5-dependent cooperation was seen for v-rasH as well as for c-rasH, which suggests that the major effect of E5 was to increase the susceptibility of the cell to transformation to a given level of ras activity. The cooperation assay was used to test the potential......, and D. R. Lowy, Mol. Cell. Biol. 6:2646-2654, 1986). To determine if some of these amino acids are more important for the biological activity of c-rasH, we have now tested many of the same insertion-deletion mutants in the c-rasH form for their ability to transform NIH 3T3 cells. Since the transforming...

  1. Predictors of dietary and fluid non-adherence in Jordanian patients with end-stage renal disease receiving haemodialysis: a cross-sectional study.

    Science.gov (United States)

    Khalil, Amani A; Darawad, Muhammad; Al Gamal, Eklas; Hamdan-Mansour, Ayman M; Abed, Mona A

    2013-01-01

    The purpose of this study is to provide insight into the relationship between dietary and fluid non-adherence, depressive symptoms, quality of life, perceived barriers and benefits of exercise, and perceived social support among Jordanian patients with end-stage renal disease receiving haemodialysis using Pender's health promotion model. Non-adherence to dietary and fluid restrictions is a leading cause of treatment failure and poor outcomes in end-stage renal disease. Yet, factors that interfere with the patients' ability to follow their dietary restrictions are unknown. A descriptive, correlational, cross-sectional design was used. Jordanian patients (n = 190) with end-stage renal disease receiving haemodialysis from three main Jordanian cities were included. The dialysis diet and fluid nonadherence questionnaire, Beck Depression Inventory-II, Quality Of Life Index, Dialysis Patient-Perceived Exercise Benefits and Barriers Scale, and the Multidimensional Perceived Social Support were employed to measure the key variables. Patients were more likely men with mean age of 48·2 ± 14·9. Only 27% of the patients showed full commitment to diet guidelines and 23% to fluid guidelines during the last 14 days. Depression (M = 18·8 ± 11·4) had significant negative association with quality of life (importance and satisfaction) (r = -0·60, r = -0·32, p = 0·001, respectively). Multiple hierarchal regressions revealed a predictive model of only two variables: age (B = -0·22, p = 0·05) and residual renal function (B = -0·23, p = 0·012) for dietary non-adherence. Non-adherence to diet and fluid guidelines association with individual characteristics, health perception and psychosocial variables should be investigated in a longitudinal design. Relationship of non-adherence with culture-related factors should deeply be assessed among Jordanian patients with end-stage renal disease receiving haemodialysis. Identification of the factors that may worsen dietary and fluid non

  2. Ras Umm Sidd Oxygen Isotope (delta 18O) Data for 1750 to 1995

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Ras Umm Sidd bimonthly coral oxygen isotope data (coral core RUS-95). Notes on the data: File (Ras Umm Sidd d18O.txt.) includes columns for Year AD (bimonthly...

  3. Characterization of sur-2, a Novel Ras-Mediated Signal Transduction Component in C. elegans

    National Research Council Canada - National Science Library

    DesJardins, Edward

    1999-01-01

    ... (oncogenes). A subset of proto-oncogenes comprise the RAS signal transduction pathway. Vulval development in the nematode worm Caenorhabditis elegans is controlled by a RAS signal transduction pathway. C...

  4. Characterization of sur-2, a Novel Ras-Mediated Signal Transduction Component in C. elegans

    National Research Council Canada - National Science Library

    DesJardins, Edward

    1998-01-01

    ... (oncogenes). A subset of proto-oncogenes comprise the RAS signal transduction pathway. Vulval development in the nematode worm Caenorhabditis elegans is controlled by a RAS signal transduction pathway...

  5. Radiosensitivity and ras oncogene expression in preneoplastic rat tracheal epithelial cells

    International Nuclear Information System (INIS)

    Thomassen, D.G.; Wuensch, S.A.; Kelly, G.

    1988-01-01

    The sensitivity of preneoplastic rat tracheal epithelial (RTE) cells to the cytotoxic effects of high- and low-LET radiation, and the modulating effect of the viral ras oncogene on this sensitivity were determined. Two lines of preneoplastic RTE cells have the same responsiveness to high-LET radiation, but differ in their responsiveness to a transfected ras oncogene and in their sensitivities to low-LET radiation. Cells that respond to ras by becoming neoplastic are more resistant to the cytotoxic effects of low-LET radiation than cells that are not transformable by ras. The radiosensitivity of ras-responsive cells was not altered by transfection with ras. However, transfection of ras-non responsive cells with ras decreased their sensitivity to low-LET radiation. These data suggest that the ability of cells to repair radiation damage changes as they progress to neoplasia. (author)

  6. Rasputin, the Drosophila homologue of the RasGAP SH3 binding protein, functions in ras- and Rho-mediated signaling.

    Science.gov (United States)

    Pazman, C; Mayes, C A; Fanto, M; Haynes, S R; Mlodzik, M

    2000-04-01

    The small GTPase Ras plays an important role in many cellular signaling processes. Ras activity is negatively regulated by GTPase activating proteins (GAPs). It has been proposed that RasGAP may also function as an effector of Ras activity. We have identified and characterized the Drosophila homologue of the RasGAP-binding protein G3BP encoded by rasputin (rin). rin mutants are viable and display defects in photoreceptor recruitment and ommatidial polarity in the eye. Mutations in rin/G3BP genetically interact with components of the Ras signaling pathway that function at the level of Ras and above, but not with Raf/MAPK pathway components. These interactions suggest that Rin is required as an effector in Ras signaling during eye development, supporting an effector role for RasGAP. The ommatidial polarity phenotypes of rin are similar to those of RhoA and the polarity genes, e.g. fz and dsh. Although rin/G3BP interacts genetically with RhoA, affecting both photoreceptor differentiation and polarity, it does not interact with the gain-of-function genotypes of fz and dsh. These data suggest that Rin is not a general component of polarity generation, but serves a function specific to Ras and RhoA signaling pathways.

  7. Statins improve NASH via inhibition of RhoA and Ras

    DEFF Research Database (Denmark)

    Schierwagen, Robert; Maybüchen, Lara; Hittatiya, Kanishka

    2016-01-01

    in NASH. SMV blunted fibrosis due to inhibition of both RhoA/Rho kinase and Ras/ERK pathways. Interestingly, inhibition of RAC1 and Ras (by LT) failed to decrease fibrosis to the same extent. Inhibition of RAC1 (by NSC) showed no significant effect at all. Inhibition of RhoA and Ras downstream signaling...

  8. Mixing and compaction recommendations for warm mix asphalt (WMA) with recycled asphalt shingles (RAS) : final report.

    Science.gov (United States)

    2017-05-01

    The use of recycled asphalt shingles (RAS) is an attractive option for asphalt mixture producers due to the : high amount of recycled asphalt binder available in RAS. By weight, RAS contains 10 to 25% asphalt by total : weight of the shingle. The asp...

  9. Activated H-Ras regulates hematopoietic cell survival by modulating Survivin

    International Nuclear Information System (INIS)

    Fukuda, Seiji; Pelus, Louis M.

    2004-01-01

    Survivin expression and Ras activation are regulated by hematopoietic growth factors. We investigated whether activated Ras could circumvent growth factor-regulated Survivin expression and if a Ras/Survivin axis mediates growth factor independent survival and proliferation in hematopoietic cells. Survivin expression is up-regulated by IL-3 in Ba/F3 and CD34 + cells and inhibited by the Ras inhibitor, farnesylthiosalicylic acid. Over-expression of constitutively activated H-Ras (CA-Ras) in Ba/F3 cells blocked down-modulation of Survivin expression, G 0 /G 1 arrest, and apoptosis induced by IL-3 withdrawal, while dominant-negative (DN) H-Ras down-regulated Survivin. Survivin disruption by DN T34A Survivin blocked CA-Ras-induced IL-3-independent cell survival and proliferation; however, it did not affect CA-Ras-mediated enhancement of S-phase, indicating that the anti-apoptotic activity of CA-Ras is Survivin dependent while its S-phase enhancing effect is not. These results indicate that CA-Ras modulates Survivin expression independent of hematopoietic growth factors and that a CA-Ras/Survivin axis regulates survival and proliferation of transformed hematopoietic cells

  10. Association of H-ras mutations with adenocarcinomas of the parotid gland

    NARCIS (Netherlands)

    van Halteren, H. K.; Top, B.; Mooi, W. J.; Balm, A. J.; Rodenhuis, S.

    1994-01-01

    We have examined 17 adenocarcinomas and 2 mixed tumors of the salivary glands for mutational activation of the oncogenes H-ras, K-ras and N-ras. The presence of mutations was determined by in vitro amplification of gene fragments spanning codons 12, 13 and 61 and the use of mutation-specific

  11. Silencing of SPRY1 Triggers Complete Regression of Rhabdomyosarcoma Tumors Carrying a Mutated RAS Gene

    NARCIS (Netherlands)

    Schaaf, Gerben; Hamdi, Mohamed; Zwijnenburg, Danny; Lakeman, Arjan; Geerts, Dirk; Versteeg, Rogier; Kool, Marcel

    2010-01-01

    RAS oncogenes are among the most frequently mutated genes in human cancer, but effective strategies for therapeutic inhibition of the RAS pathway have been elusive. Sprouty1 (SPRY1) is an upstream antagonist of RAS that is activated by extracellular signal-related kinase (ERK), providing a negative

  12. Tingkat Adopsi Inovasi Biosecurity Ayam Ras Petelur di Kabupaten Sidrap dan Faktor- Faktor yang Mempengaruhi

    OpenAIRE

    Rusny, Rusny; Masri, Mashuri; Baba, Syahdar

    2015-01-01

    Dalam rangka mendorong adopsi inovasi biosekuriti oleh peternak ayam ras petelur, maka diperlukan pemahaman tentang adopsi inovasi biosecurity ayam ras petelur dan faktor-faktor yang mempengaruhinya. Penelitian ini bertujuan untuk mengetahui tingkat adopsi inovasi biosecurity ayam ras petelur serta faktor-faktor yang mempengaruhinya. Metode penelitian ini adalah pembobotan biosecurity yang terdiri dari biosecurity sumber ayam, biosecurity hewan pengganggu, biosecu...

  13. Overexploitation and cumulative drought trend effect on Ras El Ain ...

    Indian Academy of Sciences (India)

    The deficit of Ras El Ain spring discharge due to overexploitation factors and drought effects was estimated. ... Accordingly, it requires the development of sustainable water resources management program to reduce long-term drought risks, restore the groundwater reservoir and minimize the overexploitation effects on ...

  14. Cardiovascular disease markers responses in male receiving improved-fat meat-products vary by initial LDL-cholesterol levels.

    Directory of Open Access Journals (Sweden)

    Paloma Celada

    2016-11-01

    Full Text Available Objectives: Cardiovascular disease (CVD is prevalent in people at high meat-product consumption. To study the effect of consuming different Pâté and Frankfurter formulations on clinical/emergent CVD biomarkers in male volunteers with different initial LDL-cholesterol levels (< and ³ 3.36 mmol/L. Method: Eighteen male volunteers with at least two CVD risk factors were enrolled in a crossover controlled study. Pork-products were consumed during 4wk: reduced-fat (RF, omega-3-enriched-RF (n-3RF, and normal-fat (NF. Pork-products were separated by 4wk washout. Lipids, lipoproteins, oxidized LDL (oxLDL, apolipoproteins (apo and their ratios, homocysteine (tHcys, arylesterase (AE, C-reactive protein (CRP, tumor necrotic factor (TNFa were tested. Results: The rate of change for AE, oxLDL, Lp(a, AE/HDL-cholesterol, LDL/apo B and AE/oxLDL ratios varied (p<0.05 among periods only in volunteers with LDLcholesterol ³3.36 mmol/L. TNFa decreased (p<0.05 among volunteers with low-normal LDL-cholesterol values while AE increased (p<0.01 in high LDL-cholesterol volunteers during the RF-period. AE increased while CRP decreased (both p<0.01 in low-normal LDL-cholesterol volunteers while AE (p<0.001 and apo B (p<0.01 increased in the high LDL-cholesterol group during the n-3RF-period. Total cholesterol (p<0.05 increased in the low/normal LDL-cholesterol group while tHcys decreased (p<0.05 in the high LDL-cholesterol group during the NF-period. Differences in response in volunteers with low-normal vs. high initial LDL-cholesterol levels to the n-3RF but not to the RF meat-products seem evident. Conclusions: Subjects with high LDL-cholesterol seem target for n-3RF products while subjects with LDL-cholesterol <3.36 mmol/L were more negatively affected by NF-products. Any generalization about functional meat product or consumption should be avoided.

  15. An investigation on the level of dental senior students knowledge about endocarditis prophylaxis incases with cardiac disease receiving dental treatment

    Directory of Open Access Journals (Sweden)

    Fakhraee AH

    2004-02-01

    Full Text Available Dental practices such as oral, periodontal and endodontic surgeries cause damages to"nthe intraoral tissues, so having knowledge of the dental procedures that necessiciate endocarditis prophylaxis"nis of high importance."nPurpose: The aim of the present study was to determine the knowledge level of dental senior students in"nTehran dental faculties about endocarditis,"nMaterials and Methods: In this cross- sectional descriptive- analytic study, 253 senior students of four"ndentistry faculties in Tehran took part as follows: Tehran University: 71 students (M:42, F:29, Shahid"nBeheshti University: 74 students (M:40, F:34, Shahed University: 35 students (M:35, F:38, Azad University:"n73 students (M:35, F:38. The questionnaire used in this research consisted of three parts as follows: part one:"ninformation on cardiac diseases, part two: dental procedures requiring endocarditis prophylaxis, part three:"nantibiotic diet in endocarditis prophylaxis. Sex and place of education of the students were also studied in"ndetail. For statistical analysis, Chi-square test was used."nResults: On the basis of the sex, the correct answers of the female respondents of different universities were"nranked as: Azad University: 72.5%, Tehran University: 71.1%, Shahid Beheshti: 57%, ShahedUniversity:"n55.7%. In the same way, the male respondents were reported as: Tehran Universitys: 71.6%, Azad University:"n66.2%, Shahed University: 57.3%, Shahid Behesti University: 52.1%, On the basis of the place of education,"nthe following results were reported: Tehran University students managed to answer 71.3% , Azad University,"nShahed University and Shahid Beheshti University students could answer 69.5%, 56.5% and 54.6%,"nrespectively. All these differences were statistically significant, indicating that first ranked students have more"ninformation than the students of other schools."nConclusion: It is recommended to develop more practical training programme in dental schools on

  16. Renin-angiotensin system gene expression and neurodegenerative diseases.

    Science.gov (United States)

    Goldstein, Benjamin; Speth, Robert C; Trivedi, Malav

    2016-07-01

    Single nucleotide polymorphisms and altered gene expression of components of the renin-angiotensin system (RAS) are associated with neurodegenerative diseases. Drugs that interact with the RAS have been shown to affect the course of neurodegenerative disease, suggesting that abnormalities in the RAS may contribute to neurodegenerative disease. A meta-analysis of genome-wide association studies and gene expression data for 14 RAS-related proteins was carried out for five neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, narcolepsy, amyotrophic lateral sclerosis and multiple sclerosis. No single nucleotide polymorphisms in any of the 14 RAS-related protein genes were significantly associated with the five neurodegenerative diseases investigated. There was an inverse association between expression of ATP6AP2, which encodes the (pro)renin receptor, and multiple sclerosis, Alzheimer's disease and Parkinson's disease. An association of AGTR, which encodes the AT1 angiotensin II receptor, and Parkinson's disease and Alzheimer's disease was also observed. To date, no single nucleotide polymorphisms in components of the RAS can be definitively linked to the neurodegenerative diseases evaluated in this study. However, altered gene expression of several components of the RAS is associated with several neurodegenerative diseases, which may indicate that the RAS contributes to the pathology of these diseases. © The Author(s) 2016.

  17. Ras-mediated deregulation of the circadian clock in cancer.

    Directory of Open Access Journals (Sweden)

    Angela Relógio

    Full Text Available Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.

  18. Ras-Mediated Deregulation of the Circadian Clock in Cancer

    Science.gov (United States)

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  19. Langerhans cell histiocytosis: A neoplastic disorder driven by Ras-ERK pathway mutations.

    Science.gov (United States)

    Tran, Gary; Huynh, Thy N; Paller, Amy S

    2018-03-01

    Langerhans cell histiocytosis (LCH) is a disorder of myeloid neoplasia of dendritic cells that affects 1 in 200,000 children <15 years of age and even fewer adults. LCH presents with a spectrum of clinical manifestations. High-risk stratification is reserved for infiltration of blood, spleen, liver, and lungs. After decades of debate on the disease pathogenesis, a neoplastic mechanism is now favored on the basis of LCH cell clonality, rare cases of familial clustering, and recent evidence of mutations involving the Ras/Raf/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase) pathway in lesional biopsy specimens. Somatic mutations are most often found in BRAF (BRAF V600E in 47.1% of reported patients) and MAP2K1 (21.7%) and uncommonly found in MAP3K1 or ARAF. Increased levels of phospho-ERK in lesional tissue, activation of Ras/Raf/MEK/ERK signaling with these mutations in vitro, and the mutual exclusivity of these mutations in a given patient suggest a central role for activation of the Ras/Raf/MEK/ERK oncogenic pathway in LCH. Immunohistochemical assessment of lesional tissue using the VE1 BRAF V600E mutation-specific antibody can serve as a screening tool for BRAF V600E -positive LCH. Case reports suggest that BRAF V600E -positive LCH unresponsive to standard therapy might respond to B-Raf-MEK pathway inhibition, but rigorous randomized clinical trials have yet to be performed. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  20. Serologic response after vaccination against influenza (A/H1N1)pdm09 in children with renal disease receiving oral immunosuppressive drugs.

    Science.gov (United States)

    Tanaka, Seiji; Saikusa, Tomoko; Katafuchi, Yuno; Ushijima, Kosuke; Ohtsu, Yasushi; Tsumura, Naoki; Ito, Yuhei

    2015-09-11

    A limited number of reports are available regarding the effect of the influenza vaccine in pediatric patients receiving steroid and immunosuppressant therapy. The influenza A(H1N1)pdm09 vaccine was administered to 15 children with renal disease who were receiving steroid and immunosuppressant therapy (treatment group) and 23 children with who were not receiving these drugs (non-treatment group). Titer transition of the hemagglutination inhibition antibody was compared between the 2 groups immediately before vaccination and 4 weeks and 6 months after vaccination. Multivariate analysis showed a significant correlation between geometric mean titer, SCR, and SPR with age, while no correlation was observed between treatment with immunosuppressant therapy and efficacy. No serious adverse reactions occurred after vaccination. This strain is not present in existing influenza vaccines, and A(H1N1)pdm09HA vaccination was administered alone in 2009. The children in this study had not previously been exposed to this strain. Therefore, we evaluated the effect of the A(H1N1)pdm09HA vaccine without the effects of vaccination or past infection with A(H1N1)pdm09HA or A(H3N2) vaccination in the previous year. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. The farnesyltransferase inhibitor, LB42708, inhibits growth and induces apoptosis irreversibly in H-ras and K-ras-transformed rat intestinal epithelial cells

    International Nuclear Information System (INIS)

    Kim, Han-Soo; Kim, Ju Won; Gang, Jingu; Wen, Jing; Koh, Sang Seok; Koh, Jong Sung; Chung, Hyun-Ho; Song, Si Young

    2006-01-01

    LB42708 (LB7) and LB42908 (LB9) are pyrrole-based orally active farnesyltransferase inhibitors (FTIs) that have similar structures. The in vitro potencies of these compounds against FTase and GGTase I are remarkably similar, and yet they display different activity in apoptosis induction and morphological reversion of ras-transformed rat intestinal epithelial (RIE) cells. Both FTIs induced cell death despite K-ras prenylation, implying the participation of Ras-independent mechanism(s). Growth inhibition by these two FTIs was accompanied by G1 and G2/M cell cycle arrests in H-ras and K-ras-transformed RIE cells, respectively. We identified three key markers, p21 CIP1/WAF1 , RhoB and EGFR, that can explain the differences in the molecular mechanism of action between two FTIs. Only LB7 induced the upregulation of p21 CIP1/WAF1 and RhoB above the basal level that led to the cell cycle arrest and to distinct morphological alterations of ras-transformed RIE cells. Both FTIs successfully inhibited the ERK and activated JNK in RIE/K-ras cells. While the addition of conditioned medium from RIE/K-ras reversed the growth inhibition of ras-transformed RIE cells by LB9, it failed to overcome the growth inhibitory effect of LB7 in both H-ras- and K-ras-transformed RIE cells. We found that LB7, but not LB9, decreased the expression of EGFRs that confers the cellular unresponsiveness to EGFR ligands. These results suggest that LB7 causes the induction of p21 CIP1/WAF1 and RhoB and downregulation of EGFR that may serve as critical steps in the mechanism by which FTIs trigger irreversible inhibitions on the cell growth and apoptosis in ras-transformed cells

  2. Stereotactic Radiation Therapy can Safely and Durably Control Sites of Extra-Central Nervous System Oligoprogressive Disease in Anaplastic Lymphoma Kinase-Positive Lung Cancer Patients Receiving Crizotinib

    Energy Technology Data Exchange (ETDEWEB)

    Gan, Gregory N., E-mail: gregory.gan@ucdenver.edu [Department of Radiation Oncology, University of Colorado, Aurora, Colorado (United States); Weickhardt, Andrew J.; Scheier, Benjamin; Doebele, Robert C. [Department of Medical Oncology, University of Colorado, Aurora, Colorado (United States); Gaspar, Laurie E.; Kavanagh, Brian D. [Department of Radiation Oncology, University of Colorado, Aurora, Colorado (United States); Camidge, D. Ross [Department of Medical Oncology, University of Colorado, Aurora, Colorado (United States)

    2014-03-15

    Purpose: To analyze the durability and toxicity of radiotherapeutic local ablative therapy (LAT) applied to extra-central nervous system (eCNS) disease progression in anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC) patients. Methods and Materials: Anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib and manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT. Results: Of 38 patients, 33 progressed while taking crizotinib. Of these, 14 had eCNS progression meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1-3 courses of LAT with radiation therapy. The 6- and 12-month actuarial local lesion control rates with radiation therapy were 100% and 86%, respectively. The 12-month local lesion control rate with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% versus 60% (P=.01). No acute or late grade >2 radiation therapy-related toxicities were observed. Median overall time taking crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 versus 10.1 months, respectively. Patients continuing to take crizotinib for >12 months versus ≤12 months had a 2-year overall survival rate of 72% versus 12%, respectively (P<.0001). Conclusions: Local ablative therapy safely and durably eradicated sites of individual lesion progression in anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib. A dose–response relationship for local lesion control was observed. The suppression of OPD by LAT in patients taking crizotinib allowed an extended duration of exposure to crizotinib, which was associated with longer overall survival.

  3. Renal cell carcinoma co-existent with other renal disease: clinico-pathological features in pre-dialysis patients and those receiving dialysis or renal transplantation.

    Science.gov (United States)

    Peces, Ramón; Martínez-Ara, Jorge; Miguel, José Luis; Arrieta, Javier; Costero, Olga; Górriz, José Luis; Picazo, Mari-Luz; Fresno, Manuel

    2004-11-01

    Patients on chronic dialysis are prone to developing acquired cystic kidney disease (ACKD), which may lead to the development of renal cell carcinoma (RCC). The risk factors for the development of RCC so far have not been determined in pre-dialysis patients with co-existent renal disease. The aim of this study was to evaluate the clinico-pathological features of RCC in pre-dialysis patients with associated renal diseases or in those undergoing chronic dialysis and renal transplantation. We studied 32 kidneys from 31 patients with RCC and associated renal diseases. Of those, 18 kidneys were from 17 patients not on renal replacement therapy (RRT) when diagnosed with RCC; 14 patients received dialysis or dialysis followed by renal transplantation. Several clinico-pathological features were analysed and compared between the two groups. Overall, there was a preponderance of males (75%); nephrosclerosis was the predominant co-existent disease (31%). The median intervals from renal disease to RCC in the dialysis and transplanted groups were significantly longer than in the pre-dialysis group (15.8+/-1.1 vs 2.4+/-0.7 years, P<0.0001). In contrast to pre-dialysis RCC, the dialysis and transplant RCC groups had greater frequency of ACKD (100 vs 28%, P<0.0001), papillary type RCC (43 vs 11%, P<0.05) and multifocal tumours (43 vs 5%, P<0.05). At the end of the study, 71% of dialysis and transplanted patients and 72% of pre-dialysis patients were alive. ACKD develops in dialysis patients, as it does in those with renal disease prior to RRT. The duration of renal disease, rather than the dialysis procedure itself, appears to be the main determinant of ACKD and RCC. The RCC occurring in patients with ACKD and prolonged RRT is more frequently of the papillary type and multifocal than the RCC occurring in patients with no or few acquired cysts and a short history of renal disease. Long-term outcomes did not differ between the two groups.

  4. [Expressions of Ras and Sos1 in epithelial ovarian cancer tissues and their clinical significance].

    Science.gov (United States)

    Xiao, Zheng-Hua; Linghu, Hua; Liu, Qian-Fen

    2016-11-20

    To detect the expressions of Ras and Sos1 proteins in human epithelial ovarian cancer (EOC) tissues and explore their correlation with the clinicopathological features of the patients. The expressions of Ras and Sos1 proteins were detected immunohistochemically in 62 EOC tissues, 5 borderline ovarian cancer tissues, 15 benign epithelial ovarian neoplasm tissues, and 18 normal ovarian tissues. The EOC tissues showed significantly higher expression levels of both Ras and Sos1 than the other tissues tested (Ptissues, Ras and Sos1 proteins were expressed mostly on the cell membrane and in the cytoplasm. The expression level of Ras was correlated with pathological types of the tumor (Ptissue-specific variation of Ras expression can lend support to a specific diagnosis of ovarian serous adenocarcinoma. The association of Ras and Sos1 protein expression with the tumor-free survival time of the patients awaits further investigation with a larger sample size.

  5. Gingival Bleeding and Bloody Dialysate: A Case Report of Scurvy in a Child With End-Stage Renal Disease Receiving Peritoneal Dialysis.

    Science.gov (United States)

    Kittisakmontri, Kulnipa; Swangtrakul, Napatsayod; Padungmaneesub, Wiralpatch; Charoenkwan, Pimlak

    2016-11-01

    Patients with chronic kidney disease (CKD) or end-stage renal disease are at risk for vitamin C deficiency and scurvy due to diet restriction, increased urinary loss of the water-soluble vitamin C with diuretics, and in case of patients who are on dialysis, through dialysates. The condition may be overlooked as the clinical manifestation of scurvy may be subtle, and some presentations may mimic clinical signs in CKD. We reported a case of scurvy presenting with gingival bleeding and blood dialysate in a 6-year-old girl with end-stage renal disease who was on continuous ambulatory peritoneal dialysis. Physical examination showed gingival hyperplasia and bleeding, and the pathognomonic bleeding of perifollicular hemorrhage. The typical radiographic changes were present. The clinical signs and symptoms resolved after ascorbic acid treatment. This case underscores the importance of awareness of the increased risk for vitamin C deficiency in patients with CKD and receiving dialysis. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  6. Oncogenic K-ras promotes early carcinogenesis in the mouse proximal colon

    Science.gov (United States)

    Calcagno, Shelly R.; Li, Shuhua; Colon, Migdalisel; Kreinest, Pamela A.; Thompson, E. Aubrey; Fields, Alan P.; Murray, Nicole R.

    2014-01-01

    Oncogenic K-ras mutations are frequently observed in colon cancers and contribute to transformed growth. Oncogenic K-ras is detected in aberrant crypt foci (ACF), precancerous colonic lesions, demonstrating that acquisition of a K-ras mutation is an early event in colon carcinogenesis. Here, we investigate the role of oncogenic K-ras in neoplastic initiation and progression. Transgenic mice in which an oncogenic K-rasG12D allele is activated in the colonic epithelium by sporadic recombination (K-rasLA2 mice) develop spontaneous ACF that are morphologically indistinguishable from those induced by the colon carcinogen azoxymethane (AOM). Similar neoplastic changes involving the entire colon are induced in transgenic mice constitutively expressing K-rasG12D throughout the colon (LSL-K-rasG12D/Villin-Cre mice). However, the biochemistry and fate of K-ras-induced lesions differ depending upon their location within the colon in these mice. In the proximal colon, K-rasG12D induces increased expression of procarcinogenic protein kinase CβII (PKCβII), activation of the MEK/ERK signaling axis and increased epithelial cell proliferation. In contrast, in the distal colon, K-rasG12D inhibits expression of procarcinogenic PKCβII and induces apoptosis. Treatment of K-rasLA2 mice with AOM leads to neoplastic progression of small ACF to large, dysplastic microadenomas in the proximal, but not the distal colon. Thus, oncogenic K-ras functions differently in the proximal and distal colon of mice, inducing ACF capable of neoplastic progression in the proximal colon, and ACF with little or no potential for progression in the distal colon. Our data indicate that acquisition of a K-ras mutation is an initiating neoplastic event in proximal colon cancer development in mice. PMID:18271008

  7. RasGRP1, but not RasGRP3, is required for efficient thymic β-selection and ERK activation downstream of CXCR4.

    Directory of Open Access Journals (Sweden)

    Dominic P Golec

    Full Text Available T cell development is a highly dynamic process that is driven by interactions between developing thymocytes and the thymic microenvironment. Upon entering the thymus, the earliest thymic progenitors, called CD4(-CD8(- 'double negative' (DN thymocytes, pass through a checkpoint termed "β-selection" before maturing into CD4(+CD8(+ 'double positive' (DP thymocytes. β-selection is an important developmental checkpoint during thymopoiesis where developing DN thymocytes that successfully express the pre-T cell receptor (TCR undergo extensive proliferation and differentiation towards the DP stage. Signals transduced through the pre-TCR, chemokine receptor CXCR4 and Notch are thought to drive β-selection. Additionally, it has long been known that ERK is activated during β-selection; however the pathways regulating ERK activation remain unknown. Here, we performed a detailed analysis of the β-selection events in mice lacking RasGRP1, RasGRP3 and RasGRP1 and 3. We report that RasGRP1 KO and RasGRP1/3 DKO deficient thymi show a partial developmental block at the early DN3 stage of development. Furthermore, DN3 thymocytes from RasGRP1 and RasGRP1/3 double knock-out thymi show significantly reduced proliferation, despite expression of the TCRβ chain. As a result of impaired β-selection, the pool of TCRβ(+ DN4 is significantly diminished, resulting in inefficient DN to DP development. Also, we report that RasGRP1 is required for ERK activation downstream of CXCR4 signaling, which we hypothesize represents a potential mechanism of RasGRP1 regulation of β-selection. Our results demonstrate that RasGRP1 is an important regulator of proliferation and differentiation at the β-selection checkpoint and functions downstream of CXCR4 to activate the Ras/MAPK pathway.

  8. Pioglitazone and the risk of cardiovascular events in patients with Type 2 diabetes receiving concomitant treatment with nitrates, renin-angiotensin system blockers, or insulin: results from the PROactive study (PROactive 20).

    Science.gov (United States)

    Erdmann, Erland; Spanheimer, Robert; Charbonnel, Bernard

    2010-09-01

    Patients with Type 2 diabetes mellitus (T2DM) are often treated with multiple glucose-lowering and cardiovascular agents. The concomitant use of nitrates, renin-angiotensin system (RAS) blockers, or insulin has been linked to a potential increase in myocardial ischemic risk with rosiglitazone. The PROactive database provides an opportunity to investigate the effects of these medications on the potential macrovascular benefits reported with pioglitazone. The PROactive study was a randomized double-blind prospective trial that evaluated mortality and cardiovascular morbidity in 5238 patients with T2DM and macrovascular disease. Patients received pioglitazone or placebo in addition to their baseline glucose-lowering and cardiovascular medications. The effect of pioglitazone on composite endpoints was evaluated, including all-cause death, myocardial infarction (MI), and stroke, as well as safety events of edema and serious heart failure, in subgroups using nitrates, RAS blockers, or insulin at baseline. The risk of all-cause death, MI, and stroke for pioglitazone versus placebo was similar regardless of the baseline use of nitrates, RAS blockers, or insulin, with hazard ratios ranging from 0.81 to 0.87. Similar results were obtained for the other composite endpoints analyzed. There were no significant interactions between baseline medication subgroups and treatment. The increased risk of edema and serious heart failure was consistent across the baseline medication subgroups. This post hoc analysis did not reveal an increased risk of macrovascular events with pioglitazone in patients receiving nitrates, RAS blockers, or insulin. Rather, all patients realized the same trend towards benefit with pioglitazone, and adverse events of edema and heart failure were predictable. © 2010 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

  9. Gamma band activity in the reticular activating system (RAS

    Directory of Open Access Journals (Sweden)

    Francisco J Urbano

    2012-01-01

    Full Text Available This review considers recent evidence showing that cells in three regions of the reticular activating system (RAS exhibit gamma band activity, and describes the mechanisms behind such manifestation. Specifically, we discuss how cells in the mesopontine pedunculopontine nucleus (PPN, intralaminar parafascicular nucleus (Pf, and pontine Subcoeruleus nucleus dorsalis (SubCD all fire in the beta/gamma band range when maximally activated, but no higher. The mechanisms behind this ceiling effect have been recently elucidated. We describe recent findings showing that every cell in the PPN have high threshold, voltage-dependent P/Q-type calcium channels that are essential, while N-type calcium channels are permissive, to gamma band activity. Every cell in the Pf also showed that P/Q-type and N-type calcium channels are responsible for this activity. On the other hand, every SubCD cell exhibited sodium-dependent subthreshold oscillations. A novel mechanism for sleep-wake control based on well-known transmitter interactions, electrical coupling, and gamma band activity is described. The data presented here on inherent gamma band activity demonstrates the global nature of sleep-wake oscillation that is orchestrated by brainstem-thalamic mechanism, and questions the undue importance given to the hypothalamus for regulation of sleep-wakefulness. The discovery of gamma band activity in the RAS follows recent reports of such activity in other subcortical regions like the hippocampus and cerebellum. We hypothesize that, rather than participating in the temporal binding of sensory events as seen in the cortex, gamma band activity manifested in the RAS may help stabilize coherence related to arousal, providing a stable activation state during waking and paradoxical sleep. Most of our thoughts and actions are driven by preconscious processes. We speculate that continuous sensory input will induce gamma band activity in the RAS that could participate in the

  10. Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study.

    Science.gov (United States)

    Boswood, A; Gordon, S G; Häggström, J; Wess, G; Stepien, R L; Oyama, M A; Keene, B W; Bonagura, J; MacDonald, K A; Patteson, M; Smith, S; Fox, P R; Sanderson, K; Woolley, R; Szatmári, V; Menaut, P; Church, W M; O'Sullivan, M L; Jaudon, J-P; Kresken, J-G; Rush, J; Barrett, K A; Rosenthal, S L; Saunders, A B; Ljungvall, I; Deinert, M; Bomassi, E; Estrada, A H; Fernandez Del Palacio, M J; Moise, N S; Abbott, J A; Fujii, Y; Spier, A; Luethy, M W; Santilli, R A; Uechi, M; Tidholm, A; Schummer, C; Watson, P

    2018-01-01

    Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac-related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan-treated dogs differ from dogs receiving placebo at onset of CHF. Three hundred and fifty-four dogs with MMVD and cardiomegaly. Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4-0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart-size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short-term changes in echocardiographic variables and time to CHF or CRD were explored. At day 35, heart size had reduced in the pimobendan group: median change in (Δ) LVIDDN -0.06 (IQR: -0.15 to +0.02), P dogs treated with pimobendan were indistinguishable from those receiving placebo. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  11. Association between human resources and risk of hospitalisation in end-stage renal disease outpatients receiving haemodialysis: a longitudinal cohort study using claim data during 2013-2014.

    Science.gov (United States)

    Choi, Hoon-Hee; Han, Kyu-Tae; Nam, Chung Mo; Moon, Ki Tae; Kim, Woorim; Park, Eun-Cheol

    2016-08-17

    The number of patients requiring haemodialysis has gradually increased in South Korea. Owing to this growth, concerns have been raised regarding haemodialysis quality of care, and healthcare professionals must consider alternatives for appropriate management of patients with chronic kidney disease (CKD). Therefore, we investigated the association between risk of hospitalisation of outpatients who received haemodialysis due to end-stage renal disease (ESRD) and the human resources of the haemodialysis unit. We used data from National Health Insurance (NHI) claims during October 2013 to September 2014. These data comprised 40 543 outpatients with ESRD (4 751 047 outpatient cases) who received haemodialysis. No interventions were made. We performed Poisson regression analysis using a generalised estimating equation that included both patient and haemodialysis unit characteristics to examine the factors associated with hospitalisation of outpatients with ESRD. Among 4 751 047 outpatient cases, 27 997 (0.59%) were hospitalised during the study period. A higher proportion of haemodialysis patient care specialists and a higher number of nurses experienced in haemodialysis were inversely associated with the risk of hospitalisation (per 10% increase in haemodialysis patient care specialists: relative risk (RR)=0.987, 95% CI 0.981 to 0.993; per 10-person increase in nurses who provided haemodialysis: RR=0.876, 95% CI 0.833 to 0.921). In addition, such associations were greater in severe patients. Our findings suggest that haemodialysis units with high-quality, haemodialysis-specialised human resources could positively affect the outcomes of outpatients with ESRD. Based on our findings, health policymakers and professionals should implement strategies for the optimal management of patients with CKD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  12. Clinically meaningful treatment responses after switching to galantamine and with addition of memantine in patients with Alzheimer’s disease receiving donepezil

    Directory of Open Access Journals (Sweden)

    Kano O

    2013-02-01

    Full Text Available Osamu Kano,1 Hirono Ito,1 Takanori Takazawa,1 Yuji Kawase,1 Kiyoko Murata,1 Konosuke Iwamoto,1 Tetsuro Nagaoka,1 Takehisa Hirayama,1 Ken Miura,1 Riya Nagata,1 Tetsuhito Kiyozuka,2 Jo Aoyagi,2 Ryuta Sato,2 Teruo Eguchi,3 Ken Ikeda,1 Yasuo Iwasaki11Department of Neurology, Toho University Omori Medical Center, 2Department of Neurology, Federation of National Public Service Personnel Mutual Aid Associations Mishuku Hospital, 3Sakura-kai Medical Group, Tokyo, JapanAbstract: Clinical trials have shown the benefits of acetylcholinesterase inhibitors, such as donepezil and galantamine, and an N-methyl-d-aspartate receptor antagonist, memantine, in patients with Alzheimer’s disease (AD. However, little is known regarding the effects of switching from donepezil 5 mg/day to galantamine 16 or 24 mg/day, or regarding the effects of adding memantine to established therapy compared with increasing the dose of donepezil. This report discusses two studies conducted to evaluate treatment with galantamine and memantine with respect to cognitive benefits and caregiver evaluations in patients with AD receiving donepezil 5 mg/day for more than 6 months. Patients with mild or moderate AD (scores 10–22 on the Mini-Mental State Examination were enrolled in the Galantamine Switch study and switched to galantamine (maximum doses 16 mg versus 24 mg. Patients with moderate to severe AD (Mini-Mental State Examination scores 3–14 were enrolled in the Donepezil Increase versus Additional Memantine study and either had their donepezil dose increased to 10 mg/day or memantine 20 mg/day added to their existing donepezil dose. Patients received the study treatment for 28 weeks and their Disability Assessment for Dementia, Mental Function Impairment Scale, Cohen-Mansfield Agitation Inventory, and Neuropsychiatric Inventory scores were assessed with assistance from their caregivers. For the Galantamine Switch study after 8 weeks, agitation evaluated by the Cohen

  13. Biophysical mechanism for ras-nanocluster formation and signaling in plasma membrane.

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    Thomas Gurry

    2009-07-01

    Full Text Available Ras GTPases are lipid-anchored G proteins, which play a fundamental role in cell signaling processes. Electron micrographs of immunogold-labeled Ras have shown that membrane-bound Ras molecules segregate into nanocluster domains. Several models have been developed in attempts to obtain quantitative descriptions of nanocluster formation, but all have relied on assumptions such as a constant, expression-level independent ratio of Ras in clusters to Ras monomers (cluster/monomer ratio. However, this assumption is inconsistent with the law of mass action. Here, we present a biophysical model of Ras clustering based on short-range attraction and long-range repulsion between Ras molecules in the membrane. To test this model, we performed Monte Carlo simulations and compared statistical clustering properties with experimental data. We find that we can recover the experimentally-observed clustering across a range of Ras expression levels, without assuming a constant cluster/monomer ratio or the existence of lipid rafts. In addition, our model makes predictions about the signaling properties of Ras nanoclusters in support of the idea that Ras nanoclusters act as an analog-digital-analog converter for high fidelity signaling.

  14. Specific regulation of point-mutated K-ras-immortalized cell proliferation by a photodynamic antisense strategy.

    Science.gov (United States)

    Higuchi, Maiko; Yamayoshi, Asako; Kato, Kiyoko; Kobori, Akio; Wake, Norio; Murakami, Akira

    2010-02-01

    It has been reported that point mutations in genes are responsible for various cancers, and the selective regulation of gene expression is an important factor in developing new types of anticancer drugs. To develop effective drugs for the regulation of point-mutated genes, we focused on photoreactive antisense oligonucleotides. Previously, we reported that photoreactive oligonucleotides containing 2'-O-psoralenylmethoxyethyl adenosine (2'-Ps-eom) showed drastic photoreactivity in a strictly sequence-specific manner. Here, we demonstrated the specific gene regulatory effects of 2'-Ps-eom on [(12)Val]K-ras mutant (GGT --> GTT). Photo-cross-linking between target mRNAs and 2'-Ps-eom was sequence-specific, and the effect was UVA irradiation-dependent. Furthermore, 2'-Ps-eom was able to inhibit K-ras-immortalized cell proliferation (K12V) but not Vco cells that have the wild-type K-ras gene. These results suggest that the 2'-Ps-eom will be a powerful nucleic acid drug to inhibit the expression of disease-causing point mutation genes, and has great therapeutic potential in the treatment of cancer.

  15. Investigation on the Effect of Recycled Asphalt Shingle (RAS in Portland Cement Mortar

    Directory of Open Access Journals (Sweden)

    Jinwoo An

    2016-04-01

    Full Text Available Tear-off roofing shingle, referred to as Reclaimed asphalt shingle (RAS, is the byproduct of construction demolition and it is a major solid waste stream in the U.S. Reuse of this byproduct in road construction sector can contribute to the success of materials sustainability as well as landfill conservation. Ground RAS has similar particle distribution as sand and its major component includes aggregate granules, fibers, and asphalt. To promote the beneficial utilization of RAS, this study evaluates the effect of RAS in cement mortar when used as replacement of sand. In addition, the study investigates how cellulose fibers from RAS behave under high alkaline environment during cement hydration process, which may significantly affect mortar’s strength performance. The laboratory study includes measurements of physical, mechanical, and durability behaviors of cement mortar containing RAS replacing sand up to 30%. It was found that the optimum mixture proportions are 5% and 10% for compressive strength and toughness, respectively.

  16. Ras1(CA) overexpression in the posterior silk gland improves silk yield.

    Science.gov (United States)

    Ma, Li; Xu, Hanfu; Zhu, Jinqi; Ma, Sanyuan; Liu, Yan; Jiang, Rong-Jing; Xia, Qingyou; Li, Sheng

    2011-06-01

    Sericulture has been greatly advanced by applying hybrid breeding techniques to the domesticated silkworm, Bombyx mori, but has reached a plateau during the last decades. For the first time, we report improved silk yield in a GAL4/UAS transgenic silkworm. Overexpression of the Ras1(CA) oncogene specifically in the posterior silk gland improved fibroin production and silk yield by 60%, while increasing food consumption by only 20%. Ras activation by Ras1(CA) overexpression in the posterior silk gland enhanced phosphorylation levels of Ras downstream effector proteins, up-regulated fibroin mRNA levels, increased total DNA content, and stimulated endoreplication. Moreover, Ras1 activation increased cell and nuclei sizes, enriched subcellular organelles related to protein synthesis, and stimulated ribosome biogenesis for mRNA translation. We conclude that Ras1 activation increases cell size and protein synthesis in the posterior silk gland, leading to silk yield improvement.

  17. Characterization of a novel oncogenic K-ras mutation in colon cancer

    International Nuclear Information System (INIS)

    Akagi, Kiwamu; Uchibori, Ryosuke; Yamaguchi, Kensei; Kurosawa, Keiko; Tanaka, Yoichiro; Kozu, Tomoko

    2007-01-01

    Activating mutations of RAS are frequently observed in subsets of human cancers, indicating that RAS activation is involved in tumorigenesis. Here, we identified and characterized a novel G to T transversion mutation of the K-ras gene at the third position of codon 19 (TTG) which substituted phenylalanine for leucine in 3 primary colon carcinomas. Biological and biochemical activity was examined using transformed NIH3T3 cells expressing mutant or wild-type K-ras. Transformants harboring the K-ras mutation at codon 19 showed proliferative capacity under serum-starved conditions, less contact inhibition, anchorage-independent growth, tumorigenicity in nude mice and elevation of active Ras-GTP levels. These results indicated that this novel mutation possesses high oncogenic activity

  18. Development of the Andalusian Registry of Patients Receiving Community Case Management, for the follow-up of people with complex chronic diseases.

    Science.gov (United States)

    Morales-Asencio, Jose M; Kaknani-Uttumchandani, Shakira; Cuevas-Fernández-Gallego, Magdalena; Palacios-Gómez, Leopoldo; Gutiérrez-Sequera, José L; Silvano-Arranz, Agustina; Batres-Sicilia, Juan Pedro; Delgado-Romero, Ascensión; Cejudo-Lopez, Ángela; Trabado-Herrera, Manuel; García-Lara, Esteban L; Martin-Santos, Francisco J; Morilla-Herrera, Juan C

    2015-10-01

    Complex chronic diseases are a challenge for the current configuration of health services. Case management is a service frequently provided for people with chronic conditions, and despite its effectiveness in many outcomes, such as mortality or readmissions, uncertainty remains about the most effective form of team organization, structures and the nature of the interventions. Many processes and outcomes of case management for people with complex chronic conditions cannot be addressed with the information provided by electronic clinical records. Registries are frequently used to deal with this weakness. The aim of this study was to generate a registry-based information system of patients receiving case management to identify their clinical characteristics, their context of care, events identified during their follow-up, interventions developed by case managers and services used. The study was divided into three phases, covering the detection of information needs, the design and its implementation in the health care system, using literature review and expert consensus methods to select variables that would be included in the registry. A total of 102 variables representing structure, processes and outcomes of case management were selected for their inclusion in the registry after the consensus phase. A web-based registry with modular and layered architecture was designed. The framework follows a pattern based on the model-view-controller approach. In its first 6 months after the implementation, 102 case managers have introduced an average number of 6.49 patients each one. The registry permits a complete and in-depth analysis of the characteristics of the patients who receive case management, the interventions delivered and some major outcomes as mortality, readmissions or adverse events. © 2015 John Wiley & Sons, Ltd.

  19. Effect of supportive psychotherapy on mental health status and quality of life of female cancer patients receiving chemotherapy for recurrent disease

    Directory of Open Access Journals (Sweden)

    Anindita Mukherjee

    2017-01-01

    Full Text Available Context: Cancer patients receiving chemotherapy for their recurrent disease often report the presence of anxiety and depression. Aims: In the study, we intended to find out the mental health status and overall quality of life (QOL of such patients and to identify the effect of supportive psychotherapy. Subjects and Methods: Forty cancer patients undergoing second or subsequent line chemotherapy(CCT were selected for psychotherapy session. Pre- and post-psychotherapy evaluation of anxiety and depression was determined by hospital anxiety depression scale. The QOL was measured before and after psychotherapy sessions by using WHO QOL-BREF scale. Statistical Analysis Used: Statistical analysis was done by paired t-test, using SPSS V.20. Results: Among 40 patients, 17 patients had breast cancer, and the remaining had ovarian cancer. All breast cancer and 19 ovarian cancer patients were receiving 2nd line CCT. Four ovarian cancer patients were undergoing 3rd line CCT. Results indicated that mean scores (± standard deviation of anxiety 13.95 (±4 and depression 15.5 (±4.4 both exceeded the cut-off score of 11 and mean score of QOL physical health 29.77 (±10.1, psychological health 31.3 (±10.1, social relationship 35.1 (±9.6, and environmental condition 25.9 (±9.9 was below cut-off score of 60. After psychotherapy, there was significant reduction in anxiety (P < 0.01, depression (P < 0.01 and improvement on QOL physical heath (P = 0.02, psychological health (P < 0.01, environmental condition (P < 0.01, and social relationship (P < 0.01. Conclusions: Supportive psychotherapy helps to reduce the level of anxiety, depression, and increase the QOL. Therefore, psychotherapeutic intervention should be encouraged along with chemotherapy to promote positive mental health and to obtain full benefit of their physical treatment.

  20. Evaluation of risk for graft-versus-host disease in children who receive less than the full doses of mini-dose methotrexate for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Sook Kyung Yum

    2013-11-01

    Full Text Available Purpose: The use of cyclosporine and mini-dose methotrexate (MTX is a common strategy for graftversus- host disease (GVHD prophylaxis in allogeneic transplants. We investigated whether patients who receive fewer than the planned MTX doses are at increased risk for GVHD. Methods: The study cohort included 103 patients who received allogeneic transplants at the Department of Pediatrics of The Catholic University of Korea College of Medicine, from January 2010 to December 2011. MTX was administered on days 1, 3, 6, and 11 after transplant at a dose of 5 mg/ m2 each. Within the cohort, 76 patients (74% received all 4 doses of MTX [MTX(4 group], while 27 patients (26% received 0&#8211;3 doses [MTX(0–3 group]. Results: Although there was no difference in neutrophil engraftment between the 2 groups, platelet engraftment was significantly faster in the MTX(4 group (median, 15 days, compared to the MTX(0&#8211; 3 group (median, 25 days; P =0.034. The incidence of grades II&#8211;IV acute GVHD was not different between the MTX(4 and MTX(0&#8211;3 groups (P =0.417. In the multivariate study, human leukocyte antigen mismatch was the most significant factor causing grades II&#8211;IV acute GVHD (P =0.002, followed by female donor to male recipient transplant (P =0.034. No difference was found between the MTX(4 and MTX (0&#8211;3 groups regarding grades III&#8211;IV acute GVHD, chronic GVHD, and disease-free survival. Conclusion: Our results indicate that deviations from the full dose schedule of MTX for GVHD prophylaxis do not lead to increased incidence of either acute or chronic GVHD.

  1. Targeting Ras signaling in AML: RALB is a small GTPase with big potential.

    Science.gov (United States)

    Pomeroy, Emily J; Eckfeldt, Craig E

    2017-07-06

    Acute myeloid leukemia (AML) is a devastating malignancy for which novel treatment approaches are desperately needed. Ras signaling is an attractive therapeutic target for AML because a large proportion of AMLs have mutations in NRAS, KRAS, or genes that activate Ras signaling, and key Ras effectors are activated in virtually all AML patient samples. This has inspired efforts to develop Ras-targeted treatment strategies for AML. Due to the inherent difficulty and disappointing efficacy of targeting Ras proteins directly, many have focused on inhibiting Ras effector pathways. Inhibiting the major oncogenic Ras effectors, the mitogen-activated protein kinase (MAPK) and/or phosphatidylinositiol-3-kinase (PI3K) pathways, has generally demonstrated modest efficacy for AML. While this may be in part related to functional redundancy between these pathways, it is now clear that other Ras effectors have key oncogenic roles. Specifically, the Ras-like (Ral) GTPases have emerged as critical mediators of Ras-driven transformation and AML cell survival. Our group recently uncovered a critical role for RALB signaling in leukemic cell survival and a potential mediator of relapse following Ras-targeted therapy in AML. Furthermore, we found that RALB signaling is hyperactivated in AML patient samples, and inhibiting RALB has potent anti-leukemic activity in preclinical AML models. While key questions remain regarding the importance of RALB signaling across the genetically diverse spectrum of AML, the specific mechanism(s) that promotes leukemic cell survival downstream of RALB, and how to pharmacologically target RALB signaling effectively - RALB has emerged as a critical Ras effector and potential therapeutic target for AML.

  2. MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations.

    Science.gov (United States)

    Kerstjens, Mark; Driessen, Emma M C; Willekes, Merel; Pinhanços, Sandra S; Schneider, Pauline; Pieters, Rob; Stam, Ronald W

    2017-02-28

    Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS-mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS-mutant MLL-rearranged infant ALL cells in vitro. While all RAS-mutant samples were sensitive to MEK inhibitors, we found both sensitive and resistant samples among RAS-wildtype cases. We confirmed enhanced RAS pathway signaling in RAS-mutant samples, but found no apparent downstream over-activation in the wildtype samples. However, we did confirm that MEK inhibitors reduced p-ERK levels, and induced apoptosis in the RAS-mutant MLL-rearranged ALL cells. Finally, we show that MEK inhibition synergistically enhances prednisolone sensitivity, both in RAS-mutant and RAS-wildtype cells. In conclusion, MEK inhibition represents a promising therapeutic strategy for MLL-rearranged ALL patients harboring RAS mutations, while patients without RAS mutations may benefit through prednisolone sensitization.

  3. Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

    Science.gov (United States)

    Zhou, Xinna; Wang, Xiaoli; Song, Qingkun; Yang, Huabing; Zhu, Xishan; Yu, Jing; Song, Guohong; Di, Lijun; Ren, Jun; Shao, Hong; Lyerly, Herbert Kim

    2015-11-01

    The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities. 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded. GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity. These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.

  4. Mechanisms of membrane binding of small GTPase K-Ras4B farnesylated hypervariable region.

    Science.gov (United States)

    Jang, Hyunbum; Abraham, Sherwin J; Chavan, Tanmay S; Hitchinson, Ben; Khavrutskii, Lyuba; Tarasova, Nadya I; Nussinov, Ruth; Gaponenko, Vadim

    2015-04-10

    K-Ras4B belongs to a family of small GTPases that regulates cell growth, differentiation and survival. K-ras is frequently mutated in cancer. K-Ras4B association with the plasma membrane through its farnesylated and positively charged C-terminal hypervariable region (HVR) is critical to its oncogenic function. However, the structural mechanisms of membrane association are not fully understood. Here, using confocal microscopy, surface plasmon resonance, and molecular dynamics simulations, we observed that K-Ras4B can be distributed in rigid and loosely packed membrane domains. Its membrane binding domain interaction with phospholipids is driven by membrane fluidity. The farnesyl group spontaneously inserts into the disordered lipid microdomains, whereas the rigid microdomains restrict the farnesyl group penetration. We speculate that the resulting farnesyl protrusion toward the cell interior allows oligomerization of the K-Ras4B membrane binding domain in rigid microdomains. Unlike other Ras isoforms, K-Ras4B HVR contains a single farnesyl modification and positively charged polylysine sequence. The high positive charge not only modulates specific HVR binding to anionic phospholipids but farnesyl membrane orientation. Phosphorylation of Ser-181 prohibits spontaneous farnesyl membrane insertion. The mechanism illuminates the roles of HVR modifications in K-Ras4B targeting microdomains of the plasma membrane and suggests an additional function for HVR in regulation of Ras signaling. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Mechanisms of Membrane Binding of Small GTPase K-Ras4B Farnesylated Hypervariable Region*

    Science.gov (United States)

    Jang, Hyunbum; Abraham, Sherwin J.; Chavan, Tanmay S.; Hitchinson, Ben; Khavrutskii, Lyuba; Tarasova, Nadya I.; Nussinov, Ruth; Gaponenko, Vadim

    2015-01-01

    K-Ras4B belongs to a family of small GTPases that regulates cell growth, differentiation and survival. K-ras is frequently mutated in cancer. K-Ras4B association with the plasma membrane through its farnesylated and positively charged C-terminal hypervariable region (HVR) is critical to its oncogenic function. However, the structural mechanisms of membrane association are not fully understood. Here, using confocal microscopy, surface plasmon resonance, and molecular dynamics simulations, we observed that K-Ras4B can be distributed in rigid and loosely packed membrane domains. Its membrane binding domain interaction with phospholipids is driven by membrane fluidity. The farnesyl group spontaneously inserts into the disordered lipid microdomains, whereas the rigid microdomains restrict the farnesyl group penetration. We speculate that the resulting farnesyl protrusion toward the cell interior allows oligomerization of the K-Ras4B membrane binding domain in rigid microdomains. Unlike other Ras isoforms, K-Ras4B HVR contains a single farnesyl modification and positively charged polylysine sequence. The high positive charge not only modulates specific HVR binding to anionic phospholipids but farnesyl membrane orientation. Phosphorylation of Ser-181 prohibits spontaneous farnesyl membrane insertion. The mechanism illuminates the roles of HVR modifications in K-Ras4B targeting microdomains of the plasma membrane and suggests an additional function for HVR in regulation of Ras signaling. PMID:25713064

  6. Novel molecular targets for kRAS downregulation: promoter G-quadruplexes

    Science.gov (United States)

    2016-11-01

    monitor the effect of G4 formation, rather than mutating the promoter sequence. We screened the Diversity Set II and III from the National Cancer...Bgl I (kRAS-500 plasmid) or Nhe I (all kRAS-324 plasmids) and HIND III cut sites. kRAS-324 was con- structed by Operon; the kRAS-500, 324 mt Near, and...molecular targets for breast cancer therapeutics, Molecules ( Basel , Switz.) 18 (2013) 15019–15034. [38] T.C. He, A.B. Sparks, C. Rago, H. Hermeking

  7. RAS interaction with PI3K p110α is required for tumor-induced angiogenesis.

    Science.gov (United States)

    Murillo, Miguel Manuel; Zelenay, Santiago; Nye, Emma; Castellano, Esther; Lassailly, Francois; Stamp, Gordon; Downward, Julian

    2014-08-01

    Direct interaction of RAS with the PI3K p110α subunit mediates RAS-driven tumor development: however, it is not clear how p110α/RAS-dependant signaling mediates interactions between tumors and host tissues. Here, using a murine tumor cell transfer model, we demonstrated that disruption of the interaction between RAS and p110α within host tissue reduced tumor growth and tumor-induced angiogenesis, leading to improved survival of tumor-bearing mice, even when this interaction was intact in the transferred tumor. Furthermore, functional interaction of RAS with p110α in host tissue was required for efficient establishment and growth of metastatic tumors. Inhibition of RAS and p110α interaction prevented proper VEGF-A and FGF-2 signaling, which are required for efficient angiogenesis. Additionally, disruption of the RAS and p110α interaction altered the nature of tumor-associated macrophages, inducing expression of markers typical for macrophage populations with reduced tumor-promoting capacity. Together, these results indicate that a functional RAS interaction with PI3K p110α in host tissue is required for the establishment of a growth-permissive environment for the tumor, particularly for tumor-induced angiogenesis. Targeting the interaction of RAS with PI3K has the potential to impair tumor formation by altering the tumor-host relationship, in addition to previously described tumor cell-autonomous effects.

  8. Induction of postmitotic neuroretina cell proliferation by distinct Ras downstream signaling pathways.

    Science.gov (United States)

    Peyssonnaux, C; Provot, S; Felder-Schmittbuhl, M P; Calothy, G; Eychène, A

    2000-10-01

    Ras-induced cell transformation is mediated through distinct downstream signaling pathways, including Raf, Ral-GEFs-, and phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathways. In some cell types, strong activation of the Ras-Raf-MEK-extracellular signal-regulated kinase (ERK) cascade leads to cell cycle arrest rather than cell division. We previously reported that constitutive activation of this pathway induces sustained proliferation of primary cultures of postmitotic chicken neuroretina (NR) cells. We used this model system to investigate the respective contributions of Ras downstream signaling pathways in Ras-induced cell proliferation. Three RasV12 mutants (S35, G37, and C40) which differ by their ability to bind to Ras effectors (Raf, Ral-GEFs, and the p110 subunit of PI 3-kinase, respectively) were able to induce sustained NR cell proliferation, although none of these mutants was reported to transform NIH 3T3 cells. Furthermore, they all repressed the promoter of QR1, a neuroretina growth arrest-specific gene. Overexpression of B-Raf or activated versions of Ras effectors Rlf-CAAX and p110-CAAX also induced NR cell division. The mitogenic effect of the RasC40-PI 3-kinase pathway appears to involve Rac and RhoA GTPases but not the antiapoptotic Akt (protein kinase B) signaling. Division induced by RasG37-Rlf appears to be independent of Ral GTPase activation and presumably requires an unidentified mechanism. Activation of either Ras downstream pathway resulted in ERK activation, and coexpression of a dominant negative MEK mutant or mKsr-1 kinase domain strongly inhibited proliferation induced by the three Ras mutants or by their effectors. Similar effects were observed with dominant negative mutants of Rac and Rho. Thus, both the Raf-MEK-ERK and Rac-Rho pathways are absolutely required for Ras-induced NR cell division. Activation of these two pathways by the three distinct Ras downstream effectors possibly relies on an autocrine or paracrine loop

  9. Detecting N-RAS Q61R Mutated Thyroid Neoplasias by Immunohistochemistry.

    Science.gov (United States)

    Crescenzi, A; Fulciniti, F; Bongiovanni, M; Giovanella, L; Trimboli, Pierpaolo

    2017-03-01

    Recently, the immunohistochemistry (IHC) for N-RAS Q61R has been developed and commercialized for clinical practice. Here, we investigated the reliability of IHC to identify N-RAS Q61R mutated thyroid neoplasia. A series of 24 consecutive thyroid lesions undergone surgery following indeterminate cytology were enrolled. Paraffin sections were stained for IHC using the rabbit monoclonal anti-human N-RAS Q61R, clone SP174. N-RAS mutations in codon 61 were also investigated by automated sequencing. At histology, 12 cases of follicular carcinoma, cytologically defined as follicular lesions, 1 papillary cancer, 7 follicular adenomas, and 4 hyperplastic nodules were found. Of these, 4 showed a positive IHC for anti N-RAS antibody where N-RAS expression was detected mainly at cytoplasmic level with similar intensity of reaction. The remaining cases had negative IHC. A 100% concordance between IHC and molecular analysis for N-RAS Q61R was observed. In conclusion, this study shows high reliability of IHC to identify N-RAS Q61R mutated thyroid lesions with high cost-effectiveness. These data indicate the reliability of IHC to identify N-RAS Q61R mutated thyroid neoplasia and suggest to adopt this approach for a more accurate management of patients, when indicated.

  10. Identification of H-Ras-Specific Motif for the Activation of Invasive Signaling Program in Human Breast Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Hae-Young Yong

    2011-02-01

    Full Text Available Increased expression and/or activation of H-Ras are often associated with tumor aggressiveness in breast cancer. Previously, we showed that H-Ras, but not N-Ras, induces MCF10A human breast epithelial cell invasion and migration, whereas both H-Ras and N-Ras induce cell proliferation and phenotypic transformation. In an attempt to determine the sequence requirement directing the divergent phenotype induced by H-Ras and N-Ras with a focus on the induction of human breast cell invasion, we investigated the structural and functional relationships between H-Ras and N-Ras using domain-swap and site-directed mutagenesis approaches. Here, we report that the hypervariable region (HVR, consisting of amino acids 166 to 189 in H-Ras, determines the invasive/migratory signaling program as shown by the exchange of invasive phenotype by swapping HVR sequences between H-Ras and N-Ras. We also demonstrate that the H-Ras-specific additional palmitoylation site at Cys184 is not responsible for the signaling events that distinguish between H-Ras and N-Ras. Importantly, this work identifies the C-terminal HVR, especially the flexible linker domain with two consecutive proline residues Pro173 and Pro174, as a critical domain that contributes to activation of H-Ras and its invasive potential in human breast epithelial cells. The present study sheds light on the structural basis for the Ras isoform-specific invasive program of breast epithelial cells, providing information for the development of agents that specifically target invasion-related H-Ras pathways in human cancer.

  11. A Drosophila immune response against Ras-induced overgrowth

    Directory of Open Access Journals (Sweden)

    Thomas Hauling

    2014-03-01

    Full Text Available Our goal is to characterize the innate immune response against the early stage of tumor development. For this, animal models where genetic changes in specific cells and tissues can be performed in a controlled way have become increasingly important, including the fruitfly Drosophila melanogaster. Many tumor mutants in Drosophila affect the germline and, as a consequence, also the immune system itself, making it difficult to ascribe their phenotype to a specific tissue. Only during the past decade, mutations have been induced systematically in somatic cells to study the control of tumorous growth by neighboring cells and by immune cells. Here we show that upon ectopic expression of a dominant-active form of the Ras oncogene (RasV12, both imaginal discs and salivary glands are affected. Particularly, the glands increase in size, express metalloproteinases and display apoptotic markers. This leads to a strong cellular response, which has many hallmarks of the granuloma-like encapsulation reaction, usually mounted by the insect against larger foreign objects. RNA sequencing of the fat body reveals a characteristic humoral immune response. In addition we also identify genes that are specifically induced upon expression of RasV12. As a proof-of-principle, we show that one of the induced genes (santa-maria, which encodes a scavenger receptor, modulates damage to the salivary glands. The list of genes we have identified provides a rich source for further functional characterization. Our hope is that this will lead to a better understanding of the earliest stage of innate immune responses against tumors with implications for mammalian immunity.

  12. Suspected de novo Hepatitis B in a Patient Receiving Anti-Tumor Necrosis Factor Alpha Therapy for the Treatment of Crohn's Disease

    Directory of Open Access Journals (Sweden)

    Tetsuya Ishida

    2014-01-01

    Full Text Available We report a 45-year-old female patient who developed acute hepatic disorder during anti-tumor necrosis factor α therapy for the treatment of Crohn's disease (CD. She was diagnosed as colonic CD and placed on infliximab (IFX. She was negative for hepatitis B surface antigen at the initiation of IFX therapy, but developed acute hepatitis after the 30th administration of IFX 4 years and 1 month after the first administration. She was suspected to have had occult hepatitis B virus infection before IFX therapy, and de novo hepatitis B was considered the most likely diagnosis. Hepatitis subsided after discontinuation of anti-tumor necrosis factor α therapy and initiation of treatment with entecavir. She started to receive adalimumab to prevent relapse of CD. She has continued maintenance therapy with entecavir and adalimumab and has since been asymptomatic. As de novo hepatitis B may be fatal, virological testing for hepatitis B is essential for patients who are being considered for treatment that may weaken the immune system.

  13. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health

    Science.gov (United States)

    Chappell, William H.; Steelman, Linda S.; Long, Jacquelyn M.; Kempf, Ruth C.; Abrams, Stephen L.; Franklin, Richard A.; Bäsecke, Jörg; Stivala, Franca; Donia, Marco; Fagone, Paolo; Malaponte, Graziella; Mazzarino, Maria C.; Nicoletti, Ferdinando; Libra, Massimo; Maksimovic-Ivanic, Danijela; Mijatovic, Sanja; Montalto, Giuseppe; Cervello, Melchiorre; Laidler, Piotr; Milella, Michele; Tafuri, Agostino; Bonati, Antonio; Evangelisti, Camilla; Cocco, Lucio; Martelli, Alberto M.; McCubrey, James A.

    2011-01-01

    The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging. PMID:21411864

  14. Immunohistochemical assay for detection of K-ras protein expression in metastatic colorectal cancer

    International Nuclear Information System (INIS)

    Tag Elsabah, M.; Iman Adel, I.

    2013-01-01

    Background: The monoclonal antibodies (mAbs) that target the epidermal growth factor receptor (EGFR) had expanded the range of treatment options for metastatic colorectal cancer. However, such type of treatment was shown to be ineffective if there is K-ras mutation. In most previous studies K-ras gene mutation was mainly assessed by PCR. Aim: Our work is designed to detect K-ras protein expression by immunohistochemistry (IHC) aiming to reach a preliminary method that could be confirmed by PCR and considered an alternative way for the detection of K-ras aberration. We are also aiming to find a relation between K-ras protein expression and K-ras gene mutation. Materials and methods: Paraffin embedded tissue samples from 26 metastatic colorectal cancer (mCRC) patients were analyzed for K-ras protein expression by IHC using RaplA polyclonal antibody. Staining patterns were subjectively assessed and correlated with clinicopathological features. The results were statistically evaluated using the Chi-square test. Results: K-ras cytoplasmic positivity was observed in 42.3% of cases. The positivity was either strong in 26.9% or moderate in 15.4%. With respect to adenocarcinoma variants, 50% of cases were positive for K-ras protein expression while all mucinous and signet ring types were negative. The positivity was noted in 50% of moderately differentiated GII colorectal carcinomas as compared with 38.9% in poorly differentiated GIII. Positive staining was observed in 40% of cases with positive lymph node metastasis while in the absence of nodal metastasis the positivity was 45.5%. No significant correlation was found between clinicopathological parameters and K-ras staining results. Conclusion: IHC may compliment PCR in the detection of K-ras mutation.

  15. Evidence implicating the Ras pathway in multiple CD28 costimulatory functions in CD4+ T cells.

    Directory of Open Access Journals (Sweden)

    Sujit V Janardhan

    Full Text Available CD28 costimulation is a critical event in the full activation of CD4(+ T cells that augments cytokine gene transcription, promotes cytokine mRNA stability, prevents induction of anergy, increases cellular metabolism, and increases cell survival. However, despite extensive biochemical analysis of the signaling events downstream of CD28, molecular pathways sufficient to functionally replace the diverse aspects of CD28-mediated costimulation in normal T cells have not been identified. Ras/MAPK signaling is a critical pathway downstream of T cell receptor stimulation, but its role in CD28-mediated costimulation has been controversial. We observed that physiologic CD28 costimulation caused a relocalization of the RasGEF RasGRP to the T cell-APC interface by confocal microscopy. In whole cell biochemical analysis, CD28 cross-linking with either anti-CD28 antibody or B7.1-Ig augmented TCR-induced Ras activation. To determine whether Ras signaling was sufficient to functionally mimic CD28 costimulation, we utilized an adenoviral vector encoding constitutively active H-Ras (61L to transduce normal, Coxsackie-Adenovirus Receptor (CAR transgenic CD4(+ T cells. Like costimulation via CD28, active Ras induced AKT, JNK and ERK phosphorylation. In addition, constitutive Ras signaling mimicked the ability of CD28 to costimulate IL-2 protein secretion, prevent anergy induction, increase glucose uptake, and promote cell survival. Importantly, we also found that active Ras mimicked the mechanism by which CD28 costimulates IL-2 production: by increasing IL-2 gene transcription, and promoting IL-2 mRNA stability. Finally, active Ras was able to induce IL-2 production when combined with ionomycin stimulation in a MEK-1-dependent fashion. Our results are consistent with a central role for Ras signaling in CD28-mediated costimulation.

  16. Unanticipated increases in hepatic steatosis among human immunodeficiency virus patients receiving mineralocorticoid receptor antagonist eplerenone for non-alcoholic fatty liver disease.

    Science.gov (United States)

    Chaudhury, Chloe S; Purdy, Julia B; Liu, Chia-Ying; Morse, Caryn G; Stanley, Takara L; Kleiner, David; Hadigan, Colleen

    2018-03-06

    Non-alcoholic fatty liver disease is common in human immunodeficiency virus, but there are no approved therapies. The aim of this open-label proof-of-concept study was to determine the effect of the mineralocorticoid receptor antagonist eplerenone on hepatic fat in human immunodeficiency virus-infected patients with hepatic fat ≥5% by magnetic resonance spectroscopy. Five subjects received eplerenone (25 mg daily × 1 week followed by 50 mg daily × 23 weeks). Laboratory tests were done at each visit, and the primary endpoint, change in hepatic fat content, was determined by MRI spectroscopy at baseline and week 24. The study was stopped early after observing unexpected significant increases in hepatic fat at week 24 (mean increase 13.0 ± 7.3%, P = .02). The increases in steatosis were accompanied by a tendency for transaminase values to decrease (alanine aminotransferase mean change -14 ± 16 IU/L, P = .14). There were no consistent changes in other metabolic parameters or blood pressure. Repeat assessment of hepatic steatosis 1-2 months after stopping study medication revealed improvements in steatosis towards baseline values. The unexpected observation of increased hepatic steatosis with the administration of eplerenone led to early termination of the investigation. While limited because of the small number of participants and the open-label design, this study provides data to suggest that mineralocorticoid receptor antagonism with eplerenone may not be an effective approach to treat hepatic steatosis in human immunodeficiency virus or the general population. Additional research is needed to determine the pathophysiological mechanism behind these unanticipated observations. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with myxomatous mitral valve disease receiving pimobendan or benazepril: the QUEST study.

    Science.gov (United States)

    Häggström, J; Boswood, A; O'Grady, M; Jöns, O; Smith, S; Swift, S; Borgarelli, M; Gavaghan, B; Kresken, J-G; Patteson, M; Åblad, B; Bussadori, C M; Glaus, T; Kovačević, A; Rapp, M; Santilli, R A; Tidholm, A; Eriksson, A; Belanger, M C; Deinert, M; Little, C J L; Kvart, C; French, A; Rønn-Landbo, M; Wess, G; Eggertsdottir, A; Lynne O'Sullivan, M; Schneider, M; Lombard, C W; Dukes-McEwan, J; Willis, R; Louvet, A; DiFruscia, R

    2013-01-01

    Myxomatous mitral valve disease (MMVD) is an important cause of morbidity and mortality in dogs. To compare, throughout the period of follow-up of dogs that had not yet reached the primary endpoint, the longitudinal effects of pimobendan versus benazepril hydrochloride treatment on quality-of-life (QoL) variables, concomitant congestive heart failure (CHF) treatment, and other outcome variables in dogs suffering from CHF secondary to MMVD. A total of 260 dogs in CHF because of MMVD. A prospective single-blinded study with dogs randomized to receive pimobendan (0.4-0.6 mg/kg/day) or benazepril hydrochloride (0.25-1.0 mg/kg/day). Differences in outcome variables and time to intensification of CHF treatment were compared. A total of 124 dogs were randomized to pimobendan and 128 to benazepril. No difference was found between groups in QoL variables during the trial. Time from inclusion to 1st intensification of CHF treatment was longer in the pimobendan group (pimobendan 98 days, IQR 30-276 days versus benazepril 59 days, IQR 11-121 days; P = .0005). Postinclusion, dogs in the pimobendan group had smaller heart size based on VHS score (P = .013) and left ventricular diastolic (P = .035) and systolic (P = .0044) dimensions, higher body temperature (P = .030), serum sodium (P = .0027), and total protein (P = .0003) concentrations, and packed cell volume (P = .030). Incidence of arrhythmias was similar in treatment groups. Pimobendan versus benazepril resulted in similar QoL during the study, but conferred increased time before intensification of CHF treatment. Pimobendan treatment resulted in smaller heart size, higher body temperature, and less retention of free water. Copyright © 2013 by the American College of Veterinary Internal Medicine.

  18. RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies.

    Science.gov (United States)

    Fang, Bingliang

    2016-01-01

    Activating mutations of oncogenic RAS genes are frequently detected in human cancers. The studies in genetically engineered mouse models (GEMMs) reveal that Kras-activating mutations predispose mice to early onset tumors in the lung, pancreas, and gastrointestinal tract. Nevertheless, most of these tumors do not have metastatic phenotypes. Metastasis occurs when tumors acquire additional genetic changes in other cancer driver genes. Studies on clinical specimens also demonstrated that KRAS mutations are present in premalignant tissues and that most of KRAS mutant human cancers have co-mutations in other cancer driver genes, including TP53, STK11, CDKN2A, and KMT2C in lung cancer; APC, TP53, and PIK3CA in colon cancer; and TP53, CDKN2A, SMAD4, and MED12 in pancreatic cancer. Extensive efforts have been devoted to develop therapeutic agents that target enzymes involved in RAS posttranslational modifications, that inhibit downstream effectors of RAS signaling pathways, and that kill RAS mutant cancer cells through synthetic lethality. Recent clinical studies have revealed that sorafenib, a pan-RAF and VEGFR inhibitor, has impressive benefits for KRAS mutant lung cancer patients. Combination therapy of MEK inhibitors with either docetaxel, AKT inhibitors, or PI3K inhibitors also led to improved clinical responses in some KRAS mutant cancer patients. This review discusses knowledge gained from GEMMs, human cancer cells, and patient-related studies on RAS-mediated tumorigenesis and anti-RAS therapy. Emerging evidence demonstrates that RAS mutant cancers are heterogeneous because of the presence of different mutant alleles and/or co-mutations in other cancer driver genes. Effective subclassifications of RAS mutant cancers may be necessary to improve patients' outcomes through personalized precision medicine. © The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology

  19. Literature review : performance of RAP/RAS mixes and new direction.

    Science.gov (United States)

    2014-04-01

    In the last several years reclaimed asphalt pavement (RAP) and recycled asphalt shingles (RAS) have been : widely used in asphalt mixes in Texas. The use of RAP/RAS can significantly reduce the initial cost of : asphalt mixtures, conserve energy, and...

  20. Activation of the exchange factor Ras-GRF by calcium requires an intact Dbl homology domain.

    Science.gov (United States)

    Freshney, N W; Goonesekera, S D; Feig, L A

    1997-04-21

    Ras-GRF is a guanine nucleotide exchange factor that activates Ras proteins. Its activity on Ras in cells is enhanced upon calcium influx. Activation follows calcium-induced binding of calmodulin to an IQ motif near the N-terminus of Ras-GRF. Ras-GRF also contains a Dbl homology (DH) domain C-terminal to the IQ motif. In many proteins, DH domains act as exchange factors for Rho-GTPase family members. However, we failed to detect exchange activity of this domain on well characterized Rho family members. Instead, we found that mutations analogous to those that block exchange activity of Dbl prevented Ras-GRF activation by calcium/ calmodulin in vivo. All DH domains are followed immediately by a pleckstrin homology (PH) domain. We found that a mutation at a conserved site within the PH domain following the DH domain also prevented Ras-GRF activation by calcium in vivo. These results suggest that in addition to playing a role as activators of Rho proteins, DH domains can also contribute to the coupling of cellular signals to Ras activation.

  1. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies

    DEFF Research Database (Denmark)

    De Raedt, Thomas; Beert, Eline; Pasmant, Eric

    2014-01-01

    Ras. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies...

  2. Safe use of NSAIDs and RAS-inhibitors at Agogo Presbyterian Hospital, Ghana

    NARCIS (Netherlands)

    Meulendijks, L.G.; Adomako, E.A.; Appiah, E.B.; Kramers, C.

    2016-01-01

    BACKGROUND: Preventable adverse events of medication are an important cause of hospital admissions in the developed world, in which non-steroidal anti-inflammatory drugs (NSAIDs) and renin-angiotensin system (RAS-) inhibitors are frequently involved. NSAIDs and RAS-inhibitors are also often used in

  3. Coexistence of K-ras mutations and HPV infection in colon cancer

    Directory of Open Access Journals (Sweden)

    Tezol Ayda

    2006-05-01

    Full Text Available Abstract Background Activation of the ras genes or association with human papillomavirus infection have been extensively studied in colorectal cancer. However, the correlation between K-ras mutations and HPV in colorectal cancer has not been investigated yet. In this study we aimed to investigate the presence of K-ras mutations and their correlation with HPV infection in colon cancer. Methods K-ras mutations were analyzed by a mutagenic PCR assay and digestion with specific restriction enzymes to distinguish the wild-type and mutant codons. HPV infection was analyzed by PCR amplification and hybridization with specific probes by Southern blotting. Stattistical analyses were performed by the chi-square and Fisher's exact tests Results HPV gene fragments were detected in 43 tumors and 17 normal tissue samples. HPV 18 was the prevalent type in the tumor tissue. A mutation at codon 12 of the K-ras gene was present in 31 patients. 56% of the HPV-positive tumors also harbored a K-ras mutation. Codon 13 mutations were not observed. These data indicate that infection with high risk HPV types and mutational activation of the K-ras gene are frequent events in colorectal carcinogenesis. Conclusion Our findings suggest that mutational activation of the K-ras gene is a common event in colon carcinogenesis and that HPV infection may represent an important factor in the development of the premalignant lesions leading to the neoplastic phenotype.

  4. Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling.

    Science.gov (United States)

    Dhawan, Neil S; Scopton, Alex P; Dar, Arvin C

    2016-09-01

    Deregulation of the Ras-mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes. Kinase suppressor of Ras (KSR) is a MAPK scaffold that is subject to allosteric regulation through dimerization with RAF. Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutations that selectively suppress oncogenic, but not wild-type, Ras signalling, we developed a class of compounds that stabilize a previously unrecognized inactive state of KSR. These compounds, exemplified by APS-2-79, modulate KSR-dependent MAPK signalling by antagonizing RAF heterodimerization as well as the conformational changes required for phosphorylation and activation of KSR-bound MEK (mitogen-activated protein kinase kinase). Furthermore, APS-2-79 increased the potency of several MEK inhibitors specifically within Ras-mutant cell lines by antagonizing release of negative feedback signalling, demonstrating the potential of targeting KSR to improve the efficacy of current MAPK inhibitors. These results reveal conformational switching in KSR as a druggable regulator of oncogenic Ras, and further suggest co-targeting of enzymatic and scaffolding activities within Ras-MAPK signalling complexes as a therapeutic strategy for overcoming Ras-driven cancers.

  5. The ras1 function of Schizosaccharomyces pombe mediates pheromone-induced transcription

    DEFF Research Database (Denmark)

    Nielsen, O; Davey, William John; Egel, R

    1992-01-01

    transcription of mat1-Pm in response to M factor. Furthermore, an activated ras1val17 mutant exhibits a stronger induction of the mat1-Pm transcript. However, transcription still depends on nitrogen deprivation as well as on the presence of pheromone, showing that activation of the Ras1 protein alone does...

  6. Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas

    Directory of Open Access Journals (Sweden)

    Gregory P. Way

    2018-04-01

    Full Text Available Summary: Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these “hidden responders” may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders. : Way et al. develop a machine-learning approach using PanCanAtlas data to detect Ras activation in cancer. Integrating mutation, copy number, and expression data, the authors show that their method detects Ras-activating variants in tumors and sensitivity to MEK inhibitors in cell lines. Keywords: Gene expression, machine learning, Ras, NF1, KRAS, NRAS, HRAS, pan-cancer, TCGA, drug sensitivity

  7. Ras signaling influences permissiveness of malignant peripheral nerve sheath tumor cells to oncolytic herpes.

    Science.gov (United States)

    Farassati, Faris; Pan, Weihong; Yamoutpour, Farnaz; Henke, Susann; Piedra, Mark; Frahm, Silke; Al-Tawil, Said; Mangrum, Wells I; Parada, Luis F; Rabkin, Samuel D; Martuza, Robert L; Kurtz, Andreas

    2008-12-01

    Lack of expression of neurofibromin in neurofibromatosis 1 and its lethal derivative, malignant peripheral nerve sheath tumors (MPNSTs), is thought to result in the overactivation of the Ras signaling pathway. Our previous studies have shown that cells with overactivation in the Ras pathway are more permissive to infection with herpes simplex virus 1 and its mutant version R3616. In this study, we show that among five different mouse MPNST cell lines, only the ones with elevated levels of Ras signaling are highly permissive to infection with oncolytic herpes G207. Specific inhibitors of the Ras, ERK, and JNK pathways all reduced the synthesis of viral proteins in MPNST cells. The cell lines that contained lower levels of Ras and decreased activation of downstream signaling components underwent an enhancement in apoptosis upon exposure to G207. Additionally, mouse SW10 Schwann cells were able to become infected by parental herpes but were found to be resistant to G207. The immortalization of these cell lines with the expression of SV40 large T antigen increased the levels of Ras activation and permissiveness to oncolytic herpes. A Ras/Raf kinase inhibitor reduced the synthesis of both herpes simplex virus-1 and G207 proteins in SW10 cells. The results of this study, therefore, introduce Ras signaling as a divergent turning point for the response of MPNST cells to an assault by oncolytic herpes.

  8. Thermodynamics between RAP/RAS and virgin aggregates during asphalt concrete production : a literature review.

    Science.gov (United States)

    2015-09-01

    In hot-mix asphalt (HMA) plants, virgin aggregates are heated and dried separately before being mixed with : RAP/RAS and virgin asphalt binder. RAP/RAS materials are not heated or dried directly by a burner to avoid : burning of aged binder coating o...

  9. The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer.

    Science.gov (United States)

    Akino, Kimishige; Toyota, Minoru; Suzuki, Hiromu; Mita, Hiroaki; Sasaki, Yasushi; Ohe-Toyota, Mutsumi; Issa, Jean-Pierre J; Hinoda, Yuji; Imai, Kohzoh; Tokino, Takashi

    2005-07-01

    Activation of Ras signaling is a hallmark of colorectal cancer (CRC), but the roles of negative regulators of Ras are not fully understood. Our aim was to address that question by surveying genetic and epigenetic alterations of Ras-Ras effector genes in CRC cells. The expression and methylation status of 6 RASSF family genes were examined using RT-PCR and bisulfite PCR in CRC cell lines and in primary CRCs and colorectal adenomas. Colony formation assays and flow cytometry were used to assess the tumor suppressor activities of RASSF1 and RASSF2. Immunofluorescence microscopy was used to determine the effect of altered RASSF2 expression on cell morphology. Mutations of K- ras , BRAF, and p53 were identified using single-strand conformation analysis and direct sequencing. Aberrant methylation and histone deacetylation of RASSF2 was associated with the gene's silencing in CRC. The activities of RASSF2, which were distinct from those of RASSF1, included induction of morphologic changes and apoptosis; moreover, its ability to prevent cell transformation suggests that RASSF2 acts as a tumor suppressor in CRC. Primary CRCs that showed K- ras /BRAF mutations also frequently showed RASSF2 methylation, and inactivation of RASSF2 enhanced K- ras -induced oncogenic transformation. RASSF2 methylation was also frequently identified in colorectal adenomas. RASSF2 is a novel tumor suppressor gene that regulates Ras signaling and plays a pivotal role in the early stages of colorectal tumorigenesis.

  10. cpRAS: a novel circularly permuted RAS-like GTPase domain with a highly scattered phylogenetic distribution

    Directory of Open Access Journals (Sweden)

    Novotny Marian

    2008-05-01

    Full Text Available Abstract A recent systematic survey suggested that the YRG (or YawG/YlqF family with the G4-G5-G1-G2-G3 order of the conserved GTPase motifs represents the only possible circularly permuted variation of the canonical GTPase structure. Here we show that a different circularly permuted GTPase domain actually does exist, conforming to the pattern G3-G4-G5-G1-G2. The domain, dubbed cpRAS, is a variant of RAS family GTPases and occurs in two types of larger proteins, either inserted into a region homologous to a bacterial group of proteins classified as COG2373 and potentially related to the alpha-2-macroglobulin family (so far a single protein in Dictyostelium or in combination with a von Willebrand factor type A (VWA domain. For the latter protein type, which was found in a few metazoans and several distantly related protists, existence in the common ancestor of opisthokonts, Amoebozoa and excavates followed by at least eight independent losses may be inferred. Our findings thus bring further evidence for the importance of parallel reduction of ancestral complexity in the eukaryotic evolution. Reviewers This article was reviewed by Lakshminarayan Iyer and Fyodor Kondrashov. For the full reviews, please go to the Reviewers' comments section.

  11. Kinetic characterization of apoptotic Ras signaling through Nore1-MST1 complex formation.

    Science.gov (United States)

    Koturenkiene, Agne; Makbul, Cihan; Herrmann, Christian; Constantinescu-Aruxandei, Diana

    2017-05-01

    Ras-mediated apoptotic signaling is expected to be mediated via Rassf-MST complexes, but the system has been poorly characterized in vitro until now. Here we demonstrate that active H-Ras, Nore1A and MST1 form a stable ternary complex in vitro without other external factors, Nore1A interacting simultaneously with H-Ras and MST1 via its RBD and SARAH domain, respectively. Moreover, our data show for the first time that the SARAH domain of Nore1A plays a role in the Nore1A binding to H-Ras. Finally, we analyze the relation between the electrostatic and hydrophobic forces and kinetic constants of the Nore1A - H-Ras complex.

  12. Activating Ras mutations fail to ensure efficient replication of adenovirus mutants lacking VA-RNA

    DEFF Research Database (Denmark)

    Schümann, Michael; Dobbelstein, Matthias

    2006-01-01

    Adenoviruses lacking their PKR-antagonizing VA RNAs replicate poorly in primary cells. It has been suggested that these virus recombinants still replicate efficiently in tumor cells with Ras mutations and might therefore be useful in tumor therapy. The ability of interferon-sensitive viruses...... to grow in Ras-mutant tumor cells is generally ascribed to a postulated inhibitory effect of mutant Ras on PKR. We have constructed a set of isogenic adenoviruses that lack either or both VA RNA species, and tested virus replication in a variety of cell species with different Ras status. In tendency, VA...... mutational status, upon infection with VA-less adenoviruses in the presence of interferon, but also upon addition of the PKR activator polyIC to cells. When comparing two isogenic cell lines that differ solely with regard to the presence or absence of mutant Ras, no difference was observed concerning...

  13. Electronic warfare receivers and receiving systems

    CERN Document Server

    Poisel, Richard A

    2014-01-01

    Receivers systems are considered the core of electronic warfare (EW) intercept systems. Without them, the fundamental purpose of such systems is null and void. This book considers the major elements that make up receiver systems and the receivers that go in them.This resource provides system design engineers with techniques for design and development of EW receivers for modern modulations (spread spectrum) in addition to receivers for older, common modulation formats. Each major module in these receivers is considered in detail. Design information is included as well as performance tradeoffs o

  14. Hyperglycemia promotes K-Ras-induced lung tumorigenesis through BASCs amplification.

    Directory of Open Access Journals (Sweden)

    Carla Micucci

    Full Text Available Oncogenic K-Ras represents the most common molecular change in human lung adenocarcinomas, the major histologic subtype of non-small cell lung cancer (NSCLC. The presence of K-Ras mutation is associated with a poor prognosis, but no effective treatment strategies are available for K-Ras -mutant NSCLC. Epidemiological studies report higher lung cancer mortality rates in patients with type 2 diabetes. Here, we use a mouse model of K-Ras-mediated lung cancer on a background of chronic hyperglycemia to determine whether elevated circulating glycemic levels could influence oncogenic K-Ras-mediated tumor development. Inducible oncogenic K-Ras mouse model was treated with subtoxic doses of streptozotocin (STZ to induce chronic hyperglycemia. We observed increased tumor mass and higher grade of malignancy in STZ treated diabetic mice analyzed at 4, 12 and 24 weeks, suggesting that oncogenic K-Ras increased lung tumorigenesis in hyperglycemic condition. This promoting effect is achieved by expansion of tumor-initiating lung bronchio-alveolar stem cells (BASCs in bronchio-alveolar duct junction, indicating a role of hyperglycemia in the activity of K-Ras-transformed putative lung stem cells. Notably, after oncogene K-Ras activation, BASCs show upregulation of the glucose transporter (Glut1/Slc2a1, considered as an important player of the active control of tumor cell metabolism by oncogenic K-Ras. Our novel findings suggest that anti-hyperglycemic drugs, such as metformin, may act as therapeutic agent to restrict lung neoplasia promotion and progression.

  15. Variational data assimilation system "INM RAS - Black Sea"

    Science.gov (United States)

    Parmuzin, Eugene; Agoshkov, Valery; Assovskiy, Maksim; Giniatulin, Sergey; Zakharova, Natalia; Kuimov, Grigory; Fomin, Vladimir

    2013-04-01

    Development of Informational-Computational Systems (ICS) for Data Assimilation Procedures is one of multidisciplinary problems. To study and solve these problems one needs to apply modern results from different disciplines and recent developments in: mathematical modeling; theory of adjoint equations and optimal control; inverse problems; numerical methods theory; numerical algebra and scientific computing. The problems discussed above are studied in the Institute of Numerical Mathematics of the Russian Academy of Science (INM RAS) in ICS for Personal Computers (PC). Special problems and questions arise while effective ICS versions for PC are being developed. These problems and questions can be solved with applying modern methods of numerical mathematics and by solving "parallelism problem" using OpenMP technology and special linear algebra packages. In this work the results on the ICS development for PC-ICS "INM RAS - Black Sea" are presented. In the work the following problems and questions are discussed: practical problems that can be studied by ICS; parallelism problems and their solutions with applying of OpenMP technology and the linear algebra packages used in ICS "INM - Black Sea"; Interface of ICS. The results of ICS "INM RAS - Black Sea" testing are presented. Efficiency of technologies and methods applied are discussed. The work was supported by RFBR, grants No. 13-01-00753, 13-05-00715 and by The Ministry of education and science of Russian Federation, project 8291, project 11.519.11.1005 References: [1] V.I. Agoshkov, M.V. Assovskii, S.A. Lebedev, Numerical simulation of Black Sea hydrothermodynamics taking into account tide-forming forces. Russ. J. Numer. Anal. Math. Modelling (2012) 27, No.1, 5-31 [2] E.I. Parmuzin, V.I. Agoshkov, Numerical solution of the variational assimilation problem for sea surface temperature in the model of the Black Sea dynamics. Russ. J. Numer. Anal. Math. Modelling (2012) 27, No.1, 69-94 [3] V.B. Zalesny, N.A. Diansky, V

  16. Chronic complications and quality of life of patients living with sickle cell disease and receiving care in three hospitals in Cameroon: a cross-sectional study.

    Science.gov (United States)

    Andong, Anne M; Ngouadjeu, Eveline D T; Bekolo, Cavin E; Verla, Vincent S; Nebongo, Daniel; Mboue-Djieka, Yannick; Choukem, Simeon-Pierre

    2017-01-01

    Sickle Cell Disease (SCD) is associated with chronic multisystem complications that significantly influence the quality of life (QOL) of patients early in their life. Although sub-Saharan Africa bears 75% of the global burden of SCD, there is a paucity of data on these complications and their effects on the QOL. We aimed to record these chronic complications, to estimate the QOL, and to identify the corresponding risk factors in patients with SCD receiving care in three hospitals in Cameroon. In this cross-sectional study, a questionnaire was used to collect data from consecutive consenting patients. Information recorded included data on the yearly frequency of painful crisis, the types of SCD, and the occurrence of chronic complications. A 36-Item Short Form (SF-36) standard questionnaire that examines the level of physical and mental well-being, was administered to all eligible participants. Data were analyzed with STATA® software. Of 175 participants included, 93 (53.1%) were female and 111 (aged ≥14 years) were eligible for QOL assessment. The median (interquartile range, IQR) age at diagnosis was 4.0 (2.0-8.0) years and the median (IQR) number of yearly painful crisis was 3.0 (1.0-7.0). The most frequent chronic complications reported were: nocturnal enuresis, chronic leg ulcers, osteomyelitis and priapism (30.9%, 24.6%, 19.4%, and 18.3% respectively). The prevalence of stroke and avascular necrosis of the hip were 8.0% and 13.1% respectively. The median (IQR) physical and mental scores were 47.3 (43.9-58.5) and 41.0 (38.8-44.6) respectively. Age and chronic complications such as stroke and avascular necrosis were independently associated with poor QOL. In this population of patients living with SCD, chronic complications are frequent and their QOL is consequently poor. Our results highlight the need for national guidelines for SCD control, which should include new-born screening programs and strategies to prevent chronic complications.

  17. The bovine papillomavirus E5 oncogene can cooperate with ras: identification of p21 amino acids critical for transformation by c-rasH but not v-rasH

    DEFF Research Database (Denmark)

    Willumsen, B M; Vass, W C; Velu, T J

    1991-01-01

    activity of c-rasH is low, we have used cotransfection with the bovine papillomavirus (BPV) genome to develop a more sensitive transformation assay for c-rasH mutants. The increased sensitivity of the assay, which is seen both in focal transformation and in anchorage-independent growth, is mediated......We have previously used a series of insertion-deletion mutants of the mutationally activated v-rasH gene to identify several regions of the encoded protein that are dispensable for cellular transformation (B. M. Willumsen, A. G. Papageorge, H.-F. Kung, E. Bekesi, T. Robins, M. Johnsen, W. C. Vass......, and D. R. Lowy, Mol. Cell. Biol. 6:2646-2654, 1986). To determine if some of these amino acids are more important for the biological activity of c-rasH, we have now tested many of the same insertion-deletion mutants in the c-rasH form for their ability to transform NIH 3T3 cells. Since the transforming...

  18. K-Ras-Independent Effects of the Farnesyl Transferase Inhibitor L-744,832 on Cyclin B1/Cdc2 Kinase Activity, G2/M Cell Cycle Progression and Apoptosis in Human Pancreatic Ductal Adenocarcinoma Cell

    Directory of Open Access Journals (Sweden)

    Si Young Song

    2000-05-01

    Full Text Available Pancreatic ductal adenocarcinoma is a highly lethal malignancy that is resistant to traditional cytotoxic therapy. High rates of activating codon 12 K-Ras mutations in this disease have generated considerable interest in the therapeutic application of novel farnesyl transferase inhibitors (FTIs. However, a comprehensive analysis of the effects of FTI treatment on pancreatic cancer cells has not been performed. Treatment of five different human pancreatic cancer cell lines with FTI L744,832 resulted in inhibition of anchorage-dependent growth, with wide variation in sensitivity among different lines. Effective growth inhibition by L-744,832 correlated with accumulation of cells with a tetraploid (4N DNA content and high levels of cyclin B1/cdc2 kinase activity, implying cell cycle arrest downstream from the DNA damage -inducible G2/M cell cycle checkpoint. In addition, sensitive cell lines underwent apoptosis as evidenced by changes in nuclear morphology and internucleosomal DNA fragmentation. L-744,832 at a concentration of 1 µM additively enhanced the cytotoxic effect of ionizing radiation, apparently by overriding G2/M checkpoint activation. The effects of FTI treatment on cell growth and cell cycle regulation were associated with changes in posttranslational processing of H-Ras and N-Ras, but not K-Ras. The results confirm the potential therapeutic efficacy of FTI treatment in pancreatic cancer, and suggest that farnesylated proteins other than K-Ras may act as important regulators of G2/M cell cycle kinetics.

  19. Activating FGFR2-RAS-BRAF mutations in ameloblastoma.

    Science.gov (United States)

    Brown, Noah A; Rolland, Delphine; McHugh, Jonathan B; Weigelin, Helmut C; Zhao, Lili; Lim, Megan S; Elenitoba-Johnson, Kojo S J; Betz, Bryan L

    2014-11-01

    Ameloblastoma is an odontogenic neoplasm whose overall mutational landscape has not been well characterized. We sought to characterize pathogenic mutations in ameloblastoma and their clinical and functional significance with an emphasis on the mitogen-activated protein kinase (MAPK) pathway. A total of 84 ameloblastomas and 40 non-ameloblastoma odontogenic tumors were evaluated with a combination of BRAF V600E allele-specific PCR, VE1 immunohistochemistry, the Ion AmpliSeq Cancer Hotspot Panel, and Sanger sequencing. Efficacy of a BRAF inhibitor was evaluated in an ameloblastoma-derived cell line. Somatic, activating, and mutually exclusive RAS-BRAF and FGFR2 mutations were identified in 88% of cases. Somatic mutations in SMO, CTNNB1, PIK3CA, and SMARCB1 were also identified. BRAF V600E was the most common mutation, found in 62% of ameloblastomas and in ameloblastic fibromas/fibrodentinomas but not in other odontogenic tumors. This mutation was associated with a younger age of onset, whereas BRAF wild-type cases arose more frequently in the maxilla and showed earlier recurrences. One hundred percent concordance was observed between VE1 immunohistochemistry and molecular detection of BRAF V600E mutations. Ameloblastoma cells demonstrated constitutive MAPK pathway activation in vitro. Proliferation and MAPK activation were potently inhibited by the BRAF inhibitor vemurafenib. Our findings suggest that activating FGFR2-RAS-BRAF mutations play a critical role in the pathogenesis of most cases of ameloblastoma. Somatic mutations in SMO, CTNNB1, PIK3CA, and SMARCB1 may function as secondary mutations. BRAF V600E mutations have both diagnostic and prognostic implications. In vitro response of ameloblastoma to a BRAF inhibitor suggests a potential role for targeted therapy. ©2014 American Association for Cancer Research.

  20. Investigation of medieval ceramics from Ras by physicochemical methods

    Directory of Open Access Journals (Sweden)

    Zindović Nataša D.

    2008-01-01

    Full Text Available Although early medieval Serbian ceramic is well described by the archeologists and historians, knowledge of the Balkan ceramic production is still limited. Archaeometric study of ceramics provenance, technology of preparation and used pigments as well as influence of neighboring countries and specific characteristics of different workshops has never been performed so far. The detailed knowledge of the micro-chemical and micro-structural nature of an archaeological artifact is critical in finding solutions to problems of restoration, conservation, dating and authentication in the art world. In this work we present results of systematic investigation of pottery shards from archeological site Ras. The term Ras, which signifies both the fortress and the region encompassing the upper course of Raška River, used to be the center of the medieval Serbian state. Both the ceramic body and the polychromatic glaze of the artifacts were studied by a multianalitical approach combining optical microscopy (OM, FT-IR spectroscopy and X-ray fluorescence (XRF. Mineralogical composition of pottery shards has been determined combining results obtained by FT-IR spectroscopy, after deconvolution of the spectra, and XRPD analysis. Firing temperature has been estimated based on the mineralogical composition and positions of Si-O stretching (-1000 cm-1 and banding (-460 cm-1 vibrations. Investigated samples have been classified into two groups based on the mineralogical composition, cross sections and firing temperature. Larger group consists of samples of fine-grained, homogeneous ceramics with firing temperatures bellow 800 °C which indicates imported products. Second, smaller group consists of inhomogeneous ceramics with firing temperatures between 850 and 900 °C produced in the domestic workshops. The obtained results will be used to build up a national database for the compositions of bodies, glazes and pigments.

  1. Transmitter-receiver system

    NARCIS (Netherlands)

    De Weerdt, E.; Van Kampen, E.J.; Chu, Q.P.

    2009-01-01

    The invention relates to a transmitter-receiver system comprising at least three transmitters and at least a first receiver and a second receiver, wherein the receivers are connected to a computing device that is arranged to analyse signals that said receivers receive from said transmitters and to

  2. A new mutation-independent approach to cancer therapy: Inhibiting oncogenic RAS and MYC, by targeting mitochondrial biogenesis.

    Science.gov (United States)

    Ozsvari, Bela; Sotgia, Federica; Lisanti, Michael P

    2017-10-27

    successful anti-cancer agents therapeutically target "cell phenotypes", such as increased cell proliferation, rather than specific genetic mutations. Remarkably, we demonstrated that Doxycycline inhibits the effects of diverse oncogenic stimuli, of both i) genetic (MYC/RAS) and ii) environmental (Rotenone) origins. Finally, we discuss the advantages of our "Proteomics-to-Genomics (PTG)" approach for in silico validation of new biomarkers and novel drug targets. In this context, we developed a new Myc-based Mito-Signature consisting of 3 mitochondrial genes (HSPD1; COX5B; TIMM44) for effectively predicting tumor recurrence (HR=4.69; p=2.4e-08) and distant metastasis (HR=4.94; p=2.8e-07), in ER(+) in breast cancer patients. This gene signature could serve as a new companion diagnostic for the early prediction of treatment failure in patients receiving hormonal therapy.

  3. Altered glucose metabolism in Harvey-ras transformed MCF10A cells.

    Science.gov (United States)

    Zheng, Wei; Tayyari, Fariba; Gowda, G A Nagana; Raftery, Daniel; McLamore, Eric S; Porterfield, D Marshall; Donkin, Shawn S; Bequette, Brian; Teegarden, Dorothy

    2015-02-01

    Metabolic reprogramming that alters the utilization of glucose including the "Warburg effect" is critical in the development of a tumorigenic phenotype. However, the effects of the Harvey-ras (H-ras) oncogene on cellular energy metabolism during mammary carcinogenesis are not known. The purpose of this study was to determine the effect of H-ras transformation on glucose metabolism using the untransformed MCF10A and H-ras oncogene transfected (MCF10A-ras) human breast epithelial cells, a model for early breast cancer progression. We measured the metabolite fluxes at the cell membrane by a selective micro-biosensor, [(13)C6 ]glucose flux by (13)C-mass isotopomer distribution analysis of media metabolites, intracellular metabolite levels by NMR, and gene expression of glucose metabolism enzymes by quantitative PCR. Results from these studies indicated that MCF10A-ras cells exhibited enhanced glycolytic activity and lactate production, decreased glucose flux through the tricarboxylic acid (TCA) cycle, as well as an increase in the utilization of glucose in the pentose phosphate pathway (PPP). These results provide evidence for a role of H-ras oncogene in the metabolic reprogramming of MCF10A cells during early mammary carcinogenesis. © 2013 Wiley Periodicals, Inc.

  4. RAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression.

    Science.gov (United States)

    Castellano, Esther; Molina-Arcas, Miriam; Krygowska, Agata Adelajda; East, Philip; Warne, Patricia; Nicol, Alastair; Downward, Julian

    2016-04-13

    RAS signalling through phosphoinositide 3-kinase (PI3-Kinase) has been shown to have an essential role in tumour initiation and maintenance. RAS also regulates cell motility and tumour invasiveness, but the role of direct RAS binding to PI3-Kinase in this remains uncertain. Here, we provide evidence that disruption of RAS interaction with PI3-Kinase p110α decreases cell motility and prevents activation of Rac GTPase. Analysis of gene expression in cells lacking RAS interaction with p110α reveals increased levels of the extracellular matrix glycoprotein Reelin and activation of its downstream pathway resulting in upregulation of E-cadherin expression. Induction of the Reelin/E-cadherin axis is also observed in Kras mutant lung tumours that are regressing due to blockade of RAS interaction with PI3-Kinase. Furthermore, loss of Reelin correlates with decreased survival of lung and breast cancer patients. Reelin thus plays a role in restraining RAS and PI3-kinase promotion of cell motility and potentially tumour metastasis.

  5. Reduction of metastasis, cell invasion, and adhesion in mouse osteosarcoma by YM529/ONO-5920-induced blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathway

    International Nuclear Information System (INIS)

    Tsubaki, Masanobu; Satou, Takao; Itoh, Tatsuki; Imano, Motohiro; Ogaki, Mitsuhiko; Yanae, Masashi; Nishida, Shozo

    2012-01-01

    Osteosarcoma is one of the most common primary malignant bone tumors in children and adolescents. Some patients continue to have a poor prognosis, because of the metastatic disease. YM529/ONO-5920 is a nitrogen-containing bisphosphonate that has been used for the treatment of osteoporosis. YM529/ONO-5920 has recently been reported to induce apoptosis in various tumors including osteosarcoma. However, the mode of metastasis suppression in osteosarcoma by YM529/ONO-5920 is unclear. In the present study, we investigated whether YM529/ONO-5920 inhibited tumor cell migration, invasion, adhesion, or metastasis in the LM8 mouse osteosarcoma cell line. We found that YM529/ONO-5920 significantly inhibited metastasis, cell migration, invasion, and adhesion at concentrations that did not have antiproliferative effects on LM8 cells. YM529/ONO-5920 also inhibited the mRNA expression and protein activities of matrix metalloproteinases (MMPs). In addition, YM529/ONO-5920 suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and the serine/threonine protein kinase B (Akt) by the inhibition of Ras prenylation. Moreover, U0126, a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, also inhibited LM8 cell migration, invasion, adhesion, and metastasis, as well as the mRNA expression and protein activities of MMP-1, MMP-2, MMP-9, and MT1-MMP. The results indicated that YM529/ONO-5920 suppressed the Ras/MEK/ERK and Ras/PI3K/Akt pathways, thereby inhibiting LM8 cell migration, invasion, adhesion, and metastasis. These findings suggest that YM529/ONO-5920 has potential clinical applications for the treatment of tumor cell metastasis in osteosarcoma. -- Highlights: ► We investigated whether YM529/ONO-5920 inhibited tumor metastasis in osteosarcoma. ► YM529/ONO-5920 inhibited metastasis, cell migration, invasion, and adhesion. ► YM529/ONO-5920 suppressed Ras signalings. ► YM529/ONO-5920

  6. The use of thrombopoietin-receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP): a "real life" retrospective multicenter experience of the Rete Ematologica Pugliese (REP).

    Science.gov (United States)

    Mazza, Patrizio; Minoia, Carla; Melpignano, Angela; Polimeno, Giuseppe; Cascavilla, Nicola; Di Renzo, Nicola; Specchia, Giorgina

    2016-01-01

    Immune thrombocytopenia (ITP) is a disease which sees one-third of patients failing first and subsequent therapeutic approaches, including splenectomy. Thrombopoietin-receptor agonists (TPO-RAs) are recommended for adults who relapse after splenectomy or who have contraindications for splenectomy. In this multicenter study, a total of 124 patients were retrospectively evaluated: 55 (44.3 %) were treated by romiplostim and 69 (55.6 %) by eltrombopag. Mean age, number of young patients (TPO-RA treatment, and previous lines of therapy were similar in both groups. The overall response rate was 80 % (44/55) for romiplostim and 94.2 % (65/69) for eltrombopag; the duration of response and the time to response were similar (p = NS). The response rate to both drugs in non-splenectomized patients was higher than that of splenectomized patients (p TPO-RAs could substitute splenectomy is under discussion and studies are warranted.

  7. Somatic Activation of rasK Gene in a Human Ovarian Carcinoma

    Science.gov (United States)

    Feig, L. A.; Bast, R. C.; Knapp, R. C.; Cooper, G. M.

    1984-02-01

    A tumor isolate from a patient with serous cystadenocarcinoma of the ovary contained an activated rasK gene detected by transfection of NIH/3T3 cells. In contrast, DNA from normal cells of the same patient lacked transforming activity, indicating that activation of this transforming gene was the consequence of somatic mutation in the neoplastic cells. The transforming gene product displayed an electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gels that differed from the mobilities of rasK transforming proteins in other tumors, indicating that a previously undescribed mutation was responsible for activation of rasK in this ovarian carcinoma.

  8. PTEN loss and activation of K-RAS and β-catenin cooperate to accelerate prostate tumourigenesis.

    Science.gov (United States)

    Jefferies, Matthew T; Cox, Adam C; Shorning, Boris Y; Meniel, Valerie; Griffiths, David; Kynaston, Howard G; Smalley, Matthew J; Clarke, Alan R

    2017-12-01

    Aberrant phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and WNT signalling are emerging as key events in the multistep nature of prostate tumourigenesis and progression. Here, we report a compound prostate cancer murine model in which these signalling pathways cooperate to produce a more aggressive prostate cancer phenotype. Using Cre-LoxP technology and the probasin promoter, we combined the loss of Pten (Pten fl/fl ), to activate the PI3K signalling pathway, with either dominant stabilized β-catenin [Catnb +/lox(ex3) ] or activated K-RAS (K-Ras +/V12 ) to aberrantly activate WNT and MAPK signalling, respectively. Synchronous activation of all three pathways (triple mutants) significantly reduced survival (median 96 days) as compared with double mutants [median: 140 days for Catnb +/lox(ex3) Pten fl/fl ; 182 days for Catnb +/lox(ex3) K-Ras +/V12 ; 238 days for Pten fl/fl K-Ras +/V12 ], and single mutants [median: 383 days for Catnb +/lox(ex3) ; 407 days for Pten fl/fl ], reflecting the accelerated tumourigenesis. Tumours followed a stepwise progression from mouse prostate intraepithelial neoplasia to invasive adenocarcinoma, similar to that seen in human disease. There was significantly elevated cellular proliferation, tumour growth and percentage of invasive adenocarcinoma in triple mutants as compared with double mutants and single mutants. Triple mutants showed not only activated AKT, extracellular-signal regulated kinase 1/2, and nuclear β-catenin, but also significantly elevated signalling through mechanistic target of rapamycin complex 1 (mTORC1). In summary, we show that combined deregulation of the PI3K, MAPK and WNT signalling pathways drives rapid progression of prostate tumourigenesis, and that deregulation of all three pathways results in tumours showing aberrant mTORC1 signalling. As mTORC1 signalling is emerging as a key driver of androgen deprivation therapy resistance, our findings are important for

  9. Involvement of H- and N-Ras isoforms in transforming growth factor-β1-induced proliferation and in collagen and fibronectin synthesis

    International Nuclear Information System (INIS)

    Martinez-Salgado, Carlos; Fuentes-Calvo, Isabel; Garcia-Cenador, Begona; Santos, Eugenio; Lopez-Novoa, Jose M.

    2006-01-01

    Transforming growth factor β1 (TGF-β1) has a relevant role in the origin and maintenance of glomerulosclerosis and tubule-interstitial fibrosis. TGF-β and Ras signaling pathways are closely related: TGF-β1 overcomes Ras mitogenic effects and Ras counteracts TGF-β signaling. Tubule-interstitial fibrosis is associated to increases in Ras, Erk, and Akt activation in a renal fibrosis model. We study the role of N- and H-Ras isoforms, and the involvement of the Ras effectors Erk and Akt, in TGF-β1-mediated extracellular matrix (ECM) synthesis and proliferation, using embrionary fibroblasts from double knockout (KO) mice for H- and N-Ras (H-ras -/- /N-ras -/- ) isoforms and from heterozygote mice (H-ras +/- /N-ras +/- ). ECM synthesis is increased in basal conditions in H-ras -/- /N-ras -/- fibroblasts, this increase being higher after stimulation with TGF-β1. TGF-β1-induced fibroblast proliferation is smaller in H-ras -/- /N-ras -/- than in H-ras +/- /N-ras +/- fibroblasts. Erk activation is decreased in H-ras -/- /N-ras -/- fibroblasts; inhibition of Erk activation reduces fibroblast proliferation. Akt activation is higher in double KO fibroblasts than in heterozygotes; inhibition of Akt activation also inhibits ECM synthesis. We suggest that H- and N-Ras isoforms downregulate ECM synthesis, and mediate proliferation, in part through MEK/Erk activation. PI3K-Akt pathway activation may be involved in the increase in ECM synthesis observed in the absence of H- and N-Ras

  10. Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations for estimating glomerular filtration rates in cancer patients receiving cisplatin-based chemotherapy.

    Science.gov (United States)

    Rhee, Jiyoung; Kwon, Jung Mi; Han, Sang Hoon; Kim, Sun Hyung; Park, Chang Hyun; Jeon, Ji Hyeon; Cho, Jong Tae; Lee, Eun Kyoung; Kim, So Mi

    2017-12-01

    Although the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has been recommended for accurate estimates of glomerular filtration rate (eGFR), there is little information regarding differences in GFR estimates obtained using the Cockcroft-Gault (CG) or Modification of Diet in Renal Disease (MDRD) equations in East Asian cancer patients. We investigated discrepancies in GFR and toxicities in patients treated with cisplatin-based chemotherapy using three equations equations. A total of 229 patients were retrospectively recruited. We calculated eGFR using the three equations and separated patients into three categories based on GFR 50 (group C) mL/min/1.73m 2 . We analyzed chemotherapy toxicities. The mean eGFR calculated using the CG was the lowest of the values derived using the three equations. Estimates using the MDRD and CKD-EPI equations resulted in reclassifying 32 (71.1%) and 33 (73.3%) of 45 patients, originally placed in group B using the CG into group C. However, only 1 (7.7%) of 13 patients placed in group B using the MDRD were reclassified into group C using the CKD-EPI. Twenty-eight of 45 patients classified into group B using the CG equation were treated with reduced doses of cisplatin. However, these patients did not show significant differences in toxicities compared with other patients taking full doses of cisplatin. The CG equations underestimated GFR compared to the MDRD and CKD-EPI equations. Therefore, when GFR is estimated using CG equations, East Asian cancer patients may receive insufficient doses of chemotherapeutic agents, including cisplatin.

  11. Prenatal Exposure to LPS Alters The Intrarenal RAS in Offspring, Which Is Ameliorated by Adipose Tissue-Derived Mesenchymal Stem Cells.

    Science.gov (United States)

    Ding, Xian-Fei; Sun, Mou; Guan, Fang-Xia; Guo, Li-Na; Zhang, Yan-Yan; Wan, You-Dong; Zhang, Xiao-Juan; Yu, Yan-Wu; Ma, Shan-Shan; Yao, Hai-Mu; Yao, Rui; Zhang, Rui-Fang; Sun, Tong-Wen; Kan, Quan-Cheng

    2017-11-06

    Prenatal lipopolysaccharide (LPS) exposure causes hypertension in rat offspring through an unknown mechanism. Here, we investigated the role of the intrarenal renin-angiotensin system (RAS) in hypertension induced by prenatal LPS exposure and also explored whether adipose tissue-derived mesenchymal stem cells (ADSCs) can ameliorate the effects of prenatal LPS exposure in rat offspring. Sixty-four pregnant rats were randomly divided into 4 groups (n = 16 in each), namely, a control group and an LPS group, which were intraperitoneally injected with vehicle and 0.79 mg/kg LPS, respectively, on the 8th, 10th, and 12th days of gestation; an ADSCs group, which was intravenously injected with 1.8 × 107 ADSCs on the 8th, 10th, and 12th days of gestation; and an LPS + ADSCs group, which received a combination of the treatments administered to the LPS and ADSCs groups. Prenatal LPS exposure increased blood pressure, Ang II expression, Ang II-positive, monocyte and lymphocyte, apoptotic cells in the kidney, and induced renal histological changes in offspring; however, the LPS and control groups did not differ significantly with respect to plasma renin activity levels, Ang II levels, or renal function. ADSCs treatment attenuated the blood pressure and also ameliorated the other effects of LPS-treated adult offspring. Prenatal exposure to LPS activates the intrarenal RAS but not the circulating RAS and thus induces increases in blood pressure in adult offspring; however, ADSCs treatment attenuates the blood pressure increases resulting from LPS exposure and also ameliorates the other phenotypic changes induced by LPS treatment by inhibiting intrarenal RAS activation. © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  12. Receiver Test Selection Criteria

    Science.gov (United States)

    2015-03-12

    The DOT requests that GPS manufacturers submit receivers for test in the following TWG categories: - Aviation (non-certified), cellular, general location/navigation, high precision, timing, networks, and space-based receivers - Each receiver should b...

  13. New weapons to penetrate the armor: Novel reagents and assays developed at the NCI RAS Initiative to enable discovery of RAS therapeutics.

    Science.gov (United States)

    Esposito, Dominic; Stephen, Andrew G; Turbyville, Thomas J; Holderfield, Matthew

    2018-02-09

    Development of therapeutic strategies against RAS-driven cancers has been challenging due in part to a lack of understanding of the biology of the system and the ability to design appropriate assays and reagents for targeted drug discovery efforts. Recent developments in the field have opened up new avenues for exploration both through advances in the number and quality of reagents as well as the introduction of novel biochemical and cell-based assay technologies which can be used for high-throughput screening of compound libraries. The reagents and assays developed at the NCI RAS Initiative offer a suite of new weapons that could potentially be used to enable the next generation of RAS drug discovery efforts with the hope of finding novel therapeutics for a target once deemed undruggable. Copyright © 2018. Published by Elsevier Ltd.

  14. Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes.

    Science.gov (United States)

    Nakase, Ikuhiko; Kobayashi, Nahoko Bailey; Takatani-Nakase, Tomoka; Yoshida, Tetsuhiko

    2015-06-03

    Exosomes are approximately 100-nm vesicles that consist of a lipid bilayer of cellular membranes secreted in large quantities from various types of normal and disease-related cells. Endocytosis has been reported as a major pathway for the cellular uptake of exosomes; however, the detailed mechanisms of their cellular uptake are still unknown. Here, we demonstrate the active induction of macropinocytosis (accompanied by actin reorganisation, ruffling of plasma membrane, and engulfment of large volumes of extracellular fluid) by stimulation of cancer-related receptors and show that the epidermal growth factor (EGF) receptor significantly enhances the cellular uptake of exosomes. We also demonstrate that oncogenic K-Ras-expressing MIA PaCa-2 cells exhibit intensive macropinocytosis that actively transports extracellular exosomes into the cells compared with wild-type K-Ras-expressing BxPC-3 cells. Furthermore, encapsulation of the ribosome-inactivating protein saporin with EGF in exosomes using our simple electroporation method produces superior cytotoxicity via the enhanced cellular uptake of exosomes. Our findings contribute to the biological, pharmaceutical, and medical research fields in terms of understanding the macropinocytosis-mediated cellular uptake of exosomes with applications for exosomal delivery systems.

  15. Management of rare, low anal anterior fistula exception to Goodsall′s rule with Kṣārasūtra

    Directory of Open Access Journals (Sweden)

    Pradeep S Shindhe

    2014-01-01

    Full Text Available Anal fistula (bhagandara is a chronic inflammatory condition, a tubular structure opening in the ano-rectal canal at one end and surface of perineum/peri-anal skin on the other end. Typically, fistula has two openings, one internal and other external associated with chronic on/off pus discharge on/off pain, pruritis and sometimes passing of stool from external opening. This affects predominantly male patients due to various etiologies viz., repeated peri-anal infections, Crohn′s disease, HIV infection, etc., Complex and atypical variety is encountered in very few patients, which require special treatment for cure. The condition poses difficulty for a surgeon in treating due to issues like patient hesitation, trouble in preparing kṣārasūtra, natural and routine infection with urine, stool etc., and dearth of surgical experts and technique. We would like to report a complex and atypical, single case of anterior, low anal fistula with tract reaching to median raphe of scrotum, which was managed successfully by limited application of kṣārasūtra.

  16. Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo : The EPIC Study

    NARCIS (Netherlands)

    Boswood, A; Gordon-McKeon, Shauna; Häggström, J; Wess, G; Stepien, R L; Oyama, M A; Keene, B W; Bonagura, J; MacDonald, K A; Patteson, M; Smith, S|info:eu-repo/dai/nl/35742574X; Fox, P R; Sanderson, K; Woolley, S.R.; Szatmári, V|info:eu-repo/dai/nl/272734497; Menaut, P; Church, W M; O'Sullivan, M L; Jaudon, J-P; Kresken, J-G; Rush, John; Barrett, A.K.; Rosenthal, S L; Saunders, B.A.C.; Ljungvall, I; Deinert, M; Bomassi, E; Estrada, A H; Fernandez Del Palacio, M J; Moise, N S; Abbott, J A; Fujii, Y; Spier, A; Luethy, M W; Santilli, R A; Uechi, M; Tidholm, A; Schummer, C; Watson, Poppy

    BACKGROUND: Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. OBJECTIVES: To investigate the effect of pimobendan on clinical variables and the relationship between

  17. Opposite effects of Ha-Ras and Ki-Ras on radiation-induced apoptosis via differential activation of PI3K/Akt and Rac/p38 mitogen-activated protein kinase signaling

    International Nuclear Information System (INIS)

    Choi, J.-A.; Kang, C.-M.; Lee, Y.-S.; Lee, S.-J.; Bae, S.-W.; Cho, C.-K.

    2003-01-01

    It has been well known that Ras signaling is involved in various cellular processes, including proliferation, differentiation, and apoptosis. However, distinct cellular functions of Ras isozymes are not fully understood. Here we show the opposing roles of Ha-Ras and Ki-Ras genes in the modulation of cell sensitivity to ionizing radiation. Overexpression of active isoform of Ha-Ras (12V-Ha- Ras) in Rat2 cells increases resistance to the ionizing radiation. Constitutive activation of phosphoinositide-3-kinase (PI3K) and Akt is detected specifically in 12V-Ha-Ras-overexpressing cells. The specific PI3K inhibitor LY294002 inhibits PI3K/Akt signaling and potentiates the radiation-induced apoptosis, suggesting that activation of PI3K/Akt signaling pathway is involved in the increased radio-resistance in cells overexpressing 12V-Ha-Ras. Overexpression of activated Ki-Ras (12V-Ki-Ras), on the other hand, markedly increases radiation sensitivity. The p38 mitogen-activated protein (MAP) kinase activity is selectively enhanced by ionizing radiation in cells overexpressing 12V-Ki-Ras. The specific p38 MAP kinase inhibitor, PD169316, or dominant-negative p38 MAP kinase decreases radiation-induced cell death. We further show that the mechanism that underlies potentiation of cell death in cells overexpressing 12V-Ki-Ras involves Bax translocation to the mitochondrial membrane. Elevated Bax translocation following ionizing irradiation in 12V-Ki-Ras-overexpressing cells is completely inhibited by PD169316 or dominant-negative p38 MAP kinase. In addition, introduction of cells with RacN17, a dominant negative mutant of Rac, resulted in a marked inhibition of radiation-induced Bax translocation and apoptotic cell death as well as p38 MAP kinase activation. Taken together, these findings explain the opposite effects of Ha-Ras and Ki-Ras on modulation of radio-sensitivity, and suggest that differential activation of PI3K/Akt and Rac/p38 MAP kinase signaling by Ha-Ras and Ki-Ras may

  18. Fundamental evaluation of the interaction between RAS/RAP and virgin asphalt binders.

    Science.gov (United States)

    2017-08-01

    A comprehensive laboratory testing program was conducted in this research project to examine the blending between reclaimed asphalt pavement (RAP)/recycled asphalt shingles (RAS) and virgin asphalt binders and to evaluate the factors that may affect ...

  19. [Study of the mechanism of Ras-dva small GTPase intracellular localization].

    Science.gov (United States)

    Tereshina, M B; Belousov, V V; Zaraĭskiĭ, A G

    2007-01-01

    An analysis of amino acid sequences of small GTPases of the Ras-dva family allowed us to determine the C-terminal prenylation motif, which could be responsible for the membrane localization of these proteins. We demonstrated using in vivo EGFP tracing that the Ras-dva small GTPases from Xenopus laevis embryo cells and NIH-3T3 fibroblasts are localized on both plasma membranes and endomembranes (the endoplasmic reticulum, the Golgi apparatus, and vesicles). At the same time, the replacement of the Cys residue, the SH group of which must be theoretically farnesylated, in the C-terminal prenylation motif of the Ras-dva small GTPase by the Ser residue prevented the membrane localization of the protein. These results indicate that the C-terminal prenylation site is critical for the membrane localization of small Ras-dva GTPases.

  20. Application of HEC-RAS water quality model to estimate contaminant spreading in small stream

    International Nuclear Information System (INIS)

    Halaj, Peter; Bárek, Viliam; Halajová, Anna Báreková; Halajová, Denisa

    2013-01-01

    The paper presents study of some aspects of HEC-RAS water quality model connected to simulation of contaminant transport in small stream. Authors mainly focused on one of the key tasks in process of pollutant transport modelling in streams - determination of the dispersion characteristics represented by longitudinal dispersion coefficient D. Different theoretical and empirical formulas have been proposed for D value determination and they have revealed that the coefficient is variable parameter that depends on hydraulic and morphometric characteristics of the stream reaches. Authors compare the results of several methods of coefficient D assessment, assuming experimental data obtained by tracer studies and compare them with results optimized by HEC-RAS water quality model. The analyses of tracer study and computation outputs allow us to outline the important aspects of longitudinal dispersion coefficient set up in process of the HEC-RAS model use. Key words: longitudinal dispersion coefficient, HEC-RAS, water quality modeling

  1. Expression of ras oncogene and major histocompatibility complex (MHC) antigen in carcinomas of the uterine cervix

    International Nuclear Information System (INIS)

    Cho, Kyung Ja; Jang, Ja June; Kim, Yong Dae; Ha, Chang Won; Koh, Jae Soo

    1993-01-01

    Consecutive 50 cases of squamous cell carcinomas of the uterine cervix diagnosed in 1992 were subjected to immunohistochemical study for ras oncogene product (p21) and MHC class II (DR) antigen using a microprobe immunostainer. Activated ras and aberrant DR expression were noted in 26 cases (52%) and 11 cases (22%) of cervical squamous cell carcinomas, respectively, without difference among histologic types. The reaction was mainly intracytoplasmic, with granular staining pattern and diffuse distribution. No direct histologic correlation between ras and DR expression was found. Four cases with HPV 16/18 DNA in superficial koilocytotic cells, revealed by in situ hybridization, showed various expression of ras and DR, and these 3 factors histologically did not seem to be affected one another. (Author)

  2. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells.

    Science.gov (United States)

    Commisso, Cosimo; Davidson, Shawn M; Soydaner-Azeloglu, Rengin G; Parker, Seth J; Kamphorst, Jurre J; Hackett, Sean; Grabocka, Elda; Nofal, Michel; Drebin, Jeffrey A; Thompson, Craig B; Rabinowitz, Joshua D; Metallo, Christian M; Vander Heiden, Matthew G; Bar-Sagi, Dafna

    2013-05-30

    Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.

  3. Influence of growing conditions on Ulva ohnoi composition cultivated in an IMTA-RAS system

    OpenAIRE

    Masaló Llorà, Ingrid; Oca Baradad, Joan; Ferrer, Josep; Cremades Ugarte, Javier; Pintado Valverde, José; Jiménez de Ridder, Patrícia

    2016-01-01

    Among Integrated Multitrophic Aquaculture (IMTA) techniques, the integration of fish and macroalgae cultures in Recirculating Aquaculture Systems (IMTA-RAS) is currently one of the most promising lines of action.

  4. Balanced RAP/RAS mix design and performance evaluation system for project-specific service conditions.

    Science.gov (United States)

    2012-11-01

    The use of reclaimed asphalt pavement (RAP) and recycled asphalt shingles (RAS) can significantly reduce the increasing cost of hot-mix asphalt paving, conserve energy, and protect the environment. However, the premature cracking problem has been a s...

  5. Evaluation of stone-matrix asphalt mixtures containing recycled asphalt shingles(RAS).

    Science.gov (United States)

    2017-05-01

    In recent years, there has been increased interest in the use of reclaimed material in asphalt : mixtures. The use of recycled asphalt shingles (RAS) has been of interest because of the high asphalt : content, although this asphalt is considerably st...

  6. RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma.

    Science.gov (United States)

    Chen, Xu; Wu, Qiuxia; Depeille, Philippe; Chen, Peirong; Thornton, Sophie; Kalirai, Helen; Coupland, Sarah E; Roose, Jeroen P; Bastian, Boris C

    2017-05-08

    Constitutive activation of Gαq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK. Protein kinase C (PKC) has been implicated as a link, but the mechanistic details remained unclear. We identified PKC δ and ɛ as required and sufficient to activate MAPK in GNAQ mutant melanomas. MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM. RasGRP3 activation occurs via PKC δ- and ɛ-dependent phosphorylation and PKC-independent, DAG-mediated membrane recruitment, possibly explaining the limited effect of PKC inhibitors to durably suppress MAPK in UM. The findings nominate RasGRP3 as a therapeutic target for cancers driven by oncogenic GNAQ/11. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Long-Term Outcomes in Puerto Ricans with Rheumatoid Arthritis (RA) Receiving Early Treatment with Disease-Modifying Anti-Rheumatic Drugs using the American College of Rheumatology Definition of Early RA.

    Science.gov (United States)

    Varela-Rosario, Noemí; Arroyo-Ávila, Mariangelí; Fred-Jiménez, Ruth M; Díaz-Correa, Leyda M; Pérez-Ríos, Naydi; Rodríguez, Noelia; Ríos, Grissel; Vilá, Luis M

    2017-01-01

    Early treatment of rheumatoid arthritis (RA) results in better long-term outcomes. However, the optimal therapeutic window has not been clearly established. To determine the clinical outcome of Puerto Ricans with RA receiving early treatment with conventional and/or biologic disease-modifying anti-rheumatic drugs (DMARDs) based on the American College of Rheumatology (ACR) definition of early RA. A cross-sectional study was performed in a cohort of Puerto Ricans with RA. Demographic features, clinical manifestations, disease activity, functional status, and pharmacotherapy were determined. Early treatment was defined as the initiation of DMARDs (conventional and/or biologic) in less than 6 months from the onset of symptoms attributable to RA. Patients who received early (disease duration was 14.9 years and 337 (87.0%) patients were women. One hundred and twenty one (31.3%) patients received early treatment. In the multivariate analysis adjusted for age and sex, early treatment was associated with better functional status, lower probability of joint deformities, intra-articular injections and joint replacement surgeries, and lower scores in the physician's assessments of global health, functional impairment and physical damage of patients. Using the ACR definition of early RA, this group of patients treated with DMARDs within 6 months of disease had better long-term outcomes with less physical damage and functional impairment.

  8. Mortality risk disparities in children receiving chronic renal replacement therapy for the treatment of end-stage renal disease across Europe

    DEFF Research Database (Denmark)

    Chesnaye, Nicholas C; Schaefer, Franz; Bonthuis, Marjolein

    2017-01-01

    HR) and the explained variation were modelled for patient-level and country-level factors with multilevel Cox regression. The primary outcome studied was all-cause mortality while on renal replacement therapy. FINDINGS: Between Jan 1, 2000, and Dec 31, 2013, the overall 5 year renal replacement therapy mortality rate......BACKGROUND: We explored the variation in country mortality rates in the paediatric population receiving renal replacement therapy across Europe, and estimated how much of this variation could be explained by patient-level and country-level factors. METHODS: In this registry analysis, we extracted...... patient data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry for 32 European countries. We included incident patients younger than 19 years receiving renal replacement therapy. Adjusted hazard ratios (a...

  9. Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches

    Directory of Open Access Journals (Sweden)

    Pathan AAK

    2016-05-01

    Full Text Available Akbar Ali Khan Pathan,1,2,* Bhavana Panthi,3,* Zahid Khan,1 Purushotham Reddy Koppula,4–6 Mohammed Saud Alanazi,1 Sachchidanand,3 Narasimha Reddy Parine,1 Mukesh Chourasia3,* 1Genome Research Chair (GRC, Department of Biochemistry, College of Science, King Saud University, 2Integrated Gulf Biosystems, Riyadh, Kingdom of Saudi Arabia; 3Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hajipur, India; 4Department of Internal Medicine, School of Medicine, 5Harry S. Truman Memorial Veterans Affairs Hospital, 6Department of Radiology, School of Medicine, Columbia, MO, USA *These authors contributed equally to this work Objective: Kirsten rat sarcoma (K-Ras protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras interacts with a range of effectors, resulting in the stimulation of downstream signaling pathways regulating cell proliferation, differentiation, and apoptosis. Efforts to target K-Ras have been unsuccessful until now, placing it among high-value molecules against which developing a therapy would have an enormous impact. K-Ras transduces signals when it binds to guanosine triphosphate by directly binding to downstream effector proteins, but in case of guanosine diphosphate-bound conformation, these interactions get disrupted. Methods: In the present study, we targeted the nucleotide-binding site in the “on” and “off” state conformations of the K-Ras protein to find out suitable lead compounds. A structure-based virtual screening approach has been used to screen compounds from different databases, followed by a combinatorial fragment-based approach to design the apposite lead for the K-Ras protein. Results: Interestingly, the designed compounds exhibit a binding preference for the

  10. Activated Ras alters lens and corneal development through induction of distinct downstream targets

    Directory of Open Access Journals (Sweden)

    Reneker Lixing

    2010-01-01

    Full Text Available Abstract Background Mammalian Ras genes regulate diverse cellular processes including proliferation and differentiation and are frequently mutated in human cancers. Tumor development in response to Ras activation varies between different tissues and the molecular basis for these variations are poorly understood. The murine lens and cornea have a common embryonic origin and arise from adjacent regions of the surface ectoderm. Activation of the fibroblast growth factor (FGF signaling pathway induces the corneal epithelial cells to proliferate and the lens epithelial cells to exit the cell cycle. The molecular mechanisms that regulate the differential responses of these two related tissues have not been defined. We have generated transgenic mice that express a constitutively active version of human H-Ras in their lenses and corneas. Results Ras transgenic lenses and corneal epithelial cells showed increased proliferation with concomitant increases in cyclin D1 and D2 expression. This initial increase in proliferation is sustained in the cornea but not in the lens epithelial cells. Coincidentally, cdk inhibitors p27Kip1 and p57Kip2 were upregulated in the Ras transgenic lenses but not in the corneas. Phospho-Erk1 and Erk2 levels were elevated in the lens but not in the cornea and Spry 1 and Spry 2, negative regulators of Ras-Raf-Erk signaling, were upregulated more in the corneal than in the lens epithelial cells. Both lens and corneal differentiation programs were sensitive to Ras activation. Ras transgenic embryos showed a distinctive alteration in the architecture of the lens pit. Ras activation, though sufficient for upregulation of Prox1, a transcription factor critical for cell cycle exit and initiation of fiber differentiation, is not sufficient for induction of terminal fiber differentiation. Expression of Keratin 12, a marker of corneal epithelial differentiation, was reduced in the Ras transgenic corneas. Conclusions Collectively, these

  11. Combined Inactivation of MYC and K-Ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas.

    Directory of Open Access Journals (Sweden)

    Phuoc T Tran

    2008-05-01

    Full Text Available Conditional transgenic models have established that tumors require sustained oncogene activation for tumor maintenance, exhibiting the phenomenon known as "oncogene-addiction." However, most cancers are caused by multiple genetic events making it difficult to determine which oncogenes or combination of oncogenes will be the most effective targets for their treatment.To examine how the MYC and K-ras(G12D oncogenes cooperate for the initiation and maintenance of tumorigenesis, we generated double conditional transgenic tumor models of lung adenocarcinoma and lymphoma. The ability of MYC and K-ras(G12D to cooperate for tumorigenesis and the ability of the inactivation of these oncogenes to result in tumor regression depended upon the specific tissue context. MYC-, K-ras(G12D- or MYC/K-ras(G12D-induced lymphomas exhibited sustained regression upon the inactivation of either or both oncogenes. However, in marked contrast, MYC-induced lung tumors failed to regress completely upon oncogene inactivation; whereas K-ras(G12D-induced lung tumors regressed completely. Importantly, the combined inactivation of both MYC and K-ras(G12D resulted more frequently in complete lung tumor regression. To account for the different roles of MYC and K-ras(G12D in maintenance of lung tumors, we found that the down-stream mediators of K-ras(G12D signaling, Stat3 and Stat5, are dephosphorylated following conditional K-ras(G12D but not MYC inactivation. In contrast, Stat3 becomes dephosphorylated in lymphoma cells upon inactivation of MYC and/or K-ras(G12D. Interestingly, MYC-induced lung tumors that failed to regress upon MYC inactivation were found to have persistent Stat3 and Stat5 phosphorylation.Taken together, our findings point to the importance of the K-Ras and associated down-stream Stat effector pathways in the initiation and maintenance of lymphomas and lung tumors. We suggest that combined targeting of oncogenic pathways is more likely to be effective in the

  12. International Conference-Session of the Section of Nuclear Physics of the Physical Sciences Division of RAS

    CERN Document Server

    2014-01-01

    From November 17 to 21, 2014 the Section of Nuclear Physics of the Physical Sciences Division of the Russian Academy of Sciences and the National Research Nuclear University MEPhI will hold in MEPhI, Moscow, the International Conference-Session of SNP PSD RAS "Physics of Fundamental Interactions". The program of the session covers basic theoretical and experimental aspects of particle physics and related problems of nuclear physics and cosmology, and will consist of 30-minute highlight and review talks as well as 10-15-minute contributed reports. All highlight talks and part of contributed reports will be presented at plenary sessions of the conference. The remaining reports will be presented at the sections which will be formed after receiving of abstracts. On the recommendation of the Organizing Committee reports and talks containing new unpublished results will be published in special issues of journals "Nuclear Physics" and "Nuclear Physics and Engineering". For the institutions belonging to the Rosatom s...

  13. The higher level of complexity of K-Ras4B activation at the membrane

    Science.gov (United States)

    Jang, Hyunbum; Banerjee, Avik; Chavan, Tanmay S.; Lu, Shaoyong; Zhang, Jian; Gaponenko, Vadim; Nussinov, Ruth

    2016-01-01

    Is nucleotide exchange sufficient to activate K-Ras4B? To signal, oncogenic rat sarcoma (Ras) anchors in the membrane and recruits effectors by exposing its effector lobe. With the use of NMR and molecular dynamics (MD) simulations, we observed that in solution, farnesylated guanosine 5′-diphosphate (GDP)-bound K-Ras4B is predominantly autoinhibited by its hypervariable region (HVR), whereas the GTP-bound state favors an activated, HVR-released state. On the anionic membrane, the catalytic domain adopts multiple orientations, including parallel (∼180°) and perpendicular (∼90°) alignments of the allosteric helices, with respect to the membrane surface direction. In the autoinhibited state, the HVR is sandwiched between the effector lobe and the membrane; in the active state, with membrane-anchored farnesyl and unrestrained HVR, the catalytic domain fluctuates reinlessly, exposing its effector-binding site. Dimerization and clustering can reduce the fluctuations. This achieves preorganized, productive conformations. Notably, we also observe HVR-autoinhibited K-Ras4B-GTP states, with GDP-bound-like orientations of the helices. Thus, we propose that the GDP/GTP exchange may not be sufficient for activation; instead, our results suggest that the GDP/GTP exchange, HVR sequestration, farnesyl insertion, and orientation/localization of the catalytic domain at the membrane conjointly determine the active or inactive state of K-Ras4B. Importantly, K-Ras4B-GTP can exist in active and inactive states; on its own, GTP binding may not compel K-Ras4B activation.—Jang, H., Banerjee, A., Chavan, T. S, Lu, S., Zhang, J., Gaponenko, V., Nussinov, R. The higher level of complexity of K-Ras4B activation at the membrane. PMID:26718888

  14. The higher level of complexity of K-Ras4B activation at the membrane.

    Science.gov (United States)

    Jang, Hyunbum; Banerjee, Avik; Chavan, Tanmay S; Lu, Shaoyong; Zhang, Jian; Gaponenko, Vadim; Nussinov, Ruth

    2016-04-01

    Is nucleotide exchange sufficient to activate K-Ras4B? To signal, oncogenic rat sarcoma (Ras) anchors in the membrane and recruits effectors by exposing its effector lobe. With the use of NMR and molecular dynamics (MD) simulations, we observed that in solution, farnesylated guanosine 5'-diphosphate (GDP)-bound K-Ras4B is predominantly autoinhibited by its hypervariable region (HVR), whereas the GTP-bound state favors an activated, HVR-released state. On the anionic membrane, the catalytic domain adopts multiple orientations, including parallel (∼180°) and perpendicular (∼90°) alignments of the allosteric helices, with respect to the membrane surface direction. In the autoinhibited state, the HVR is sandwiched between the effector lobe and the membrane; in the active state, with membrane-anchored farnesyl and unrestrained HVR, the catalytic domain fluctuates reinlessly, exposing its effector-binding site. Dimerization and clustering can reduce the fluctuations. This achieves preorganized, productive conformations. Notably, we also observe HVR-autoinhibited K-Ras4B-GTP states, with GDP-bound-like orientations of the helices. Thus, we propose that the GDP/GTP exchange may not be sufficient for activation; instead, our results suggest that the GDP/GTP exchange, HVR sequestration, farnesyl insertion, and orientation/localization of the catalytic domain at the membrane conjointly determine the active or inactive state of K-Ras4B. Importantly, K-Ras4B-GTP can exist in active and inactive states; on its own, GTP binding may not compel K-Ras4B activation.-Jang, H., Banerjee, A., Chavan, T. S, Lu, S., Zhang, J., Gaponenko, V., Nussinov, R. The higher level of complexity of K-Ras4B activation at the membrane. © FASEB.

  15. Safe use of NSAIDs and RAS-inhibitors at Agogo Presbyterian Hospital, Ghana.

    Science.gov (United States)

    Meulendijks, Lieke G; Adomako, Emmanuel A; Appiah, Emmanuel B; Kramers, Cornelis

    2016-03-01

    Preventable adverse events of medication are an important cause of hospital admissions in the developed world, in which non-steroidal anti-inflammatory drugs (NSAIDs) and renin-angiotensin system (RAS-) inhibitors are frequently involved. NSAIDs and RAS-inhibitors are also often used in Ghana. The purpose of this study is to assess whether biochemical monitoring in patients on RAS-inhibitors, and co-administration of gastro protective agents (GPAs) in patients on NSAIDs, is done properly in Ghana. Two retrospective cross-sectional studies were carried out at the Agogo Presbyterian Hospital, Ghana, in 2013. In 114 out-and inpatients who are on NSAIDs, the risk for gastrointestinal side effects and the frequency of co-administration of GPAs were determined. In 301 outpatients who are on RAS-inhibitors, the risk for renal dysfunction and the frequency of biochemical monitoring were determined. Fisher's exact test was used to determine the statistical strength. Co-administration of GPAs was done in 1.8% of patients on NSAIDs. Serum creatinine and potassium monitoring within one month after initiation of treatment with RAS-inhibitors were performed in 6.3% and 3.7%, respectively. Risk factors were neither associated with prescription of a GPA in patients on NSAIDs (p=0.134), nor in performing biochemical monitoring in patients on RAS-inhibitors (p=0.219 for creatinine, p=0.062 for potassium). Biochemical monitoring in patients on RAS-inhibitors and use of GPAs in patients on NSAIDs is poorly performed at the Agogo Presbyterian Hospital in Ghana. Improving the already existing Ghanaian guidelines, especially those for RAS-inhibitors, and encouraging their widespread use among prescribers should be pursued.

  16. Decrease in specific micronutrient intake in colorectal cancer patients with tumors presenting Ki-ras mutation

    OpenAIRE

    JORDI SALAS; NURIA LASO; SERGI MAS; M. JOSE LAFUENTE; XAVIER CASTERAD; MANUEL TRIAS; ANTONIO BALLESTA; RAFAEL MOLINA; CARLOS ASCASO; SHICHUN ZHENG; JOHN K. WIENCKE; AMALIA LAFUENTE

    2004-01-01

    Decrease in specific micronutrient intake in colorectal cancer patients with tumors presenting Ki-ras mutation BACKGROUND: The diversity of the Mediterranean diet and the heterogeneity of acquired genetic alterations in colorectal cancer (CRC) led us to examine the possible association between dietary factors and mutations, such as Ki-ras mutations, in genes implicated in the pathogenesis of these neoplasms. PATIENTS AND METHODS: The study was based on 246 cases and 296 controls. For th...

  17. Membrane curvature enables N-Ras lipid anchor sorting to liquid-ordered membrane phases

    DEFF Research Database (Denmark)

    Larsen, Jannik Bruun; Jensen, Martin Borch; Bhatia, Vikram Kjøller

    2015-01-01

    Trafficking and sorting of membrane-anchored Ras GTPases are regulated by partitioning between distinct membrane domains. Here, in vitro experiments and microscopic molecular theory reveal membrane curvature as a new modulator of N-Ras lipid anchor and palmitoyl chain partitioning. Membrane curva...... curvature was essential for enrichment in raft-like liquid-ordered phases; enrichment was driven by relief of lateral pressure upon anchor insertion and most likely affects the localization of lipidated proteins in general....

  18. Immune system deregulation in hypertensive patients chronically RAS suppressed developing albuminuria

    OpenAIRE

    Martin-Lorenzo, Marta; Gonzalez-Calero, Laura; Martinez, Paula J.; Baldan-Martin, Montserrat; Lopez, Juan Antonio; Ruiz-Hurtado, Gema; de la Cuesta, Fernando; Segura, Juli?n; Vazquez, Jes?s; Vivanco, Fernando; Barderas, Maria G.; Ruilope, Luis M.; Alvarez-Llamas, Gloria

    2017-01-01

    Albuminuria development in hypertensive patients is an indicator of higher cardiovascular (CV) risk and renal damage. Chronic renin-angiotensin system (RAS) suppression facilitates blood pressure control but it does not prevent from albuminuria development. We pursued the identification of protein indicators in urine behind albuminuria development in hypertensive patients under RAS suppression. Urine was collected from 100 patients classified in three groups according to albuminuria developme...

  19. Changes in microbial water quality in RAS following altered feed loading

    DEFF Research Database (Denmark)

    Rojas-Tirado, Paula Andrea; Pedersen, Per Bovbjerg; Vadstein, Olav

    2018-01-01

    Intensive recirculating aquaculture systems (RAS) with its hyper-eutrophic water offer ideal conditions for bacterial growth, abundance and activity, potentially affecting fish and system performance. Feed composition and feed loading in particular will have significant impact on organic and inor......Intensive recirculating aquaculture systems (RAS) with its hyper-eutrophic water offer ideal conditions for bacterial growth, abundance and activity, potentially affecting fish and system performance. Feed composition and feed loading in particular will have significant impact on organic...

  20. Beta1 integrin promotes but is not essential for metastasis of ras-myc transformed fibroblasts

    DEFF Research Database (Denmark)

    Brakebusch, C; Wennerberg, K; Krell, H W

    1999-01-01

    To investigate the role of beta1 integrin during tumor metastasis, we established a ras-myc transformed fibroblastoid cell line with a disrupted beta1 integrin gene on both alleles (GERM 11). Stable transfection of this cell line with an expression vector encoding beta1A integrin resulted in beta1A......, and collagen type I. Beta1 integrin, therefore, increases but is not essential for metastasis of ras-myc transformed fibroblasts....

  1. Transcriptional Profile of Ki-Ras-Induced Transformation of Thyroid Cells

    DEFF Research Database (Denmark)

    Visconti, Roberta; Federico, Antonella; Coppola, Valeria

    2007-01-01

    Abstract In the last years, an increasing number of experiments has provided compelling evidence for a casual role of Ras protein mutations, resulting in their constitutive activation, in thyroid carcinogenesis. However, despite the clear involvement of Ras proteins in thyroid carcinogenesis, the...... in human thyroid carcinoma cell lines and tumor samples, our results, therefore, providing a new molecular profile of the genes involved in thyroid neoplastic transformation....

  2. Locally advanced breast cancer: comparison of mammography, sonography and MR imaging in evaluation of residual disease in women receiving neoadjuvant chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Londero, Viviana; Bazzocchi, Massimo; Del Frate, Chiara; Francescutti, Giuliana; Zuiani, Chiara [Institute of Radiology, University of Udine, via Colugna 50, 33100, Udine (Italy); Puglisi, Fabio [Department of Oncology, University of Udine, via Colugna 50, 33100, Udine (Italy); Di Loreto, Carla [Institute of Pathology, University of Udine, via Colugna 50, 33100, Udine (Italy)

    2004-08-01

    The accuracy of mammography, sonography and magnetic resonance imaging (MRI) in identifying residual disease after neoadjuvant chemotherapy is evaluated and imaging findings are correlated with pathologic findings. Fifteen patients enrolled in an experimental protocol of preoperative neoadjuvant chemotherapy underwent clinical examination, mammography, sonography and dynamic MRI, performed in this order, before and respectively after 2 and 4 cycles of neoadjuvant chemotherapy. Four radiologists, two for mammography, one for sonography and one for MR, examined the images, blinded to the results of the other examinations. All patients underwent radical or conservative surgery, and imaging findings were compared with pathologic findings. MRI identified 2/15 (13.3.%) clinically complete response (CR), 9/15 (60%) partial response (PR), 3/15 (20%) stable disease (SD) and 1/15 (6.7%) progressive disease. Mammography identified 1/15 (6.7%) clinically CR, 8/15 (53.3%) PR and 4/15 (27%) SD, and was not able to evaluate the disease in 2/15 (13%) cases. Sonography presented the same results as MRI. Therefore, MRI and sonography compared to mammography correctly identified residual disease in 100 vs. 86%. MRI resulted in two false-negative results because of the presence of microfoci of in situ ductal carcinoma (DCIS) and invasive lobular carcinoma (LCI). MRI was superior to mammography in cases of multifocal or multicentric disease (83 vs. 33%). Sonography performed after MRI improves the accuracy in evaluation of uncertain foci of multifocal disease seen on MR images with an increase of diagnostic accuracy from 73 to 84.5%. MRI assesses response to neoadjuvant chemotherapy better than traditional methods of physical examination and mammography. (orig.)

  3. Locally advanced breast cancer: comparison of mammography, sonography and MR imaging in evaluation of residual disease in women receiving neoadjuvant chemotherapy

    International Nuclear Information System (INIS)

    Londero, Viviana; Bazzocchi, Massimo; Del Frate, Chiara; Francescutti, Giuliana; Zuiani, Chiara; Puglisi, Fabio; Di Loreto, Carla

    2004-01-01

    The accuracy of mammography, sonography and magnetic resonance imaging (MRI) in identifying residual disease after neoadjuvant chemotherapy is evaluated and imaging findings are correlated with pathologic findings. Fifteen patients enrolled in an experimental protocol of preoperative neoadjuvant chemotherapy underwent clinical examination, mammography, sonography and dynamic MRI, performed in this order, before and respectively after 2 and 4 cycles of neoadjuvant chemotherapy. Four radiologists, two for mammography, one for sonography and one for MR, examined the images, blinded to the results of the other examinations. All patients underwent radical or conservative surgery, and imaging findings were compared with pathologic findings. MRI identified 2/15 (13.3.%) clinically complete response (CR), 9/15 (60%) partial response (PR), 3/15 (20%) stable disease (SD) and 1/15 (6.7%) progressive disease. Mammography identified 1/15 (6.7%) clinically CR, 8/15 (53.3%) PR and 4/15 (27%) SD, and was not able to evaluate the disease in 2/15 (13%) cases. Sonography presented the same results as MRI. Therefore, MRI and sonography compared to mammography correctly identified residual disease in 100 vs. 86%. MRI resulted in two false-negative results because of the presence of microfoci of in situ ductal carcinoma (DCIS) and invasive lobular carcinoma (LCI). MRI was superior to mammography in cases of multifocal or multicentric disease (83 vs. 33%). Sonography performed after MRI improves the accuracy in evaluation of uncertain foci of multifocal disease seen on MR images with an increase of diagnostic accuracy from 73 to 84.5%. MRI assesses response to neoadjuvant chemotherapy better than traditional methods of physical examination and mammography. (orig.)

  4. Argos induces programmed cell death in the developing Drosophila eye by inhibition of the Ras pathway.

    Science.gov (United States)

    Sawamoto, K; Taguchi, A; Hirota, Y; Yamada, C; Jin, M H; Okano, H

    1998-04-01

    We studied the role of Ras signaling in the regulation of cell death during Drosophila eye development. Overexpression of Argos, a diffusible inhibitor of the EGF receptor and Ras signaling, caused excessive cell death in developing eyes at pupal stages. The Argos-induced cell death was suppressed by coexpression of the anti-apoptotic genes p35, diap1, or diap2 in the eye as well as by the Df(3L)H99 chromosomal deletion that lacks three apoptosis-inducing genes, reaper, head involution defective (hid) and grim. Transient misexpression of the activated Ras1 protein (Ras1V12) later in pupal development suppressed the Argos-induced cell death. Thus, Argos-induced cell death seemed to have resulted from the suppression of the anti-apoptotic function of Ras. Conversely, cell death induced by overexpression of Hid was suppressed by gain-of-function mutations of the genes coding for MEK and ERK. These results support the idea that Ras signaling functions in two distinct processes during eye development, first triggering the recruitment of cells and later negatively regulating cell death.

  5. The Anticancer Peptide TAT-RasGAP317−326 Exerts Broad Antimicrobial Activity

    Directory of Open Access Journals (Sweden)

    Mathieu Heulot

    2017-06-01

    Full Text Available Antibiotic resistance has become a major health issue. Nosocomial infections and the prevalence of resistant pathogenic bacterial strains are rising steadily. Therefore, there is an urgent need to develop new classes of antibiotics effective on multi-resistant nosocomial pathogenic bacteria. We have previously shown that a cell-permeable peptide derived from the p120 Ras GTPase-activating protein (RasGAP, called TAT-RasGAP317−326, induces cancer cell death, inhibits metastatic progression, and sensitizes tumor cells to various anti-cancer treatments in vitro and in vivo. We here report that TAT-RasGAP317−326 also possesses antimicrobial activity. In vitro, TAT-RasGAP317−326, but not mutated or truncated forms of the peptide, efficiently killed a series of bacteria including Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa. In vivo experiments revealed that TAT-RasGAP317−326 protects mice from lethal E. coli-induced peritonitis if administrated locally at the onset of infection. However, the protective effect was lost when treatment was delayed, likely due to rapid clearance and inadequate biodistribution of the peptide. Peptide modifications might overcome these shortcomings to increase the in vivo efficacy of the compound in the context of the currently limited antimicrobial options.

  6. Distinct roles of the RasGAP family proteins in C. elegans associative learning and memory.

    Science.gov (United States)

    Gyurkó, M Dávid; Csermely, Péter; Sőti, Csaba; Steták, Attila

    2015-10-15

    The Ras GTPase activating proteins (RasGAPs) are regulators of the conserved Ras/MAPK pathway. Various roles of some of the RasGAPs in learning and memory have been reported in different model systems, yet, there is no comprehensive study to characterize all gap genes in any organism. Here, using reverse genetics and neurobehavioural tests, we studied the role of all known genes of the rasgap family in C. elegans in associative learning and memory. We demonstrated that their proteins are implicated in different parts of the learning and memory processes. We show that gap-1 contribute redundantly with gap-3 to the chemosensation of volatile compounds, gap-1 plays a major role in associative learning, while gap-2 and gap-3 are predominantly required for short- and long-term associative memory. Our results also suggest that the C. elegans Ras orthologue let-60 is involved in multiple processes during learning and memory. Thus, we show that the different classes of RasGAP proteins are all involved in cognitive function and their complex interplay ensures the proper formation and storage of novel information in C. elegans.

  7. Concurrent mutation in exons 1 and 2 of the K-ras oncogene in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Fiorella Guadagni

    2012-01-01

    Full Text Available The K-ras gene is frequently mutated in colorectal cancer and has been associated with tumor initiation and progression; approximately 90% of the activating mutations are found in codons 12 and 13 of exon 1 and just under 5% in codon 61 located in exon 2. These mutations determine single aminoacidic substitutions in the GTPase pocket leading to a block of the GTP hydrolytic activity of the K-ras p21 protein, and therefore to its constitutive activation. Point mutations in sites of the K-ras gene, other than codons 12, 13 and 61, and other types of genetic alterations, may occur in a minority of cases, such as in the less frequent cases of double mutations in the K-ras gene. However, all mutations in this gene, even those which occur in non-canonical sites or double mutations, are relevant oncogenic alterations in colorectal cancer and may underlie K-ras pathway hyperactivation. In the present study, we report the case of a patient with colorectal cancer presenting a concurrent point mutation in exons 1 and 2 of the K-ras gene, a GGT to TGT substitution (Glycine to Cysteine at codon 12, and a GAC to AAC substitution (Aspartic Acid to Asparagine at codon 57. In addition, we found in the same patient’s sample a silent polymorphism at codon 11 (Ala11Ala of exon 1. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 4, pp. 729–733

  8. Targeted elimination of senescent Ras-transformed cells by suppression of MEK/ERK pathway.

    Science.gov (United States)

    Kochetkova, Elena Y; Blinova, Galina I; Bystrova, Olga A; Martynova, Marina G; Pospelov, Valery A; Pospelova, Tatiana V

    2017-11-14

    The Ras-Raf-MEK-ERK pathway plays a central role in tumorigenesis and is a target for anticancer therapy. The successful strategy based on the activation of cell death in Ras-expressing cells is associated with the suppression of kinases involved in Ras pathway. However, activation of cytoprotective autophagy overcomes antiproliferative effect of the inhibitors and develops drug resistance. We studied whether cellular senescence induced by HDAC inhibitor sodium butyrate in E1a+cHa-Ras -transformed rat embryo fibroblasts (ERas) and A549 human Ki-Ras mutated lung adenocarcinoma cells would enhance the tumor suppressor effect of MEK/ERK inhibition. Treatment of control ERas cells with PD0325901 for 24 h results in mitochondria damage and apoptotic death of a part of cellular population. However, the activation of AMPK-dependent autophagy overcomes pro-apoptotic effects of MEK/ERK inhibitor and results in restoration of the mitochondria and rescue of viability. Senescent ERas cells do not develop cytoprotective autophagy upon inhibition of MEK/ERK pathway due to spatial dissociation of lysosomes and autophagosomes in the senescent cells. Senescent cells are unable to form the autophagolysosomes and to remove the damaged mitochondria resulting in apoptotic death. Our data show that suppression of MEK/ERK pathway in senescent cells provides a new strategy for elimination of Ras-expressing cells.

  9. Nitric oxide induces thioredoxin-1 nuclear translocation: Possible association with the p21Ras survival pathway

    International Nuclear Information System (INIS)

    Arai, Roberto J.; Masutani, H.; Yodoi, J.; Debbas, V.; Laurindo, Francisco R.; Stern, A.; Monteiro, Hugo P.

    2006-01-01

    One of the major redox-regulating molecules with thiol reducing activity is thioredoxin-1 (TRX-1). TRX-1 is a multifunctional protein that exists in the extracellular millieu, cytoplasm, and nucleus, and has a distinct role in each environment. It is well known that TRX-1 promptly migrates to the nuclear compartment in cells exposed to oxidants. However, the intracellular location of TRX-1 in cells exposed to nitrosothiols has not been investigated. Here, we demonstrated that the exposure of HeLa cells to increasing concentrations of the nitrosothiol S-nitroso-N-acetylpenicillamine (SNAP) promoted TRX-1 nuclear accumulation. The SNAP-induced TRX-1 translocation to the nucleus was inhibited by FPTIII, a selective inhibitor of p21Ras. Furthermore, TRX-1 migration was attenuated in cells stably transfected with NO insensitive p21Ras (p21 RasC118S ). Downstream to p21Ras, the MAP Kinases ERK1/2 were activated by SNAP under conditions that promote TRX-1 nuclear translocation. Inhibition of MEK prevented SNAP-stimulated ERK1/2 activation and TRX-1 nuclear migration. In addition, cells treated with p21Ras or MEK inhibitor showed increased susceptibility to cell death induced by SNAP. In conclusion, our observations suggest that the nuclear translocation of TRX-1 is induced by SNAP involving p21Ras survival pathway

  10. EVALUASI VARIASI GENETIK TIGA RAS IKAN GURAME ( Osphronemus gouramy DENGAN MENGGUNAKAN ISOZYME

    Directory of Open Access Journals (Sweden)

    Estu Nugroho

    2016-11-01

    Full Text Available Evaluasi variasi genetik tiga ras ikan gurame dilakukan sebagai tahap awal dalam mengatasi masalah budi daya ikan gurame yaitu tumbuh lambat. Variasi genetik ras ikan gurame yaitu bastar, bule, dan blusafir yang dikoleksi dari daerah Parung-Bogor, Jawa Barat telah dievaluasi dengan menggunakan isozyme. Tidak terdapat perbedaan yang nyata di antara tiga ras ikan gurame yang diuji. Jumlah alel per lokus dan alel polymorfik berturut-turut berkisar 1,25—1,375 dan 25%--37,5%; sedangkan heterosigositas berkisar 0,125--0,137. Jarak genetik antara ras blusafir dengan bastar atau bule adalah lebih besar dibandingkan jarak genetik antara ras bastar dengan bule. Jarak genetik rata-rata di antara ketiga ras ikan gurame adalah 0,0003. Evaluation of genetic variability of three giant gouramy races is an initial effort to solve the problem in culturing giant gouramy i.e. low growth. Genetic variability of three giant gouramy races, i.e. bastar, bule, and blusafir collected from ParungBogor,  West Java is evaluated using isozyme. There is no significant difference among three giant gouramy races. Number of allele per locus and polymorphism allele were ranged 1.25--1.375 and 25.0%--37.5% respectively, while heterozygosity was ranged 0.125--0.137. Genetic distance between blusafir and bastar or bule is farthest than genetic distance between bastar and bule. The average genetic distance among giant gouramy races is 0.0003.

  11. Loss of RASSF1A Expression in Colorectal Cancer and Its Association with K-ras Status

    Directory of Open Access Journals (Sweden)

    Dan Cao

    2013-01-01

    Full Text Available Background. The RAS-association domain family 1 A (RASSF1A is a classical member of RAS effectors regulating cell proliferation and apoptosis. Loss of RASSF1A expression may shift the balance towards a growth-promoting effect without the necessity of activating K-ras mutations. Its potential association with K-ras mutations in colorectal cancer (CRC is unclear. Methods. RASSF1A expression was examined in normal mucosa, adenoma, and tumor tissues of colon and rectum, respectively. We examined the association of RASSF1A expression, mutations of K-ras, and EGFR status in 76 primary CRCs. The relationship between clinicopathological characteristics and RASSF1A expression was also analyzed. Results. RASSF1A expression level decreased progressively in normal mucosa, adenoma and, tumor tissues, and the loss of RASSF1A expression occurred more frequently in tumor tissues. Of 76 primary CRCs, loss of RASSF1A expression and/or K-ras mutations were detected in 77% cases. Loss of RASSF1A expression was more frequent in K-ras wild-type than in mutation cases (63% versus 32%, . Conclusions. Our study indicates that loss of RASSF1A may be involved in pathogenesis of CRC, its expression was found predominantly in K-ras wild-type CRCs, suggesting that it may be another way of affecting RAS signaling, in addition to K-ras mutations.

  12. c-Ha-ras BamHI RFLP in human urothelial tumors and point mutations in hot codons

    International Nuclear Information System (INIS)

    Weismanova, E; Skovraga, M.; Kaluz, S.

    1993-01-01

    High-molecular weights DNAs from 30 bladder and renal cell carcinomas (RCC) were isolated and the c-Ha-ras the c-Ha-ras gene BamHI RFLP was examined. Amplification of c-Ha-ras with normal localization with regard to the size of alleles was found only in the case. One of the normally localized c-Ha-ras allele termed RCC c-H-ras of a length of about 6.6 kbp was cloned and an oncogene-activating point mutation was identified using two restriction enzymes. After comparison of CfrI and Cfr10I cleavage maps of RCC c-Ha-ras to complete nucleotide sequences of EJ/T24 c-Ha-ras oncogene and its normal counterpart, a point mutation was identified within codon 11 or 12. The use of CfrI and Cfr10I is of value for clinical practice in identification of point mutations in c-Ha-ras PCR product in neoplasia accompanied by somatic mutation of c-Ha-ras. The correlation among c-Ha-ras allele, amplification/loss, presence of point mutation and progression of neoplasia is discussed. (author)

  13. Imaging of Ras/Raf activity induced by low energy laser irradiation in living cell using FRET

    Science.gov (United States)

    Wang, Fang; Chen, Tong-Sheng; Xing, Da

    2005-01-01

    Ras/Raf signaling pathway is an important signaling pathway that governs cell proliferation, differential and apoptosis. Low-energy laser irradiation (LELI) was found to modulate various processes. Generally, cell proliferation is induced by low doses LELI and apoptosis is induced by high doses LELI. Mechanism of biological effect of LELI has not been clear. Recently, activation of MEK (mitogen-activated protein kinase) and ERK (extracellular-signal-regulated kinase), which are downstream protein kinases of Ras/Raf, are observed during LELI-induced cell proliferation by immunoprecipitation and western blot analysis. RaichuRas reporter consisting of fusions of H-ras, the Ras-binding domain of Raf (RafRBD), a cyan fluorescent protein (CFP) and a yellow fluorescent protein (YFP). Therefore, intramolecular binding of GTP-Ras to RafRBD brings CFP close to YFP and increases FRET between CFP and YFP. Human lung adenocarcinoma cell line (ASTC-a-1) was transfected with the plasmid (pRaichuRas) and then treated with LELI at dose of 60J/cm2. Effect of LELI on Ras/Raf in physiological condition of living cells was observed by fluorescence resonance energy transfer (FRET) technique during lung adenocarcinoma cell apoptosis induced by high dose (60J/cm2) LELI. Experimental results showed that after high dose LELI treatment, the binding of Ras and Raf decreases obviously, Ras/Raf signaling pathway deregulates and cell apoptosis occurs.

  14. A drosophila model for EGFR-Ras and PI3K-dependent human glioma.

    Directory of Open Access Journals (Sweden)

    Renee D Read

    2009-02-01

    Full Text Available Gliomas, the most common malignant tumors of the nervous system, frequently harbor mutations that activate the epidermal growth factor receptor (EGFR and phosphatidylinositol-3 kinase (PI3K signaling pathways. To investigate the genetic basis of this disease, we developed a glioma model in Drosophila. We found that constitutive coactivation of EGFR-Ras and PI3K pathways in Drosophila glia and glial precursors gives rise to neoplastic, invasive glial cells that create transplantable tumor-like growths, mimicking human glioma. Our model represents a robust organotypic and cell-type-specific Drosophila cancer model in which malignant cells are created by mutations in signature genes and pathways thought to be driving forces in a homologous human cancer. Genetic analyses demonstrated that EGFR and PI3K initiate malignant neoplastic transformation via a combinatorial genetic network composed primarily of other pathways commonly mutated or activated in human glioma, including the Tor, Myc, G1 Cyclins-Cdks, and Rb-E2F pathways. This network acts synergistically to coordinately stimulate cell cycle entry and progression, protein translation, and inappropriate cellular growth and migration. In particular, we found that the fly orthologs of CyclinE, Cdc25, and Myc are key rate-limiting genes required for glial neoplasia. Moreover, orthologs of Sin1, Rictor, and Cdk4 are genes required only for abnormal neoplastic glial proliferation but not for glial development. These and other genes within this network may represent important therapeutic targets in human glioma.

  15. Gastroprotective effects of several H2RAs on ibuprofen-induced gastric ulcer in rats.

    Science.gov (United States)

    Liu, Jing; Sun, Dan; He, Jinfeng; Yang, Chengli; Hu, Tingting; Zhang, Lijing; Cao, Hua; Tong, Ai-Ping; Song, Xiangrong; Xie, Yongmei; He, Gu; Guo, Gang; Luo, Youfu; Cheng, Ping; Zheng, Yu

    2016-03-15

    Ibuprofen is the first line of treatment for osteoarthritis and arthritis. The main side effects of ibuprofen especially in long-term treatment include gastric ulcer, duodenal ulcer and indigestion etc. Therefore, screening drugs with effective gastric protective effects and low toxicity for combination therapy with ibuprofen is necessary. The mechanism of gastric damage induced by ibuprofen is still unclear, however, cell damage caused by reactive oxygen species (ROS) is considered as the main reason. Preliminary screening of literature with the criteria of low toxicity led to four histamine-2 receptor antagonists (H2RAs): nizatidine, famotidine, lafutidine, and roxatidine acetate, which were selected for further investigation. These drugs were evaluated systemically by examining the gastric ulcer index, lipid peroxidation (LPO), membrane permeability, toxicity to main organs, and the influence on the activity of antioxidant enzymes, and myeloperoxidase (MPO). Nizatidine was found to be the best gastric protective agent. It exhibited excellent protective effect by increasing antioxidant enzyme activity, decreasing MPO activity, reducing LPO, and membrane permeability. Combination treatment with nizatidine and ibuprofen did not show any significant toxicity. Nizatidine was considered as a good option for combination therapy with ibuprofen especially for diseases that require long-term treatment such as arthritis and osteoarthritis. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. [Ras-associated autoimmune leukoproliferative disorder: a report of 2 cases and literature review].

    Science.gov (United States)

    He, T Y; Li, C R; Xia, Y; Liang, F F; Luo, Y; Yang, J

    2017-11-02

    Objective: To investigate the clinical features and genetic characteristics of cases with Ras-associated autoimmune leukoproliferative disorder(RALD). Method: Characteristics of clinical data and gene mutation of the first two cases in China with RALD were retrospectively analyzed. The related literature was searched by using search terms "NRAS" , "KRAS" or "RALD" . Result: Case1, a seven-year-seven-month old girl, was admitted due to "thrombocytopenia and splenomegaly for three years" . Palpation showed enlargement of submandibular lymph nodes and hepatosplenomegaly.The platelet count fluctuated between 15×10(9)/L and 60×10(9)/L. Hemoglobin was as 57 g/L and Coomb's test was positive.Lung computed tomography revealed interstitial lung disease, bilateral pleural effusion, pericardial effusion, myocardial injury and ascites. Case2, a seven-year-five-month old girl, was admitted due to "recurrent thrombocytopenia for seven years, intermittent eyelid and abdominal swelling for three years" . Palpation showed enlargement of cervical and right inguinal lymph nodes, and hepatosplenomegaly.The number of platelet and monocyte were 9×10(9)/L and 5.46×10(9)/L, respectively. Bone marrow smear revealed an increase in the proportion of primitive immature cells (0.09 to 0.11). Lung computed tomography revealed interstitial lung disease, pericardial effusion, cardiac enlargement and pulmonary hypertension. The gene sequencing results showed KRAS gene c.38G> A somatic mutation in case1, and p.G12D and NRAS gene c.38G> A, p.G13D somatic mutation in case2. A total of 8 reports were retrieved including 23 cases caused by NRAS(10 cases) or KRAS(13 cases) gene somatic mutation. All the 23 cases showed hypergammaglobulinemia, splenomegaly, B cells hyperplasia or mononucleosis. Conclusion: RALD often manifests as hepatosplenomegaly,lymphoproliferation, autoimmune hematocytopenia, B cells hyperplasia or mononucleosis, hypergammaglobulinemia. Gene sequencing analysis can help diagnose

  17. Epidermal Growth Factor Receptor (EGFR gene copy number (GCN correlates with clinical activity of irinotecan-cetuximab in K-RAS wild-type colorectal cancer: a fluorescence in situ (FISH and chromogenic in situ hybridization (CISH analysis

    Directory of Open Access Journals (Sweden)

    Scartozzi Mario

    2009-08-01

    Full Text Available Abstract Background K-RAS wild type colorectal tumors show an improved response rate to anti-EGFR monoclonal antibodies. Nevertheless 70% to 40% of these patients still does not seem to benefit from this therapeutic approach. FISH EGFR GCN has been previously demonstrated to correlate with clinical outcome of colorectal cancer treated with anti-EGFR monoclonal antibodies. CISH also seemed able to provide accurate EGFR GCN information with the advantage of a simpler and reproducible technique involving immunohistochemistry and light microscopy. Based on these findings we investigated the correlation between both FISH and CISH EGFR GCN and clinical outcome in K-RAS wild-type colorectal cancer treated with irinotecan-cetuximab. Methods Patients with advanced K-RAS wild-type, colorectal cancer receiving irinotecan-cetuximab after failure of irinotecan-based chemotherapy were eligible. A cut-off value for EGFR GCN of 2.6 and 2.12 for FISH and CISH respectively was derived from ROC curve analysis. Results Forty-four patients were available for analysis. We observed a partial remission in 9 (60% and 2 (9% cases with a FISH EGFR GCN ≥ 2.6 and Conclusion FISH and CISH EGFR GCN may both represent effective tools for a further patients selection in K-RAS wild-type colorectal cancer treated with cetuximab.

  18. Stressing fish in Recirculating Aquaculture Systems (RAS): Does stress induced in one group of fish affect the feeding motivation of other fish sharing the same RAS?

    NARCIS (Netherlands)

    Martins, C.I.; Eding, E.H.; Verreth, J.A.J.

    2011-01-01

    As a consequence of water re-use and high stocking densities, Recirculating Aquaculture Systems (RAS) may lead to an accumulation of substances released by the fish into the water, e.g. cortisol and alarm pheromones. This study investigated the effect of stressing fish on the feeding motivation of

  19. Preliminary studies of radiation port in children receiving cranial irradiation for preventing central nervous system (CNS) disease of acute lymphoblastic leukemia (ALL)

    International Nuclear Information System (INIS)

    Miyoshi, Takeyoshi; Sato, Takeyuki; Okimoto, Yuri; Sunami, Shosuke; Komori, Isao; Oda, Hideaki; Shima, Yukichi; Arimizu, Noboru; Nakajima, Hironori

    1986-01-01

    For preventing CNS leukemia in children with ALL, simple whole skull irradiation that included only retro-orbital spaces and not anterior part of the cribriform plate and first two cervical vertebrae had been given until March 1982 to patients who had remission after drug therapy. Since March 1982, however, such patients have received new modified cranial irradiation of Pinkel's method of preventive CNS therapy to include the cribriform plate. Pinkel's method usually includes first two cervical vertebrae in radiation port, but sometimes his method of radiation fails to reach the brain and the meninges on the anterior parts of the lamina cribrosa. In this study, a comparison of CNS-relapes ratio between these two methods of preventive CNS therapy was carried out. The frequency of CNS leukemia was remarkably high in patients given the simple whole skull irradiation. Of 18 patients, 7 developed CNS leukemia. Among these 7, 5 patients (71 %) had occurence of CNS-relapse within 1 year 7 months with the other one patient, making a total of 86 %, having CNS-relapse within 1 year 11 months. On the other hand, 17 of 39 patients who received new modified cranial irradiation were followed up for more than 1 year 9 months, and all patient had no CNS-relapse to date. This result showed that the irradiation of whole circulation areas of cerebrospinal fluid of the brain and the spine at first two cervical vertebra levels had great importance in preventing CNS-relapse after achievement of drug-induced remission. (author)

  20. Suppression of survivin expression in glioblastoma cells by the Ras inhibitor farnesylthiosalicylic acid promotes caspase-dependent apoptosis.

    Science.gov (United States)

    Blum, Roy; Jacob-Hirsch, Jasmine; Rechavi, Gideon; Kloog, Yoel

    2006-09-01

    The Ras inhibitor farnesylthiosalicylic acid (FTS) has been shown to induce apoptosis in glioblastoma multiforme, but its mechanism of action was unknown. We show that FTS or dominant-negative Ras, by deregulating extracellular signal-regulated kinase and Akt signaling, decreases survivin gene transcripts in U87 glioblastoma multiforme, leading to disappearance of survivin protein and cell death. FTS affected both Ras-controlled regulators of survivin transcription and Ras-regulated survival signals. Thus, Ras inhibition by FTS resulted in release of the survivin "brake" on apoptosis and in activation of the mitochondrial apoptotic pathway: dephosphorylation of Bad, activation of Bax, release of cytochrome c, and caspase activation. FTS-induced apoptosis of U87 cells was strongly attenuated by forced expression of survivin or by caspase inhibitors. These results show that resistance to apoptosis in glioblastoma multiforme can be abolished by a single Ras inhibitor, which targets both survivin, a critical inhibitor of apoptosis, and the intrinsic mitochondrial apoptotic machinery.

  1. Comparison of prophylactic effect of UGIB and effects on platelet function between PPIs and H2RAs combined with DAPT: systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Yi Z

    2017-03-01

    Full Text Available Zhan-Miao Yi,1 Ting-Ting Qiu,1,2 Yuan Zhang,3 Zhi-Yan Liu,1 Suo-Di Zhai1 1Department of Pharmacy, Peking University Third Hospital, Beijing, 2Department of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 3Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada Objective: We compared prophylactic effects of proton pump inhibitors (PPIs and histamine-2 receptor antagonists (H2RAs on upper gastrointestinal bleeding (UGIB associated with dual antiplatelet therapy (DAPT and explored this influence on platelet function. Methods: Randomized controlled trials and cohort studies comparing PPIs with H2RAs in adults receiving DAPT were collected from PubMed, EMBASE and Cochrane databases. Dichotomous data were pooled to obtain risk ratios (RRs for UGIB, major adverse cardiovascular events (MACEs, poor responders to clopidogrel and rehospitalization, and continuous data were pooled to obtain mean differences (MDs for P2Y12 reaction units (PRUs, with 95% confidence intervals (CIs. Results: Twelve clinical trials (n=3,301 met the inclusion criteria. Compared to H2RAs, PPIs lessened UGIB (RR =0.16, 95% CI: 0.03–0.70, and there was no significant difference in the incidence of PRUs (MD =18.21 PRUs, 95% CI: -4.11–40.54, poor responders to clopidogrel (RR =1.21, 95% CI: 0.92–1.61, incidence of MACEs (RR =0.89, 95% CI: 0.45–1.75 or rehospitalization (RR =1.76, 95% CI: 0.79–3.92. Subgroup analysis confirmed fewer PRUs in the H2RAs group compared to the omeprazole group (2 studies, n=189, MD =31.80 PRUs, 95% CI: 11.65–51.96. However, poor responder data for clopidogrel and MACEs might be unreliable because few studies of this kind were included. Conclusion: Limited evidence indicates that PPIs were better than H2RAs for prophylaxis of UGIB associated with DAPT and had no effect on platelet function. Further study is needed to confirm these observations. Keywords: proton pump

  2. Antroquinonol blocks Ras and Rho signaling via the inhibition of protein isoprenyltransferase activity in cancer cells.

    Science.gov (United States)

    Ho, Ching-Liang; Wang, Jui-Ling; Lee, Cheng-Chung; Cheng, Hsiu-Yi; Wen, Wu-Che; Cheng, Howard Hao-Yu; Chen, Miles Chih-Ming

    2014-10-01

    Antroquinonol is the smallest anticancer molecule isolated from Antrodia camphorata thus far. The ubiquinone-like structure of Antroquinonol exhibits a broad spectrum of activity against malignancies in vivo and in vitro. However, the mechanism of action of Antroquinonol remains unclear. Here, we provide evidence that Antroquinonol plays a role in the inhibition of Ras and Ras-related small GTP-binding protein functions through the inhibition of protein isoprenyl transferase activity in cancer cells. Using cell line-based assays, we found that the inactive forms of Ras and Rho proteins were significantly elevated after treatment with Antroquinonol. We also demonstrated that Antroquinonol binds directly to farnesyltransferase and geranylgeranyltransferase-I, which are key enzymes involved in activation of Ras-related proteins, and inhibits enzymes activities in vitro. Furthermore, a molecular docking analysis illustrated that the isoprenoid moiety of Antroquinonol binds along the hydrophobic cavity of farnesyltransferase similar to its natural substrate, farnesyl pyrophosphate. In contrast, the ring structure of Antroquinonol lies adjacent to the Ras-CAAX motif-binding site on farnesyltransferase. The molecular docking study also showed a reasonable correlation with the IC50 values of Antroquinonol analogues. We also found that the levels of LC3B-II and the autophagosome-associated LC3 form were also significantly increased in H838 after Antroquinonol administration. In conclusion, Antroquinonol inhibited Ras and Ras-related GTP-binding protein activation through inhibition of protein isoprenyl transferase activity, leading to activation of autophagy and associated mode of cell death in cancer cells. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  3. MEK-1 Activates C-Raf Through a Ras-Independent Mechanism

    Science.gov (United States)

    Leicht, Deborah T.; Balan, Vitaly; Zhu, Jun; Kaplun, Alexander; Bronisz, Agnieszka; Rana, Ajay; Tzivion, Guri

    2013-01-01

    C-Raf is a member of the Ras-Raf-MEK-ERK mitogen-activated protein kinase (MAPK) signaling pathway that plays key roles in diverse physiological processes and is upregulated in many human cancers. C-Raf activation involves binding to Ras, increased phosphorylation and interactions with co-factors. Here, we describe a Ras-independent in vivo pathway for C-Raf activation by its downstream target MEK. Using 32P-metabolic labeling and 2D-phosphopeptide mapping experiments, we show that MEK increases C-Raf phosphorylation by up-to 10-fold. This increase was associated with C-Raf kinase activation, matching the activity seen with growth factor stimulation. Consequently, coexpression of wildtype C-Raf and MEK was sufficient for full and constitutive activation of ERK. Notably, the ability of MEK to activate C-Raf was completely Ras independent, since mutants impaired in Ras binding that are irresponsive to growth factors or Ras were fully activated by MEK. The ability of MEK to activate C-Raf was only partially dependent on MEK kinase activity but required MEK binding to C-Raf, suggesting that the binding results in a conformational change that increases C-Raf susceptibility to phosphorylation and activation or in the stabilization of the phosphorylated-active form. These findings propose a novel Ras-independent mechanism for activating C-Raf and the MAPK pathway without the need for mutations in the pathway. This mechanism could be of significance in pathological conditions or cancers overexpressing C-Raf and MEK or in conditions where C-Raf-MEK interaction is enhanced due to the downregulation of RKIP and MST2. PMID:23360980

  4. Ras1 interacts with multiple new signaling and cytoskeletal loci in Drosophila eggshell patterning and morphogenesis.

    Science.gov (United States)

    Schnorr, J D; Holdcraft, R; Chevalier, B; Berg, C A

    2001-10-01

    Little is known about the genes that interact with Ras signaling pathways to regulate morphogenesis. The synthesis of dorsal eggshell structures in Drosophila melanogaster requires multiple rounds of Ras signaling followed by dramatic epithelial sheet movements. We took advantage of this process to identify genes that link patterning and morphogenesis; we screened lethal mutations on the second chromosome for those that could enhance a weak Ras1 eggshell phenotype. Of 1618 lethal P-element mutations tested, 13 showed significant enhancement, resulting in forked and fused dorsal appendages. Our genetic and molecular analyses together with information from the Berkeley Drosophila Genome Project reveal that 11 of these lines carry mutations in previously characterized genes. Three mutations disrupt the known Ras1 cell signaling components Star, Egfr, and Blistered, while one mutation disrupts Sec61beta, implicated in ligand secretion. Seven lines represent cell signaling and cytoskeletal components that are new to the Ras1 pathway; these are Chickadee (Profilin), Tec29, Dreadlocks, POSH, Peanut, Smt3, and MESK2, a suppressor of dominant-negative Ksr. A twelfth insertion disrupts two genes, Nrk, a "neurospecific" receptor tyrosine kinase, and Tpp, which encodes a neuropeptidase. These results suggest that Ras1 signaling during oogenesis involves novel components that may be intimately associated with additional signaling processes and with the reorganization of the cytoskeleton. To determine whether these Ras1 Enhancers function upstream or downstream of the Egf receptor, four mutations were tested for their ability to suppress an activated Egfr construct (lambdatop) expressed in oogenesis exclusively in the follicle cells. Mutations in Star and l(2)43Bb had no significant effect upon the lambdatop eggshell defect whereas smt3 and dock alleles significantly suppressed the lambdatop phenotype.

  5. ACE variants interact with the RAS pathway to confer risk and protection against type 2 diabetic nephropathy.

    Science.gov (United States)

    Ahluwalia, Tarunveer Singh; Ahuja, Monica; Rai, Taranjit Singh; Kohli, Harbir Singh; Bhansali, Anil; Sud, Kamal; Khullar, Madhu

    2009-03-01

    Genetic predisposition has been proposed to be a major determinant in the development of renal complications of diabetes. Among candidate genes examined for susceptibility to diabetic nephropathy, angiotensin-converting enzyme (ACE) gene has been found to be associated with pathogenesis and progression of diabetic nephropathy. However, the role of other renin-angiotensin system (RAS) polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Recent studies also show that ACE haplotypes may be better predictors to disease susceptibility. Thus, in the present study, we evaluated the association of ACE haplotypes and the interactions of ACE, angiotensinogen (AGT), and angiotensin II receptor type I (AGTR1) gene polymorphisms with DNP in Asian Indians. We genotyped seven variants of the RAS pathway genes (ACE, AGT, and AGTR1) in type 2 diabetic cohorts without nephropathy (DM) and with nephropathy (DNP), using allele-specific oligonucleotide-PCR, and PCR-restriction fragment length polymorphism assays. We studied the interaction of these variants with each other and ACE I/D polymorphism. Frequency of ACE D allele and DD genotype (ACE I/D) was significantly higher in DNP (p < 0.005) and was associated with increased risk of nephropathy. The frequency of T allele, MT/TT genotypes (AGT: M235T), and C allele 1166CC genotype (AGTR1: A1166C) was higher and associated with increased risk of DNP (235T, p < 0.0001; 235TT/MT, p < 0.01; 1166C, p < 0.007; 1166CC, p < 0.0001). The ACE locus revealed a near doubling in the prevalence of T-D-G risk haplotype (odds ratio, 1.76) in DNP (0.13) compared to DM (0.08; p < 0.02). ACE haplotypes carrying the I allele were associated with a lower risk of DNP (C-I-A, p < 0.04; C-I-G, p < 0.008). ACE ID/DD genotypes in combination with ACE rs4311, rs4343, and AGT rs699 mutant genotypes increased the risk of DNP development fourfold (p < 0.01). This study provides the first evidence for a disease

  6. The relationship between recurrent aphthous stomatitis, and periodontal disease and Helicobacter Pylori infection.

    Science.gov (United States)

    Gülseren, D; Karaduman, A; Kutsal, D; Nohutcu, R M

    2016-11-01

    Recurrent aphthous stomatitis (RAS) is a common oral mucosal disease with unknown etiology. This cross-sectional study aimed to test the hypothesis that Helicobacter pylori and periodontal disease might play an etiological role in RAS. Dental plaque samples obtained from 38 patients with RAS and 43 healthy individuals via periodontal examinations were examined for H. pylori colonization. H. pylori was identified using the rapid urease test (RUT). The periodontal status of the patients and controls was based on the following periodontal parameters: periodontal pocket depth (PPD), the plaque index (PI), the gingival index (GI), and clinical attachment loss (CAL). RUT results were positive in 34 (89.5 %) of the 38 patients and 24 (55.8 %) of the 43 controls (P = 0.002). There were not any significant differences in mean PPD, PI, GI, or CAL between the patient and control groups (P > 0.05). Mean PPD, PI, GI, and CAL were higher in the RUT-positive RAS patients than in the RUT-negative patients (P > 0.05, for all). The present findings show that H. pylori might have played an etiological role in RAS and might have caused periodontal disease, but RAS was not associated with any of the periodontal parameters examined in this study. The present study indicates that H. pylori plays a role in the development of RAS, but periodontal diseases have no effect on it. Eradicating H. pylori might be useful to prevent RAS.

  7. Solar heat receiver

    Science.gov (United States)

    Hunt, Arlon J.; Hansen, Leif J.; Evans, David B.

    1985-01-01

    A receiver for converting solar energy to heat a gas to temperatures from 700.degree.-900.degree. C. The receiver is formed to minimize impingement of radiation on the walls and to provide maximum heating at and near the entry of the gas exit. Also, the receiver is formed to provide controlled movement of the gas to be heated to minimize wall temperatures. The receiver is designed for use with gas containing fine heat absorbing particles, such as carbon particles.

  8. Mortality risk disparities in children receiving chronic renal replacement therapy for the treatment of end-stage renal disease across Europe: an ESPN-ERA/EDTA registry analysis.

    Science.gov (United States)

    Chesnaye, Nicholas C; Schaefer, Franz; Bonthuis, Marjolein; Holman, Rebecca; Baiko, Sergey; Baskın, Esra; Bjerre, Anna; Cloarec, Sylvie; Cornelissen, Elisabeth A M; Espinosa, Laura; Heaf, James; Stone, Rosário; Shtiza, Diamant; Zagozdzon, Ilona; Harambat, Jérôme; Jager, Kitty J; Groothoff, Jaap W; van Stralen, Karlijn J

    2017-05-27

    We explored the variation in country mortality rates in the paediatric population receiving renal replacement therapy across Europe, and estimated how much of this variation could be explained by patient-level and country-level factors. In this registry analysis, we extracted patient data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry for 32 European countries. We included incident patients younger than 19 years receiving renal replacement therapy. Adjusted hazard ratios (aHR) and the explained variation were modelled for patient-level and country-level factors with multilevel Cox regression. The primary outcome studied was all-cause mortality while on renal replacement therapy. Between Jan 1, 2000, and Dec 31, 2013, the overall 5 year renal replacement therapy mortality rate was 15·8 deaths per 1000 patient-years (IQR 6·4-16·4). France had a mortality rate (9·2) of more than 3 SDs better, and Russia (35·2), Poland (39·9), Romania (47·4), and Bulgaria (68·6) had mortality rates more than 3 SDs worse than the European average. Public health expenditure was inversely associated with mortality risk (per SD increase, aHR 0·69, 95% CI 0·52-0·91) and explained 67% of the variation in renal replacement therapy mortality rates between countries. Child mortality rates showed a significant association with renal replacement therapy mortality, albeit mediated by macroeconomics (eg, neonatal mortality reduced from 1·31 [95% CI 1·13-1·53], p=0·0005, to 1·21 [0·97-1·51], p=0·10). After accounting for country distributions of patient age, the variation in renal replacement therapy mortality rates between countries increased by 21%. Substantial international variation exists in paediatric renal replacement therapy mortality rates across Europe, most of which was explained by disparities in public health expenditure, which seems to limit the availability and

  9. RAS2/PKA pathway activity is involved in the nitrogen regulation of L-leucine uptake in Saccharomyces cerevisiae.

    Science.gov (United States)

    Sáenz, D A; Chianelli, M S; Stella, C A; Mattoon, J R; Ramos, E H

    1997-03-01

    The aim of the present work is to study the participation of RAS2/PKA signal pathway in the nitrogen regulation of L-leucine transport in yeast cells. The study was performed on Saccharomyces cerevisiae isogenic strains with the normal RAS2 gene, the RAS2val19 mutant and the disrupted ras2::LEU2. These strains bring about different activities of the RAS2/PKA signal pathway, L-(14C)-Amino acid uptake measurements were determined in cells grown in a rich YPD medium with a mixed nitrogen source or in minimal media containing NH4+ or L-proline as the sole nitrogen source. We report herein that in all strains used, even in those grown in a minimal proline medium, the activity of the general amino acid permease (GAP1) was not detected. L-Leucine uptake in these strains is mediated by two kinetically characterized transport systems. Their KT values are of the same order as those of S1 and S2 L-leucine permeases. Mutation in the RAS2 gene alters initial velocities and Jmax values in both high and low affinity L-leucine transport systems. Activation of the RAS2/PKA signalling pathway by the RAS2val19 mutation, blocks the response to a poor nitrogen source whereas inactivation of RAS2 by gene disruption, results in an increase of the same response.

  10. Survey to determine the efficacy and safety of guideline-based pharmacological therapy for chronic obstructive pulmonary disease patients not previously receiving maintenance treatment.

    Science.gov (United States)

    Setoguchi, Yasuhiro; Izumi, Shinyu; Nakamura, Hidenori; Hanada, Shigeo; Marumo, Kazuyoshi; Kurosaki, Atsuko; Akata, Shouichi

    2015-01-01

    To investigate the potential beneficial effects of guideline-based pharmacological therapy on pulmonary function and quality of life (QOL) in Japanese chronic obstructive pulmonary disease (COPD) patients without prior treatment. Multicenter survey, open-label study of 49 Japanese COPD patients aged ≥ 40 years; outpatients with >10 pack years of smoking history; ratio of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) patients. Significant changes over time were not observed for FEV1 and FVC, indicating lung function at initiation of treatment was maintained during the observation period. COPD assessment test scores showed statistical and clinical improvements. Cough, sputum, breathlessness, and shortness of breath were significantly improved. Lung function and QOL of untreated Japanese COPD patients improved and improvements were maintained by performing a therapeutic intervention that conformed to published guidelines.

  11. Social media for health promotion: What messages are women receiving about cardiovascular disease risk by the Canadian Heart and Stroke Foundation?

    Science.gov (United States)

    Gonsalves, Christine A; McGannon, Kerry R; Schinke, Robert J

    2017-11-01

    The aim of this study was to explore the meanings of women's cardiovascular disease constructed within the Canadian Heart and Stroke Foundation Facebook page. Posts from Heart and Stroke Foundation and public user comments surrounding the launch of the Heart and Stroke Foundation re-branding were of interest. Ethnographic content analysis was employed to analyse text ( n = 40), images ( n = 32), videos ( n = 6), user comments and replies ( n = 42) from November 2016 to March 2017. Constructions (re)presented on Facebook of 'typical' women at risk and risk reduction were problematic as women most at risk were excluded through the use of consumerist, medicalized identities which also excluded promotion of healthy behaviour changes.

  12. Expression of Transketolase like gene 1 (TKTL1 predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy

    Directory of Open Access Journals (Sweden)

    Hofmann Wolf-Karsten

    2011-08-01

    Full Text Available Abstract Background For patients with locally advanced rectal cancer (LARC neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor (VEGF-R and Transketolase-like-1 (TKTL1 are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of VEGFR-1, VEGFR-2 and TKTL1 in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab. Methods Tumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy were analysed by quantitative PCR. Results Significantly higher expression of VEGFR-1/2 was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High TKTL1 expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers. Conclusion High TKTL-1 expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.

  13. Factors affecting disease-free survival in patients with human epidermal growth factor receptor 2-positive breast cancer who receive adjuvant trastuzumab

    Science.gov (United States)

    GÜNDÜZ, SEYDA; GÖKSU, SEMA SEZGIN; ARSLAN, DENIZ; TATLI, ALI MURAT; UYSAL, MÜKREMIN; GÜNDÜZ, UMUT RIZA; SEVINÇ, MERT MAHSUNI; COŞKUN, HASAN SENOL; BOZCUK, HAKAN; MUTLU, HASAN; SAVAS, BURHAN

    2015-01-01

    Breast cancer is the most frequently diagnosed cancer in women worldwide and the second cause of cancer-related mortality. A total of 20–30% of patients with early-stage breast cancer develop recurrence within the first 5 years following diagnosis. Trastuzumab significantly improves overall survival and disease-free survival (DFS) in women with human epidermal growth factor receptor 2 (HER2)-positive early and locally advanced breast cancer. This study aimed to determine the factors that affect DFS following adjuvant transtuzumab therapy. A total of 62 patients treated with trastuzumab for early and locally advanced breast cancer were included in our study. Data, including pathology, treatment and treatment outcome, rate of recurrence and laboratory tests, were retrospectively collected. There was no significant association between DFS and age, menopausal status, disease stage and hormone receptor status. The median follow-up was 48.4 months. The median DFS of patients treated with adjuvant trastuzumab was 64.1 months. In addition, the median DFS was 44.3 vs. 66.8 months in patients with platelet-lymphocyte ratio (PLR) ≤200 vs. >200, respectively (log-rank test; P=0.001), and 70 vs. 45 months in patients with eosinophil count ≤70 vs. >70×103/mm3 (log-rank test; P=0.001). Our data revealed the prognostic relevance of a decrease in the peripheral blood eosinophil count and PLR value following trastuzumab therapy in breast cancer. PLR and eosinophil count measurements are cost-effective, readily available worldwide, non-invasive and safe. Combined with other markers, such as patient age, tumor stage and tumor histology, may be effectively used for patients with breast cancer. PMID:26623060

  14. Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas.

    Science.gov (United States)

    Way, Gregory P; Sanchez-Vega, Francisco; La, Konnor; Armenia, Joshua; Chatila, Walid K; Luna, Augustin; Sander, Chris; Cherniack, Andrew D; Mina, Marco; Ciriello, Giovanni; Schultz, Nikolaus; Sanchez, Yolanda; Greene, Casey S

    2018-04-03

    Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these "hidden responders" may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  15. Role of the YAP Oncoprotein in Priming Ras-Driven Rhabdomyosarcoma.

    Directory of Open Access Journals (Sweden)

    Katherine K Slemmons

    Full Text Available Rhabdomyosarcoma (RMS, a cancer characterized by features of skeletal muscle histogenesis, is the most common soft tissue sarcoma of childhood and adolescence. Survival for high-risk groups is less than 30% at 5 years. RMS also occurs during adulthood, with a lower incidence but higher mortality. Recently, mutational profiling has revealed a correlation between activating Ras mutations in the embryonal (eRMS and pleomorphic (pRMS histologic variants of RMS, and a poorer outcome for those patients. Independently, the YAP transcriptional coactivator, an oncoprotein kept in check by the Hippo tumor suppressor pathway, is upregulated in eRMS. Here we show that YAP promotes cell proliferation and antagonizes apoptosis and myogenic differentiation of human RMS cells bearing oncogenic Ras mutations in cell culture studies in vitro and in murine xenografts in vivo. Pharmacologic inhibition of YAP by the benzoporphyrin derivative verteporfin decreased cell proliferation and tumor growth in vivo. To interrogate the temporal contribution of YAP in eRMS tumorigenesis, we used a primary human cell-based genetic model of Ras-driven RMS. Constitutively active YAP functioned as an early genetic lesion, permitting bypass of senescence and priming myoblasts to tolerate subsequent expression of hTERT and oncogenic Ras, which were necessary and sufficient to generate murine xenograft tumors mimicking RMS in vivo. This work provides evidence for cooperation between YAP and oncogenic Ras in RMS tumorigenesis, laying the foundation for preclinical co-targeting of these pathways.

  16. How do K-RAS-activated cells evade cellular defense mechanisms?

    Science.gov (United States)

    Lee, Y-S; Bae, S-C

    2016-02-18

    Lung adenocarcinomas, like other cancers, develop through the accumulation of epigenetic and genetic alterations. Numerous studies have shown that K-RAS mutation is among the most important early events in carcinogenesis of the lung. However, it is also well established that growth-stimulating signals feed back into growth-suppressing pathways, and any imbalance in these signaling networks will cause the cell to exit the cell cycle, thereby preventing uncontrolled cell growth. How, then, do K-RAS-activated cells evade cellular defense mechanisms? To answer this question, it is necessary to identify the molecular event(s) responsible for the development of early dysplastic lesions that are unable to defend against aberrant oncogene activation. Lineage-determining transcriptional regulators govern differentiation status during normal lung development, as well as in lung adenocarcinoma. Among the genes involved in K-RAS-induced lung tumorigenesis, RUNX3 is unique: inactivation of Runx3 in mouse lung induces lung adenoma and abrogates the ARF-p53 pathway. This observation raises the possibility of intimate cross-talk between the differentiation program and oncogene surveillance. In this review, we summarized evidences suggesting that K-RAS-activated cells do not evade cellular defense mechanisms per se; instead, cells with K-RAS mutations are selected only if they occur in cells in which defense mechanism is abrogated.

  17. Programmed Cell-to-Cell Variability in Ras Activity Triggers Emergent Behaviors during Mammary Epithelial Morphogenesis

    Directory of Open Access Journals (Sweden)

    Jennifer S. Liu

    2012-11-01

    Full Text Available Variability in signaling pathway activation between neighboring epithelial cells can arise from local differences in the microenvironment, noisy gene expression, or acquired genetic changes. To investigate the consequences of this cell-to-cell variability in signaling pathway activation on coordinated multicellular processes such as morphogenesis, we use DNA-programmed assembly to construct three-dimensional MCF10A microtissues that are mosaic for low-level expression of activated H-Ras. We find two emergent behaviors in mosaic microtissues: cells with activated H-Ras are basally extruded or lead motile multicellular protrusions that direct the collective motility of their wild-type neighbors. Remarkably, these behaviors are not observed in homogeneous microtissues in which all cells express the activated Ras protein, indicating that heterogeneity in Ras activity, rather than the total amount of Ras activity, is critical for these processes. Our results directly demonstrate that cell-to-cell variability in pathway activation within local populations of epithelial cells can drive emergent behaviors during epithelial morphogenesis.

  18. miR-11 regulates pupal size of Drosophila melanogaster via directly targeting Ras85D.

    Science.gov (United States)

    Li, Yao; Li, Shengjie; Jin, Ping; Chen, Liming; Ma, Fei

    2017-01-01

    MicroRNAs play diverse roles in various physiological processes during Drosophila development. In the present study, we reported that miR-11 regulates pupal size during Drosophila metamorphosis via targeting Ras85D with the following evidences: pupal size was increased in the miR-11 deletion mutant; restoration of miR-11 in the miR-11 deletion mutant rescued the increased pupal size phenotype observed in the miR-11 deletion mutant; ectopic expression of miR-11 in brain insulin-producing cells (IPCs) and whole body shows consistent alteration of pupal size; Dilps and Ras85D expressions were negatively regulated by miR-11 in vivo; miR-11 targets Ras85D through directly binding to Ras85D 3'-untranslated region in vitro; removal of one copy of Ras85D in the miR-11 deletion mutant rescued the increased pupal size phenotype observed in the miR-11 deletion mutant. Thus, our current work provides a novel mechanism of pupal size determination by microRNAs during Drosophila melanogaster metamorphosis. Copyright © 2017 the American Physiological Society.

  19. Active Erk Regulates Microtubule Stability in H-ras-Transformed Cells

    Directory of Open Access Journals (Sweden)

    Rene E. Harrison

    2001-01-01

    Full Text Available Increasing evidence suggests that activated erk regulates cell functions, at least in part, by mechanisms that do not require gene transcription. Here we show that the map kinase, erk, decorates microtubules (MTs and mitotic spindles in both parental and mutant active rastransfected 10T1 /2 fibroblasts and MCF10A breast epithelial cells. Approximately 20% of total cellular erk decorated MTs in both cell lines. A greater proportion of activated erk was associated with MTs in the presence of mutant active H-ras than in parental cells. Activation of erk by the ras pathway coincided with a decrease in the stability of MT, as detected by a stability marker. The MKK1 inhibitor, PD98059 and transfection of a dominant negative MKK1 blocked ras-induced instability of MTs but did not modify the association of erk with MTs or affect MT stability of the parental cells. These results indicate that the subset of active erk kinase that associates with MTs contributes to their instability in the presence of a mutant active ras. The MT-associated subset of active erk likely contributes to the enhanced invasive and proliferative abilities of cells containing mutant active H-ras.

  20. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth.

    Science.gov (United States)

    Gaglio, Daniela; Metallo, Christian M; Gameiro, Paulo A; Hiller, Karsten; Danna, Lara Sala; Balestrieri, Chiara; Alberghina, Lilia; Stephanopoulos, Gregory; Chiaradonna, Ferdinando

    2011-08-16

    Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed ¹³C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of ¹⁵N-labeled glutamine, and transcriptomic profiling in mouse fibroblast and human carcinoma cell lines. Stable isotope-labeled glucose and glutamine tracers and computational determination of intracellular fluxes indicated that cells expressing oncogenic K-Ras exhibited enhanced glycolytic activity, decreased oxidative flux through the tricarboxylic acid (TCA) cycle, and increased utilization of glutamine for anabolic synthesis. Surprisingly, a non-canonical labeling of TCA cycle-associated metabolites was detected in both transformed cell lines. Transcriptional profiling detected elevated expression of several genes associated with glycolysis, glutamine metabolism, and nucleotide biosynthesis upon transformation with oncogenic K-Ras. Chemical perturbation of enzymes along these pathways further supports the decoupling of glycolysis and TCA metabolism, with glutamine supplying increased carbon to drive the TCA cycle. These results provide evidence for a role of oncogenic K-Ras in the metabolic reprogramming of cancer cells.

  1. Alphavirus production is inhibited in neurofibromin 1-deficient cells through activated RAS signalling

    International Nuclear Information System (INIS)

    Kolokoltsova, Olga A.; Domina, Aaron M.; Kolokoltsov, Andrey A.; Davey, Robert A.; Weaver, Scott C.; Watowich, Stanley J.

    2008-01-01

    Virus-host interactions essential for alphavirus pathogenesis are poorly understood. To address this shortcoming, we coupled retrovirus insertional mutagenesis and a cell survival selection strategy to generate clonal cell lines broadly resistant to Sindbis virus (SINV) and other alphaviruses. Resistant cells had significantly impaired SINV production relative to wild-type (WT) cells, although virus binding and fusion events were similar in both sets of cells. Analysis of the retroviral integration sites identified the neurofibromin 1 (NF1) gene as disrupted in alphavirus-resistant cell lines. Subsequent analysis indicated that expression of NF1 was significantly reduced in alphavirus-resistant cells. Importantly, independent down-regulation of NF1 expression in WT HEK 293 cells decreased virus production and increased cell viability during SINV infection, relative to infected WT cells. Additionally, we observed hyperactive RAS signalling in the resistant HEK 293 cells, which was anticipated because NF1 is a negative regulator of RAS. Expression of constitutively active RAS (HRAS-G12V) in a WT HEK 293 cell line resulted in a marked delay in virus production, compared with infected cells transfected with parental plasmid or dominant-negative RAS (HRAS-S17N). This work highlights novel host cell determinants required for alphavirus pathogenesis and suggests that RAS signalling may play an important role in neuronal susceptibility to SINV infection

  2. Subcellular Distribution of S-Nitrosylated H-Ras in Differentiated and Undifferentiated PC12 Cells during Hypoxia.

    Science.gov (United States)

    Barbakadze, Tamar; Goloshvili, Galina; Narmania, Nana; Zhuravliova, Elene; Mikeladze, David

    2017-10-01

    Hypoxia or exposure to excessive reactive oxygen or nitrogen species could induce S-nitrosylation of various target proteins, including GTPases of the Ras-superfamily. Under hypoxic conditions, the Ras-protein is translocated to the cytosol and interacts with the Golgi complex, endoplasmic reticulum, mitochondria. The mobility/translocation of Ras depend on the cells oxidative status. However, the importance of relocated Snitrosylated- H-Ras (NO-H-Ras) in proliferation/differentiation processes is not completely understood. We have determined the content of soluble- and membrane-bound-NO-HRas in differentiated (D) and undifferentiated (ND) rat pheochromocytoma (PC12) cells under hypoxic and normoxic conditions. In our experimental study, we analyzed NO-H-Ras levels under hypoxic/normoxic conditions in membrane and soluble fractions of ND and D PC12 cells with/without nitric oxide donor, sodium nitroprusside (SNP) treatment. Cells were analyzed by the S-nitrosylated kit, immunoprecipitation, and Western blot. We assessed the action of NO-H-Ras on oxidative metabolism of isolated mitochondria by determining mitochondrial hydrogen peroxide generation via the scopoletin oxidation method and ATPproduction as estimated by the luminometric method. Hypoxia did not influence nitrosylation of soluble H-Ras in ND PC12 cells. Under hypoxic conditions, the nitrosylation of soluble-H-Ras greatly decreased in D PC12 cells. SNP didn't change the levels of nitrosylation of soluble-H-Ras, in either hypoxic or normoxic conditions. On the other hand, hypoxia, per se, did not affect the nitrosylation of membrane-bound-H-Ras in D and ND PC12 cells. SNP-dependent nitrosylation of membrane-bound-H-Ras greatly increased in D PC12 cells. Both unmodified normal and mutated H-Ras enhanced the mitochondrial synthesis of ATP, whereas the stimulatory effects on ATP synthesis were eliminated after S-nitrosylation of H-Ras. According to the results, it may be proposed that hypoxia can decrease S

  3. Clinical Impact of Education Provision on Determining Advance Care Planning Decisions among End Stage Renal Disease Patients Receiving Regular Hemodialysis in University Malaya Medical Centre.

    Science.gov (United States)

    Hing Wong, Albert; Chin, Loh Ee; Ping, Tan Li; Peng, Ng Kok; Kun, Lim Soo

    2016-01-01

    Advance care planning (ACP) is a process of shared decision-making about future health-care plans between patients, health care providers, and family members, should patients becomes incapable of participating in medical treatment decisions. ACP discussions enhance patient's autonomy, focus on patient's values and treatment preferences, and promote patient-centered care. ACP is integrated as part of clinical practice in Singapore and the United States. To assess the clinical impact of education provision on determining ACP decisions among end-stage renal disease patients on regular hemodialysis at University Malaya Medical Centre (UMMC). To study the knowledge and attitude of patients toward ACP and end-of-life issues. Fifty-six patients were recruited from UMMC. About 43 questions pretest survey adapted from Lyon's ACP survey and Moss's cardiopulmonary resuscitation (CPR) attitude survey was given to patients to answer. An educational brochure is then introduced to these patients, and a posttest survey carried out after that. The results were analyzed using SPSS version 22.0. Opinion on ACP, including CPR decisions, showed an upward trend on the importance percentage after the educational brochure exposure, but this was statistically not significant. Seventy-five percent of participants had never heard of ACP before, and only 3.6% had actually prepared a written advanced directive. The ACP educational brochure clinically impacts patients' preferences and decisions toward end-of-life care; however, this is statistically not significant. Majority of patients have poor knowledge on ACP. This study lays the foundation for execution of future larger scale clinical trials, and ultimately, the incorporation of ACP into clinical practice in Malaysia.

  4. Nonalcoholic fatty liver disease in Japanese patients with severe obesity who received laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) in comparison to non-Japanese patients

    International Nuclear Information System (INIS)

    Kakizaki, Satoru; Takizawa, Daichi; Yamazaki, Yuichi; Nakajima, Yuka; Ichikawa, Takeshi; Sato, Ken; Takagi, Hitoshi; Mori, Masatomo; Kasama, Kazunori

    2008-01-01

    The number of patients with morbid obesity is increasing worldwide. However, the prevalence of morbid obesity is still low in Japan, and therefore few systematic investigations of liver dysfunction in this population have so far been carried out. This study aimed to investigate the clinical characteristics in severe obese Japanese patients undergoing laparoscopic Roux-en-Y gastric bypass surgery (LRYGB). Eighty-four patients with severe obesity, including 61 Japanese and 23 non-Japanese patients, were analyzed. The mean body mass index (BMI) was 43.7±7.8 kg/m 2 , and there was no difference between Japanese and non-Japanese patients. Nonalcoholic fatty liver disease (NAFLD) was observed in 45/59 (76.2%) of the Japanese patients. Although there were no differences in the BMI and body weight, serum alanine aminotransferase (ALT) was higher in Japanese patients in comparison to non-Japanese patients (P<0.05). The indices for insulin resistance were significantly higher in the Japanese patients in comparison to non-Japanese patients (P<0.01). The liver/spleen computed tomography (CT) ratios were lower in Japanese patients (P<0.05). The laboratory data and BMI significantly improved at 1 year after LRYGB in both groups. Racial difference may exist difference may exist in NAFLD in patients with severe obesity. When the BMI is similar, liver dysfunction among Japanese patients with severe obesity tends to be higher than in non-Japanese patients. Japanese patients with severe obesity must therefore reduce their body weight to a greater degree in comparison to non-Japanese patients with the same BMI. LRYGB can achieve effective weight control and lower ALT levels in Japanese patients with severe obesity. (author)

  5. Novel approach to abuse the hyperactive K-Ras pathway for adenoviral gene therapy of colorectal cancer

    International Nuclear Information System (INIS)

    Naumov, Inna; Kazanov, Dina; Lisiansky, Victoria; Starr, Alex; Aroch, Ilan; Shapira, Shiran; Kraus, Sarah; Arber, Nadir

    2012-01-01

    Background: Functional activation of oncogenic K-Ras signaling pathway plays an important role in the early events of colorectal carcinogenesis (CRC). K-Ras proto-oncogene is involved in 35–40% of CRC cases. Mutations in the Ras gene trigger the transduction of proliferative and anti-apoptotic signals, even in the absence of extra cellular stimuli. The objective of the current study was to use a gene-targeting approach to kill human CRC cells selectively harboring mutated K-Ras. Results: A recombinant adenovirus that carries a lethal gene, PUMA, under the control of a Ras responsive promoter (Ad-Py4-SV40-PUMA) was used selectively to target CRC cells (HCT116, SW480, DLD1 and RIE-Ras) that possess a hyperactive Ras pathway while using HT29 and RIE cells as a control that harbors wild type Ras and exhibit very low Ras activity. Control vector, without the Ras responsive promoter elements was used to assess the specificity of our “gene therapy” approach. Both adenoviral vectors were assed in vitro and in xenograft model in vivo. Ad-Py4-SV40-PUMA showed high potency to induce ∼ 50% apoptosis in vitro, to abolish completely tumor formation by infecting cells with the Ad-Py4-SV40-PUMA prior xenografting them in nude mice and high ability to suppress by ∼ 35% tumor progression in vivo in already established tumors. Conclusions: Selective targeting of CRC cells with the activated Ras pathway may be a novel and effective therapy in CRC. The high potency of this adenoviral vector may help to overcome an undetectable micro metastasis that is the major hurdle in challenging with CRC.

  6. Novel approach to abuse the hyperactive K-Ras pathway for adenoviral gene therapy of colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Naumov, Inna [Integrated Cancer Prevention Center, Tel Aviv (Israel); Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Kazanov, Dina [Integrated Cancer Prevention Center, Tel Aviv (Israel); Lisiansky, Victoria [Integrated Cancer Prevention Center, Tel Aviv (Israel); Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Starr, Alex [Lung and Allergy Institute, Tel Aviv Sourasky Medical Center, Tel Aviv (Israel); Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Aroch, Ilan; Shapira, Shiran; Kraus, Sarah [Integrated Cancer Prevention Center, Tel Aviv (Israel); Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Arber, Nadir, E-mail: narber@post.tau.ac.il [Integrated Cancer Prevention Center, Tel Aviv (Israel); Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv (Israel); Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel)

    2012-01-15

    Background: Functional activation of oncogenic K-Ras signaling pathway plays an important role in the early events of colorectal carcinogenesis (CRC). K-Ras proto-oncogene is involved in 35-40% of CRC cases. Mutations in the Ras gene trigger the transduction of proliferative and anti-apoptotic signals, even in the absence of extra cellular stimuli. The objective of the current study was to use a gene-targeting approach to kill human CRC cells selectively harboring mutated K-Ras. Results: A recombinant adenovirus that carries a lethal gene, PUMA, under the control of a Ras responsive promoter (Ad-Py4-SV40-PUMA) was used selectively to target CRC cells (HCT116, SW480, DLD1 and RIE-Ras) that possess a hyperactive Ras pathway while using HT29 and RIE cells as a control that harbors wild type Ras and exhibit very low Ras activity. Control vector, without the Ras responsive promoter elements was used to assess the specificity of our 'gene therapy' approach. Both adenoviral vectors were assed in vitro and in xenograft model in vivo. Ad-Py4-SV40-PUMA showed high potency to induce {approx} 50% apoptosis in vitro, to abolish completely tumor formation by infecting cells with the Ad-Py4-SV40-PUMA prior xenografting them in nude mice and high ability to suppress by {approx} 35% tumor progression in vivo in already established tumors. Conclusions: Selective targeting of CRC cells with the activated Ras pathway may be a novel and effective therapy in CRC. The high potency of this adenoviral vector may help to overcome an undetectable micro metastasis that is the major hurdle in challenging with CRC.

  7. Low complexity MIMO receivers

    CERN Document Server

    Bai, Lin; Yu, Quan

    2014-01-01

    Multiple-input multiple-output (MIMO) systems can increase the spectral efficiency in wireless communications. However, the interference becomes the major drawback that leads to high computational complexity at both transmitter and receiver. In particular, the complexity of MIMO receivers can be prohibitively high. As an efficient mathematical tool to devise low complexity approaches that mitigate the interference in MIMO systems, lattice reduction (LR) has been widely studied and employed over the last decade. The co-authors of this book are world's leading experts on MIMO receivers, and here they share the key findings of their research over years. They detail a range of key techniques for receiver design as multiple transmitted and received signals are available. The authors first introduce the principle of signal detection and the LR in mathematical aspects. They then move on to discuss the use of LR in low complexity MIMO receiver design with respect to different aspects, including uncoded MIMO detection...

  8. Bioinformatics of non small cell lung cancer and the ras proto-oncogene

    CERN Document Server

    Kashyap, Amita; Babu M, Naresh

    2015-01-01

    Cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes. Mutations in the K-ras proto-oncogene are responsible for 10–30% of adenocarcinomas. Clinical Findings point to a wide variety of other cancers contributing to lung cancer incidence. Such a scenario makes identification of lung cancer difficult and thus identifying its mechanisms can contribute to the society. Identifying unique conserved patterns common to contributing proto-oncogenes may further be a boon to Pharmacogenomics and pharmacoinformatics. This calls for ab initio/de novo drug discovery that in turn will require a comprehensive in silico approach of Sequence, Domain, Phylogenetic and Structural analysis of the receptors, ligand screening and optimization and detailed Docking studies. This brief involves extensive role of the RAS subfamily that includes a set of proteins, which cause an over expression of cancer-causing genes like M-ras and initiate tumour formation in lungs. SNP Studies and Structure based ...

  9. Bacillus subtilis Intramembrane Protease RasP Activity in Escherichia coli andIn Vitro.

    Science.gov (United States)

    Parrell, Daniel; Zhang, Yang; Olenic, Sandra; Kroos, Lee

    2017-10-01

    RasP is a predicted intramembrane metalloprotease of Bacillus subtilis that has been proposed to cleave the stress response anti-sigma factors RsiW and RsiV, the cell division protein FtsL, and remnant signal peptides within their transmembrane segments. To provide evidence for direct effects of RasP on putative substrates, we developed a heterologous coexpression system. Since expression of catalytically inactive RasP E21A inhibited expression of other membrane proteins in Escherichia coli , we added extra transmembrane segments to RasP E21A, which allowed accumulation of most other membrane proteins. A corresponding active version of RasP appeared to promiscuously cleave coexpressed membrane proteins, except those with a large periplasmic domain. However, stable cleavage products were not observed, even in clpP mutant E. coli Fusions of transmembrane segment-containing parts of FtsL and RsiW to E. coli maltose-binding protein (MBP) also resulted in proteins that appeared to be RasP substrates upon coexpression in E. coli , including FtsL with a full-length C-terminal domain (suggesting that prior cleavage by a site 1 protease is unnecessary) and RsiW designed to mimic the PrsW site 1 cleavage product (suggesting that further trimming by extracytoplasmic protease is unnecessary). Purified RasP cleaved His 6 -MBP-RsiW(73-118) in vitro within the RsiW transmembrane segment based on mass spectrometry analysis, demonstrating that RasP is an intramembrane protease. Surprisingly, purified RasP failed to cleave His 6 -MBP-FtsL(23-117). We propose that the lack of α-helix-breaking residues in the FtsL transmembrane segment creates a requirement for the membrane environment and/or an additional protein(s) in order for RasP to cleave FtsL. IMPORTANCE Intramembrane proteases govern important signaling pathways in nearly all organisms. In bacteria, they function in stress responses, cell division, pathogenesis, and other processes. Their membrane-associated substrates are

  10. Delphi Accounts Receivable Module -

    Data.gov (United States)

    Department of Transportation — Delphi accounts receivable module contains the following data elements, but are not limited to customer information, cash receipts, line of accounting details, bill...

  11. Utilizing ras signaling pathway to direct selective replication of herpes simplex virus-1.

    Directory of Open Access Journals (Sweden)

    Weihong Pan

    Full Text Available Re-engineering the tropism of viruses is an attractive translational strategy for targeting cancer cells. The Ras signal transduction pathway is a central hub for a variety of pro-oncogenic events with a fundamental role in normal and neoplastic physiology. In this work we were interested in linking Ras activation to HSV-1 replication in a direct manner in order to generate a novel oncolytic herpes virus which can target cancer cells. To establish such link, we developed a mutant HSV-1 in which the expression of ICP4 (infected cell protein-4, a viral protein necessary for replication is controlled by activation of ELK, a transcription factor down-stream of the Ras pathway and mainly activated by ERK (extracellular signal-regulated kinase, an important Ras effector pathway. This mutant HSV-1 was named as Signal-Smart 1 (SS1. A series of prostate cells were infected with the SS1 virus. Cells with elevated levels of ELK activation were preferentially infected by the SS1 virus, as demonstrated by increased levels of viral progeny, herpetic glycoprotein C and overall SS1 viral protein production. Upon exposure to SS1, the proliferation, invasiveness and colony formation capabilities of prostate cancer cells with increased ELK activation were significantly decreased (p<0.05, while the rate of apoptosis/necrosis in these cells was increased. Additionally, high Ras signaling cells infected with SS1 showed a prominent arrest in the G1 phase of the cell cycle as compared to cells exposed to parental HSV-1. The results of this study reveal the potential for re-modeling the host-herpes interaction to specifically interfere with the life of cancer cells with increased Ras signaling. SS1 also serves as a "prototype" for development of a family of signal-smart viruses which can target cancer cells on the basis of their signaling portfolio.

  12. Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics.

    Directory of Open Access Journals (Sweden)

    Barry J Grant

    2009-03-01

    Full Text Available Ras mediates signaling pathways controlling cell proliferation and development by cycling between GTP- and GDP-bound active and inactive conformational states. Understanding the complete reaction path of this conformational change and its intermediary structures is critical to understanding Ras signaling. We characterize nucleotide-dependent conformational transition using multiple-barrier-crossing accelerated molecular dynamics (aMD simulations. These transitions, achieved for the first time for wild-type Ras, are impossible to observe with classical molecular dynamics (cMD simulations due to the large energetic barrier between end states. Mapping the reaction path onto a conformer plot describing the distribution of the crystallographic structures enabled identification of highly populated intermediate structures. These structures have unique switch orientations (residues 25-40 and 57-75 intermediate between GTP and GDP states, or distinct loop3 (46-49, loop7 (105-110, and alpha5 C-terminus (159-166 conformations distal from the nucleotide-binding site. In addition, these barrier-crossing trajectories predict novel nucleotide-dependent correlated motions, including correlations of alpha2 (residues 66-74 with alpha3-loop7 (93-110, loop2 (26-37 with loop10 (145-151, and loop3 (46-49 with alpha5 (152-167. The interconversion between newly identified Ras conformations revealed by this study advances our mechanistic understanding of Ras function. In addition, the pattern of correlated motions provides new evidence for a dynamic linkage between the nucleotide-binding site and the membrane interacting C-terminus critical for the signaling function of Ras. Furthermore, normal mode analysis indicates that the dominant collective motion that occurs during nucleotide-dependent conformational exchange, and captured in aMD (but absent in cMD simulations, is a low-frequency motion intrinsic to the structure.

  13. Utilizing ras signaling pathway to direct selective replication of herpes simplex virus-1.

    Science.gov (United States)

    Pan, Weihong; Bodempudi, Vidya; Esfandyari, Tuba; Farassati, Faris

    2009-08-04

    Re-engineering the tropism of viruses is an attractive translational strategy for targeting cancer cells. The Ras signal transduction pathway is a central hub for a variety of pro-oncogenic events with a fundamental role in normal and neoplastic physiology. In this work we were interested in linking Ras activation to HSV-1 replication in a direct manner in order to generate a novel oncolytic herpes virus which can target cancer cells. To establish such link, we developed a mutant HSV-1 in which the expression of ICP4 (infected cell protein-4, a viral protein necessary for replication) is controlled by activation of ELK, a transcription factor down-stream of the Ras pathway and mainly activated by ERK (extracellular signal-regulated kinase, an important Ras effector pathway). This mutant HSV-1 was named as Signal-Smart 1 (SS1). A series of prostate cells were infected with the SS1 virus. Cells with elevated levels of ELK activation were preferentially infected by the SS1 virus, as demonstrated by increased levels of viral progeny, herpetic glycoprotein C and overall SS1 viral protein production. Upon exposure to SS1, the proliferation, invasiveness and colony formation capabilities of prostate cancer cells with increased ELK activation were significantly decreased (p<0.05), while the rate of apoptosis/necrosis in these cells was increased. Additionally, high Ras signaling cells infected with SS1 showed a prominent arrest in the G1 phase of the cell cycle as compared to cells exposed to parental HSV-1. The results of this study reveal the potential for re-modeling the host-herpes interaction to specifically interfere with the life of cancer cells with increased Ras signaling. SS1 also serves as a "prototype" for development of a family of signal-smart viruses which can target cancer cells on the basis of their signaling portfolio.

  14. Notch and Ras promote sequential steps of excretory tube development in C. elegans.

    Science.gov (United States)

    Abdus-Saboor, Ishmail; Mancuso, Vincent P; Murray, John I; Palozola, Katherine; Norris, Carolyn; Hall, David H; Howell, Kelly; Huang, Kai; Sundaram, Meera V

    2011-08-01

    Receptor tyrosine kinases and Notch are crucial for tube formation and branching morphogenesis in many systems, but the specific cellular processes that require signaling are poorly understood. Here we describe sequential roles for Notch and Epidermal growth factor (EGF)-Ras-ERK signaling in the development of epithelial tube cells in the C. elegans excretory (renal-like) organ. This simple organ consists of three tandemly connected unicellular tubes: the excretory canal cell, duct and G1 pore. lin-12 and glp-1/Notch are required to generate the canal cell, which is a source of LIN-3/EGF ligand and physically attaches to the duct during de novo epithelialization and tubulogenesis. Canal cell asymmetry and let-60/Ras signaling influence which of two equivalent precursors will attach to the canal cell. Ras then specifies duct identity, inducing auto-fusion and a permanent epithelial character; the remaining precursor becomes the G1 pore, which eventually loses epithelial character and withdraws from the organ to become a neuroblast. Ras continues to promote subsequent aspects of duct morphogenesis and differentiation, and acts primarily through Raf-ERK and the transcriptional effectors LIN-1/Ets and EOR-1. These results reveal multiple genetically separable roles for Ras signaling in tube development, as well as similarities to Ras-mediated control of branching morphogenesis in more complex organs, including the mammalian kidney. The relative simplicity of the excretory system makes it an attractive model for addressing basic questions about how cells gain or lose epithelial character and organize into tubular networks.

  15. PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers.

    Directory of Open Access Journals (Sweden)

    Filip Janku

    Full Text Available Oncogenic mutations of PIK3CA, RAS (KRAS, NRAS, and BRAF have been identified in various malignancies, and activate the PI3K/AKT/mTOR and RAS/RAF/MEK pathways, respectively. Both pathways are critical drivers of tumorigenesis.Tumor tissues from 504 patients with diverse cancers referred to the Clinical Center for Targeted Therapy at MD Anderson Cancer Center starting in October 2008 were analyzed for PIK3CA, RAS (KRAS, NRAS, and BRAF mutations using polymerase chain reaction-based DNA sequencing.PIK3CA mutations were found in 54 (11% of 504 patients tested; KRAS in 69 (19% of 367; NRAS in 19 (8% of 225; and BRAF in 31 (9% of 361 patients. PIK3CA mutations were most frequent in squamous cervical (5/14, 36%, uterine (7/28, 25%, breast (6/29, 21%, and colorectal cancers (18/105, 17%; KRAS in pancreatic (5/9, 56%, colorectal (49/97, 51%, and uterine cancers (3/20, 15%; NRAS in melanoma (12/40, 30%, and uterine cancer (2/11, 18%; BRAF in melanoma (23/52, 44%, and colorectal cancer (5/88, 6%. Regardless of histology, KRAS mutations were found in 38% of patients with PIK3CA mutations compared to 16% of patients with wild-type (wtPIK3CA (p = 0.001. In total, RAS (KRAS, NRAS or BRAF mutations were found in 47% of patients with PIK3CA mutations vs. 24% of patients wtPIK3CA (p = 0.001. PIK3CA mutations were found in 28% of patients with KRAS mutations compared to 10% with wtKRAS (p = 0.001 and in 20% of patients with RAS (KRAS, NRAS or BRAF mutations compared to 8% with wtRAS (KRAS, NRAS or wtBRAF (p = 0.001.PIK3CA, RAS (KRAS, NRAS, and BRAF mutations are frequent in diverse tumors. In a wide variety of tumors, PIK3CA mutations coexist with RAS (KRAS, NRAS and BRAF mutations.

  16. Muzeja IT infrastruktūras modernizēšana

    OpenAIRE

    Liparts, Arnis

    2014-01-01

    Kvalifikācijas darba nosaukums ir „Muzeja IT infrastruktūras modernizācija”. Darbā tiek aprakstīts kā tika modernizēts jau esošs un salīdzinoši sarežģīts datoru tīkls. Darbā lielā mērā tika izmantoti Mikrotik maršrutētāji IT infrastruktūras modernizācijai. Atslēgas vārdi : Karstvieta, automatizēšana, Mikrotik, IT

  17. Farming different species in RAS in Nordic countries: Current status and future perspectives

    DEFF Research Database (Denmark)

    Dalsgaard, Anne Johanne Tang; Lund, Ivar; Thorarinsdottir, Ragnheidur

    2013-01-01

    Recirculating aquaculture systems (RAS) have gained increasing interest in recent years as a means to intensify fish production while at the same time minimize the environmental impact. Considerable hands-on experience has accumulated within the Nordic countries over the last 20-30 years in desig......Recirculating aquaculture systems (RAS) have gained increasing interest in recent years as a means to intensify fish production while at the same time minimize the environmental impact. Considerable hands-on experience has accumulated within the Nordic countries over the last 20-30 years...

  18. The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway.

    Science.gov (United States)

    Stevenson, David A; Schill, Lisa; Schoyer, Lisa; Andresen, Brage S; Bakker, Annette; Bayrak-Toydemir, Pinar; Burkitt-Wright, Emma; Chatfield, Kathryn; Elefteriou, Florent; Elgersma, Ype; Fisher, Michael J; Franz, David; Gelb, Bruce D; Goriely, Anne; Gripp, Karen W; Hardan, Antonio Y; Keppler-Noreuil, Kim M; Kerr, Bronwyn; Korf, Bruce; Leoni, Chiara; McCormick, Frank; Plotkin, Scott R; Rauen, Katherine A; Reilly, Karlyne; Roberts, Amy; Sandler, Abby; Siegel, Dawn; Walsh, Karin; Widemann, Brigitte C

    2016-08-01

    The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation-arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Ras signalling regulates differentiation and UCP1 expression in models of brown adipogenesis

    DEFF Research Database (Denmark)

    Murholm, Maria; Dixen, Karen; Hansen, Jacob B

    2010-01-01

    BACKGROUND: The Ras/Raf/MEK/ERK pathway has been recognised as an important signalling module in adipogenesis and adipocyte function, but whether it promotes or inhibits the formation of fat cells has not been reconciled. METHODS: Here we investigate the significance of Ras signalling intensity...... of differentiation was inefficiently rescued by forced expression of the adipogenic transcription factors C/EBPalpha and PPARgamma. However, the defective differentiation was alleviated by MEK inhibitors, suggesting that the obstruction of differentiation was dependent on activation of ERK. A dominant interfering H...

  20. Consequences of RAS and MAPK activation in the ovary: the good, the bad and the ugly

    Science.gov (United States)

    Fan, Heng-Yu; Liu, Zhilin; Mullany, Lisa K.; Richards, JoAnne S.

    2012-01-01

    This review summarizes studies providing evidence 1) that endogenous RAS activation regulates important physiological events during ovulation and luteinization 2) that expression of the mutant, active KRASG12D in granulosa cells in vivo causes abnormal follicle growth arrest leading to premature ovarian failure and 3) that KRASG12D expression in ovarian surface epithelial (OSE) cells renders them susceptible to the pathological outcome of transformation and tumor formation. These diverse effects of RAS highlight how critical its activation is linked to cell- and stage-specific events in the ovary that control normal processes and that can also lead to altered granulosa cell and OSE cell fates. PMID:22197887

  1. A screen for mutations that prevent lethality caused by expression of activated sevenless and Ras1 in the Drosophila embryo.

    Science.gov (United States)

    Maixner, A; Hecker, T P; Phan, Q N; Wassarman, D A

    1998-01-01

    Ras1 plays a critical role in receptor tyrosine kinase (RTK) signal transduction pathways that function during Drosophila development. We demonstrate that mis-expression of constitutively active forms of Ras1 (Ras1V12) and the Sevenless (Sev) RTK (SevS11) during embryogenesis causes lethality due to inappropriate activation of RTK/Ras1 signaling pathways. Genetic and molecular data indicate that the rate of SevS11/sev-Ras1V12 lethality is sensitive to the expression level of both transgenes. To identify genes that encode components of RTK/Ras1 signaling pathways or modulators of RNA polymerase II transcription, we took advantage of the dose-sensitivity of the system and screened for second site mutations that would dominantly suppress the lethality. The collection of identified suppressors includes the PR55 subunit of Protein Phosphatase 2A indicating that downstream of Sev and Ras1 this subunit acts as a negative regulator of phosphatase activity. The isolation of mutations in the histone deacetylase RPD3 suggests that it functions as positive regulator of sev enhancer-driven transcription. Finally, the isolation of mutations in the Trithorax group gene devenir and the characterized allelism with the Breathless RTK encoding gene provides evidence for Ras1-mediated regulation of homeotic genes.

  2. Product (P1) from project 0-6738 : performance studies and future directions for mixes containing RAP and RAS.

    Science.gov (United States)

    2013-01-01

    In recent years both reclaimed asphalt pavement (RAP) and recycled asphalt shingles (RAS) have been widely used in asphalt mixes by the asphalt paving industry in Texas. The use of RAP and RAS can save tax payers money, and it is also good for the...

  3. Absence of activating mutations in ras and gsp oncogenes in a cohort of nine patients with sporadic pediatric thyroid tumors.

    Science.gov (United States)

    Pauws, E; Tummers, R F; Ris-Stalpers, C; de Vijlder, J J; Voûte, T

    2001-06-01

    Characterization of the genetic background of pediatric thyroid carcinomas could aid in distinguishing between differently staged tumors with respect to treatment and prognosis. Two known genetic factors associated with thyroid carcinoma, the proto-oncogenes gsp and ras were investigated. DNA was extracted from paraffin sections from both tumor and normal thyroid tissue of nine patients (ages 9-16 years). Of these patients, eight were diagnosed with papillary carcinoma and one with follicular adenoma. The coding exons of gsp and the three known ras genes (H, K, and N-ras) were screened for mutations using SSCP-analysis. There were no mutations present in the ras and gsp proto-oncogenes hot spots, however, LOH of H-ras (chromosome location 11p15.5) was found in tumor tissue from one patient and a homozygous mutation in exon 12 of gsp causing a Pro-->Ser conversion was present in the thyroid tumor tissue from another patient. Two silent polymorphisms were detected, H-ras exon1, 86T-->C and gsp exon 5, 81T-->C. Our results indicate that the ras/gsp mutations found are probably late events in the tumorigenesis representing general oncogenic stress. In conclusion, it seems that ras/gsp activation is not a factor in the mechanism causing sporadic thyroid carcinoma in children. Copyright 2001 Wiley-Liss, Inc.

  4. A Corpus-Based Lexical Study on Frequency and Distribution of Coxhead's Awl Word Families in Medical Research Articles (RAs)

    Science.gov (United States)

    Chen, Qi; Guang-Chun, Ge

    2007-01-01

    We conducted a lexical study on the word frequency and the text coverage of the 570 word families from Coxhead's Academic Word List (AWL) in medical research articles (RAs) based on a corpus of 50 medical RAs written in English with 190425 running words. By computer analysis, we found that the text coverage of the AWL words accounted for around…

  5. Mixture Growth Models of RAN and RAS Row by Row: Insight into the Reading System at Work over Time

    Science.gov (United States)

    Amtmann, Dagmar; Abbott, Robert D.; Berninger, V. W.

    2007-01-01

    Children (n = 122) and adults (n = 200) with dyslexia completed rapid automatic naming (RAN) letters, rapid automatic switching (RAS) letters and numbers, executive function (inhibition, verbal fluency), and phonological working memory tasks. Typically developing 3rd (n = 117) and 5th (n = 103) graders completed the RAS task. Instead of analyzing…

  6. Heterotrophic bacterial production on solid fish waste: TAN and nitrate as nitrogen source under practical RAS conditions

    NARCIS (Netherlands)

    Schneider, O.; Sereti, V.; Eding, E.H.; Verreth, J.A.J.

    2007-01-01

    The drumfilter effluent from a recirculation aquaculture system (RAS) can be used as substrate for heterotrophic bacteria production. This biomass can be re-used as aquatic feed. RAS effluents are rich in nitrate and low in total ammonia nitrogen (TAN). This might result in 20% lower bacteria

  7. IRF1 Downregulation by Ras/MEK Is Independent of Translational Control of IRF1 mRNA.

    Science.gov (United States)

    Komatsu, Yumiko; Derwish, Leena; Hirasawa, Kensuke

    2016-01-01

    Oncogenic activation of Ras/MEK downregulates the expression of interferon regulatory factor 1 (IRF1), which is a prerequisite for oncolytic viruses to replicate in cancer cells [1]. Moreover, restoration of IRF1 expression is essential to induce apoptosis of cancer cells treated with a MEK inhibitor [2]. However, the molecular mechanisms that underlie IRF1 downregulation by Ras/MEK remain unclear. In this study, we determined whether Ras/MEK activation modulates IRF1 expression at its translational level. MEK inhibition increased the activity of IRF1 promoter construct in Ras transformed NIH3T3 cells and wild type MEF, but not in IRF1 deficient MEF, indicating that IRF1 protein is required for the transcriptional activation of IRF1. By conducting reporter analysis using IRF1 5'- and 3'- UTR constructs, we determined that cis elements on 5'- and 3'-UTR of IRF1 mRNA are not involved in the IRF1 regulation by Ras/MEK. We further compared the recruitment of ribosomes to IRF1 mRNA in RasV12 cells treated with or without the MEK inhibitor by conducting polysome analysis. No difference was observed in the polysomal distribution of IRF1 mRNA between RasV12 cells treated with and without the MEK inhibitor. These results suggest that regulation of IRF1 translation is independent of IRF1 downregulation by Ras/MEK.

  8. Ras induces NBT-II epithelial cell scattering through the coordinate activities of Rac and MAPK pathways.

    Science.gov (United States)

    Edme, Natacha; Downward, Julian; Thiery, Jean-Paul; Boyer, Brigitte

    2002-06-15

    Cell dissociation and cell migration are the two main components of epithelium-mesenchyme transitions (EMT). We previously demonstrated that Ras is required for the accomplishment of both of these processes during the EGF-induced EMT of the NBT-II rat carcinoma cell line in vitro. In this study, we examined the downstream targets of Ras that are responsible for the dissociation and motility of NBT-II cells. Overexpression of activated forms of c-Raf and MEK1 (a component of the mitogen-activated protein kinase pathway, MAPK) led to cell dissociation, as inferred by the loss of desmosomes from the cell periphery. By contrast, active PI3K, RalA and RalB did not induce desmosome breakdown. The MEK1 inhibitor PD098059 inhibited EGF- and Ras-induced cell dispersion, whereas the PI3K inhibitor LY294002 had no effect. Accordingly, among the partial loss-of-function mutants of Ras (RasV12) that were used to distinguish between downstream targets of Ras, we found that the Raf-specific Ras mutants RasV12S35 and RasV12E38 induced cell dissociation. The PI3K- and RalGDS-activating Ras mutants had, in contrast, no effect on cell dispersion. However, MEK1 was unable to promote cell motility, whereas RasV12S35 and RasV12E38 induced cell migration, suggesting that another Ras effector was responsible for cell motility. We found that the small GTPase Rac is necessary for EGF-mediated cell dispersion since overexpression of a dominant-negative mutant of Rac1 (Rac1N17) inhibited EGF-induced NBT-II cell migration. All stimuli that promoted cell migration also induced Rac activation. Finally, coexpression of active Rac1 and active MEK1 induced the motility of NBT-II cells, suggesting that Ras mediates NBT-II cell scattering through the coordinate activation of Rac and the Raf/MAPK pathway.

  9. Low concentrations of hydrogen peroxide or nitrite induced of Paracoccidioides brasiliensis cell proliferation in a Ras-dependent manner.

    Science.gov (United States)

    Haniu, Ana Eliza Coronel Janu; Maricato, Juliana Terzi; Mathias, Pedro Paulo Moraes; Castilho, Daniele Gonçalves; Miguel, Rodrigo Bernardi; Monteiro, Hugo Pequeno; Puccia, Rosana; Batista, Wagner Luiz

    2013-01-01

    Paracoccidioides brasiliensis, a causative agent of paracoccidioidomycosis (PCM), should be able to adapt to dramatic environmental changes inside the infected host after inhalation of air-borne conidia and transition to pathogenic yeasts. Proteins with antioxidant functions may protect fungal cells against reactive oxygen (ROS) and nitrogen (RNS) species generated by phagocytic cells, thus acting as potential virulence factors. Ras GTPases are involved in stress responses, cell morphology, and differentiation in a range of organisms. Ras, in its activated form, interacts with effector proteins and can initiate a kinase cascade. In lower eukaryotes, Byr2 kinase represents a Ras target. The present study investigated the role of Ras in P. brasiliensis after in vitro stimulus with ROS or RNS. We have demonstrated that low concentrations of H2O2 (0.1 mM) or NO2 (0.1-0.25 µM) stimulated P. brasiliensis yeast cell proliferation and that was not observed when yeast cells were pre-incubated with farnesyltransferase inhibitor. We constructed an expression plasmid containing the Byr2 Ras-binding domain (RBD) fused with GST (RBD-Byr2-GST) to detect the Ras active form. After stimulation with low concentrations of H2O2 or NO2, the Ras active form was observed in fungal extracts. Besides, NO2 induced a rapid increase in S-nitrosylated Ras levels. This alternative posttranslational modification of Ras, probably in residue Cys123, would lead to an exchange of GDP for GTP and consequent GTPase activation in P. brasiliensis. In conclusion, low concentrations of H2O2 or NO2 stimulated P. brasiliensis proliferation through Ras activation.

  10. Low concentrations of hydrogen peroxide or nitrite induced of Paracoccidioides brasiliensis cell proliferation in a Ras-dependent manner.

    Directory of Open Access Journals (Sweden)

    Ana Eliza Coronel Janu Haniu

    Full Text Available Paracoccidioides brasiliensis, a causative agent of paracoccidioidomycosis (PCM, should be able to adapt to dramatic environmental changes inside the infected host after inhalation of air-borne conidia and transition to pathogenic yeasts. Proteins with antioxidant functions may protect fungal cells against reactive oxygen (ROS and nitrogen (RNS species generated by phagocytic cells, thus acting as potential virulence factors. Ras GTPases are involved in stress responses, cell morphology, and differentiation in a range of organisms. Ras, in its activated form, interacts with effector proteins and can initiate a kinase cascade. In lower eukaryotes, Byr2 kinase represents a Ras target. The present study investigated the role of Ras in P. brasiliensis after in vitro stimulus with ROS or RNS. We have demonstrated that low concentrations of H2O2 (0.1 mM or NO2 (0.1-0.25 µM stimulated P. brasiliensis yeast cell proliferation and that was not observed when yeast cells were pre-incubated with farnesyltransferase inhibitor. We constructed an expression plasmid containing the Byr2 Ras-binding domain (RBD fused with GST (RBD-Byr2-GST to detect the Ras active form. After stimulation with low concentrations of H2O2 or NO2, the Ras active form was observed in fungal extracts. Besides, NO2 induced a rapid increase in S-nitrosylated Ras levels. This alternative posttranslational modification of Ras, probably in residue Cys123, would lead to an exchange of GDP for GTP and consequent GTPase activation in P. brasiliensis. In conclusion, low concentrations of H2O2 or NO2 stimulated P. brasiliensis proliferation through Ras activation.

  11. Alexandrite Lidar Receiver

    National Research Council Canada - National Science Library

    Wilkerson, Thomas

    2000-01-01

    ...". The chosen vendor, Orca Photonics, In. (Redmond, WA), in close collaboration with USU personnel, built a portable, computerized lidar system that not only is suitable as a receiver for a near IR alexandrite laser, but also contains an independent Nd...

  12. JSSG - SPACED RECEIVER MEASUREMENTS.

    Science.gov (United States)

    The height of ionospheric irregularities was measured by several laboratories belonging to the Joint Satellite Studies Group, using spaced receiver techniques. The method of analysis and results obtained are presented. (Author)

  13. Solar energy receiver

    Science.gov (United States)

    Schwartz, Jacob

    1978-01-01

    An improved long-life design for solar energy receivers provides for greatly reduced thermally induced stress and permits the utilization of less expensive heat exchanger materials while maintaining receiver efficiencies in excess of 85% without undue expenditure of energy to circulate the working fluid. In one embodiment, the flow index for the receiver is first set as close as practical to a value such that the Graetz number yields the optimal heat transfer coefficient per unit of pumping energy, in this case, 6. The convective index for the receiver is then set as closely as practical to two times the flow index so as to obtain optimal efficiency per unit mass of material.

  14. Receiver Gain Modulation Circuit

    Science.gov (United States)

    Jones, Hollis; Racette, Paul; Walker, David; Gu, Dazhen

    2011-01-01

    A receiver gain modulation circuit (RGMC) was developed that modulates the power gain of the output of a radiometer receiver with a test signal. As the radiometer receiver switches between calibration noise references, the test signal is mixed with the calibrated noise and thus produces an ensemble set of measurements from which ensemble statistical analysis can be used to extract statistical information about the test signal. The RGMC is an enabling technology of the ensemble detector. As a key component for achieving ensemble detection and analysis, the RGMC has broad aeronautical and space applications. The RGMC can be used to test and develop new calibration algorithms, for example, to detect gain anomalies, and/or correct for slow drifts that affect climate-quality measurements over an accelerated time scale. A generalized approach to analyzing radiometer system designs yields a mathematical treatment of noise reference measurements in calibration algorithms. By treating the measurements from the different noise references as ensemble samples of the receiver state, i.e. receiver gain, a quantitative description of the non-stationary properties of the underlying receiver fluctuations can be derived. Excellent agreement has been obtained between model calculations and radiometric measurements. The mathematical formulation is equivalent to modulating the gain of a stable receiver with an externally generated signal and is the basis for ensemble detection and analysis (EDA). The concept of generating ensemble data sets using an ensemble detector is similar to the ensemble data sets generated as part of ensemble empirical mode decomposition (EEMD) with exception of a key distinguishing factor. EEMD adds noise to the signal under study whereas EDA mixes the signal with calibrated noise. It is mixing with calibrated noise that permits the measurement of temporal-functional variability of uncertainty in the underlying process. The RGMC permits the evaluation of EDA by

  15. Comparative analysis of radiosensitizers for K-RAS mutant rectal cancers.

    Directory of Open Access Journals (Sweden)

    Laura B Kleiman

    Full Text Available Approximately 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with poor clinical response to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs that synergize with ionizing radiation (IR ("radiosensitizers" that could be incorporated into current treatment strategies for locally advanced rectal cancers (LARCs expressing mutant K-RAS. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU, which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC.

  16. Mutated N-ras does not induce p19 arf in CO25 cell line | Saleh ...

    African Journals Online (AJOL)

    The mouse cell line (CO25) used in this study was transfected with a glucocorticoid inducible mutated human N-ras oncogene under transcriptional control of the steroid-sensitive promoter of the mouse mammary tumors virus long terminal repeat MMTV-LTR. This study was aimed to investigate the expression of p19arf and ...

  17. Report Task 2.3: Particulate waste and turbidity in (marine) RAS

    NARCIS (Netherlands)

    Kals, J.; Schram, E.; Brummelhuis, E.B.M.; Bakel, van B.

    2006-01-01

    Particulate waste management and removal is one of the most problematic parts of recirculation aquaculture systems (RAS). Particulate waste and thereby turbidity originates from three major sources: fish (faeces), feed and biofilm (heterotrophic bacteria and fungi). Based on size and density there

  18. RAS1, a quantitative trait locus for salt tolerance and ABA sensitivity in Arabidopsis

    KAUST Repository

    Ren, Zhonghai

    2010-03-08

    Soil salinity limits agricultural production and is a major obstacle for feeding the growing world population. We used natural genetic variation in salt tolerance among different Arabidopsis accessions to map a major quantitative trait locus (QTL) for salt tolerance and abscisic acid (ABA) sensitivity during seed germination and early seedling growth. A recombinant inbred population derived from Landsberg erecta (Ler; salt and ABA sensitive) x Shakdara (Sha; salt and ABA resistant) was used for QTL mapping. High-resolution mapping and cloning of this QTL, Response to ABA and Salt 1 (RAS1), revealed that it is an ABA- and salt stress-inducible gene and encodes a previously undescribed plant-specific protein. A premature stop codon results in a truncated RAS1 protein in Sha. Reducing the expression of RAS1 by transfer-DNA insertion in Col or RNA interference in Ler leads to decreased salt and ABA sensitivity, whereas overexpression of the Ler allele but not the Sha allele causes increased salt and ABA sensitivity. Our results suggest that RAS1 functions as a negative regulator of salt tolerance during seed germination and early seedling growth by enhancing ABA sensitivity and that its loss of function contributes to the increased salt tolerance of Sha.

  19. Parasexual genetics of Dictyostelium gene disruptions: identification of a ras pathway using diploids

    Directory of Open Access Journals (Sweden)

    Insall Robert H

    2003-07-01

    Full Text Available Abstract Background The relative ease of targeted gene disruption in the social amoeba Dictyostelium has stimulated its widespread use as an experimental organism for cell and developmental biology. However, the field has been hamstrung by the lack of techniques to recombine disrupted genes. Results We describe new techniques for parasexual fusion of strains in liquid medium, selection and maintenance of the resulting stable diploid strains, and segregation to make recombined haploids. We have used these techniques to isolate rasS/gefB double nulls. The phenotypes of these mutants are no more severe than either parent, with movement, phagocytosis and fluid-phase endocytosis affected to the same degree as in rasS or gefB single nulls. In addition, we have produced diploids from one AX2- and one AX3-derived parent, providing an axenic strain with fewer secondary phenotypes than has been previously available. Conclusions The phenotype of the rasS/gefB double mutant suggests that the RasS and GefB proteins lie on the same linear pathway. In addition, axenic diploids and the techniques to generate, maintain and segregate them will be productive tools for future work on Dictyostelium. They will particularly facilitate generation of multiple mutants and manuipulation of essential genes.

  20. BAD enables ceramide to signal apoptosis via Ras and Raf-1.

    Science.gov (United States)

    Basu, S; Bayoumy, S; Zhang, Y; Lozano, J; Kolesnick, R

    1998-11-13

    Prior investigations document that proliferative signaling cascades, under some circumstances, initiate apoptosis, although mechanisms that dictate the final outcome are largely unknown. In COS-7 cells, ceramide signals Raf-1 activation through Ras (Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X. H., Basu, S., McGinley, M., Chan-Hui, P. Y., Lichenstein, H., and Kolesnick, R. (1997) Cell 89, 63-72), but not apoptosis. However, expression of small amounts of the pro-apoptotic Bcl-2 family member, BAD, conferred ceramide-induced apoptosis onto COS-7 cells. Ceramide signaled apoptosis in BAD-expressing cells by a pathway involving sequentially kinase suppressor of Ras (KSR)/ceramide-activated protein kinase, Ras, c-Raf-1, and MEK1. Downstream, this pathway linked to BAD dephosphorylation at serine 136 by prolonged inactivation of Akt/PKB. Further, mutation of BAD at serine 136 abrogated ceramide signaling of apoptosis. The present study indicates that when ceramide signals through the Ras/Raf cascade, the availability of a single target, BAD, may dictate an apoptotic outcome.

  1. Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1.

    Science.gov (United States)

    Farassati, F; Yang, A D; Lee, P W

    2001-08-01

    The importance of herpes simplex viruses (HSV) as human pathogens and the emerging prospect of using mutant derivatives of HSV-1 as potential anti-cancer therapeutics have necessitated a thorough investigation into the molecular basis of host-cell permissiveness to HSV. Here we show that NIH-3T3 cells transformed with the oncogenes v-erbB, activated sos or activated ras become significantly more permissive to HSV-1. Inhibitors of the Ras signalling pathway, such as farnesyl transferase inhibitor 1 and PD98059, effectively suppressed HSV-1 infection of ras-transformed cells. Enhanced permissiveness of the transformed cells was linked to the inhibition of virus-induced activation (phosphorylation) of the double-stranded RNA-activated protein kinase (PKR), thereby allowing viral transcripts to be translated in these cells. An HSV-1-derived oncolytic mutant, R3616, was also found to infect preferentially both transformed cells and PKR-/- (but not PKR+/+) mouse embryo fibroblasts. These observations suggest that HSV-1 specifically targets cells with an activated Ras signalling pathway, and have important ramifications in the use of engineered HSV in cancer therapy, the development of strategies against HSV infections, and the controversial role of HSV in human cancers.

  2. Demonstration of pb-PSHA with Ras-Elhekma earthquake, Egypt

    Directory of Open Access Journals (Sweden)

    Elsayed Fergany

    2017-06-01

    Full Text Available The main goal of this work is to: (1 argue for the importance of a physically-based probabilistic seismic hazard analysis (pb-PSHA methodology and show examples to support the argument from recent events, (2 demonstrate the methodology with the ground motion simulations of May 28, 1998, Mw = 5.5 Ras-Elhekma earthquake, north Egypt. The boundaries for the possible rupture parameters that may have been identified prior to the 1998 Ras-Elhekma earthquake were estimated. A range of simulated ground-motions for the Ras-Elhekma earthquake was “predicted” for frequency 0.5–25 Hz at three sites, where the large earthquake was recorded, with average epicentral distances of 220 km. The best rupture model of the 1998 Ras-Elhekma earthquake was identified by calculated the goodness of fit between observed and synthesized records at sites FYM, HAG, and KOT. We used the best rupture scenario of the 1998 earthquake to synthesize the ground motions at interested sites where the main shock was not recorded. Based on the good fit of simulated and observed seismograms, we concluded that this methodology can provide realistic ground motion of an earthquake and highly recommended for engineering purposes in advance or foregoing large earthquakes at non record sites. We propose that there is a need for this methodology for good-representing the true hazard with reducing uncertainties.

  3. Active ras triggers death in glioblastoma cells through hyperstimulation of macropinocytosis.

    Science.gov (United States)

    Overmeyer, Jean H; Kaul, Aparna; Johnson, Erin E; Maltese, William A

    2008-06-01

    Expression of activated Ras in glioblastoma cells induces accumulation of large phase-lucent cytoplasmic vacuoles, followed by cell death. This was previously described as autophagic cell death. However, unlike autophagosomes, the Ras-induced vacuoles are not bounded by a double membrane and do not sequester organelles or cytoplasm. Moreover, they are not acidic and do not contain the autophagosomal membrane protein LC3-II. Here we show that the vacuoles are enlarged macropinosomes. They rapidly incorporate extracellular fluid-phase tracers but do not sequester transferrin or the endosomal protein EEA1. Ultimately, the cells expressing activated Ras detach from the substratum and rupture, coincident with the displacement of cytoplasm with huge macropinosome-derived vacuoles. These changes are accompanied by caspase activation, but the broad-spectrum caspase inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethylketone does not prevent cell death. Moreover, the majority of degenerating cells do not exhibit chromatin condensation typical of apoptosis. These observations provide evidence for a necrosis-like form of cell death initiated by dysregulation of macropinocytosis, which we have dubbed "methuosis." An activated form of the Rac1 GTPase induces a similar form of cell death, suggesting that Ras acts through Rac-dependent signaling pathways to hyperstimulate macropinocytosis in glioblastoma. Further study of these signaling pathways may lead to the identification of other chemical and physiologic triggers for this unusual form of cell death.

  4. Activation of myc and ras oncogenes in radiation-induced rat skin carcinogenesis

    International Nuclear Information System (INIS)

    Sawey, M.J.

    1987-01-01

    The radiation-induced rat skin carcinogenesis model system was used to examine oncogene activation from both the ras and myc complementation groups. Six of twelve tumors tested were positive in the NIH3T3 transfection assay and the rat K-ras oncogene was found to be activated in representative transformed foci. Southern analysis of the tumor DNAs revealed evidence for c-myc gene amplification and extensive restriction fragment polymorphisms in 9 of the 12 tumors. The appearance of several new c-myc restriction fragments was seen after digestion with Eco RI, Hind III, and Bam HI, and may represent gene rearrangement or activation of a c-myc homologous gene. Rehybridization of the filters with N-myc, K-ras, and H-ras probes failed to detect any differences compared to normal rat DNA. In addition, when probes from other oncogenes known to be activated by gene amplification and translocation mechanisms, were hybridized to these RAD tumor DNAs, no differences in either band intensity nor restriction fragment pattern were found

  5. Epidermal Growth Factor Receptor and K-RAS status in two cohorts of squamous cell carcinomas

    International Nuclear Information System (INIS)

    Van Damme, Nancy; Pauwels, Patrick; Peeters, Marc; Deron, Philippe; Van Roy, Nadine; Demetter, Pieter; Bols, Alain; Dorpe, Jo Van; Baert, Filip; Van Laethem, Jean-Luc; Speleman, Franki

    2010-01-01

    With the availability of effective anti-EGFR therapies for various solid malignancies, such as non-cell small lung cancer, colorectal cancer and squamous cell carcinoma of the head and neck, the knowledge of EGFR and K-RAS status becomes clinically important. The aim of this study was to analyse EGFR expression, EGFR gene copy number and EGFR and K-RAS mutations in two cohorts of squamous cell carcinomas, specifically anal canal and tonsil carcinomas. Formalin fixed, paraffin-embedded tissues from anal and tonsil carcinoma were used. EGFR protein expression and EGFR gene copy number were analysed by means of immunohistochemistry and fluorescence in situ hybridisation. The somatic status of the EGFR gene was investigated by PCR using primers specific for exons 18 through 21. For the K-RAS gene, PCR was performed using exon 2 specific primers. EGFR immunoreactivity was present in 36/43 (83.7%) of anal canal and in 20/24 (83.3%) of tonsil squamous cell carcinomas. EGFR amplification was absent in anal canal tumours (0/23), but could be identified in 4 of 24 tonsil tumours. From 38 anal canal specimens, 26 specimens were successfully analysed for exon 18, 30 for exon 19, 34 for exon 20 and 30 for exon 21. No EGFR mutations were found in the investigated samples. Thirty samples were sequenced for K-RAS exon 2 and no mutation was identified. From 24 tonsil specimens, 22 were successfully analysed for exon 18 and all 24 specimens for exon 19, 20 and 21. No EGFR mutations were found. Twenty-two samples were sequenced for K-RAS exon 2 and one mutation c.53C > A was identified. EGFR mutations were absent from squamous cell carcinoma of the anus and tonsils, but EGFR protein expression was detected in the majority of the cases. EGFR amplification was seen in tonsil but not in anal canal carcinomas. In our investigated panel, only one mutation in the K-RAS gene of a tonsil squamous cell carcinoma was identified. This indicates that EGFR and K-RAS mutation analysis is not

  6. Intracellular oxygen determined by respiration regulates localization of Ras and prenylated proteins.

    Science.gov (United States)

    Kim, A; Davis, R; Higuchi, M

    2015-07-16

    Reduction of mitochondrial DNA (mtDNA) content induces the reduction of oxidative phosphorylation and dependence on fermentative glycolysis, that is, the Warburg effect. In aggressive prostate cancer (PCa), the reduction of mtDNA reduces oxygen consumption, increases intracellular oxygen concentration, and induces constitutive activation of Ras. Many essential proteins for cell death, growth, differentiation, and development, such as Ras, require prenylation for subcellular localization and activation. Prenylation of a protein is defined as the attachment of isoprenoids to a cysteine residue at or near the C-terminus. 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR) produces isoprenoids, and is posttranslationally regulated by oxygen. We investigated a critical role of intracellular oxygen in membrane localization of prenylated proteins. Localization of prenylated proteins (H-Ras, prelamin A/C, and Rab5a) was observed in poorly differentiated PCa (PC-3) and well-differentiated PCa (LNCaP) cells. PC-3 cells exhibited high intracellular oxygen concentration, and H-Ras, prelamin A/C, and Rab5a were localized to various membranes (Golgi and plasma membrane, nuclear membrane, and early endosomes, respectively). Remarkably, exogenous hypoxia (0.2% O2) in PC-3 cells induced intracellular hypoxia and changed the localization of the prenylated proteins. H-Ras and Rab5a were translocated to cytosol, and prelamin A/C was in the nucleus forming an abnormal nuclear envelope. The localization was reversed by mevalonate indicating the involvement of mevalonate pathway. In contrast, in LNCaP cells, exhibiting low intracellular oxygen concentration, H-Ras and Rab5a were localized in the cytosol, and prelamin A/C was inside the nucleus forming an inadequate nuclear envelope. Exogenous hyperoxia (40% O2) increased the intracellular oxygen concentration and induced Ras translocation from cytosol to the membrane. Prelamin A/C was translocated to the nuclear membrane and formed a

  7. Sequence analysis of the Ras-MAPK pathway genes SOS1, EGFR & GRB2 in silver foxes (Vulpes vulpes): candidate genes for hereditary hyperplastic gingivitis.

    Science.gov (United States)

    Clark, Jo-Anna B J; Tully, Sara J; Dawn Marshall, H

    2014-12-01

    Hereditary hyperplastic gingivitis (HHG) is an autosomal recessive disease that presents with progressive gingival proliferation in farmed silver foxes. Hereditary gingival fibromatosis (HGF) is an analogous condition in humans that is genetically heterogeneous with several known autosomal dominant loci. For one locus the causative mutation is in the Son of sevenless homologue 1 (SOS1) gene. For the remaining loci, the molecular mechanisms are unknown but Ras pathway involvement is suspected. Here we compare sequences for the SOS1 gene, and two adjacent genes in the Ras pathway, growth receptor bound protein 2 (GRB2) and epidermal growth factor receptor (EGFR), between HHG-affected and unaffected foxes. We conclude that the known HGF causative mutation does not cause HHG in foxes, nor do the coding regions or intron-exon boundaries of these three genes contain any candidate mutations for fox gum disease. Patterns of molecular evolution among foxes and other mammals reflect high conservation and strong functional constraints for SOS1 and GRB2 but reveal a lineage-specific pattern of variability in EGFR consistent with mutational rate differences, relaxed functional constraints, and possibly positive selection.

  8. SCD1 Expression is dispensable for hepatocarcinogenesis induced by AKT and Ras oncogenes in mice.

    Directory of Open Access Journals (Sweden)

    Lei Li

    Full Text Available Increased de novo lipogenesis is one of the major metabolic events in cancer. In human hepatocellular carcinoma (HCC, de novo lipogenesis has been found to be increased and associated with the activation of AKT/mTOR signaling. In mice, overexpression of an activated form of AKT results in increased lipogenesis and hepatic steatosis, ultimately leading to liver tumor development. Hepatocarcinogenesis is dramatically accelerated when AKT is co-expressed with an oncogenic form of N-Ras. SCD1, the major isoform of stearoyl-CoA desaturases, catalyzing the conversion of saturated fatty acids (SFA into monounsaturated fatty acids (MUFA, is a key enzyme involved in de novo lipogenesis. While many studies demonstrated the requirement of SCD1 for tumor cell growth in vitro, whether SCD1 is necessary for tumor development in vivo has not been previously investigated. Here, we show that genetic ablation of SCD1 neither inhibits lipogenesis and hepatic steatosis in AKT-overexpressing mice nor affects liver tumor development in mice co-expressing AKT and Ras oncogenes. Molecular analysis showed that SCD2 was strongly upregulated in liver tumors from AKT/Ras injected SCD1(-/- mice. Noticeably, concomitant silencing of SCD1 and SCD2 genes was highly detrimental for the growth of AKT/Ras cells in vitro. Altogether, our study provides the evidence, for the first time, that SCD1 expression is dispensable for AKT/mTOR-dependent hepatic steatosis and AKT/Ras-induced hepatocarcinogenesis in mice. Complete inhibition of stearoyl-CoA desaturase activity may be required to efficiently suppress liver tumor development.

  9. The Role of Conserved Waters in Conformational Transitions of Q61H K-ras

    Science.gov (United States)

    Prakash, Priyanka; Sayyed-Ahmad, Abdallah; Gorfe, Alemayehu A.

    2012-01-01

    To investigate the stability and functional role of long-residence water molecules in the Q61H variant of the signaling protein K-ras, we analyzed all available Ras crystal structures and conformers derived from a series of independent explicit solvent molecular dynamics (MD) simulations totaling 1.76 µs. We show that the protein samples a different region of phase space in the presence and absence of several crystallographically conserved and buried water molecules. The dynamics of these waters is coupled with the local as well as the global motions of the protein, in contrast to less buried waters whose exchange with bulk is only loosely coupled with the motion of loops in their vicinity. Aided by two novel reaction coordinates involving the distance (d) between the Cα atoms of G60 at switch 2 and G10 at the P-loop and the N-Cα-C-O dihedral (ξ) of G60, we further show that three water molecules located in lobe1, at the interface between the lobes and at lobe2, are involved in the relative motion of residues at the two lobes of Q61H K-ras. Moreover, a d/ξ plot classifies the available Ras x-ray structures and MD-derived K-ras conformers into active GTP-, intermediate GTP-, inactive GDP-bound, and nucleotide-free conformational states. The population of these states and the transition between them is modulated by water-mediated correlated motions involving the functionally critical switch 2, P-loop and helix 3. These results suggest that water molecules act as allosteric ligands to induce a population shift among distinct switch 2 conformations that differ in effector recognition. PMID:22359497

  10. ESR Studies and Dating of Egyptian Gypsum at Ras Mala'ab, Sinai, Egypt

    International Nuclear Information System (INIS)

    Abdel-Monem, A. A.; Abdei-Razek, Y. A.; Rasheed, N. M.; Hassan, G.M.; Eissa, H.M.; El-Morsy, M.

    2007-01-01

    A gypsum sample from the famous gypsum-anhydrite evaporitic deposit composing the Ras Mala'ab Formation, Upper Miocene, occurring at Ras Mala'ab, on the east coast of the Gulf of Suez, was subjected to (ESR) dosimetric studies. Also, (ESR) was used to date the formation or most recent recrystallization of that gypsum. The gypsum derivative (ESR) spectrum is characterized by the large broad Fe 2+ signal (g=2.50) and HF-sixtet Mn 2+ signals. Only the characteristic gypsum signal (G l, g=2.0040) was detected between the third and fourth lines of the HF-Mn 2+ which is attributed to the electron-center SO 3 - . This signal was sensitive to artificial γ-irradiation and showed significant enhancement using a γ-dose of 550 Gy. Also, the signal was very stable up to 400 o C. The gypsum sample with a total dose (TD) of 1500 Gy, determined graphically by extrapolating the linear relationship between defect concentration and the artificial γ-doses for (G l, g=2.0040) and an annual dose (D) due to cosmic rays (0.3 mGy), yielded an age of 5.00 Ma. This could mean the age of formation or latest recrystallization of this gypsum deposit. The geologic age assignment of the Ras Mala'ab Group including the evaporitic gypsum unit, is Middle to Late Miocene. It is directly overlain by the Pliocene elastics at the locality of Ras Mala'ab. This might suggest that these evaporitic gypsum facies represent the top of the Miocene in the Gulf of Suez area, since the Miocene-Pliocene boundary is now put at 5.00-5.50 Ma ago. Therefore, the ESR age of the Ras Mala'ab gypsum is consistent with the geologic age assignment

  11. Alterations in the K-ras and p53 genes in rat lung tumors

    Energy Technology Data Exchange (ETDEWEB)

    Belinsky, S.A.; Swafford, D.S.; Finch, G.L.; Mitchell, C.E. [Inhalation Toxicology Research Institute, Albuquerque, NM (United States)] [and others

    1997-06-01

    Activation of the K-ras protooncogene and inactivation of the p53 tumor suppressor gene are events common to many types of human cancers. Molecular epidemiology studies have associated mutational profiles in these genes with specific exposures. The purpose of this paper is to review investigations that have examined the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by mutagenic and nonmutagenic exposures. Mutation profiles within the K-ras and p53 genes, if present in rat lung tumors, would help to define some of the molecular mechanisms underlying cancer induction by various environmental agents. Pulmonary adenocarcinomas or squamous cell carcinomas were induced by tetranitromethane (TNM), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), beryllium metal, plutonium-239, X-ray, diesel exhaust, or carbon black. These agents were chosen because the tumors they produced could arise via different types of DNA damage. Mutation of the K-ras gene was determined by approaches that included DNA transfection, direct sequencing, mismatch hybridization, and restriction fragment length polymorphism analysis. The frequency for mutation of the K-ras gene was exposure dependent. The transition mutations formed could have been derived from deamination of cytosine. Alteration in the p53 gene was assessed by immunohistochemical analysis for p53 protein and single-strand conformation polymorphism (SSCP) analysis of exons 4 to 9. None of the 93 adenocarinomas examined was immunoreactive toward the anti-p53 antibody CM1. In contrast, 14 of 71 squamous cell carcinomas exhibited nuclear p53 immunoreactivity with no correlation to type of exposure. However, SSCP analysis only detected mutations in 2 of 14 squamous cell tumors that were immunoreactive, suggesting that protein stabilization did not stem from mutations within the p53 gene. Thus, the p53 gene does not appear to be involved in the genesis of most rat lung tumors. 2 figs., 2 tabs., 48 refs.

  12. Primary Tumour Resection Could Improve the Survival of Unresectable Metastatic Colorectal Cancer Patients Receiving Bevacizumab-Containing Chemotherapy

    Directory of Open Access Journals (Sweden)

    Zhiming Wang

    2016-09-01

    Full Text Available Background: The effect of primary tumour resection (PTR among metastatic colorectal cancer (mCRC patients remains controversial. Combination chemotherapy with bevacizumab could improve the clinical outcomes of these patients, which might change the importance of PTR in the multi-disciplinary treatment pattern. Methods: We performed a non-randomized prospective controlled study of mCRC pts whose performance status (PS scored ≤2 and who received bevacizumab combination chemotherapy (FOLFOX/XELOX/FOLFIRI as a first-line therapy. These patients were classified into the PTR group and the IPT (intact primary tumour group according to whether they underwent PTR before receiving the systemic therapy. The progression free survival (PFS time and overall survival (OS time, which were recorded from the start of the primary diagnosis until disease progression and death or last follow-up, were analysed. We also compared severe clinical events (such as emergency surgery, radiation therapy, and stent plantation between the two groups. Results: One hundred and nighty-one mCRC pts (108 male patients and 93 female patients were entered in this prospective observational study. The median age was 57.5 years old. The clinical characteristics (age, gender, performance status, primary tumour site, RAS status, and the number of metastatic organs did not significantly differ between the two groups. The median PFS and OS times of the PTR group were superior than those of the IPT group (10.0 vs 7.8 months, p Conclusions: The mCRC patients who received PTR and bevacizumab combination chemotherapy had better clinical outcomes than patients who did not receive PTR. PTR also decreased the incidence of severe clinical events and improved quality of life.

  13. 'Chaos' in superregenerative receivers

    International Nuclear Information System (INIS)

    Commercon, Jean-Claude; Badard, Robert

    2005-01-01

    The superregenerative principle has been known since the early 1920s. The circuit is extremely simple and extremely sensitive. Today, superheterodyne receivers generally supplant superregenerative receivers in most applications because there are several undesirable characteristics: poor selectivity, reradiation, etc. Superregenerative receivers undergo a revival in recent papers for wireless systems, where low cost and very low power consumption are relevant: house/building meters (such as water, energy, gas counter), personal computer environment (keyboard, mouse), etc. Another drawback is the noise level which is higher than that of a well-designed superheterodyne receiver; without an antenna input signal, the output of the receiver hears in an earphone as a waterfall noise; this sound principally is the inherent input noise amplified and detected by the circuit; however, when the input noise is negligible with respect of an antenna input signal, we are faced to an other source of 'noise' self-generated by the superregenerative working. The main objective of this paper concerns this self-generated noise coming from an exponential growing followed by a re-injection process for which the final state is a function of the phase of the input signal

  14. [Effects of subchronic aluminum exposure on long-term potentiation and activities of RAS and extracellular regulated protein kinases in rats].

    Science.gov (United States)

    Song, J; Li, Z Y; Zhang, L; Niu, Q

    2017-05-20

    Objective: To study the effects of subchronic aluminum exposure on LTP and activities of RAS and ERK in rats in vivo. Methods: 24 Wistar rats were randomly divided into control group、low-dose group、medium-dose group and high-dose group, and received saline (control group) or Al (mal) (3) (15 μmol、kg、30 μmol、kg or 45 μmol/kg) via intraperitoneal injection (i.p.) for 8 weeks, respectively. The fEPSP in CA1 region were recorded by field potentiation technique in vivo and the hippocampal activities of RAS and ERK were examined by ELISA. Results: The fEPSP amplitudes of the control group were 1.90±0.19, 1.64±0.15 and 1.54±0.08 at 1, 30 and 60 min after HFS, respectively. The fEPSP amplitudes of the low-dose group were 1.40±0.06 at 60 min, which represented a statistically significant decrease compared to the control group ( P memory induced by aluminum.

  15. Predicting the Extent of Inundation due to Sea-Level Rise: Al Hamra Development, Ras Al Khaimah, UAE. A Pilot Project

    Directory of Open Access Journals (Sweden)

    Arthur Robert M.

    2016-06-01

    Full Text Available As new information is received, predictions of sea-level rise resulting from global warming continue to be revised upwards. Measurements indicate that the rise in sea-level is continuing at, or close to, the worst case forecasts (Kellet et al. 2014. Coastal areas are coming under increasing risk of inundation and flooding as storms are predicted to increase in frequency and severity, adding to the risk of inundation due to higher sea levels. Stakeholders, government agencies, developers and land owners require accurate, up to date information to be able to protect coastal areas. Geographic Information Systems (GIS along with accurate remote sensing technologies such as LiDAR provides the best means for delivering this information. Using these technologies, this paper predicts the risk posed to a large multi-use development in the emirate of Ras Al Khaimah, UAE. This development, Al Hamra Village, is situated on the coast of the Arabian Gulf. Al Hamra’s physical relationship to the Gulf is in common with other developments in Ras Al Khaimah in its and for this reason has been used as a pilot project. The resulting GIS model shows that Al Hamra is indeed at risk from predicted flood events. How this information can be used as a planning tool for numerous strategies is discussed in this paper.

  16. Central solar energy receiver

    Science.gov (United States)

    Drost, M. Kevin

    1983-01-01

    An improved tower-mounted central solar energy receiver for heating air drawn through the receiver by an induced draft fan. A number of vertically oriented, energy absorbing, fin-shaped slats are radially arranged in a number of concentric cylindrical arrays on top of the tower coaxially surrounding a pipe having air holes through which the fan draws air which is heated by the slats which receive the solar radiation from a heliostat field. A number of vertically oriented and wedge-shaped columns are radially arranged in a number of concentric cylindrical clusters surrounding the slat arrays. The columns have two mirror-reflecting sides to reflect radiation into the slat arrays and one energy absorbing side to reduce reradiation and reflection from the slat arrays.

  17. 1, 25 Dihydroxyvitamin D Regulation of Glucose Metabolism in Harvey-ras Transformed MCF10A Human Breast Epithelial Cells

    Science.gov (United States)

    Zheng, Wei; Tayyari, Fariba; Gowda, G. A. Nagana; Raftery, Daniel; McLamore, Eric S.; Shi, Jin; Porterfield, D. Marshall; Donkin, Shawn; Bequette, Brian; Teegarden, Dorothy

    2014-01-01

    This study was designed to investigate the impact of 1,25 dihydroxyvitamin D (1,25(OH)2D) on glucose metabolism during early cancer progression. Untransformed and ras-oncogene transfected (ras) MCF10A human breast epithelial cells were employed to model early breast cancer progression. 1,25(OH)2D modified the response of the ras cells to glucose restriction, suggesting 1,25(OH)2D may reduce the ras cell glucose addiction noted in cancer cells. To understand the 1,25(OH)2D regulation of glucose metabolism, following four-day 1,25(OH)2D treatment, metabolite fluxes at the cell membrane were measured by a nanoprobe biosensor, [13C6]glucose flux by 13C-mass isotopomer distribution analysis of media metabolites, intracellular metabolite levels by NMR, and gene expression of related enzymes assessed. Treatment with 1,25(OH)2D reduced glycolysis as flux of glucose to 3-phosphoglycerate was reduced by 15% (P = 0.017) and 32% (P MCF10A and ras cells respectively. In the ras cells, 1,25(OH)2D reduced lactate dehydrogenase activity by 15% (P MCF10A and ras cells, respectively, suggesting a reduction in tricarboxylic acid (TCA) cycle activity. The results suggest a novel mechanism involving the regulation of glucose metabolism by which 1,25(OH)2D may prevent breast cancer progression. PMID:23619337

  18. The Yeast Saccharomyces cerevisiae as a Model for Understanding RAS Proteins and Their Role in Human Tumorigenesis

    Science.gov (United States)

    Cazzanelli, Giulia; Francisco, Rita; Azevedo, Luísa; Carvalho, Patrícia Dias; Almeida, Ana; Côrte-Real, Manuela; Oliveira, Maria José; Lucas, Cândida; Sousa, Maria João

    2018-01-01

    The exploitation of the yeast Saccharomyces cerevisiae as a biological model for the investigation of complex molecular processes conserved in multicellular organisms, such as humans, has allowed fundamental biological discoveries. When comparing yeast and human proteins, it is clear that both amino acid sequences and protein functions are often very well conserved. One example of the high degree of conservation between human and yeast proteins is highlighted by the members of the RAS family. Indeed, the study of the signaling pathways regulated by RAS in yeast cells led to the discovery of properties that were often found interchangeable with RAS proto-oncogenes in human pathways, and vice versa. In this work, we performed an updated critical literature review on human and yeast RAS pathways, specifically highlighting the similarities and differences between them. Moreover, we emphasized the contribution of studying yeast RAS pathways for the understanding of human RAS and how this model organism can contribute to unveil the roles of RAS oncoproteins in the regulation of mechanisms important in the tumorigenic process, like autophagy. PMID:29463063

  19. Evaluation of K-ras and p53 expression in pancreatic adenocarcinoma using the cancer genome atlas.

    Directory of Open Access Journals (Sweden)

    Liming Lu

    Full Text Available Genetic alterations in K-ras and p53 are thought to be critical in pancreatic cancer development and progression. However, K-ras and p53 expression in pancreatic adenocarcinoma have not been systematically examined in The Cancer Genome Atlas (TCGA Data Portal. Information regarding K-ras and p53 alterations, mRNA expression data, and protein/protein phosphorylation abundance was retrieved from The Cancer Genome Atlas (TCGA databases, and analyses were performed by the cBioPortal for Cancer Genomics. The mutual exclusivity analysis showed that events in K-ras and p53 were likely to co-occur in pancreatic adenocarcinoma (Log odds ratio = 1.599, P = 0.006. The graphical summary of the mutations showed that there were hotspots for protein activation. In the network analysis, no solid association between K-ras and p53 was observed in pancreatic adenocarcinoma. In the survival analysis, neither K-ras nor p53 were associated with both survival events. As in the data mining study in the TCGA databases, our study provides a new perspective to understand the genetic features of K-ras and p53 in pancreatic adenocarcinoma.

  20. Structural insight into the rearrangement of the switch I region in GTP-bound G12A K-Ras.

    Science.gov (United States)

    Xu, Shenyuan; Long, Brian N; Boris, Gabriel H; Chen, Anqi; Ni, Shuisong; Kennedy, Michael A

    2017-12-01

    K-Ras, a molecular switch that regulates cell growth, apoptosis and metabolism, is activated when it undergoes a conformation change upon binding GTP and is deactivated following the hydrolysis of GTP to GDP. Hydrolysis of GTP in water is accelerated by coordination to K-Ras, where GTP adopts a high-energy conformation approaching the transition state. The G12A mutation reduces intrinsic K-Ras GTP hydrolysis by an unexplained mechanism. Here, crystal structures of G12A K-Ras in complex with GDP, GTP, GTPγS and GppNHp, and of Q61A K-Ras in complex with GDP, are reported. In the G12A K-Ras-GTP complex, the switch I region undergoes a significant reorganization such that the Tyr32 side chain points towards the GTP-binding pocket and forms a hydrogen bond to the GTP γ-phosphate, effectively stabilizing GTP in its precatalytic state, increasing the activation energy required to reach the transition state and contributing to the reduced intrinsic GTPase activity of G12A K-Ras mutants.

  1. Ki-ras gene mutations are invariably present in low-grade mucinous tumors of the vermiform appendix.

    Science.gov (United States)

    Zauber, Peter; Berman, Errol; Marotta, Stephen; Sabbath-Solitare, Marlene; Bishop, Timothy

    2011-07-01

    Low-grade mucinous tumors of the appendix appear to have a simple histological structure. Paradoxically, reports have suggested a greater frequency of Ki-ras gene mutation in these lesions than in more complex lesions such as benign colonic adenomas and carcinomas. We assessed several molecular genetic changes, including Ki-ras gene mutations, in a large series of low-grade mucinous tumors of the appendix. We retrospectively ascertained low-grade mucinous tumors of the appendix from computerized pathology records. Extracted DNA was analyzed for APC and DCC gene loss of heterozygosity, microsatellite instability and for the presence of Ki-ras gene mutation using standard molecular techniques. Controls consisted of normal appendices, other appendiceal neoplasms, and ovarian mucinous cystadenomas. A total of 31 low-grade appendiceal mucinous tumors were identified. All were microsatellite stable and none demonstrated loss of heterozygosity for the APC or DCC genes. By contrast, all 31 lesions contained a Ki-ras gene mutation. The presence of a Ki-ras gene mutation in all lesions, with no other molecular changes identified, strongly suggests a possible etiological role of the Ki-ras mutation in the development of this particular lesion of the appendix. Based on other work regarding intestinal bacteria, we hypothesize a relationship between chronic inflammation of the appendix from bacterial overgrowth and Ki-ras gene mutation.

  2. Wideband CMOS receivers

    CERN Document Server

    Oliveira, Luis

    2015-01-01

    This book demonstrates how to design a wideband receiver operating in current mode, in which the noise and non-linearity are reduced, implemented in a low cost single chip, using standard CMOS technology.  The authors present a solution to remove the transimpedance amplifier (TIA) block and connect directly the mixer’s output to a passive second-order continuous-time Σ∆ analog to digital converter (ADC), which operates in current-mode. These techniques enable the reduction of area, power consumption, and cost in modern CMOS receivers.

  3. Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 1: risk assessment

    Directory of Open Access Journals (Sweden)

    Dong Il Park

    2018-01-01

    Full Text Available Because anti-tumor necrosis factor (anti-TNF therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised 2 parts: risk of TB infection Recommendaduring anti-TNF therapy, and screening for TB infection prior to commencing anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

  4. Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 2: management

    Directory of Open Access Journals (Sweden)

    Dong Il Park

    2018-01-01

    Full Text Available Because anti-tumor necrosis factor (anti-TNF therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised 3 parts: management of latent TB in preparation for anti-TNF therapy, monitoring during anti-TNF therapy, and management of an active TB infection after anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

  5. Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti-tumor necrosis factor treatment. Part 2: management.

    Science.gov (United States)

    Park, Dong Il; Hisamatsu, Tadakazu; Chen, Minhu; Ng, Siew Chien; Ooi, Choon Jin; Wei, Shu Chen; Banerjee, Rupa; Hilmi, Ida Normiha; Jeen, Yoon Tae; Han, Dong Soo; Kim, Hyo Jong; Ran, Zhihua; Wu, Kaichun; Qian, Jiaming; Hu, Pin-Jin; Matsuoka, Katsuyoshi; Andoh, Akira; Suzuki, Yasuo; Sugano, Kentaro; Watanabe, Mamoru; Hibi, Toshifumi; Puri, Amarender S; Yang, Suk-Kyun

    2018-01-01

    Because anti-tumor necrosis factor (anti-TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti-TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti-TNF treatment. Twenty-three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web-based consensus voting was performed by 211 IBD specialists from 9 Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised 3 parts: management of latent TB in preparation for anti-TNF therapy, monitoring during anti-TNF therapy, and management of an active TB infection after anti-TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti-TNF treatment.

  6. Ras-dva is a novel Pit-1- and glucocorticoid-regulated gene in the embryonic anterior pituitary gland.

    Science.gov (United States)

    Ellestad, Laura E; Porter, Tom E

    2013-01-01

    Glucocorticoids play a role in functional differentiation of pituitary somatotrophs and lactotrophs during embryogenesis. Ras-dva was identified as a gene regulated by anterior neural fold protein-1/homeobox expressed in embryonic stem cells-1, a transcription factor known to be critical in pituitary development, and has an expression profile in the chicken embryonic pituitary gland that is consistent with in vivo regulation by glucocorticoids. The objective of this study was to characterize expression and regulation of ras-dva mRNA in the developing chicken anterior pituitary. Pituitary ras-dva mRNA levels increased during embryogenesis to a maximum on embryonic day (e) 18 and then decreased and remained low or undetectable after hatch. Ras-dva expression was highly enriched in the pituitary gland on e18 relative to other tissues examined. Glucocorticoid treatment of pituitary cells from mid- and late-stage embryos rapidly increased ras-dva mRNA, suggesting it may be a direct transcriptional target of glucocorticoids. A reporter construct driven by 4 kb of the chicken ras-dva 5'-flanking region, containing six putative pituitary-specific transcription factor-1 (Pit-1) binding sites and two potential glucocorticoid receptor (GR) binding sites, was highly activated in embryonic pituitary cells and up-regulated by corticosterone. Mutagenesis of the most proximal Pit-1 site decreased promoter activity in chicken e11 pituitary cells, indicating regulation of ras-dva by Pit-1. However, mutating putative GR binding sites did not substantially reduce induction of ras-dva promoter activity by corticosterone, suggesting additional DNA elements within the 5'-flanking region are responsible for glucocorticoid regulation. We have identified ras-dva as a glucocorticoid-regulated gene that is likely expressed in cells of the Pit-1 lineage within the developing anterior pituitary gland.

  7. Highlighting the role of Ras and Rap during Dictyostelium chemotaxis

    NARCIS (Netherlands)

    Kortholt, Arjan; van Haastert, Peter J. M.

    Chemotaxis, the directional movement towards a chemical compound, is an essential property of many cells and has been linked to the development and progression of many diseases. Eukaryotic chemotaxis is a complex process involving gradient sensing, cell polarity, remodelling of the cytoskeleton and

  8. Sender-Receiver Games

    NARCIS (Netherlands)

    Peeters, R.J.A.P.; Potters, J.A.M.

    1999-01-01

    Standard game-theoretic solution concepts do not guarantee meaningful commu- nication in cheap-talk games. In this paper, we define a solution concept which guarantees communication for a large class of games by designing a behavior pro- tocol which the receiver uses to judge messages sent by the

  9. H-ras transformation sensitizes volume-activated anion channels and increases migratory activity of NIH3T3 fibroblasts

    DEFF Research Database (Denmark)

    Schneider, Linda; Klausen, Thomas K; Stock, Christian

    2008-01-01

    The expression of the H-ras oncogene increases the migratory activity of many cell types and thereby contributes to the metastatic behavior of tumor cells. Other studies point to an involvement of volume-activated anion channels (VRAC) in (tumor) cell migration. In this paper, we tested whether...... 35%. Consistent with higher VRAC activity in H-ras than in wild-type fibroblasts, more VRAC blocker is needed to achieve a comparable degree of inhibition of migration. We suggest that H-ras modulates the volume set point of VRAC and thus facilitates transient changes of cell volume required...

  10. Inhibition of DNA synthesis by carvacrol in mouse myoblast cells bearing a human N-RAS oncogene.

    Science.gov (United States)

    Zeytinoglu, H; Incesu, Z; Baser, K H C

    2003-05-01

    Monoterpenes are dietary components found in the essential oils of a wide variety of plants. A number of these monoterpenes have antitumor activity. We have investigated the effects of carvacrol obtained by fractional distillation of Origanum onites L. essential oil, on DNA synthesis of N-ras transformed myoblast cells, CO25. Incubation of the cells with different doses of carvacrol prevented DNA synthesis in the growth medium and ras-activating medium, which contains dexamethasone. This result demonstrates that carvacrol inhibits growth of myoblast cells even after activation of mutated N-ras oncogene, suggesting the possibility that carvacrol may find application in cancer therapy.

  11. Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway

    OpenAIRE

    Wu, C-H; Chen, Y-F; Wang, J-Y; Hsieh, M-C; Yeh, C-S; Lian, S-T; Shin, S-J; Lin, S-R

    2002-01-01

    The result of our previous study has shown that the K-ras mutant (pK568MRSV) transfected human adrenocortical cells can significantly increase cortisol production and independently cause cell transformation. The aim of this study is to investigate the effect of the active K-ras oncogene on the cortisol production in normal human adrenocortical cells. First we used isopropyl thiogalactoside to induce the inducible mutant K-ras expression plasmid, pK568MRSV, in the stable transfected human adre...

  12. Assessing risk of liver enzyme elevation in patients with immune-mediated diseases and different hepatitis B virus serostatus receiving anti-TNF agents: a nested case-control study.

    Science.gov (United States)

    Chiu, Ying-Ming; Lai, Mei-Shu; Chan, K Arnold

    2017-11-01

    Liver enzyme elevation is an important and common adverse effect among patients with immune-mediated diseases who receive tumour necrosis factor inhibitors (anti-TNF), and has various causes. Hence, we evaluated the relative risks of developing liver enzyme elevation in anti-TNF users with differing hepatitis B virus (HBV) infection status. At a hospital in central Taiwan, 407 patients with rheumatoid arthritis, ankylosing spondylitis, or psoriasis/psoriatic arthritis received anti-TNF therapy between 1 January 2004 and 30 June 2012. We performed a nested case-control study (n = 368) of cases with serum alanine aminotransferase (ALT) > 40 international units/L ≤ 12 months after starting anti-TNF therapy, and corresponding controls without liver enzyme elevation. Conditional logistic regression was used to evaluate associations between liver enzyme elevation and HBV serostatus, as well as other risk factors. Thirty cases were compared to 338 controls. After adjustment for potential confounders, HBV surface antigen-positive (HBsAg + ) serostatus was associated with substantially higher likelihood of developing elevated ALT (adjusted odds ratio 7.91, 95% confidence interval (CI) 2.16-31.31) relative to those with an uninfected HBV status; no such association was observed among HBsAg-negative/HBV core antibody-positive (HBsAg - /HBcAb + ) patients (adjusted odds ratio 1.00, 95% CI 0.33-3.25). Increased risk of ALT elevation was associated with methotrexate used alone, without folic acid (adjusted odds ratio 11.60, 95% CI 2.52-56.46), and history of ALT elevation (adjusted odds ratio 13.71, 95% CI 4.32-45.75). HBsAg + patients with immune-mediated diseases who received anti-TNF therapy had an approximately eight-fold higher likelihood of liver enzyme elevation than those without HBV infection, whereas patients with HBsAg - /HBcAb + serostatus had a risk similar to that of uninfected patients.

  13. Textural features in pre-treatment [F18]-FDG-PET/CT are correlated with risk of local recurrence and disease-specific survival in early stage NSCLC patients receiving primary stereotactic radiation therapy

    International Nuclear Information System (INIS)

    Pyka, Thomas; Bundschuh, Ralph A; Andratschke, Nicolaus; Mayer, Benedikt; Specht, Hanno M; Papp, Laszló; Zsótér, Norbert; Essler, Markus

    2015-01-01

    Textural features in FDG-PET have been shown to provide prognostic information in a variety of tumor entities. Here we evaluate their predictive value for recurrence and prognosis in NSCLC patients receiving primary stereotactic radiation therapy (SBRT). 45 patients with early stage NSCLC (T1 or T2 tumor, no lymph node or distant metastases) were included in this retrospective study and followed over a median of 21.4 months (range 3.1–71.1). All patients were considered non-operable due to concomitant disease and referred to SBRT as the primary treatment modality. Pre-treatment FDG-PET/CT scans were obtained from all patients. SUV and volume-based analysis as well as extraction of textural features based on neighborhood gray-tone difference matrices (NGTDM) and gray-level co-occurence matrices (GLCM) were performed using InterView Fusion™ (Mediso Inc., Budapest). The ability to predict local recurrence (LR), lymph node (LN) and distant metastases (DM) was measured using the receiver operating characteristic (ROC). Univariate and multivariate analysis of overall and disease-specific survival were executed. 7 out of 45 patients (16%) experienced LR, 11 (24%) LN and 11 (24%) DM. ROC revealed a significant correlation of several textural parameters with LR with an AUC value for entropy of 0.872. While there was also a significant correlation of LR with tumor size in the overall cohort, only texture was predictive when examining T1 (tumor diameter < = 3 cm) and T2 (>3 cm) subgroups. No correlation of the examined PET parameters with LN or DM was shown. In univariate survival analysis, both heterogeneity and tumor size were predictive for disease-specific survival, but only texture determined by entropy was determined as an independent factor in multivariate analysis (hazard ratio 7.48, p = .016). Overall survival was not significantly correlated to any examined parameter, most likely due to the high comorbidity in our cohort. Our study adds to the growing evidence

  14. Evaluation of the combined effects of reclaimed asphalt pavement (RAP), reclaimed asphalt shingles (RAS), and different virgin binder sources on the performance of blended binders for mixes with higher percentages of RAP and RAS : a national center for su

    Science.gov (United States)

    2015-11-01

    This report summarizes the main findings from a project funded by the National Center for : Sustainable Transportation (NCST) to investigate the use of higher percentages of reclaimed : asphalt pavement (RAP) and reclaimed asphalt shingles (RAS) as a...

  15. Evaluation of the combined effects of reclaimed asphalt pavement (RAP), reclaimed asphalt shingles (RAS), and different virgin binder sources on the performance of blended binders for mixes with higher percentages of RAP and RAS : a research report from t

    Science.gov (United States)

    2015-11-01

    This report summarizes the main findings from a project funded by the National Center for : Sustainable Transportation (NCST) to investigate the use of higher percentages of reclaimed : asphalt pavement (RAP) and reclaimed asphalt shingles (RAS) as a...

  16. Epidermal Growth Factor Receptor (EGFR) gene copy number (GCN) correlates with clinical activity of irinotecan-cetuximab in K-RAS wild-type colorectal cancer: a fluorescence in situ (FISH) and chromogenic in situ hybridization (CISH) analysis.

    Science.gov (United States)

    Scartozzi, Mario; Bearzi, Italo; Mandolesi, Alessandra; Pierantoni, Chiara; Loupakis, Fotios; Zaniboni, Alberto; Negri, Francesca; Quadri, Antonello; Zorzi, Fausto; Galizia, Eva; Berardi, Rossana; Biscotti, Tommasina; Labianca, Roberto; Masi, Gianluca; Falcone, Alfredo; Cascinu, Stefano

    2009-08-27

    K-RAS wild type colorectal tumors show an improved response rate to anti-EGFR monoclonal antibodies. Nevertheless 70% to 40% of these patients still does not seem to benefit from this therapeutic approach. FISH EGFR GCN has been previously demonstrated to correlate with clinical outcome of colorectal cancer treated with anti-EGFR monoclonal antibodies. CISH also seemed able to provide accurate EGFR GCN information with the advantage of a simpler and reproducible technique involving immunohistochemistry and light microscopy. Based on these findings we investigated the correlation between both FISH and CISH EGFR GCN and clinical outcome in K-RAS wild-type colorectal cancer treated with irinotecan-cetuximab. Patients with advanced K-RAS wild-type, colorectal cancer receiving irinotecan-cetuximab after failure of irinotecan-based chemotherapy were eligible. A cut-off value for EGFR GCN of 2.6 and 2.12 for FISH and CISH respectively was derived from ROC curve analysis. Forty-four patients were available for analysis. We observed a partial remission in 9 (60%) and 2 (9%) cases with a FISH EGFR GCN >or= 2.6 and CISH EGFR GCN >or= 2.12 and CISH EGFR GCN whereas it was 2.9 and 3.1 months in those with low FISH and CISH EGFR GCN (p = 0.04 and 0.02 respectively). FISH and CISH EGFR GCN may both represent effective tools for a further patients selection in K-RAS wild-type colorectal cancer treated with cetuximab.

  17. Epidermal Growth Factor Receptor (EGFR) gene copy number (GCN) correlates with clinical activity of irinotecan-cetuximab in K-RAS wild-type colorectal cancer: a fluorescence in situ (FISH) and chromogenic in situ hybridization (CISH) analysis

    International Nuclear Information System (INIS)

    Scartozzi, Mario; Galizia, Eva; Berardi, Rossana; Biscotti, Tommasina; Labianca, Roberto; Masi, Gianluca; Falcone, Alfredo; Cascinu, Stefano; Bearzi, Italo; Mandolesi, Alessandra; Pierantoni, Chiara; Loupakis, Fotios; Zaniboni, Alberto; Negri, Francesca; Quadri, Antonello; Zorzi, Fausto

    2009-01-01

    K-RAS wild type colorectal tumors show an improved response rate to anti-EGFR monoclonal antibodies. Nevertheless 70% to 40% of these patients still does not seem to benefit from this therapeutic approach. FISH EGFR GCN has been previously demonstrated to correlate with clinical outcome of colorectal cancer treated with anti-EGFR monoclonal antibodies. CISH also seemed able to provide accurate EGFR GCN information with the advantage of a simpler and reproducible technique involving immunohistochemistry and light microscopy. Based on these findings we investigated the correlation between both FISH and CISH EGFR GCN and clinical outcome in K-RAS wild-type colorectal cancer treated with irinotecan-cetuximab. Patients with advanced K-RAS wild-type, colorectal cancer receiving irinotecan-cetuximab after failure of irinotecan-based chemotherapy were eligible. A cut-off value for EGFR GCN of 2.6 and 2.12 for FISH and CISH respectively was derived from ROC curve analysis. Forty-four patients were available for analysis. We observed a partial remission in 9 (60%) and 2 (9%) cases with a FISH EGFR GCN ≥ 2.6 and < 2.6 respectively (p = 0.002) and in 10 (36%) and 1 (6%) cases with a CISH EGFR GCN ≥ 2.12 and < 2.12 respectively (p = 0.03). Median TTP was 7.7 and 6.4 months in patients showing increased FISH and CISH EGFR GCN whereas it was 2.9 and 3.1 months in those with low FISH and CISH EGFR GCN (p = 0.04 and 0.02 respectively). FISH and CISH EGFR GCN may both represent effective tools for a further patients selection in K-RAS wild-type colorectal cancer treated with cetuximab

  18. A Rare Case of Aeromonas Hydrophila Catheter Related Sepsis in a Patient with Chronic Kidney Disease Receiving Steroids and Dialysis: A Case Report and Review of Aeromonas Infections in Chronic Kidney Disease Patients

    Directory of Open Access Journals (Sweden)

    Muhammad Abdul Mabood Khalil

    2013-01-01

    Full Text Available Aeromonas hydrophila (AH is an aquatic bacterium. We present a case of fifty-five-year-old gentleman with chronic kidney disease (CKD due to crescentic IgA nephropathy who presented to us with fever. He was recently pulsed with methyl prednisolone followed by oral prednisolone and discharged on maintenance dialysis through a double lumen dialysis catheter. Blood culture from peripheral vein and double lumen dialysis catheter grew AH. We speculate low immunity due to steroids and uremia along with touch contamination of dialysis catheter by the patient or dialysis nurse could have led to this rare infection. Dialysis catheter related infection by AH is rare. We present our case here and take the opportunity to give a brief review of AH infections in CKD patients.

  19. omiRas: a Web server for differential expression analysis of miRNAs derived from small RNA-Seq data.

    Science.gov (United States)

    Müller, Sören; Rycak, Lukas; Winter, Peter; Kahl, Günter; Koch, Ina; Rotter, Björn

    2013-10-15

    Small RNA deep sequencing is widely used to characterize non-coding RNAs (ncRNAs) differentially expressed between two conditions, e.g. healthy and diseased individuals and to reveal insights into molecular mechanisms underlying condition-specific phenotypic traits. The ncRNAome is composed of a multitude of RNAs, such as transfer RNA, small nucleolar RNA and microRNA (miRNA), to name few. Here we present omiRas, a Web server for the annotation, comparison and visualization of interaction networks of ncRNAs derived from next-generation sequencing experiments of two different conditions. The Web tool allows the user to submit raw sequencing data and results are presented as: (i) static annotation results including length distribution, mapping statistics, alignments and quantification tables for each library as well as lists of differentially expressed ncRNAs between conditions and (ii) an interactive network visualization of user-selected miRNAs and their target genes based on the combination of several miRNA-mRNA interaction databases. The omiRas Web server is implemented in Python, PostgreSQL, R and can be accessed at: http://tools.genxpro.net/omiras/.

  20. Clonal origin of multiple lung cancers: K-ras and p53 mutations determined by nonradioisotopic single-strand conformation polymorphism analysis.

    Science.gov (United States)

    Lau, D H; Yang, B; Hu, R; Benfield, J R

    1997-08-01

    Disease stage is the most important factor in determining prognosis and treatment of lung cancer. Staging of lung cancer is complicated by presentation of multiple pulmonary malignant lesions with a similar histology. It is a dilemma to decide if these lesions are synchronous primaries arising from different malignant clones or metastases from a single clone. Lung cancer is associated with multiple genetic abnormalities including mutations of K-ras and p53, which are believed to occur prior to onset of metastasis. To determine the clonal origin of multiple pulmonary malginant nodules, we analyzed point-mutations of K-ras and p53 by microdissection, polymerase chain reactions (PCR), nonradioisotopic single-strand conformation polymorphism (SSCP) analysis, and DNA sequencing. Each pulmonary lesion was microdissected from paraffin slides. Genomic DNA was amplified by two sequential PCRs followed by electrophoresis in a minigel and silver staining. Deoxyribonucleic acid sequencing was performed if necessary to confirm a mutation found upon SSCP analysis. Applying this molecular approach, we were able to differentiate the clonal origins of multiple malignant nodules of the lung as exemplified by the two cases presented.

  1. The levels of mutant K-RAS and mutant N-RAS are rapidly reduced in a Beclin1 / ATG5 -dependent fashion by the irreversible ERBB1/2/4 inhibitor neratinib.

    Science.gov (United States)

    Booth, Laurence; Roberts, Jane L; Poklepovic, Andrew; Kirkwood, John; Sander, Cindy; Avogadri-Connors, Francesca; Cutler, Richard E; Lalani, Alshad S; Dent, Paul

    2018-02-01

    The FDA approved irreversible inhibitor of ERBB1/2/4, neratinib, was recently shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET and mutant K-RAS via autophagic degradation. In the present studies, in a dose-dependent fashion, neratinib reduced the expression levels of mutant K-RAS or of mutant N-RAS, which was augmented in an additive to greater than additive fashion by the HDAC inhibitors sodium valproate and AR42. Neratinib could reduce PDGFRα levels in GBM cells, that was enhanced by sodium valproate. Knock down of Beclin1 or of ATG5 prevented neratinib and neratinib combined with sodium valproate / AR42 from reducing the expression of mutant N-RAS in established PDX and fresh PDX models of ovarian cancer and melanoma, respectively. Neratinib and the drug combinations caused the co-localization of mutant RAS proteins and ERBB2 with Beclin1 and cathepsin B. The drug combination activated the AMP-dependent protein kinase that was causal in enhancing HMG Co A reductase phosphorylation. Collectively, our data reinforce the concept that the irreversible ERBB1/2/4 inhibitor neratinib has the potential for use in the treatment of tumors expressing mutant RAS proteins.

  2. Laboratory evaluation of high asphalt binder replacement with recycled asphalt shingles (RAS) for a low n-design asphalt mixture.

    Science.gov (United States)

    2012-10-01

    This study investigated the effect of high asphalt binder replacement for a low N-design asphalt mixture including : RAP and RAS on performance indicators such as permanent deformation, fracture, fatigue potentials, and : stiffness, was studied. An e...

  3. End-of-pipe denitrification using RAS effluent waste streams: Effect of C/N-ratio and hydraulic retention time

    DEFF Research Database (Denmark)

    Suhr, Karin Isabel; Pedersen, Per Bovbjerg; Arvin, Erik

    2013-01-01

    Environmentally sustainable aquaculture development requires increased nitrogen removal from recirculating aquaculture systems (RAS). In this study, removed solids from a large commercial outdoor recirculated trout farm (1000 MT year−1) were explored as an endogenous carbon source...

  4. Absence of activating mutations in ras and gsp oncogenes in a cohort of nine patients with sporadic pediatric thyroid tumors

    NARCIS (Netherlands)

    Pauws, E.; Tummers, R. F.; Ris-Stalpers, C.; de Vijlder, J. J.; Voûte, T.

    2001-01-01

    BACKGROUND: Characterization of the genetic background of pediatric thyroid carcinomas could aid in distinguishing between differently staged tumors with respect to treatment and prognosis. Two known genetic factors associated with thyroid carcinoma, the proto-oncogenes gsp and ras were

  5. Harvey murine sarcoma virus p21 ras protein: biological and biochemical significance of the cysteine nearest the carboxy terminus

    DEFF Research Database (Denmark)

    Willumsen, B M; Norris, K; Papageorge, A G

    1984-01-01

    localization. We have now further characterized the post-translational processing of these mutants and have also studied two C-terminal v-rasH point mutants: one encodes serine in place of cysteine-186, the other threonine for valine-187. The Thr-187 mutant was transformation-competent, and its p21 protein...... not undergo the posttranslational processing common to biologically active ras proteins: their electrophoretic migration rate did not change, they remained in the cytosol, and they failed to bind lipid. Since the cell-encoded ras proteins also contain this cysteine, we conclude that this amino acid residue......Previous studies of premature chain termination mutants and in frame deletion mutants of the p21 ras transforming protein encoded by the transforming gene of Harvey murine sarcoma virus (Ha-MuSV) have suggested that the C terminus is required for cellular transformation, lipid binding, and membrane...

  6. The effect of aquaporin 5 overexpression on the Ras signaling pathway

    International Nuclear Information System (INIS)

    Woo, Janghee; Lee, Juna; Kim, Myoung Sook; Jang, Se Jin; Sidransky, David; Moon, Chulso

    2008-01-01

    Human aquaporin 5 (AQP5) has been shown to be overexpressed in multiple cancers, such as pancreatic cancer and colon cancer. Furthermore, it has been reported that ectopic expression of AQP5 leads to many phenotypic changes characteristic of transformation. However, the biochemical mechanism leading to transformation in AQP5-overexpressing cells has not been clearly elucidated. In this report, the overexpression of AQP5 in NIH3T3 cells demonstrated a significant effect on Ras activity and, thus, cell proliferation. Furthermore, this influence was shown to be mediated by phosphorylation of the PKA consensus site of AQP5. This is the first evidence demonstrating an association between AQP5 and a signaling pathway, namely the Ras signal transduction pathway, which may be the basis of the oncogenic properties seen in AQP-overexpressing cells

  7. Carcinogenicity evaluation for the application of carbon nanotubes as biomaterials in rasH2 mice.

    Science.gov (United States)

    Takanashi, Seiji; Hara, Kazuo; Aoki, Kaoru; Usui, Yuki; Shimizu, Masayuki; Haniu, Hisao; Ogihara, Nobuhide; Ishigaki, Norio; Nakamura, Koichi; Okamoto, Masanori; Kobayashi, Shinsuke; Kato, Hiroyuki; Sano, Kenji; Nishimura, Naoyuki; Tsutsumi, Hideki; Machida, Kazuhiko; Saito, Naoto

    2012-01-01

    The application of carbon nanotubes (CNTs) as biomaterials is of wide interest, and studies examining their application in medicine have had considerable significance. Biological safety is the most important factor when considering the clinical application of CNTs as biomaterials, and various toxicity evaluations are required. Among these evaluations, carcinogenicity should be examined with the highest priority; however, no report using transgenic mice to evaluate the carcinogenicity of CNTs has been published to date. Here, we performed a carcinogenicity test by implanting multi-walled CNTs (MWCNTs) into the subcutaneous tissue of rasH2 mice, using the carbon black present in black tattoo ink as a reference material for safety. The rasH2 mice did not develop neoplasms after being injected with MWCNTs; instead, MWCNTs showed lower carcinogenicity than carbon black. Such evaluations should facilitate the clinical application and development of CNTs for use in important medical fields.

  8. Novel determinants of H-Ras plasma membrane localization and transformation

    DEFF Research Database (Denmark)

    Willumsen, B M; Cox, A D; Solski, P A

    1996-01-01

    cysteine did not abolish palmitoylation. However, despite continued lipid modification the mutant proteins failed to bind to plasma membranes and instead accumulated on internal membranes and, importantly, were not transforming. Addition of an N-terminal myristoylation signal to these defective mutants......, or to proteins entirely lacking the C-terminal 25 residues restored both plasma membrane association and transforming activity. Thus, H-Ras does not absolutely require prenylation or palmitoylation nor indeed its hypervariable domain in order to interact with effectors that ultimately cause transformation....... However, in this native state, the C-terminus appears to provide a combination of lipids and a previously unrecognized signal for specific plasma membrane targeting that are essential for the correct localization and biological function of H-Ras....

  9. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners

    Energy Technology Data Exchange (ETDEWEB)

    Vaehaekangas, K.H.; Metcalf, R.A.; Welsh, J.A.; Bennett, W.P.; Harris, C.C. (National Cancer Inst., Bethesda, MD (United States)); Samet, J.M. (New Mexico Univ., Albuquerque, NM (United States). UNM Medical Center); Lane, D.P. (Dundee Univ. (United Kingdom). Dept. of Biochemistry)

    1992-03-07

    Radon increases the risk of lung cancer in smoking and non-smoking underground miners. To investigate the mutational spectrum associated with exposure to high levels of radon, the authors sequenced exons 5-9 of the p53 tumour suppressor gene and codons 12-13 of the Ki-ras protooncogene in 19 lung cancers from uranium miners exposed to radon and tobacco smoke. Mutations were not found in Ki-ras, but 9 p53 mutations, including 2 deletions, were found in 7 patients by direct DNA sequencing after polymerase chain reaction amplification of DNA from formalin-fixed, paraffin-embedded tissue. In tumours from 5 patients, the mutation produced an aminoacid change and an increased nuclear content of p53 protein. (author).

  10. Histamine-2 Receptor Antagonist Cannot Prevent Recurrent Peptic Ulcers in Patients With Atherosclerotic Diseases Who Receive Platelet ADP Receptor Antagonist Monotherapy: A Randomized-Controlled, Double-Blind, and Double-Dummy Trial.

    Science.gov (United States)

    Hsu, Ping-I; Wu, Deng-Chyang; Tsay, Feng-Woei; Cheng, Jin-Shiung; Liu, Chun-Peng; Lai, Kwok-Hung; Chen, Wen-Chi; Wang, Huay-Min; Tsai, Tzung-Jiun; Tsai, Kuo-Wang; Kao, Sung-Shuo

    2017-02-01

    Proton pump inhibitor can effectively prevent recurrent peptic ulcers among atherosclerotic patients receiving clopidogrel monotherapy. However, the interaction between proton pump inhibitors and clopidogrel has raised concerns over the safety of combined use of the two medicines in clinical practice. The aims of this randomized-controlled, double-blind and double-dummy trial were to investigate the efficacy of histamine-2 receptor antagonist (H2RA) in the prevention of recurrent peptic ulcer in patients undergoing thienopyridine monotherapy. From January 2012 to 2016, long-termed thienopyridine users with a peptic ulcer history who did not have peptic ulcers at initial endoscopy were randomly assigned to receive either famotidine (40 mg, before bedtime) or placebo (before bedtime) for 6 months. Follow-up endoscopy was performed at the end of the 6th month and whenever dyspepsia, hematemesis, or melena occurred. The cumulative incidence of recurrent peptic ulcer during the 6-month period was 7.0% in famotidine group (n=114) and 11.4% in the placebo group (n=114). The two patient groups had comparable cumulative incidence of peptic ulcer (difference, 4.4%; 95% confidence interval (CI), -11.7 to 2.9%; P=0.239). Additionally, there was no difference in the cumulative incidence of ulcer bleeding (2.6% vs. 1.8%; difference, 0.8%; 95% CI, -0.6 to 2.4%, P=1.000) between famotidine and placebo groups. However, the former had a lower incidence of gastroduodenal erosion than the latter (21.1% vs. 36.8%; difference, 15.7%; 95% CI, -27.3 to -4.1%; P=0.013). Famotidine cannot decrease the incidence of peptic ulcer or ulcer bleeding in thienopyridine users with atherosclerotic disease and a history of peptic ulcer.

  11. Representasi Ras Kulit Hitam Dan Kulit Putih Dalam Film “the Avengers”

    OpenAIRE

    Yufandar, Berril Theo

    2016-01-01

    Fenomena rasisme merupakan sebuah isu yang selalu kencang berhembus dimasyarakat. Bahkan fenomena ini juga terdapat di dunia perfilman. Penelitian ini dilakukan untuk mengetahui bagaimana ras kulit hitam dan kulit putih dalam film “The Avengers”. Pendekatan yang dipakai dalam penelitian ini adalah kualitatif dengan jenis penelitian deskriptif. Metode yang dipergunakan adalah semiotika televisi John Fiske dengan 3 level, yaitu level realitas, level representasi dan level ideologi. Berdasarkan...

  12. Regulation of an H-ras-related transcript by parathyroid hormone in rat osteosarcoma cells

    Science.gov (United States)

    Scott, D. K.; Weaver, W. R.; Clohisy, J. C.; Brakenhoff, K. D.; Kahn, A. J.; Partridge, N. C.

    1992-01-01

    The rat osteosarcoma cell line UMR 106-01 is a commonly used model system for the study of osteoblast function. However, it also expresses a phenotype characteristic of transformed cells. To test whether the latter could be accounted for by aberrant oncogene expression, we probed Northern blots of UMR and other osteoblastic cells with a panel of oncogene probes. These blots, when probed with a cDNA specific for v-H-ras, revealed a 7.0-kilobase (kb) H-ras-related transcript (designated HRRT) in UMR 106-01 cells that was not expressed in other osteoblastic cells. Osteoblast-enriched calvarial cells expressed the typical 1.1-kb H-ras mRNA, which was absent in UMR cells. Additionally, Western blots of lysates of UMR cells documented the presence of three proteins immunologically related to H-rasp21. To determine whether HRRT represented a recombinant retrovirus product, Northern blots were probed with a cDNA specific for the highly conserved gag-pol region of Moloney murine leukemia virus. These blots showed parallel cross-reactivity with an apparently identical transcript of 7.0 kb. The 7.0-kb transcripts detected by both v-H-ras and gag-pol probes declined to the same extent after treatment with concentrations of PTH known to inhibit proliferation of these cells. PTH regulated the abundance of HRRT in a time- and dose-dependent manner, with greatest repression of the transcript after 8 h of treatment with 10(-8) M PTH. The decrease in HRRT could not be completely accounted for by changes in transcriptional activity, as determined by nuclear run-on assays.(ABSTRACT TRUNCATED AT 250 WORDS).

  13. Andrographolide Sensitizes Ras-Transformed Cells to Radiation in vitro and in vivo

    International Nuclear Information System (INIS)

    Hung, Shih-Kai; Hung, Ling-Chien; Kuo, Cheng-Deng

    2010-01-01

    Purpose: Increasing the sensitivity of tumor cells to radiation is a major goal of radiotherapy. The present study investigated the radiosensitizing effects of andrographolide and examined the molecular mechanisms of andrographolide-mediated radiosensitization. Methods and Materials: An H-ras-transformed rat kidney epithelial (RK3E) cell line was used to measure the radiosensitizing effects of andrographolide in clonogenic assays, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assays, and a xenograft tumor growth model. The mechanism of andrographolide-sensitized cell death was analyzed using annexin V staining, caspase 3 activity assays, and terminal transferase uridyl nick end labeling assays. The roles of nuclear factor kappa B (NF-κB) and Akt in andrographolide-mediated sensitization were examined using reporter assays, electrophoretic mobility shift assays, and Western blotting. Results: Concurrent andrographolide treatment (10 μM, 3 h) sensitized Ras-transformed cells to radiation in vitro (sensitizer enhancement ratio, 1.73). Andrographolide plus radiation (one dose of 300 mg/kg peritumor andrographolide and one dose of 6 Gy radiation) resulted in significant tumor growth delay (27 ± 2.5 days) compared with radiation alone (22 ± 1.5 days; p <.05). Radiation induced apoptotic markers (e.g., caspase-3, membrane reversion, DNA fragmentation), and andrographolide treatment did not promote radiation-induced apoptosis. However, the protein level of activated Akt was significantly reduced by andrographolide. NF-κB activity was elevated in irradiated Ras-transformed cells, and andrographolide treatment significantly reduced radiation-induced NF-κB activity. Conclusion: Andrographolide sensitized Ras-transformed cells to radiation both in vitro and in vivo. Andrographolide-mediated radiosensitization was associated with downregulation of Akt and NF-κB activity. These observations indicate that andrographolide is a novel radiosensitizing agent

  14. Andrographolide sensitizes Ras-transformed cells to radiation in vitro and in vivo.

    Science.gov (United States)

    Hung, Shih-Kai; Hung, Ling-Chien; Kuo, Cheng-Deng; Lee, Kuan-Yi; Lee, Moon-Sing; Lin, Hon-Yi; Chen, Yu-Jen; Fu, Shu-Ling

    2010-07-15

    Increasing the sensitivity of tumor cells to radiation is a major goal of radiotherapy. The present study investigated the radiosensitizing effects of andrographolide and examined the molecular mechanisms of andrographolide-mediated radiosensitization. An H-ras-transformed rat kidney epithelial (RK3E) cell line was used to measure the radiosensitizing effects of andrographolide in clonogenic assays, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assays, and a xenograft tumor growth model. The mechanism of andrographolide-sensitized cell death was analyzed using annexin V staining, caspase 3 activity assays, and terminal transferase uridyl nick end labeling assays. The roles of nuclear factor kappa B (NF-kappaB) and Akt in andrographolide-mediated sensitization were examined using reporter assays, electrophoretic mobility shift assays, and Western blotting. Concurrent andrographolide treatment (10 microM, 3 h) sensitized Ras-transformed cells to radiation in vitro (sensitizer enhancement ratio, 1.73). Andrographolide plus radiation (one dose of 300 mg/kg peritumor andrographolide and one dose of 6 Gy radiation) resulted in significant tumor growth delay (27 +/- 2.5 days) compared with radiation alone (22 +/- 1.5 days; p andrographolide treatment did not promote radiation-induced apoptosis. However, the protein level of activated Akt was significantly reduced by andrographolide. NF-kappaB activity was elevated in irradiated Ras-transformed cells, and andrographolide treatment significantly reduced radiation-induced NF-kappaB activity. Andrographolide sensitized Ras-transformed cells to radiation both in vitro and in vivo. Andrographolide-mediated radiosensitization was associated with downregulation of Akt and NF-kappaB activity. These observations indicate that andrographolide is a novel radiosensitizing agent with potential application in cancer radiotherapy. Copyright 2010 Elsevier Inc. All rights reserved.

  15. Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover

    DEFF Research Database (Denmark)

    Hong, Xin; Nguyen, Thanh Hung; Chen, Qingfeng

    2014-01-01

    Cancer genomes accumulate numerous genetic and epigenetic modifications. Yet, human cellular transformation can be accomplished by a few genetically defined elements. These elements activate key pathways required to support replicative immortality and anchorage independent growth, a predictor...... the endogenous EGFR pathway, which is required for transformation. Thus, the oncogenic activity of Ras(V12) depends on its ability to counteract Hippo pathway activity, creating a positive feedback loop, which depends on stabilization of YAP1....

  16. The cell cycle regulator ecdysoneless cooperates with H-Ras to promote oncogenic transformation of human mammary epithelial cells

    Science.gov (United States)

    Bele, Aditya; Mirza, Sameer; Zhang, Ying; Ahmad Mir, Riyaz; Lin, Simon; Kim, Jun Hyun; Gurumurthy, Channabasavaiah Basavaraju; West, William; Qiu, Fang; Band, Hamid; Band, Vimla

    2015-01-01

    The mammalian ortholog of Drosophila ecdysoneless (Ecd) gene product regulates Rb-E2F interaction and is required for cell cycle progression. Ecd is overexpressed in breast cancer and its overexpression predicts shorter survival in patients with ErbB2-positive tumors. Here, we demonstrate Ecd knock down (KD) in human mammary epithelial cells (hMECs) induces growth arrest, similar to the impact of Ecd Knock out (KO) in mouse embryonic fibroblasts. Furthermore, whole-genome mRNA expression analysis of control vs. Ecd KD in hMECs demonstrated that several of the top 40 genes that were down-regulated were E2F target genes. To address the role of Ecd in mammary oncogenesis, we overexpressed Ecd and/or mutant H-Ras in hTERT-immortalized hMECs. Cell cycle analyses revealed hMECs overexpressing Ecd+Ras showed incomplete arrest in G1 phase upon growth factor deprivation, and more rapid cell cycle progression in growth factor-containing medium. Analyses of cell migration, invasion, acinar structures in 3-D Matrigel and anchorage-independent growth demonstrated that Ecd+Ras-overexpressing cells exhibit substantially more dramatic transformed phenotype as compared to cells expressing vector, Ras or Ecd. Under conditions of nutrient deprivation, Ecd+Ras-overexpressing hMECs exhibited better survival, with substantial upregulation of the autophagy marker LC3 both at the mRNA and protein levels. Significantly, while hMECs expressing Ecd or mutant Ras alone did not form tumors in NOD/SCID mice, Ecd+Ras-overexpressing hMECs formed tumors, clearly demonstrating oncogenic cooperation between Ecd and mutant Ras. Collectively, we demonstrate an important co-oncogenic role of Ecd in the progression of mammary oncogenesis through promoting cell survival. PMID:25616580

  17. Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence

    OpenAIRE

    Scaglioni, Pier Paolo; Rabellino, Andrea; Yung, Thomas M; Bernardi, Rosa; Choi, Sooyeon; Konstantinidou, Georgia; Nardella, Caterina; Cheng, Ke; Pandolfi, Pier Paolo

    2012-01-01

    Expression of oncogenic K-RAS in primary cells elicits oncogene-induced cellular senescence (OIS), a form of growth arrest that potently opposes tumourigenesis. This effect has been largely attributed to transcriptional mechanisms that depend on the p53 tumour suppressor protein. The PML tumour suppressor was initially identified as a component of the \\(PML-RAR\\alpha\\) oncoprotein of acute promyelocytic leukaemia (APL). PML, a critical OIS mediator, is upregulated by oncogenic K-RAS in vivo a...

  18. RGS6 Suppresses Ras-induced Cellular Transformation by Facilitating Tip60-mediated Dnmt1 Degradation and Promoting Apoptosis

    Science.gov (United States)

    Huang, Jie; Stewart, Adele; Maity, Biswanath; Hagen, Jussara; Fagan, Rebecca L.; Yang, Jianqi; Quelle, Dawn E.; Brenner, Charles; Fisher, Rory A.

    2014-01-01

    The RAS protooncogene plays a central role in regulation of cell proliferation, and point mutations leading to oncogenic activation of Ras occur in a large number of human cancers. Silencing of tumor suppressor genes by DNA methyltransferase 1 (Dnmt1) is essential for oncogenic cellular transformation by Ras, and Dnmt1 is over-expressed in numerous human cancers. Here we provide new evidence that the pleiotropic Regulator of G protein Signaling (RGS) family member RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated degradation of Dmnt1 and promoting apoptosis. Employing mouse embryonic fibroblasts (MEFs) from wild type (WT) and RGS6−/− mice, we found that oncogenic Ras induced up-regulation of RGS6, which in turn blocked Ras-induced cellular transformation. RGS6 functions to suppress cellular transformation in response to oncogenic Ras by down regulating Dnmt1 protein expression leading to inhibition of Dnmt1-mediated anti-apoptotic activity. Further experiments showed that RGS6 functions as a scaffolding protein for both Dnmt1 and Tip60 and is required for Tip60-mediated acetylation of Dnmt1 and subsequent Dnmt1 ubiquitylation and degradation. The RGS domain of RGS6, known only for its GAP activity toward Gα subunits, was sufficient to mediate Tip60 association with RGS6. This work demonstrates a novel signaling action for RGS6 in negative regulation of oncogene-induced transformation and provides new insights into our understanding of the mechanisms underlying Ras-induced oncogenic transformation and regulation of Dnmt1 expression. Importantly, these findings identify RGS6 as an essential cellular defender against oncogenic stress and a potential therapeutic target for developing new cancer treatments. PMID:23995786

  19. Induction of Non-Apoptotic Cell Death by Activated Ras Requires Inverse Regulation of Rac1 and Arf6

    OpenAIRE

    Bhanot, Haymanti; Young, Ashley M.; Overmeyer, Jean H.; Maltese, William A.

    2010-01-01

    Methuosis is a unique form of non-apoptotic cell death triggered by alterations in the trafficking of clathrin-independent endosomes, ultimately leading to extreme vacuolization and rupture of the cell. Methuosis can be induced in glioblastoma cells by expression of constitutively active Ras. This study identifies the small GTPases, Rac1 and Arf6, and the Arf6 GTPase-activating-protein, GIT1, as key downstream components of the signaling pathway underlying Ras-induced methuosis. The extent to...

  20. Activating the expression of human K-rasG12D stimulates oncogenic transformation in transgenic goat fetal fibroblast cells.

    Directory of Open Access Journals (Sweden)

    Jianhua Gong

    Full Text Available Humane use of preclinical large animal cancer models plays a critical role in understanding cancer biology and developing therapeutic treatments. Among the large animal candidates, goats have great potentials as sustainable sources for large animal cancer model development. Goats are easier to handle and cheaper to raise. The genome of the goats has been sequenced recently. It has been known that goats develop skin, adrenal cortex, breast and other types of cancers. Technically, goats are subject to somatic cell nuclear transfer more efficiently and exhibit better viability through the cloning process. Towards the development of a goat cancer model, we created a transgenic goat fetal fibroblast (GFF cell as the donor cell for SCNT. Human mutated K-ras (hK-rasG12D was chosen as the transgene, as it is present in 20% of cancers. Both hK-rasG12D and a herpes simplex viral thymidine kinase (HSV1-tk reporter genes, flanked by a pair of LoxP sites, were knocked in the GFF endogenous K-ras locus through homologous recombination. Following Cre-mediated activation (with a 95% activation efficiency, hK-rasG12D and HSV1-tk were expressed in the transgenic GFF cells, evidently through the presence of corresponding mRNAs, and confirmed by HSV1-tk protein function assay. The hK-rasG12D expressing GFF cells exhibited enhanced proliferation rates and an anchorage-independent growth behavior. They were able to initiate tumor growth in athymic nude mice. In conclusion, after activating hK-rasG12D gene expression, hK-rasG12D transgenic GFF cells were transformed into tumorgenesis cells. Transgenic goats via SCNT using the above-motioned cells as the donor cells have been established.

  1. Assessment of brain activation regulation in first graders via RAN / RAS test

    Directory of Open Access Journals (Sweden)

    Tatiana V. Akhutina

    2015-03-01

    Full Text Available RAN / RAS test (Rapid Automatized Naming / Rapid Alternating Stimulus has been used successfully used by many psychologists, primarily to predict the risk of dyslexia, as it includes a language component and requires good visual-verbal connections. However, The research demonstrates that the low speed of naming is an effective indicator of neurocognitive problems of information processing as a whole (learning difficulties in general, not just reading difficulties. This can be explained in two ways: disturbance of executive mental control and the difficulties of automatization: the difficulties of the transition from a controlled energy-consuming assignment to a less energy-consuming one. The second interpretation describes the problems of energy resources of cognitive functioning. It is similar to weak maintenance of cortical structures activation. However, using the test mentioned herewith for assessing functions of activation regulation has not been described previously. In terms of the Luria’s three functional units of the brain theory the RAN / RAS test can be considered as sensitive to the weakness of the first unit, whose function is to maintain the activity of cortical structures. So the aim of the research is to prove the possibility of assessing the activation regulation using the RAN / RAS test. This issue is relevant because neuropsychological tools for determining the weakness of Unit I functions are not quite sufficient, while the problem of “energetic” unit ranks first in the frequency of occurrence in children with learning disabilities.

  2. Depletion of Pokemon gene inhibits hepatocellular carcinoma cell growth through inhibition of H-ras.

    Science.gov (United States)

    Zhang, Quan-Le; Tian, De-An; Xu, Xiang-Jiang

    2011-01-01

    Pokemon is a transcription repressor which plays a critical role in cell transformation and malignancy. However, little is known about its effect on the development and progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the expression of Pokemon in human HCC tissues and the biological behavior of Pokemon in HCC cells in which it is overexpressed. We also explored the expression of potential downstream cofactors of Pokemon. Reverse transcription polymerase chain reaction and Western blot analysis were used to investigate the expression of Pokemon in tissues of 30 HCC patients. We then examined cell proliferation or apoptosis and β-catenin or H-ras expression in Pokemon-depleted HepG(2) cells using DNA vector-based RNA interference technology. Pokemon was markedly expressed in 22/30 (73.3%) HCC tissues, with expression levels higher than in adjacent normal liver tissues (p Pokemon inhibited proliferation of HepG(2) or induced apoptosis. Also, H-ras expression decreased to a large extent. Pokemon exerts its oncogenic activity in the development of HCC by promoting cancer cell growth and reducing apoptosis, and the effect may be mediated by H-ras. Copyright © 2011 S. Karger AG, Basel.

  3. A Diaphanous-related formin links Ras signaling directly to actin assembly in macropinocytosis and phagocytosis.

    Science.gov (United States)

    Junemann, Alexander; Filić, Vedrana; Winterhoff, Moritz; Nordholz, Benjamin; Litschko, Christof; Schwellenbach, Helena; Stephan, Till; Weber, Igor; Faix, Jan

    2016-11-22

    Phagocytosis and macropinocytosis are Ras-regulated and actin-driven processes that depend on the dynamic rearrangements of the plasma membrane that protrudes and internalizes extracellular material by cup-shaped structures. However, the regulatory mechanisms underlying actin assembly in large-scale endocytosis remain elusive. Here, we show that the Diaphanous-related formin G (ForG) from the professional phagocyte Dictyostelium discoideum localizes to endocytic cups. Biochemical analyses revealed that ForG is a rather weak nucleator but efficiently elongates actin filaments in the presence of profilin. Notably, genetic inactivation of ForG is associated with a strongly impaired endocytosis and a markedly diminished F-actin content at the base of the cups. By contrast, ablation of the Arp2/3 (actin-related protein-2/3) complex activator SCAR (suppressor of cAMP receptor) diminishes F-actin mainly at the cup rim, being consistent with its known localization. These data therefore suggest that ForG acts as an actin polymerase of Arp2/3-nucleated filaments to allow for efficient membrane expansion and engulfment of extracellular material. Finally, we show that ForG is directly regulated in large-scale endocytosis by RasB and RasG, which are highly related to the human proto-oncogene KRas.

  4. Hip hop subkultūras virtuālās kopienas

    OpenAIRE

    Kovaļčuka, Oksana

    2008-01-01

    Pētījuma mērķis ir apskatīt Latvijas hip hop subkultūru virtuālajā vidē un noskaidrot, vai Latvijas hip hop subkultūras tīmekļa lapu lietotājus var uzskatīt par virtuālās kopienas locekļiem, hip hop subkultūras pārstāvjiem. Lai sasniegtu darba mērķi tika izanalizētas Latvijas hip hop subkultūras tīmekļa lapas (dokumentu analīze), ka arī veiktas intervijas ar „Forum” (www.lvhh.lv) tīmekļa lapas reģistrētiem lietotājiem. Pētījumā secināts, ka „Forum” tīmekļa lapu var uzskatīt par Latvi...

  5. Cancer resistance to therapies against the EGFR-RAS-RAF pathway: The role of MEK.

    Science.gov (United States)

    Martinelli, Erika; Morgillo, Floriana; Troiani, Teresa; Ciardiello, Fortunato

    2017-02-01

    The mitogen-activated protein kinases (MAPKs) mediate intracellular signals activated by a wide variety of extracellular stimuli. The activation of the RAS-RAF-MEK-MAPK cascade culminates in the regulation of gene transcription promoting cancer cell proliferation, survival, migration and angiogenesis. MEK (mitogen-activated protein kinase kinase-MAPKK) 1/2 is a transducer of the growth factor receptor-RAS-RAF-MAPK signalling cascade and plays a relevant role in development and progression of human cancers, such as colorectal cancer (CRC), non small cell lung cancer (NSCLC). Direct inhibition of MEK is a promising strategy and several inhibitors are currently under evaluation in clinical trials showing initial clinical activity in different tumours. MEK activation, by different genetic mechanisms, has been described for both intrinsic and acquired resistance to drugs targeting the EGFR (Epidermal Growth Factor Receptor)-RAS-RAF pathway in CRC, NSCLC. Combination therapies with chemotherapy and/or with molecular targeted agents are warranted and biomarkers studies are needed to identify those tumours dependent on MEK signalling. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. EMT-induced stemness and tumorigenicity are fueled by the EGFR/Ras pathway.

    Directory of Open Access Journals (Sweden)

    Dominic Chih-Cheng Voon

    Full Text Available Recent studies have revealed that differentiated epithelial cells would acquire stem cell-like and tumorigenic properties following an Epithelial-Mesenchymal Transition (EMT. However, the signaling pathways that participate in this novel mechanism of tumorigenesis have not been fully characterized. In Runx3 (-/- p53 (-/- murine gastric epithelial (GIF-14 cells, EMT-induced plasticity is reflected in the expression of the embryonal proto-oncogene Hmga2 and Lgr5, an exclusive gastrointestinal stem cell marker. Here, we report the concurrent activation of an EGFR/Ras gene expression signature during TGF-β1-induced EMT in GIF-14 cells. Amongst the altered genes was the induction of Egfr, which corresponded with a delayed sensitization to EGF treatment in GIF-14. Co-treatment with TGF-β1 and EGF or the expression of exogenous KRas led to increased Hmga2 or Lgr5 expression, sphere initiation and colony formation in soft agar assay. Interestingly, the gain in cellular plasticity/tumorigenicity was not accompanied by increased EMT. This uncoupling of EMT and the induction of plasticity reveals an involvement of distinct signaling cues, whereby the EGFR/Ras pathway specifically promotes stemness and tumorigenicity in EMT-altered GIF-14 cells. These data show that the EGFR/Ras pathway requisite for the sustenance of gastric stem cells in vivo and in vitro is involved in the genesis and promotion of EMT-induced tumor-initiating cells.

  7. Ultra-wideband receiver

    Science.gov (United States)

    McEwan, Thomas E.

    1994-01-01

    An ultra-wideband (UWB) receiver utilizes a strobed input line with a sampler connected to an amplifier. In a differential configuration, .+-.UWB inputs are connected to separate antennas or to two halves of a dipole antenna. The two input lines include samplers which are commonly strobed by a gating pulse with a very low duty cycle. In a single ended configuration, only a single strobed input line and sampler is utilized. The samplers integrate, or average, up to 10,000 pulses to achieve high sensitivity and good rejection of uncorrelated signals.

  8. A negative-feedback loop regulating ERK1/2 activation and mediated by RasGPR2 phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Jinqi [Departments of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599 (United States); Cook, Aaron A.; Bergmeier, Wolfgang [Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599 (United States); Sondek, John, E-mail: sondek@med.unc.edu [Departments of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599 (United States); Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599 (United States); Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 (United States)

    2016-05-20

    The dynamic regulation of ERK1 and -2 (ERK1/2) is required for precise signal transduction controlling cell proliferation, differentiation, and survival. However, the underlying mechanisms regulating the activation of ERK1/2 are not completely understood. In this study, we show that phosphorylation of RasGRP2, a guanine nucleotide exchange factor (GEF), inhibits its ability to activate the small GTPase Rap1 that ultimately leads to decreased activation of ERK1/2 in cells. ERK2 phosphorylates RasGRP2 at Ser394 located in the linker region implicated in its autoinhibition. These studies identify RasGRP2 as a novel substrate of ERK1/2 and define a negative-feedback loop that regulates the BRaf–MEK–ERK signaling cascade. This negative-feedback loop determines the amplitude and duration of active ERK1/2. -- Highlights: •ERK2 phosphorylates the guanine nucleotide exchange factor RasGRP2 at Ser394. •Phosphorylated RasGRP2 has decreased capacity to active Rap1b in vitro and in cells. •Phosphorylation of RasGRP2 by ERK1/2 introduces a negative-feedback loop into the BRaf-MEK-ERK pathway.

  9. Structural insight into the rearrangement of the switch I region in GTP-bound G12A K-Ras

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Shenyuan; Long, Brian N.; Boris, Gabriel H.; Chen, Anqi; Ni, Shuisong; Kennedy, Michael A.

    2017-11-10

    K-Ras, a molecular switch that regulates cell growth, apoptosis and metabolism, is activated when it undergoes a conformation change upon binding GTP and is deactivated following the hydrolysis of GTP to GDP. Hydrolysis of GTP in water is accelerated by coordination to K-Ras, where GTP adopts a high-energy conformation approaching the transition state. The G12A mutation reduces intrinsic K-Ras GTP hydrolysis by an unexplained mechanism. Here, crystal structures of G12A K-Ras in complex with GDP, GTP, GTPγS and GppNHp, and of Q61A K-Ras in complex with GDP, are reported. In the G12A K-Ras–GTP complex, the switch I region undergoes a significant reorganization such that the Tyr32 side chain points towards the GTP-binding pocket and forms a hydrogen bond to the GTP γ-phosphate, effectively stabilizing GTP in its precatalytic state, increasing the activation energy required to reach the transition state and contributing to the reduced intrinsic GTPase activity of G12A K-Ras mutants.

  10. Induction of non-apoptotic programmed cell death by oncogenic RAS in human epithelial cells and its suppression by MYC overexpression.

    Science.gov (United States)

    Dendo, Kasumi; Yugawa, Takashi; Nakahara, Tomomi; Ohno, Shin-Ichi; Goshima, Naoki; Arakawa, Hirofumi; Kiyono, Tohru

    2018-02-09

    Oncogenic mutations of RAS genes, found in about 30% of human cancers, are considered to play important roles in cancer development. However, oncogenic RAS can also induce senescence in mouse and human normal fibroblasts. In some cell lines, oncogenic RAS has been reported to induce non-apoptotic programed cell death (PCD). Here, we investigated effects of oncogenic RAS expression in several types of normal human epithelial cells. Oncogenic RAS but not wild-type RAS stimulated macropinocytosis with accumulation of large-phase lucent vacuoles in the cytoplasm, subsequently leading to cell death which was indistinguishable from a recently proposed new type of PCD, methuosis. A RAC1 inhibitor suppressed accumulation of macropinosomes and overexpression of MYC attenuated oncogenic RAS-induced such accumulation, cell cycle arrest and cell death. MYC suppression or rapamycin treatment in some cancer cell lines harbouring oncogenic mutations in RAS genes induced cell death with accumulation of macropinosomes. These results suggest that this type of non-apoptotic PCD is a tumour-suppressing mechanism acting against oncogenic RAS mutations in normal human epithelial cells, which can be overcome by MYC overexpression, raising the possibility that its induction might be a novel approach to treatment of RAS-mutated human cancers. © The Author(s) 2017. Published by Oxford University Press.

  11. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors

    Science.gov (United States)

    Loi, Sherene; Dushyanthen, Sathana; Beavis, Paul A; Salgado, Roberto; Denkert, Carsten; Savas, Peter; Combs, Susan; Rimm, David L.; Giltnane, Jennifer M.; Estrada, Monica V.; Sánchez, Violeta; Sanders, Melinda E.; Cook, Rebecca S.; Pilkinton, Mark A.; Mallal, Simon A.; Wang, Kai; Miller, Vincent A.; Stephens, Phil J.; Yelensky, Roman; Doimi, Franco D.; Gómez, Henry; Ryzhov, Sergey V.; Darcy, Phillip K.; Arteaga, Carlos L.; Balko, Justin M.

    2015-01-01

    Purpose Tumor-infiltrating lymphocytes (TILs) in the residual disease (RD) of triple-negative breast cancers (TNBCs) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. Experimental Design We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer. Results Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras/MAPK signaling were significantly correlated with lower TILs. MEK inhibition up-regulated cell-surface major histocompatibility complex (MHC) expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PDL-1/PD-1 inhibition enhanced anti-tumor immune responses in mouse models of breast cancer. Conclusions These data suggest the possibility that Ras/MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1-targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. PMID:26515496

  12. Evaluation of psychopharmacological and neurosafety profile of Swas Kas Chintamani Ras (SKC in Swiss-Webster mice

    Directory of Open Access Journals (Sweden)

    Tarequl Islam

    2017-12-01

    Full Text Available Objectives: Swas Kas Chintamani Ras (SKC is an ayurvedic preparation indicated for respiratory diseases. Our study was aimed to determine the psychopharmacological and neurosafety profile of SKC. Materials and Methods: Psychopharmacological effects and neurosafety profile of this drug were determined by nine complementary test methods namely, open field, locomotor activity, hole cross, hole board test, elevated plus maze, staircase, forced swimming test, and rotarod test. Male mice (Swiss-Webster strain, 20-40 g body weight bred in the Animal House of the Department of Pharmacy, Jahangirnagar University, were used for the pharmacological experiments. Results: The drug decreased total ambulation and movement in the central region and standing up behavior and lowered emotional defecation. The drug also made the mice to take a shorter time to come out of the cage. Also, animals spent less time in open arm and the movement in the closed arm and locomotors reduced (p=0.003, where a number of rearing (p=0.04 behaviour indicating possible anxiolytic activity.  Also, no signs of anti-depressant activity were observed among SKC-treated group. Conclusion: We concluded that our drug showed no neurotoxic effect and it also showed some beneficial neuropharmacological properties.

  13. BTB-Zinc Finger Oncogenes Are Required for Ras and Notch-Driven Tumorigenesis in Drosophila.

    Science.gov (United States)

    Doggett, Karen; Turkel, Nezaket; Willoughby, Lee F; Ellul, Jason; Murray, Michael J; Richardson, Helena E; Brumby, Anthony M

    2015-01-01

    During tumorigenesis, pathways that promote the epithelial-to-mesenchymal transition (EMT) can both facilitate metastasis and endow tumor cells with cancer stem cell properties. To gain a greater understanding of how these properties are interlinked in cancers we used Drosophila epithelial tumor models, which are driven by orthologues of human oncogenes (activated alleles of Ras and Notch) in cooperation with the loss of the cell polarity regulator, scribbled (scrib). Within these tumors, both invasive, mesenchymal-like cell morphology and continual tumor overgrowth, are dependent upon Jun N-terminal kinase (JNK) activity. To identify JNK-dependent changes within the tumors we used a comparative microarray analysis to define a JNK gene signature common to both Ras and Notch-driven tumors. Amongst the JNK-dependent changes was a significant enrichment for BTB-Zinc Finger (ZF) domain genes, including chronologically inappropriate morphogenesis (chinmo). chinmo was upregulated by JNK within the tumors, and overexpression of chinmo with either RasV12 or Nintra was sufficient to promote JNK-independent epithelial tumor formation in the eye/antennal disc, and, in cooperation with RasV12, promote tumor formation in the adult midgut epithelium. Chinmo primes cells for oncogene-mediated transformation through blocking differentiation in the eye disc, and promoting an escargot-expressing stem or enteroblast cell state in the adult midgut. BTB-ZF genes are also required for Ras and Notch-driven overgrowth of scrib mutant tissue, since, although loss of chinmo alone did not significantly impede tumor development, when loss of chinmo was combined with loss of a functionally related BTB-ZF gene, abrupt, tumor overgrowth was significantly reduced. abrupt is not a JNK-induced gene, however, Abrupt is present in JNK-positive tumor cells, consistent with a JNK-associated oncogenic role. As some mammalian BTB-ZF proteins are also highly oncogenic, our work suggests that EMT

  14. BTB-Zinc Finger Oncogenes Are Required for Ras and Notch-Driven Tumorigenesis in Drosophila.

    Directory of Open Access Journals (Sweden)

    Karen Doggett

    Full Text Available During tumorigenesis, pathways that promote the epithelial-to-mesenchymal transition (EMT can both facilitate metastasis and endow tumor cells with cancer stem cell properties. To gain a greater understanding of how these properties are interlinked in cancers we used Drosophila epithelial tumor models, which are driven by orthologues of human oncogenes (activated alleles of Ras and Notch in cooperation with the loss of the cell polarity regulator, scribbled (scrib. Within these tumors, both invasive, mesenchymal-like cell morphology and continual tumor overgrowth, are dependent upon Jun N-terminal kinase (JNK activity. To identify JNK-dependent changes within the tumors we used a comparative microarray analysis to define a JNK gene signature common to both Ras and Notch-driven tumors. Amongst the JNK-dependent changes was a significant enrichment for BTB-Zinc Finger (ZF domain genes, including chronologically inappropriate morphogenesis (chinmo. chinmo was upregulated by JNK within the tumors, and overexpression of chinmo with either RasV12 or Nintra was sufficient to promote JNK-independent epithelial tumor formation in the eye/antennal disc, and, in cooperation with RasV12, promote tumor formation in the adult midgut epithelium. Chinmo primes cells for oncogene-mediated transformation through blocking differentiation in the eye disc, and promoting an escargot-expressing stem or enteroblast cell state in the adult midgut. BTB-ZF genes are also required for Ras and Notch-driven overgrowth of scrib mutant tissue, since, although loss of chinmo alone did not significantly impede tumor development, when loss of chinmo was combined with loss of a functionally related BTB-ZF gene, abrupt, tumor overgrowth was significantly reduced. abrupt is not a JNK-induced gene, however, Abrupt is present in JNK-positive tumor cells, consistent with a JNK-associated oncogenic role. As some mammalian BTB-ZF proteins are also highly oncogenic, our work suggests that

  15. [Screening for K-ras mutations in colorectal and lung cancers by using a novel real-time PCR with ADx-K-ras kit and Sanger DNA sequencing].

    Science.gov (United States)

    Zhang, Hai-Ping; Fu, Li; Chen, Pei-Qiong; Ye, Yun-Bin; Ji, Tian-Hai; Zheng, Li-Mou

    2010-11-01

    to map out the frequency and types of K-ras gene mutations present in colorectal and lung cancer patients; to evaluate the clinical applicability of a novel real-time double-loop probe PCR using the ADx-K-ras kit, and to compare its performance with the result by using traditional Sanger DNA sequencing in detection of somatic mutations of the tumor genes. a total of 827 formalin-fixed paraffin-embedded (FFPE) blocks including 583 from the colorectal and 244 from the lung cancer patients were assayed. Genomic DNA of the sample tissues was extracted, purified and subjected to PCR amplification of K-ras gene codon 12 and 13 and DNA sequencing was carried on using both the traditional Sanger sequencing method and the ADx's K-ras mutation detection kit, respectively. The mutation rates for K-ras gene at codon 12 and 13, and the mutation frequencies detected by using both methods were analyzed. 533 out of 583 (91.4%) colorectal cancer samples and 144 out of 244 lung cancer samples (59.0%) were detected using the traditional Sanger DNA sequencing technique, and 583 out of 583 (100.0%) colorectal plus 244 out of 244(100.0%) lung cancers were detected, respectively by using the ADx-K-ras kit. Of the 583 colorectal cancer samples, 192 (32.9%) showed mutations by using the ADx-K-ras kit in comparing with a result of 160 samples (27.4%) with K-ras gene mutation by using the traditional Sanger DNA sequencing technique. Of the 244 lung cancer samples, 26 (10.7%) showed K-ras gene mutations by using ADx-K-ras kit, while in 144 samples detected by using the traditional Sanger DNA sequencing technique, only 12 samples (8.3%) showed K-ras gene mutations. In colorectal cancer analyzed, GGT→GAT at codon 12 was the most common event with 35.1% (66/188) mutations, followed by GGC→GAC at codon 13 with 26.6% (50/188) and GGT→GTT at codon 12 with 18.6% (35/188), while GGT→GCT at codon12 was the most rare with only 1.6% (3/188) of the total mutation cases. In patients with lung

  16. Solar thermal energy receiver

    Science.gov (United States)

    Baker, Karl W. (Inventor); Dustin, Miles O. (Inventor)

    1992-01-01

    A plurality of heat pipes in a shell receive concentrated solar energy and transfer the energy to a heat activated system. To provide for even distribution of the energy despite uneven impingement of solar energy on the heat pipes, absence of solar energy at times, or failure of one or more of the heat pipes, energy storage means are disposed on the heat pipes which extend through a heat pipe thermal coupling means into the heat activated device. To enhance energy transfer to the heat activated device, the heat pipe coupling cavity means may be provided with extensions into the device. For use with a Stirling engine having passages for working gas, heat transfer members may be positioned to contact the gas and the heat pipes. The shell may be divided into sections by transverse walls. To prevent cavity working fluid from collecting in the extensions, a porous body is positioned in the cavity.

  17. E-Ras improves the efficiency of reprogramming by facilitating cell cycle progression through JNK–Sp1 pathway

    Directory of Open Access Journals (Sweden)

    Yoo-Wook Kwon

    2015-11-01

    Full Text Available We have previously shown that pluripotent stem cells can be induced from adult somatic cells which were exposed to protein extracts isolated from mouse embryonic stem cells (mESC. Interestingly, generation of induced pluripotent stem (iPS cells depended on the background of ES cell lines; possible by extracts from C57, but not from E14. Proteomic analysis of two different mES cell lines (C57 and E14 shows that embryonic Ras (E-Ras is expressed differently in two mES cell lines; high level of E-Ras only in C57 mESC whose extracts allows iPS cells production from somatic cells. Here, we show that E-Ras augments the efficiency in reprogramming of fibroblast by promoting cell proliferation. We found that over-expression of E-Ras in fibroblast increased cell proliferation which was caused by specific up-regulation of cyclins D and E, not A or B, leading to the accelerated G1 to S phase transition. To figure out the common transcription factor of cyclins D and E, we used TRANSFAC database and selected SP1 as a candidate which was confirmed as enhancer of cyclins D and E by luciferase promoter assay using mutants. As downstream signaling pathways, E-Ras activated only c-Jun N-terminal kinases (JNK but not ERK or p38. Inhibition of JNK prevented E-Ras-mediated induction of pSP1, cyclins D, E, and cell proliferation. Finally, E-Ras transduction to fibroblast enhanced the efficiency of iPS cell generation by 4 factors (Oct4/Klf4/Sox2/C-myc, which was prevented by JNK inhibitor. In conclusion, E-Ras stimulates JNK, enhances binding of Sp1 on the promoter of cyclins D and E, leading to cell proliferation. E-Ras/JNK axis is a critical mechanism to generate iPS cells by transduction of 4 factors or by treatment of mESC protein extracts.

  18. Growth factor-dependent activation of the Ras-Raf-MEK-MAPK pathway in the human pancreatic carcinoma cell line PANC-1 carrying activated K-ras: implications for cell proliferation and cell migration.

    Science.gov (United States)

    Giehl, K; Skripczynski, B; Mansard, A; Menke, A; Gierschik, P

    2000-06-08

    Human ductal adenocarcinoma of the pancreas frequently carry activating point mutations in the K-ras protooncogene. We have analysed the activity of the Ras-Raf-MEK-MAPK cascade in the human pancreatic carcinoma cell line PANC-1 carrying an activating K-ras mutation. Serum-starved cells and cells grown in medium with serum did not show constitutively activated c-Raf, MEK-1, or p42 MAPK. Stimulation of cells with epidermal growth factor (EGF) or fetal calf serum (FCS) resulted in activation of N-Ras, but not K-Ras, as well as activation of c-Raf, MEK-1, and p42 MAPK. Preincubation of serum-starved cells with MEK-1 inhibitor PD98059 abolished EGF- and FCS-induced MAPK activation, identifying MEK as the upstream activator of MAPK. PANC-1 cells exhibited marked serum-dependence of anchorage-dependent and -independent cell growth as well as cell migration. EGF, alone or in combination with insulin and transferrin, did not induce cell proliferation of serum-starved PANC-1 cells, indicating that activation of MAPK alone was not sufficient to induce cell proliferation. FCS-induced DNA synthesis was inhibited by 40% by the MEK-1 inhibitor. On the other hand, treatment with either FCS or EGF alone resulted in marked, MEK-dependent increase of directed cell migration. Collectively, our results show that the activating K-ras mutation in PANC-1 cells does not result in constitutively increased Raf-MEK-MAPK signaling. Signal transduction via the Ras-Raf-MEK-MAPK cascade is maintained in these cells and is required for growth factor-induced cell proliferation and directed cell migration. Oncogene (2000).

  19. River analysis and floodplain modeling using HEC-GeoRAS/RAS, GIS and ArcGIS: a case study for the Salinas River

    Science.gov (United States)

    Mishra, P. K.; Bernini Campos, H. E.

    2016-12-01

    The lower portion of the Salinas River in Monterey bay, California has a history of flood, lots of study has been made ab out the water quality since the river provides water for the crops around, but is still in need a detailed study about the river behavior and flood analysis. The floods did significant damage, affecting valuable landing farms, residences and businesses in Monterey County. The first step for this study is comprehend and collect the river bathymetry and surroundings and then analyze the discharge and how it is going to change with time. This thesis develops a model about the specific site, recruiting real data from GIS and performing a flow simulation according to flow data provided by USGS, to verify water surface elevation and floodplain. The ArcMap, developed by ESRI, was used along with an extension (HEC-GeoRAS) because it was indeed the most appropriate model to work with the Digital Elevation Model, develop the floodplain and characterizing the land surface accurately in the study site. The HEC-RAS software, developed by US Army Corp of Engineers, was used to compute one-dimension steady flow and two-dimension unsteady flow, providing flow velocity, water surface elevation and profiles, total surface area, head and friction loss and other characteristics, allowing the analysis of the flow. A mean discharge, a mean peak streamflow and a peak discharge were used for the steady flow and a Hydrograph was used for the unsteady flow, both are based on the 1995 flood and discharge history. This study provides important information about water surface elevation and water flow, allowing stakeholders and the government to analyze solutions to avoid damage to the society and landowners.

  20. CERN apprentice receives award

    CERN Multimedia

    2008-01-01

    Another CERN apprentice has received an award for the quality of his work. Stéphane Küng (centre), at the UIG ceremony last November, presided over by Geneva State Councillor Pierre-François Unger, Head of the Department of Economics and Health. Electronics technician Stéphane Küng was honoured in November by the Social Foundation of the Union Industrielle Genevoise (UIG) as one of Geneva’s eight best apprentices in the field of mechatronics. The 20-year-old Genevan obtained his Federal apprentice’s certificate (Certificat fédéral de capacité - CFC) in June 2007, achieving excellent marks in his written tests at the Centre d’Enseignement Professionnel Technique et Artisanal (CEPTA). Like more than 200 youngsters before him, Stéphane Küng spent part of his four-year sandwich course working at CERN, where he followed many practical training courses and gained valuable hands-on experience in various technical groups and labs. "It’ always very gr...

  1. A functional screen reveals an extensive layer of transcriptional and splicing control underlying RAS/MAPK signaling in Drosophila.

    Directory of Open Access Journals (Sweden)

    Dariel Ashton-Beaucage

    2014-03-01

    Full Text Available The small GTPase RAS is among the most prevalent oncogenes. The evolutionarily conserved RAF-MEK-MAPK module that lies downstream of RAS is one of the main conduits through which RAS transmits proliferative signals in normal and cancer cells. Genetic and biochemical studies conducted over the last two decades uncovered a small set of factors regulating RAS/MAPK signaling. Interestingly, most of these were found to control RAF activation, thus suggesting a central regulatory role for this event. Whether additional factors are required at this level or further downstream remains an open question. To obtain a comprehensive view of the elements functionally linked to the RAS/MAPK cascade, we used a quantitative assay in Drosophila S2 cells to conduct a genome-wide RNAi screen for factors impacting RAS-mediated MAPK activation. The screen led to the identification of 101 validated hits, including most of the previously known factors associated to this pathway. Epistasis experiments were then carried out on individual candidates to determine their position relative to core pathway components. While this revealed several new factors acting at different steps along the pathway--including a new protein complex modulating RAF activation--we found that most hits unexpectedly work downstream of MEK and specifically influence MAPK expression. These hits mainly consist of constitutive splicing factors and thereby suggest that splicing plays a specific role in establishing MAPK levels. We further characterized two representative members of this group and surprisingly found that they act by regulating mapk alternative splicing. This study provides an unprecedented assessment of the factors modulating RAS/MAPK signaling in Drosophila. In addition, it suggests that pathway output does not solely rely on classical signaling events, such as those controlling RAF activation, but also on the regulation of MAPK levels. Finally, it indicates that core splicing

  2. The LIM-only protein FHL2 mediates ras-induced transformation through cyclin D1 and p53 pathways.

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    Charlotte Labalette

    Full Text Available BACKGROUND: Four and a half LIM-only protein 2 (FHL2 has been implicated in multiple signaling pathways that regulate cell growth and tissue homeostasis. We reported previously that FHL2 regulates cyclin D1 expression and that immortalized FHL2-null mouse embryo fibroblasts (MEFs display reduced levels of cyclin D1 and low proliferative activity. METHODOLOGY/PRINCIPAL FINDINGS: Here we address the contribution of FHL2 in cell transformation by investigating the effects of oncogenic Ras in FHL2-null context. We show that H-RasV12 provokes cell cycle arrest accompanied by accumulation of p53 and p16(INK4a in immortalized FHL2(-/- MEFs. These features contrast sharply with Ras transforming activity in wild type cell lines. We further show that establishment of FHL2-null cell lines differs from conventional immortalization scheme by retaining functional p19(ARF/p53 checkpoint that is required for cell cycle arrest imposed by Ras. However, after serial passages of Ras-expressing FHL2(-/- cells, dramatic increase in the levels of D-type cyclins and Rb phosphorylation correlates with the onset of cell proliferation and transformation without disrupting the p19(ARF/p53 pathway. Interestingly, primary FHL2-null cells overexpressing cyclin D1 undergo a classical immortalization process leading to loss of the p19(ARF/p53 checkpoint and susceptibility to Ras transformation. CONCLUSIONS/SIGNIFICANCE: Our findings uncover a novel aspect of cellular responses to mitogenic stimulation and illustrate a critical role of FHL2 in the signalling network that implicates Ras, cyclin D1 and p53.

  3. Recovery assessment scale: Examining the factor structure of the German version (RAS-G) in people with schizophrenia spectrum disorders.

    Science.gov (United States)

    Cavelti, M; Wirtz, M; Corrigan, P; Vauth, R

    2017-03-01

    The recovery framework has found its way into local and national mental health services and policies around the world, especially in English speaking countries. To promote this process, it is necessary to assess personal recovery validly and reliably. The Recovery Assessment Scale (RAS) is the most established measure in recovery research. The aim of the current study is to examine the factor structure of the German version of the RAS (RAS-G). One hundred and fifty-six German-speaking clients with schizophrenia or schizoaffective disorder from a community mental health service completed the RAS-G plus measures of recovery attitudes, self-stigma, psychotic symptoms, depression, and functioning. A confirmatory factor analysis of the original 24-item RAS version was conducted to examine its factor structure, followed by reliability and validity testing of the extracted factors. The CFA yielded five factors capturing 14 items which showed a substantial overlap with the original subscales Personal Confidence and Hope, Goal and Success Orientation, Willingness to Ask for Help, Reliance on Others, and No Domination by Symptoms. The factors demonstrated mean to excellent reliability (0.59-0.89) and satisfactory criterial validity by positive correlations with measures of recovery attitudes and functioning, and negative correlations with measures of self-stigma, and psychotic and depressive symptoms. The study results are discussed in the light of other studies examining the factor structure of the RAS. Overall, they support the use of the RAS-G as a means to promote recovery oriented services, policies, and research in German-speaking countries. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  4. ERK2-regulated TIMP1 Induces Hyperproliferation of K-RasG12D-Transformed Pancreatic Ductal Cells

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    Gregory P. Botta

    2013-04-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC commonly contains a mutation in K-RasG12D and is characterized by a desmoplastic reaction composed of deregulated, proliferating cells embedded in an abnormal extracellular matrix (ECM. Our previous observations imply that inhibiting the mitogen-activated protein kinase (MAPK-extracellular signal-regulated kinase (ERK2 kinase signal pathway reverses a matrix metalloproteinase 1-specific invasive phenotype. Here, we investigated the specific genes downstream of MAPK-ERK2 responsible for the hyperproliferative abilities of human and murine primary ductal epithelial cells (PDCs within an ECM. Compared with control, DNA synthesis and total cell proliferation was significantly increased in human PDCs harboring the PDAC common p53, Rb/p16INK4a, and K-RasG12D mutations. Both of these effects were readily reversed following small-molecule inhibition or lentiviral silencing of ERK2. Microarray analysis of PDCs in three-dimensional (3D culture revealed a unique, MAPK-influenced gene signature downstream of K-RasG12D. Unbiased hierarchical analysis permitted filtration of tissue inhibitor of matrix metalloproteinase 1 (TIMP1. Pancreatic cells isolated from Pdx1-Cre; LSL-K-rasG12D/+-mutated mice exhibit increased TIMP1 RNA transcription compared to wild-type littermate controls. Analyses of both 3D, in vitro human K-RasG12D PDCs and data mining of publicly annotated human pancreatic data sets correlatively indicate increased levels of TIMP1 RNA. While silencing TIMP1 did not significantly effect PDC proliferation, exogenous addition of human recombinant TIMP1 significantly increased proliferation but only in transformed K-RasG12D PDCs in 3D. Overall, TIMP1 is an upregulated gene product and a proliferative inducer of K-RasG12D-mutated PDCs through the ERK2 signaling pathway.

  5. Toll-like receptor 9 agonist IMO cooperates with cetuximab in K-ras mutant colorectal and pancreatic cancers.

    Science.gov (United States)

    Rosa, Roberta; Melisi, Davide; Damiano, Vincenzo; Bianco, Roberto; Garofalo, Sonia; Gelardi, Teresa; Agrawal, Sudhir; Di Nicolantonio, Federica; Scarpa, Aldo; Bardelli, Alberto; Tortora, Giampaolo

    2011-10-15

    K-Ras somatic mutations are a strong predictive biomarker for resistance to epidermal growth factor receptor (EGFR) inhibitors in patients with colorectal and pancreatic cancer. We previously showed that the novel Toll-like receptor 9 (TLR9) agonist immunomodulatory oligonucleotide (IMO) has a strong in vivo activity in colorectal cancer models by interfering with EGFR-related signaling and synergizing with the anti-EGFR monoclonal antibody cetuximab. In the present study, we investigated, both in vitro and in vivo, the antitumor effect of IMO alone or in combination with cetuximab in subcutaneous colon and orthotopic pancreatic cancer models harboring K-Ras mutations and resistance to EGFR inhibitors. We showed that IMO was able to significantly restore the sensitivity of K-Ras mutant cancer cells to cetuximab, producing a marked inhibition of cell survival and a complete suppression of mitogen-activated protein kinase phosphorylation, when used in combination with cetuximab. IMO interfered with EGFR-dependent signaling, modulating the functional interaction between TLR9 and EGFR. In vivo, IMO plus cetuximab combination caused a potent and long-lasting cooperative antitumor activity in LS174T colorectal cancer and in orthotopic AsPC1 pancreatic cancer. The capability of IMO to restore cetuximab sensitivity was further confirmed by using K-Ras mutant colorectal cancer cell models obtained through homologous recombination technology. We showed that IMO markedly inhibits growth of K-Ras mutant colon and pancreatic cancers in vitro and in nude mice and cooperates with cetuximab via multiple mechanisms of action. Therefore, we propose IMO plus cetuximab as a therapeutic strategy for K-Ras wild-type as well for K-Ras mutant, cetuximab-resistant colorectal and pancreatic cancers. ©2011 AACR.

  6. Transcription factors down-stream of Ras as molecular indicators for targeting malignancies with oncolytic herpes virus.

    Science.gov (United States)

    Esfandyari, Tuba; Tefferi, Ayalew; Szmidt, Anna; Alain, Tommy; Zwolak, Pawel; Lasho, Terra; Lee, Patrick W; Farassati, Faris

    2009-12-01

    Overactivation in Ras signaling has been under intensive study as the molecular basis for development of cancer. Such overactivation can occur in the presence or absence of mutations in Ras gene resulting in activation of a series of down-stream effectors such as transcription factors. Different studies have shown the activation of Ras down-stream effectors in non-Hodgkin lymphoma (NHL) although mutations in Ras are not prevalent in this malignancy. Since overactivation in Ras signaling also increases permissiveness of cancer cells to infection by oncolytic versions of herpes simplex virus (e.g. R3616), we were interested in evaluating the value of transcription factors down-stream of Ras as molecular indicators for permissiveness to herpes therapy. In order to accomplish this, and also to assess the permissiveness of lymphoma cells to infection with R3616, we used NHL cell lines Daudi, Jurkat, NC37, Raji, Ramos and ST486. Once the levels of phosphorylation (activation) of extracellular-signal regulated kinase (ERK, a Ras effector pathway) and its down-stream transcription factor ELK were evaluated, Raji and NC37 showed a significant increase in the phosphorylation levels of both molecules while ATF2 (another transcription factor down-stream of p38-kinase pathway) seemed to be activated in all studied cells. Raji and NC37 cells were also most permissive cells to infection with R3616 while their permissiveness was decreased upon treatment of cells with an inhibitor of ELK-DNA binding portraying ERK/ELK as a suitable predictive indicator for selection of cancer cells with increased sensitivity to R3616. This study, therefore, for the first time documents permissiveness of lymphoma cells to oncolytic herpes viruses and introduces ELK as a suitable factor for predicting tumor susceptibility to these novel anticancer agents.

  7. Mobility and invasiveness of metastatic esophageal cancer are potentiated by shear stress in a ROCK- and Ras-dependent manner.

    Science.gov (United States)

    Lawler, Karen; Foran, Eilis; O'Sullivan, Gerald; Long, Aideen; Kenny, Dermot

    2006-10-01

    To metastasize, tumor cells must adopt different morphological responses to resist shear forces encountered in circulating blood and invade through basement membranes. The Rho and Ras GTPases play a critical role in regulating this dynamic behavior. Recently, we demonstrated shear-induced activation of adherent esophageal metastatic cells, characterized by formation of dynamic membrane blebs. Although membrane blebbing has only recently been characterized as a rounded mode of cellular invasion promoted through Rho kinase (ROCK), the role of shear forces in modulating membrane blebbing activity is unknown. To further characterize membrane blebbing in esophageal metastatic cells (OC-1 cell line), we investigated the role of shear in cytoskeletal remodeling and signaling through ROCK and Ras. Our results show that actin and tubulin colocalize to the cortical ring of the OC-1 cell under static conditions. However, under shear, actin acquires a punctuate distribution and tubulin localizes to the leading edge of the OC-1 cell. We show for the first time that dynamic bleb formation is induced by shear alone independent of integrin-mediated adhesion (P Y-27632, a specific inhibitor of ROCK, causes a significant reduction in shear-induced bleb formation and inhibits integrin alpha(v)beta(3)-Ras colocalization at the leading edge of the cell. Direct measurement of Ras activation shows that the level of GTP-bound Ras is elevated in sheared OC-1 cells and that the shear-induced increase in Ras activity is inhibited by Y-27632. Finally, we show that shear stress significantly increases OC-1 cell invasion (P Y-27632. Together our findings suggest a novel physiological role for ROCK and Ras in metastatic cell behavior.

  8. Induction of nonapoptotic cell death by activated Ras requires inverse regulation of Rac1 and Arf6.

    Science.gov (United States)

    Bhanot, Haymanti; Young, Ashley M; Overmeyer, Jean H; Maltese, William A

    2010-10-01

    Methuosis is a unique form of nonapoptotic cell death triggered by alterations in the trafficking of clathrin-independent endosomes, ultimately leading to extreme vacuolization and rupture of the cell. Methuosis can be induced in glioblastoma cells by expression of constitutively active Ras. This study identifies the small GTPases, Rac1 and Arf6, and the Arf6 GTPase-activating protein, GIT1, as key downstream components of the signaling pathway underlying Ras-induced methuosis. The extent to which graded expression of active H-Ras(G12V) triggers cytoplasmic vacuolization correlates with the amount of endogenous Rac1 in the active GTP state. Blocking Rac1 activation with the specific Rac inhibitor, EHT 1864, or coexpression of dominant-negative Rac1(T17N), prevents the accumulation of vacuoles induced by H-Ras(G12V). Coincident with Rac1 activation, H-Ras(G12V) causes a decrease in the amount of active Arf6, a GTPase that functions in the recycling of clathrin-independent endosomes. The effect of H-Ras(G12V) on Arf6 is blocked by EHT 1864, indicating that the decrease in Arf6-GTP is directly linked to the activation of Rac1. Constitutively active Rac1(G12V) interacts with GIT1 in immunoprecipitation assays. Ablation of GIT1 by short hairpin RNA prevents the decrease in active Arf6, inhibits vacuolization, and prevents loss of cell viability in cells expressing Rac1(G12V). Together, the results suggest that perturbations of endosome morphology associated with Ras-induced methuosis are due to downstream activation of Rac1 combined with reciprocal inactivation of Arf6. The latter seems to be mediated through Rac1 stimulation of GIT1. Further insights into this pathway could suggest opportunities for the induction of methuosis in cancers that are resistant to apoptotic cell death.

  9. Induction of Non-Apoptotic Cell Death by Activated Ras Requires Inverse Regulation of Rac1 and Arf6

    Science.gov (United States)

    Bhanot, Haymanti; Young, Ashley M.; Overmeyer, Jean H.; Maltese, William A.

    2010-01-01

    Methuosis is a unique form of non-apoptotic cell death triggered by alterations in the trafficking of clathrin-independent endosomes, ultimately leading to extreme vacuolization and rupture of the cell. Methuosis can be induced in glioblastoma cells by expression of constitutively active Ras. This study identifies the small GTPases, Rac1 and Arf6, and the Arf6 GTPase-activating-protein, GIT1, as key downstream components of the signaling pathway underlying Ras-induced methuosis. The extent to which graded expression of active H-Ras(G12V) triggers cytoplasmic vacuolization correlates with the amount of endogenous Rac1 in the active GTP state. Blocking Rac1 activation with the specific Rac inhibitor, EHT 1864, or co-expression of dominant-negative Rac1(T17N), prevents the accumulation of vacuoles induced by H-Ras(G12V). Coincident with Rac1 activation, H-Ras(G12V) causes a decrease in the amount of active Arf6, a GTPase that functions in recycling of clathrin-independent endosomes. The effect of H-Ras(G12V) on Arf6 is blocked by EHT 1864, indicating that the decrease in Arf6-GTP is directly linked to activation of Rac1. Constitutively active Rac1(G12V) interacts with GIT1 in immunoprecipitation assays. Ablation of GIT1 by shRNA prevents the decrease in active Arf6, inhibits vacuolization, and prevents loss of cell viability in cells expressing Rac1(G12V). Together the results suggest that perturbations of endosome morphology associated with Ras-induced methuosis are due to downstream activation of Rac1, combined with reciprocal inactivation of Arf6. The latter appears to be mediated through Rac1 stimulation of GIT1. Further insights into this pathway could suggest opportunities for induction of methuosis in cancers that are resistant to apoptotic cell death. PMID:20713492

  10. The N-terminal pleckstrin, coiled-coil, and IQ domains of the exchange factor Ras-GRF act cooperatively to facilitate activation by calcium.

    Science.gov (United States)

    Buchsbaum, R; Telliez, J B; Goonesekera, S; Feig, L A

    1996-09-01

    We have recently shown that the neuronal exchange factor p140 Ras-GRF becomes activated in vivo in response to elevated calcium levels [C. L. Farnsworth, N. W. Freshney, L. B. Rosen, A. Ghosh, M. E. Greenberg, and L. A. Feig, Nature (London) 376:524-527, 1995]. Activation is mediated by calcium-induced calmodulin binding to an IQ domain near the N terminus of Ras-GRF. Here we show that the adjacent N-terminal pleckstrin homology (PH), coiled-coil, and IQ domains function cooperatively to allow Ras-GRF activation. Deletion of the N-terminal PH domain redistributes a large percentage of Ras-GRF from the particulate to the cytosolic fraction of cells and renders the protein insensitive to calcium stimulation. A similar cellular distribution and biological activity are observed when only the core catalytic domain is expressed. Although the PH domain is necessary for particulate association of Ras-GRF, it is not sufficient for targeting the core catalytic domain to this cellular location. This requires the PH domain and the adjacent coiled-coil and IQ sequences. Remarkably, this form of Ras-GRF is constitutively activated. The PH and coiled-coil domains must also perform an additional function, since targeting to the particulate fraction of cells is not sufficient to allow Ras-GRF activation by calcium. A Ras-GRF mutant containing the PH domain from Ras-GTPase-activating protein in place of its own N-terminal PH domain localizes to the particulate fraction of cells but does not respond to calcium. Similar phenotypes are seen with mutant Ras-GRFs containing point mutations in either the PH or coiled-coil domain. These findings argue that the N-terminal PH, coiled-coil, and IQ domains of Ras-GRF function together to connect Ras-GRF to multiple components in the particulate fractions of cells that are required for responsiveness of the protein to calcium signaling.

  11. Ras-dva, a member of novel family of small GTPases, is required for the anterior ectoderm patterning in the Xenopus laevis embryo.

    Science.gov (United States)

    Tereshina, Maria B; Zaraisky, Andrey G; Novoselov, Vladimir V

    2006-02-01

    Ras-like small GTPases are involved in the regulation of many processes essential for the specification of the vertebrate body plan. Recently, we identified the gene of novel small GTPase Ras-dva, which is specifically expressed at the anterior margin of the neural plate of the Xenopus laevis embryo. Now, we demonstrate that Ras-dva and its homologs in other species constitute a novel protein family, distinct from the previously known families of small GTPases. We show that the expression of Ras-dva begins during gastrulation throughout the anterior ectoderm and is activated by the homeodomain transcription factor Otx2; however, later on, Ras-dva expression is inhibited in the anterior neural plate by another homeodomain factor Xanf1. Downregulation of Ras-dva functioning by the dominant-negative mutant or by the antisense morpholino oligonucleotides results in severe malformations of the forebrain and derivatives of the cranial placodes. Importantly, although the observed abnormalities can be rescued by co-injection of the Ras-dva mRNA, they cannot be rescued by the mRNA of the closest Ras-dva homolog from another family of small GTPases, Ras. This fact indicates functional specificity of the Ras-dva signaling pathway. At the molecular level, downregulation of Ras-dva inhibits the expression of several regulators of the anterior neural plate and folds patterning, such as Otx2, BF-1 (also known as Foxg1), Xag2, Pax6, Slug and Sox9, and interferes with FGF8 signaling within the anterior ectoderm. By contrast, expression of the epidermal regulator BMP4 and its target genes, Vent1, Vent2b and Msx1, is upregulated. Together, the data obtained indicate that Ras-dva is an essential component of the signaling network that patterns the early anterior neural plate and the adjacent ectoderm in the Xenopus laevis embryos.

  12. Oncogenic Ras-Induced Morphologic Change Is through MEK/ERK Signaling Pathway to Downregulate Stat3 at a Posttranslational Level in NIH3T3 Cells

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    Hsuan-Heng Yeh

    2008-01-01

    Full Text Available Ras is a key regulator of the MAP kinase-signaling cascade and may cause morphologic change of Ras-transformed cells. Signal transducer and activator of transcription 3 (Stat3 can be activated by cytokine stimulation. In this study, we unravel that Ha-rasV12 overexpression can downregulate the expression of Stat3 protein at a posttranslational level in NIH3T3 cells. Furthermore, we demonstrate that Stat3 expression downregulated by Ha-rasV12 overexpression is through proteosome degradation and not through a mTOR/p70S6K-related signaling pathway. The suppression of Stat3 accompanied by the morphologic change induced by Ha-rasV12 was through mitogen extracellular kinase (MEK/extracellular-regulated kinase (ERK signaling pathway. Microtubule disruption is involved in Ha-rasV12-induced morphologic change, which could be reversed by overexpression of Stat3. Taken together, we are the first to demonstrate that Stat3 protein plays a critical role in Ha-rasV12-induced morphologic change. Oncogenic Ras-triggered morphologic change is through the activation of MEK/ERK to posttranslationally downregulate Stat3 expression. Our finding may shed light on developing novel therapeutic strategies against Ras-related tumorigenesis.

  13. Society News: Monica Grady awarded CBE; Grubb Parsons Lecture 2012; Join the RAS; Astronomy on radio for kids; New Fellows; Peter D Hingley

    Science.gov (United States)

    2012-08-01

    RAS Fellow Prof. Monica Grady has been made a Commander of the Most Excellent Order of the British Empire (CBE), in recognition of her services to space science. The RAS sponsors the annual Grubb Parsons Lecture, which this year took place on 6 June at the University of Durham. If you are a professional astronomer, geophysicist, or similar, a student studying these disciplines, or simply someone with a serious interest in them, we urge you to apply for membership of the RAS. Outreach is an important activity for the RAS. We recently supported an astronomy series called Deep Space High on the digital radio channel Fun Kids.

  14. Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Tae Hoon; Chennakrishnaiah, Shilpa [Montreal Children’s Hospital, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec (Canada); Audemard, Eric [McGill University and Genome Quebec Innovation Centre, Montreal, Quebec (Canada); Montermini, Laura; Meehan, Brian [Montreal Children’s Hospital, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec (Canada); Rak, Janusz, E-mail: janusz.rak@mcgill.ca [Montreal Children’s Hospital, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec (Canada)

    2014-08-22

    Highlights: • Oncogenic H-ras stimulates emission of extracellular vesicles containing double-stranded DNA. • Vesicle-associated extracellular DNA contains mutant N-ras sequences. • Vesicles mediate intercellular transfer of mutant H-ras DNA to normal fibroblasts where it remains for several weeks. • Fibroblasts exposed to vesicles containing H-ras DNA exhibit increased proliferation. - Abstract: Cell free DNA is often regarded as a source of genetic cancer biomarkers, but the related mechanisms of DNA release, composition and biological activity remain unclear. Here we show that rat epithelial cell transformation by the human H-ras oncogene leads to an increase in production of small, exosomal-like extracellular vesicles by viable cancer cells. These EVs contain chromatin-associated double-stranded DNA fragments covering the entire host genome, including full-length H-ras. Oncogenic N-ras and SV40LT sequences were also found in EVs emitted from spontaneous mouse brain tumor cells. Disruption of acidic sphingomyelinase and the p53/Rb pathway did not block emission of EV-related oncogenic DNA. Exposure of non-transformed RAT-1 cells to EVs containing mutant H-ras DNA led to the uptake and retention of this material for an extended (30 days) but transient period of time, and stimulated cell proliferation. Thus, our study suggests that H-ras-mediated transformation stimulates vesicular emission of this histone-bound oncogene, which may interact with non-transformed cells.

  15. High-density growth arrest in Ras-transformed cells: low Cdk kinase activities in spite of absence of p27Kip Cdk-complexes

    DEFF Research Database (Denmark)

    Groth, Anja; Willumsen, Berthe Marie

    2005-01-01

    The ras oncogene transforms immortalized, contact-inhibited non-malignant murine fibroblasts into cells that are focus forming, exhibit increased saturation density, and are malignant in suitable hosts. Here, we examined changes in cell cycle control complexes as normal and Ras-transformed cells...... and Cdk2 complexes, as these kinases were inactivated. Ras-transformed cells failed to arrest at normal saturation density and showed no significant alterations in cell control complexes at this point. Yet, at an elevated density the Ras-transformed cells ceased to proliferate and entered a quiescent...... response to contact inhibition, a separate back-up mechanism enforced cell cycle arrest at higher cell density....

  16. Korelasi antara dimensi vertikal oklusi dengan panjang jari kelingking pada sub-ras Deutro Melayu

    Directory of Open Access Journals (Sweden)

    Cytha Nilam Chairani

    2016-12-01

    yaitu metode antropometri. Metode ini dilakukan dengan cara pengukuran panjang jari kelingking. DVO dan panjang jari kelingking berbeda pada setiap ras manusia karena masing-masing ras memiliki ciri-ciri spesifik yang berbeda antara satu dengan yang lain. Sub ras Deutro Melayu merupakan salah satu sub ras di Indonesia. Penelitian ini bertujuan untuk mengetahui korelasi antara hasil pengukuran DVO dan panjang jari kelingking pada sub ras Deutro Melayu di Kota Padang. Penelitian ini merupakan penelitian observasional analitik dengan pendekatan cross sectional. Sampel sebanyak 112 warga Kota Padang yang merupakan sub ras Deutro Melayu dan memenuhi kriteria, terdiri dari 56 orang laki-laki dan 56 orang perempuan. Data diuji secara statistik dengan analisis Pearson correlation. Terdapat korelasi yang bermakna antara hasil pengukuran DVO dengan panjang jari kelingking dengan nilai r=0,768 dan hasil kedua pengukuran ini menunjukkan nilai yang hampir sama dengan nilai p=0,000, sehingga signifikan secara statistik (p<0,05. Pengukuran antropometri panjang jari kelingking merupakan metode yang dapat digunakan untuk menentukan DVO.

  17. The steps to recovery program: Evaluation of a group-based intervention for older individuals receiving mental health services.

    Science.gov (United States)

    Flaherty-Jones, Graeme M; Carne, Alexandra S; Dexter-Smith, Sarah

    2016-03-01

    This study reports on the evaluation of a group-based intervention for older individuals receiving mental health services. A prospective cohort repeated-measure design was used for 48 participants who accessed secondary care mental health services for older people. Changes on the Recovery Assessment Scale (RAS), the Warwick-Edinburgh Mental Well-Being Scale (WEMWEBS), and a postevaluation questionnaire were analyzed. A paired sample t test examined changes in participant's scores on the WEMWEBS and RAS from baseline to postintervention. Participants qualitatively evaluated the Steps to Recovery group as having a positive effect on their recovery. Following involvement in this group intervention, participants reported improved mental well-being and recovery from mental health difficulty. These results suggest that the program has the potential to provide an accessible framework for developing recovery-orientated approaches in mental health care that can be delivered by care staff at all levels. (c) 2016 APA, all rights reserved).

  18. Activation of RAS/ERK alone is insufficient to inhibit RXRα function and deplete retinoic acid in hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ai-Guo, E-mail: wangaiguotl@hotmail.com; Song, Ya-Nan; Chen, Jun; Li, Hui-Ling; Dong, Jian-Yi; Cui, Hai-Peng; Yao, Liang; Li, Xue-Feng; Gao, Wen-Ting; Qiu, Ze-Wen; Wang, Fu-Jin; Wang, Jing-Yu, E-mail: wangjingyus@163.com

    2014-09-26

    Highlights: • The activation of RAS/ERK is insufficient to inhibit RXRα function and deplete RA. • The retinoid metabolism-related genes are down-regulated by ras oncogene. • The atRA has no effect on preventing hepatic tumorigenesis or curing the developed hepatic nodules. - Abstract: Activation of RAS/ERK signaling pathway, depletion of retinoid, and phosphorylation of retinoid X receptor alpha (RXRα) are frequent events found in liver tumors and thought to play important roles in hepatic tumorigenesis. However, the relationships among them still remained to be elucidated. By exploring the transgenic mouse model of hepatic tumorigenesis induced by liver-specific expression of H-ras12V oncogene, the activation of RAS/ERK, the mRNA expression levels of retinoid metabolism-related genes, the contents of retinoid metabolites, and phosphorylation of RXRα were determined. RAS/ERK signaling pathway was gradually and significantly activated in hepatic tumor adjacent normal liver tissues (P) and hepatic tumor tissues (T) of H-ras12V transgenic mice compared with normal liver tissues (Wt) of wild type mice. On the contrary, the mRNA expression levels of retinoid metabolism-related genes were significantly reduced in P and T compared with Wt. Interestingly, the retinoid metabolites 9-cis-retinoic acid (9cRA) and all-trans-retinoic acid (atRA), the well known ligands for nuclear transcription factor RXR and retinoic acid receptor (RAR), were significantly decreased only in T compared with Wt and P, although the oxidized polar metabolite of atRA, 4-keto-all-trans-retinoic-acid (4-keto-RA) was significantly decreased in both P and T compared with Wt. To our surprise, the functions of RXRα were significantly blocked only in T compared with Wt and P. Namely, the total protein levels of RXRα were significantly reduced and the phosphorylation levels of RXRα were significantly increased only in T compared with Wt and P. Treatment of H-ras12V transgenic mice at 5-week

  19. Calibration of HEC-Ras hydrodynamic model using gauged discharge data and flood inundation maps

    Science.gov (United States)

    Tong, Rui; Komma, Jürgen

    2017-04-01

    The estimation of flood is essential for disaster alleviation. Hydrodynamic models are implemented to predict the occurrence and variance of flood in different scales. In practice, the calibration of hydrodynamic models aims to search the best possible parameters for the representation the natural flow resistance. Recent years have seen the calibration of hydrodynamic models being more actual and faster following the advance of earth observation products and computer based optimization techniques. In this study, the Hydrologic Engineering River Analysis System (HEC-Ras) model was set up with high-resolution digital elevation model from Laser scanner for the river Inn in Tyrol, Austria. 10 largest flood events from 19 hourly discharge gauges and flood inundation maps were selected to calibrate the HEC-Ras model. Manning roughness values and lateral inflow factors as parameters were automatically optimized with the Shuffled complex with Principal component analysis (SP-UCI) algorithm developed from the Shuffled Complex Evolution (SCE-UA). Different objective functions (Nash-Sutcliffe model efficiency coefficient, the timing of peak, peak value and Root-mean-square deviation) were used in single or multiple way. It was found that the lateral inflow factor was the most sensitive parameter. SP-UCI algorithm could avoid the local optimal and achieve efficient and effective parameters in the calibration of HEC-Ras model using flood extension images. As results showed, calibration by means of gauged discharge data and flood inundation maps, together with objective function of Nash-Sutcliffe model efficiency coefficient, was very robust to obtain more reliable flood simulation, and also to catch up with the peak value and the timing of peak.

  20. A Novel Ras Inhibitor (MDC-1016 Reduces Human Pancreatic Tumor Growth in Mice

    Directory of Open Access Journals (Sweden)

    Gerardo G Mackenzie

    2013-10-01

    Full Text Available Pancreatic cancer has one of the poorest prognoses among all cancers partly because of its persistent resistance to chemotherapy. The currently limited treatment options for pancreatic cancer underscore the need for more efficient agents. Because activating Kras mutations initiate and maintain pancreatic cancer, inhibition of this pathway should have a major therapeutic impact. We synthesized phospho-farnesylthiosalicylic acid (PFTS; MDC-1016 and evaluated its efficacy, safety, and metabolism in preclinical models of pancreatic cancer. PFTS inhibited the growth of human pancreatic cancer cells in culture in a concentration- and time-dependent manner. In an MIA PaCa-2 xenograft mouse model, PFTS at a dose of 50 and 100 mg/kg significantly reduced tumor growth by 62% and 65% (P < .05 vs vehicle control. Furthermore, PFTS prevented pancreatitis-accelerated acinar-to-ductal metaplasia in mice with activated Kras. PFTS appeared to be safe, with the animals showing no signs of toxicity during treatment. Following oral administration, PFTS was rapidly absorbed, metabolized to FTS and FTS glucuronide, and distributed through the blood to body organs. Mechanistically, PFTS inhibited Ras-GTP, the active form of Ras, both in vitro and in vivo, leading to the inhibition of downstream effector pathways c-RAF/mitogen-activated protein-extracellular signal-regulated kinase (ERK kinase (MEK/ERK1/2 kinase and phosphatidylinositol 3-kinase/AKT. In addition, PFTS proved to be a strong combination partner with phospho-valproic acid, a novel signal transducer and activator of transcription 3 (STAT3 inhibitor, displaying synergy in the inhibition of pancreatic cancer growth. In conclusion, PFTS, a direct Ras inhibitor, is an efficacious agent for the treatment of pancreatic cancer in preclinical models, deserving further evaluation.

  1. Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors.

    Science.gov (United States)

    Merchant, Mark; Moffat, John; Schaefer, Gabriele; Chan, Jocelyn; Wang, Xi; Orr, Christine; Cheng, Jason; Hunsaker, Thomas; Shao, Lily; Wang, Stephanie J; Wagle, Marie-Claire; Lin, Eva; Haverty, Peter M; Shahidi-Latham, Sheerin; Ngu, Hai; Solon, Margaret; Eastham-Anderson, Jeffrey; Koeppen, Hartmut; Huang, Shih-Min A; Schwarz, Jacob; Belvin, Marcia; Kirouac, Daniel; Junttila, Melissa R

    2017-01-01

    Mitogen-activated protein kinase (MAPK) pathway dysregulation is implicated in >30% of all cancers, rationalizing the development of RAF, MEK and ERK inhibitors. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, these inhibitors had limited success in other MAPK dysregulated tumors, with insufficient pathway suppression and likely pathway reactivation. In this study we show that inhibition of either MEK or ERK alone only transiently inhibits the MAPK pathway due to feedback reactivation. Simultaneous targeting of both MEK and ERK nodes results in deeper and more durable suppression of MAPK signaling that is not achievable with any dose of single agent, in tumors where feedback reactivation occurs. Strikingly, combined MEK and ERK inhibition is synergistic in RAS mutant models but only additive in BRAF mutant models where the RAF complex is dissociated from RAS and thus feedback productivity is disabled. We discovered that pathway reactivation in RAS mutant models occurs at the level of CRAF with combination treatment resulting in a markedly more active pool of CRAF. However, distinct from single node targeting, combining MEK and ERK inhibitor treatment effectively blocks the downstream signaling as assessed by transcriptional signatures and phospho-p90RSK. Importantly, these data reveal that MAPK pathway inhibitors whose activity is attenuated due to feedback reactivation can be rescued with sufficient inhibition by using a combination of MEK and ERK inhibitors. The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents, and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse (GEM) models. Collectively, these data demonstrate that combined MEK and ERK inhibition is functionally unique, yielding greater than additive anti-tumor effects and elucidates a highly

  2. [Arnold-Chiari malformation in Noonan syndrome and other syndromes of the RAS/MAPK pathway].

    Science.gov (United States)

    Ejarque, Ismael; Millán-Salvador, José M; Oltra, Silvestre; Pesudo-Martínez, José V; Beneyto, Magdalena; Pérez-Aytés, Antonio

    2015-05-01

    Noonan syndrome (NS) and other syndromes with a similar phenotype, such as LEOPARD, cardiofaciocutaneous, Costello and Legius, are associated to mutations in genes included in the RAS/MAPK pathway (RASopathies), which is an important signalling pathway related to cell proliferation. Tonsillar descent into the upper cervical spinal canal, known as Arnold-Chiari malformation (ACM), has been reported in patients with NS and this has led some researchers to suggest that ACM could be part of the phenotypic spectrum of NS. We report two cases of NS and ACM. Case 1: 29-year-old female with Noonan phenotype who underwent surgery at the age of nine years due to pulmonary valve stenosis. At the age of 27, she presented symptomatic ACM that required surgical decompression. She presented the c.922A>G (N308D) mutation in the gene PTPN that belongs to the RAS/MAPK pathway. Case 2: a 10-year-old female with Noonan phenotype and asymptomatic ACM detected in magnetic resonance imaging of the brain. She was a carrier of the c.923A>G (N308S) mutation in gene PTPN11. Six patients with this association have been found in the literature, four with the Noonan phenotype and two with LEOPARD. Our two patients provide supplementary evidence that backs up the hypothesis by which ACM would be part of the phenotypic spectrum of NS. The small number of reported cases of patients with this association does not allow us to draw up recommendations about when and how often neuroimaging studies should be performed; a careful neurological examination, however, should be included in the anticipatory health guidelines in syndromes involving the RAS/MAPK pathway.

  3. Estimation of Channel-Forming Discharge and Large-Event Geomorphic Response Using HEC-RAS

    Science.gov (United States)

    Hamilton, P.; Strom, K.; Hosseiny, S. M. H.

    2015-12-01

    The goal of the present work was to consider the functionality and applicability of HEC-RAS sediment transport simulations in two situations. The first was as a mode for obtaining quick estimates of the effective discharge, one measure of channel-forming discharge, and the second was as a mode to quickly estimate sediment transport and the commensurate potential erosion and deposition during large flood events. Though there are many other sediment transport and morphodynamic models available, e.g., CCHE1D, Nays2DH, we were interested in using HEC-RAS since this is the model of choice for many regulatory bodies, e.g., FEMA, cities, and counties. This makes using the sediment transport capability of HEC-RAS a natural extension of models that already otherwise exist and are well calibrated. In first looking at the utility of these models, we wanted to estimate the effective discharge of streams. Effective discharge is one way of defining the channel-forming discharge for a stream and is therefore an important parameter in natural channel design and restoration efforts. By running this range of floods, one can easily obtain an estimate for recurrence interval most responsible for moving the majority of sediment over a long time period. Results were compared to data collected within our research group on the Brazos River (TX). Effective discharge is an important estimate, particularly in understanding the equilibrium channel condition. Nevertheless, large floods are contemporaneously catastrophic and understanding their potential effects is desirable. Finally, we performed some sensitivity analysis to better understand the underlying assumptions of the various sediment transport model options and how they might affect the outcome of the aforementioned computations.

  4. FLI-1 Flightless-1 and LET-60 Ras control germ line morphogenesis in C. elegans

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    Dentler William L

    2008-05-01

    Full Text Available Abstract Background In the C. elegans germ line, syncytial germ line nuclei are arranged at the cortex of the germ line as they exit mitosis and enter meiosis, forming a nucleus-free core of germ line cytoplasm called the rachis. Molecular mechanisms of rachis formation and germ line organization are not well understood. Results Mutations in the fli-1 gene disrupt rachis organization without affecting meiotic differentiation, a phenotype in C. elegans referred to here as the germ line morphogenesis (Glm phenotype. In fli-1 mutants, chains of meiotic germ nuclei spanned the rachis and were partially enveloped by invaginations of germ line plasma membrane, similar to nuclei at the cortex. Extensions of the somatic sheath cells that surround the germ line protruded deep inside the rachis and were associated with displaced nuclei in fli-1 mutants. fli-1 encodes a molecule with leucine-rich repeats and gelsolin repeats similar to Drosophila flightless 1 and human Fliih, which have been shown to act as cytoplasmic actin regulators as well as nuclear transcriptional regulators. Mutations in let-60 Ras, previously implicated in germ line development, were found to cause the Glm phenotype. Constitutively-active LET-60 partially rescued the fli-1 Glm phenotype, suggesting that LET-60 Ras and FLI-1 might act together to control germ line morphogenesis. Conclusion FLI-1 controls germ line morphogenesis and rachis organization, a process about which little is known at the molecular level. The LET-60 Ras GTPase might act with FLI-1 to control germ line morphogenesis.

  5. Hubungan Antara Aktivitas Poligalakturonase Dengan Virulensi RAS 4 Fusarium oxysporum f.sp. cubense

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    Arif Wibowo

    2008-07-01

    Full Text Available One of the major constraints of banana plantation in Indonesia is the occurrence of fusarium wilt disease caused by Fusarium oxysporum f.sp. cubense. The pathogen produced series of cell wall degradation extracellular enzymes which have important roles in pathogenicity. Many studies have been conducted to know the role of degrading enzyme banana pectin is the major component of cell wall. Many pectinolytic enzymes such as polygalacturonase and others have been isolated from many fungal plant pathogens. The study was aimed to know the role of polygalacturonase towards the virulence of race 4 of F. oxysporum f.sp. cubense. The result showed that from 10 isolates of race 4 of F. oxysporum f.sp. cubense, the most virulent isolate was Lmp1 followed by Srg1, Bgl6, Mln1, Bgl3, A13, Bnt2, Gnk3, Kjg1 dan Wsb5. This was indicated by high and low percentage of wilting leaves of banana cultivar Cavendish when they were inoculated with these isolates. Incubation period varied from 3 to 6 weeks after inoculation SDS-PAGE showed that polygalacturonase, mostly PG1 and PG2, was secreted by these isolates, whereas PG3 was only found in growing cultures of Gnk3 and Wsb5 isolates. Detection of polygalacturonase activity with diffusion agar and reducing sugar methods showed that the activity of polygalacturonase secreted by F. oxysporum f.sp. cubense in the growing culture had no correlation with the virulence of the fungal pathogen.   Salah satu kendala utama dalam budidaya pisang di Indonesia adalah gangguan penyakit layu fusarium yang disebabkan oleh jamur Fusarium oxysporum f.sp. cubense. Jamur patogen ini menghasilkan serangkaian enzim ekstraselular pendegradasi dinding sel yang berperan dalam patogenesis. Beberapa penelitian telah dilakukan untuk mengetahui peran enzim yang mendegradasi pektin, yang merupakan komponen penting dinding sel tanaman. Beberapa enzim pektinolitik seperti poligalakturonase dan yang lainnya telah berhasil diisolasi dari berbagai

  6. Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations.

    Science.gov (United States)

    Gollins, Simon; West, Nick; Sebag-Montefiore, David; Myint, Arthur Sun; Saunders, Mark; Susnerwala, Shabbir; Quirke, Phil; Essapen, Sharadah; Samuel, Leslie; Sizer, Bruce; Worlding, Jane; Southward, Katie; Hemmings, Gemma; Tinkler-Hundal, Emma; Taylor, Morag; Bottomley, Daniel; Chambers, Philip; Lawrie, Emma; Lopes, Andre; Beare, Sandy

    2017-10-24

    The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain. In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen. Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73-88%) (four patients with clinical complete response declined surgery). Twenty-four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05-1.03, P=0.055). This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss.

  7. Noninvasive detection through REMS-PCR technique of K-ras mutations in stool DNA of patients with colorectal cancer.

    Science.gov (United States)

    Mixich, Francisc; Ioana, Mihai; Voinea, Florea; Săftoiu, Adrian; Ciurea, Tudorel

    2007-03-01

    Tumor exfoliated cells that shed into stool are attractive targets for molecular screening and early detection of colon malignancies. Many studies have suggested that the detection of activated ras may have diagnostic or prognostic importance. The aim of this study was to establish the suitability for use in diagnostic laboratories of the noninvasive screening test of K-ras mutation determination in the stool and its routine prognostic value in colorectal cancer. Paired stool and tissue specimens obtained after polypectomy and colorectal biopsy from 28 patients diagnosed solely by histopathological findings with primary colorectal carcinoma, were prospectively studied for K-ras codon 12 mutations by restriction endonuclease-mediated selective (REMS)-PCR. DNA was obtained in 28 of tissue samples (100%) and 26 of stool samples (92.8%). K-ras codon 12 mutation was seen in 14 (50.0%) paired stool and tissue samples. Mutation detection was possible in 1000-fold excess of wild-type sequence. These results may be important in the design of genetic screening programs, determination of prognosis, early detection and treatment for patients with colon malignancy. The sensitivity and specificity of K-ras determination on stool-derived DNA in patients with colorectal carcinoma, support the opportunity of a large-scale trial to validate its use as a screening test. REMS- PCR is not labor intensive, but a sensitive, rapid, and robust assay for the detection of point mutations, and was introduced by us in a routine diagnostic laboratory.

  8. Zonation of heme synthesis enzymes in mouse liver and their regulation by β-catenin and Ha-ras.

    Science.gov (United States)

    Braeuning, Albert; Schwarz, Michael

    2010-11-01

    Cytochrome P450 (CYP) hemoproteins play an important role in hepatic biotransformation. Recently, β-catenin and Ha-ras signaling have been identified as players controlling transcription of various CYP genes in mouse liver. The aim of the present study was to analyze the role of β-catenin and Ha-ras in the regulation of heme synthesis. Heme synthesis-related gene expression was analyzed in normal liver, in transgenic mice expressing activated β-catenin or Ha-ras, and in hepatomas. Regulation of the aminolevulinate dehydratase promoter was studied in vitro. Elevated expression of mRNAs and proteins involved in heme biosynthesis was linked to β-catenin activation in perivenous hepatocytes, in transgenic hepatocytes, and in hepatocellular tumors. Stimulation of the aminolevulinate dehydratase promoter by β-catenin was independent of the β-catenin/T-cell-specific transcription factor dimer. By contrast, activation of Ha-ras repressed heme synthesis-related gene expression. The present data suggest that β-catenin enhances the expression of both CYPs and heme synthesis-related genes, thus coordinating the availability of CYP apoprotein and its prosthetic group heme. The reciprocal regulation of heme synthesis by β-catenin and Ha-ras-dependent signaling supports our previous hypothesis that antagonistic action of these pathways plays a major role in the control of zonal gene expression in healthy mouse liver and aberrant expression patterns in hepatocellular tumors.

  9. Immunodetection of rasP21 and c-myc oncogenes in oral mucosal swab preparation from clove cigarette smokers

    Directory of Open Access Journals (Sweden)

    Silvi Kintawati

    2008-12-01

    Full Text Available Background: Smoking is the biggest factor for oral cavity malignancy. Some carcinogens found in cigar will stimulate epithel cell in oral cavity and cause mechanism disturbance on tissue resistance and produce abnormal genes (oncogenes. Oncogenes ras and myc are found on malignant tumor in oral cavity which are associated with smoking. Purpose: This research is to find the expression of oncogenes rasP21 and c-myc in oral mucosa epithelial of smoker with immunocytochemistry reaction. Methods: An oral mucosal swab was performed to 30 smokers categorized as light, moderate, and chain, and 10 non smokers which was followed by immunocytochemistry reaction using antibody towards oncogene rasP21 and c-myc is reacted to identify the influence of smoking towards malignant tumor in oral cavity. The result is statistically analyzed using Kruskal-Wallis test. Result: Based on the observation result of oncogene rasP21reaction, it shows that there is significant difference between non smoker group and light smoker, compared to moderate and chain smoker group (p < 0.01. On the other side, the observation result of oncogene c-myc indicates that there is no significant difference between the group of non smokers and the group of light, moderate, and chain smokers (p > 0.05. Conclusion: The higher the possibility of oral cavity malignancy and that the antibody for rasP21 oncogene can be used as a marker for early detection of oral cavity malignancy caused by smoking.

  10. In Silico Screening of Mutated K-Ras Inhibitors from Malaysian Typhonium flagelliforme for Non-Small Cell Lung Cancer

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    Ayesha Fatima

    2014-01-01

    Full Text Available K-ras is an oncogenic GTPase responsible for at least 15–25% of all non-small cell lung cancer cases worldwide. Lung cancer of both types is increasing with an alarming rate due to smoking habits in Malaysia among men and women. Natural products always offer alternate treatment therapies that are safe and effective. Typhonium flagelliforme or Keladi Tikus is a local plant known to possess anticancer properties. The whole extract is considered more potent than individual constituents. Since K-ras is the key protein in lung cancer, our aim was to identify the constituents of the plant that could target the mutated K-ras. Using docking strategies, reported potentially active compounds of Typhonium flagelliforme were docked into the allosteric surface pockets and switch regions of the K-ras protein to identify possible inhibitors. The selected ligands were found to have a high binding affinity for the switch II and the interphase region of the ras-SOS binding surface.

  11. Change in residents' perceptions of teaching: following a one day "Residents as Teachers" (RasT) workshop.

    Science.gov (United States)

    Aiyer, Meenakshy; Woods, Gordon; Lombard, Gwen; Meyer, Lynne; Vanka, Anita

    2008-05-01

    The objective of this study was to assess the perceptions and attitudes of resident physicians toward teaching before and after participation in a mandatory "Residents as Teachers" (RasT) workshop in four domains: (1) setting goals and expectations, (2) use of clinical microskills in teaching, (3) evaluation and feedback, and (4) enthusiasm and preparedness toward teaching. Pre- and postintervention questionnaires were utilized. Data were analyzed for all respondents. Subgroup analyses were performed for each academic year and for primary care versus nonprimary care specialties. Over a 5-year period, 15 RasT workshops were presented to 276 residents from 10 different residency programs. Eighty-six percent completed the questionnaire before participation in the workshop, and 88% completed the questionnaire immediately after participation. The difference between the mean post-RasT and pre-RasT ratings on each item was used to measure the change in that item resulting from participation in the workshop. Overall, residents' self-assessed ratings of their attitudes toward teaching were positively impacted by participation in a RasT workshop. Further subanalysis showed that residents in primary care specialties showed a significantly greater increase in their ratings than residents in nonprimary care specialties.

  12. CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling.

    Science.gov (United States)

    Manara, Maria Cristina; Terracciano, Mario; Mancarella, Caterina; Sciandra, Marika; Guerzoni, Clara; Pasello, Michela; Grilli, Andrea; Zini, Nicoletta; Picci, Piero; Colombo, Mario P; Morrione, Andrea; Scotlandi, Katia

    2016-11-29

    CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles, whose excessive accumulation provokes methuosis. This process, which is not detected in CD99-expressing normal mesenchymal cells, is inhibited by disruption of the IGF-1R signaling, whereas enhanced by IGF-1 stimulation. Induction of IGF-1R/RAS/Rac1 was also observed in the EWS xenografts that respond to anti-CD99 mAb, further supporting the role of the IGF/RAS/Rac1 axis in the hyperstimulation of macropinocytosis and selective death of EWS cells. Thus, we describe a vulnerability of EWS cells, including those resistant to standard chemotherapy, to a treatment with anti-CD99 mAb, which requires IGF-1R/RAS signaling but bypasses the need for their direct targeting. Overall, we propose CD99 targeting as new opportunity to treat EWS patients resistant to canonical apoptosis-inducing agents.

  13. Evaluation of Control and Adjustment Structures of the Shibab Main Canal Using HEC-RAS

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    maryam mohammadi

    2017-02-01

    Full Text Available Introduction: Poor performance of irrigation and drainage networks causes to reduce the transfer and distribution throughputs and in result comes useless water and makes too much consumption in forming. A significant portion of water losses in irrigation and drainage networksis related to transmission and distribution. Therefor more consideration in thrirrigation network management, improve irrigation efficiency and also the exploitation of water resources, especially in the agricultural sector is necessary. Controlling and adjusting structures of water level in the direction of drainage and irrigation canals can influence on increasing of throughput and decrease the use of water. So, right choosing and recognition of the deficiencies of these structures helps carry up the throughput of the networks and prevents to waste water. It is hard to solve equations of water flow in canals and related institutions by using analytic methods. For this reason, this research was done with HEC-RAS hydraulical model in the main channelof irrigation and drainage network of Sistan plain. Materials and Methods: Sistan plain is located in southeastern of Iran with good potential for agricultural production because of the alluvial sediments from Hirmand River. 23820 ha of the Sistan plain is covered by 5 blocksof the Shibab irrigation and drainage network. While Sistan’sShibab irrigation network efficiency is low, HEC-RAS Hydraulics model in unsteady condition was performed to control and adjust this network’s main canal in approximately 19 Km length. In this research, the evaluation model in the canal was performed for more suitable intakingwater in the quadruple order 2 canals . So, the existing structure’s operation was analyzed on controlling structures in management and lack of management situations.This research was assessed during a 15-day impounding period using hydraulic model of HEC-RAS with the aim of performance and operation evaluation of

  14. FluoRAS Sensor - Online organic matter for optimising recirculating aquaculture systems

    DEFF Research Database (Denmark)

    Hambly, Adam; Stedmon, Colin

    2018-01-01

    FluorRAS will develop a sensor that can save recycled fish farms 30% per year in water and energy consumption for water treatment, as well as optimize nitrogen removal. The sensor will be developed in a partnership between engineers (Krüger A / S) and researchers (DTU), and the product will be made...... available to the entire sector through Danish Aquaculture. Global aquaculture production is expected to double within the next 15 years. Recycling technology has a great potential for supporting environmentally and economically sustainable production. However, the technology has some challenges in balancing...

  15. The prognostic value of simultaneous tumor and serum RAS/RAF mutations in localized colon cancer

    DEFF Research Database (Denmark)

    Brenner Thomsen, Caroline Emilie; Appelt, Ane Lindegaard; Andersen, Rikke Fredslund

    2017-01-01

    The impact of RAS/RAF mutations in localized colon cancer needs clarification. Based on analysis of tumor-specific DNA, this study aimed at elucidating the prognostic influence of mutational status in tumor and serum using an extended panel of mutations. The study retrospectively included 294...... patients with curatively resected stage I-III adenocarcinoma of the colon. Mutations in tumor and serum were determined at time of surgery. Analyses were performed with droplet digital PCR technology. Hazard ratio (HR) for the association between mutational status and survival was estimated in multivariate...

  16. Lack of susceptibility of transgenic mice carrying the human c-Ha-ras proto-oncogene (rasH2 mice) to phenolphthalein in a 6-month carcinogenicity study.

    Science.gov (United States)

    Koujitani, T; Yasuhara, K; Usui, T; Nomura, T; Onodera, H; Takagi, H; Hirose, M; Mitsumori, K

    2000-05-01

    Phenolphthalein has carcinogenic activity, causing malignant lymphomas in B6C3F1 mice at a dietary dose of 3000 ppm in a 2-year carcinogenicity study and in heterozygous p53-deficient female mice at the same dose in a 6-month study. To examine whether phenolphthalein carcinogenic potential can be detected in male and female transgenic (Tg) mice carrying the human c-Ha-ras gene (rasH2 mice) and their wild-type littermates (non-Tg mice), a diet containing 3000, 6000 or 12000 ppm was given for 6 months. Unequivocal induction of neoplastic lesions was not apparent, suggesting that rasH2 mice are resistant to the induction of malignant lymphomas by the treatment of phenolphthalein.

  17. The opinion of patients with inflammatory bowel disease on healthcare received Opinión de los pacientes con enfermedad inflamatoria intestinal sobre la atención sanitaria recibida

    Directory of Open Access Journals (Sweden)

    F. Casellas

    2004-03-01

    Full Text Available Backgrounds and aim: an item to consider in analyzing a healthcare model for a population group suffering from chronic disease is necessary health-care resources, their use, and their rating by endusers. Regarding inflammatory bowel disease (IBD, healthcare resources used by patients are numerous and varied, and yet they have been never assessed. Design: an anonymous self-rated questionnaire has been developed with 24 basic questions on overall disease, who is monitoring the patient, how are visits scheduled, need for urgent care, patient view on how control may be improved, etc. This questionnaire was sent to 393 patients who were asked to fill it out and then return it by mail. Results: two hundred and thirty-seven patients returned a filled-out questionnaire. Most patients were followed up in a hospital, and only 8.8% were being monitored by a general practitioner or area specialist. Ninety-two percent of patients reported visits were routinely scheduled irrespective of clinical status, and 79.6% of patients reported having occasionally presented to an emergency department, because of not knowing what to do or due to having no other resources available in 25.2% of times. This entails that 38% of visits to an emergency unit may be prevented with a better understanding of disease or by means of a phone call. Thirty percent of patients reported that current healthcare is inadequate in terms of contents, form, or waiting time. In all, 97.8% of patients feel that information and knowledge on their disease would help in its control, and 69.6% consider that adequate information would allow them to initiate a proper treatment before visiting their doctor. Family care is another poorly lookedafter aspect that 74.6% of subjects believe would be of help in controlling their disease. Conclusions: overall, the opinion of patients with IBD on healthcare received is good; however, a number of deficiencies were detected, as is the case with insufficient

  18. Correlations of IGF-1R and COX-2 Expressions with Ras and BRAF Genetic Mutations, Clinicopathological Features and Prognosis of Colorectal Cancer Patients.

    Science.gov (United States)

    Jin, Mei; Long, Zi-Wen; Yang, Jing; Lin, Xiang

    2018-01-01

    This case-control study aims to investigate the correlations of insulin-like growth factor receptor 1 (IGF-1R) and cyclooxygenase 2 (COX-2) expressions with Ras and BRAF genetic mutations, clinicopathological features and prognosis of colorectal cancer (CRC) patients. A total of 213 CRC patients (case group) and 200 healthy individuals (control group) were selected from our hospital. Ras (K-Ras/N-Ras) and BRAF genetic mutations were detected by direct sequencing. The positive expression rates of IGF-IR and COX-2 in CRC and normal tissues were detected using immunohistochemistry. RT-qPCR and Western blotting were applied to detect the mRNA and protein expressions of IGF-IR and COX-2 in CRC tissues and normal tissues. Total mutation rate of N-Ras, BRAF and K-Ras in case group were 5.2%, 12.2% and 47.4%, respectively. The expressions of IGF-IR and COX-2 were higher in CRC tissues with Ras and BRAF mutations than in those without. CRC tissues with Ras mutation showed higher COX-2 expression than those with BRAF mutation. IGF-IR and COX-2 expressions were correlated to infiltration degree, lymphatic metastasis (in CRC tissues with and without Ras and BRAF mutations), and Dukes stages (only in CRC tissues with Ras and BRAF mutations). CRC patients with negative expressions of IGF-IR and COX-2 had significantly higher accumulative survival rate and longer mean survival duration than those with positive expressions of IGF-IR and COX-2. These findings indicate that IGF-1R and COX-2 expressions may be associated with Ras and BRAF genetic mutations, clinicopathological feature and prognosis of CRC patients.

  19. Neutron Crystal Structure of RAS GTPase Puts in Question the Protonation State of the GTP γ-Phosphate*

    Science.gov (United States)

    Knihtila, Ryan; Holzapfel, Genevieve; Weiss, Kevin; Meilleur, Flora; Mattos, Carla

    2015-01-01

    RAS GTPase is a prototype for nucleotide-binding proteins that function by cycling between GTP and GDP, with hydrogen atoms playing an important role in the GTP hydrolysis mechanism. It is one of the most well studied proteins in the superfamily of small GTPases, which has representatives in a wide range of cellular functions. These proteins share a GTP-binding pocket with highly conserved motifs that promote hydrolysis to GDP. The neutron crystal structure of RAS presented here strongly supports a protonated γ-phosphate at physiological pH. This counters the notion that the phosphate groups of GTP are fully deprotonated at the start of the hydrolysis reaction, which has colored the interpretation of experimental and computational data in studies of the hydrolysis mechanism. The neutron crystal structure presented here puts in question our understanding of the pre-catalytic state associated with the hydrolysis reaction central to the function of RAS and other GTPases. PMID:26515069

  20. Evolution of AF6-RAS association and its implications in mixed-lineage leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Matthew J.; Ottoni, Elizabeth; Ishiyama, Noboru; Goudreault, Marilyn; Haman, André; Meyer, Claus; Tucholska, Monika; Gasmi-Seabrook, Genevieve; Menezes, Serena; Laister, Rob C.; Minden, Mark D.; Marschalek, Rolf; Gingras, Anne-Claude; Hoang, Trang; Ikura, Mitsuhiko

    2017-10-23

    Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved α-helix to bind RAS, unique to AF6 and the classical RASSF effectors. Further, all patients with MLL-AF6 translocations express fusion proteins missing only this helix from AF6, resulting in exposure of hydrophobic residues that induce dimerization. We provide evidence that oligomerization is the dominant mechanism driving oncogenesis from rare MLL translocation partners and employ our mechanistic understanding of MLL-AF6 to examine how dimers induce leukemia. Proteomic data resolve association of dimerized MLL with gene expression modulators, and inhibiting dimerization disrupts formation of these complexes while completely abrogating leukemogenesis in mice. Oncogenic gene translocations are thus selected under pressure from protein structure/function, underscoring the complex nature of chromosomal rearrangements.

  1. Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

    Science.gov (United States)

    Papale, Alessandro; Morella, Ilaria Maria; Indrigo, Marzia Tina; Bernardi, Rick Eugene; Marrone, Livia; Marchisella, Francesca; Brancale, Andrea; Spanagel, Rainer; Brambilla, Riccardo; Fasano, Stefania

    2016-01-01

    Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction. DOI: http://dx.doi.org/10.7554/eLife.17111.001 PMID:27557444

  2. The Drosophila secreted protein Argos regulates signal transduction in the Ras/MAPK pathway.

    Science.gov (United States)

    Sawamoto, K; Okabe, M; Tanimura, T; Mikoshiba, K; Nishida, Y; Okano, H

    1996-08-25

    The Drosophila argos gene encodes a secreted protein with an EGF motif which acts as an inhibitor of cellular differentiation in multiple developmental processes. To investigate the cellular pathways regulated by Argos, we screened for mutations which could modify the phenotype caused by overexpression of argos. We show that the effects of argos overexpression on the eye and wing vein development are suppressed by gain-of-function mutations of the MAPKK/D-MEK gene (Dsor1/D-mek) and the MAPK/ERK-A gene (rolled) and were enhanced by loss-of-function mutations of Star. Loss-of-function mutations in components of the Ras/MAPK signaling cascade act as dominant suppressors of the phenotype caused by the argos null mutations. A loss-of-function argos mutation enhanced the overproduction of R7 neurons caused by gain-of-function alleles of Son of sevenless and Dsor1. Conversely, overexpression of argos inhibited formation of the extra R7 cells that was caused by high-level MAPK/ERK-A activity. A phenotype of the sev; argos double mutants revealed that sev is epistatic to argos. These results provide evidence that Argos negatively regulates signal transduction events in the Ras/MAPK cascade.

  3. Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1

    Directory of Open Access Journals (Sweden)

    Hirotada Tajiri

    2017-05-01

    Full Text Available Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells. By screening chemical libraries, we have identified 1-(2-(3′-(trifluoromethyl-[1,1′-biphenyl]-4-yl-2-oxoethyl-5-pyrrolidinylsulfonyl-2(1H-pyridone (TBOPP as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion.

  4. Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors.

    Science.gov (United States)

    Papale, Alessandro; Morella, Ilaria Maria; Indrigo, Marzia Tina; Bernardi, Rick Eugene; Marrone, Livia; Marchisella, Francesca; Brancale, Andrea; Spanagel, Rainer; Brambilla, Riccardo; Fasano, Stefania

    2016-08-24

    Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction.

  5. Ķīnas tējas kultūras vēsture

    OpenAIRE

    Skvorcova, Olga

    2009-01-01

    Bakalaura darba mērķis ir pastāstīt par tējas kultūras attīstību Ķīnā.Darbs ietver četras nodaļas,kuras ir veltītas tējas vēsturei;tējas apstrādei un pagatavošanai;tradicionālo Ķīnas tējas trauku veidošanas vēsturei;Ķīnas tējas tradīcijām kopumā. Savācot informāciju par tējas kultūras vēsturi Ķīnā, var izdalīt trīs galvenos etapus tās attīstībā. Tā ir: mistiska imperatora Šeņ Nuna, kurš atklāja tējas lietderīgās īpašības, tējas atklāšana; tējas attīstība Tan dinastijas laikos, kad tēja kļu...

  6. Black Rice Anthocyanins Suppress Metastasis of Breast Cancer Cells by Targeting RAS/RAF/MAPK Pathway.

    Science.gov (United States)

    Chen, Xiang-Yan; Zhou, Jie; Luo, Li-Ping; Han, Bin; Li, Fei; Chen, Jing-Yao; Zhu, Yan-Feng; Chen, Wei; Yu, Xiao-Ping

    2015-01-01

    Overexpression of human epidermal growth factor receptor 2 (HER2) drives the biology of 30% of breast cancer cases. As a transducer of HER2 signaling, RAS/RAF/MAPK pathway plays a pivotal role in the development of breast cancer. In this study, we examined the molecular mechanisms underlying the chemopreventive effects of black rice anthocyanins (BRACs) extract and identified their molecular targets in HER2(+) breast cancer cells. Treatment of MDA-MB-453 cells (HER2(+)) with BRACs inhibited cell migration and invasion, suppressed the activation of mitogen-activated protein kinase kinase kinase (RAF), mitogen-activated protein kinase kinase (MEK), and c-Jun N-terminal kinase (JNK), and downregulated the secretion of matrix metalloproteinase 2 (MMP2) and MMP9. BRACs also weakened the interactions of HER2 with RAF, MEK, and JNK proteins, respectively, and decreased the mRNA expression of raf, mek, and jnk. Further, we found combined treatment with BRACs and RAF, MEK, or JNK inhibitors could enhance the antimetastatic activity, compared with that of each treatment. Transient transfection with small interfering RNAs (siRNAs) specific for raf, mek, and jnk inhibited their mRNA expression in MDA-MB-453 cells. Moreover, cotreatment with BRACs and siRNA induces a more remarkable inhibitory effect than that by either substance alone. In summary, our study suggested that BRACs suppress metastasis in breast cancer cells by targeting the RAS/RAF/MAPK pathway.

  7. Estimating design flood and HEC-RAS modelling approach for flood analysis in Bojonegoro city

    Science.gov (United States)

    Prastica, R. M. S.; Maitri, C.; Hermawan, A.; Nugroho, P. C.; Sutjiningsih, D.; Anggraheni, E.

    2018-03-01

    Bojonegoro faces flood every year with less advanced prevention development. Bojonegoro city development could not peak because the flood results material losses. It affects every sectors in Bojonegoro: education, politics, economy, social, and infrastructure development. This research aims to analyse and to ensure that river capacity has high probability to be the main factor of flood in Bojonegoro. Flood discharge analysis uses Nakayasu synthetic unit hydrograph for period of 5 years, 10 years, 25 years, 50 years, and 100 years. They would be compared to the water maximum capacity that could be loaded by downstream part of Bengawan Solo River in Bojonegoro. According to analysis result, Bengawan Solo River in Bojonegoro could not able to load flood discharges. Another method used is HEC-RAS analysis. The conclusion that shown by HEC-RAS analysis has the same view. It could be observed that flood water loading is more than full bank capacity elevation in the river. To conclude, the main factor that should be noticed by government to solve flood problem is river capacity.

  8. Development of Inundation Map for Hypothetical Asa Dam Break using HEC-RAS and ARC GIS

    Directory of Open Access Journals (Sweden)

    O. S. Balogun

    2017-12-01

    Full Text Available Asa Dam in Ilorin, Nigeria was constructed in the1980s. The dam made of earth material has a length of 507 meters and height of 27 meters. The maximum capacity of the impoundment during the raining season is approximately 43 x 106 m3. Years after construction, tremendous physical development is taking place along the river channel starting from the dam axis towards downstream for a distance of approximately 12 km. It is estimated that several thousands of people are currently living and performing various activities within the vicinity of the river channel. It is therefore necessary to evaluate the risk involved in case of a possible dam break disaster. In view of this, a hypothetical dam break scenario was studied and analyzed using Hydrologic Engineering Center’s River Analysis System computer model. Unsteady flow simulation was performed using geometric data obtained from Digital Terrain Model with 100-year, 24 hr flow event. The HEC-RAS was used in concert with HEC-GeoRAS to assess the flood hazard along the approximately 12 km river channel. The simulated water surface elevations were exported to Arc GIS to produce an inundation map that graphically indicates the extent of the flood hazard. The results show that some important locations such as industrial, residential, motor parks, recreational and places of worship along the river length are prone to significant flood impact. This map serves as an input for emergency preparation programme in the event of the dam break.

  9. Reversal of the Migratory and Invasive Phenotype of Ras-Transfected Mammary Cells by Photodynamic Therapy Treatment.

    Science.gov (United States)

    Calvo, Gustavo; Sáenz, Daniel; Simian, Marina; Sampayo, Rocío; Mamone, Leandro; Vallecorsa, Pablo; Batlle, Alcira; Casas, Adriana; Di Venosa, Gabriela

    2017-03-01

    Photodynamic therapy (PDT) is a non-thermal technique for inducing tumor damage following administration of a light-activated photosensitizing drug (PS). In a previous work we found that PDT induces cytoskeleton changes in HB4a-Ras cells (human mammary breast carcinoma HB4a cells transfected with the RAS oncogene). In the present work we have studied the migratory and invasive features and the expression of proteins related to these processes on HB4a-Ras cells after three successive cycles of PDT using different PSs: 5-aminolevulinic acid (ALA), Verteporfin (Verte), m-tetrahydroxyphenylchlorin (m-THPC), and Merocyanine 540 (MC). A slight (1.25- to 2-fold) degree of resistance was acquired in cell populations subjected to the three successive PDT treatments. However, complete cell killing was achieved after a light dose increase. Regardless of the PS employed, all the PDT-treated populations had shorter stress fibres than the untreated control HB4a-Ras cells, and the number of dorsal stress fibres was decreased in the PDT-treated populations. E-Cadherin distribution, which was already aberrant in HB4a-Ras cells, became even more diffuse in the PDT-treated populations, though its expression was increased in some of them. The strong migratory and invasive ability of HB4a-Ras cells in vitro was impaired in all the PDT-treated populations, with a behavior that was similar to the parental non-tumoral HB4a cells. MMP-2 and -9 metalloproteinase activities were also impaired in the PDT-treated populations. The evidence presented herein suggests that the cells surviving PDT would be less metastatic than the initial population. These findings encourage the use of PDT in combination with other treatments such as intraoperative or post-surgery therapeutic procedures. J. Cell. Biochem. 118: 464-477, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. Mitochondrial STAT3 contributes to transformation of Barrett's epithelial cells that express oncogenic Ras in a p53-independent fashion.

    Science.gov (United States)

    Yu, Chunhua; Huo, Xiaofang; Agoston, Agoston T; Zhang, Xi; Theiss, Arianne L; Cheng, Edaire; Zhang, Qiuyang; Zaika, Alexander; Pham, Thai H; Wang, David H; Lobie, Peter E; Odze, Robert D; Spechler, Stuart J; Souza, Rhonda F

    2015-08-01

    Metaplastic epithelial cells of Barrett's esophagus transformed by the combination of p53-knockdown and oncogenic Ras expression are known to activate signal transducer and activator of transcription 3 (STAT3). When phosphorylated at tyrosine 705 (Tyr705), STAT3 functions as a nuclear transcription factor that can contribute to oncogenesis. STAT3 phosphorylated at serine 727 (Ser727) localizes in mitochondria, but little is known about mitochondrial STAT3's contribution to carcinogenesis in Barrett's esophagus, which is the focus of this study. We introduced a constitutively active variant of human STAT3 (STAT3CA) into the following: 1) non-neoplastic Barrett's (BAR-T) cells; 2) BAR-T cells with p53 knockdown; and 3) BAR-T cells that express oncogenic H-Ras(G12V). STAT3CA transformed only the H-Ras(G12V)-expressing BAR-T cells (evidenced by loss of contact inhibition, formation of colonies in soft agar, and generation of tumors in immunodeficient mice), and did so in a p53-independent fashion. The transformed cells had elevated levels of both mitochondrial (Ser727) and nuclear (Tyr705) phospho-STAT3. Introduction of a STAT3CA construct with a mutated tyrosine phosphorylation site into H-Ras(G12V)-expressing Barrett's cells resulted in high levels of mitochondrial phospho-STAT3 (Ser727) with little or no nuclear phospho-STAT3 (Tyr705), and the cells still formed tumors in immunodeficient mice. Thus tyrosine phosphorylation of STAT3 is not required for tumor formation in Ras-expressing Barrett's cells. We conclude that mitochondrial STAT3 (Ser727) can contribute to oncogenesis in Barrett's cells that express oncogenic Ras. These findings suggest that agents targeting STAT3 might be useful for chemoprevention in patients with Barrett's esophagus. Copyright © 2015 the American Physiological Society.

  11. GNSS Software Receiver for UAVs

    DEFF Research Database (Denmark)

    Olesen, Daniel Madelung; Jakobsen, Jakob; von Benzon, Hans-Henrik

    2016-01-01

    This paper describes the current activities of GPS/GNSS Software receiver development at DTU Space. GNSS Software receivers have received a great deal of attention in the last two decades and numerous implementations have already been presented. DTU Space has just recently started development of ...... of our own GNSS software-receiver targeted for mini UAV applications, and we will in in this paper present our current progress and briefly discuss the benefits of Software Receivers in relation to our research interests.......This paper describes the current activities of GPS/GNSS Software receiver development at DTU Space. GNSS Software receivers have received a great deal of attention in the last two decades and numerous implementations have already been presented. DTU Space has just recently started development...

  12. Influence of the H-ras oncogene on radiation responses of a rat rhabdomyosarcoma cell line.

    Science.gov (United States)

    Hermens, A F; Bentvelzen, P A

    1992-06-01

    Rat R2k rhabdomyosarcoma cells were transfected with the human H-ras oncogene, which resulted in increased resistance to cell kill in vitro by a single dose of 137Cs gamma-rays. A subline carrying one oncogene showed an increase in the quasi-threshold dose (Dq) from 0.88 to 1.48 Gy. Another subline containing six oncogenes not only had an increased Dq of 1.59 Gy but also showed an increase in the dose reducing cell survival to a fraction of e-1 = 0.37 (D0) from 1.25 to 1.76 Gy. Analysis of the cell survival data according to the linear-quadratic formalism indicated that a decrease in the value of the coefficient of the linear component alpha is associated with a H-ras-mediated increase in radioresistance. In fractionated irradiation experiments it was observed that with a dose of 1 Gy/fraction a 1.8 times higher dose for an isoeffect of 10% cell survival (D10) was needed for a subline with one H-ras oncogene, while with fraction doses of 2 or 4 Gy only a 1.2 times higher D10 was found. This indicates a more efficient repair of radiation-induced damage in the transfected subline. Tumors arising in the rat gastrocnemius muscle inoculated with cultured cells were irradiated with different doses of 300-kV X-rays. A single dose of 45 Gy was found to result in a 6% cure rate for the subline containing one H-ras oncogene and a 32% for the parental line. When a priming dose of 45 Gy was followed by fractionated irradiation with 1 Gy/fraction, an extra dose of 51 Gy would be needed to obtain a 75% cure rate for the transfected subline. An extra dose of only 10 Gy would be needed for the parental line. The percentage cure per unit of dose for the parental line irradiated with 1 Gy/fraction was estimated to be 4.3%.Gy-1, whereas for the transfected tumor line it was 1.4%.Gy-1. This means that a 3.0 times higher cumulated absorbed dose would be needed for enhancing the cure rate from 32% to 75% in the subline with H-ras than for the parental line. With 2 Gy/fraction the

  13. Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group

    NARCIS (Netherlands)

    Dubé, M. P.; Sprecher, D.; Henry, W. K.; Aberg, J. A.; Torriani, F. J.; Hodis, H. N.; Schouten, J. [=Judith; Levin, J.; Myers, G.; Zackin, R.; Nevin, T.; Currier, J. S.

    2000-01-01

    Dyslipidemia is a prevalent condition that affects patients infected with human immunodeficiency virus (HIV) who are receiving antiretroviral therapy, These preliminary recommendations summarize the curr