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The p53 status can influence the role of Sam68 in tumorigenesis. - Oncotarget
The expression and activities of RNA binding proteins are frequently dysregulated in human cancer. Their roles, however, appears to be complex, with reports indicating both pro-tumorigenic and tumor suppressive functions. Here we show, using two classical mouse cancer models, that the role of KH-type RNA binding protein, Sam68, in tumor development can be influenced by the status of the p53 tumor suppressor. We demonstrate that in mice expressing wild type p53, Sam68-deficiency resulted in a higher incidence and malignancy of carcinogen-induced tumors, suggesting a tumor suppressive role for Sam68. In marked contrast, Sam68-haploinsufficiency significantly delayed the onset of tumors in mice lacking p53 and prolonged their survival, indicating that Sam68 accelerates the development of p53-deficient tumors. These findings provide considerable insight into a previously unknown relationship between Sam68 and the p53 tumor suppressor in tumorigenesis.
Chronological, geographical, and seasonal trends of human cases of avian influenza A (H5N1) in Vietnam, 2003-2014: a spatial analysis. - BMC infectious diseases
Human cases of highly pathogenic avian influenza A (H5N1) virus infection continue to occur in Southeast Asia. The objective of this study was to identify when and where human H5N1 cases have occurred in Vietnam and how the situation has changed from the beginning of the H5N1 outbreaks in 2003 through 2014, to assist with implementing methods of targeted disease management.We assessed the disease clustering and seasonal variation of human H5N1 cases in Vietnam to evaluate the geographical and monthly timing trends. The clustering of H5N1 cases and associated mortality were examined over three time periods: the outbreak period (2003-2005), the post-outbreak (2006-2009), and the recent period (2010-2014) using the flexibly shaped space-time scan statistic. The most likely cases to co-cluster and the elevated risks for incidence and mortality were assessed via calculation of the relative risk (RR). The H5N1 case seasonal variation was analysed as the cyclic trend in incidence data using Roger's statistical test.Between 2003 and 2005, H5N1 cases (RR: 2.15, p = 0.001) and mortality (RR: 2.49, p = 0.021) were significantly clustered in northern Vietnam. After 2010, H5N1 cases tended to occur on the border with Cambodia in the south, while H5N1 mortality clustered significantly in the Mekong delta area (RR: 6.62, p = 0.002). A significant seasonal variation was observed (p < 0.001), with a higher incidence of morbidity in December through April.These findings indicate that clinical preparedness for H5N1 in Vietnam needs to be strengthened in southern Vietnam in December-April.
The efficacy and nephrotoxicity associated with colistin use in an intensive care unit in Vietnam: Use of colistin in a population of lower body weight. - International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
There has been a growing need for colistin as a key drug for the treatment of MDR-GNB infection. Information on colistin use in Asian population is limited.A retrospective observational study was conducted to assess the efficacy and nephrotoxicity in critically ill adult patients who received intravenous colistin for MDR-GNB infection in the intensive care unit (ICU) at Bach Mai Hospital in Hanoi, Vietnam. Colistin was administered according to the dosing guideline that was based on pharmacokinetic, pharmacodynamic and toxicodynamic principles, adjusted by body weight and creatinine clearance.Twenty-eight eligible patients were included. The mean patient age was 60Â±20.4 years. The mean body weight was 53Â±8.6kg. The mean daily dose of colistin was 4.1Â±1.6 MIU, and the mean cumulative dose of colistin was 48.2Â±22.8 MIU. Colistin therapies were classified as clinically effective in 19 (67.9%) cases. Six (21.4%) patients developed nephrotoxicity during the study period according to RIFLE criteria.A personalized dosing protocol of colistin was effective, with low nephrotoxicity, among critically ill Vietnamese patients with low body weight. Further studies are warranted for assessing the efficacy and toxicity in a larger cohort.Copyright Â© 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
Lung cancer staging now and in the future. - Respirology (Carlton, Vic.)
For a long time lung cancer was associated with a fatalistic approach by healthcare professionals. In recent years, advances in imaging, improved diagnostic techniques and more effective treatment modalities are reasons for optimism. Accurate lung cancer staging is vitally important because treatment options and prognosis differ significantly by stage. The staging algorithm should include a contrast computed tomography (CT) of the chest and the upper abdomen including adrenals, positron emission tomography/CT for staging the mediastinum and to rule out extrathoracic metastasis in patients considered for surgical resection, endosonography-guided needle sampling procedure replacing mediastinoscopy for near complete mediastinal staging, and brain imaging as clinically indicated. Applicability of evidence-based guidelines for staging of lung cancer depends on the available expertise and level of resources and is directly impacted by financial issues. Considering the diversity of healthcare infrastructure and economic performance of Asian countries, optimal and cost-effective use of staging methods appropriate to the available resources is prudent. The pulmonologist plays a central role in the multidisciplinary approach to lung cancer diagnosis, staging and management. Regional respiratory societies such as the Asian Pacific Society of Respirology should work with national respiratory societies to strive for uniform standards of care. For developing countries, a minimum set of care standards should be formulated. Cost-effective delivery of optimal care for lung cancer patients, including staging within the various healthcare systems, should be encouraged and most importantly, tobacco control implementation should receive an absolute priority status in all countries in Asia.Â© 2015 Asian Pacific Society of Respirology.
Clinical preparedness for severe pneumonia with highly pathogenic avian influenza A (H5N1): experiences with cases in Vietnam. - Respiratory investigation
Avian influenza A (H5N1) in human presents a global pandemic threat, and preparedness is urgently required in high-risk countries.A retrospective chart review was conducted on 8 patients with H5N1 infection (aged 2-30 years; 3 fatal) who were hospitalized in Bach Mai Hospital (BMH), Vietnam, or in affiliated hospitals with consultation by physicians in BMH between 2007 and 2010. Demographic background, chest radiographs, and clinical and laboratory data were evaluated to determine the critical issues in relation to clinical outcomes. Treatment of 4 patients with acute respiratory distress syndrome (ARDS) (2 fatal) was assessed for renal replacement therapy using continuous hemodiafiltration (CHDF), polymyxin B-immobilized (PMX) hemoperfusion, or their combination.Patients had direct contact with dead/sick poultry infected with H5N1 virus or lived in areas where H5N1 poultry outbreaks had been reported at the same time as their illness. Time to initiation of oseltamivir from symptom onset was 2-6 days for survivors and 7-9 days for non-survivors. All patients except one had infiltrative shadows on chest radiographs on admission. Patients with delayed treatment developed ARDS. Renal replacement therapy contributed to patient survival, with improvement of oxygenation and a dramatic decrease in serum cytokine levels if initiated earlier.Understanding local H5N1 poultry outbreaks and chest radiography assist early diagnosis and initiation of antiviral treatment. Developing a network among local and tertiary care hospitals can reduce the time to initiation of treatment. CHDF and PMX hemoperfusion are possible candidates for effective treatment of ARDS with H5N1 if applied earlier.Copyright Â© 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
The Sam68 STAR RNA-binding protein regulates mTOR alternative splicing during adipogenesis. - Molecular cell
We report that mice ablated for the Sam68 RNA-binding protein exhibit a lean phenotype as a result of increased energy expenditure, decreased commitment to early adipocyte progenitors, and defects in adipogenic differentiation. The Sam68(-/-) mice were protected from obesity, insulin resistance, and glucose intolerance induced with a high-fat diet. To identify the alternative splice events regulated by Sam68, genome-wide exon usage profiling in white adipose tissue was performed. Adipocytes from Sam68(-/-) mice retained intron 5 within the mTOR transcript introducing a premature termination codon, leading to an unstable mRNA. Consequently, Sam68-depleted cells had reduced mTOR levels resulting in lower levels of insulin-stimulated S6 and Akt phosphorylation leading to defects in adipogenesis, and this defect was rescued by the exogenous expression of full-length mTOR. Sam68 bound intronic splice elements within mTOR intron 5 required for the usage of the 5' splice site. We propose that Sam68 regulates alternative splicing during adipogenesis.Copyright Â© 2012 Elsevier Inc. All rights reserved.
Selective laser melting: a unit cell approach for the manufacture of porous, titanium, bone in-growth constructs, suitable for orthopedic applications. II. Randomized structures. - Journal of biomedical materials research. Part B, Applied biomaterials
In this study, the unit cell approach, which has previously been demonstrated as a method of manufacturing porous components suitable for use as orthopedic implants, has been further developed to include randomized structures. These random structures may aid the bone in-growth process because of their similarity in appearance to trabecular bone and are shown to carry legacy properties that can be related back to the original unit cell on which they are ultimately based. In addition to this, it has been shown that randomization improves the mechanical properties of regular unit cell structures, resulting in anticipated improvements to both implant functionality and longevity. The study also evaluates the effect that a post process sinter cycle has on the components, outlines the improved mechanical properties that are attainable, and also the changes in both the macro and microstructure that occur.(c) 2009 Wiley Periodicals, Inc.
Clinical features of human influenza A (H5N1) infection in Vietnam: 2004-2006. - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
The first cases of avian influenza A (H5N1) in humans in Vietnam were detected in early 2004, and Vietnam has reported the second highest number of cases globally.We obtained retrospective clinical data through review of medical records for laboratory confirmed cases of influenza A (H5N1) infection diagnosed in Vietnam from January 2004 through December 2006. Standard data was abstracted regarding clinical and laboratory features, treatment, and outcome.Data were obtained for 67 (72%) of 93 cases diagnosed in Vietnam over the study period. Patients presented to the hospital after a median duration of illness of 6 days with fever (75%), cough (89%), and dyspnea (81%). Diarrhea and mucosal bleeding at presentation were more common in fatal than in nonfatal cases. Common findings were bilateral pulmonary infiltrates on chest radiograph (72%), lymphopenia (73%), and increased serum transaminase levels (aspartate aminotransferase, 69%; alanine aminotransferase, 61%). Twenty-six patients died (case fatality rate, 39%; 95% confidence interval, 27%-51%) and the most reliable predictor of a fatal outcome was the presence of both neutropenia and raised alanine aminotransferase level at admission, which correctly predicted 91% of deaths and 82% of survivals. The risk of death was higher among persons aged < or =16 years, compared with older persons (P < .001), and the risk of death was higher among patients who did not receive oseltamivir treatment (P = .048). The benefit of oseltamivir treatment remained after controlling for potential confounding by 1 measure of severity (odds ratio, 0.15; 95% confidence interval, 0.026-0.893; P = .034).In cases of infection with Influenza A (H5N1), the presence of both neutropenia and raised serum transaminase levels predicts a poor outcome. Oseltamivir treatment shows benefit, but treatment with corticosteroids is associated with an increased risk of death.
Oseltamivir is adequately absorbed following nasogastric administration to adult patients with severe H5N1 influenza. - PloS one
In the absence of a parenteral drug, oral oseltamivir is currently recommended by the WHO for treating H5N1 influenza. Whether oseltamivir absorption is adequate in severe influenza is unknown. We measured the steady state, plasma concentrations of nasogastrically administered oseltamivir 150 mg bid and its active metabolite, oseltamivir carboxylate (OC), in three, mechanically ventilated patients with severe H5N1 (male, 30 yrs; pregnant female, 22 yrs) and severe H3N2 (female, 76 yrs). Treatments were started 6, 7 and 8 days after illness onset, respectively. Both females were sampled while on continuous venovenous haemofiltration. Admission and follow up specimens (trachea, nose, throat, rectum, blood) were tested for RNA viral load by reverse transcriptase PCR. In vitro virus susceptibility to OC was measured by a neuraminidase inhibition assay. Admission creatinine clearances were 66 (male, H5N1), 82 (female, H5N1) and 6 (H3N2) ml/min. Corresponding AUC(0-12) values (5932, 10,951 and 34,670 ng.h/ml) and trough OC concentrations (376, 575 and 2730 ng/ml) were higher than previously reported in healthy volunteers; the latter exceeded 545 to 3956 fold the H5N1 IC(50) (0.69 ng/ml) isolated from the H5N1 infected female. Two patients with follow-up respiratory specimens cleared their viruses after 5 (H5N1 male) and 5 (H3N2 female) days of oseltamivir. Both female patients died of respiratory failure; the male survived. 150 mg bid of oseltamivir was well absorbed and converted extensively to OC. Virus was cleared in two patients but two patients died, suggesting viral efficacy but poor clinical efficacy.
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