YAF2 promotes TP53-mediated genotoxic stress response via stabilization of PDCD5

AbstractProgrammed cell death 5 (PDCD5) plays a crucial role in TP53-mediated apoptosis, but the regulatory mechanism of PDCD5 itself during apoptosis remains obscure. We identified YY1-associated factor 2 (YAF2) as a novel PDCD5-interacting protein in a yeast two-hybrid screen for PDCD5-interacting proteins. We found that YY1-associated factor 2 (YAF2) binds to and increases PDCD5 stability by inhibiting the ubiquitin-dependent proteosomal degradation pathway. However, knocking-down of YAF2 diminishes the levels of PDCD5 protein but not the levels of PDCD5 mRNA. Upon genotoxic stress response, YAF2 promotes TP53 activation via association with PDCD5. Strikingly, YAF2 failed to promote TP53 activation in the deletion of PDCD5, whereas restoration of wild-type PDCD5WT efficiently reversed the ineffectiveness of YAF2 on TP53 activation. Conversely, PDCD5 efficiently overcame the knockdown effect of YAF2 on ET-induced TP53 activation. Finally, impaired apoptosis upon PDCD5 ablation was substantially rescued by restoration of PDCD5WT but not YAF2-interacting defective PDCD5E4D nor TP53-interacting defective PDCD5E16D mutant. Our findings uncovered an apoptotic signaling cascade linking YAF2, PDCD5, and TP53 during genotoxic stress responses

Management of viral hepatitis in liver transplant recipients

Recurrence of viral hepatitis after liver transplantation (LT) can progress to graft failure and lead to a decrease in long-term survival. Recently, there have been remarkable improvement in the treatment of chronic hepatitis B (CHB) using potent antiviral agents. Combination of hepatitis B immunoglobulin and potent antiviral therapy has brought marked advances in the management of CHB for liver transplant recipients. Post-transplant antiviral therapy for hepatitis C virus infection is generally reserved for patients showing progressive disease. Acheiving a sustained virological response in patients with LT greatly ameliorates graft and overall survival, however this only occurs in 30% of transplant recipient using pegylated interferon and ribavirin (RBV). Direct acting antivirals such as protease inhibitors, polymerase or other non-structural proteins inhibitors are anticipated to establish the new standard of care for transplant recipients. In liver transplant recipients, hepatitis E virus infection is an uncommon disease. However, it can lead to chronic hepatitis and cirrhosis and may require retransplantation. Recently, 3-month course of RBV monotherapy has been reported as an effective treatment. This review focuses on the recent management and therapeutic approaches of viral hepatitis in liver transplant recipient

The role of phosphodiesterase 3 in endotoxin-induced acute kidney injury

Background: Acute kidney injury frequently accompanies sepsis. Endotoxin is known to reduce tissue levels of cAMP and low levels of cAMP have been associated with renal injury. We, therefore, hypothesized that endotoxin induced renal injury by activating phosphodiesterase 3 (PDE3) which metabolizes cAMP and that amrinone an inhibitor of PDE3 would prevent the renal injury. Methods: Animals were divided into three groups (n = 7/group): 1) Control (0.9% NaCl infusion without LPS); 2) LPS (0.9% NaCl infusion with LPS); 3) Amrinone+LPS (Amrinone infusion with LPS). Either lipopolysaccharide (LPS) or vehicle was injected via the jugular vein and the rats followed for 3 hours. We explored the expression of PDE3 isoenzymes and the concentrations of cAMP in the tissue. Results: The PDE3B gene but not PDE3A was upregulated in the kidney of LPS group. Immunohistochemistry also showed that PDE3B was expressed in the distal tubule in the controls and LPS caused PDE3B expression in the proximal as well. However, PDE3A was not expressed in the kidney either in the control or LPS treated groups. Tissue level of cAMP was decreased after LPS and was associated with an increase in blood urea nitrogen, creatinine, ultrastructural proximal tubular changes, and expression of inducible nitric oxide synthase (iNOS) in the endotoxemic kidney. In septic animals the phosphodiesterase 3 inhibitor, amrinone, preserved the tissue cAMP level, renal structural changes, and attenuated the increased blood urea nitrogen, creatinine, and iNOS expression in the kidney. Conclusion: These findings suggest a significant role for PDE3B as an important mediator of LPS-induced acute kidney injury

Monovacancy-induced magnetism in graphene bilayers

Vacancy-induced magnetism in graphene bilayers is investigated using spin-polarized density functional theory calculations. One of two graphene layers has a monovacancy. Two atomic configurations for bilayers are considered with respect to the position of the monovacancy. We find that spin magnetic moments localized at the vacancy site decreases by ~10 % for our two configurations, compared with the graphene monolayer with a monovacancy. The reduction of the spin magnetic moment in the graphene bilayers is attributed to the interlayer charge transfer from the adjacent layer to the layer with the monovacancy, compensating for spin magnetic moments originating from quasilocalized defect state.Comment: 14 pages, 1 table and 4 figure

Prevalence of sarcopenia and sarcopenic obesity in Korean adults: The Korean Sarcopenic Obesity Study (KSOS)

*Context:* Sarcopenic obesity (SO), a combination of excess weight and reduced muscle mass and/or strength, is suggested to be associated with an increased risk of adverse health outcomes. 
*Objectives:* To examine the prevalence and characteristics of Sarcopenic and SO defined by using different indices such as Appendicular Skeletal muscle Mass (ASM)/height^2^ and Skeletal Muscle Index (SMI (%): skeletal muscle mass (kg)/weight (kg) × 100) for Korean adults. 
*Methods:* 591 participants were recruited from the Korean Sarcopenic Obesity Study (KSOS) which is an ongoing prospective observational cohort study. Analysis was conducted in 526 participants (328 women, 198 men) who had complete data on body composition using Dual X-ray absorptiometry and computed tomography. 
*Results:* The prevalence of sarcopenia and SO increases with aging. Using two or more standard deviations (SD) of ASM/height^2^ below reference values from young, healthy adults as a definition of sarcopenia, the prevalence of sarcopenia and SO was 6.3% and 1.3% in men and 4.1% and 1.7% in women over 60 years of age. However, using two or more SD of SMI, the prevalence of sarcopenia and SO was 5.1% and 5.1% respectively in men and 14.2% and 12.5% respectively in women. As defined by SMI, subjects with SO had 3 times the risk of metabolic syndrome (OR = 3.03, 95% confidence interval (CI) = 1.26-7.26) and subjects with non-sarcopenic obesity had approximately 2 times the risk of metabolic syndrome (OR = 1.89, 95% CI = 1.18-3.02) compared with normal subjects. 
*Conclusion:* Obese subjects with relative sarcopenia were associated with a greater likelihood for metabolic syndrome. As Koreans were more obese and aging, the prevalence of SO and its impact on health outcomes are estimated to be rapidly grow. Further research is requested to establish the definition, cause and consequences of SO.
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Helical tomotherapy with concurrent capecitabine for the treatment of inoperable pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>Helical tomotherapy, an advanced intensity-modulated radiation therapy with integrated CT imaging, permits highly conformal irradiation with sparing of normal tissue. Capecitabine, a pro-drug of 5-FU that induces thymidine phosphorylase can achieve higher levels of intracellular 5-FU when administered concurrently with radiation. We evaluated the feasibility as well as the clinical outcome of concurrent administration of capecitabine with tomotherapy in patients with advanced pancreatic cancer.</p> <p>Methods</p> <p>Nineteen patients with advanced pancreatic cancer including primarily unresectable disease and recurrence after curative surgery were included in the study. Two planning target volumes (PTV) were entered: PTV1 is gross tumor volume; and PTV2, the volume of the draining lymph nodes. The total doses to target 1 and target 2 were 55 and 50 Gy, respectively. Capecitabine at 1600 mg/m²/day was administered on each day of irradiation.</p> <p>Results</p> <p>Twenty six measurable lesions were evaluated. Overall in-field response rate was 42.3%; partial responses were achieved in 53.3% of the pancreatic masses, 28.6% of distant metastatic lesions and 25.0% of regional lymph nodes. The median duration of follow-up after tomotherapy was 6.5 months. None of the lesions showed in-field progression. Treatment was well tolerated with only minor toxicities such as grade 1 nausea (one patient), grade 1 hand-foot syndrome (one patient) and grade 1/2 fatigue (three patients).</p> <p>Conclusions</p> <p>Helical tomotherapy with concurrent capecitabine is a feasible option without significant toxicities in patients with advanced pancreatic cancer. We achieved excellent conformal distribution of radiation doses and minimal treatment-related toxicities with promising target volume responses.</p

Atelectasis Induced by Thoracotomy Causes Lung Injury during Mechanical Ventilation in Endotoxemic Rats

Atelectasis can impair arterial oxygenation and decrease lung compliance. However, the effects of atelectasis on endotoxemic lungs during ventilation have not been well studied. We hypothesized that ventilation at low volumes below functional residual capacity (FRC) would accentuate lung injury in lipopolysaccharide (LPS)-pretreated rats. LPS-pretreated rats were ventilated with room air at 85 breaths/min for 2 hr at a tidal volume of 10 mL/kg with or without thoracotomy. Positive end-expiratory pressure (PEEP) was applied to restore FRC in the thoracotomy group. While LPS or thoracotomy alone did not cause significant injury, the combination of endotoxemia and thoracotomy caused significant hypoxemia and hypercapnia. The injury was observed along with a marked accumulation of inflammatory cells in the interstitium of the lungs, predominantly comprising neutrophils and mononuclear cells. Immunohistochemistry showed increased inducible nitric oxide synthase (iNOS) expression in mononuclear cells accumulated in the interstitium in the injury group. Pretreatment with PEEP or an iNOS inhibitor (1400 W) attenuated hypoxemia, hypercapnia, and the accumulation of inflammatory cells in the lung. In conclusion, the data suggest that atelectasis induced by thoracotomy causes lung injury during mechanical ventilation in endotoxemic rats through iNOS expression