Topoisomerase II is regulated by translationally controlled tumor protein for cell survival during organ growth in Drosophila.

Regulation of cell survival is critical for organ development. Translationally controlled tumor protein (TCTP) is a conserved protein family implicated in the control of cell survival during normal development and tumorigenesis. Previously, we have identified a human Topoisomerase II (TOP2) as a TCTP partner, but its role in vivo has been unknown. To determine the significance of this interaction, we examined their roles in developing Drosophila organs. Top2 RNAi in the wing disc leads to tissue reduction and caspase activation, indicating the essential role of Top2 for cell survival. Top2 RNAi in the eye disc also causes loss of eye and head tissues. Tctp RNAi enhances the phenotypes of Top2 RNAi. The depletion of Tctp reduces Top2 levels in the wing disc and vice versa. Wing size is reduced by Top2 overexpression, implying that proper regulation of Top2 level is important for normal organ development. The wing phenotype of Tctp RNAi is partially suppressed by Top2 overexpression. This study suggests that mutual regulation of Tctp and Top2 protein levels is critical for cell survival during organ development

Pretransplant malnutrition, inflammation, and atherosclerosis affect cardiovascular outcomes after kidney transplantation

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background Malnutrition, inflammation, and atherosclerosis (MIA) syndrome is associated with a high mortality rate in patients with end-stage renal disease. However, the clinical relevance of MIA syndrome in kidney transplantation (KT) recipients remains unknown. Methods We enrolled 1348 adult KT recipients. Recipients were assessed based on serum albumin, cholesterol, or body mass index for the malnutrition factor and C-reactive protein level for the inflammation factor. Any history of cardiovascular (CV), cerebrovascular, or peripheral vascular disease satisfied the atherosclerosis factor. Each MIA factors were assessed by univariate analysis and we calculated an overall risk score by summing up scores for each independent variable. The enrolled patients were divided into 4 groups depending on the MIA score (0, 2–4, 6, 8–10). Results The patients with higher MIA score showed worse outcome of fatal/non-fatal acute coronary syndrome (ACS) (p < 0.001) and composite outcomes of ACS and all-cause mortality (p < 0.001) than with the lower MIA score. In multivariate analysis, ACS showed significantly higher incidence in the MIA score 8-10 group than in the MIA score 0 group (Hazard ratio 6.12 95 % Confidence interval 1.84–20.32 p = 0.003). Conclusions The presence of MIA factors before KT is an independent predictor of post-transplant CV outcomes

Comparison of Clinico-Physiologic and CT Imaging Risk Factors for COPD Exacerbation

To date, clinico-physiologic indices have not been compared with quantitative CT imaging indices in determining the risk of chronic obstructive pulmonary disease (COPD) exacerbation. We therefore compared clinico-physiologic and CT imaging indices as risk factors for COPD exacerbation in patients with COPD. We retrospectively analyzed 260 COPD patients from pulmonary clinics at 11 hospitals in Korea from June 2005 to November 2009 and followed-up for at least one year. At the time of enrollment, none of these patients had COPD exacerbations for at least 2 months. All underwent clinico-physiologic and radiological evaluation for risk factors of COPD exacerbation. After 1 yr, 106 of the 260 patients had at least one exacerbation of COPD. Multiple logistic regression analysis showed that old age, high Charlson Index, and low FEV1 were significant in a clinico-physiologic model, with C-statistics of 0.69, and that increased age and emphysema index were significant in a radiologic model, with C-statistics of 0.64. The difference between the two models was statistically significant (P = 0.04 by bootstrap analysis). Combinations of clinico-physiologic risk factors may be better than those of imaging risk factors in predicting COPD exacerbation

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Stability and safety of transbronchial dye mixture for preoperative localization in a porcine model

Abstract Objective For thoracoscopy, the usefulness of a dye mixture of indigo carmine and Lipiodol for localizing lung lesions has been reported. However, little is known about the stability and safety of this dye mixture injected on the visceral pleura through a bronchoscope. Methods Porcine models were divided into three groups according to the detection time of the dye mixture: group A with a detection time of 4 h; group B, 8 h; and group C, 24 h. A dye mixture of indigo carmine and Lipiodol (0.5 mL each) was sprayed onto the visceral pleura both in the ventral and dorsal regions via a spray catheter. Results Twelve markings were created on the visceral pleura of the porcine lung (six ventral and six dorsal) in the six porcine models. At predetermined detection times, all 12 dye markings (100%) were visible on the visceral pleura. The mean longest diameter of the dye marking in the ventral and dorsal regions was 18.8 mm and 24.3 mm, respectively. In groups B and C, pathological changes in the lymphatic system, such as lymphatic dilatations, were found; minimal changes were found in group B, however, these changes with oval‐shaped lymphatic cysts and Lipiodol accumulation, were more evident in group C. Conclusions The dye mixture of indigo carmine and Lipiodol had reliable stability and visibility. In terms of safety, it may be necessary to check the dye mixture on the lung surface within 8 h

STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells

Aberrantly enhanced vascular endothelial growth factor (VEGF) gene expression is associated with increased tumor growth and metastatic spread of solid malignancies, including human renal carcinomas. Persistent activation of STAT3 is linked to tumor-associated angiogenesis, but underlying mechanisms remain unclear. Therefore, we examined whether STAT3 modulates the stability and activity of hypoxia-inducible factor-1alpha (HIF-1alpha), and in turn enhances VEGF expression. We found that STAT3 was activated in ischemic rat kidneys and hypoxic human renal carcinoma cells. We also found that hypoxia-induced activation of STAT3 transactivated the VEGF promoter and increased the expression of VEGF transcripts. Consistent with these findings, STAT3 inhibition attenuated the hypoxic induction of VEGF. Interestingly, activated STAT3 increased HIF-1alpha protein levels due to the HIF-1alpha stability by blocking HIF-1alpha degradation and accelerated its de novo synthesis. The novel interaction of STAT3 with HIF-1alpha was identified in hypoxic renal carcinoma cells. Furthermore, hypoxia recruited STAT3, HIF-1alpha, and p300 to the VEGF promoter and induced histone H3 acetylation. Therefore, these findings provide compelling evidence that a causal relationship exists between STAT3 activation and HIF-1-dependent angiogenesis and suggest that therapeutic modalities designed to disrupt STAT3 signaling hold considerable promise for the blocking tumor growth and enhancing apoptosis of cancer cells and tissues