2017年 · 第130卷第18期

Background: Core fucosylation (CF), catalyzed by α-1,6 fucosyltransferase (Fut8) in mammals, plays an important role in pathological processes through posttranslational modification of key signaling receptor proteins, including transforming growth factor (TGF)-β receptors and platelet-derived growth factor (PDGF) receptors. However, its effect on peritoneal fibrosis is unknown. Here, we investigated its influence on epithelial-mesenchymal transition (EMT) of rat peritoneal mesothelial cells (PMCs) in vitro induced by a high-glucose (HG) culture solution. Methods: Rat PMCs were first cultured in a HG (2.5%) culture solution to observe the CF expression level (fluorescein isothiocyanate-lens culinaris agglutinin), we next established a knockdown model of rat PMCs in vitro with Fut8 small interfering RNA (siRNA) to observe whether inhibiting CF decreases the messenger RNA (mRNA) expression and protein expression of Fut8 and reverses EMT status. Rat PMCs were randomly divided into control group, mock group (transfected with scrambled siRNA), Fut8 siRNA group, HG group, HG + mock group, and HG + Fut8 siRNA group. Finally, we examined the activation of TGF-β/Smad2/3 signaling and PDGF/extracellular signal-regulated kinase (ERK) signaling to observe the influence of CF on them. Results: CF, Fut8 mRNA, and protein expression were all significantly upregulated in HG- induced EMT model than those in the control rat PMCs (P < 0.05). Fut8 siRNA successfully blocked CF of TGF-β receptors and PDGF receptors and attenuated the EMT status (E-cadherin and α-SMA and phenotypic changes) in HG-induced rat PMCs. In TGF-β/Smad2/3 signaling, Fut8 siRNA did not suppress the protein expression of TGF-β receptors and Smad2/3; however, it significantly suppressed the phosphorylation of Smad2/3 (relative expression folds of HG + Fut8 group vs. HG group: 7.6 ± 0.4 vs. 15.1 ± 0.6, respectively, P < 0.05). In PDGF/ERK signaling, Fut8 siRNA did not suppress the protein expression of PDGF receptors and ERK, but it significantly suppressed the phosphorylation of ERK (relative expression folds of HG+ Fut8 group vs. HG group: 8.7 ± 0.9 vs. 15.6 ± 1.2, respectively, P < 0.05). Blocking CF inactivated the activities of TGF-β and PDGF signaling pathways, and subsequently blocked EMT. Conclusions: These results demonstrate that CF contributes to rat PMC EMT, and that blocking it attenuates EMT. CF regulation is a potential therapeutic target of peritoneal fibrosis.

Background: Cyclosporine A (CsA) is a commonly used clinical immunosuppressant. However, CsA exposure in rabbits during the gestation period was shown to cause a postnatal decrease in the number of nephrons, with the effects remaining unknown. In this study, we aimed to explore the effects of CsA on metanephros development in the pregnant BALB/c mice. Methods: Pregnant mice were randomly divided into two groups, and CsA (10 mg·kg−1·d−1) was subcutaneously injected from gestation day 10.5 to day 16.5 in the CsA group, whereas a comparable volume of normal saline was given to the control group. All of the mice were sacrificed on gestation day 17.5 and serum CsA concentration was measured. The fetuses were removed and weighed, and their kidneys were prepared for histological assessment and polymerase chain reaction assay. In an in vitro experiment, embryo kidneys of fetal mice on gestation day 12.5 were used, and CsA (10 μmol/L) was added in the culture of the CsA group. The growth pattern of the ureteric bud and nephrons was assessed by lectin staining. Results: No significant differences in the weight of embryo (4.54 ± 1.22 vs. 3.26 ± 1.09 mg) were observed between the CsA and control groups, the thickness of the cortical (510.0 ± 30.3 vs. 350.0 ± 29.7 μm, P < 0.05) and nephrogenic zone (272.5 ± 17.2 vs. 173.3 ± 24.0 μm, P < 0.05), and the number of glomeruli (36.5 ± 0.7 vs. 27.5 ± 2.1, P < 0.05) were reduced in the CsA group when compared to the control group. The cell proliferation of Ki-67 positive index between control and CsA group (307.0 ± 20.0 vs. 219.0 ± 25.0, P < 0.05) in the nephrogenic zone was decreased with the increase of apoptotic cells (17.0 ± 2.0 vs. 159.0 ± 33.0, P < 0.05). The mRNA expression of WT-1, Pax2, and Pax8 was downregulated by CsA treatment. As for the in vitro CsA group, the branch number of the ureteric bud was decreased in the CsA-treated group with the nephrons missing in contrast to control after the incubation for 24 h and 72 h (all P < 0.0001). Conclusion: Treatment of CsA suppressed metanephros development in the pregnant mice; however, the potential action of mechanism needs to be further investigated.

Background: Acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis. Inflammation plays an important role in the development of rhabdomyolysis-induced AKI. This study aimed to investigate the kidney model of AKI caused by rhabdomyolysis to verify the role of macrophage Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway. Methods: C57BL/6 mice were injected with a 50% glycerin solution at bilateral back limbs to induce rhabdomyolysis, and CLI-095 or pyrrolidine dithiocarbamate (PDTC) was intraperitoneally injected at 0.5 h before molding. Serum creatinine levels, creatine kinase, the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and hematoxylin and eosin stainings of kidney tissues were tested. The infiltration of macrophage, mRNA levels, and protein expression of TLR4 and NF-κB were investigated by immunofluorescence double-staining techniques, reverse transcriptase-quantitative polymerase chain reaction, and Western blotting, respectively. In vitro, macrophage RAW264.7 was stimulated by ferrous myoglobin; the cytokines, TLR4 and NF-κB expressions were also detected. Results: In an in vivo study, using CLI-095 or PDTC to block TLR4/NF-κB, functional and histologic results showed that the inhibition of TLR4 or NF-κB alleviated glycerol-induced renal damages (P < 0.01). CLI-095 or PDTC administration suppressed proinflammatory cytokine (TNF-α, IL-6, and IL-1β) production and macrophage infiltration into the kidney (P < 0.01). Moreover, in an in vitro study, CLI-095 or PDTC suppressed myoglobin-induced expression of TLR4, NF-κB, and proinflammatory cytokine levels in macrophage RAW264.7 cells (P < 0.01). Conclusion: The pharmacological inhibition of TLR4/NF-κB exhibited protective effects on rhabdomyolysis-induced AKI by the regulation of proinflammatory cytokine production and macrophage infiltration.

Background: Preoperative anatomical scoring system is conducive to comparison between treatment options and evaluation of postoperative outcomes in patients with small renal tumors. This study aimed to evaluate the clinical application efficacy of the R.E.N.A.L. nephrometry score (RNS) in predicting perioperative outcomes in patients with renal tumor who underwent laparoscopic partial nephrectomy (LPN). Methods: The clinical data of 139 patients with renal tumors who underwent LPN between 2009 and 2015 were collected and analyzed. Patients were divided into three groups according to their RNS (low, moderate, and high). Clinical characteristics including perioperative variables, complications, and RNS were compared to evaluate the differences between the three groups. Multivariable logistic regression analysis was used to analyze the risk factors of postoperative complications. Results: According to the RNS, there were 74, 50, and 15 patients in the low, moderate, and high RNS groups, respectively. There were significant differences in estimated blood loss (EBL; χ2 = 7.285, P = 0.026), warm ischemia time (WIT; χ2 = 13.718, P = 0.001), operation time (OT; χ2 = 6.882, P = 0.032), perioperative creatinine clearance change (PCCC; χ2 = 6.206, P = 0.045), and number of patients with complications (NPC; P = 0.002) among the three groups. The values for EBL, WIT, OT, PCCC, and NPC for patients in the high RNS group were higher than those for patients in the low RNS group. After adjustment for OT, WIT, and EBL, RNS was statistically significantly associated with the risk of postoperative complications in a multivariable logistic regression model (odds ratio = 1.541, 95% confidence interval: 1.059–2.242, P = 0.024). Conclusions: The RNS is a valuable tool for evaluating the complexity of renal tumor anatomy. It can aid surgeons in preoperative decision-making concerning management therapy. Future multicenter, large sample size studies are warranted for evaluating its predicting performance of perioperative outcomes.

Background: Renal cell carcinoma (RCC) is frequently associated with paraneoplastic inflammatory syndrome (PIS). This study aimed at exploring the connections between the survival rate and specific gene alterations and the potential mechanism. Methods: We retrospectively studied 69 surgical RCC cases from August 2014 to February 2016, including 18 cases of clear cell RCC (ccRCC) demonstrating elevated pretreatment serum C-reactive protein (CRP, Group A). Twelve of the 18 cases were symptomized with febrile episode. We also selected 49 cases of ccRCC with normal pretreatment CRP (Group B). Using 22 microsatellite markers, we compared the incidence of loss of heterozygosity (LOH) between Group A and Group B. All statistical tests are two-sided. Results: The 3p LOH was common in both Group A (89%) and Group B (92%). The frequency of 14q LOH in Group A (16 of 18) was higher than Group B (4 of 49, χ2 = 40.97 P < 0.0001). The 3p and 14q LOH were the characteristics of ccRCC with elevated acute phase reactants, including PIS, regardless of the presence of metastasis. On the contrary, 14q LOH was a rare genomic alternation in advanced-staged ccRCC without PIS. The overall survival of patients with elevated CRP (33.3%) was lower than its counterparts (6.1%, hazard ratio=1.852, P < 0.0001) in Kaplan-Meier curve. Conclusions: The results imply that the disruption of a 14q gene(s) might result in not only the inflammatory manifestations in the tumor host but also the poor survival rate as well. The isolation of the gene(s) on 14q might be a vital goal in the treatment of PIS-associated RCC.

Background: Portal-vein stent combined with one iodine-125 (125I) seed strand has become a new treatment for portal vein tumor thrombosis. However, dosimetric aspects of this irradiation stent have not been reported. Therefore, we aimed to undertake dosimetric analyses comparing portal-vein stents combined with different numbers of 125I seed strands. Methods: A water cylinder was created by a treatment-planning system to simulate a portal-vein stent. The stent was combined with one, two, or three 125I seed strands (Groups I, II, and III, respectively). At different prescribed doses (PDs), 125I seeds of identical activities were loaded on Groups I–III. Conformation number (CN), external volume index, and homogeneity index were calculated. Linear regression analyses were used to evaluate the obtained data. Results: For identical 125I seed activity, when the 125I seed strand increased from one chain to two, D90 (dose delivered to 90% of the target volume) increased by ≥184%; when it increased from two chains to three, D90 increased by ≥63%. When the PD was 105 Gy and 125I seed strands increased from one chain to two, V100 (percentage of the target volume receiving ≥90% of the PD) increased by 158–249%; when it increased from two chains to three, V100 increased by 7–175%. CN was correlated positively with 125I seed activity (B = 0.479, P < 0.001) and number of 125I seed strands (B = 0.201, P < 0.001) and was independent of PD (B = −0.002, P = 0.078). Conclusions: A portal-vein stent combined with a single 125I seed strand could not meet dosimetry requirements. For a stent combined with two 125I seed strands, when the PD was 105 Gy and seed activity was 0.7 mCi, the dose distribution could satisfy dosimetry requirements. For a stent combined with three 125I seed strands, if the PD was 105, 125, or 145 Gy, the recommended seed activities were 0.5, 0.5, and 0.6 mCi, respectively.

Background: Entecavir (ETV) has been shown to be effective in randomized controlled trials in highly selected patients with hepatitis B virus (HBV) infection. This study aimed to evaluate the efficacy of ETV in chronic hepatitis B (CHB) patients in the real-world setting. Methods: A total of 233 treatment-naïve, CHB patients who received at least 12 months of ETV treatment were included in this retrospective study. Rates of virological response (VR), hepatitis B s antigen (HBsAg) loss, hepatitis B e antigen (HBeAg) clearance/seroconversion, virological breakthrough, cirrhosis, and hepatocellular carcinoma were evaluated. Results: Of 233 patients, 175 patients were male, with mean age of 43 years old, and 135 patients were HBeAg positive. The mean baseline levels of serum alanine aminotransferase and HBV DNA in all patients were 230 U/L and 6.6 log 10 IU/ml, respectively. The mean follow-up period was 28 months. The cumulative rates of achieving VR increased from 3.4% at 3 months to 94.4% at 60 months. Primary nonresponse occurred in 3 (1.3%) patients. Partial VR (PVR) occurred in 61 (26.2%) patients at 12 months. The baseline serum HBV DNA level (hazard ratio [HR], 2.054; P < 0.001) was an independent risk factor for PVR. HBsAg loss did not occur. The cumulative rates of HBeAg clearance increased from 2.2% at 3 months to 28.2% at 60 months. PVR was the significant determinant of HBeAg clearance (HR, 0.341; P = 0.026). Age (HR, 1.072; P = 0.013) and PVR (HR, 5.131; P = 0.017) were the significant determinants of cirrhosis. Conclusions: ETV treatment was effective for HBV DNA suppression in this study, but HBsAg loss and HBeAg clearance/seroconversion rates were lower compared with previous clinical trials. PVR was associated with HBeAg clearance and cirrhosis.

Background: Quantifying syphilis prevalence is important for planning interventions and advocating for resources on syphilis. However, data on large sample studies regarding the prevalence of syphilis among reproductive-age women in rural China were not available for analysis. The aim of the study was to determine the prevalence, epidemiological characteristics, and related factors of syphilis infection among reproductive-age women in rural China. Methods: Data were obtained from a nationwide, population-based, cross-sectional study under the National Free Preconception Health Examination Project which covered all the 31 provinces in Mainland China. Women intending to get pregnant within the next 6 months were enrolled between January 1, 2010, and December 31, 2012. Sociodemographic, gynecological and obstetric characteristics, and other relevant information were obtained through face-to-face interviews. Treponema pallidum particle agglutination assay test was used to detect positive samples of syphilis. Univariate and multivariate logistic regressions were performed to assess the associations between syphilis seropositivity and related factors. Results: The overall seroprevalence of syphilis (SPS) among the 2,044,126 women who received syphilis screening test during 2010–2012 was 0.37% (95% confidence interval [CI]: 0.36–0.37%). The SPS appeared 0.24% (95% CI: 0.23–0.26%) and 0.66% (95% CI: 0.59–0.72%) in women at 21–24 and 40–44 years of age, respectively, showing an increase of SPS, parallel with age, and the difference was significant. SPS was significantly higher in ethnic minorities than that in Han nationality (0.58% vs. 0.35%, respectively, odds ratio [OR] = 1.41, 95% CI: 1.30–1.53) and higher in workers than that in farmers (0.45% vs. 0.36%, respectively, OR = 1.27, 95% CI: 1.14–1.41). Women with primary school or below level had a higher SPS as compared to those with college or above educational level (0.61% vs. 0.32%, respectively, OR = 2.49, 95% CI: 2.14–2.89), and the increase reversely correlated with the levels of education. Women whose spouses were syphilis seropositive had significant greater risk (OR = 48.26, 95% CI: 44.38–52.48) as compared those whose spouses were seronegative. Women who reported having had a history of sexually transmitted infections were more likely to be tested positive for serological syphilis (OR = 27.17, 95% CI: 20.44–36.11) as compared to those without. Conclusions: High SPS is seen among reproductive-age women in rural China that calls for targeted interventions on syphilis prevention and control in this target population, with emphasis on those who are 35 years of age and above, less educated, being minor ethnicity, workers, and living in the western regions of China.

Background: PM2.5 (aerodynamic diameter ≤ 2.5 µm) is a dominant and ubiquitous air pollutant that has become a global concern as PM2.5 exposure has been linked to many adverse health effects including cardiovascular and pulmonary diseases. Emerging evidence supports a correlation between increased air PM2.5 levels and skin disorders although reports on the underlying pathophysiological mechanisms are limited. Oxidative stress is the most common mechanism of PM2.5-induced adverse health effects. This study aimed to investigate PM2.5-induced oxidative damage and apoptosis in immortalized human keratinocyte (HaCaT) cells. Methods: HaCaT cells were exposed to 0, 25, 50, 100, or 200 µg/ml PM2.5 for 24 h. Reactive oxygen species (ROS) generation, lipid peroxidation products, antioxidant activity, DNA damage, apoptotic protein expression, and cell apoptosis were measured. Results: PM2.5 exposure (0–200 µg/ml) for 24 h resulted in increased ROS levels (arbitrary unit: 201.00 ± 19.28, 264.50 ± 17.91, 305.05 ± 19.57, 427.95 ± 18.32, and 436.70 ± 17.77) and malondialdehyde production (0.54 ± 0.05 nmol/mg prot, 0.61 ± 0.06 nmol/mg prot, 0.68 ± 0.05 nmol/mg prot, 0.70 ± 0.05 nmol/mg prot, and 0.76 ± 0.05 nmol/mg prot), diminished superoxide dismutase activity (6.47 ± 0.28 NU/mg prot, 5.97 ± 0.30 NU/mg prot, 5.15 ± 0.42 NU/mg prot, 4.08 ± 0.20 NU/mg prot, and 3.76 ± 0.37 NU/mg prot), and increased DNA damage and apoptosis in a dose-dependent manner in HaCaT cells. Moreover, cytochrome-c, caspase-3, and caspase-9 expression also increased proportionately with PM2.5 dosing. Conclusion: PM2.5 might elicit oxidative stress and mitochondria-dependent apoptosis that likely manifests as skin irritation and damage.

Background: Limb-salvage surgery is the standard procedure for the treatment of appendicular osteosarcoma. Precise resection is the trend in limb-salvage surgery. The aim of this study was to evaluate a large series of cases to identify the histological relationship between the tumor and marrow and determine the intramedullary transition type and width from the tumor to normal marrow in patients with osteosarcoma after neoadjuvant chemotherapy. Methods: One hundred and six osteosarcoma specimens were evaluated. The tissue specimens were sectioned through the coronal axis by an electronic saw. The tissue was immersed in formalin solution for fixation and subsequently decalcified. The interface between the tumor and normal bone marrow was grossly determined and submitted for microscopic evaluation to detect the relationship between the tumor and bone marrow and identify the transition type and width. All histological slides were examined by experienced orthopedic pathologists. Results: Histologically, the interface between the tumor and normal bone marrow was classified into two patterns: "clear" and "infiltrated." The clear pattern, characterized by a clear boundary between the tumor and marrow, was identified in sixty cases (56.6%). A subtype of the clear type, characterized by fibrous bands between the tumor and marrow, was found in 13 cases (12.3%). The infiltrated pattern, characterized by a boundary with tumor cell clusters embedded in the marrow, was found in 46 cases (43.4%). The infiltrating depth varied from 1 to 4 mm (mean, 2.6 ± 0.7 mm). No tumor cells were observed in the normal bone marrow areas next to the interface. Conclusions: The transition from osteosarcoma tissue to bone marrow after neoadjuvant chemotherapy can be divided into two histological patterns: clear and infiltrated. The greatest infiltration width was 4 mm from tumor to normal marrow in this study. This depth should be considered in the presurgical plan.

Background: Studies on the association between spicy food intake and cancer risk have reported inconsistent results. We quantitatively assessed this association by conducting a meta-analysis based on evidence from case–control studies. Methods: PubMed, EMBASE, and the Cochrane Library were searched for eligible publications. Combined odds ratios (ORs) with their 95% confidence interval (CI) were calculated using a random- or fixed-effects model. The methodological quality of the included articles was assessed using the Newcastle–Ottawa scale (NOS). All data were analyzed using STATA 11.0 software (version 11.0; StataCorp., College Station, TX, USA). Subgroup analyses were also performed with stratification by region, sex, number of cases, cancer subtype, source of the control group, and NOS score. Results: A total 39 studies from 28 articles fulfilled the inclusion criteria for the meta-analysis (7884 patients with cancer and 10,142 controls). Comparison of the highest versus lowest exposure category in each study revealed a significant OR of 1.76 (95% CI = 1.35–2.29) in spite of significant heterogeneity (P < 0.001). In the subgroup analyses, this positive correlation was still found for gastric cancer, different regions, different numbers of cases, different sources of the control group, and high-quality articles (NOS score of ≥ 7). However, no statistically significant association was observed for women, esophageal cancer, gallbladder cancer, or low-quality articles (NOS score of <7). No evidence of publication bias was found. Conclusions: Evidence from case–control studies suggested that a higher level of spicy food intake may be associated with an increased incidence of cancer despite significant heterogeneity. More studies are warranted to clarify our understanding of the association between high spicy food intake and the risk of cancer.

Objective: In the upcoming era of precision medicine, searching for the early, noninvasive biomarkers has been the cornerstone and major challenge in the management of chronic kidney disease (CKD). Urine contains rich biological information which could be the ideal source for noninvasive biomarkers of CKD. This review will discuss the recent advance in urinary biomarker. Data Sources: This review was based on data in articles published in the PubMed databases up to June 20, 2017, with the following keywords: "Chronic kidney disease" , "Biomarker" , and "Urine" . Study Selection: Original articles and important reviews on urinary biomarker were selected for this review. Results: Urinary biomarker studies of CKD mainly focused on urine sediment, supernatant, and urinary extracellular vesicles. The gene transcript (microRNA [miRNA], messenger RNA [mRNA]) biomarkers have been recently shown with diagnostic potential for CKD reflecting kidney function and histological change. However, challenges regarding technique and data analysis need to be resolved before translation to clinic. Conclusions: Different fractions of urine contain rich information for biomarker discovery, among which urine (extracellular vesicles) mRNA, miRNA, might represent promising biomarker for CKD.