Search

Background: Acute kidney injury (AKI) is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is currently available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this dilemma. Methods We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model following renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. Results REVs targeted with Kim-1-binding LTH peptide (REVLTH) efficiently homed to and accumulated at the injured tubules in kidney following I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to chronic kidney disease. Conclusions A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.

Background Urinary sediment messenger RNAs (mRNAs) have been shown as novel biomarkers of kidney disease. We aimed to identify targeted urinary mRNAs in diabetic nephropathy (DN) based on bioinformatics analysis and clinical validation. Methods Microarray studies of DN were searched in the GEO database and Nephroseq platform. Gene modules negatively correlated with estimated glomerular filtration rate (eGFR) were identified by informatics methods. Hub genes were screened within the selected modules. In validation cohorts, a quantitative polymerase chain reaction assay was used to compare the expression levels of candidate mRNAs. Patients with renal biopsy–confirmed DN were then followed up for a median time of 21 months. End-stage renal disease (ESRD) was defined as the primary endpoint. Multivariate Cox proportional hazards regression was developed to evaluate the prognostic values of candidate mRNAs. Results Bioinformatics analysis revealed four chemokines (CCL5, CXCL1, CXLC6 and CXCL12) as candidate mRNAs negatively correlated with eGFR, of which CCL5 and CXCL1 mRNA levels were upregulated in the urinary sediment of patients with DN. In addition, urinary sediment mRNA of CXCL1 was negatively correlated with eGFR (r = −0.2275, P = 0.0301) and CCL5 level was negatively correlated with eGFR (r = −0.4388, P Conclusions Urinary sediment CCL5 and CXCL1 mRNAs were upregulated in DN patients and associated with a decline in renal function and degree of renal interstitial fibrosis. Urinary sediment CCL5 mRNA could be used as a potential prognostic biomarker of DN.

OBJECTIVE To investigate the expression of triggering receptor expressed on myeloid cells 2 (TREM-2) in the healthy and diseased tissue, including gingivitis or periodontitis, and then to assess whether it has an impact on the development of periodontitis. METHODS AND MATERIALS The gingival tissues from healthy controls, gingivitis, and periodontitis underwent hematoxylin-eosin and immunohistochemical staining, and the association of TREM-2 expression or TREM-2+ cell counts with clinical parameters was assessed. An anti-TREM-2 antibody was used to block the osteoclastogenesis in vitro and during the experimental periodontitis by injection into the gingiva. The relative gene expression of TREM-2 in different gingival tissues was analyzed by quantitative PCR. RESULTS In the gingival tissues of periodontitis, TREM-2 expression and TREM-2+ cell counts were significantly higher than those of gingivitis and healthy controls (p

Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from posttranslational hydroxylation, the mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia-reperfusion-, unilateral ureteral obstruction-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB, which plays a central role in the inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only under hypoxic conditions but also under normoxic conditions. Moreover, the induced HIF-1α by inflammation protected against tubular injury in AKI. Thus, our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.NEW & NOTEWORTHY Here, the mechanism of hypoxia-inducible factor-α (HIF-α) regulation in acute kidney injury (AKI) was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB was involved in the increasing expression of HIF-1α in AKI. Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription. Our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.

Purpose Hybrid PET/MRI has been increasingly incorporated into the practice of radiation oncologists since it contains both anatomical and biological data and may bring about personalized radiation plans for each patient. The objective of this study was to evaluate the feasibility of GTV delineation from hybrid PET/MRI compared with that from current-practice MRI during radiotherapy planning in patients with colorectal liver metastases. Patients and Methods Twenty-four patients (thirty lesions) with colorectal liver metastases were prospectively enrolled in this study. Three physicians delineated the target volume with the most popular delineating methods—the visual method. First of all, differences among the three observers were assessed. The difference and correlation of GTV values obtained by MRI, PET, and hybrid PET/MRI were subjected to statistical analysis afterwards. Finally, the dice similarity coefficient (DSC) was calculated to assess the spatial overlap. Based on the value of DSC, we also evaluate the correlation between DSC and tumor size. GTV-MRI was set as a reference. Results There was no significant difference among observers in GTV-MRI (F=0.118, p=0.889), GTV-PET (F=0.070, p=0.933) and GTV-PET/MRI (F=0.40, p=0.961). 83.33% of GTV-PET/MRI and 63.33% of GTV-PET were larger than the reference GTV-MRI. Statistical analysis revealed that GTV-PET/MRI (p

Mesenchymal stem cells-derived exosomes (MSC-exos) have attracted great interest as a cell-free therapy for acute kidney injury (AKI). However, the in vivo biodistribution of MSC-exos in ischemic AKI has not been established. The potential of MSC-exos in promoting tubular repair and the underlying mechanisms remain largely unknown. Methods: Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of human umbilical cord mesenchymal stem cells (hucMSCs) derived exosomes. The biodistribution of MSC-exos in murine ischemia/reperfusion (I/R) induced AKI was imaged by the IVIS spectrum imaging system. The therapeutic efficacy of MSC-exos was investigated in renal I/R injury. The cell cycle arrest, proliferation and apoptosis of tubular epithelial cells (TECs) were evaluated in vivo and in HK-2 cells. The exosomal miRNAs of MSC-exos were profiled by high-throughput miRNA sequencing. One of the most enriched miRNA in MSC-exos was knockdown by transfecting miRNA inhibitor to hucMSCs. Then we investigated whether this candidate miRNA was involved in MSC-exos-mediated tubular repair. Results: Ex vivo imaging showed that MSC-exos was efficiently homing to the ischemic kidney and predominantly accumulated in proximal tubules by virtue of the VLA-4 and LFA-1 on MSC-exos surface. MSC-exos alleviated murine ischemic AKI and decreased the renal tubules injury in a dose-dependent manner. Furthermore, MSC-exos significantly attenuated the cell cycle arrest and apoptosis of TECs both in vivo and in vitro. Mechanistically, miR-125b-5p, which was highly enriched in MSC-exos, repressed the protein expression of p53 in TECs, leading to not only the up-regulation of CDK1 and Cyclin B1 to rescue G2/M arrest, but also the modulation of Bcl-2 and Bax to inhibit TEC apoptosis. Finally, inhibiting miR-125b-5p could mitigate the protective effects of MSC-exos in I/R mice. Conclusion: MSC-exos exhibit preferential tropism to injured kidney and localize to proximal tubules in ischemic AKI. We demonstrate that MSC-exos ameliorate ischemic AKI and promote tubular repair by targeting the cell cycle arrest and apoptosis of TECs through miR-125b-5p/p53 pathway. This study provides a novel insight into the role of MSC-exos in renal tubule repair and highlights the potential of MSC-exos as a promising therapeutic strategy for AKI.

Background Early screening and intervention therapies are crucial to improve the prognosis of hepatocellular carcinoma (HCC) patients with bone metastasis. We aimed to identify serum lncRNA as a prediction biomarker in HCC bone metastasis. Methods The expression levels of lnc34a in serum samples from 157 HCC patients were detected by quantitative real-time polymerase chain reaction (PCR). Univariate analysis and multivariate analysis were performed to determine statistically significant variables. Results Expression levels of lnc34a in serum from HCC patients with bone metastasis were significantly higher than those without bone metastasis. The high expressions of lnc34a, vascular invasion and Barcelona Clinic Liver Cancer (BCLC) stage were associated with bone metastasis by analysis. Moreover, lnc34a expression was specifically associated with bone metastasis rather than lung or lymph node metastasis in HCC. Conclusions High serum lnc34a expression was a independent risk factor for developing bone metastasis in HCC.

Background: Chemotherapy combined with radiotherapy is the main treatment strategy for unresectable rectal cancer. However, the prognostic factors of patients with unresectable rectal cancer treated with radiotherapy and chemotherapy have not been systematically studied. Therefore, this study investigated the prognostic factors and prognosis based on surveillance, epidemiology and final results of the SEER medical insurance database. Methods: Primary rectum patients were selected from the SEER database. The independent prognostic factors associated with overall survival (OS), cancer-specific survival (CSS) and noncancer-related death were evaluated using the Kaplan-Meier method and log-rank test, a competing risk model, and the Cox proportional hazards regression model. Two nomograms were established for predicting the 1- and 3-year OS and CSS of patients. Results: A total of 3,998 rectal adenocarcinoma cancer patients who received chemoradiotherapy but had not undergone surgery were included in this study and divided into training (n = 3559) and validation cohorts (n = 439). Patients in the training cohort had a 1-year OS rate of 65.7±0.8%, a 3-year OS rate of 26.6±0.8%, a 5-year OS rate of 1.6±0.8%, and a median survival rate of 20.0 months (range, 19.22-20.8 months). The following factors were significant prognostic factors of OS: age (p< 0.001); tumour grade (p< 0.001); T stage (p< 0.001); M stage (p< 0.001); bone metastasis (p

Background/purpose: Dental implantation has become an efficient and important method of replacing lost teeth. However, the success rate of dental-implant treatment in diabetics is higher than patients without diabetes. The aim of this study was to prospectively evaluate long-term marginal bone loss (MBL) and the stability of a self-assembling nano-modified implant in patients with type 2 diabetes mellitus compared with a conventional implant. Materials and methods: Twenty-five patients with type 2 diabetes were recruited for this study. Through a random selection process, one site in each patient received a conventional implant and the other site received a nano-modified implant. The implant stability quotient was measured using resonance frequency analysis (RFA), and MBL was measured using panoramic radiography from uncovering to four-year follow-up. Results: No significant difference in implant stability quotient was found between the two groups (P > 0.05), except for the time at implant insertion (P 0.05). Conclusion: There was potentially increased implant stability and diminished MBL around the self-assembling nano-modified implant in the uncovering-loading stage of early osseointegration in patients with type 2 diabetes.

Background Major depressive disorder (MDD) is a serious and common mood disorder with unknown etiology. Emerging evidence has demonstrated the critical roles of SIRT1 and microRNAs (miRNAs) in the progression of MDD. However, the underlying molecular mechanisms remain to be fully understood. Methods In the present study, the expression level of miR-138 and SIRT1 were analyzed by RT-PCR or Western blotting in a chronic unpredictable mild stress (CUMS) model. The depressive-like behaviors were analyzed by forced swimming test (FST) and sucrose preference test (SPT) in mice injected with miR-138 and SIRT1 overexpression lentivirus. The luciferase reporter assay was used to assess the direct regulation of miR-138 on SIRT1 expression. Results The upregulation of miR-138 was found in the hippocampus of the CUMS mice and correlated with decreased SIRT1 expression. C57BL/6J mice treated with SIRT1- and miR-138-expressing (miR-138) lentivirus showed increased depressive-like behaviors. In contrast, SIRT1 or si-miR-138 lentivirus treated C57BL/6J mice showed decreased depressive-like behaviors. Moreover, the Sirt1/PGC-1α/FNDC5/BDNF pathway was downregulated following miR-138 overexpression and increased upon miR-138 knockdown in hippocampus in CUMS mice and cultured primary neuronal cells. Mechanistically, luciferase reporter assay demonstrated that SIRT1 gene was a downstream transcriptional target of miR-138. Conclusion Our data demonstrated the regulation role of miR-138 on SIRT1 gene expression, miR-138 increased depressive-like behaviors by regulating SIRT1 expression in hippocampus.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are orally active first-in-class new generation drugs for renal anemia. This extensive meta-analysis of randomized controlled trials (RCTs) was designed to provide clear information on the efficacy and safety of HIF-PHIs on anemia in chronic kidney disease (CKD) patients. Searches included PubMed, Web of Science, Ovid MEDLINE, and Cochrane Library database up to October 2019. RCTs of patients with CKD comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in the treatment of anemia. The primary outcome was hemoglobin change from baseline (Hb CFB); the secondary outcomes included iron-related parameters and the occurrence of each adverse event. 26 trials in 17 articles were included, with a total of 2804 dialysis or patients with CKD. HIF-PHIs treatment produced a significant beneficial effect on Hb CFB compared with the placebo group (MD, 0.69; 95% CI, 0.36 to 1.02). However, this favored effect of HIF-PHIs treatment was not observed in subgroup analysis among trials compared with ESAs (MD, 0.06; 95% CI, −0.20 to 0.31). The significant reduction in hepcidin by HIF-PHIs was observed in all subgroups when compared with the placebo group, whereas this effect was observed only in NDD-CKD patients when compared with ESAs. HIF-PHIs increased the risk of nausea (RR, 2.20; 95% CI, 1.06 to 4.53) and diarrhea (RR, 1.75; 95% CI, 1.06 to 2.92). We conclude that orally given HIF-PHIs are at least as efficacious as ESAs treatment to correct anemia short term in patients with CKD. In addition, HIF-PHIs improved iron metabolism and utilization in patients with CKD.

Background Parotid gland adenocarcinoma not otherwise specified (PANOS) is a rare malignancy, and the characteristics and prognosis of this disease remain unclear. This study aims to characterize PANOS and establish prognostic prediction models for patients with PANOS. Methods Cases from 2004–2016 were retrieved from the Surveillance, Epidemiology, and End Results Program database (SEER database). Univariate and multivariate Cox regression analyses, Gray's test and propensity score matching (PSM) were conducted to analyze demographics, treatments, and survival outcomes . Results The 446 patients ( 289 men) selected for analysis had a median age of 66 (19–95) years, and 307 patients were diagnosed with stage III/IV disease. The median survival of all patients was 66 months, with a 51.8% 5-year overall survival (OS) rate. Surgical treatment clearly improved survival time (p p

Background and Aims Hypoxia inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is a novel small molecule inhibitor in clinical treatment for renal anemia. Several studies have shown that sustained HIF activation may also have deleterious effects, such as tubulointerstitial fibrosis. Here, the potential effects of different treatment frequency of HIF-PHI (FG-4592) on CKD (chronic kidney disease) mice were investigated. Method Male C57BL/6J mice were constructed by subtotal nephrectomy of 5/6 to serve as a model for CKD. We then compared four different strategies based on the frequency of FG-4592(intragastric administration, 30mg/kg) over 9 weeks: once a week (qw), twice a week (biw), three times a week (tiw), and every day (qd). In vitro, HK-2 cells were divided into three groups according to the different administration methods of FG-4592(30μM): FG-4592 for 20h (FG0); FG-4592 for 8h, followed by washing with medium for 12h(FG1); twice FG-4592 for 8h, followed by washing twice with medium for2h(FG2). Results Hemoglobin in the biw group, tiw group or qd group was significantly higher than that in vehicle group. EPO, HIF-1α and HIF-2α of tiw group, biw group and qd group were significantly higher than those in vehicle group. Makers of fibrosis and inflammation in qd group were higher than that in vehicle group, while there was no statistical difference in the changes of the above indicators in tiw group and biw group. HIF-1α and HIF-2α were increased in intermittent administration, but the expression of VEGF, makers of fibrosis or inflammation were not affected. In HK2, HIF-1α and HIF-2α were activated by continuous administration of FG-4592. At the same time, the expression of VEGF, inflammatory and fibrosis indicators were increased significantly during continuous administration. In HepG2, EPO was increased in intermittent administration in HepG2 cells without VEGF increasing. Conclusion Taken together, our studies demonstrated that FG-4592 administration 2-3 times a week can effectively improve renal anemia without side effects on inflammatory and fibrosis.

Background: Radiotherapy is a primary treatment strategy for patients with unresectable hepatocellular carcinoma (HCC); however, the prognostic factors among HCC patients who have received radiotherapy but not undergone surgery have not been systematically studied. Thus, the prognostic factors were investigated in this study based on the Surveillance, Epidemiology, and End Results (SEER) Medicare database. Methods: A screening process was used for select cases from the SEER database. Survival was analyzed using the Kaplan-Meier method and log-rank test, the Cox proportional hazards regression model, and a competing risk model. A nomogram was established for predicting 1- and 3-year overall survival (OS) of patients. Results: A total of 1305 HCC patients who received radiotherapy but had not undergone surgery were included in this study and divided into training (n = 1175) and validation cohorts (n = 130). Patients in the training cohort had a 1-year OS rate of 30.9±1.3%, a 3-year OS rate of 10.0±1.0%, and a median survival rate of 6.0 months (range, 5.4-6.6 months). Race (p = 0.025), T stage (p < 0.001), N stage (p < 0.001), M stage (p < 0.001), and chemotherapy (p < 0.001) were identified as independent risk factors by multivariate analyses in the training cohort, while sex, age, grade, marital status, and insurance status were not independent factors. Survival in patients who received radiotherapy was worse with respect to the following characteristics: black race; higher T, N, or M stage; and no chemotherapy. A nomogram was established based on the results of the multivariate analysis, which was internally validated by a concordance index (C-index) of 0.731±0.016 and a group of calibration plots. External validation was carried out and the C-index was 0.738±0.049, which demonstrated the effectiveness of the nomogram we constructed. Conclusions: Race, T stage, N stage, M stage, and chemotherapy were independent risk factors for survival of HCC patients who received radiotherapy but had not undergone surgery. A validated nomogram was formulated to predict 1- and 3-year OS in these patients based on individual clinical characteristics.

IgA nephropathy (IgAN) features variable renal pathology and a heterogeneous clinical course. Our aim was to search noninvasive biomarkers from urinary exosomes for IgAN patients; membrane nephropathy and minimal change disease were included as other glomerulopathy controls. Transmission electron microscopy and nanoparticle tracking analysis confirmed the size and morphology characteristic of urinary exosomes. Exosome markers (Alix and CD63) as well as renal cell markers [aquaporin 2 (AQP2) and nephrin] were detected, which indicate the renal origin of urinary exosomes. Exosome excretion was increased markedly in IgAN patients compared with controls and correlated with levels of proteinuria and tubular injury. More important, urinary exosome excretion correlated with greater histologic activity (mesangial hypercellularity, crescents, and endocapillary hypercellularity). Profiling of the inflammation-related mRNA revealed that exosomal chemokine (C-C motif) ligand 2 (CCL2) was up-regulated in IgAN patients. In a validation study, CCL2 was exclusively highly expressed in IgAN patients compared with healthy controls as well as minimal change disease and membrane nephropathy patients. Also, a correlation between exosomal CCL2 and estimated glomerular filtration rate levels was found in IgAN. Exosomal CCL2 was correlated with tubulointerstitial inflammation and C3 deposition. High CCL2 levels at the time of renal biopsy were associated with subsequent deterioration in renal function. Thus, urinary exosomes and exosomal CCL2 mRNA are promising biomarkers reflecting active renal histologic injury and renal function deterioration in IgAN.

Incomplete recovery from episodes of acute kidney injury (AKI) can predispose patients to develop chronic kidney disease (CKD). Although hypoxia-inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia/ischemia, the role of HIF-1α in CKD progression following incomplete recovery from AKI is poorly understood. Here, we investigated this issue using moderate and severe ischemia/reperfusion injury (I/RI) mouse models. We found that the outcomes of AKI were highly associated with the time course of tubular HIF-1α expression. Sustained activation of HIF-1α, accompanied by the development of renal fibrotic lesions, was found in kidneys with severe AKI. The AKI to CKD progression was markedly ameliorated when PX-478 (a specific HIF-1α inhibitor, 5 mg· kg(−1)·d(−1), i.p.) was administered starting on day 5 after severe I/RI for 10 consecutive days. Furthermore, we demonstrated that HIF-1α C-terminal transcriptional activation domain (C-TAD) transcriptionally stimulated KLF5, which promoted progression of CKD following severe AKI. The effect of HIF-1α C-TAD activation on promoting AKI to CKD progression was also confirmed in in vivo and in vitro studies. Moreover, we revealed that activation of HIF-1α C-TAD resulted in the loss of FIH-1, which was the key factor governing HIF-1α-driven AKI to CKD progression. Overexpression of FIH-1 inhibited HIF-1α C-TAD and prevented AKI to CKD progression. Thus, FIH-1-modulated HIF-1α C-TAD activation was the key mechanism of AKI to CKD progression by transcriptionally regulating KLF5 pathway. Our results provide new insights into the role of HIF-1α in AKI to CKD progression and also the potential therapeutic strategy for the prevention of renal diseases progression.

Using extracellular vesicles for targeted delivery of IL-10 is an efficient therapeutic strategy against ischemic AKI., Recently, extracellular vesicles (EVs) have been attracting strong research interest for use as natural drug delivery systems. We report an approach to manufacturing interleukin-10 (IL-10)–loaded EVs (IL-10+ EVs) by engineering macrophages for treating ischemic acute kidney injury (AKI). Delivery of IL-10 via EVs enhanced not only the stability of IL-10, but also its targeting to the kidney due to the adhesive components on the EV surface. Treatment with IL-10+ EVs significantly ameliorated renal tubular injury and inflammation caused by ischemia/reperfusion injury, and potently prevented the transition to chronic kidney disease. Mechanistically, IL-10+ EVs targeted tubular epithelial cells, and suppressed mammalian target of rapamycin signaling, thereby promoting mitophagy to maintain mitochondrial fitness. Moreover, IL-10+ EVs efficiently drove M2 macrophage polarization by targeting macrophages in the tubulointerstitium. Our study demonstrates that EVs can serve as a promising delivery platform to manipulate IL-10 for the effective treatment of ischemic AKI.

Background and Aims Acute kidney injury (AKI) is increasingly recognized as a major risk factor for progression to CKD. However, the mechanisms governing AKI to CKD progression are poorly understood. Hypoxia is a key player in the pathophysiology of the AKI to CKD transition. Thus, we aimed to investigate the exact mechanisms of AKI to CKD progression mediated by hypoxia. Method Mild ischemic injury and severe ischemic injury (AKI-to-CKD transition) were established by clamping renal pedicle for 30 and 40 minutes, respectively. Meanwhile, the mice model of AKI-to-CKD transition was treated with HIF-1α inhibitor, PX-478. In vitro, PHD inhibition and combined PHD with FIH inhibition mimic the HIF-1α activation caused by mild or severe hypoxia, respectively. Besides the human proximal tubular epithelial cell line HK-2, tubular cells were isolated from mice for primary culture. KLF5 knockdown, FIH and HIF-1α C-terminal transcriptional activation domain (C-TAD) overexpression in tubular cells were achieved by Lentiviral transfection. Immunocoprecipitation was used to explore the relationship between the HIF-1α and FIH-1. Luciferase reporter assay was used to investigate whether KLF5 was regulated transcriptionally by HIF-1α C-TAD. To explore the roles of FIH-1 and HIF-1α C-TAD in vivo, FIH-1 and HIF-1α C-TAD overexpression (Lentivirus-mediated) was given after severe ischemic injury or mild ischemic injury via tail vein injection, respectively. Results AKI to CKD progression was highly associated with the time-course expression of tubular HIF-1α in severe ischemia/reperfusion injury. Interestingly, ameliorated AKI-to-CKD transition was observed by treating PX-478, which destabilized HIF-1α. In vitro, fibrogenesis could be induced by combined PHD with FIH inhibitor treatment in TEC. More interestingly, alleviated fibrogenesis could be achieved by knockdown of KLF5 and overexpression of FIH, respectively, while HIF-1α C-TAD overexpression promoted fibrogenesis in tubular cells. Immunocoprecipitation results indicated that HIF-1α and FIH-1 are interactive. Furthermore, we demonstrated that KLF5 could be regulated transcriptionally by HIF-1α C-TAD by luciferase reporter assay. In vivo, AKI to CKD progression was ameliorated significantly when mice model of AKI-to-CKD transition intervened with FIH-1 overexpression (Lentivirus-mediated). However, treatment of HIF-1α C-TAD (Lentivirus-mediated) in mild ischemic injury model could promote progression of CKD significantly. Conclusion FIH-1 mediated HIF-1α C-TAD activation was the key mechanism of AKI to CKD transition by transcriptionally regulating the KLF5 pathway in tubules. Blockade of FIH-1 mediated HIF-1α C-TAD in tubules may serve as a novel therapeutic approach to ameliorate AKI to CKD progression.

Muscle wasting and diminished physical performance contribute to the morbidity and mortality of chronic kidney disease (CKD), for which no curative therapy exists. Accumulating evidence indicates that impaired angiogenesis occurs in the muscles of CKD models. Therefore, proangiogenesis therapy is considered a potentially effective strategy for limiting CKD-associated myopathy. Hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF and enhances muscle angiogenesis during acute ischemia; however, little evidence was available from CKD models. Here, we assessed whether pharmacological activation of HIF by MK-8617 (MK), a novel orally active HIF-PHI, improves CKD-associated myopathy. Mice were divided into sham or CKD groups, and CKD mice were subdivided into CKD + vehicle or MK treatment groups (1.5, 5, or 12.5 mg/kg for 12 wk). In CKD mice, skeletal muscle mass, mitochondrial amount, and exercise capacity decreased compared with sham mice. Compared with the CKD + vehicle group, low (1.5 mg/kg) and medium (5 mg/kg) doses of MK, but not the high dose (12.5 mg/kg), significantly restored these changes and was accompanied by incremental increases in HIF-1α. Furthermore, increased capillary density and area were observed in a MK dose-dependent manner, which is likely related to an improved VEGF response in the skeletal muscle of CKD mice. In addition, macrophage and proinflammatory cytokines, including monocyte chemoattractant protein 1, TNF-α, and IL-6, significantly increased in the high-dose MK group. These results indicate that HIF-PHI provides a potential therapeutic strategy to improve CKD-associated myopathy.

Background/Aims: Chronic kidney disease (CKD) is a worldwide public health problem. Regardless of the underlying primary disease, CKD tends to progress to end-stage kidney disease, resulting in unsatisfactory and costly treatment. Its common pathogenesis, however, remains unclear. The aim of this study was to provide an unbiased catalog of common gene-expression changes of CKD and reveal the underlying molecular mechanism using an integrative bioinformatics approach. Methods: We systematically collected over 250 Affymetrix microarray datasets from the glomerular and tubulointerstitial compartments of healthy renal tissues and those with various types of established CKD (diabetic kidney disease, hypertensive nephropathy, and glomerular nephropathy). Then, using stringent bioinformatics analysis, shared differentially expressed genes (DEGs) of CKD were obtained. These shared DEGs were further analyzed by the gene ontology (GO) and pathway enrichment analysis. Finally, the protein-protein interaction networks(PINs) were constructed to further refine our results. Results: Our analysis identified 176 and 50 shared DEGs in diseased glomeruli and tubules, respectively, including many transcripts that have not been previously reported to be involved in kidney disease. Enrichment analysis also showed that the glomerular and tubulointerstitial compartments underwent a wide range of unique pathological changes during chronic injury. As revealed by the GO enrichment analysis, shared DEGs in glomeruli were significantly enriched in exosomes. By constructing PINs, we identified several hub genes (e.g. OAS1, JUN, and FOS) and clusters that might play key roles in regulating the development of CKD. Conclusion: Our study not only further reveals the unifying molecular mechanism of CKD pathogenesis but also provides a valuable resource of potential biomarkers and therapeutic targets.

Inflammation is a major contributor to the pathogenesis of ischemic acute kidney injury (AKI), which complicates the post-operative outcomes of large numbers of hospitalized surgical patients. Hydroxychloroquine (HCQ), a well-known anti-malarial drug, is commonly used in clinical practice for its anti-inflammatory actions. However, little is known about its role in renal ischemia/reperfusion (I/R) injury. In the current study, mice were subjected to I/R injury and HCQ was administered for seven days by gavage prior to surgery. In parallel, HK-2 human renal proximal tubule cells were prophylactically treated with HCQ and then were exposed to hypoxia/reoxygenation (H/R). The results showed that HCQ significantly attenuated renal dysfunction evidenced by blunted decreases in serum creatinine and kidney injury molecular-1 expression and the improvement of HK-2 cell viability. Additionally, HCQ markedly reduced macrophage and neutrophil infiltration, pro-inflammatory cytokine production, and NLRP3 inflammasome activation. Mechanistic studies showed that HCQ could inhibit the priming of the NLRP3 inflammasome by down-regulating I/R or H/R-induced NF-κB signaling. Moreover, HCQ reduced cathepsin (CTS) B, CTSD and CTSL activity, and their redistribution from lysosomes to cytoplasm. CTSB and CTSL (not CTSD) were implicated in I/R triggered NLRP3 inflammasome activation. Notably, we found that HCQ attenuated renal injury through downregulation of CTSB and CTSL-mediated NLRP3 inflammasome activation. This study provides new insights into the anti-inflammatory effect of HCQ in the treatment of AKI.

// Zuo-Lin Xiang 1, * , Xiao-Mei Zhao 1, * , Li Zhang 1 , Ping Yang 1 , Jia Fan 2 , Zhao-You Tang 2 , Zhao-Chong Zeng 1 1 Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China 2 Department of Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Zhao-Chong Zeng, email: zeng.zhaochong@zs-hospital.sh.cn Keywords: hepatocellular carcinoma, bone metastasis, microRNA-34a, serum, tissue microarray Received: July 05, 2016 Accepted: November 07, 2016 Published: November 23, 2016 ABSTRACT Hepatocellular carcinoma (HCC) patients with bone metastasis (BM) suffer from pain and other symptoms that significantly reduce their quality of life. We screened a microRNA (miRNA) microarray to identify potential serum biomarkers for BM in HCC patients. A miRNA microarray was used to screen for BM-related miRNAs in paired serum samples from HCC patients with BM and from HCC patients without BM. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to quantify candidate miRNAs in serum samples from 106 independent HCC patients. Levels of candidate miRNAs in tissue samples from an independent cohort of 296 HCC patients were evaluated by in situ hybridization and intratumoral tissue microarray. The migration and invasion capabilities of HCCLM3 and SMMC-7721 cells were evaluated following treatment with a mimic and an inhibitor of miR-34a. Ninety miRNAs were differentially expressed in sera from HCC patients with BM when compared with sera from non-BM HCC patients ( P < 0.05). Only miR-34a and miR-498 had false discovery rates (FDRs) < 0.05. In cohorts of 106 and 296 HCC patients, we found that reduced serum and intratumoral miR-34a expression levels were independent risk factors for developing BM. Migration and invasion experiments indicated that a reverse correlation existed between miR-34a and HCC tumor migration and invasion. This study demonstrates the potential for the use of miR-34a as a serum and intratumoral tissue biomarker for predicting the risk of BM in HCC patients.

Background: Recently, cinacalcet (CINA) has been shown to be effective for attenuating bone loss in the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD), which might be associated with the reduction in serum parathyroid hormone (PTH) levels. However, the exact mechanism is largely unclear. Emerging studies have revealed that an increased number of bone marrow adipocytes (BMAs) are involved in bone loss and the endothelial-to-adipocyte transition via the endothelial-to-mesenchymal transition (EndMT) might play a key role in this pathological process. Here, we assessed whether CINA could attenuate bone loss via inhibiting endothelial-to-adipocyte transition in CKD rats. Methods: A rat model of CKD was induced by adenine and a high phosphorus diet. CINA was orally administrated to CKD animals (10 mg/kg once a day). Dual energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and bone mechanical tests were used to determine the skeletal changes. The bone marrow expression of EndMT markers was also examined. The effect of elevated PTH levels on the endothelial-to-adipocyte transition was studied in endothelial cells (ECs). Results: Elevation of serum PTH levels, remarkable bone loss and increased numbers of BMAs were observed in rats with CKD compared with the controls, and these changes were attenuated after treatment with CINA. Furthermore, the CINA treatment abolished the upregulation of mesenchymal markers (FSP1 and α-SMA) and the downregulation of an endothelial marker (CD31) in bone tissues from rats with CKD. The serum PTH concentrations were correlated with the bone marrow protein levels of these EndMT-related proteins. An in vitro treatment in ECs demonstrated that PTH induced the EndMT in a concentration- and time-dependent manner. Accordingly, ECs treated with PTH exhibited adipogenic potential following growth in adipogenic culture medium. Conclusions: Our study indicated CINA treatment attenuated bone loss in CKD rats, which might be associated with inhibiting PTH-induced endothelial-to-adipocyte transition in CKD rats.

Background Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in the world. Emerging evidence has shown that urinary mRNAs may serve as early diagnostic and prognostic biomarkers of DKD. In this article, we aimed to first establish a novel bioinformatics-based methodology for analyzing the “urinary kidney-specific mRNAs” and verify their potential clinical utility in DKD. Methods To select candidate mRNAs, a total of 127 Affymetrix microarray datasets of diabetic kidney tissues and other tissues from humans were compiled and analyzed using an integrative bioinformatics approach. Then, the urinary expression of candidate mRNAs in stage 1 study (n = 82) was verified, and the one with best performance moved on to stage 2 study (n = 80) for validation. To avoid potential detection bias, a one-step Taqman PCR assay was developed for quantification of the interested mRNA in stage 2 study. Lastly, the in situ expression of the selected mRNA was further confirmed using fluorescent in situ hybridization (FISH) assay and bioinformatics analysis. Results Our bioinformatics analysis identified sixteen mRNAs as candidates, of which urinary BBOX1 (uBBOX1) levels were significantly upregulated in the urine of patients with DKD. The expression of uBBOX1 was also increased in normoalbuminuric diabetes subjects, while remained unchanged in patients with urinary tract infection or bladder cancer. Besides, uBBOX1 levels correlated with glycemic control, albuminuria and urinary tubular injury marker levels. Similar results were obtained in stage 2 study. FISH assay further demonstrated that BBOX1 mRNA was predominantly located in renal tubular epithelial cells, while its expression in podocytes and urothelium was weak. Further bioinformatics analysis also suggested that tubular BBOX1 mRNA expression was quite stable in various types of kidney diseases. Conclusions Our study provided a novel methodology to identify and analyze urinary kidney-specific mRNAs. uBBOX1 might serve as a promising biomarker of DKD. The performance of the selected urinary mRNAs in monitoring disease progression needs further validation. Electronic supplementary material The online version of this article (10.1186/s12967-019-1818-2) contains supplementary material, which is available to authorized users.

Although glucocorticoids are the mainstays in the treatment of renal diseases for decades, the dose dependent side effects have largely restricted their clinical use. Microvesicles (MVs) are small lipid-based membrane-bound particles generated by virtually all cells. Here we show that RAW 264.7 macrophage cell-derived MVs can be used as vectors to deliver dexamethasone (named as MV-DEX) targeting the inflamed kidney efficiently. Methods: RAW macrophages were incubated with dexamethasone and then MV-DEX was isolated from the supernatants by centrifugation method. Nanoparticle tracking analysis, transmission electron microscopy, western blot and high-performance liquid chromatography were used to analyze the properties of MV-DEX. The LC-MS/MS was applied to investigate the protein compositions of MV-DEX. Based on the murine models of LPS- or Adriamycin (ADR)-induced nephropathy or in-vitro culture of glomerular endothelial cells, the inflammation-targeting characteristics and the therapeutic efficacy of MV-DEX was examined. Finally, we assessed the side effects of chronic glucocorticoid therapy in MV-DEX-treated mice. Results: Proteomic analysis revealed distinct integrin expression patterns on the MV-DEX surface, in which the integrin αLβ2 (LFA-1) and α4β1 (VAL-4) enabled them to adhere to the inflamed kidney. Compared to free DEX treatment, equimolar doses of MV-DEX significantly attenuated renal injury with an enhanced therapeutic efficacy against renal inflammation and fibrosis in murine models of LPS- or ADR-induced nephropathy. In vitro, MV-DEX with about one-fifth of the doses of free DEX achieved significant anti-inflammatory efficacy by inhibiting NF-κB activity. Mechanistically, MV-DEX could package and deliver glucocorticoid receptors to renal cells, thereby, increasing cellular levels of the receptor and improving cell sensitivity to glucocorticoids. Notably, delivering DEX in MVs significantly reduced the side effects of chronic glucocorticoid therapy (e.g., hyperglycemia, suppression of HPA axis). Conclusion: In summary, macrophage-derived MVs efficiently deliver DEX into the inflamed kidney and exhibit a superior capacity to suppress renal inflammation and fibrosis without apparent glucocorticoid adverse effects. Our findings demonstrate the effectiveness and security of a novel drug delivery strategy with promising clinical applications.

Hypoxia, one of the most common causes of kidney injury, is a key pathological condition in various kidney diseases. Renal fibrosis is the terminal pathway involved in the continuous progression of chronic kidney disease (CKD), characterized by glomerulosclerosis and tubulointerstitial fibrosis (TIF). Recent studies have shown that hypoxia is a key factor promoting the progression of TIF. Loss of microvasculature, reduced oxygen dispersion, and metabolic abnormality of cells in the kidney are the main causes of the hypoxic state. Hypoxia can, in turn, profoundly affect the tubular epithelial cells, endothelial cells, pericytes, fibroblasts, inflammatory cells, and progenitor cells. In this chapter, we reviewed the critical roles of hypoxia in the pathophysiology of TIF and discussed the potential of anti-hypoxia as its promising therapeutic target.

Background and Objectives. Lymph node metastasis (LNM) is common in hepatocellular carcinoma (HCC). In order to intervene HCC LNM in advance, we developed a prediction nomogram based on serum long noncoding RNA (lncRNA). Methods. Serum samples from 242 HCC patients were gathered and randomly enrolled into the training and validation cohorts. LncRNAs screened out from microarray were quantified with qRT-PCR. Univariate and multivariate analyses were applied for screening independent risk factors. A prediction nomogram was ultimately developed for HCC LNM. The nomogram was estimated by discrimination and calibration tests in the validation cohort. The effects of the candidate lncRNA on the malignant phenotypes of HCC cells were further explored by wound healing assay and colony formation assay. Results. ENST00000418803, lnc-ZNF35-4:1, lnc-EPS15L1-2:1, BCLC stage, and vascular invasion were selected as components of the nomogram according to the adjusted multivariate analysis. The nomogram effectively predicted the HCC LNM risk among the cohorts with suitable calibration fittings and displayed high discrimination with C-index of 0.89 and 0.85. Moreover, the abnormally high expression of lnc-EPS15L1-2:1 in HCC cell lines showed significant carcinogenic effects. Conclusions. The noninvasive nomogram may provide more diagnostic basis for treatments of HCC. The biomarkers identified can bring new clues to basic researches.

Tubulointerstitial inflammation is a common characteristic of acute and chronic kidney injury. However, the mechanism by which the initial injury of tubular epithelial cells (TECs) drives interstitial inflammation remains unclear. This paper aims to explore the role of exosomal miRNAs derived from TECs in the development of tubulointerstitial inflammation. Global microRNA(miRNA) expression profiling of renal exosomes was examined in a LPS induced acute kidney injury (AKI) mouse model and miR-19b-3p was identified as the miRNA that was most notably increased in TEC-derived exosomes compared to controls. Similar results were also found in an adriamycin (ADR) induced chronic proteinuric kidney disease model in which exosomal miR-19b-3p was markedly released. Interestingly, once released, TEC-derived exosomal miR-19b-3p was internalized by macrophages, leading to M1 phenotype polarization through targeting NF-κB/SOCS-1. A dual-luciferase reporter assay confirmed that SOCS-1 was the direct target of miR-19b-3p. Importantly, the pathogenic role of exosomal miR-19b-3p in initiating renal inflammation was revealed by the ability of adoptively transferred of purified TEC-derived exosomes to cause tubulointerstitial inflammation in mice, which was reversed by inhibition of miR-19b-3p. Clinically, high levels of miR-19b-3p were found in urinary exosomes and were correlated with the severity of tubulointerstitial inflammation in patients with diabetic nephropathy. Thus, our studies demonstrated that exosomal miR-19b-3p mediated the communication between injured TECs and macrophages, leading to M1 macrophage activation. The exosome/miR-19b-3p/SOCS1 axis played a critical pathologic role in tubulointerstitial inflammation, representing a new therapeutic target for kidney disease.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been recognized as a new strategy for maxillary sinus floor elevation. However, little is known concerning the effect of the biomechanical pressure (i.e., sinus pressure, masticatory pressure, and respiration) on the differentiation of BM-MSCs and the formation of new bone during maxillary sinus floor elevation. The differentiation of BM-MSCs into osteoblasts was examined in vitro under cyclic compressive pressure using the Flexcell® pressure system, and by immunohistochemical analysis, qRT-PCR, and Western blot. Micro-CT was used to detect bone formation and allow image reconstruction of the entire maxillary sinus floor elevation area. Differentiation of BM-MSCs into osteoblasts was significantly increased under cyclic compressive pressure. The formation of new bone was enhanced after implantation of the pressured complex of BM-MSCs and Bio-Oss during maxillary sinus floor elevation. The pressured complex of BM-MSCs and Bio-Oss promoted new bone formation and maturation in the rabbit maxillary sinus. Stem cell therapy combined with this tissue engineering technique could be effectively used in maxillary sinus elevation and bone regeneration.

We developed an efficient microRNA (miRNA) model that could predict the risk of lymph node metastasis (LNM) in hepatocellular carcinoma (HCC). We first evaluated a training cohort of 192 HCC patients after hepatectomy and found five LNM associated predictive factors: vascular invasion, Barcelona Clinic Liver Cancer stage, miR-145, miR-31, and miR-92a. The five statistically independent factors were used to develop a predictive model. The predictive value of the miRNA-based model was confirmed in a validation cohort of 209 consecutive HCC patients. The prediction model was scored for LNM risk from 0 to 8. The cutoff value 4 was used to distinguish high-risk and low-risk groups. The model sensitivity and specificity was 69.6 and 80.2 %, respectively, during 5 years in the validation cohort. And the area under the curve (AUC) for the miRNA-based prognostic model was 0.860. The 5-year positive and negative predictive values of the model in the validation cohort were 30.3 and 95.5 %, respectively. Cox regression analysis revealed that the LNM hazard ratio of the high-risk versus low-risk groups was 11.751 (95 % CI, 5.110–27.021; P < 0.001) in the validation cohort. In conclusion, the miRNA-based model is reliable and accurate for the early prediction of LNM in patients with HCC.

Global solar radiation is a crucial variable for scientific researches and solar energy application, while it is measured at very few sites mainly due to the technical and fiscal obstacles. Developing robust and accurate models for estimating global solar radiation had been being a focus for many studies. This study was conducted to develop integrated models combining Moderate Resolution Imaging Spectroradiometer atmospheric products and meteorological variables. 43 empirical models based on the meteorological variables were collected. A total of 645 integrated models incorporating atmospheric constituents into the empirical models were developed. The researched models were evaluated and compared at Chongqing in Three Gorges Reservoir Area, China. The results showed that the integrated models outperformed the empirical models. The best integrated model had the root mean square error of 0.817 MJ m−2 and relative root mean square error of 8.11%. On average, the integrated models had the root mean square error of 1.071 MJ m−2, 15.6% smaller than the empirical models. The results suggest that coupling Moderate Resolution Imaging Spectroradiometer atmospheric products with meteorological variables can enhance the performance of the conventional empirical models, which may provide a promising alternative to generate global solar radiation data with better accuracy.

Extracellular vesicles (EVs) are nanosized, membrane‐bound vesicles released from different cells. Recent studies have revealed that EVs may participate in renal tissue damage and regeneration through mediating inter‐nephron communication. Thus, the potential use of EVs as therapeutic vector has gained considerable interest. In this review, we will discuss the basic characteristics of EVs and its role in nephron cellular communication. Then, the application of EVs as therapeutic vector based on its natural content or as carriers of drug, in acute and chronic kidney injury, was discussed. Finally, perspectives and challenges of EVs in therapy of kidney disease were described.

Minimizing the parasitic capacitance and the number of photo-masks can improve operational speed and reduce fabrication costs. Therefore, in this study, a new two-photo-mask process is proposed that exhibits a self-aligned structure without an etching-stop layer. Combining the backside-ultraviolet (BUV) exposure and backside-lift-off (BLO) schemes can not only prevent the damage when etching the source/drain (S/D) electrodes but also reduce the number of photo-masks required during fabrication and minimize the parasitic capacitance with the decreasing of gate overlap length at same time. Compared with traditional fabrication processes, the proposed process yields that thin-film transistors (TFTs) exhibit comparable field-effect mobility (9.5 cm2/V·s), threshold voltage (3.39 V), and subthreshold swing (0.3 V/decade). The delay time of an inverter fabricated using the proposed process was considerably decreased.

Background and Aim Liver cirrhosis is one of the major consequences of hepatitis B virus (HBV) infection, and transplantation of autologous bone marrow mesenchymal stem cells (ABMSCs) is one of promising therapies for patients with HBV-related liver cirrhosis (HBV-LC). However, the mechanism is unclear. The aim of the current study was to explore the role of Treg/Th17 cells in ABMSCs transplantation in patients with HBV-LC. Methods In this prospective study, 56 patients were enrolled and randomly assigned to transplantation group and control group. After 24-week follow-up, 39 patients completed the study (20 cases in transplantation group and 19 cases in control group). The Model for End-Stage Liver Disease scores, liver function, changes of Treg/Th17 cells, as well as related transcription factors and serum cytokines, were determined. Results Although patients in both groups showed significant improvement after Entecavir treatment, ABMSC transplantation further improved patients' liver function. Moreover, there was a significant increase in Treg cells and a marked decrease in Th17 cells in the transplantation group compared with control, leading to an increased Treg/Th17 ratio. Furthermore, mRNA levels of Treg-related transcription factor (Foxp3) and Th17-related transcription factor (RORγt) were increased and decreased, respectively. In addition, serum transforming growth factor-β levels were significantly higher at early weeks of transplantation, while serum levels of interleukin-17, tumor necrosis factor-α, and interleukin-6 were significantly lower in patients in the transplantation group compared with control. Conclusion ABMSCs transplantation was effective in improving liver function in patients with HBV-LC, which was mediated, at least in part, through the regulation of Treg/Th17 cell balance.

Saikosaponin-d (Ssd) is a triterpenoid saponin derived from Bupleurum falcatum L., which has been shown to exhibit a variety of pharmacological properties, including anti-inflammatory, antibacterial and antiviral properties. The aim of the present study was to investigate the effect of Ssd on the differentiation, maturation and function of human monocyte-derived dendritic cells (DCs) isolated from condylomata acuminata patients. The results of the present study demonstrated that Ssd reduced the differentiation of DCs, as evidenced by decreased expression levels of cluster of differentiation (CD)1a, CD80 and CD86 molecules and increased CD14 expression. Expression levels of the mannose receptor and CD32 were also significantly elevated , which was associated with enhanced fluorescein isothiocyanate -dextran endocytic activity. Furthermore, Ssd treatment promoted DC maturation by increasing the expression levels of CD40, CD83, CD80 and CD86. In addition, the function of mature DCs, including the secretion of IL-12 and the stimulation of lymphocyte proliferation, was significantly increased following Ssd administration. In conclusion, the present study indicated that Ssd exhibited immunomodulatory effects and may be a novel potent chemopreventive drug candidate for the treatment of condylomata acuminata.

In this study, Pr3+ ion-doped Ca2LaTaO6 phosphors were synthesized using a vibrating milled solid-state reaction with metal oxides and calcined in air at 1100°C for 8 h. The crystal structure and photoluminescence properties were also investigated. The x-ray powder diffraction patterns show that all of the peaks can be attributed to monoclinic Ca2LaTaO6 phase with increasing Pr3+ ion doping. The scanning electron microscopy images show that the particles are irregular, with the most uniform distribution being obtained for Pr3+ ion concentration of 3 mol.%. The emission spectra of Ca2(La1−xPrx)TaO6 phosphors showed a dominant green emission peak at 490 nm under excitation at 451 nm, which was due to the 3P0 → 3H4 transition. A series of weak emission peaks at 531 nm, 544 nm, 615 nm, 621 nm, and 652 nm were assigned to the 3P0 → 3H5, 1D2 → 3H4, 3P0 → 3H6, and 3P0 → 3F2 transitions of Pr3+ ions, respectively. In addition, the emission intensities of the Ca2(La1−x Prx)TaO6 phosphors increased then decreased as the Pr3+ ion concentration was increased, and the maximum emission intensity occurred for x of 0.03, corresponding to an average grain size of 41.5 nm with critical distance of 16.32 A. The Commission Internationale de l’Eclairage color chromaticity coordinates for the Ca2LaTaO6:Pr3+ phosphors were all located in the green region, but shifted from (x = 0.145, y = 0.463) to (x = 0.119, y = 0.471) as the Pr3+ ion concentration was increased from 0.5 mol.% to 10 mol.%.

This paper presents a pentacene-based organic thin-film transistor (OTFT) with a submicrometer channel length of 0.5 μm that uses a planar bottom-contact (pBC) structure to achieve high electrical performance. The performance of the submicrometer OTFT is dominantly influenced by the growth continuity of pentacene near the edge of the source/drain (S/D). The pBC structure with a bilayer dielectric can provide a continuous plane for improving the growth continuity and quality of pentacene near the edge of the S/D. This results in high electrical performance for the submicrometer OTFT with pBC structure, such as a mobility of 0.14 cm 2 /V s and an on/off current ratio of 1.9 × 10 5 .

We demonstrate a bilayer passivation method using a Teflon and SiO2 combination layer to improve the electrical reliability of pentacene-based organic thin-film transistors (OTFTs). The Teflon was deposited as a buffer layer using a thermal evaporator that exhibited good compatibility with the underlying pentacene channel layer, and can effectively protect the OTFTs from plasma damage during the SiO2 deposition process, resulting in a negligible initial performance drop in OTFTs. Furthermore, because of the excellent moisture barrier ability of SiO2, the OTFTs exhibited good time-dependent electrical performance, even after 168 h of aging in ambient air with 60–80% relative humidity.

The biology underlying bone-specific metastasis (BM) of hepatocellular carcinoma (HCC) is poorly understood. The goal of the present study is to further elucidate the molecular and cellular mechanisms underlying HCC with BM. The expression of connective tissue growth factor (CTGF) and interleukin-11 (IL-11) in RNA extracted from 127 formalin-fixed, paraffin-embedded HCC specimens was examined by quantitative real-time polymerase chain reaction. A cellular hypoxic model was established in vitro to investigate CTGF and osteoprotegerin (OPG) expression and roles in hypoxia-induced tumor aggressiveness. The mean CTGF expression in BM versus non-metastatic samples was 3.63-times higher, and IL-11 expression was detected in 62.5 % (10/16) of BM samples versus only in 18.9 % (21/111) of the non-metastatic ones. Highly metastatic HCC cell lines tended to show strong expression of CTGF and IL-11, but low expression of OPG. Hypoxic stimulation of HCC 97L cells increased the level of CTGF mRNA by 2.80-fold within 1.5 h, and hypoxia-inducible factor-1α mRNA levels in these cells could be increased by stimulation with recombinant CTGF protein. Furthermore, OPG and matrix metalloproteinase-2 and -9 levels were also induced under hypoxic conditions. Expression levels of intratumoral CTGF or IL-11 were independent prognostic factors for the development of BM in HCC patients. Tumor hypoxia enhanced the expression of CTGF, which initiates the invasive angiogenesis cascade and enhances expression of many hypoxia-associated genes. Cellular release of OPG may play a role in tumor cell survival. The hypoxia-induced cascade in HCC cells may contribute to invasion and metastasis in vivo.

This study proposes an alternative planar bottom-contact (pBC) structure to enhance the electrical performance of pentacene-based organic thin-film transistors (OTFTs). This pBC structure uses a bilayer dielectric to control planarization with a precise etch depth and introduces a bilayer photoresist lift-off method to ensure that planarization produces an optimum flatness. Because of the improved growth continuity of pentacene near the edge of the source/drain electrodes, the contact resistance between the source/drain and the pentacene was reduced significantly, thereby enhancing the electrical performance of OTFTs. The mechanism for the enhanced performance was also verified by a physics-based numerical simulation.

OBJECTIVE The objective of this study was to summarize our experience of using local flaps for the reconstruction of neck defects after cervical contractures release, particularly of using the extended deltopectoral flaps whose distal margin was beyond the anterior axillary line even reaching dorsalis for reconstruction of anterior neck scar contractures in a single-stage procedure. METHODS From 1987 to 2008, neck scar contractures were reconstructed using various local flaps in 68 patients with postburn anteriorly located neck contractures. The local flaps used consisted of 36 deltopectoral flaps, 6 extended deltopectoral flaps, 4 free scapular flaps, 8 neck-shoulder flaps, and 14 Z-plasties. The distal end of extended deltopectoral flaps was transferred as microvascular-free flap provided by the posterior circumflex humeral artery, but the proximal end as pedicle flap supplied by the anterior perforating branches of internal mammary artery. Other flaps were elevated conventionally as described previously in the articles. RESULTS Of 68 patients, there were 59 cases (86.8%) whose release of the contractures was excellent. For 51 patients, the whole process of treatment was finished only in a single-stage procedure. We used extended deltopectoral flap, which was developed from our own anatomic studies and from previous reports in the literature, in 6 patients. This new flap extends the volume of the original deltopectoral flap, from 22 to 32 cm in length and 10 to 22 cm in width (at the apex). Postoperatively, all flaps survived completely. Patients were satisfied with their results. The follow-up period ranged 1 to 10 years; no obvious recontractures have been noted. There were no severe donor-site complications. CONCLUSIONS The local flap with matching texture, color, elasticity, and pliability is still the best choice for reconstruction of postburn anteriorly located neck contractures. The extended deltopectoral flap has been used successfully to yield satisfactory outcomes for the scar contractures in the anterior neck and should be conserved as a selective method for reconstructive surgeons.

In this paper, the top-contact (TC) pentacene-based organic thin-film transistor (OTFT) with a tetrafluorotetracyanoquinodimethane (F4TCNQ)-doped pentacene interlayer between the source/drain electrodes and the pentacene channel layer were fabricated using the co-evaporation method. Compared with a pentacene-based OTFT without an interlayer, OTFTs with an F4TCNQ:pentacene ratio of 1:1 showed considerably improved electrical characteristics. In addition, the dependence of the OTFT performance on the thickness of the F4TCNQ-doped pentacene interlayer is weaker than that on a Teflon interlayer. Therefore, a molecular doping-type F4TCNQ-doped pentacene interlayer is a suitable carrier injection layer that can improve the TC-OTFT performance and facilitate obtaining a stable process window.

A USB2.0-based transmission system of micro-projection video signal is designed and implemented.In the system,frame images and the data of video on a media player are grabbed in real time,which are transmitted with USB interface and acquired with external FPGA logic circuit on the USB equipment.The design is verified on a FLCOS microprojection platform,and it shows that a transmission rate of 18.75 Mbyte/s is obtained,and video of 16-bit color,640×480 resolution and 30 frame/s can be transmitted in real time with the system.

We aimed to develop a clinicopathological model that would predict the risk of bone metastasis (BM) in hepatocellular carcinoma (HCC). We first evaluated a training cohort of 201 HCC patients who had undergone hepatectomy and found that the following factors independently predicted BM development: vascular invasion, tumor-node-metastasis stage, CXCR4, connective tissue growth factor, and interleukin-11. These variables were used to construct a clinicopathological prediction model that may be scored from 0 to 19. The predictive value of the model was demonstrated in a validation cohort of 179 post-hepatectomy HCC patients. During a median follow-up of 54.3 months for the training cohort and 52.5 months for the validation cohort, 23 patients (11.4%) in the former and 19 patients (10.6%) in the latter developed BM. A cutoff value of 9.4 best discriminated BM risk and was able to exclude future BM development with high accuracy in the validation cohort. The sensitivity and specificity of the method were 73.7 and 78.7%, respectively, the positive predictive value was 29.2%, and the negative predictive value 96.2%. The 1- and 2-year cumulative BM rates were (respectively) 10.8% and 27.4% in the high-risk group and 2.4 and 4.3% in the low-risk group. The hazard ratio for BM of the high- versus low-risk group was 9.240 (95% CI: 3.319–25.722). The simple prediction model constructed from clinicopathological parameters is accurate in predicting BM development in HCC patients.

Purpose: Hepatocellular carcinoma (HCC) most often develops in patients infected with hepatitis B or hepatitis C virus. Differential gene expression profiling is useful for investigating genes associated with lymph node metastasis (LNM). We screened genes to identify potential biomarkers for LNM in HCC. Experimental Design: RNA was extracted from formalin-fixed specimens of paired intratumoral and peritumoral tissues of patients with lymph node–positive (n = 36) or negative (n = 36) HCC. A cDNA-mediated annealing, selection, extension, and ligation assay was done with an array of 502 known cancer-related genes to identify differentially expressed genes in 20 pairs of patients with or without LNM. Candidate biomarkers were evaluated by using immunohistochemistry and tissue microarrays in an independent cohort of 309 HCC patients who had undergone hepatectomy. Of the 309 patients, 235 (76.1%) patients were infected with hepatitis B. Results: Compared with lymph node–negative patients, lymph node–positive patients had 17 overexpressed genes and 19 underexpressed genes in intratumoral tissues, and 25 overexpressed genes and 22 underexpressed genes in peritumoral tissues. Hypoxia-inducible factor (HIF)-1α, VEGF, and matrix metalloproteinase (MMP)-2 were selected for analysis in the cohort of 309 HCC patients. We found that intratumoral protein levels of HIF-1α, VEGF, and MMP-2 were independent risk factors for developing LNM. Conclusion: We identified 83 cancer genes that were differentially expressed in lymph node–positive and lymph node–negative HCC. Our findings show that the combination of intratumoral HIF-1α, VEGF, and MMP-2 may be useful as a molecular prediction model for LNM. Clin Cancer Res; 17(16); 5463–72. ©2011 AACR.

The purpose of this study was to evaluate the relationship between hypoxia-inducible factor-1α (HIF-1α) protein expression in hepatocellular carcinoma (HCC), and responses of abdominal metastatic lymph nodes (LNs) from HCC patients treated with external beam radiotherapy (EBRT). HIF-1α immunohistochemical staining was performed on tissue microarrays (TMAs) of primary HCC specimens from 69 HCC patients with abdominal LN metastases. All patients received abdominal metastatic LN EBRT at the Department of Radiation Oncology at Zhongshan Hospital. A receiver-operating characteristic (ROC)-based approach and logistical regression analysis were used to determine the predictive value of HIF-1α expression in primary tumors with HCC metastatic LN EBRT response. Kaplan-Meier curves and log-rank tests were used to analyze patient survival. Cox proportional hazards regression model was used to analyze independent prognostic factors. HIF-1α expression was correlated with blood hemoglobin (Hb: r = -0.280, P = 0.020), response of abdominal metastatic LNs to EBRT (r = 0.286, P = 0.017), locoregional recurrence (r = 0.278, P = 0.021), and cancer-specific deaths (r = 0.298, P = 0.013). HIF-1α expression was predictive of EBRT response of metastatic LNs [area under the curve (AUC): 0.646; 95% confidence interval (CI): 0.499-0.793; P = 0.047], locoregional recurrence (AUC: 0.657; 95% CI: 0.509-0.805; P = 0.049) and cancer-specific deaths (AUC: 0.671; 95% CI: 0.531-0.812; P = 0.035). Patients with tumors exhibiting high HIF-1α expression had significantly poorer overall survival (OS) than those with low tumor expression of HIF-1α (P = 0.016). Multivariate analysis showed that Hb (P = 0.035), vascular invasion (P = 0.026), Child-Pugh score (P < 0.001), intrahepatic tumor control (P < 0.001), and HIF-1α (P = 0.020) were independent prognosis factors for OS of HCC patients after receiving abdominal metastatic LN EBRT. HIF-1α expression in primary HCCs was associated with EBRT response of abdominal metastatic LNs and poor prognosis.