Cetuximab versus bevacizumab following prior FOLFOXIRI and bevacizumab in postmenopausal women with advanced KRAS and BRAF wild-type colorectal cancer: a retrospective study.

BACKGROUND: An upgraded understanding of factors (sex/estrogen) associated with survival benefit in advanced colorectal carcinoma (CRC) could improve personalised management and provide innovative insights into anti-tumour mechanisms. The aim of this study was to assess the efficacy and safety of cetuximab (CET) versus bevacizumab (BEV) following prior 12 cycles of fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus BEV in postmenopausal women with advanced KRAS and BRAF wild-type (wt) CRC. METHODS: Prospectively maintained databases were reviewed from 2013 to 2017 to assess postmenopausal women with advanced KRAS and BRAF wt CRC who received up to 12 cycles of FOLFOXIRI plus BEV inductive treatment, followed by CET or BEV maintenance treatment. The primary endpoints were overall survival (OS), progression-free survival (PFS), response rate. The secondary endpoint was the rate of adverse events (AEs). RESULTS: At a median follow-up of 27.0 months (IQR 25.1-29.2), significant difference was detected in median OS (17.7 months [95% confidence interval [CI], 16.2-18.6] for CET vs. 11.7 months [95% CI, 10.4-12.8] for BEV; hazard ratio [HR], 0.63; 95% CI, 0.44-0.89; p=0.007); Median PFS was 10.7 months (95% CI, 9.8-11.3) for CET vs. 8.4 months (95% CI, 7.2-9.6) for BEV (HR, 0.67; 95% CI 0.47-0.94; p=0.02). Dose reduction due to intolerable AEs occurred in 29 cases (24 [24.0%] for CET vs. 5 [4.8%] for BEV; p< 0.001). CONCLUSIONS: CET tends to be superior survival benefit when compared with BEV, with tolerated AEs.

Resveratrol attenuates hIAPP amyloid formation and restores the insulin secretion ability in hIAPP-INS1 cell line via enhancing autophagy.

It has been proved that human islet amyloid polypeptide (hIAPP), the main constituent of islet amyloid deposition, is one of the important factors that can induce type 2 diabetes or graft failure after islet transplantation. As there is no research on whether resveratrol degrading the amyloid deposition by its special chemical structure or enhancing autophagy had been published, we decided to detect the function of resveratrol in degrading the amyloid deposition in pancreatic beta cells. We established stable hIAPP-INS1 cell line via transfecting INS1 cells by lentivirus that overexpresses hIAPP. Our research demonstrates that amyloid deposition existed in hIAPP-INS1 cell by the thioflavin S fluorescent staining, meanwhile the function of insulin secretion of hIAPP-INS1 cells was decreased significantly (p < 0.01). After treatment with resveratrol (20 µM) for 24 h, amyloid deposition in hIAPP-INS1 cells was decreased significantly, and the insulin secretion was restored significantly (p < 0.01). Once inhibited the autophagy of hIAPP-INS1 cells by 3-methyladenine for 24 h, resveratrol does not effectively remove hIAPP deposits again, and cannot improve the function of insulin secretion. These results provide a novel thought that resveratrol can degrade the amyloid deposition in type 2 diabetes and the graft after islet transplantation.

miR-663a inhibits tumor growth and invasion by regulating TGF-ß1 in hepatocellular carcinoma.

BACKGROUND: The dysregulation of miR-663a is frequently observed in many human cancers. However, the functional role and precise mechanism of miR-663a have been controversial in hepatocellular carcinoma (HCC) and need to be studied in depth. METHODS: The expression of miR-663a was detected in human cell lines and HCC tissues by quantitative RT-PCR (qRT-PCR), and data from the Cancer Genome Atlas (TCGA). Cell proliferation was investigated using MTS, EdU, colony formation assays, and xenograft animal experiments, and the cell invasion capacity was evaluated using the transwell assay. The target gene of miR-663a was identified by qRT-PCR, Western blot, and dual-luciferase reporter assays. The clinicopathological features of miR-663a and the correlation between miR-663a and TGF-ß1 expression were also investigated in the clinical samples of HCC. RESULTS: miR-663a was significantly downregulated in HCC cells relative to immortal normal liver cells, as indicated using qRT-PCR, and the lower expression of miR-663a was also confirmed in HCC tissue samples and the data from TCGA. The expression of miR-663a in HCC tissue samples was statistically significantly associated with size and the number of tumors. In addition, the upregulation of miR-663a inhibited the proliferation and invasion of HCC cells in vitro. Further study showed that miR-663a directly targeted transforming growth factor beta 1 (TGF-ß1) to suppress HCC invasion, and that the inhibitory effect of miR-663a on cell invasion could be regulated by TGF-ß1. In vivo studies showed that miR-663a significantly inhibited tumor growth. A negative correlation between miR-663a and TGF-ß1 expression was also confirmed from the clinical samples of HCC. CONCLUSIONS: miR-663a acts as a tumor suppressor and exerts a substantial role in inhibiting the proliferation, invasion, and tumorigenesis of HCC by regulating TGF-ß1 in vitro and in vivo. These observations indicate that miR-663a may be a suitable diagnostic, therapeutic, and prognostic target for the treatment of HCC.

Basiliximab application on liver recipients: a meta-analysis of randomized controlled trials.

BACKGROUND: The benefits of the application of basiliximab induction therapy in liver transplantation are not clear. The present meta-analysis was to evaluate the pros and cons of basiliximab use in liver transplantation. DATA SOURCES: We searched the associated publications in English from July 1998 to December 2015 in the following databases: MEDLINE, PubMed, Ovid, EMBASE, Web of Science and Cochrane Library. RESULTS: Basiliximab significantly decreased the incidence of de novo diabetes mellitus after liver transplantation (RR=0.56; 95% CI: 0.34-0.91; P=0.02). Subgroup analysis showed that basiliximab in combination with steroids-free immunosuppressant significantly decreased the incidence of biopsy-proven acute rejection (RR=0.62; 95% CI: 0.39-0.97; P=0.04) and new-onset hypertension (RR=0.62; 95% CI: 0.42-0.93; P=0.02). CONCLUSIONS: Basiliximab may be effective in reducing de novo diabetes mellitus. What is more, basiliximab in combination with steroids-free immunosuppressant shows statistical benefit to reduce biopsy-proven acute rejection and de novo hypertension.

TBX15 facilitates malignant progression of glioma by transcriptional activation of TXDNC5.

T-box transcription factor 15 (TBX15) plays important role in various cancers; however, its expression and role in glioma is still unclear. In this study, our findings indicated that TBX15 was increased in gliomas compared to normal brain tissues, and high levels of TBX15 were related to poor survival. Furthermore, TBX15 silencing in glioma cells not only inhibited their proliferation, migration, and invasion in vitro, but also weakened their ability to recruit macrophages and polarize the latter to the M2 subtype. Mechanism study indicated that thioredoxin domain containing 5 (TXNDC5) lies downstream of TBX15. Furthermore, rescue assays verified that the role of TBX15 in glioma cells is dependent on TXNDC5. Moreover, sh-TBX15 loaded into DNA origami nanocarrier suppressed the malignant phenotype of glioma in vitro and in vivo. Taken together, the TBX15/TXNDC5 axis is involved in the genesis and progression of glioma, and is a potential therapeutic target.

Radiomic Prediction of CCND1 Expression Levels and Prognosis in Low-grade Glioma Based on Magnetic Resonance Imaging.

OJECTIVES: Low-grade glioma (LGG) is associated with increased mortality owing to recrudescence and the tendency for malignant transformation. Therefore, it is imperative to discover novel prognostic biomarkers as existing traditional prognostic biomarkers of glioma, including clinicopathological features and imaging examinations, are unable to meet the clinical demand for precision medicine. Accordingly, we aimed to evaluate the prognostic value of cyclin D1 (CCND1) expression levels and construct radiomic models to predict these levels in patients with LGG MATERIALS AND METHODS: A total of 412 LGG cases from The Cancer Genome Atlas (TCGA) were used for gene-based prognostic analysis. Using magnetic resonance imaging (MRI) images stored in The Cancer Imaging Archive with genomic data from TCGA, 149 cases were selected for radiomics feature extraction and model construction. After feature extraction, the radiomic signature was constructed using logistic regression (LR) and support vector machine (SVM) analyses. RESULTS: CCND1 was identified as a prognosis-related gene with differential expression in tumor and normal samples and plays a role in regulating both the cell cycle and immune response. Landmark analysis revealed that high-expression levels of CCND1 were beneficial for survival (P < 0.05) in advanced LGG. Four optimal radiomics features were selected to construct radiomics models. The performance of LR and SVM achieved areas under the curve of 0.703 and 0.705, as well as 0.724 and 0.726 in the training and validation sets, respectively. CONCLUSION: Elevated levels of CCND1 expression could impact the prognosis of patients with LGG. MRI-based radiomics, especially the AUC values, can serve as a novel tool for predicting CCND1 expression and understanding the correlation between elevated CCND1 expression and prognosis. AVAILABILITY OF DATA AND MATERIALS: The datasets analyzed during the current study are available in the TCGA, TCIA, UCSC XENA and GTEx repository, https://portal.gdc.cancer.gov/, https://www.cancerimagingarchive.net/, https://xenabrowser.net/datapages/, https://www.gtexportal.org/home/.

Long noncoding RNA HOXC-AS3 remodels lipid metabolism and promotes the proliferation of transformed macrophages in the glioma stem cell microenvironment by regulating the hnRNPA1/CaM axis.

Metabolism remodelling of macrophages in the glioblastoma microenvironment contributes to immunotherapeutic resistance. However, glioma stem cell (GSC)-initiated lipid metabolism remodelling of transformed macrophages (tMΦs) and its effect on the glioblastoma microenvironment have not been fully elucidated. Total cholesterol (TC) levels and lipid metabolism enzyme expression in macrophages in the GSC microenvironment were evaluated and found that the TC levels of tMΦs were increased, and the expression of the lipid metabolism enzymes calmodulin (CaM), apolipoprotein E (ApoE), and liver X receptor (LXR) was upregulated. Knockdown of HOXC-AS3 led to a decrease in the proliferation, colony formation, invasiveness, and tumorigenicity of tMΦs. Downregulation of CaM resulted in a decline in TC levels. HOXC-AS3 overexpression led to increases in both CaM expression levels and TC levels in tMΦs. RNA pull down and mass spectrometry experiments were conducted and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was screened as the HOXC-AS3 binding proteins related to lipid metabolism. RIP and RNA pull down assays verified that HOXC-AS3 can form a complex with hnRNPA1. Knockdown of hnRNPA1 downregulated CaM expression; however, downregulation of HOXC-AS3 did not affect hnRNPA1 expression.TMΦs underwent lipid metabolism remodelling induced by GSC via the HOXC-AS3/hnRNPA1/CaM pathway, which enhanced the protumor activities of tMΦs, and may serve as a potential metabolic intervening target to improve glioblastoma immunotherapy.

RNA-binding protein DHX9 promotes glioma growth and tumor-associated macrophages infiltration via TCF12.

BACKGROUND: Glioma is the most common malignant tumor of the central nervous system, with high heterogeneity, strong invasiveness, high therapeutic resistance, and poor prognosis, comprehending a serious challenge in neuro-oncology. Until now, the mechanisms underlying glioma progression have not been fully elucidated. METHODS: The expression of DExH-box helicase 9 (DHX9) in tissues and cells was detected by qRT-PCR and western blot. EdU and transwell assays were conducted to assess the effect of DHX9 on proliferation, migration and invasion of glioma cells. Cocultured model was used to evaluate the role of DHX9 on macrophages recruitment and polarization. Animal study was performed to explore the role of DHX9 on macrophages recruitment and polarization in vivo. Bioinformatics analysis, dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay was used to explore the relation between DHX9 and TCF12/CSF1. RESULTS: DHX9 was elevated in gliomas, especially in glioblastoma multiforme (GBM). Besides promoting the proliferation, migration, and invasion of glioma cells, DHX9 facilitated the infiltration of macrophages into glioma tissues and polarization to M2-like macrophages, known as tumor-associated macrophages (TAMs). DHX9 silencing decreased the expression of colony-stimulating factor 1 (CSF1), which partially restored the inhibitory effect on malignant progress of glioma and infiltration of TAMs caused by DHX9 knockdown by targeting the transcription factor 12 (TCF12). Moreover, TCF12 could directly bind to the promoter region of CSF1. CONCLUSION: DHX9/TCF12/CSF1 axis regulated the increases in the infiltration of TAMs to promote glioma progression and might be a novel potential target for future immune therapies against gliomas.

Zero Shear Viscosity of Hybrid Modified Asphalts and Its Gray Correlation with Other Properties.

The viscosity of modified asphalt binders is the most important property to ensure the durability of open-graded friction course (OGFC). Zero shear viscosity (ZSV) is considered to be the optimum result to reflect the rutting characterization of high viscosity modified asphalt binders, compared with conventional vacuum capillary viscosity. However, there are few reports on using ZSV to evaluate the material characteristics of hybrid modified asphalt binders and to establish the relationship between ZSV and other properties. In this paper, a high viscosity hybrid modified asphalt binder was prepared with Sty-rene-butadiene-styrene (SBS) and Crumb rubber modifier (CRM). ZSV, three major indicators, 60 °C dynamic viscosity, 135 °C Brookfield viscosity, and a dynamic rheological test were used to determine the properties of the hybrid modified asphalt binders. The relationship between ZSV and other properties was studied by the gray correlation analysis method. Results indicated that: (1) The viscosity of hybrid modified asphalt binders increases with the decreasing frequency. When the frequency tends to 0, the viscosity of asphalt at this time is zero shear viscosity; (2) The values of the ZSV of hybrid modified asphalt binders have a large increase as the dose of both CRM and SBS modifiers were increased; and (3) The ZSV at 60 °C correlated well with the performance properties of rutting factor (G*/sin(θ)), indicating that the ZSV of hybrid modified asphalt binders could be a good indicator of performance.

Cetuximab versus bevacizumab maintenance following prior 8-cycle modified FOLFOXIRI plus cetuximab in Asian postmenopausal women with treatment-naive KRAS and BRAF wild-type metastatic colorectal cancer.

OBJECTIVE: To assess the efficacy and safety of cetuximab (CE) versus bevacizumab (BE) maintenance treatment after prior 8-cycle modified 5-fluorouracil, folinate, oxaliplatin, and irinotecan (FOLFOXIRI) plus CE induction therapy in treatment-naive KRAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC). METHODS: From 2012 to 2017, prospectively maintained databases were reviewed to assess Asian postmenopausal women with treatment-naive KRAS and BRAF wt mCRC who underwent modified FOLFOXIRI plus CE induction therapy, followed by CE or BE maintenance until disease progression or death. Co-primary clinical endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 222 women were included (CE n = 110 and BE n = 112). At a median follow-up of 27.0 months (interquartile range, 6.5-38.6 months), median PFS was 21.9 months (95% confidence interval [CI] 16.4-24.4) and 17.7 months (95% CI 11.3-19.0) for CE and BE groups, respectively (hazard ratio [HR] 0.31, 95% CI 0.15-0.46); median OS was 26.0 months (95% CI 23.4-28.7) and 22.7 months (95% CI 21.2-24.3) for CE and BE groups, respectively (HR 0.22, 95% CI 0.11-0.37). CONCLUSIONS: CE maintenance treatment is more poorly tolerated but has a slightly more modest survival benefit compared with BE maintenance treatment in mCRC.

Cemented versus uncemented total hip replacement for femoral neck fractures in elderly patients: a retrospective, multicentre study with a mean 5-year follow-up.

BACKGROUND: Cemented or uncemented total hip replacement (CTR or UTR) for femoral neck fractures (AO/OTA type 31B/C) is a relatively common procedure in elderly individuals. The recent literature is limited regarding long-term outcomes following CTR versus UTR in the Asian population. METHODS: Using our institutional database, we performed long-term outcome analysis on 268 patients with femoral neck fractures (AO/OTA type 31B/C) who had undergone a primary UTR or CTR (CTR: n = 132, mean age, 67.43 ± 6.51 years; UTR: n = 136, mean age, 67.65 ± 6.13 years) during 2007-2014, and these patients were followed until 2019. Follow-up occurred 1, 3, 6, and 12 months postoperatively and yearly thereafter. The primary endpoint was the Harris hip score (HHS); the secondary endpoint was the incidence of orthopaedic complications. RESULTS: The mean follow-up time was 62.5 months (range, 50.1-76.1 months). At the final follow-up, the HHS was 79.39 ± 16.92 vs 74.18 ± 17.55 (CTR vs UTR, respectively, p = 0.011). Between-group significant differences were observed regarding the incidence of prosthesis revision, prosthesis loosening, and periprosthetic fracture (7.6% [95% CI, 6.4-8.2] for CTR vs 16.9% [95% CI, 14.7-17.3] for UTR, p = 0.020; 9.8% [95% CI, 8.3-10.7] for CTR vs 19.9% [95% CI, 18.2-20.9] for UTR, p = 0.022; 5.3% [95% CI, 4.4-6.7] for CTR vs 13.2% [95% CI, 12.1-13.8] for UTR, p = 0.026, respectively). CONCLUSION: CTR showed superiority to UTR by improving the HHS and decreasing the incidence of orthopaedic complications. Our findings need to be confirmed in a prospective, randomized controlled study to verify whether they can be applicable to a broader population.

Simulated Cholinergic Reinnervation of ß (INS-1) Cells: Antidiabetic Utility of Heterotypic Pseudoislets Containing ß Cell and Cholinergic Cell.

Cholinergic neurons can functionally support pancreatic islets in controlling blood sugar levels. However, in islet transplantation, the level of cholinergic reinnervation is significantly lower compared to orthotopic pancreatic islets. This abnormal reinnervation affects the survival and function of islet grafts. In this study, the cholinergic reinnervation of beta cells was simulated by 2D and 3D coculture of INS-1 and NG108-15 cells. In 2D culture conditions, 20 mM glucose induced a 1.24-fold increase (p < 0.0001) in insulin secretion from the coculture group, while in the 3D culture condition, a 1.78-fold increase (p < 0.0001) in insulin secretion from heterotypic pseudoislet group was observed. Glucose-stimulated insulin secretion (GSIS) from 2D INS-1 cells showed minimal changes when compared to 3D structures. E-cadherin expressed in INS-1 and NG108-15 cells was the key adhesion molecule for the formation of heterotypic pseudoislets. NG108-15 cells hardly affected the proliferation of INS-1 cells in vitro. Heterotypic pseudoislet transplantation recipient mice reverted to normoglycemic levels faster and had a greater blood glucose clearance compared to INS-1 pseudoislet recipient mice. In conclusion, cholinergic cells can promote insulin-secreting cells to function better in vitro and in vivo and E-cadherin plays an important role in the formation of heterotypic pseudoislets.

Using Illumina Infinium HumanMethylation 450K BeadChip to explore genome­wide DNA methylation profiles in a human hepatocellular carcinoma cell line.

Aberrant DNA methylation is the most common type of epigenetic alteration and is associated with many types of cancer. Although previous studies have provided a few novel DNA methylation markers in hepatocellular carcinoma (HCC), specific DNA methylation patterns and comparisons of the aberrant alterations in methylation between HCC and normal liver cell lines have not yet been reported. Therefore, in the present study the Illumina Infinium HumanMethylation 450K BeadChip was employed to identify the genome­wide aberrant DNA methylation profiles of Huh7 and L02 cells. Following Bonferroni adjustment, 102,254 differentially methylated CpG sites (covering 26,511 genes) were detected between Huh7 and L02 cells. Of those CpG sites, 62,702 (61.3%) sites were hypermethylated (covering 12,665 genes) and 39,552 (38.7%) sites were hypomethylated (covering 13,846 genes). The results of the present study indicated that 40.3% of the CpG sites were in CpG island regions, 20.7% were in CpG shores and 8.8% were in shelf regions. A total of 57.3% hypermethylated CpG sites and 39.4% of the hypomethylated CpG sites had a |ß­Difference| ≥50%. Within the significant differentially methylated CpG sites, 490 genes were located within 598 differentially methylated regions. Gene Ontology enrichment analysis revealed that 2,107 differentially methylated genes were associated with 'biological process', 13,351 differentially methylated genes were associated with 'molecular function', and 18,041 differentially methylated genes were associated with 'cellular component'. Kyoto Encyclopedia of Genes and Genomes pathway­based analysis revealed 43 signaling pathways that were associated with 5,195 differentially methylated genes. These results demonstrated that aberrant DNA methylation may be a key and common event underlying the tumorigenesis of Huh7 cells. The present study also identified many subsets of hypo­ or hyper­methylated CpG sites, genes and signaling pathways, which have an importance in the occurrence and development of HCC.

Scoring System to Predict the Risk of Surgical Site Infection in Patients with Esophageal Cancer after Esophagectomy with Cervical Anastomosis.

BACKGROUND: Surgical site infection (SSI) surveillance has become increasingly important during the peri-operative period of esophagectomy with cervical anastomosis (McKeown esophagectomy). This study sought to clarify the risk factors for SSI and to develop a stratification scoring system to predict SSI after esophagectomy with cervical anastomosis. PATIENTS AND METHODS: All patients who underwent elective esophagectomy with cervical anastomosis were studied between January 2010 and December 2016 in the Chinese Academy of Medical Sciences Cancer Hospital (CAMS). Univariable analysis and multivariable logistic regression were used to screen the independent risk factors. A risk stratification scoring system was developed based on multivariable logistic regression parameters. The model derivation set involved 711 consecutive cases, and the validation set involved 168 consecutive cases. RESULTS: In the model derivation set, there were 711 patients, of whom 146 were found to have SSI and the incidence rate was 20.53%. Multivariable analysis found that SSI was associated independently with the following adverse risk factors: peripheral vascular disease, prior chest surgery, no pre-operative surgical antibiotic prophylaxis (SAP) administration within 120 minutes prior to incision, low serum albumin, and low pre-albumin at post-operative day zero to three, respectively. Each of these factors contributed one point to the risk score and a risk stratification scoring system was established. The SSI rates were increased gradually in the low, intermediate, high, and extremely high-risk groups (p < 0.001). The area under the receiver operating characteristic (AUROC) curve was 0.706 for the logistic regression model and 0.704 for the scoring system. In the validation set, the model performed equivalently (AUC = 0.824). CONCLUSIONS: The validated stratification scoring system could predict accurately the risk of SSI after esophagectomy with cervical anastomosis. This could be helpful in the selection of high-risk patients requiring frequent monitoring and more aggressive interventions to decrease the incidence of SSI.

Effect of levothyroxine on the progression of carotid intima-media thickness in subclinical hypothyroidism patients: a meta-analysis.

BACKGROUND: Subclinical hypothyroidism (SCH) has been associated with increased carotid intima-media thickness (C-IMT) in recent studies, but the effects of levothyroxine (L-T4) therapy on C-IMT in SCH patients are still controversial. AIM: To evaluate the effect of L-T4 therapy on endothelial function as determined by C-IMT in patients with SCH. METHODS: BeforeJuly 2016, we searched the PubMed, Embase, Cochrane Library and Google Scholar databases, selecting published randomised controlled trials (RCTs) and self-controlled trials for the meta-analysis. RESULTS: Three RCTs with 117 patients were considered appropriate for the meta-analysis. The results of the meta-analysis indicated that L-T4 significantly decreased the development of C-IMT (weighted mean difference (WMD) -0.05 mm, 95% CI -0.08 to -0.01 mm; p=0.025). We also analysed nine studies (self-controlled trials) with 247 patients and extracted the IMT of SCH patients before and after L-T4 treatment. After L-T4 therapy, the pooled estimate of the WMD of decreased C-IMT was -0.04 mm (95% CI -0.07 to -0.02 mm; p=0.05). Subgroup analysis showed that L-T4 therapy was associated with a decrease in C-IMT among patients of mixed genders (WMD -0.03 mm, 95% CI -0.06 to -0.01 mm; p=0.145). L-T4 therapy was associated with a decrease in C-IMT among female patients (WMD -0.07 mm, 95% CI -0.14 to -0.01; p=0.186). Longer treatment (>6 months) also resulted in a significant decrease in C-IMT (WMD -0.05 mm, 95% CI -0.08 to -0.02; p=0.335). CONCLUSION: This meta-analysis indicates that L-T4 treatment of SCH patients can reduce C-IMT, possibly as a result of the reduction of total cholesterol, triglyceride, low density lipoprotein, systolic blood pressure, diastolic blood pressure, lipoprotein(a), and flow-mediated dilatation. Decreased C-IMT was observed in SCH patients after long-term (>6 months) L-T4 treatment. RCTs with larger samples are needed to verify these observations.

The benefit of immunonutrition in patients undergoing hepatectomy: a systematic review and meta-analysis.

Perioperative immunonutrition in liver resection remains doubtful. A systematic review and meta-analysis was conducted to compare postoperative outcomes between patients undergoing hepatectomy who received perioperative immunonutrition and those who did not.A PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Knowledge database search was performed to retrieve all of the randomized controlled trials (RCTs) evaluating the value of perioperative immunonutrition in patients undergoing hepatectomy until the end of September 2016. Data extraction and quality assessment of RCTs were performed in accordance with PRISMA guidelines. The quality of evidence for each postoperative outcome was assessed using the GRADEpro analysis. A random-effects model was used to conduct a meta-analysis with RevMan 5.3.5 software. Eight RCTs including 805 patients (402 with and 403 without immunonutrition) were identified. Immunonutrition, mainly ω-3 fatty acids, significantly reduced the incidence of postoperative total complications (risk ratio [RR] = 0.59; 95% confidence interval [CI], 0.46-0.75; p < 0.0001) and infectious complications (RR = 0.46; 95% CI, 0.32-0.68; p < 0.0001), and shortened the length of hospital stay (standardized mean difference, -0.49; 95% CI, -0.81 to -0.16; p = 0.0004). There was no significant between-group difference in postoperative mortality (RR = 0.46; 95% CI, 0.16-1.31; p = 0.15). Immunonutrition, mainly ω-3 fatty acids, is potentially beneficial in reducing overall and infectious postoperative complications and in shortening the hospital stay for patients undergoing hepatectomy.

Production of soluble tumor necrosis factor receptors and tumor necrosis factor-alpha by alveolar macrophages in sarcoidosis and extrinsic allergic alveolitis.

BACKGROUND: Alveolar macrophage (AM)-derived tumor necrosis factor (TNF)-alpha plays a pivotal role in the pathogenesis of sarcoidosis and extrinsic allergic alveolitis (EAA). The effects of TNF-alpha are mediated by membrane TNF receptor (mTNFR)-1 and mTNFR-2, and can be blocked by soluble TNF receptor (sTNFR)-1 and sTNFR-2. METHODS: We measured the production of the two sTNFRs and TNF-alpha in AM culture supernatants from 10 patients with active sarcoidosis, 12 patients with EAA, and 9 control subjects using an enzyme-linked immunosorbent assay method. RESULTS: Compared with control subjects, the spontaneous and lipopolysaccharide (LPS)-stimulated production of sTNFR-1, sTNFR-2, and TNF-alpha was significantly increased in patients with sarcoidosis and EAA. The concentrations of both sTNFRs, but especially of sTNFR-2, were closely related to those of TNF-alpha. The LPS-induced increase was 1.5-fold for sTNFR-1, at least fourfold for sTNFR-2, and at least 25-fold for TNF-alpha in all study populations. CONCLUSION: These results indicate that AMs can release the two sTNFRs in relation to TNF-alpha. sTNFR-2 may be more liable to shedding than sTNFR-1. Both sTNFR-1 and sTNFR-2 may be involved in the pathogenesis of sarcoidosis and EAA, possibly as counterregulators of TNF-alpha.

Alteration of DNA damage signaling pathway profile in radiation-treated glioblastoma stem-like cells.

The present study aimed to investigate the alteration of the DNA damage signaling pathway profile in radiation-treated glioblastoma stem-like cells (GSLCs), and also aimed to explore potential targets for overcoming glioblastoma radioresistance. Serum-free medium was used to isolate and culture GSLCs. Cell growth was detected using a cell counting kit-8 assay and cell sorting analysis was performed by flow cytometry. X-ray irradiation was produced by a Siemens-Primus linear accelerator. Reverse transcription-quantitative polymerase chain reaction (qPCR)was performed to investigate target genes. SPSS 15.0 was used for all statistical analyses. Human glioblastoma U251 and U87 cells were cultured in serum-free medium supplemented with epidermal growth factor and fibroblast growth factor 2, which constitutes tumor sphere medium, and demonstrated sphere formation, with significantly increased the proportion of CD133+ and Nestin+ cells, which are referred to as GSLCs. The present data revealed that treatment with 10 Gy X-ray radiation alters the expression profile of DNA damage-associated genes in GSLCs. The expression levels of 12 genes demonstrated a ≥2-fold increase in the irradiated U87 GSLCs compared with the untreated U87 GSLCs. Three genes, consisting of XPA, RAD50 and PPP1R15A, were selected from the 12 genes by gene functional searching and qPCR confirmatory studies, as these genes were considered to be potential targets for overcoming radioresistance. The expression of XPA, RAD50 and PPP1R15A is significantly increased in U87 and U251 radiation resistant GSLCs, indicating three potential targets for overcoming the radioresistance of GSLCs.

Inhibition of cytokine release from alveolar macrophages in pulmonary sarcoidosis by pentoxifylline: comparison with dexamethasone.

STUDY OBJECTIVES: Pentoxifylline (POF) has been shown to suppress the cytokine production from lipopolysaccharide (LPS)-stimulated monocytes/alveolar macrophages (AMs). Sarcoidosis is a granulomatous disease that is driven by the action of tumor necrosis factor (TNF)-alpha and other proinflammatory cytokines. In this study, we aimed to investigate the effects of POF on the production of TNF-alpha, interleukin (IL)-1 beta, IL-6, IL-8, IL-10, and the soluble TNF receptors (sTNFRs) 1 and 2 from AMs in sarcoidosis, and we also compared them with those of dexamethasone (DEX). METHODS: AMs from 14 patients with sarcoidosis were cultured for 24 h with RPMI medium alone or with LPS (100 ng/mL), and with POF at concentrations of 0.01, 0.1, and 1 mmol/L, or with 0.1 mmol/L DEX. Cytokines in the culture supernatants were analyzed by enzyme-linked immunosorbent assay. RESULTS: The results showed that POF induced a dose-dependent suppression of the spontaneous TNF-alpha release from AMs in sarcoidosis (p < 0.001), and that the spontaneous release of the other cytokines was unaffected by POF at all tested concentrations, but a trend for the inhibition of IL-10 production was found (p = 0.092). DEX inhibited the spontaneous release of TNF-alpha (p < 0.001), sTNFR2 (p < 0.05), IL-1 beta (p < 0.05), and IL-10 (p < 0.01). POF also suppressed the LPS-stimulated production of these cytokines except for that of sTNFR1. Similar to POF, DEX inhibited the LPS-stimulated production of these cytokines, but not that of sTNFR1 and IL-1 beta. CONCLUSIONS: Compared with DEX, POF may improve therapeutic regimens in patients with sarcoidosis either by sparing or by replacing corticosteroids. However, the precise clinical value of POF in the treatment of sarcoidosis and other lung diseases will have to be determined in further clinical trials.

Production of IL-12, IL-18 and TNF-alpha by alveolar macrophages in hypersensitivity pneumonitis.

BACKGROUND AND AIM OF THE WORK: Hypersensitivity pneumonitis (HP) is characterized by a macrophage-lymphocyte alveolitis and granuloma formation. A wide range of cytokines have been implicated in the pathophysiology and development of granulomas in HP, but there is no information about the production of interleukin-12 (IL-12) and IL-18 by alveolar macrophages (AM) in human HP. We evaluated whether the production of IL-12, IL-18 and tumor necrosis factor-alpha (TNF-alpha) is locally increased in HP, and whether there is a correlation between these cytokines, as well as with the cellular profile of bronchoalveolar lavage (BAL) fluid in HP. METHODS: AM from 11 patients with HP and 10 control subjects were cultured for 24h in 10% RPMI medium alone, or with RPMI medium and lipopolysaccharide (LPS) (100 ng/ml). Cytokines in the culture supernatants were assayed by ELISA. RESULTS: The production of IL-18 and TNFalpha was increased in patients with HP in either absence or presence of LPS compared with controls. Although the spontaneous production of IL-12 was low, with LPS stimulation it was significantly elevated in HP. The concentration of the LPS-stimulated IL-12 production positively correlated with the percentage of lymphocytes (r = 0.72, p = 0.011), and negatively correlated with the percentage of macrophages (r = -0.88, p < 0.001). CONCLUSIONS: These observations suggest that IL-12, IL-18 and TNFalpha may be involved in the pathogenesis of HP.