Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11

Effect of Extracellular Vesicles on Neural Functional Recovery and Immunologic Suppression after Rat Cerebral Apoplexy

Background: Previous studies have demonstrated that mesenchymal stem cells (MSCs) can promote the recovery of neural function after cerebral apoplexy by secreting multiple cytokines. In addition, cell factor-derived extracellular vesicles play an important role in recovery of neural function. The aim of this study was to determine the effect of extracellular vesicles on neural functional recovery and brain tissue remodeling after cerebral apoplexy in a rat model. Methods: The rat models with local ischemic stroke was established and three random groups were created. In groups A and B, human bone marrow-derived MSCs and MSC-derived extracellular vesicles were transplanted into rats. In the control group (group C), only normal saline was injected. Then, we evaluated motor coordination ability, pathologic changes of the brain, immune responses in the central and peripheral nervous systems, regeneration of blood vessels, and nervous tissue in 4 weeks after cerebral apoplexy. Results: Obvious regeneration of blood vessels and nervous tissues were identified in groups A and B. There was no significant difference with respect to coordination between groups A and B, but coordination in groups A and B was significantly better than the control group. Immunohistochemical staining of brain tissue showed that extracellular vesicles exerted no effect on infiltration of immune cells in the central nervous system. Weakened immune suppression was noted 1 week after cerebral apoplexy, which provided a favorable environment for remodeling of brain tissue. Conclusion: MSC-derived extracellular vesicles accelerated neural functional recovery after cerebral apoplexy. The weakened immune suppression was beneficial to remodeling of brain tissue

Development of an Immune Infiltration-Related Eight-Gene Prognostic Signature in Colorectal Cancer Microenvironment

Objective. Stromal cells and immune cells have important clinical significance in the microenvironment of colorectal cancer (CRC). This study is aimed at developing a CRC gene signature on the basis of stromal and immune scores. Methods. A cohort of CRC patients (n=433) were adopted from The Cancer Genome Atlas (TCGA) database. Stromal/immune scores were calculated by the ESTIMATE algorithm. Correlation between prognosis/clinical characteristics and stromal/immune scores was assessed. Differentially expressed stromal and immune genes were identified. Their potential functions were annotated by functional enrichment analysis. Cox regression analysis was used to develop an eight-gene risk score model. Its predictive efficacies for 3 years, 5 years, overall survival (OS), and progression-free survival interval (PFI) were evaluated using time-dependent receiver operating characteristic (ROC) curves. The correlation between the risk score and the infiltering levels of six immune cells was analyzed using TIMER. The risk score was validated using an independent dataset. Results. Immune score was in a significant association with prognosis and clinical characteristics of CRC. 736 upregulated and two downregulated stromal and immune genes were identified, which were mainly enriched into immune-related biological processes and pathways. An-eight gene prognostic risk score model was conducted, consisting of CCL22, CD36, CPA3, CPT1C, KCNE4, NFATC1, RASGRP2, and SLC2A3. High risk score indicated a poor prognosis of patients. The area under the ROC curves (AUC) s of the model for 3 years, 5 years, OS, and PFI were 0.71, 0.70, 0.73, and 0.66, respectively. Thus, the model possessed well performance for prediction of patients’ prognosis, which was confirmed by an external dataset. Moreover, the risk score was significantly correlated with immune cell infiltration. Conclusion. Our study conducted an immune-related prognostic risk score model, which could provide novel targets for immunotherapy of CRC

Synthesis, Characterization, and Specific Localization of Mitochondrial-Targeted Antioxidant Peptide SS31 Probe

The aim of this study is to investigate the targeting efficiency of FITC-SS31 to mitochondria in both normal and H2O2-induced oxidative damaged 661W cells, characterizing the properties of FITC-SS31 in the biological assays. The purity and molecular weight of FITC-SS31 were identified using HPLC and MS. MTT and LDH assays were used to evaluate the cytotoxicity and cell permeability. The binding ability of FITC-SS31 to cells was demonstrated by flow cytometry. The colocalization of FITC-SS31 and MitoTracker both in normal and oxidative cells was analyzed by a laser confocal microscope. We detected the DEGs between SS31+H2O2 and H2O2-alone-treated cells by RNA seq. GO and KEGG analyses were performed to predict the functional gene of SS31. The molecular weight of FITC-SS31 was 1142.2 with the 97.76% purity. The flow cytometry results showed that the MFI (mean fluorescence intensity) of FITC-SS31 in normal cells in the 4 h probe treatment group was higher than that in the 2 h and the 0 h group. The MFI in the 2 h probe treatment group was much higher than that in the 4 h and 0 h groups in damaged cells. The positive rate of 10 μM FITC-SS31 was higher than that of 1 μM and 5 μM. Fluorescein imaging analysis confirmed that FITC-SS31 was overlapped with MitoTracker. Through the analysis, DEGs were highly expressed in “localization, organelle, antioxidant activity, binding” functions and enriched in “AMPK signaling pathway, MAPK targets/nuclear events mediated by MAP kinase pathway and PI3K-Akt signaling pathway.” It is speculated that SS31 exerts an antioxidant effect through one of these pathways. We hypothesized that SS31 could play a more efficient role in the pathological cells in the half-life period to avoid cell death due to oxidative damage. The functions of the DEGs in SS31+H2O2 and H2O2-alone samples are related to the localization and antioxidant activity of SS31. DEGs are mostly enriched in the AMPK signaling pathway, which needs further studies

Association of circulating leptin and adiponectin with periodontitis: a systematic review and meta-analysis

Abstract Background This study aimed to assess the difference in serum levels of leptin and adiponectin in patients with periodontitis and in periodontally healthy individuals and evaluate the changes in circulating leptin and adiponectin after periodontal therapy. Leptin and adiponectin are the most generally studied adipokines that function as inflammatory cytokines. Although the association between periodontitis and serum levels of leptin and adiponectin has been studied extensively, the results were not consistent. Methods A systematic search of the Pubmed, Embase, Web of Science, and Cochrane Library up to September 2016 was conducted. The studies were screened and selected by two writers according to the specific eligibility criteria. The quality of included cross-sectional studies was assessed using the quality assessment form recommended by the Agency for Healthcare Research and Quality and Methodological Index for Nonrandomized Studies. The meta-analyses were conducted using the STATA 12.0 software. Results A total of 399 manuscripts were yielded and 25 studies were included in the present meta-analysis. Significantly elevated serum levels of leptin and decreased serum levels of adiponectin in patients with periodontitis were observed in the subgroup analysis of body mass index (BMI) <30. The overall and subgroup analyses showed no significant change in the serum levels of leptin in patients with periodontitis after periodontal treatment. The subgroup analysis of systemically healthy patients showed no significant change in serum levels of adiponectin in patients with periodontitis after periodontal treatment. Conclusions The present meta-analysis supported elevated serum levels of leptin and decreased serum levels of adiponectin in patients with periodontitis compared with controls in the BMI <30 population. In systemically healthy patients with periodontitis, serum levels of leptin and adiponectin do not significantly change after periodontal treatment

NormaCurve: a SuperCurve-based method that simultaneously quantifies and normalizes reverse phase protein array data.

MOTIVATION: Reverse phase protein array (RPPA) is a powerful dot-blot technology that allows studying protein expression levels as well as post-translational modifications in a large number of samples simultaneously. Yet, correct interpretation of RPPA data has remained a major challenge for its broad-scale application and its translation into clinical research. Satisfying quantification tools are available to assess a relative protein expression level from a serial dilution curve. However, appropriate tools allowing the normalization of the data for external sources of variation are currently missing. RESULTS: Here we propose a new method, called NormaCurve, that allows simultaneous quantification and normalization of RPPA data. For this, we modified the quantification method SuperCurve in order to include normalization for (i) background fluorescence, (ii) variation in the total amount of spotted protein and (iii) spatial bias on the arrays. Using a spike-in design with a purified protein, we test the capacity of different models to properly estimate normalized relative expression levels. The best performing model, NormaCurve, takes into account a negative control array without primary antibody, an array stained with a total protein stain and spatial covariates. We show that this normalization is reproducible and we discuss the number of serial dilutions and the number of replicates that are required to obtain robust data. We thus provide a ready-to-use method for reliable and reproducible normalization of RPPA data, which should facilitate the interpretation and the development of this promising technology. AVAILABILITY: The raw data, the scripts and the normacurve package are available at the following web site: http://microarrays.curie.fr