Fiber connectivity density mapping in end-stage renal disease patients: a preliminary study.

Abnormal brain structural connectivity of end-stage renal disease(ESRD) is associated with cognitive impairment. However, the characteristics of cortical structural connectivity have not been investigated in ESRD patients. Here, we study structural connectivity of the entire cerebral cortex using a fiber connectivity density(FiCD) mapping method derived from diffusion tensor imaging(DTI) data of 25 ESRD patients and 20 healthy controls, and between-group differences were compared in a vertexwise manner. We also investigated the associations between these abnormal cortical connectivities and the clinical variables using Pearson correlation analysis and multifactor linear regression analysis. Our results demonstrated that the mean global FiCD value was significantly decreased in ESRD patients. Notably, FiCD values were significantly changed(decreased or increased) in certain cortical regions, which mainly involved the bilateral dorsolateral prefrontal cortex(DLPFC), inferior parietal cortex, lateral temporal cortex and middle occipital cortex. In ESRD patients, we found a trend of negative correlation between the increased FiCD values of bilateral middle frontal gyrus and serum creatinine, urea, parathyroid hormone(PTH) levels and dialysis duration. Only the white matter hyperintensity(WMH) scores were significantly negatively correlated with the global FiCD value in multifactor regression analysis. Our results suggested that ESRD patients exhibited extensive impaired cortical structural connectivity, which was related to the severity of WMHs. A compensation mechanism of cortical structural recombination may play a role in how the brain adapts to maintain optimal network function. Additionally, the serum creatinine, urea and PTH levels may be risk factors for brain structural network decompensation in ESRD patients.

GPER-Induced ERK Signaling Decreases Cell Viability of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis. Effective biomarkers and specific therapeutic targets for HCC are therefore urgently needed. G protein-coupled estrogen receptor (GPER) plays a crucial role in numerous cancer types; however, its functions in HCC require further exploration. In the present study, we found a remarkable difference in GPER staining between tumor tissue (100/141, 70.9%) and matched non-tumor tissue (27/30, 90.0%). Compared with the GPER-negative patients, the GPER-positive patients with HCC were closely associated with female sex, negative hepatitis B surface antigen, small tumor size, low serum alpha fetoprotein level, and longer overall survival. Treatment with GPER-specific agonist G1 led to the sustained and transient activation of the EGFR/ERK and EGFR/AKT signaling pathways, respectively, in the HCC cell lines HCCLM3 and SMMC-7721, which express high levels of GPER. Interestingly, G1-induced EGFR/ERK signaling, rather than EGFR/AKT signaling mediated by GPER, was involved in decreasing cell viability by blocking cell cycle progression, thereby promoting apoptosis and inhibiting cell growth. Clinical analysis indicated that simultaneous high expression of GPER and phosphorylated-ERK (p-ERK) predicted improved prognosis for HCC. Finally, the activation of GPER/ERK signaling remarkably suppressed tumor growth in an HCC xenograft model, and this result was consistent with the in vitro data. Our findings suggest that specific activation of the GPER/ERK axis may serve as a novel tumor-suppressive mechanism and that this axis could be a therapeutic target for HCC.

Paclitaxel-loaded trimethyl chitosan-based polymeric nanoparticle for the effective treatment of gastroenteric tumors.

Gastroenteric cancer is one of the most prevalent cancers and is responsible for most cancer-related deaths worldwide. Paclitaxel (PTX), a classical microtubule inhibitor, is indicated in the treatment of gastric/gastroenteric cancers. In the present study, trimethyl chitosan (TMC)-loaded PTX (TMC-PTX) was prepared and evaluated for its therapeutic effect in gastric cancers. A spherical shaped nanosized TMC-PTX particle was formed with high loading capacity (~30%) for PTX. The nanoparticles (NPs) showed a sustained release pattern (~70%) for up to 96 h of study period. The positively charged NPs were preferentially internalized by Caco-2 cells. TMC-PTX inhibited the gastric cell proliferation with an IC50 value of 0.6 µg in NCI-N87 cells while it was 1.26 µg in the SGC-7901 cell line after 24 h exposure. The apoptosis assay (Annexin V/PI) showed a large presence of cells in the early and late apoptosis chamber, while cell cycle analysis showed a marked G2/M phase arrest (50-60%) in NCI-N87 and SGC-7901 cell lines indicating its potent anti-proliferative effect. The in vivo antitumor study in NCI-N87 and SGC-7901 bearing xenograft model showed a superior chemotherapeutic efficacy for TMC-PTX NP. The NP group significantly reduced the tumor growth with no obvious sign of systemic side-effects (safety). Collectively, our results suggest that the microtubule inhibitory effect of PTX-loaded polymer NP could be a promising system for the treatment of gastroenteric cancers.