Explore the vast range of titles available.

Abstract Context Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and ITIM domain (TIGIT) are considered major immune co-inhibitory receptors (CIRs) and the most promising immunotherapeutic targets in cancer treatment, but they are largely unexplored in medullary thyroid carcinoma (MTC). Objective We aimed to provide the first evidence regarding the expression profiles and clinical significance of CIRs in a large cohort of MTC patients. Design and Patients In total, 200 MTC patients who received initial surgery in our hospital were included. Immunohistochemistry was performed to evaluate CIR expressions in tissue microarrays (TMAs). Combined with the results of our previous programmed cell death ligand-1 (PD-L1) study, clinicopathologic and prognostic correlations of these proteins were retrospectively analyzed. Results TIM-3, PD-1, CTLA-4, LAG-3, and TIGIT positivity was detected in 96 (48.0%), 27 (13.5%), 25 (12.5%), 6 (3.0%), and 6 (3.0%) patients, respectively, in whom TIM-3, PD-1, and CTLA-4 expressions were positively correlated. Log-rank tests and multivariate Cox analyses both indicated that TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression were associated with worse structural recurrence-free survival. In addition, among 20 patients who developed advanced disease during follow-up, 12 (60%) showed TIM-3 positivity, among whom 6 cases also had concurrent moderate to strong PD-1, PD-L1, or CTLA-4 expression. Conclusions Using the currently largest TMA cohort of this rare cancer, we delineated the CIR expression profiles in MTC, and identified TIM-3, CTLA-4 expression, and PD-1/PD-L1 coexpression as promising biomarkers for tumor recurrence. Furthermore, a subset of advanced MTCs are probably immunogenic, for which single or combined immunotherapy including TIM-3, PD-1, PD-L1, or CTLA-4 blockade may be potential therapeutic approaches in the future.

Both anaplastic thyroid cancer (ATC) and papillary thyroid cancer (PTC) originate from thyroid follicular epithelial cells, but ATC has a significantly worse prognosis and shows resistance to conventional therapies. However, clinical trials found that immunotherapy works better in ATC than late-stage PTC. Here, we utilized single-cell RNA sequencing (scRNA-seq) to generate a single-cell atlas of thyroid cancer. Differences in ATC and PTC tumor microenvironment (TME) components (including malignant cells, stromal cells, and immune cells) leading to the polarized prognoses were identified. Intriguingly, we found that CXCL13+ T lymphocytes were enriched in ATC samples and might promote the development of early tertiary lymphoid structure (TLS). Lastly, murine experiments and scRNA-seq analysis of a treated patient's tumor demonstrated that Famitinib plus anti-PD-1 antibody could advance TLS in thyroid cancer. Conclusively, we displayed the cellular landscape of ATC and PTC, finding that CXCL13+ T cells and early TLS might make ATC more sensitive to immunotherapy.

For the rare but aggressive insular thyroid carcinoma (ITC), there's no clear evidence to determine whether prophylactic central compartment neck dissection (CCND) is necessary for cN0 disease. This study provides the first evidence that treating cN0 ITC without prophylactic CCND is associated with decreased survival regardless of T staging and administration of RAI therapy. Background. Regarding the rare but aggressive insular thyroid carcinoma (ITC), the value of prophylactic central compartment neck dissection (CCND) for clinically node-negative (cN0) disease is unclear. We aimed to provide the first evidence. Methods. N0 and pN1a ITC patients were identified from the Surveillance, Epidemiology, and End Results database. These patients were divided into thyroid-surgery + CCND group (pN0/pN1a patients confirmed by CCND) and thyroid-surgery group (cN0 patients without CCND). Differences in overall survival (OS) and disease-specific survival (DSS) between the two groups were evaluated. Subgroup analyses were also conducted. Results. Of the overall 112 patients, 44 (39.3%) received CCND. On multivariate analyses, the lobectomy ± isthmusectomy/total-thyroidectomy (Lob/TT) group demonstrated poorer OS and DSS than the Lob/TT + CCND group (P<0.05). When we separately analyzed patients treated by TT, multivariate analyses showed the TT group still revealed compromised OS and DSS than the TT + CCND group (P<0.05). Furthermore, absence of CCND independently predicted decreased OS no matter whether radioactive iodine (RAI) was administered. Similar results were obtained for T3/T4 patients. Moreover, for T1/T2 patients receiving CCND, 0/12 died during the study period, while for T1/T2 patients without CCND, 8/23 (34.8%) died, 5/23 (21.7%) due to ITC. Conclusion. Regardless of T staging and RAI treatment, cN0-ITC patients without CCND had decreased survival compared with pN0/pN1a patients receiving CCND. Therefore, if a cN0 patient is diagnosed with ITC, prophylactic CCND may be considered as a secondary procedure (postoperatively diagnosed) or a primary procedure (preoperatively/intraoperatively diagnosed). Prospective studies are expected to validate the conclusion.

Aim： To determine whether the flavonoid baicalin attenuates oxygen-glucose deprivation （OGD）-induced injury by inhibiting oxidative stress-mediated 5-1ipoxygenase （5-LOX） activation in PC12 cells. Methods： The effects of baicalin and the 5-LOX inhibitor zileuton on the changes induced by OGD/recovery or H2O2 （an exogenous reactive oxygen species [ROS]） in green fluorescent protein-5-LOX-transfected PC12 cells were compared. Results： Both baicalin and zileuton attenuated OGD/recovery- and H2O2-induced injury and inhibited OGD/recovery-induced production of 5-LOX metabolites （cysteinyl leukotrienes） in a concentration-dependent manner. However, baicalin did not reduce baseline cysteinyl leukotriene levels. Baicalin also reduced OGD/recovery-induced ROS production and inhibited 5-LOX translocation to the nuclear enve- lope and p38 phosphorylation induced by OGD/recovery and H2O2. In contrast, zileuton did not show these effects. Conclusion： Baicalin can inhibit 5-LOX activation after ischemic injury, which may partly result from inhibition of the ROS/p38 mitogenactivated protein kinase pathway.

Gliomas are the most common primary brain tumor in adults, but the efficacy of chemotherapy is limited. Artemisinin and its analogs, such as dihydroartemisinin (DHA), can kill cancer cells via generating free radicals. In the present study, we determined whether DHA at low concentrations potentiates the cytotoxic effect of temozolomide in rat glioma C6 cells. We found that the IC 50 values of DHA and temozolomide for cell viability were 23.4 and 560 µmol/l, respectively. The cytotoxic effect of temozolomide was enhanced by 177% at a nontoxic DHA concentration (1 µmol/l), and by 321% at a low-toxic DHA concentration (5 µmol/l). DHA substantially increased temozolomide-induced apoptosis and necrosis. The generation of intracellular reactive oxygen species (ROS) was increased by temozolomide combined with DHA at noneffective concentrations of both agents. Edaravone (20 µmol/l), a ROS scavenger, reversed the effects of temozolomide/DHA on both ROS generation and cell viability reduction. These results indicate that DHA at low concentrations potentiates the cytotoxic effects of temozolomide in C6 cells partly via generating ROS, suggesting a beneficial combination for the chemotherapy of gliomas.

In this study, we explored the neural mechanism of global topological perception in the human visual system. We showed strong evidence that the retinotectal pathway in the archicortex of the human brain is responsible for global topological perception, and for modulating the local feature processing in the classical ventral visual pathway. Inspired by this recent cognitive discovery, we developed a novel CogNet architecture to emulate the global-local dichotomy of human visual cognitive mechanisms. The thorough experimental results indicate that the proposed CogNet not only significantly improves image classification accuracies but also effectively addresses the texture bias problem observed in baseline CNN models. We have also conducted mathematical analysis for the generalization gap for general neural networks. Our theoretical derivations suggest that the Hurst parameter, a measure of the curvature of the loss landscape, can closely bind the generalization gap. A larger Hurst parameter corresponds to a better generalization ability. We found that our proposed CogNet achieves a lower test error and attains a larger Hurst parameter, strengthening its superiority over the baseline CNN models further.

The aim of study was to optimize the extraction process of ginsenosides and investigate the anti-fatigue effect of ginseng and acanthopanax extracts. Orthogonal test was used to optimize the extraction process, loading swimming experiment was used to observe the ant-fatigue effect, and BUN, LDH, CK, glycogen, T-SOD, MDA, GSH-Px and LD were taken as the anti-fatigue indeses to be observed. The yield of ginsenoside was 3.8%. The swimming time of mice in the treatment group was significantly prolonged compared with that in the control group (P< 0.05). The hepatic glycogen storage, LDH, GSH-PX and SOD in the treatment groups were obviously increased (P<0.05). Serum MDA and LD levels in the treatment groups were decreased, but no statistical significance compared with those in the control group. The serum BUN was significantly decreased in the middle-dose group (P<0.05). There was no significant difference in the serum CK between the treatment groups and the control group.LDH levels in the middle-dose and high-dose groups were significantly different from those in the control group. The ginseng and acanthopanax extracts can exert its anti-fatigue effect through increasing the amount of liver glycogen reserve and reducing the damage of negative metabolic products caused by an excessive exercise to the body.

Aim： Tanshinone II-A sodium sulfonate （DS-201）, a water-soluble derivative of Tanshinone II-A, has been found to induce vascular relaxation and activate BKca channels. The aim of this study was to explore the mechanisms underlying the action of DS-201 on BKca channels. Methods： Human BKca channels containing α subunit alone or α plus β1 subunits were expressed in HEK293 cells. BKca currents were recorded from the cells using patch-clamp technique. The expression and trafficking of BKca subunits in HEK293 cells or vascular smooth muscle cells （VSMCs） were detected by Western blotting, flow cytometry and confocal microscopy. Results： DS-201 （40-160 μmol/L） concentration-dependently increased the total open probability of BKca channels in HEK293 cells, associated with enhancements of Ca2＋ and voltage dependence as well as a delay in deactivation. Coexpression of β1 subunit did not affect the action of DS-201： the values of EC50 for BKca channels containing α subunit alone and α plus β1 subunit were 66.6±1.5 and 62.0±1.1 pmol/L, respectively. In both HEK293 cells and VSMCs, DS-201 （80 pmol/L） markedly increased the expression of αsubunit without affecting α1 subunit. In HEK293 cells, DS-201 enriched the membranous level of α subunit, likely by accelerating the trafficking and suppressing the internalization of α subunit. In both HEK293 cells and VSMCs, DS-201 （≥320 pmol/L） induced significant cytotoxicity. Conclusion： DS-201 selectively targets the pore-forming α subunit of human BKca channels, thus enhancing the channel activities and increasing the subunit expression and trafficking, whereas the β1 subunit does not contribute to the action of DS-201.