Incomplete radiofrequency ablation (IRFA) triggers mild protective autophagy in residual tumor cells and results in an immunosuppressive microenvironment. This accelerates the recurrence of residual tumors and causes resistance to anti-PD-1/PDL1 therapy, which bringing a great clinical challenge in residual tumors immunotherapy. Mild autophagy activation can promote cancer cell survival while further amplification of autophagy contributes to immunogenic cell death (ICD). To this regard, we constructed active targeting zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) loaded with STF62247 or both STF62247 and BMS202, namely STF62247@ZIF-8/PEG-FA (SZP) or STF62247-BMS202@ZIF-8/PEG-FA (SBZP) NPs. We found that SZP NPs inhibited proliferation and stimulated apoptosis of residual tumor cells exposed to sublethal heat stress in an autophagy-dependent manner. Further results discovered that SZP NPs could amplify autophagy in residual tumor cells and evoke their ICD, which dramatically boosted the maturation of dendritic cells (DCs). Through vaccination experiments, we found for the first time that vaccination with heat + SZP treatment could efficiently suppress the growth of new tumors and establish long-term immunological memory. Furthermore, SBZP NPs could remarkably promote the ICD of residual tumor cells, obviously activate the anti-tumor immune microenvironment, and significantly inhibit the growth of residual tumors. Thus, amplified autophagy coupled with anti-PD-1/PDL1 therapy is potentially a novel strategy for treating residual tumors after IRFA. Graphical Abstract

Injury to corpus cavernosal endothelial cells (CCECs) is an important pathological basis of diabetes mellitus-induced erectile dysfunction (DMED), while low-intensity pulsed ultrasound (LIPUS) has been shown to improve erectile function in DMED. To further understand its therapeutic mechanism of action, in this study, we first demonstrated increased apoptosis and shedding in the CCECs of DMED patients, accompanied by significant mitochondrial injury by immunohistochemistry and electron microscopy of corpus cavernosum tissue. Next, we used advanced glycation end products (AGEs) to simulate the diabetic environment in vitro and found that AGES damaged mitochondria and inhibited angiogenesis in CCECs in a dose-dependent manner, while LIPUS treatment significantly reversed its effects. Mechanistic studies based on transcriptome sequencing showed that LIPUS significantly up-regulated LC3 and PARKIN protein levels in mitochondria, promoted mitophagy, and affected mitochondrial dynamics and reactive oxygen species (ROS) production. In addition, the protective effects of LIPUS were abrogated when mitophagy was inhibited by 3-methyladenine. In summary, LIPUS exerted potent inhibitory effects on AGES-induced CCEC failure via mitophagy, providing a theoretical basis for DMED treatment that encompasses the protection of endothelial structure and function.

Previous observational research has documented an association between age at first childbirth (AFB) and postpartum depression (PPD). However, the causal relationship remains unclear. This study aimed to assess the causal effects of AFB on PPD using a two-sample Mendelian randomization (MR) analysis. Three sets of instrumental variables were obtained from the United Kingdom Biobank (UK Biobank), Neale Lab consortium and a meta-analysis of genome-wide association studies (GWAS). Single-nucleotide polymorphisms (SNPs) associated with the PPD phenotype were obtained from the Finngen consortium, which included 13,657 cases and 236,178 controls. Inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger methods to evaluate causal effects. Heterogeneity was assessed using Cochran's Q test and funnel plots. Horizontal pleiotropy and sensitivity were assessed using the MR-Egger intercept test and “leave-one-out” analysis, respectively. Further meta-analysis was performed to validate the robustness of this relationship. Additionally, the potential mediating effects of risk factors associated with PPD were analyzed. Strong causal effects between AFB and PPD was found in both IVW and weighted median methods, which was further supported by meta-analysis (IVW, odds ratio [OR] 0.59 [95% confidence interval (CI) 0.36–0.96, p = 0.03]; weighted median, OR 0.59 [95% CI 0.37–0.95, p = 0.03]). The power of the MR supports the robustness of the findings. Heterogeneity or horizontal pleiotropy was not observed. Major depressive disorders, family income levels, and marital stress were identified as potential mediating factors in the causal relationships. Results of MR analysis supported the causal effect of increased AFB in reducing the risk for PPD.

Thermally activated delayed fluorescence (TADF) molecules have emerged as a promising class of third-generation organic light-emitting diode (OLED) emitters that can achieve 100% internal quantum efficiency without the use of noble metals. However, the design of high-efficiency red TADF materials has been challenging due to limitations imposed by the energy-gap law. To overcome this challenge, two new TADF emitters, namely, 6-(4-(diphenylamino)phenyl)-2-phenyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (NI-TPA) and 6-(10H-phenothiazin-10-yl)-2-phenyl-1H-benzo[de]-isoquinoline-1,3(2H)-dione (NI-Pz), have been synthesized and characterized. These compounds exhibit strong TADF characteristics with a small energy gap (ΔE_ST) between the lowest excited singlet and triplet states, short delayed fluorescence lifetimes, high thermal stability, and high photoluminescence quantum yields. The OLED devices fabricated using NI-TPA and NI-Pz as emitters show orange and red electroluminescence with emission peaks at 593 nm and 665 nm, respectively, and maximum external quantum efficiencies (EQEs) of 11.3% and 7.6%, respectively. Furthermore, applying NI-TPA to cell imaging yielded excellent imaging results, indicating the potential of red TADF materials in the field of biological imaging.

Background: Microvascular invasion (MVI) is an independent risk factor for postoperative recurrence of hepatocellular carcinoma (HCC). However, MVI cannot be detected by conventional imaging. To localize MVI precisely on magnetic resonance (MR) images, we evaluated the feasibility and accuracy of 3-dimensional (3D) histology-MR image fusion of the liver. Methods: Animal models of VX2 liver tumors were established in 10 New Zealand white rabbits under ultrasonographic guidance. The whole liver lobe containing the VX2 tumor was extracted and divided into 4 specimens, for a total of 40 specimens. MR images were obtained with a T2-weighted sequence for each specimen, and then histological images were obtained by intermittent, serial pathological sections. 3D histology-MR image fusion was performed via landmark registration in 3D Slicer software. We calculated the success rate and registration errors of image fusion, and then we located the MVI on MR images. Regarding influencing factors, we evaluated the uniformity of tissue thickness after sampling and the uniformity of tissue shrinkage after dehydration. Results: The VX2 liver tumor model was successfully established in the 10 rabbits. The incidence of MVI was 80% (8/10). 3D histology-MR image fusion was successfully performed in the 39 specimens, and the success rate was 97.5% (39/40). The average registration error was 0.44±0.15 mm. MVI was detected in 20 of the 39 successfully registered specimens, resulting in a total of 166 MVI lesions. The specific location of all MVI lesions was accurately identified on MR images using 3D histology-MR image fusion. All MVI lesions showed as slightly hyperintense on the high-resolution MR T2-weighted images. The results of the influencing factor assessment showed that the tissue thickness was uniform after sampling (P=0.38), but the rates of the tissue shrinkage was inconsistent after dehydration (P<0.001). Conclusions: 3D histology-MR image fusion of the isolated liver tumor model is feasible and accurate and allows for the successful identification of the specific location of MVI on MR images.