Discovery of Novel HDAC3 Inhibitors with PD-L1 Downregulating/Degrading and Antitumor Immune Effects.

Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is one of the most promising cancer treatment strategies. Studies have shown that HDAC inhibitors can enhance the antitumor immune response by modulating the expression of PD-L1. Herein, we designed and synthesized a series of novel hydrazide-based small molecule HDAC inhibitors; among them, compound HQ-30 showed selective HDAC3 inhibition (IC50 = 89 nM) and remarkable PD-L1-degrading activity (DC50 = 5.7 µM, Dmax = 80% at 10 µM). Further studies revealed that HQ-30 induced the degradation of PD-L1 by regulating cathepsin B (CTSB) in the lysosomes. Further, HQ-30 could enhance the infiltration of CD3+ CD4+ helper T and CD3+ CD8+ cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, HQ-30 possessed a benign toxicity profile (LD50 > 1000 mg/kg) and favorable pharmacokinetic properties (F = 57%). Taken together, HQ-30 is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.

Melatonin ameliorates 10-hydroxycamptothecin-induced oxidative stress and apoptosis via autophagy-regulated p62/Keap1/Nrf2 pathway in mouse testicular cells.

10-Hydroxycamptothecin (HCPT) is a widely used clinical anticancer drug but has a significant side effect profile. Melatonin has a beneficial impact on the chemotherapy of different cancer cells and reproductive processes, but the effect and underlying molecular mechanism of melatonin's involvement in the HCPT-induced side effects in cells, especially in the testicular cells, are poorly understood. In this study, we found that melatonin therapy significantly restored HCPT-induced testicular cell damage and did not affect the antitumor effect of HCPT. Further analysis found that melatonin therapy suppressed HCPT-induced DNA damage associated with ataxia-telangiectasia mutated- and Rad3-related and CHK1 phosphorylation levels in the testis. Changes in apoptosis-associated protein levels (Bax, Bcl-2, p53, and Cleaved caspase-3) and in reactive oxygen species-associated proteins (Nrf2 and Keap1) and index (malondialdehyde and glutathione) suggested that melatonin treatment relieved HCPT-induced cell apoptosis and oxidative damage, respectively. Mechanistically, melatonin-activated autophagy proteins (ATG7, Beclin1, and LC3bII/I) may induce p62-dependent autophagy to degrade Keap1, eliciting Nrf2 from Keap1-Nrf2 interaction to promote antioxidant enzyme expression such as HO-1, which would salvage HCPT-induced ROS production and mitochondrial dysfunction. Collectively, this study reveals that melatonin therapy may protect testicular cells from HCPT-induced damage via the activation of autophagy, which alleviates oxidative stress, mitochondrial dysfunction, and cell apoptosis.

Laser-activable murine ferritin nanocage for chemo-photothermal therapy of colorectal cancer.

Chemotherapy, as a conventional strategy for tumor therapy, often leads to unsatisfied therapeutic effect due to the multi-drug resistance and the serious side effects. Herein, we genetically engineered a thermal-responsive murine Ferritin (mHFn) to specifically deliver mitoxantrone (MTO, a chemotherapeutic and photothermal agent) to tumor tissue for the chemotherapy and photothermal combined therapy of colorectal cancer, thanks to the high affinity of mHFn to transferrin receptor that highly expressed on tumor cells. The thermal-sensitive channels on mHFn allowed the effective encapsulation of MTO in vitro and the laser-controlled release of MTO in vivo. Upon irradiation with a 660 nm laser, the raised temperature triggered the opening of the thermal-sensitive channel in mHFn nanocage, resulting in the controlled and rapid release of MTO. Consequently, a significant amount of reactive oxygen species was generated, causing mitochondrial collapse and tumor cell death. The photothermal-sensitive controlled release, low systemic cytotoxicity, and excellent synergistic tumor eradication ability in vivo made mHFn@MTO a promising candidate for chemo-photothermal combination therapy against colorectal cancer.

A Systematic Review and Meta-Analysis of MRI Radiomics for Predicting Microvascular Invasion in Patients with Hepatocellular Carcinoma.

BACKGROUND: The prediction power of MRI radiomics for microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC) remains uncertain. OBJECTIVE: To investigate the prediction performance of MRI radiomics for MVI in HCC. METHODS: Original studies focusing on preoperative prediction performance of MRI radiomics for MVI in HCC, were systematically searched from databases of PubMed, Embase, Web of Science and Cochrane Library. Radiomics quality score (RQS) and risk of bias of involved studies were evaluated. Meta-analysis was carried out to demonstrate the value of MRI radiomics for MVI prediction in HCC. Influencing factors of the prediction performance of MRI radiomics were identified by subgroup analyses. RESULTS: 13 studies classified as type 2a or above according to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis statement were eligible for this systematic review and meta-analysis. The studies achieved an average RQS of 14 (ranging from 11 to 17), accounting for 38.9% of the total points. MRI radiomics achieved a pooled sensitivity of 0.82 (95%CI: 0.78 - 0.86), specificity of 0.79 (95%CI: 0.76 - 0.83) and area under the summary receiver operator characteristic curve (AUC) of 0.88 (95%CI: 0.84 - 0.91) to predict MVI in HCC. Radiomics models combined with clinical features achieved superior performances compared to models without the combination (AUC: 0.90 vs 0.85, P < 0.05). CONCLUSION: MRI radiomics has the potential for preoperative prediction of MVI in HCC. Further studies with high methodological quality should be designed to improve the reliability and reproducibility of the radiomics models for clinical application. The systematic review and meta-analysis was registered prospectively in the International Prospective Register of Systematic Reviews (No. CRD42022333822).

CT radiomics for prediction of microvascular invasion in hepatocellular carcinoma: A systematic review and meta-analysis.

The power of computed tomography (CT) radiomics for preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) demonstrated in current research is variable. This systematic review and meta-analysis aim to evaluate the value of CT radiomics for MVI prediction in HCC, and to investigate the methodologic quality in the workflow of radiomics research. Databases of PubMed, Embase, Web of Science, and Cochrane Library were systematically searched. The methodologic quality of included studies was assessed. Validation data from studies with Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement type 2a or above were extracted for meta-analysis. Eleven studies were included, among which nine were eligible for meta-analysis. Radiomics quality scores of the enrolled eleven studies varied from 6 to 17, accounting for 16.7%-47.2% of the total points, with an average score of 14. Pooled sensitivity, specificity, and Area Under the summary receiver operator Characteristic Curve (AUC) were 0.82 (95% CI 0.77-0.86), 0.79 (95% CI 0.75-0.83), and 0.87 (95% CI 0.84-0.91) for the predictive performance of CT radiomics, respectively. Meta-regression and subgroup analyses showed radiomics model based on 3D tumor segmentation, and deep learning model achieved superior performances compared to 2D segmentation and non-deep learning model, respectively (AUC: 0.93 vs. 0.83, and 0.97 vs. 0.83, respectively). This study proves that CT radiomics could predict MVI in HCC. The heterogeneity of the included studies precludes a definition of the role of CT radiomics in predicting MVI, but methodology warrants uniformization in the radiology community regarding radiomics in HCC.

Whole-tumor histogram analysis of apparent diffusion coefficients for predicting lymphovascular space invasion in stage IB-IIA cervical cancer.

Objectives: To investigate the value of apparent diffusion coefficient (ADC) histogram analysis based on whole tumor volume for the preoperative prediction of lymphovascular space invasion (LVSI) in patients with stage IB-IIA cervical cancer. Methods: Fifty consecutive patients with stage IB-IIA cervical cancer were stratified into LVSI-positive (n = 24) and LVSI-negative (n = 26) groups according to the postoperative pathology. All patients underwent pelvic 3.0T diffusion-weighted imaging with b-values of 50 and 800 s/mm2 preoperatively. Whole-tumor ADC histogram analysis was performed. Differences in the clinical characteristics, conventional magnetic resonance imaging (MRI) features, and ADC histogram parameters between the two groups were analyzed. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of ADC histogram parameters in predicting LVSI. Results: ADCmax, ADCrange, ADC90, ADC95, and ADC99 were significantly lower in the LVSI-positive group than in the LVSI-negative group (all P-values < 0.05), whereas no significant differences were reported for the remaining ADC parameters, clinical characteristics, and conventional MRI features between the groups (all P-values > 0.05). For predicting LVSI in stage IB-IIA cervical cancer, a cutoff ADCmax of 1.75×10-3 mm2/s achieved the largest area under ROC curve (Az) of 0.750, followed by a cutoff ADCrange of 1.36×10-3 mm2/s and ADC99 of 1.75×10-3 mm2/s (Az = 0.748 and 0.729, respectively), and the cutoff ADC90 and ADC95 achieved an Az of <0.70. Conclusion: Whole-tumor ADC histogram analysis has potential value for preoperative prediction of LVSI in patients with stage IB-IIA cervical cancer. ADCmax, ADCrange, and ADC99 are promising prediction parameters.

Renal ectopic lipid deposition in rats with early-stage diabetic nephropathy evaluated by the MR mDixon-Quant technique: association with the expression of SREBP-1 and PPARα in renal tissue.

Background: Renal ectopic lipid deposition (ELD) plays a significant role in the development of diabetic nephropathy (DN). This study aimed to use the magnetic resonance (MR) mDixon-Quant technique to evaluate renal ELD and its association with the expression of sterol regulatory element binding protein 1 (SREBP-1) and peroxisome proliferator-activated receptor alpha (PPARα) in renal tissue. Methods: Seventy male Sprague-Dawley (SD) rats were randomly divided into experimental (n=50) and control groups (n=20). A high-fat diet combined with low-dose streptozotocin (STZ) was administered to the experimental group to establish a type 2 diabetes mellitus (T2DM) model. The rats received renal mDixon-Quant scans and blood lipid and histopathological examinations in batches after the T2DM model was established. According to the histopathological findings, the included rats were stratified into control and early DN groups. Renal fat fraction (FF), blood lipid level, the ratio of the integrated optical density of intracellular lipid droplets and the total area of all the cells (IOD/TAC), and the expression of SREBP-1 and PPARɑ in renal tissue were analyzed. Results: Compared to the controls, renal FF, IOD/TAC, the expression of SREBP-1 in renal tissue, and serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) levels were higher in the early DN group, while the expression of PPARɑ in renal tissue and the high-density lipoprotein (HDL) level were lower (all P values <0.001). Renal FF gradually increased with the progression of disease [r=0.810 (95% CI: 0.675-0.928), P<0.001]. Positive correlations between renal FF and each of the following: TC, TG, LDL, IOD/TAC, and the expression of SREBP-1 [r=0.479 (95% CI: 0.353-0.640, P=0.012), 0.576 (95% CI: 0.283-0.842, P=0.002), 0.441 (95% CI: 0.305-0.606, P=0.021), 0.911 (95% CI: 0.809-0.964, P<0.001) and 0.800 (95% CI: 0.640-0.910, P<0.001), respectively] and negative correlations between renal FF and each of the following: HDL and the expression of PPARɑ [r=-0.611 (95% CI: -0.809 to -0.469, P=0.001) and -0.748 (95% CI: -0.886 to -0.585, P<0.001), respectively] were found. Conclusions: Renal lipid deposition evaluated by the MR mDixon-Quant technique is associated with the blood lipid level, histological fat quantification, and the expression of SREBP-1 and PPARɑ in renal tissue. The renal FF value might serve as a biomarker for better understanding of renal lipid metabolism in early-stage DN.

Elevated intracellular pH of zygotes during mouse aging causes mitochondrial dysfunction associated with poor embryo development.

The mortality of preimplantation embryos is positively correlated with maternal age. However, the underlying mechanism for the poor quality of embryos remains unclear. Here, we found that aging caused elevated intracellular pH (pHi) in zygotes, which could trigger aberrant mitochondrial membrane potential, increased reactive oxygen species (ROS) levels, and poor embryo development. Moreover, single-cell transcriptome sequencing of mouse zygotes identified 120 genes that were significantly differentially expressed (DE) between young and older zygotes. These include genes such as Slc14a1, Fxyd5, CD74, and Bst, which are related to cell division, ion transporter, and cell differentiation. Further analysis indicated that these DE genes were enriched in apoptosis, the NF-kappa B signaling pathway, and the chemokine signaling pathway, which might be the key regulatory pathway affecting the quality of zygotes and subsequent embryo development. Taken together, our study helps elucidate the poor quality and development of older preimplantation embryos.

Biomimetic Gold Nanostructure with a Virus-like Topological Surface for Enhanced Antigen Cross-Presentation and Antitumor Immune Response.

The internalization of antigens by dendritic cells (DCs) is the initial critical step for vaccines to activate the immune response; however, the systemic delivery of antigens into DCs is hampered by various technical challenges. Here we show that a virus-like gold nanostructure (AuNV) can effectively bind to and be internalized by DCs due to its biomimetic topological morphology, thereby significantly promoting the maturation of DCs and the cross-presentation of the model antigen ovalbumin (OVA). In vivo experiments demonstrate that AuNV efficiently delivers OVA to draining lymph nodes and significantly inhibits the growth of MC38-OVA tumors, generating a ∼80% decrease in tumor volume. Mechanistic studies reveal that the AuNV-OVA vaccine induces a remarkable increase in the rate of maturation of DCs, OVA presentation, and CD4+ and CD8+ T lymphocyte populations in both lymph node and tumor and an obvious decrease in myeloid-derived suppressor cells and regulatory T cell populations in spleen. The good biocompatibility, strong adjuvant activity, enhanced uptake of DCs, and improved T cell activation make AuNV a promising antigen delivery platform for vaccine development.

Knockdown of disheveled-associated activator of morphogenesis 2 disrupts cytoskeletal organization and phagocytosis in rat Sertoli cells.

Disheveled-associated activator of morphogenesis 2 (DAAM2) regulates actin polymerization and cell motility. In this study, we investigated the role of DAAM2 in the cytoskeleton and phagocytosis of rat Sertoli cells in vitro and in vivo through siRNA transfection and intratesticular injection. We found that knockdown of DAAM2 significantly attenuated cytoskeletal and tight junction marker expression and reduced the integrity of the Sertoli cell monolayer. In rats, loss of DAAM2 induced disarrangement and deformation of sperms and promoted accumulation of apoptotic sperms in the testis, accompanied by morphological abnormalities in the blood-testis barrier. DAAM2 silencing also reduced the ability of Sertoli cells to engulf apoptotic spermatogenic cells and green fluorescence-labeled beads. RNA sequencing and bioinformatics analysis revealed that phagocytosis and cytoskeleton-related genes and pathways were significantly associated with DAAM2. Our study suggests that DAAM2 may be involved in spermatogenesis possibly by regulating cytoskeleton organization and phagocytosis of Sertoli cells.