Purpose: Breast cancer (BC) is a predominant malignancy globally, surpassing lung cancer in terms of diagnostic frequency, with an escalating incidence rate in recent decades.Recent studies have investigated the role of protein kinase C zeta (PRKCZ) in diverse cellular processes in cancer biology. In this study, we evaluated the association between PRKCZ and deleterious outcomes in BC and elucidated the mechanisms underlying its expression in breast carcinoma. Methods: The correlation between PRKCZ and survival rates of patients with BC was investigated using The Cancer Genome Atlas database. The methylation status of the PRKCZ promoter was analyzed using the UALCAN database. Furthermore, we investigated the mechanisms underlying PRKCZ inactivation in BC by treatment with transferase inhibitors, methylation-specific polymerase chain reaction (PCR) analysis, western blotting, and luciferase reporter gene assays. The degree of methylation and expression levels of PRKCZ, as regulated by DNA methyltransferase 1 (DNMT1), were quantified using quantitative PCR and western blotting. Results: Our analysis revealed that decreased expression of PRKCZ in BC was significantly correlated with poor clinical prognosis. Furthermore, we observed that hypermethylation of the PRKCZ promoter contributed to its reduced expression in BC. Notably, DNMT1 has been identified as a critical regulator of PRKCZ methylation. Conclusion Our findings elucidate the tumor-suppressive function of PRKCZ and provide insights into the molecular mechanisms underlying its downregulation in BC.

Purpose: Breast cancer (BC) is a predominant malignancy globally, surpassing lung cancer in terms of diagnostic frequency, with an escalating incidence rate in recent decades.Recent studies have investigated the role of protein kinase C zeta (PRKCZ) in diverse cellular processes in cancer biology. In this study, we evaluated the association between PRKCZ and deleterious outcomes in BC and elucidated the mechanisms underlying its expression in breast carcinoma. Methods: The correlation between PRKCZ and survival rates of patients with BC was investigated using The Cancer Genome Atlas database. The methylation status of the PRKCZ promoter was analyzed using the UALCAN database. Furthermore, we investigated the mechanisms underlying PRKCZ inactivation in BC by treatment with transferase inhibitors, methylation-specific polymerase chain reaction (PCR) analysis, western blotting, and luciferase reporter gene assays. The degree of methylation and expression levels of PRKCZ, as regulated by DNA methyltransferase 1 (DNMT1), were quantified using quantitative PCR and western blotting. Results: Our analysis revealed that decreased expression of PRKCZ in BC was significantly correlated with poor clinical prognosis. Furthermore, we observed that hypermethylation of the PRKCZ promoter contributed to its reduced expression in BC. Notably, DNMT1 has been identified as a critical regulator of PRKCZ methylation. Conclusion Our findings elucidate the tumor-suppressive function of PRKCZ and provide insights into the molecular mechanisms underlying its downregulation in BC.

Objective To identify potential biomarkers for proliferative diabetic retinopathy(PDR)using proteomics and transcriptomics data.Methods In this study,the proteomics dataset(PXD046630)and two transcriptomics datasets(GSE60436 and GSE102485)were derived from the aqueous humor samples and fibrovascular membranes of PDR patients,respectively.Differentially expressed genes(DEGs)were identified via R software,specifically the limma and edgeR pack-ages.The shared DEGs between PXD046630 and GSE60436 were analyzed via protein-protein interaction(PPI),Gene On-tology(GO)enrichment,and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses.The key DEGs were validated in GSE102485 via receiver operating characteristic(ROC)curve analysis.A quantitative polymerase chain reaction(qPCR)assay was used to confirm the mRNA of these candidate biomarkers in human retinal microvascular endothelial cells(HRMECs)cultured in high glucose and low oxygen conditions.Results A total of 59 shared DEGs and 26 hub genes were identified from the PXD046630 and GSE60436 datasets.KEGG analysis revealed that six pathways,inclu-ding extracellular matrix-receptor interaction,proteoglycans in cancer,and complement and coagulation cascades,were enriched in 12 key DEGs.Fibronectin 1(FN1),tissue inhibitor of metalloproteinase 3(TIMP3),complement factor H(CFH),decorin(DCN),and lipoprotein receptor-related protein-2(LRP2)were identified as potential biomarkers on the basis of their AUC values being greater than 0.900(CI≥95％).The mRNA expression levels of FN1,CFH,and LRP2 were significantly increased in HRMECs cultured in high glucose and low oxygen conditions.Conclusion FN1,CFH,and LRP2 are potential biomarkers for PDR,and further studies are needed to explore their roles and therapeutic potential in PDR.

Objective To summarize the imaging characteristics of occult rib fracture(ORF),analyze the causes of missed diagnosis and misdiagnosis of ORF,and explore strategies to improve the detection rate of ORF.Methods A total of 142 patients with rib fractures who underwent multi spiral computed tomography(MSCT)were selected.The initial examination was conducted within 1 week after the injury,and follow-up examinations were performed at multiple time points after 1 week post-injury.A retrospective analysis was conducted to review the fracture detection and locations during the follow-up period.The time of fracture edge sclerosis or callus growth was observed in the young group(17 cases),middle-aged group(64 cases),and elderly group(61 cases).Results The anterior segment of the ribs was the predilection site for occult fractures,with 199 cases(53.4％).The missed diagnosis rates of fracture were higher for fractures near the costal cartilage segment and the posterior segment of the ribs,with missed diagnosis rates of 49.4％and 58.8％,respectively.Compared with the number of rib fractures identified in the initial examination,there was a statistically significant difference in the number of rib fractures at 3-6 weeks after injury(P＜0.05).The time of local sclerosis or callus growth in the young,middle-aged and elderly groups was(18.76±3.849)d,(26.14±6.597)d,and(37.69±5.726)d,respectively,with statistically significantl differences between the groups(P＜0.05).Conclusion MSCT has certain limits in diagnosing ORF in the short term after injury.Primarily observing the predilection sites and missed sites of occult fractures,systematically recognizing the imaging characteristics of ORF,and adopting the optimal detection-time window for patients of different age groups can reduce the missed diagnosis rate and misdiagnosis rate of ORF and improve the detection rate of fractures.This provides accurate and objective basis for clinical and forensic identification,with significant clinical importance and application value.

BACKGROUND: Several studies have demonstrated the occurrence of secondary tumors as a rare but significant complication of chimeric antigen receptor T (CAR-T) cell therapy, underscoring the need for a detailed investigation. Given the limited variety of secondary tumor types reported to date, a comprehensive characterization of the various secondary tumors arising after CAR-T therapy is essential to understand the associated risks and to define the role of the immune microenvironment in malignant transformation. This study aims to characterize the immune microenvironment of a newly identified secondary tumor post-CAR-T therapy, to clarify its pathogenesis and potential therapeutic targets. METHODS: In this study, the bone marrow (BM) samples were collected by aspiration from the primary and secondary tumors before and after CD19 CAR-T treatment. The CD45 + BM cells were enriched with human CD45 microbeads. The CD45 + cells were then sent for 10× genomics single-cell RNA sequencing (scRNA-seq) to identify cell populations. The Cell Ranger pipeline and CellChat were used for detailed analysis. RESULTS: In this study, a rare type of secondary chronic myelomonocytic leukemia (CMML) were reported in a patient with diffuse large B-cell lymphoma (DLBCL) who had previously received CD19 CAR-T therapy. The scRNA-seq analysis revealed increased inflammatory cytokines, chemokines, and an immunosuppressive state of monocytes/macrophages, which may impair cytotoxic activity in both T and natural killer (NK) cells in secondary CMML before treatment. In contrast, their cytotoxicity was restored in secondary CMML after treatment. CONCLUSIONS This finding delineates a previously unrecognized type of secondary tumor, CMML, after CAR-T therapy and provide a framework for defining the immune microenvironment of secondary tumor occurrence after CAR-T therapy. In addition, the results provide a rationale for targeting macrophages to improve treatment strategies for CMML treatment.
Humans ; Lymphoma, Large B-Cell, Diffuse/therapy* ; Tumor Microenvironment/genetics* ; Antigens, CD19/metabolism* ; Leukemia, Myelomonocytic, Chronic/genetics* ; Immunotherapy, Adoptive/adverse effects* ; Male ; Single-Cell Analysis/methods* ; Female ; Sequence Analysis, RNA/methods* ; Receptors, Chimeric Antigen ; Middle Aged

Objective:To evaluate the role of stimulator of interferon genes (STING) in postoperative cognitive dysfunction (POCD) and the relationship with pyroptosis in hippocampal cells in aged mice.Methods:Forty-eight SPF healthy male C57BL/6 mice, aged 18 months, weighing 23-28 g, were assigned to 4 groups ( n=12 each) using a random number table method: control group (C group), POCD group (P group), STING inhibitor C-176 group (PC group), and C-176 solvent group (PV group). The mice underwent Morris water maze training for 4 days prior to model establishment. Mice in P, PC and PV groups underwent tibial fracture and intramedullary pin fixation under sevoflurane anesthesia to establish the POCD model, while mice in C group received no treatment. The STING inhibitor C-176 (750 nmol/200 μl) and an equal volume of C-176 solvent were intraperitoneally injected at 30 min before establishment of the model in PC and PV groups, respectively. The open field test was performed on the 5th day after model preparation, the novel object recognition test was conducted on the 6th day, and the Morris water maze test was performed on the 7th day. Mice were sacrificed under anesthesia to collect the hippocampus for determination of the expression of STING, phosphorylated STING (p-STING), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), cleaved caspase-1, and gasdermin-D (GSDMD)-NT by Western blot. Results:There were no statistically significant differences in the parameters of the training phase of the Morris water maze test and the open field test among the four groups ( P>0.05). Compared with C group, the recognition index in the novel object recognition test was significantly decreased, the number of crossing the original platform was reduced and the duration spent in the target quadrant was shortened in the Morris water maze test, and the expression of STING, NLRP3, cleaved caspase-1, and GSDMD-NT in hippocampal neurons was up-regulated in P, PC and PV groups, and the expression of p-STING was significantly up-regulated in P and PV groups ( P<0.05). Compared with P group, the recognition index in the novel object recognition test was significantly increased, the number of crossing the original platform was reduced and the duration spent in the target quadrant was prolonged in the Morris water maze test, and the expression of p-STING, NLRP3, cleaved caspase-1, and GSDMD-NT in hippocampal neurons was down-regulated in PC group ( P<0.05). Compared with PC group, the recognition index in the novel object recognition test was significantly decreased, the number of crossing the original platform was reduced and the duration spent in the target quadrant was shortened in the Morris water maze test, and the expression of p-STING, NLRP3, cleaved caspase-1 and GSDMD-NT was up-regulated in PV group ( P<0.05). Conclusions:STING is involved in the development of POCD in aged mice, and the mechanism may be related to promotion of pyroptosis in hippocampal cells.

Objective To evaluate the association between self-reported neighborhood walkability environments and mortality in China.Methods The Prospective Urban Rural Epidemiology study in China(PURE-China)recruited 47 931 participants aged 35-70 from 12 provinces in China between 2005 and 2009.Neighborhood environmental indicators were collected using the Neighborhood Environment Walkability Scale(NEWS)questionnaire,with higher scores indicating better walkable environments.The primary outcomes were all-cause mortality and cardiovascular mortality,using Cox fragile model to evaluate the association between community walkability and outcomes,as well as exploring mediating pathways.Results Of 35 490 participants included in this study,60%were female,with a mean(SD)age of 51.5(9.6)years.The median follow-up was 11.7 years.This study found an association between higher community walkability score and reduced risk of all-cause mortality,with the total score(HR=0.85;95%CI,0.80-0.89),land-use mix(HR=0.84;95%CI,0.79-0.88),and crime safety(HR=0.84;95%CI,0.80-0.89)showing the most significant associations.NEWS can affect long-term adverse outcomes through lifestyle.Conclusions In the Chinese population,favorable community walkability is associated with lower all-cause mortality risk,which may support policymakers to take actions to mitigate the adverse effects of poor community en-vironments on health.

OBJECTIVES: To evaluate the early clinical efficacy and safety of trans-catheter aortic valve replacement (TAVR) for patients with severe pure native aortic regurgitation (PNAR) who are not suitable for conventional surgical aortic valve replace-ment. METHODS: A retrospective analysis was conducted on 48 patients with PNAR who underwent TAVR at the Department of Cardiac Surgery, the First Affiliated Hospital of Sun Yat-sen University between March 2019 and February 2025. These included 25 cases with transfemoral approach (TF-TAVR group) and 23 cases with transapical approach (TA-TAVR group). Efficacy and safety were assessed by analyzing baseline characteristics, all-cause mortality, and procedure-related complications. RESULTS: Compared with the TA-TAVR group, the TF-TAVR group exhibited significantly smaller aortic annulus circumference and diameter, left ventricular outflow tract circumference and diameter, diameters of the left, right, and non-coronary sinuses, and sinotubular junction (STJ) diameter, along with a shorter distance from the STJ to the aortic annular plane ring plane, a smaller annulus angle (all P<0.05). Additionally, the TF-TAVR group showed a deeper prosthesis implantation depth relative to the aortic annular plane (P<0.01). The overall technical success rate was 91.67%, and the device success rate was 83.33%. Post-TAVR, both groups demonstrated significant improvement in left ventricular end-diastolic diameter (both P<0.05), while only the TA-TAVR group showed significant reduction in left ventricular end-systolic diameter (P<0.05). For primary outcomes, in-hospital mortality occurred in 2 patients (4.17%). No additional deaths were reported at 60 or 90 d after surgery. During 90-180 d after surgery, one patient in the TF-TAVR group died of sudden cardiac death, and one in the TA-TAVR group died of gastroin-testinal bleeding. During 180 d-1 year after surgery, one patient in the TF-TAVR group died of low cardiac output syndrome. No statistically significant differences were observed in 1-year Kaplan-Meier survival curves between the two groups (P>0.05). No conduction block events occurred in TA-TAVR group during hospitalization or 1-year follow-up, while high-grade atrioventricular block, left bundle branch block, permanent pacemaker implantation occurred in TF-TAVR group during hospitalization (12.00%, 4.00%, and 12.00%, respectively). CONCLUSIONS TAVR demonstrates high feasibility and acceptable safety for severe PNAR patients who are not suitable for conventional SAVR. Both TF-TAVR and TA-TAVR show comparable early postoperative efficacy and safety profiles.
Humans ; Transcatheter Aortic Valve Replacement/adverse effects* ; Aortic Valve Insufficiency/surgery* ; Retrospective Studies ; Male ; Female ; Aged ; Treatment Outcome ; Aortic Valve/surgery* ; Aged, 80 and over ; Heart Valve Prosthesis

OBJECTIVES: To investigate the effect of orexin-A-mediated regulation of ionotropic glutamate receptors for promoting motor function recovery in rats with spinal cord injury (SCI). METHODS: Thirty-six newborn SD rats (aged 7-14 days) were randomized into 6 groups (n=6), including a normal control group, a sham-operated group, and 4 SCI groups with daily intrathecal injection of saline, DNQX, orexin-A, or orexin-A+DNQX for 3 consecutive days after PCI. Motor function of the rats were evaluated using blood-brain barrier (BBB) score and inclined plane test 1 day before and at 1, 3, and 7 days after SCI. For patch-clamp experiment, spinal cord slices from newborn rats in the control, sham-operated, SCI, and SCI+orexin groups were prepared, and ventral horn neurons were acutely isolated to determine the reversal potential and dynamic indicators of glutamate receptor-mediated currents under glutamate perfusion. RESULTS: At 3 and 7 days after SCI, the orexin-A-treated rats showed significantly higher BBB scores and grip tilt angles than those with other interventions. Compared with those treated with DNQX alone, the rats receiving the combined treatment with orexin and DNQX had significantly higher BBB scores and grip tilt angles on day 7 after PCI. In the patch-clamp experiment, the ventral horn neurons from SCI rat models exhibited obviously higher reversal potential and greater rise slope of glutamate current with shorter decay time than those from sham-operated and orexin-treated rats. CONCLUSIONS Orexin-A promotes motor function recovery in rats after SCI possibly by improving the function of the ionotropic glutamate receptors.
Animals ; Spinal Cord Injuries/drug therapy* ; Rats ; Rats, Sprague-Dawley ; Receptors, Ionotropic Glutamate/metabolism* ; Recovery of Function/drug effects* ; Orexins/pharmacology* ; Male ; Female ; Animals, Newborn ; Neuropeptides/pharmacology* ; Intracellular Signaling Peptides and Proteins/pharmacology*

IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis. However, their involvement in optic neuropathy due to trauma and glaucoma remains unclear. Here, we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina. Deletion of IL-33 or ST2 exacerbated retinal ganglion cell (RGC) loss, retinal thinning, and nerve fiber degeneration following optic nerve (ON) injury. This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33^-/- mice. In vitro, rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors, thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants. Exogenous IL-33 treatment improved RGC survival in Il33^-/- and WT mice after ON injury, but not in ST2^-/- mice. Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.
Animals ; Interleukin-33/genetics* ; Interleukin-1 Receptor-Like 1 Protein/genetics* ; Optic Nerve Injuries/pathology* ; Retinal Ganglion Cells/pathology* ; Astrocytes/pathology* ; Mice ; Mice, Knockout ; Mice, Inbred C57BL ; Neuroprotection/physiology*