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T cell receptor (TCR)-engineered T cell therapy is a promising potential treatment for solid tumors, with preliminary efficacy demonstrated in clinical trials. However, obtaining clinically effective TCR molecules remains a major challenge. We have developed a strategy for cloning tumor-specific TCRs from long-term surviving patients who have responded to immunotherapy. Here, we report the identification of a TCR (10F04), which is human leukocyte antigen (HLA)-DRA/DRB1*09:01 restricted and human papillomavirus type 18 (HPV18) E7 84-98 specific, from a multiple antigens stimulating cellular therapy (MASCT) benefited metastatic cervical cancer patient. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4 + and CD8 + T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity and outstanding safety profiles. As a result, this TCR is currently being investigated in a phase I clinical trial for treating HPV18-positive cancers. This study provides an approach for developing safe and effective TCR-T therapies, while underscoring the potential of HLA class II-restricted TCR-T therapy as a cancer treatment. The use of TCR engineered T cells holds promise for treatment of tumours, but is limited by awareness of clinically effective TCR molecules. Here the authors identify an MHC II restricted TCR that targets viral E7 of human papillomavirus type 18 and show effectivity in a murine model of solid tumour.

Background To develop a dynamic prediction model for diabetic retinopathy (DR) using systemic risk factors. Methods This retrospective study included type 2 diabetes mellitus (T2DM) patients discharged from the Second Affiliated Hospital of Kunming Medical University between May 2020 and February 2022. The early patients (80%) were used for the training set and the late ones (20%) for the validation set. Results Finally, 1257 patients (1049 [80%] in the training set and 208 [20%] in the validation set) were included; 360 (28.6%) of them had DR. The areas under the curves (AUCs) for the multivariate regression (MR), least absolute shrinkage and selection operator regression (LASSO), and backward elimination stepwise regression (BESR) models were 0.719, 0.727, and 0.728, respectively. The Delong test showed that the BESR model had a better predictive value than the MR (p = 0.04899) and LASSO (P = 0.04999) models. The DR nomogram risk model was established according to the BESR model, and it included disease duration, age at onset, treatment method, total cholesterol, urinary albumin to creatinine ratio (UACR), and urine sugar. The AUC, kappa coefficient, sensitivity, specificity, and compliance of the nomogram risk model in the validation set were 0.79, 0.48, 71.2%, 78.9%, and 76.4%, respectively. Conclusions A relatively reliable DR nomogram risk model was established based on the BESR model.

We systematically assessed whether a digital polymerase chain reaction (PCR) could detect pathogenic microorganisms in patients with sepsis early and accurately. We searched the Cochrane Library, MEDLINE, Embase, CNKI, CBM, and Wanfang Data databases for eligible studies to compare the detection of pathogenic microorganisms in blood samples by digital PCR with the gold standard. The Quality Assessment of Diagnostic Accuracy Studies 2 was used to evaluate bias risk, and a random-effects meta-analysis approach was used for sensitivity and specificity calculations. Among the eight articles, there were eight identified studies with a total of 1278 subjects. The pooled sensitivity of digital PCR was 94% (95% confidence interval [CI], 85%–98%), the specificity was 87% (95% CI, 76%–94%), the positive likelihood ratio was 7.3 (95% CI, 3.8–14.2), the negative likelihood ratio was 0.07 (95% CI, 0.03–0.17), the positive predictive value was 84.7%, the negative predictive value was 89.2%, the diagnostic odds ratio was 105 (95% CI, 37–303), and the area under the receiver operating characteristic curve was 0.97 (95% CI, 0.95–1.00). Digital PCR can shorten the detection time of pathogenic microorganisms in patients with sepsis. Digital PCR can detect pathogenic microorganisms in patients with sepsis earlier than blood culture. Therefore, digital PCR can be used as a potential strategy for the detection of pathogenic microorganisms in patients with sepsis. •Digital PCR is an exciting and fairly new tool in the world of clinical infectious disease management.•It is important to keep evaluating its place and role in the diagnosis and management of infectious diseases.•This paper made a good attempt at evaluating the currently available literature by using a meta-analysis approach.

Neurodegeneration in early-stage diabetes retinopathy (DR) is mainly caused by the loss of retinal ganglion cells (RGCs), and high glucose-treated cell pyroptosis contributes to an important cause. However, the detailed molecular regulatory mechanism has not yet been thoroughly examined. In this study, primary mouse RGCs were stimulated with different concentrations of glucose, and mouse was intraperitoneally injected with streptozotocin (STZ) to construct DR model in vitro and in vivo. We found that compared to normal controls, RNA binding motif protein 15 (RBM15) was significantly upregulated in high glucose-treated RGCs and STZ-induced mice. RBM15 silence restored cell viability and inhibited cell apoptosis and cell death in high glucose-triggered RGCs. In parallel, RBM15 knockdown distinctly improved pathological damage such as thinning of retinal tissue thickness and loss of RGCs in STZ-modeling mice. Interestingly, the production of inflammatory cytokines and the expression of Cleaved caspase-1, NLRP3 and GSDMD-N were significantly reduced by RBM15 silence in vivo and in vitro. Mechanistically, RBM15 bound to kruppel like factor 6 (KLF6) mRNA to promote m6A modification and stabilize KLF6 mRNA, upregulating KLF6 expression in model cells and model mice retinal tissues. KLF6 overexpression increased the production of inflammatory cytokines and the expression of proteins related to pyroptosis, reversing the protective effects of RBM15 silence in high glucose-treated RGCs and diabetic retina. In conclusion, RBM15 is upregulated by high glucose, and stabilizes KLF6 mRNA to activate NLRP3-mediated pyroptosis pathway, exacerbating inflammation and apoptosis of RGCs and accelerating the progression of DR.

One of the leading causes of poor prognosis in colorectal cancer (CRC) patients is the presence of colorectal cancer-initiating cells (CCICs). The tumor microenvironment (TME) plays a role in the acquisition of CCICs characteristics. However, the underlying mechanisms remain unclear. Candidate molecules were identified by analyzing the differentially expressed genes (DEGs) between spheroid and planar cells, as well as between CD24 CD44 cells and CD24 CD44 cells. The relationship between prognosis and ARRDC4 was assessed using RT-qPCR and Western blot assays. Mitochondrial analysis was conducted to examine the role of ARRDC4 in metabolic reprogramming. Coimmunoprecipitation (co-IP) assays with exosomes were performed to investigate the downstream molecule WWP1. Clinical samples were collected for validation. We identified a novel TME-responsive protein involved in the reprogramming of CRC cells. ARRDC4 was upregulated in CCICs and responsive to the TME. In CCICs, ARRDC4 translocated to the mitochondrial matrix, where it reprogrammed lipid metabolism. Upregulation of ARRDC4 promoted exosome secretion. WWP1 primarily binds to ARRDC4 and is released through exosomes. Released WWP1 is taken up by surrounding CRC cells, inhibiting epithelial-mesenchymal transition (EMT) and migration. TME-responsive ARRDC4 inhibits CRC progression by regulating metabolic reprogramming and exosome secretion. Increased WWP1 in ARRDC4 CCIC-derived exosomes suppresses CRC metastasis. We identified ARRDC4/WWP1 pathway as a novel mechanism and potential therapeutic target for CRC progression.

Presenile cataract is a relatively rare type of cataract, but its genetic mechanisms are currently not well understood. The precise identification of these causative genes is crucial for effective genetic counseling for patients and their families. The aim of our study was to identify the causative gene associated with presenile cataract in a Chinese family. In February 2020, a four-generation pedigree of presenile cataract patients was recruited at the 2nd Affiliated Hospital of Kunming Medical University. One patient and her healthy husband from the family underwent whole exome sequencing. The variant was validated through sanger sequencing, and co-segregation analysis was conducted in all family members to assess its pathogenicity. Molecular dynamics simulation (MDS) was used to analyze the conformation of both the wild type and pathogenic mutant loci p.Y153H of CRYBA2. We identified presenile cataract in the pedigree, which follows an autosomal-dominant pattern of inheritance. The family includes five clinically affected patients who all developed presenile cataract between the ages from 24 to 30. We confirmed the pathogenicity of a heterozygous missense variant (NM_057093:c.457T >C) in CRYBA2 within this family. The affected amino acid demonstrates high conservation across species. Subsequent sanger sequencing confirmed co-segregation of the disease in all family members. MDS analysis revealed that the p.Y153H mutant disrupted hydrogen bond formation between Y153 and R193 within the two β-strands of the fourth Greek key domain, leading to destabilization of the βA2-crystallin. In conclusion, a novel causative mutation (NM_057093:c.457T>C) in CRYBA2 might contribute to autosomal dominant presenile cataract.

Diabetic retinopathy (DR) caused visual performance degradation seriously endangers human beings, uncovering the underlying mechanism might shed light on the discovery of DR therapeutic treatments. In this study, we found that the effects of glucose on retinal pigment epithelium (RPE) varies in a dose dependent manner, high-glucose promotes ROS generation and cell apoptosis, inhibits mitophagy as well as proliferative abilities, while low-glucose induces ROS production and cell mitophagy, but has little impacts on cell apoptosis and proliferation. Of note, the toxic effects of high-glucose on RPE are alleviated by ROS scavengers and aggravated by autophagy inhibitor 3-methyladenine (3-MA) or mitophagy inhibitor cyclosporin A (CsA). High-glucose induced ROS generation is merely eliminated by ROS scavengers instead of mitophagy or autophagy inhibitor. We also proved that high-glucose inhibits cell proliferation and promotes cell apoptosis by regulating ROS mediated inhibition of mitophagy. In addition, mitophagy associated proteins PINK1 and Parkin are downregulated by high-glucose or hydrogen peroxide treatments, which are reversed by ROS scavengers. Of note, Knock-down of PINK1 decreases phospharylated Parkin instead of total Parkin levels in RPE. Intriguingly, the inhibiting effects of high-glucose on cell mitophagy as well as proliferation and its promoting effects on cell apoptosis are reversed by either PINK1 or Parkin overexpression. Therefore, we concluded that high-glucose promotes RPE apoptosis and inhibits cell proliferation as well as mitophagy by regulating oxidative stress mediated inactivation of ROS/PINK1/Parkin signal pathway.

The inflammatory microenvironment formed by chronic inflammation is not only a major risk factor for cancer but also a well-recognized precursor to bladder cancer. However, the immunological transitions that occur along the inflammation-to-cancer continuum remain incompletely understood. This mini-review synthesizes recent advances in understanding how the immune microenvironment evolves from an inflamed yet non-malignant urothelium to invasive carcinoma. First, we discuss how persistent stimuli—such as chronic infection or exposure to carcinogens—disrupt immune homeostasis, leading to sustained interferon signaling, cytokine secretion, and immune cell infiltration. Second, during preneoplastic and dysplastic stages, the immune landscape gradually shifts toward an environment enriched in regulatory T cells and characterized by dysfunctional cytotoxic T cells. Furthermore, in established tumors, immune evasion is primarily driven by T cell exhaustion, myeloid cell–mediated immunosuppression, and fibroblast-associated immune exclusion. Finally, advances in spatial transcriptomics, single-cell technologies, and urinary exosomal profiling have enabled precise “immune snapshots” of these transitions, providing new avenues for biomarker development and therapeutic strategy selection. Mapping these dynamic immune states holds great promise for improving risk stratification, facilitating early detection, and enabling personalized immunotherapy, ultimately translating immune snapshots into actionable strategies for bladder cancer prevention and treatment.

Background The prevalence of carbapenem-resistant Klebsiella pneumoniae bloodstream infection (CRKP-BSI) is increasing worldwide. CRKP-BSI is associated with high rates of morbidity and mortality due to limited antibiotic choices. Here, we aim to identify the prevalence and risk factors for infection and mortality of CRKP BSI. Methods This was a retrospective study of the past data from January 1st, 2012 to December 31st, 2019 of adult patients with KP-BSI in Xiangya Hospital, China. Results Among the 706 incidences included in this study, 27.4% of them (212/753) being CR-KP strains. The occurrence of CRKP-BSI was increased from 20.69 to 37.40% from 2012 to 2019. Hematologic malignancies and ICU acquired infection were identified to be substantial risk factors of carbapenem resistance. The overall 28-day mortality rates of CRKP-BSI patients was significantly higher than that of CSKP-BSI ( P  < 0.001). Logistic regression analysis identified severe sepsis or septic shock incidents, inadequate empirical antimicrobial therapy and corticosteroids use preceding infection onset as the independent predictors of 28-day mortality of CRKP-BSI patients. However, high dose carbapenem combination therapy was identified as anticipated factors of low 28-day mortality. Conclusion The occurrence of CRKP-BSI was significantly increased during the study period. Hematologic malignancies and ICU acquired infection were associated with the development of CRKP BSI. Severe sepsis or septic shock incidents, inadequate empirical antimicrobial therapy and corticosteroids use preceding infection onset caused significant increase of mortality rates in CRKP-BSI patients. High dose carbapenem combination therapy was associated with better outcome.

A fault diagnosis method using bond graphs in an expert system is proposed for a reactor coolant system. Firstly, the time causality graph and the variable relationship graph are derived from the bond graph. Secondly, the fault signature matrix is obtained by combining the change relationship of fault parameters. Finally, the fault signature matrix is used as the rule of the inference engine design in the expert system for fault diagnosis. In this paper, the key equipment of the reactor coolant system is used to verify the fault diagnosis method of the bond graph expert system, and the path reasoning relationship between alarms is obtained, which can accurately obtain the deep knowledge required by the operators. A new idea for fault diagnosis in a nuclear power plant’s expert system is provided by this method.