Uveal melanoma(UM)is the most common primary intraocular malignancy in adults, characterized by high invasiveness and unique metastatic biological features. Although local treatments(such as proton beam therapy and brachytherapy)can effectively control the primary lesion, approximately 50% of patients eventually develop distant metastasis, with the liver being the primary target organ(occurring in 90% of cases). This highlights a paradigm shift in treatment focus from mere local control to systemic prevention and management. For metastatic UM(mUM), current treatment strategies encompass biomarker-guided molecular targeted therapy, immunotherapy(including Tebentafusp, vaccines, and oncolytic virus therapy), and liver-directed therapy. Focusing on the synergy between local and systemic prevention and control, this article systematically elaborates on the precision local treatment for primary UM, the decision-making pathway for systemic treatment of metastatic UM based on molecular subtyping, the integration of local and systemic therapies for liver metastases, and the translational value of nanomedicine in addressing therapeutic bottlenecks. It provides insights for optimizing clinical management of mUM and developing novel therapeutic strategies.

Objective To investigate the differences of type 2 innate lymphocytes (ILC2) and interlukin 9 (IL-9) between chronic lymphocytic leukemia (CLL) patients and healthy controls, and to understand the effects of ILC2 on the function of regulatory T cells (Tregs), CD8⁺ T cells and CLL cells through IL-9. Methods Flow cytometry was used to detect the levels of ILC2 and Tregs in the peripheral blood of 45 newly diagnosed CLL patients and 24 healthy controls, and the expressions of granzyme B and perforin in CD8⁺ T cells in the peripheral blood of 28 patients and 15 healthy controls; ELISA was used to detect the level of IL-9 in the serum. ILC2 of patients and healthy controls was sorted by immunomagnetic beads and cultured separately, and the level of IL-9 in the culture supernatant was measured by ELISA. ILC2 sorted from CLL patients and healthy control-derived peripheral blood mononuclear cells(PBMCs) were co-cultured with the B cell leukemia MEC-1 cells, one group was supplemented with IL-9 antibody and the other group was not. After 72 hours of culture, the ratio of Tregs, programmed death 1 (PD-1), T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), cytotoxic T lymphocyte antigen 4 (CTLA-4) on Tregs, granzyme B and perforin in CD8⁺ T cells were measured by flow cytometry, IL-9 level of the culture supernatant was measured by ELISA, the apoptosis of MEC-1 cells was measured by Annexin V-PI. Results Compared with the healthy control group, the levels of ILC2, Tregs and IL-9 in the CLL group increased significantly. The levels of granzyme B and perforin in CD8⁺ T cells were positively correlated in the peripheral blood of CLL patients. Compared with the healthy control group, IL-9 levels in the supernatant of sorted ILC2 from CLL patients increased. In the anti-IL9 antibody group, the level of PD-1 and TIGIT on Tregs decreased, and the level of granzyme B in CD8⁺ T cells increased significantly. The level of IL-9 in the anti-IL9 antibody group decreased statistically. And MEC-1 cells showed increased early apoptotic rate in the anti-IL9 antibody group statistically. Conclusion In CLL, ILC2 affects CD8⁺ T cells and Tregs through IL-9, which weakens the anti-tumor effect of CD8⁺ T cells, enhances the immunosuppressive effect of Tregs, and plays a role in the occurrence and development of CLL disease.
Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology* ; CD8-Positive T-Lymphocytes/immunology* ; T-Lymphocytes, Regulatory/immunology* ; Middle Aged ; Male ; Female ; Interleukin-9/blood* ; Aged ; Granzymes/metabolism* ; Perforin/metabolism* ; Immunity, Innate ; Adult ; Lymphocytes/immunology*

Delirium is a common cause and complication of hospitalization in the elderly and is associated with higher risk of future dementia and progression of existing dementia, of which 70% is Alzheimer's disease (AD). AD and delirium, which are known to be aggravated by one another, represent significant societal challenges, especially in light of the absence of effective treatments. The intricate biological mechanisms have led to numerous clinical trial setbacks and likely contribute to the limited efficacy of existing therapeutics. Artificial intelligence (AI) presents a promising avenue for overcoming these hurdles by deploying algorithms to uncover hidden patterns across diverse data types. This review explores the pivotal role of AI in revolutionizing drug discovery for AD and delirium from target identification to the development of small molecule and protein-based therapies. Recent advances in deep learning, particularly in accurate protein structure prediction, are facilitating novel approaches to drug design and expediting the discovery pipeline for biological and small molecule therapeutics. This review concludes with an appraisal of current achievements and limitations, and touches on prospects for the use of AI in advancing drug discovery in AD and delirium, emphasizing its transformative potential in addressing these two and possibly other neurodegenerative conditions.

Reactive astrocytes, which exhibit a correlation with the degeneration of dopaminergic neurons, are present in a considerable number during the progression of Parkinson's disease (PD). However, the underlying factors shaping astrocyte reactivity and neuroinflammation in PD remain inadequately elucidated. Here, we demonstrate that fibroblast growth factor 7 (FGF7)/FGF receptor 2 (FGFR2) autocrine signaling intensifies astrocyte reactivity and inflammation. Genetic deletion of Arrb2, β-Arrestin2 encoding gene, led to escalated astrocyte reactivity in MPTP-treated mice, which was further substantiated in astrocyte-specific Arrb2 knockdown mice. RNA sequencing profiling of Arrb2 knockout astrocytes identified Fgf7 as a critical effector of astrocyte reactivity. Subsequently, conditional knockdown of Fgf7 and its receptor Fgfr2 in astrocytes elicited advantageous effects for MPTP-treated mice by restraining the inflammatory phenotypic transition of reactive astrocytes. Furthermore, deletion of astrocytic Fgf7 mitigated MPTP-induced pathology in Arrb2 knockout mice. Mechanistically, STAT1 was distinguished as the transcription factor suppressing Fgf7 expression, while β-Arrestin2 counteracted the proteasomal degradation of STAT1 by binding to RNF220, an E3 ubiquitin ligase for STAT1. More importantly, selectively engaging dopamine D2 receptor (Drd2)/β-Arrestin2-biased signaling using the agonist UNC9995 exhibited therapeutic potential in MPTP-treated mice via moderation of astrocytic FGF7 production, thereby restoring balance in astrocyte reactivity. Collectively, our study bridges a crucial knowledge gap by elucidating the novel functions of FGF family members within the central nervous system, particularly within the context of PD. The autocrine signaling of FGF7/FGFR2 represents a novel mechanism and a potential druggable target for modulating astrocyte-derived inflammation.

Objective:To investigate the clinical efficacy of haploidentical high-dose in vitro non-T-cell-depleted peripheral blood hematopoietic stem cell transplantation (haplo-HDPSCT) in treating adult patients with Ph + acute lymphoblastic leukemia (Ph + ALL) . Method:This retrospective analysis was conducted on the clinical efficacy of 25 adult patients with Ph + ALL who underwent haplo-HDPSCT from July 2011 to June 2022 at our hospital. Results:This study included 25 patients with a median age of 27 (16-61) years, consisting of 12 males and 13 females. CR1 and ≥CR2 before transplantation were found in 23 and 2 cases, positive and negative minimal residual lesions were observed in 8 and 17 cases, and myeloablative conditioning and reduced-intensity conditioning were reported in 21 and 4 cases, respectively. Hematopoietic function was restored in all 25 patients after stem cell infusion. Of the 25 patients who underwent transplantation, 16 developed acute graft-versus-host disease (aGVHD). The cumulative incidence rates of Ⅱ-Ⅳ and Ⅲ-Ⅳ aGVHD were (40.4±11.3) % and (4.8±4.6) %, respectively. Four patients experienced relapse after transplantation, the cumulative relapse rates at 1 and 2 years after transplantation were (4.0±3.9) % and (14.5±7.9) %, respectively. The 2-year overall survival rate after transplantation was (81.3±8.5) % and the disease-free survival rate was (77.1±9.1) %.Conclusion:This study reveals that the unique haplo-HDPSCT protocol achieves good clinical efficacy in Ph + ALL treatment.

Objective:To investigate the therapeutic efficacy of autologous hematopoietic stem cell transplantation (auto-HSCT) for treatment of diffuse large B-cell lymphoma (DLBCL) and the factors affecting the prognosis.Methods:A retrospective case series study was conducted. The clinical data of 51 patients with DLBCL who underwent auto-HSCT in the First Affiliated Hospital of Xinjiang Medical University from March 2019 to January 2024 were retrospectively analyzed. Patients were divided into high-risk group (19 cases) and non-high-risk group (low-risk, low-moderate-risk and moderate-high-risk groups, 32 cases) based on different risk stratifications; patients were divided into the germinal center B-cell (GCB) group (29 cases) and non-GCB group (22 cases) based on different cellular origins; patients were divided into BEAM group (39 cases) and BeEAM group (12 cases) based on different conditioning regimens before auto-HSCT; patients were divided into auto-HSCT consolidation therapy group (41 cases) and auto-HSCT after relapsed/refractory group (10 cases) based on different transplantation timings. The Kaplan-Meier method was used for survival analysis and log-rank was used for subgroup comparison.Results:All 51 patients achieved the hematopoietic reconstitution with no transplantation-related death within 100 d. Before auto-HSCT, 39 cases achieved complete remission and 12 cases (23.5%) achieved partial remission. After auto-HSCT, all cases achieved complete remission. Follow-up was until May 31, 2024, and the median follow-up time [ M ( Q1, Q3)] of 51 DLBCL patients was 33 (8, 43) months. After 51 DLBCL patients receiving auto-HSCT, 7 patients relapsed and 6 cases died including 3 cases with relapse-related death and 3 cases with non relapse-related death. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 78.5% (95% CI: 64.4%-92.6%) and 85.5% (95% CI: 73.2%-97.8%), respectively. The 3-year PFS rate was 94.7% (95% CI: 84.7%-104.7%) in the high-risk group, 82.2% (95% CI: 67.9%-96.5%) in the non-high-risk group, and the difference in the PFS was not statistically significant between the high-risk group and the non-high-risk group ( P = 0.158). The 3-year PFS rate was 80.1% (95% CI: 64.4%-95.8%) in the GCB group, 88.1% (95% CI: 72.3%-104.2%) in the non-GCB group, and the difference in PFS was not statistically significant between the 2 groups ( P = 0.803). The 3-year PFS rate was 84.9% (95% CI: 72.6%-97.2%) in BEAM group, 61.1% (95% CI: 25.0%-97.2%) in the BeEAM group, and the difference in PFS was not statistically significant between the 2 groups ( P = 0.106). The 3-year PFS rate was 85.4% (95% CI: 73.4%-97.4%) in the auto-HSCT consolidation therapy group, 64.3% (95% CI: 31.4%-96.4%) in the auto-HSCT after relapsed/refractory group, and the difference in PFS was not statistically significant between the 2 groups ( P = 0.171). Conclusions:auto-HSCT is an effective therapy method for DLBCL.

Objective:To investigate the clinical efficacy of haploidentical high-dose in vitro non-T-cell-depleted peripheral blood hematopoietic stem cell transplantation (haplo-HDPSCT) in treating adult patients with Ph + acute lymphoblastic leukemia (Ph + ALL) . Method:This retrospective analysis was conducted on the clinical efficacy of 25 adult patients with Ph + ALL who underwent haplo-HDPSCT from July 2011 to June 2022 at our hospital. Results:This study included 25 patients with a median age of 27 (16-61) years, consisting of 12 males and 13 females. CR1 and ≥CR2 before transplantation were found in 23 and 2 cases, positive and negative minimal residual lesions were observed in 8 and 17 cases, and myeloablative conditioning and reduced-intensity conditioning were reported in 21 and 4 cases, respectively. Hematopoietic function was restored in all 25 patients after stem cell infusion. Of the 25 patients who underwent transplantation, 16 developed acute graft-versus-host disease (aGVHD). The cumulative incidence rates of Ⅱ-Ⅳ and Ⅲ-Ⅳ aGVHD were (40.4±11.3) % and (4.8±4.6) %, respectively. Four patients experienced relapse after transplantation, the cumulative relapse rates at 1 and 2 years after transplantation were (4.0±3.9) % and (14.5±7.9) %, respectively. The 2-year overall survival rate after transplantation was (81.3±8.5) % and the disease-free survival rate was (77.1±9.1) %.Conclusion:This study reveals that the unique haplo-HDPSCT protocol achieves good clinical efficacy in Ph + ALL treatment.

Objective:To explore the structural characteristics of intestinal microflora in children with non-alcoholic fatty liver disease（NAFLD）and the relationship between intestinal microflora and the occurrence as well as development of NAFLD in children.Methods:Fifteen children with NAFLD diagnosed at the First People's Hospital of Yunnan Province from January 2022 to December 2022 were selected as subjects，and 15 healthy children who received routine physical examinations at the outpatient clinic during the same period were randomly selected as healthy control group.The height，weight，waist circumference，blood pressure，blood biochemistry of all children were collected.At the same time，the fresh fecal samples of all children were collected，and the biological information of intestinal flora was analyzed by 16S rRNA sequencing.Results:In the NAFLD group，there were eight males and seven females，with an average age of（11.13±1.77）years.In healthy control group，there were seven males and eight females，with an average age of（9.73±2.25）years.There were no significant differences in sex，age，blood pressure between two groups.Compared with the healthy control group，the levels of body mass index，waist circumference，waist-to-height ratio，alanine aminotransferase，aspartate transaminase，gamma-glutamyl transpeptidase，total bilirubin，direct bilirubin，unconjugated bilirubin，low density lipoprotein cholesterol，uric acid and serum insulin significantly increased and high density lipoprotein cholesterol significantly decreased in NAFLD group（ P<0.05）.The results of species diversity analysis showed that chaol index and observed-species index in NAFLD group were significantly higher than those in healthy control group（ P<0.05）.Species diversity analysis showed that the species with increased abundance in NAFLD group included：Proteobacteria，Gammaproteobacteria，Enterobacteriaceae，Klebsiella，Escherichia-Shigella，Escherichia-Shigella-unclassified.Differential species with increased abundance in the healthy control group included：Bifidobacterium species，Bifidobacterium，Bifidobacteriaceae，Bifidobacteriales，Actinobacteria，Actinobacteriota，Bacteroidia，Bacteroidales，Streptococcus-thermophilus. Conclusion:There are metabolic abnormalities and obvious changes in the structure of intestinal flora in children with NAFLD.Exogenous supplementation of Bifidobacterium，Streptococcus thermophilus and Bacteroides may prevent the occurrence of NAFLD，delay the progression of disease and improve fat deposition in the liver.

Despite decades of research,cancer continues to be a major global health concern.The human mouth appears to be a multiplicity of local environments communicating with other organs and causing diseases via microbes.Nowadays,the role of oral microbes in the development and progression of cancer has received increasing scrutiny.At the same time,bioengineering technology and nanotechnology is growing rapidly,in which the physiological activities of natural bacteria are modified to improve the therapeutic efficiency of cancers.These engineered bacteria were transformed to achieve directed genetic reprogramming,selective functional reorganization and precise control.In contrast to endotoxins produced by typical genetically modified bacteria,oral flora exhibits favorable biosafety characteristics.To outline the current cognitions upon oral microbes,engineered microbes and human cancers,related literatures were searched and reviewed based on the PubMed database.We focused on a number of oral microbes and related mechanisms associated with the tumor microenvironment,which involve in cancer occurrence and development.Whether engineering oral bacteria can be a possible application of cancer therapy is worth consideration.A deeper understanding of the relationship between engineered oral bacteria and cancer therapy may enhance our knowledge of tumor pathogenesis thus providing new insights and strategies for cancer prevention and treatment.

Objective To investigate the predictive value of preoperative blood inflammatory markers for the recurrence risk in patients with basal cell carcinoma(BCC).Methods A total of 225 patients with BCC were divided into the high-risk recurrence group(155 cases)and the low-risk recurrence group(70 cases).General information and preoperative hematological indicators were collected in the two groups of patients.The neutrophil-to-lymphocyte ratio(NLR),lymphocyte-to-monocyte ratio(LMR),systemic inflammation marker(SIM)and platelet-to-lymphocyte ratio(PLR)were calculated.Receiver operating characteristic(ROC)curves were used to determine the predictive value of hematological markers with statistically significant differences between the two groups for BCC recurrence and to establish optimal cutoff values.Univariate and multivariate Logistic regression analyses were conducted to identify factors influencing BCC recurrence.A multivariate Logistic regression model was established to predict the recurrence risk of BCC.Area under the curve(AUC)and the Hosmer-Lemeshow test were used to evaluate the prediction efficiency and goodness-of-fit of the model.Results ROC analysis identified that optimal cutoff values for LMR and SIM were 5.12 and 0.86,respectively.Univariate Logistic regression analysis showed that LMR,SIM,ulceration at the primary tumor site,UV exposure and tumor maximum diameter were factors influencing BCC recurrence.Multivariate Logistic regression revealed that SIM≥0.86,tumor maximum diameter≥2.0 cm and UV exposure were risk factors for BCC recurrence,while LMR≥5.12 had a protective effect.The Logistic prediction model for BCC recurrence risk was Logit(P)=-1.598-1.517×LMR+1.323×SIM+2.406×UV exposure+3.465×tumor maximum diameter,with good model fit(P=0.725)and an AUC of 0.869(95%CI:0.822-0.917)for predicting BCC recurrence risk.Conclusion Monitoring preoperative LMR and SIM levels can assist in assessing the risk of recurrence in BCC patients and provide important guidance for clinical decision-making.