OBJECTIVES: To investigate the causal associations between autoimmune diseases and aplastic anemia (AA) using Mendelian randomization analysis. METHODS: Publicly available genome-wide association study (GWAS) data were utilized to obtain single nucleotide polymorphisms (SNPs) associated with autoimmune diseases and AA for analysis. The inverse variance weighted (IVW) method was employed as the primary analytical approach, with MR Egger, Weighted Mode, Weighted Median, and Simple Mode methods serving as complementary analyses. Heterogeneity and pleiotropy analyses were conducted using designated functions, and the robustness of Mendelian randomization results was assessed using leave-one-out analysis. RESULTS: The two-sample Mendelian randomization analysis using the IVW method revealed significant positive causal associations of rheumatoid arthritis (OR=1.094, 95% CI: 1.023-1.170, P=0.009, adjusted P=0.042), systemic lupus erythematosus (OR=1.111, 95% CI: 1.021-1.208, P=0.015, adjusted P=0.036), Hashimoto thyroiditis (OR=1.206, 95% CI: 1.049-1.387, P=0.009, adjusted P=0.029), and Sicca syndrome (OR=1.173, 95% CI: 1.054-1.306, P=0.004, adjusted P=0.035) with AA, which was supported by the results from the Weighted Median method. Sensitivity analyses indicated no evidence of pleiotropy or heterogeneity, and leave-one-out analysis confirmed the robustness of the causal relationships. No direct evidence was found linking Graves' disease, ulcerative colitis, Crohn's disease, autoimmune hepatitis, primary biliary cholangitis, or primary sclerosing cholangitis with AA (P>0.05, adjusted P>0.05), indicating a lack of causal association. Reverse Mendelian randomization results and multiple corrections indicated that AA was not an influencing factor for autoimmune diseases (adjusted P>0.05). CONCLUSIONS Our findings support at the genetic level that rheumatoid arthritis, systemic lupus erythematosus, Hashimoto thyroiditis, and Sicca syndrome are risk factors for AA, and confirm a causal association of the these 4 autoimmune diseases with an increased risk of AA.
Humans ; Mendelian Randomization Analysis ; Anemia, Aplastic/genetics* ; Autoimmune Diseases/complications* ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Arthritis, Rheumatoid/genetics* ; Lupus Erythematosus, Systemic/genetics* ; Genetic Predisposition to Disease

Objective To explore the biological mechanism of radiation resistance in esophageal squamous cell carcinoma(ESCC)and search for effective sensitization targets.Methods We retrieved 186 signaling pathways and related gene information from the MSigDB database.We also obtained RNA transcriptome data of ESCC patients using the Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.We collected clinical pathological characteristics and tissue samples of 97 ESCC patients in our hospital from 2013 to 2020.Gene set variation analysis(GSVA)was made to calculate KEGG signaling pathway score,radiotherapy resistance related signaling pathways were screened through random forest algorithm,key genes in the pathway were screened using DESeq2,and a radiotherapy efficacy prediction model was constructed based on support vector machine-recursive feature elimination(SVM-RFE).The results were validated through experiments such as Western blotting and clonogenic assay.Results Based on the KEGG signaling pathway and GSVA enrichment score,random forest analysis showed that in the TCGA and GSE45670 cohorts,the contribution of tryptophan metabolism pathway enrichment values to radiation resistance in ESCC was significantly better than that of the other pathways.DESeq2 analysis revealed that key molecules in the tryptophan metabolism pathway,namely,IDO1,ALDH1B1,AOC1,INMT,AFMID and ALDH7A1,were significantly differentially expressed in the resistant and sensitive groups of ESCC.Based on the SVM-RFE algorithm,the AUC was 0.77,which could accurately predict the radiotherapy efficacy of ESCC.Western blotting experiments showed that IDO1 was highly expressed in ESCC cells,and IDO1 inhibitor treatment significantly inhibited the survival ability and radiosensitivity of KYSE-410 cells.In the enrolled patients of our hospital,immunohistochemical studies showed that IDO1 was highly expressed in the radiotherapy resistant group of ESCC and was associated with poor radiotherapy prognosis in ESCC patients.In addition,further testing showed that the expression of IDO1 in patient samples from our hospital was positively correlated with its PD-L1 expression,but negatively correlated with the infiltration ratio of CD3/CD8 immune cells.Conclusion Tryptophan catabolism is associated with radiation resistance in ESCC,and the key enzyme IDO1 in tryptophan metabolism can be used as a therapeutic target for radiosensitization in ESCC.

Objective:To explore the clinical efficacy of the splenic vessel-oriented anatomical plane priority strategy in Da Vinci robotic Kimura distal pancreatectomy.Methods:A retrospective analysis was conducted on 26 patients who underwent robotic-assisted distal pancreatectomy at Zhejiang Provincial People’s Hospital from January 2019 to September 2024. The cohort included 7 male and 19 female patients, aged (49.3±16.7) years. Surgical outcomes, including operative time, intraoperative blood loss, postoperative complications, and hospital stay, were analyzed, and surgical techniques were summarized.Results:All 26 patients successfully completed the surgery. Pathological diagnoses included 5 cases of intraductal papillary mucinous neoplasm, 5 serous cystadenomas, 1 pancreatic neuroendocrine tumor, 6 solid pseudopapillary neoplasms, 4 mucinous cystic neoplasms, and 5 neuroendocrine tumors. The maximum tumor diameter was (2.3±1.1) cm, and the operative time was (183.2±77.4) min. The spleen preservation rate was 100% (26/26). Intraoperative blood loss was 50.0 (17.5, 125) ml, and postoperative hospital stay was (10.1±3.7) d. No Clavien-Dindo grade III or higher complications occurred. The post-operative pancreatic fistula (POPF) rate was 53.8% (14/26), including 38.5% (10/26) biochemical leak and 15.3% (4/26) grade B POPF, with no grade C POPF.Conclusion:The splenic vessel-oriented anatomical plane priority strategy in robotic-assisted spleen-preserving distal pancreatectomy (Kimura technique) is safe and feasible, significantly improving the spleen preservation rate.

Objective:To evaluate the interventional effect of online mental health education for subthreshold depression (SD) in elderly individuals.Methods:Using a randomized controlled trial (RCT) design, a total of 105 older adults with SD were recruited from 6 long-term care (LTC) settings in Ningbo city between September and November in 2023. The subjects were randomized to a intervention group (35 cases), a control group (35 cases) and a waiting list group (35 cases) in a 1∶1∶1 ratio using a random number generator. The intervention method was mental health education, comprising basic knowledge of depressive symptoms, knowledge and skills of cognitive therapy, knowledge and skills of behavioral therapy and life education for the elderly. The intervention group received online mental health education, while the control group was given face-to-face mental health education. After the intervention group and control group have completed the intervention and post-intervention data collection, the waiting list group would choose either online or face-to-face mental health education independently based on personal preference. The 3 groups received identical interventions with a 4-week duration. During the intervention and follow-up periods, 7 cases dropped out, resulting in 34 cases in the intervention group, 31 in the control group, and 33 in the waiting list group being included in the final analysis. The 3 groups were checked-up with the Center for Epidemiologic Studies Depression Scale (CES-D), Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) at baseline, post-intervention and 6-month follow-up. One-way ANOVA and χ2 tests were employed to compare the baseline characteristics across the 3 groups. Mixed-effects model for repeated measures were employed to compare mean between-group differences and mean changes for each group at each time point, with the specific aim of analyzing the intervention effect of online mental health education for SD in older adults. Results:There was no statistically significant differences in the baseline characteristics among the 3 groups (all P>0.05). The time × group interaction effects of CES-D, PHQ-9, and GAD-7 scores were significant across 3 groups ( Finteraction=6.58, 7.24, 8.42) (all P<0.01). Further pairwise comparisons revealed that the CES-D, PHQ-9, and GAD-7 scores in the intervention group were all significantly lower than those in the waiting list group [(14.36±4.56) vs (15.51±3.21), (5.13±2.46) vs (7.20±2.62), (4.63±2.41) vs (7.13±2.42)], and all significantly lower than those in the control group [(14.36±4.56) vs (15.53±3.19), (5.13±2.46) vs (6.32±2.57), (4.63±2.41) vs (6.23±2.41)] at post-intervention (all P<0.05). The PHQ-9 and GAD-7 scores in the intervention group were both significantly lower than those in the control group [(4.62±2.35) vs (6.23±2.20), (4.72±2.38) vs (6.26±2.32)] at 6-month follow-up (both P<0.001). Conclusion:Online mental health education may alleviate depressive and anxiety symptoms among older adults with SD, and it may be equally effective as face-to-face mental health education.

Objective To explore the biological mechanism of radiation resistance in esophageal squamous cell carcinoma(ESCC)and search for effective sensitization targets.Methods We retrieved 186 signaling pathways and related gene information from the MSigDB database.We also obtained RNA transcriptome data of ESCC patients using the Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)databases.We collected clinical pathological characteristics and tissue samples of 97 ESCC patients in our hospital from 2013 to 2020.Gene set variation analysis(GSVA)was made to calculate KEGG signaling pathway score,radiotherapy resistance related signaling pathways were screened through random forest algorithm,key genes in the pathway were screened using DESeq2,and a radiotherapy efficacy prediction model was constructed based on support vector machine-recursive feature elimination(SVM-RFE).The results were validated through experiments such as Western blotting and clonogenic assay.Results Based on the KEGG signaling pathway and GSVA enrichment score,random forest analysis showed that in the TCGA and GSE45670 cohorts,the contribution of tryptophan metabolism pathway enrichment values to radiation resistance in ESCC was significantly better than that of the other pathways.DESeq2 analysis revealed that key molecules in the tryptophan metabolism pathway,namely,IDO1,ALDH1B1,AOC1,INMT,AFMID and ALDH7A1,were significantly differentially expressed in the resistant and sensitive groups of ESCC.Based on the SVM-RFE algorithm,the AUC was 0.77,which could accurately predict the radiotherapy efficacy of ESCC.Western blotting experiments showed that IDO1 was highly expressed in ESCC cells,and IDO1 inhibitor treatment significantly inhibited the survival ability and radiosensitivity of KYSE-410 cells.In the enrolled patients of our hospital,immunohistochemical studies showed that IDO1 was highly expressed in the radiotherapy resistant group of ESCC and was associated with poor radiotherapy prognosis in ESCC patients.In addition,further testing showed that the expression of IDO1 in patient samples from our hospital was positively correlated with its PD-L1 expression,but negatively correlated with the infiltration ratio of CD3/CD8 immune cells.Conclusion Tryptophan catabolism is associated with radiation resistance in ESCC,and the key enzyme IDO1 in tryptophan metabolism can be used as a therapeutic target for radiosensitization in ESCC.

Objective:To evaluate the interventional effect of online mental health education for subthreshold depression (SD) in elderly individuals.Methods:Using a randomized controlled trial (RCT) design, a total of 105 older adults with SD were recruited from 6 long-term care (LTC) settings in Ningbo city between September and November in 2023. The subjects were randomized to a intervention group (35 cases), a control group (35 cases) and a waiting list group (35 cases) in a 1∶1∶1 ratio using a random number generator. The intervention method was mental health education, comprising basic knowledge of depressive symptoms, knowledge and skills of cognitive therapy, knowledge and skills of behavioral therapy and life education for the elderly. The intervention group received online mental health education, while the control group was given face-to-face mental health education. After the intervention group and control group have completed the intervention and post-intervention data collection, the waiting list group would choose either online or face-to-face mental health education independently based on personal preference. The 3 groups received identical interventions with a 4-week duration. During the intervention and follow-up periods, 7 cases dropped out, resulting in 34 cases in the intervention group, 31 in the control group, and 33 in the waiting list group being included in the final analysis. The 3 groups were checked-up with the Center for Epidemiologic Studies Depression Scale (CES-D), Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) at baseline, post-intervention and 6-month follow-up. One-way ANOVA and χ2 tests were employed to compare the baseline characteristics across the 3 groups. Mixed-effects model for repeated measures were employed to compare mean between-group differences and mean changes for each group at each time point, with the specific aim of analyzing the intervention effect of online mental health education for SD in older adults. Results:There was no statistically significant differences in the baseline characteristics among the 3 groups (all P>0.05). The time × group interaction effects of CES-D, PHQ-9, and GAD-7 scores were significant across 3 groups ( Finteraction=6.58, 7.24, 8.42) (all P<0.01). Further pairwise comparisons revealed that the CES-D, PHQ-9, and GAD-7 scores in the intervention group were all significantly lower than those in the waiting list group [(14.36±4.56) vs (15.51±3.21), (5.13±2.46) vs (7.20±2.62), (4.63±2.41) vs (7.13±2.42)], and all significantly lower than those in the control group [(14.36±4.56) vs (15.53±3.19), (5.13±2.46) vs (6.32±2.57), (4.63±2.41) vs (6.23±2.41)] at post-intervention (all P<0.05). The PHQ-9 and GAD-7 scores in the intervention group were both significantly lower than those in the control group [(4.62±2.35) vs (6.23±2.20), (4.72±2.38) vs (6.26±2.32)] at 6-month follow-up (both P<0.001). Conclusion:Online mental health education may alleviate depressive and anxiety symptoms among older adults with SD, and it may be equally effective as face-to-face mental health education.

Objective:To explore the clinical efficacy of the splenic vessel-oriented anatomical plane priority strategy in Da Vinci robotic Kimura distal pancreatectomy.Methods:A retrospective analysis was conducted on 26 patients who underwent robotic-assisted distal pancreatectomy at Zhejiang Provincial People’s Hospital from January 2019 to September 2024. The cohort included 7 male and 19 female patients, aged (49.3±16.7) years. Surgical outcomes, including operative time, intraoperative blood loss, postoperative complications, and hospital stay, were analyzed, and surgical techniques were summarized.Results:All 26 patients successfully completed the surgery. Pathological diagnoses included 5 cases of intraductal papillary mucinous neoplasm, 5 serous cystadenomas, 1 pancreatic neuroendocrine tumor, 6 solid pseudopapillary neoplasms, 4 mucinous cystic neoplasms, and 5 neuroendocrine tumors. The maximum tumor diameter was (2.3±1.1) cm, and the operative time was (183.2±77.4) min. The spleen preservation rate was 100% (26/26). Intraoperative blood loss was 50.0 (17.5, 125) ml, and postoperative hospital stay was (10.1±3.7) d. No Clavien-Dindo grade III or higher complications occurred. The post-operative pancreatic fistula (POPF) rate was 53.8% (14/26), including 38.5% (10/26) biochemical leak and 15.3% (4/26) grade B POPF, with no grade C POPF.Conclusion:The splenic vessel-oriented anatomical plane priority strategy in robotic-assisted spleen-preserving distal pancreatectomy (Kimura technique) is safe and feasible, significantly improving the spleen preservation rate.

Objective:To investigate the effects of intra-articular injection of exosomes derived from dental pulp stem cells from hu-man exfoliated deciduous teeth(SHED-EXO)on subchondral bone homeostasis in rat temporomandibular joint osteoarthritis(TMJ OA)process.Methods:36 male SD rats were randomly divided into 3 groups(n=12):control(CON),sodium iodoacetate(MIA)-induced TMJ OA(MIA),and SHED-EXO injection into TMJ OA(SHED-EXO)groups.At 2 and 6 weeks post-treatment,Micro-CT,Double labeling,TRAP staining,and immunohistochemical staining were employed to detect osteoclasts and osteoblasts in the subchondral bone.Additionally,the mRNA expression levels of ADAMTs5,IL-1β,OCN and OPG/RANKL were analyzed by qRT-PCR.Results:The MIA group exhibited significant bone loss and an enlarged bone marrow cavity.In comparison with the CON group,BV/TV and Tb.Th were lower(P＜0.001),while BS/BV,Tb.Sp,and Tb.N were higher(P＜0.01).Additionally,the bone formation rate within 5 days was low-er than that of the control group(P＜0.001).When compared to the MIA group,the SHED-EXO group showed a significant increase in bone morphology and bone mass.BV/TV and Tb.Th were increased(P＜0.01),while BS/BV,Tb.Sp and Tb.N were decreased(P＜0.05).The bone formation rate was higher(P＜0.01).Compared with both the control and treatment groups,the MIA group exhibited a significant increase in the number of osteoclasts in the subchondral bone(P＜0.01),along with a notable decrease in H-type blood vessels and OCN-positive areas(P＜0.01).Conclusion:Intra-articular injection of SHED-EXO can reg-ulate condylar subchondral bone homeostasis in TMJ OA of rats by promoting osteogenesis and inhibiting osteoclasts.

Oral squamous cell carcinoma(OSCC)associated pain commonly predicts adverse events among patients.This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy.However,it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression.In this study,we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo,as evidenced by clinical tissue microarray analysis and murine lingual denervation.We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort.Notably,such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A2A receptor(A2AR)on trigeminal ganglia.Antagonism of trigeminal A2AR with a selective A2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo.We showed that trigeminal A2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP,an effect counteracted by SCH58261.We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP.Finally,we diminished the impact of CGRP on OSCC with istradefylline,a clinically available drug that targets neuronal A2AR.Therefore,we established trigeminal A2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.

Oral squamous cell carcinoma(OSCC)associated pain commonly predicts adverse events among patients.This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy.However,it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression.In this study,we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo,as evidenced by clinical tissue microarray analysis and murine lingual denervation.We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort.Notably,such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A2A receptor(A2AR)on trigeminal ganglia.Antagonism of trigeminal A2AR with a selective A2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo.We showed that trigeminal A2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP,an effect counteracted by SCH58261.We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP.Finally,we diminished the impact of CGRP on OSCC with istradefylline,a clinically available drug that targets neuronal A2AR.Therefore,we established trigeminal A2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.