Thymocyte selection-associated high mobility group box (TOX), a member of the high mobility group protein super-family, plays an important role in T cell development, functional maintenance, and exhaustion. It has been recently found that TOX exerts critical immunoregulatory functions during pathogen infections, and TOX expression is strongly associated with the intensity and tolerance of host immune responses. This review systematically summarizes the structural and functional features of TOX and focuses on its expression dynamics, mechanisms of action, and immunomodulatory effects during viral, bacterial, and parasitic infections, which provides a theoretical support to better understanding of the role of TOX in infectious diseases and provides new insights into development of potential immunotherapeutic strategies targeting TOX.

Immunotherapy has emerged as a revolutionary approach to treat immune-related diseases. Dendritic cells (DCs) play a pivotal role in orchestrating immune responses, making them an attractive target for immunotherapeutic interventions. Modulation of gene expression in DCs using genome editing techniques, such as the CRISPR-Cas system, is important for regulating DC functions. However, the precise delivery of CRISPR-based therapies to DCs has posed a significant challenge. While lipid nanoparticles (LNPs) have been extensively studied for gene editing in tumor cells, their potential application in DCs has remained relatively unexplored. This study investigates the important role of cholesterol in regulating the efficiency of BAMEA-O16B lipid-assisted nanoparticles (BLANs) as carriers of CRISPR/Cas9 for gene editing in DCs. Remarkably, BLANs with low cholesterol density exhibit exceptional mRNA uptake, improved endosomal escape, and efficient single-guide RNA release capabilities. Administration of BLAN_mCas9/gPD-L1 results in substantial PD-L1 gene knockout in conventional dendritic cells (cDCs), accompanied by heightened cDC1 activation, T cell stimulation, and significant suppression of tumor growth. The study underscores the pivotal role of cholesterol density within LNPs, revealing potent influence on gene editing efficacy within DCs. This strategy holds immense promise for the field of cancer immunotherapy, offering a novel avenue for treating immune-related diseases.

Background::Although the treatment of peripheral T-cell lymphoma (PTCL) has undergone advancements during the past several years, the response rate and long-term effects with respect to patients with PTCL remain unsatisfactory—particularly for relapsed or refractory (R/R) patients. This phase II trial was designed to explore the efficacy and safety of an all-oral regimen of chidamide plus prednisone, cyclophosphamide, and thalidomide (CPCT) for R/R PTCL patients who could not tolerate the standard chemotherapy for a variety of reasons.Methods::We conducted a multicenter phase II clinical trial in which we combined chidamide (30 mg twice weekly) with prednisone (20 mg daily after breakfast), cyclophosphamide (50 mg daily after lunch), and thalidomide (100 mg daily at bedtime) (the CPCT regimen) for a total of fewer than 12 cycles as an induction-combined treatment period, and then applied chidamide as single-drug maintenance. Forty-five patients were ultimately enrolled from August 2016 to April 2021 with respect to Chinese patients at nine centers. Our primary objective was to assess the overall response rate (ORR) after the treatment with CPCT.Results::Of the 45 enrolled patients, the optimal ORR and complete response (CR)/CR unconfirmed (CRu) were 71.1% (32/45) and 28.9% (13/45), respectively, and after a median follow-up period of 56 months, the median progression-free survival (PFS) and overall survival (OS) were 8.5 months and 17.2 months, respectively. The five-year PFS and OS rates were 21.2% (95% confidence interval [CI], 7.9-34.5%) and 43.8% (95% CI, 28.3-59.3%), respectively. The most common adverse event was neutropenia (20/45, 44.4%), but we observed no treatment-related death.Conclusion::The all-oral CPCT regimen was an effective and safe regimen for R/R PTCL patients who could not tolerate standard chemotherapy for various reasons.Trial Registration::ClinicalTrials.gov, NCT02879526.

Aim To study the effect of liraglutide on myocardial metabolites and related metabolic pathways in diabetic cardiomyopathy(DCM)rats.Methods Among 60 SPF male SD rats aged 3 weeks,10 rats were randomly selected as normal control group(n=10),and the remaining 50 rats were established by peritoneal injection of streptozoto-cin combined with high-sugar and high-fat diet for DCM rat model.A total of 36 rats were successfully modeled for DCM and randomly divided into DCM model group(DCM group,n=12),low-dose liraglutide treatment group(LL group,n=12)and high-dose liraglutide treatment group(HL group,n=12).Rats in LL group(100 μg/kg)and HL group(200μg/kg)were given intraperitoneal injection of liraglutide once a day.And after 12 weeks of intervention,the rats were killed under anesthesia after echocardiography to detect cardiac function,and the heart tissues were taken for metabolomics detection.The differential metabolites and related pathways that may be related to liraglutide improving myocardial metab-olism in DCM rats were screened and enriched.Results Compared with normal control group,left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFS)in DCM group were significantly decreased,and the ra-tio of early to late diastolic mitralflow velocities(E/A)was significantly increased(P＜0.05).Compared with DCM group,LVEF and LVFS in LL group and HL group were significantly increased,and E/A ratio was significantly decreased(P＜0.05),suggesting that the impairment of left ventricular systolic and diastolic function in LL group and HL group was significantly alleviated.395 metabolites were detected by metabolomics,among which 239,116 and 187 different metab-olites and 13,6 and 20 metabolic pathways were enriched in DCM group and normal control group,LL group and DCM group,HL group and DCM group.In the above three groups,29 key differential metabolites were identified related to 3 metabolic pathways including choline metabolic pathway,caffeine metabolic pathway and valine,leucine and isoleucine bi-osynthesis pathway,among which choline metabolic pathway had the most significant differences.Conclusion These results indicated that liraglutide can ameliorate cardiac dysfunction in DCM rats through improving myocardial metabolism in which choline metabolism pathway may play a key role.

Objective:To assess the efficacy, safety, and related prognostic factors associated with the P-GemDOx regimen as a first-line treatment for patients with early-stage extranodal natural killer (NK) /T cell lymphoma (ENKTL) .Methods:A retrospective analysis was performed on sixty early-stage ENKTL patients treated with the P-GemDOx regimen who were admitted to the First Affiliated Hospital of Nanjing Medical University between August 2015 and May 2021. The Chi-square test or Fisher's exact test was used to compare group differences, and the Log-rank test was used to compare the differences in survival. Survival outcomes and prognostic factors were examined.Results:After completing 4 to 6 cycles of P-GemDOx chemotherapy, the overall response rate (ORR) was 88.3%, with forty-six patients (76.7% ) achieving complete response (CR). The 4-year progression-free survival (PFS) and overall survival (OS) rates were (66.3±7.1) % and (79.5±6.0) %, respectively. According to the PINK/PINK-E model, there was no significant difference in survival outcomes among risk groups. 23.3% of patients experienced progression of disease within 24 months (POD<24). OS estimates differed significantly ( P<0.001) between the POD<24 group ( n=14) and the POD≥24 group ( n=46). Analysis showed that SUVmax > 12.8 at diagnosis, non-single nasal cavity infiltration, and response less than CR after 4–6 cycles all had a significant association with POD24. We used these data as the basis for predicting POD<24 international prognostic index (POD24-IPI). Patients were stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high risk (two or three risk factors). These groups were associated with 4-year OS rate of 100%, (85.6±9.7) %, and (65.0±10.2) %, respectively ( P=0.014). The P-GemDOx regimen was well tolerated, with hematological toxicity being the main side effect. Conclusion:This study demonstrated that the P-GemDOx regimen is effective and safe in the first-line treatment of early-stage ENKTL, and POD24-IPI is a promising prognostic model.

Objective:To investigate the efficacy and safety of orelabrutinib combined with R-CHOP in the treatment of MCD subtype diffuse large B cell lymphoma (DLBCL) .Methods:Twenty-three MCD subtype patients whose gene-subtype classification was based on baseline tumor tissue and/or baseline plasma using the LymphGen algorithm from June 2022 to June 2023 in the First Affiliated Hospital of Nanjing Medical University were retrospectively enrolled in the analysis. All patients were treated with R-CHOP or R-miniCHOP in Course 1, OR-CHOP or OR-miniCHOP (21 days for one course) in Courses 2-6, and R-monotherapy in Courses 7-8.Results:Of the 23 patients, the median age was 58 years (range: 30-81 years), and 11 (47.8% ) aged >60 years. Fifteen cases (65.2% ) had international prognostic index (IPI) scores of 3 to 5. The top 10 mutated genes in the gDNA tissues were PIM1 (78.3% ), MYD88 (69.6% ), ETV6 (43.5% ), BTG1 (39.1% ), CD79B (43.5% ), HIST1H1E (39.1% ), BTG2 (34.8% ), KMT2D (30.4% ), CD58 (26.1% ), and CDKN2B (21.7% ). The consistency rate of the tissue and plasma mutations was 80%, while the baseline plasma ctDNA burden was closely correlated with the LDH levels and IPI scores ( P<0.05). All patients received 5 courses of OR-CHOP regimens. The mid-term (after 3 courses) evaluation showed that the overall response rate (ORR) was 100% (23/23), with 22 patients (95.65% ) achieving complete remission (CR), and 1 patient (4.35% ) achieving partial remission (PR). The ORR after the end of treatment (EOT) was 95.65% (22/23). Moreover, 21 patients (91.30% ) obtained CR, 1 patient (4.35% ) obtained PR, and 1 patient (4.35% ) obtained progression disease (PD). Of the 21 patients who had the dynamic EOT-ctDNA burden, only four patients (19.0% ) did not achieve EOT-ctDNA clearance, while the other 17 patients (81.0% ) achieved EOT-ctDNA clearance. The median follow-up time was 20.8 (15.3-30.0) months, while the median progression-free survival (PFS) and overall survival (OS) were not reached. The 2-year PFS rate was 71.8% (95% CI 54.7% -94.2% ), while the 2-year OS rate was 91.3% (95% CI 80.5% -100.0% ). Furthermore, the OR-CHOP regimen was generally well tolerated during clinical use, with hematological toxicity being the main adverse effect. Conclusion:This study revealed that the OR-CHOP regimen can be used as an effective and safe first-line treatment for MCD subtype DLBCL.

Humans ; Hematopoietic Stem Cell Transplantation ; Transplantation, Autologous ; Lymphoma, Non-Hodgkin/drug therapy* ; Aminopyridines/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols

Objective:To investigate the efficacy and cognitive function of 3 new antiepileptic drugs Oxcarbazepine (OXC), Lamotrigine (LTG) and Levetiracetam (LEV) in children with self-limited epilepsy with centrotemporal spikes (SeLECTS).Methods:This was a prospective study.A total of 98 children with SeLECTS who were treated in the Second Affiliated Hospital of Xinxiang Medical University from January 2014 to June 2020 were divided into OXC group, LTG group and LEV group according to the applied therapeutic drugs.Video electroencephalograph (EEG), Wechsler Intelligence Scale for Children (WISC) and event-related potentials (ERPs) of the children were collected before treatment and 48 weeks of treatment.Clinical efficacy and impact on cognitive function among the 3 groups were compared.Results:(1)Efficacy: There was no significant difference in the effective rate of seizure reduction after treatment among the 3 groups( χ2=0.808, P=0.668). There was no significant difference in EEG remission rate among the 3 groups( χ2=0.763, P=0.683). (2)Cognitive function: ①Intragroup comparison of WISC findings showed that the full scale score (FIQ) and verbal intelligence quotient (VIQ) were significantly enhanced, and the scores of comprehension, vocabulary, arithmetic, decoding and spelling subtests were more significantly enhanced in OXC group after treatment (all P<0.05). In the LTG group, FIQ, VIQ and operational intelligence quotient (PIQ) were significantly enhanced after treatment (all P<0.05), and the subtest scores of comprehension, vocabulary, arithmetic, mapping and layout were significantly enhanced (all P<0.05). In LEV group, FIQ, VIQ and PIQ were significantly enhanced after treatment (all P<0.05), especially the increase in the VIQ, and the scores of vocabulary, understanding, similarity, arithmetic, decoding and puzzle subtests were significantly enhanced (all P<0.05). Pairwise comparison of WISC findings showed that there were no significant differences in the FIQ, VIQ, PIQ and subtest scores before treatment among the 3 groups (all P>0.05). After treatment, the arithmetic and decoding scores of OXC group were significantly higher than those of LTG group (all P<0.05), which were comparable between OXC group and LEV group (all P>0.05). The PIQ and the scores of mapping and layout in LTG group were significantly higher than those of the other 2 groups (all P<0.05). The LEV group had higher scores in vocabulary, comprehension and spelling than those of the other 2 groups (all P<0.05), which had higher decoding scores than those of the LTG group (all P<0.05). No significant differences were found in decoding scores between LEV and OXC group (all P>0.05). Higher VIQ and FIQ were detected in LEV group than those of the other 2 groups (all P<0.05). ②Intragroup comparison of ERPs showed that the latency of LEV group after treatment was significantly shorter than that before treatment ( P<0.05), and there was no significant difference between the other 2 groups before and after treatment (all P>0.05). Pairwise comparison of ERPs showed that before treatment, there were no significant differences in P300 amplitude and latency among the 3 groups (all P>0.05). After treatment, the latency of LEV group was significantly shorter than that of the other 2 groups ( P<0.05), and there was no significant difference in the amplitude between the 3 groups before and after treatment ( P>0.05). Conclusions:(1)In the treatment of SeLECTS in children, OXC, LTG and LEV have reliable and equivalent effects.(2)OXC, LTG and LEV have protective effects on cognitive function in children with SeLECTS.After treatment, LEV provides the strongest protective effect on FIQ, and the protective effect on VIQ is equivalent to OXC, but better than LTG.LTG is superior in protecting spatial perception and PIQ.

Porcine deltacoronavirus (PDCoV) has been recently recognized as an emerging viral pathogen that causes diarrhea in newborn piglets. A total of 254 small intestinal or fecal samples collected from 10 provinces including Henan, Hunan, Zhejiang, Jiangxi, Anhui, Hebei, Heilongjiang, Jiangsu, Shandong and Shanghai between 2014 and 2015, were screened by quantitative RT-PCR targeting the viral M gene. Eleven PDCoV positive samples were identified with a total positive rate of 4.33%. An indirect enzyme-linked immunosorbent assay (ELISA) was developed based on the recombinant S1 protein of PDCoV. This assay was used to test 609 serum samples of pigs with diarrhea symptoms collected from 10 provinces between 2015 and 2016. The positive rate of PDCoV antibody was 44.17% (269/609). The two methods can be used to monitor the PDCoV epidemiology in the levels of PDCoV specific RNA or antibody, helping better prevent and control PDCoV.

Objective To explore the reactive inhibition and electrophysiological changes under the GO/NOGO paradigm in patients with alcohol dependence (AD) in order to provide a theoretical basis for neuromechanism study of AD executive dysfunctions.Methods The GO/NOGO paradigm event related potentials (ERP) were tested in 51 AD patients and 29 healthy controls, this paradigm behavior and ERP-N1, N2 and P3 latency and amplitude were analyzed.ERPs and execution functions were followed at different time points of withdrawal(4, 9,13 weeks).Results The number of correct responses (29.18±3.03)lowered and error responses (5.16±3.77) heightened in AD patients, and differences had statistical significance compared with those in control group(32.35±2.58,3.19± 1.84, P＜0.05), and there was no group difference in response time.There was no statistical significance in group difference in N1 component under the GO/NOGO tasks and in P3 latency under GO.N2 ((3.48±2.21) μV, (4.49±3.00) pV) and P3 amplitude ((3.47±2.31) μV, (3.92±4.09) μV) decreased and N2 latency ((256.30±31.62) ms, (256.09±33.77)ms) prolonged in AD group under both GO/NOGO tasks and so did P3 latency ((355.33±25.96) ms) under the NOGO, and the differences had statistical significance.Group main effects in N2 and P3 component (P=0.000) and task main effects in N2 amplitude and P3 latency (P＜0.05) were significant,group and task interaction was significant only in P3 latency (P＜0.01).ERPs of AD patients had no notable changes at different time points of withdrawal, executive dysfunctions were the worst within the 1st week of withdrawal and gradually recovered to pre-withdrawal levels.Conclusion AD patients have lower reactive inhibition manifested mainly by weakened capacity to inhibit and adjust conflict monitor and pre-executive motor program, ERP and executive functions cannot be well improved during short-term withdrawal, and the GO/NOGO-ERP can completely reflect electrophysiological changes of reactive inhibition process of AD patients.