Myelodysplastic syndrome (MDS), a myeloid tumor derived from the malignant clones of hematopoietic stem cells, has an annually increasing incidence. The contemporary research direction has shifted to analyzing the synergistic effect of immune surveillance collapse and abnormal bone marrow microenvironment in the pathological process of MDS. Against this backdrop, the immune checkpoint molecule TIM3 has emerged as a key target because of its persistently high expression on the surface of important immune cells such as T and NK cells. The abnormal activation of the TIM3 pathway is the mechanism by which solid tumors and hematological malignancies achieve immune escape and is a key hub in the formation of immune exhaustion phenotypes. This work integrates the original discoveries of our team with the latest international progress, systematically demonstrating the bidirectional regulatory network of TIM3 between the malignant clone proliferation of MDS and the immunosuppressive microenvironment. Integrating the evidence from emerging clinical trials allows us to consider the clinical significance of TIM3-targeted blocking for MDS, providing a transformative path to overcome the resistance of traditional treatments and marking a new chapter in the active immune reconstitution of MDS treatment.

Allergic rhinitis (AR), a globally prevalent immune-mediated inflammatory condition, is still an incurable disease. In the present study, we have validated the impact of the Kelch-like ECH associated protein 1 (Keap1)-related oxidative stress and inflammatory response in clinical AR patient peripheral blood and nasal swab samples, emphasizing the biological relevance of Keap1 and AR. Targeting Keap1 -nuclear factor erythroid 2-related factor 2 (Nrf2) related anti-oxidative stress may be effective for AR intervention. Drawing inspiration from the Keap1 homodimerization and the E3 ligase characteristics, we herein present a design of novel bivalent molecules for chemical knockdown of Keap1. For the first time, we characterized ternary complexes of Keap1 dimer and one molecule of bivalent compounds. The best bivalent molecule 8 encompasses robust capacity to degrade Keap1 as a homoPROTAC^KEAP1. It efficaciously suppresses inflammatory cytokines in extensively different cells, including human nasal epithelial cells. Moreover, in an AR mouse model, we confirmed that the chemical degradation induced by homoPROTAC^KEAP1 led to therapeutic benefits in managing AR symptoms, oxidative stress and inflammation. In summary, our findings underscore the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.

Objective:To explore the role of serum cholinesterase (CHE) levels in the prognosis of patients with acute decompensated heart failure (ADHF).Methods:Total of 244 consecutive patients with ADHF who were admitted to the emergency department and were successfully discharged were prospectively enrolled from January 2018 to June 2020. Patients were divided into groups according to the first and third quartile of CHE level and the clinical data, laboratory tests and other nutritional indices were recorded after discharge, and then were followed up. The primary end points were the composites of cardiovascular death and hospitalization for worsening HF (composite end points). The secondary end points were all-cause mortality and cardiovascular death. Cox proportional risk analysis, time-dependent Cox regression model or stratified cox regression were used to identify the risk of primary and secondary endpoints. Clinical, biomarker and the compound models of clinical and biomarker were constructed. Kaplan-Meier method was used to plot the survival curves of different groups and compare their differences. Receiver Operating characteristics (ROC) curves were used to compare the area under the curve for CHE levels and other nutritional or prognostic indicators to identify composite end-point events.Results:During a follow-up period of 350(100,683) days, 158 patients reached the composite end points. In the multivariable Cox analysis, cholinesterase level was significantly associated with the composite end points after adjustment for major confounders. Cox proportional risk analysis or time-dependent Cox regression model showed that CHE level was significantly associated with the composite end points, all-cause mortality and cardiovascular mortality in both clinical, biomarker and composite models (all P< 0.05). A Kaplan–Meier analysis revealed that patients with low cholinesterase levels had significantly greater risk of reaching the composite end points than those with middle or high cholinesterase levels (78.1% vs 66.7% vs. 46.7%, P<0.001); Cholinesterase level showed the largest area under the receiver operating characteristic curve (AUROC) of 0.736 (95% CI, 0.664-0.888) for prediction of the composite end points among other nutritional indices. The AUROC of the Global Meta-Analysis Group Chronic Heart Failure (MAGGIC) Risk Score for prediction of the composite end points was increased from 0.704 to 0.762 ( P=0.038), when cholinesterase level was added. Conclusions:Cholinesterase may serve as a simple and effective prognostic marker for predicting adverse outcomes in ADHF patients.

Humans ; Aged ; Lung Diseases ; Pneumonia/drug therapy* ; Adrenal Cortex Hormones/therapeutic use* ; Pulmonary Disease, Chronic Obstructive/drug therapy* ; Administration, Inhalation ; Community-Acquired Infections/drug therapy*

ObjectiveTo evaluate the clinical efficacy and safety of Tongluo Mingmu capsules in the treatment of diabetic retinopathy with blood stasis， collateral obstruction， and Qi and Yin deficiency syndrome. MethodA randomized， double-blind， positive-control， and multi-center clinical trial design method was used. 416 patients with diabetic retinopathy with blood stasis， collateral obstruction， and Qi and Yin deficiency syndrome in four test centers were included （the ratio of the treatment group to the control group was 3∶1）. On the basis of standardized hypoglycemic treatment， the treatment group was given both four Tongluo Mingmu capsules and two Calcium Dobesilate capsule agents three times a day， while the control group were given both two Calcium Dobesilate capsules and four Tongluo Mingmu capsule agents three times a day. The course of treatment was 12 weeks. The curative effect of Tongluo Mingmu capsules was evaluated by comparing the comprehensive curative effect of diabetic retinopathy， traditional Chinese medicine（TCM） syndrome score， corrected visual acuity， fundus changes， fundus fluorescence angiography， and other curative effect indexes before and after treatment in the two groups. At the same time， general examination， laboratory examination， and adverse events were performed to evaluate the safety of the drug. ResultThe baseline demographic data and disease characteristics of the treatment group and the control group were balanced and comparable， with the difference not statistically significant. After 12 weeks of treatment， the total effective rate of the comprehensive curative effect of diabetic retinopathy in the treatment group （61.0%， 189/310） was better than that in the control group （44.1%， 45/102）， and the difference was statistically significant （χ²=8.880， P<0.01）. The total effective rate of TCM syndromes in the treatment group （88.4%， 259/293） was better than that in the control group （69.9%， 65/93）， and the difference was statistically significant （χ²=17.927， P<0.01）. The disappearance rate of dry eyes （χ²=8.305）， dull complexion （χ²=4.053）， lassitude （χ²=10.267）， shortness of breath （χ²=8.494）， and dry stool （χ²=8.657） in the treatment group was higher than that in the control group， and the difference between the groups was statistically significant （P<0.05， P<0.01）. In terms of improving corrected visual acuity （χ²=8.382）， fundus changes （χ²=6.026） ， the treatment group was significantly better than the control group （P<0.05）. During the trial， the incidence of adverse events in the treatment group and the control group was 1.3% and 2.9%， respectively. There was no significant difference between the two groups. In addition， there were no serious adverse events and adverse events leading to withdrawal in both groups. ConclusionTongluo Mingmu capsules can improve the comprehensive curative effect of diabetic retinopathy and enhance the efficacy of TCM syndromes， visual acuity， fundus changes， and fundus fluorescein angiography， with great safety. Therefore， it can provide a new alternative therapeutic drug for patients with diabetic retinopathy.

[摘 要] 目的：探究伴有肾损害（RI）的多发性骨髓瘤（MM）患者与无RI患者间是否存在免疫学指标差异。方法：用2017年1月至2023年8月在兰州大学第二医院收治的134例首次确诊为MM的患者相关信息进行回顾性分析，研究对比RI组和非RI组及Durie⁃Salmon（DS）分期和危险分层两个亚组的10种免疫学指标和6个常规血液学参数的差异。结果：RI组外周血中性粒细胞/淋巴细胞比值（NLR）、外周血单核细胞/淋巴细胞比值（MLR）、CD8+ T细胞比例、IL-10均较非RI组高（均P<0.05），淋巴细胞绝对值、CD4/CD8比值均较非RI组低（均P<0.05）。DS-Ⅲ分期患者中，RI组NLR、MLR、CD8+ T细胞比例、IL-8、IL-10均较非RI组升高（均P<0.05），而DS-Ⅰ和DS-Ⅱ患者中，RI组和非RI组患者免疫指标无明显差异。高危MM患者RI组淋巴细胞数、NLR、IL-10均较非RI有明显差异（均P<0.05）。结论：伴RI的MM患者免疫相关指标异常更为明显，DS-Ⅲ分期和高危险度分层表现出明显的免疫指标异常，本研究结果对进一步阐明MM伴有RI患者预后较差的原因及个体化治疗提供参考依据。

Objective:To explore the construction and application of an evidence-based practice plan for early postoperative activity in postoperative patients with large area cerebral infarction.Methods:Ninety-six postoperative patients with large area cerebral infarction admitted to Wenzhou Central Hospital from July 2021 to April 2023 were selected as the study subjects for a Clinical trial. They were divided into the control group (48 cases) and the observation group (48 cases) by random number table method. The control group received routine postoperative care for neurosurgery, while the observation group received evidence-based systematic early activity training. Both groups were followed up until 1 month after the patient was discharged from the hospital. The time of postoperative hospitalization, hospitalization expenses, vital signs and pain investigation 48 h after surgery, daily living ability before intervention and 7 d, 1 month after discharge, neurological function before intervention and 7 d and 1 month after surgery, and complications during follow-up between the two groups were compared.Results:In the control group, there were 29 males and 19 females, with an average age of 43-67(56.87 ± 1.76) years. In the observation group, there were 31 males and 17 females, with an average age of 43-68 (57.02 ± 1.82) years. The postoperative hospital stay in the observation group was (6.87 ± 0.65) d, in the control group was (9.06 ± 0.72) d, the difference between them was significant ( t=15.64, P<0.05). 48 hours after surgery, the heart rate, breathing rate and mean arterial pressure in the observation group were (71.65 ± 0, 45) times/min, (14.76 ± 0.36) times/min and (76.98 ± 5.65) mmHg(1 mmHg=0.133 kPa), which were different with those in the control group, (82.76 ± 2.65) times/min, (18.76 ± 2.87) times/min and (93.76 ± 5.93) mmHg ( t=28.64, 9.58 and 14.19, all P<0.05). Seven days after discharge, the score of Activities of Daily Living and the National Institutes of Health Neurological Impairment Scale in the observation group were (84.65 ± 2.45) and (23.65 ± 2.65), which were different than the (79.76 ± 1.97) and (28.54 ± 2.73) in the control group ( t=10.26, 8.91, both P<0.05). A month after discharge, the score of Activities of Daily Living and the National Institutes of Health Neurological Impairment Scale in the observation group were (95.45 ± 1.43) and (18.65 ± 1.98), while in the control group were (87.87 ± 1.39) and (21.54 ± 2.76), the difference between them were significant ( t=26.33, 5.90, both P<0.05). The total incidence of complications such as postoperative bleeding, postoperative infection and hypoxemia in the observation group was 20.83% (10/48), which was significant lower than the 68.75% (33/48) in the control group ( χ2=22.28, P<0.05). Conclusions:Evidence-based systematic early activity training could significantly alleviate postoperative pain in patients with large area cerebral infarction after surgery, improve their daily living ability and neurological function, further effectively shorten their hospitalization time, and reduce the occurrence of complications.

Objective:To evaluate the effects of different types of psychological interventions on the fear of cancer recurrence through a network Meta-analysis.Methods:Randomized controlled trials on the effects of different types of psychological interventions on the fear of cancer recurrence were retrieved from PubMed, PsycINFO, Web of Science, The Cochrane Library, Embase, EBSCO, China Biomedical Literature Database, CNKI, Wanfang Database and Vip Database. The retrieval period was from the establishment of the database to December, 31 2022. Two researchers conducted literature screening, extraction and quality evaluation, and used Stata14.0 software to conduct network Meta-analysis.Results:A total of 29 pieces of research involving 3 068 cancer patients and 11 psychological intervention measures. The results of network Meta-analysis showed that narrative therapy, PERMA(Positive, Engagement, Relationship, Meaning, Accomplishment) happiness theory model, acceptance and commitment therapy and cognitive behavior therapy had statistically significant differences in the intervention effect on the fear of cancer recurrence compared with conventional nursing ( SMD values were -1.93--0.83, all P<0.05); there was no significant difference among narrative therapy, PERMA happiness model, acceptance and commitment therapy and gratitude-expansion behavior theory (all P>0.05). The results of the cumulative probability map showed the best intervention was narrative therapy. Conclusions:The results of this study suggest that narrative therapy, acceptance and commitment therapy, and cognitive behavior therapy may be effective psychological intervention measures to improve the fear of cancer recurrence. However, more studies are still needed for further verification.

BACKGROUND:In the initial stage of multiple sclerosis,central immune cells activate and release a large number of inflammatory factors,causing white matter demyelination and even involving gray matter neurons.The equilibrium of differentiation between different subsets of CD4+ T cells plays an important role in the progression of experimental autoimmune encephalomyelitis.The previous results of the research group showed that the active ingredient astragalus glycoprotein in astragalus can regulate the immune response in experimental autoimmune encephalomyelitis mice,and whether it has a regulatory effect on the differentiation of T cell subsets has not been determined. OBJECTIVE:To explore the therapeutic effects and immune regulatory mechanisms of astragaloside IV on experimental autoimmune encephalomyelitis mice. METHODS:Female C57BL/6 mice were divided into the normal control group,experimental autoimmune encephalomyelitis disease model group,and astragaloside IV treatment group(n=8 per group).Myelin oligodendrocyte glycoprotein peptides 35-55 were used for experimental autoimmune encephalomyelitis model induction in the last two groups.On day 10 to 28 after immunization,the astragaloside IV treatment group was treated with 40 mg/kg per day astragaloside IV intragastrically.Body weight and clinical scores of mice in each group were recorded from the immunization day to the 28th day.On the 28th day after immunization,the mouse spinal cord was taken and made into frozen sections for hematoxylin-eosin staining and Lux fast blue staining to observe pathological changes in the spinal cord.Percentage of splenic T cell subsets was detected using flow cytometry.Western blot assay was used to determine the protein expression of interferon-γ,interleukin-17 and interleukin-6 in the spinal cord.Levels of interferon-γ,interleukin-17,interleukin-6 and interleukin-4 in supernatants of cultured splenocytes were determined by ELISA. RESULTS AND CONCLUSION:(1)Compared with the experimental autoimmune encephalomyelitis disease model group,astragaloside IV could reduce the degree of weight loss in experimental autoimmune encephalomyelitis mice(P<0.05),ameliorate clinical symptoms(P<0.05),inhibit the infiltration of inflammatory cells and alleviate myelin loss(P<0.01,P<0.05).(2)Compared with the experimental autoimmune encephalomyelitis disease model group,astragaloside IV could inhibit the proportion of CD4+T cell subsets expressing interferon-γ(P<0.001)and interleukin-17(P<0.001),but increase percentages of CD4+ interleukin-10+(P<0.001)and CD4+ transforming growth factor-β+(P<0.01)T cell subsets.(3)Astragaloside IV could inhibit the expression of interferon-γ(P<0.05,P<0.01),interleukin-17(P<0.05,P<0.05),and interleukin-6(P<0.05,P<0.05)in the spinal cord and spleen,and up-regulate the expression of interleukin-4(P<0.01)in spleen.(4)These findings confirm that astragaloside IV alleviates clinical symptoms in experimental autoimmune encephalomyelitis mice,which may be related to regulating the splenic T cell subsets,therefore,inhibiting the infiltration of inflammatory cells into the center and reducing the demyelination.

BACKGROUND:Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system mediated by T cells.The Toll-like receptors(TLRs)/myeloid differentiation factor 88(MyD88)/nuclear factor kappa-B(NF-κB)signaling pathway plays an important role in the development of the disease.Exploring the specific mechanism of the signaling pathway is essential for further treatment of the disease and improving the prognosis of patients. OBJECTIVE:To review the TLRs/MyD88/NF-κB signaling pathway and its role in multiple sclerosis/experimental autoimmune encephalomyelitis models,which provides new ideas and strategies for the treatment of multiple sclerosis by inhibiting the TLRs/MyD88/NF-κB signaling pathway. METHODS:The literature related to the topic from January 2002 to December 2022 was searched in CNKI,WanFang and PubMed databases.A total of 61 articles were finally included for analysis. RESULTS AND CONCLUSION:The TLRs/MyD88/NF-κB signaling pathway is an important pathway that triggers a pro-inflammatory immune response.The TLRs/MyD88/NF-κB signaling pathway plays an important role in the development of multiple sclerosis by regulating the antigen presentation of dendritic cells,destroying the integrity of the blood-brain barrier,and promoting the activation of T cells,B cells and microglia.By targeting TLRs,MyD88 and NF-κB molecules,inhibiting the activation or signal transduction of TLRs,MyD88 and NF-κB,and reducing the secretion of pro-inflammatory factors,multiple sclerosis can be treated.Animal studies have shown that active ingredients of traditional Chinese medicines,such as flavonoids and glycosides,and traditional Chinese medicine compound formulas,such as Buyang Huanwu Tang,can also treat experimental autoimmune encephalomyelitis by regulating the TLRs/MyD88/NF-κB signaling pathway,which points to the direction of searching for medicines targeting the TLRs/MyD88/NF-κB signaling pathway for the treatment of multiple sclerosis.