HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML.

Dendritic cells (DCs) serve as the primary antigen-presenting cells in autoimmune diseases, like rheumatoid arthritis (RA), and exhibit distinct signaling profiles due to antigenic diversity. Type II collagen (CII) has been recognized as an RA-specific antigen; however, little is known about CII-stimulated DCs, limiting the development of RA-specific therapeutic interventions. In this study, we show that CII-stimulated DCs display a preferential gene expression profile associated with migration, offering a new perspective for targeting DC migration in RA treatment. Then, saikosaponin D (SSD) was identified as a compound capable of blocking CII-induced DC migration and effectively ameliorating arthritis. Optineurin (OPTN) is further revealed as a potential SSD target, with Optn deletion impairing CII-pulsed DC migration without affecting maturation. Function analyses uncover that OPTN prevents the proteasomal transport and ubiquitin-dependent degradation of C-C chemokine receptor 7 (CCR7), a pivotal chemokine receptor in DC migration. Optn-deficient DCs exhibit reduced CCR7 expression, leading to slower migration in CII-surrounded environment, thus alleviating arthritis progression. Our findings underscore the significance of antigen-specific DC activation in RA and suggest OPTN is a crucial regulator of CII-specific DC migration. OPTN emerges as a promising drug target for RA, potentially offering significant value for the therapeutic management of RA.

Objective:To observe the pathological changes of myocardial tissue under differentdegrees of coronary atherosclerotic le-sions,to measure the expression levels of proteins associated with the cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)signaling pathway in coronary arteries,and to investigate the role of cGAS-STING in the development and progression of coronary heart disease.Methods:Eligible cases of coronary heart disease and control cases were selected and divided into control group with normal coronary arteries and grade Ⅰ,Ⅱ,Ⅲ,and Ⅳ coronary artery stenosis groups.HE staining was used to observe and evaluate the pathological conditions of coronary arteries,Western blotting was used to measure the expression levels of downstream pro-teins of the cGAS-STING pathway in coronary tissue,and ELISA was used to measure the levels of inflammatory factors in coronary tis-sue.A correlation analysis was performed to investigate the correlation of the expression levels of downstream proteins of the cGAS-STING signaling pathway and related inflammatory factors with the development and progression of coronary heart disease.Results:Mi-croscopic examination showed that compared with the control group,the other four groups had varying degrees of pathological changes such as vascular wall thickening and luminal stenosis,with a gradual increase in the degree of stenosis from grade Ⅰ to grade Ⅳ coronary lesions.Compared with the control group,the grade Ⅰ,Ⅱ,Ⅲ,and Ⅳ coronary artery stenosis groups had significant increases in the expression levels of downstream proteins of the cGAS-STING signaling pathway and related inflammatory factors in coronary tis-sue,with a trend of increase from grade Ⅰ to grade Ⅳ coronary le-sions.The expression levels of downstream proteins of the cGAS-STING signaling pathway in coronary tissue were positively correlated with the development and progression of coronary heart disease(cGAS:r=0.927,P<0.001;p-Sting:r=0.889,P<0.001;p-TBK1:r=0.910,P<0.001;p-IRF3:r=0.936,P<0.001;IFN-1:r=0.936,P<0.001;TNF-α:r=0.945,P<0.001;IL-1β:r=0.962,P<0.001;IL-6:r=0.933,P<0.001).Conclusion:There are significant differences in the expression levels of downstream proteins of the cGAS-STING signaling pathway and related inflammatory factors,and this signaling pathway may be a potential target for the treatment of coronary heart disease.

Objective To explore the time-varying characteristics and correlation degree of autonomous rehabili-tation behavior and related symptoms of middle-aged stroke patients,and to provide a basis for clinical transitional nursing and precise rehabilitation.Methods Ecological momentary assessment was used to select 57 middle-aged stroke patients who underwent rehabilitation treatment in the Rehabilitation Medicine Department of a tertiary com-prehensive hospital in Wuhan from March 15 to August 30,2024,using convenience sampling method.Their au-tonomous rehabilitation behavior and related symptoms(fatigue,pain,emotion,sensation)were continuously monitored for 2 weeks.A hierarchical linear model was used to analyze the correlation between behavior and symptoms.Results The autonomous rehabilitation behavior of middle-aged stroke patients showed a fluctuating increasing trend,and the symptom score showed a slow decreasing trend.The hierarchical linear model showed that compared with female patients,male patients have longer duration of autonomous rehabilitation behavior(P＜0.05).The number and duration of autonomous rehabilitation behaviors in patients without fatigue were higher(P＜0.05).The number of autonomous rehabilitation behaviors in patients without pain was higher than that in patients with pain(P＜0.05).The number of autonomous rehabilitation behavior items among patients who perceived more pleasure in rehabilitation was higher than that among patients with greater difficulty in rehabilitation challenges(P＜0.05).Patients with high rehabilitation confidence have higher numbers and duration of autonomous rehabilitation behaviors compared to pa-tients with low rehabilitation confidence(P＜0.05).Conclusion There are significant individual differences and dy-namic changes in the autonomous rehabilitation behavior and related symptoms of middle-aged stroke patients.Nurs-ing staff should accurately implement personalized rehabilitation services during the transition period,enhance pa-tients'autonomy and self-management ability in home-based rehabilitation,in order to improve the overall rehabilita-tion effect.

Objective:To observe effectiveness of combining diffusion tensor imaging (DTI) with motor evoked potentials (MEPs) in evaluating the upper limb motor functioning of stroke survivors.Methods:Thirty-seven stroke survivors with upper limb motor dysfunction were selected. At the 4th, 12th and 24th week after their onset, each was were assessed using Fugl-Meyer Upper Limb (FMA-UE) scoring, the National Institutes of Health stroke scale (NIHSS), the modified Rankin Scale (mRS), the Barthel Index (BI) and hemiplegic hand function classification. DTI was also applied and MEPs were measured. The patients were divided into an MEP positive group and an MEP negative group according to the existence of the MEP waveform. The DTI and MEP parameters were correlated with the FMA-UE scores, linear regressions were evaluated and a receiver operating characteristics curve was prepared to estimate the utility of DTI in predicting hand function. The sensitivity and specificity of MEPs in predicting hand function recovery were evaluated.Results:The asymmetry index (FAa) of the average anisotropy score of the posterior limb of the internal capsule and the FAa of the cerebral peduncle were both significantly correlated with the FMA-UE scores at the 12th and 24th weeks. The best cut-off points for predicting functional recovery of a patient′s hand were 0.155 for the FAa of the posterior limb of the internal capsule and 0.145 for the cerebral peduncle. Among the 37 patients, the MEPs of 8 (the MEP positive group) could be extracted, and their hand functions recovered completely. The sensitivity of the MEPs in predicting the complete recovery of hand function was 80% with 100% specificity. The linear regression analysis showed 77% prediction accuracy for the FAa and MEPs of the cerebral peduncle for upper limb motor function at the 24th week after onset. In the MEP negative group, two patients completely recovered their hand function, with one′s FAa less than 0.145, and the other′s more than 0.145. When the MEP was negative, the sensitivity of DTI in predicting the recovery of hand function was 50% with 81.5% specificity.Conclusions:DTI combined with MEPs can be used as an index to evaluate the prognosis of upper limb motor function in stroke patients.

Objective To explore the time-varying characteristics and correlation degree of autonomous rehabili-tation behavior and related symptoms of middle-aged stroke patients,and to provide a basis for clinical transitional nursing and precise rehabilitation.Methods Ecological momentary assessment was used to select 57 middle-aged stroke patients who underwent rehabilitation treatment in the Rehabilitation Medicine Department of a tertiary com-prehensive hospital in Wuhan from March 15 to August 30,2024,using convenience sampling method.Their au-tonomous rehabilitation behavior and related symptoms(fatigue,pain,emotion,sensation)were continuously monitored for 2 weeks.A hierarchical linear model was used to analyze the correlation between behavior and symptoms.Results The autonomous rehabilitation behavior of middle-aged stroke patients showed a fluctuating increasing trend,and the symptom score showed a slow decreasing trend.The hierarchical linear model showed that compared with female patients,male patients have longer duration of autonomous rehabilitation behavior(P＜0.05).The number and duration of autonomous rehabilitation behaviors in patients without fatigue were higher(P＜0.05).The number of autonomous rehabilitation behaviors in patients without pain was higher than that in patients with pain(P＜0.05).The number of autonomous rehabilitation behavior items among patients who perceived more pleasure in rehabilitation was higher than that among patients with greater difficulty in rehabilitation challenges(P＜0.05).Patients with high rehabilitation confidence have higher numbers and duration of autonomous rehabilitation behaviors compared to pa-tients with low rehabilitation confidence(P＜0.05).Conclusion There are significant individual differences and dy-namic changes in the autonomous rehabilitation behavior and related symptoms of middle-aged stroke patients.Nurs-ing staff should accurately implement personalized rehabilitation services during the transition period,enhance pa-tients'autonomy and self-management ability in home-based rehabilitation,in order to improve the overall rehabilita-tion effect.

Objective:To observe effectiveness of combining diffusion tensor imaging (DTI) with motor evoked potentials (MEPs) in evaluating the upper limb motor functioning of stroke survivors.Methods:Thirty-seven stroke survivors with upper limb motor dysfunction were selected. At the 4th, 12th and 24th week after their onset, each was were assessed using Fugl-Meyer Upper Limb (FMA-UE) scoring, the National Institutes of Health stroke scale (NIHSS), the modified Rankin Scale (mRS), the Barthel Index (BI) and hemiplegic hand function classification. DTI was also applied and MEPs were measured. The patients were divided into an MEP positive group and an MEP negative group according to the existence of the MEP waveform. The DTI and MEP parameters were correlated with the FMA-UE scores, linear regressions were evaluated and a receiver operating characteristics curve was prepared to estimate the utility of DTI in predicting hand function. The sensitivity and specificity of MEPs in predicting hand function recovery were evaluated.Results:The asymmetry index (FAa) of the average anisotropy score of the posterior limb of the internal capsule and the FAa of the cerebral peduncle were both significantly correlated with the FMA-UE scores at the 12th and 24th weeks. The best cut-off points for predicting functional recovery of a patient′s hand were 0.155 for the FAa of the posterior limb of the internal capsule and 0.145 for the cerebral peduncle. Among the 37 patients, the MEPs of 8 (the MEP positive group) could be extracted, and their hand functions recovered completely. The sensitivity of the MEPs in predicting the complete recovery of hand function was 80% with 100% specificity. The linear regression analysis showed 77% prediction accuracy for the FAa and MEPs of the cerebral peduncle for upper limb motor function at the 24th week after onset. In the MEP negative group, two patients completely recovered their hand function, with one′s FAa less than 0.145, and the other′s more than 0.145. When the MEP was negative, the sensitivity of DTI in predicting the recovery of hand function was 50% with 81.5% specificity.Conclusions:DTI combined with MEPs can be used as an index to evaluate the prognosis of upper limb motor function in stroke patients.

Objective The objective of this study was to analyze the incidence and mortality of female breast cancer in canc-er registration areas of Gansu province in 2019 and the change trend of female breast cancer incidence and mortality from 2010 to 2019,so as to provide data support for the prevention and treatment of breast cancer.Methods The incidence and mortality data of breast cancer and related demographic data in all cancer registration areas in Gansu province from 2010 to 2019 were collected.The incidence,mortality,age-standardized incidence by Chinese standard population(ASIRC),age-standardized mortality by Chinese standard population(ASMRC),age-standardized incidence by World standard population(ASIRW)and age-standardized mortality by World standard population(ASMRW),cumulative incidence and other key indicators of female breast cancer in each cancer registra-tion area were calculated according to urban and rural distribution and age groups.Joinpoint linear regression was used to analyze the annual change trend of incidence and mortality of female breast cancer in cancer registration areas in Gansu province from 2010 to 2019.Results In 2019,the number of new cases from female breast cancer in the cancer registration areas of Gansu province was 1,502 cases,accounting for 13.14%of all new malignant tumors in women.The incidence was 33.00/100,000,ASIRC and ASIRW were 23.83/100,000 and 23.81/100,000,respectively,and a cumulative rate of 0-74 years old was 2.34%.The incidence of breast cancer in urban and rural areas was 22.25/100,000 and 26.59/100,000,respectively.In 2019,the number of female breast cancer deaths in the cancer registration areas of Gansu province was 254,accounting for 5.61%of all female malignant tumor deaths.The crude mortality was 5.58/100,000,ASMRC and ASMRW were 3.70/100,000 and 3.90/100,000,respectively.The cumulative rate of 0-74 years old was 0.39%.The ASMRC of breast cancer in urban and rural areas was 3.63/100,000 and 3.79/100,000,respec-tively.The annual change trend in the ASIRC of female breast cancer in the province from 2010 to 2019 was not statistically significant(APC=-0.35%,P=0.81),while ASMRC decreased by an average of 9.85%per year(APC=-9.85%,P=0.03).Conclusion Breast cancer is a high incidence malignant tumor that threatens the physical and mental health of female residents in Gansu province,and it is a kind of cancer that women focus on.We should actively screen the risk group of women.

OBJECTIVES: To investigate the effects and mechanisms of deubiquitinating enzyme Josephin domain containing 2 (JOSD2) on susceptibility of non-small cell lung carcinoma (NSCLC) cells to anti-cancer drugs. METHODS: The transcriptome expression and clinical data of NSCLC were downloaded from the Gene Expression Omnibus. Principal component analysis and limma analysis were used to investigate the deubiquitinating enzymes up-regulated in NSCLC tissues. Kaplan-Meier analysis was used to investigate the relationship between the expression of deubiquitinating enzymes and overall survival of NSCLC patients. Gene ontology enrichment and gene set enrichment analysis (GSEA) were used to analyze the activation of signaling pathways in NSCLC patients with high expression of JOSD2. Gene set variation analysis and Pearson correlation were used to investigate the correlation between JOSD2 expression levels and DNA damage response (DDR) pathway. Western blotting was performed to examine the expression levels of JOSD2 and proteins associated with the DDR pathway. Immunofluorescence was used to detect the localization of JOSD2. Sulforhodamine B staining was used to examine the sensitivity of JOSD2-knock-down NSCLC cells to DNA damaging drugs. RESULTS: Compared with adjacent tissues, the expression level of JOSD2 was significantly up-regulated in NSCLC tissues (P<0.05), and was significantly correlated with the prognosis in NSCLC patients (P<0.05). Compared with the tissues with low expression of JOSD2, the DDR-related pathways were significantly upregulated in NSCLC tissues with high expression of JOSD2 (all P<0.05). In addition, the expression of JOSD2 was positively correlated with the activation of DDR-related pathways (all P<0.01). Compared with the control group, overexpression of JOSD2 significantly promoted the DDR in NSCLC cells. In addition, DNA damaging agents significantly increase the nuclear localization of JOSD2, whereas depletion of JOSD2 significantly enhanced the sensitivity of NSCLC cells to DNA damaging agents (all P<0.05). CONCLUSIONS Deubiquitinating enzyme JOSD2 may regulate the malignant progression of NSCLC by promoting DNA damage repair pathway, and depletion of JOSD2 significantly enhances the sensitivity of NSCLC cells to DNA damaging agents.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Antineoplastic Agents/pharmacology* ; Lung Neoplasms/genetics* ; DNA Damage ; DNA ; Deubiquitinating Enzymes/genetics*

Lipids have been found to modulate tumor biology, including proliferation, survival, and metastasis. With the new understanding of tumor immune escape that has developed in recent years, the influence of lipids on the cancer-immunity cycle has also been gradually discovered. First, regarding antigen presentation, cholesterol prevents tumor antigens from being identified by antigen presenting cells. Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells, impairing antigen presentation to T cells. Prostaglandin E2 (PGE2) reduce the accumulation of tumor-infiltrating dendritic cells. Regarding T-cell priming and activation, cholesterol destroys the structure of the T-cell receptor and reduces immunodetection. In contrast, cholesterol also promotes T-cell receptor clustering and relative signal transduction. PGE2 represses T-cell proliferation. Finally, regarding T-cell killing of cancer cells, PGE2 and cholesterol weaken granule-dependent cytotoxicity. Moreover, fatty acids, cholesterol, and PGE2 can improve the activity of immunosuppressive cells, increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines. Given the regulatory role of lipids in the cancer-immunity cycle, drugs that modulate fatty acids, cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy. These strategies have been studied in both preclinical and clinical studies.