Objective : To explore the correlation between the clinical, pathological, genetic features, prognosis, and tumor lymph node metastasis in patients with stage ⅠA-Ⅲ B lung invasive non-mucinous adenocarcinoma(INMA). Methods: A retrospective analysis was conducted on 67 eligible patients with INMA. Clinical data, histopathological assessments, and genetic testing were collected. Disease progression-free survival(PFS) was the primary endpoint through follow-up. The chi-square test or Fisher's exact test was used to analyse the correlation between tumour lymph node metastasis and clinicopathological and genetic characteristics. The Cox proportional hazards regression model and Kaplan-Meier method were used to analyse the impact of tumour lymph node metastasis on prognosis. Results: A total of 67 patients were included, aged 46-77 years, with a median age of 61 years. Age, gender, and smoking history were not significantly associated with tumor lymph node metastasis. Larger tumor diameter, tumor progression, and receiving postoperative adjuvant treatment were associated with tumour lymph node metastasis(P<0.05). Poorer differentiated tumors according to International Association for the Study of Lung Cancer(IASLC) grading system was more likely to have lymph node metastasis(P=0.043). There was no significant difference in the types of driver gene mutations and lymph node metastasis. However,EGFRmutations were more common in patients without lymph node metastasis, while co-mutations were more common in patients with lymph node metastasis. Lymph node metastasis was significantly associated with PFS. Patients without lymph node metastasis had a significantly better PFS compared to those with lymph node metastasis(P=0.002). Under different treatment conditions, patients without lymph node metastasis exhibited a significant advantage in PFS when untreated. While treatment showed a trend toward improved PFS, the difference did not reach statistical significance. Additionally, no significant differences in PFS were observed between patients with or without lymph node metastasis following chemotherapy or targeted therapy. Conclusion Lymph node metastasis in INMA patients is related to tumor size, progression status, and gene co-mutations, and is a key prognostic indicator affecting PFS.

BACKGROUND:Programmed cell death protein 1 belongs to the immunoglobulin gene superfamily and can regulate the differentiation of osteoblasts and affect bone homeostasis.However,there are few studies on the regulatory role and mechanism of programmed cell death protein 1 in diabetic osteoporosis.OBJECTIVE:To investigate the regulatory role and mechanism of programmed cell death protein 1 on osteogenic differentiation of rat bone marrow mesenchymal stem cells under high-glucose environment.METHODS:(1)Animal experiment:A total of 12 Sprageu-Dawley rats were randomized into a control group(n=6)and a model group(n=6).The control group was fed routinely,whereas the model group was injected intraperitoneally with streptozotocin to establish a model of type 1 diabetes mellitus,and the high-fat feed was fed for 8 weeks to establish a model of type 1 diabetic osteoporosis.After 8 weeks of feeding,the femurs of rats in the two groups were taken and subjected to hematoxylin-eosin staining and micro-CT assay.The mRNA expression of programmed cell death protein 1 and programmed death ligand 1 was detected.(2)Cell experiment:Passage 3 rat bone marrow mesenchymal stem cells were randomly divided into four groups:normal control group,high-glucose model group cultured in low glucose medium,programmed cell death protein 1-silenced group transfected with programmed cell death protein 1 siRNA,and programmed cell death protein 1-silenced null group transfected with siRNA-NC.After 48 hours of transfection,the normal control group was cultured in a new low-glucose medium,and the other three groups were cultured in a high-glucose medium for another 48 hours of culture followed by osteogenic induction.After 21 days of osteogenic induction,alizarin red staining,and qRT-PCR(programmed cell death protein 1 and RUNX2 mRNA expression)and western blot(β-catenin,GSK-3β,p-GSK-3β and Axin2 protein expression)were performed.RESULTS AND CONCLUSION:In the animal experiment,hematoxylin-eosin staining and micro-CT assay showed successful modeling of type 1 diabetic osteoporosis in the model group.qRT-PCR assay showed that the mRNA expression of programmed cell death protein 1 and programmed cell death ligand 1 was higher in the model group than the control group(P<0.05).In the cell experiment,the results of alizarin red staining showed that the ability of mineralized nodule formation was lower in the high-glucose model group and the programmed cell death protein 1-silenced null group than in the control group and the programmed cell death protein 1-silenced group.Compared with the normal control group,the programmed cell death protein 1 mRNA expression and GSK3β and Axin2 protein expression were elevated in the high-glucose model group and the programmed cell death protein 1-silenced null group(P<0.05),and the RUNX2 mRNA expression and p-GSK3β and β-catenin protein expression were decreased(P<0.05).Compared with the high-glucose model group and the programmed cell death protein 1-silenced null group,programmed cell death protein 1 mRNA expression and GSK3β and Axin2 protein expression were decreased in the programmed cell death protein 1-silenced group(P<0.05),and RUNX2 mRNA expression and p-GSK3β and β-catenin protein expression were elevated(P<0.05).To conclude,programmed cell death protein 1 silencing can activate the Wnt/β-catenin and improve the osteogenic differentiation of rat bone marrow mesenchymal stem cells under high-glucose conditions.

BACKGROUND:Programmed cell death protein 1 belongs to the immunoglobulin gene superfamily and can regulate the differentiation of osteoblasts and affect bone homeostasis.However,there are few studies on the regulatory role and mechanism of programmed cell death protein 1 in diabetic osteoporosis.OBJECTIVE:To investigate the regulatory role and mechanism of programmed cell death protein 1 on osteogenic differentiation of rat bone marrow mesenchymal stem cells under high-glucose environment.METHODS:(1)Animal experiment:A total of 12 Sprageu-Dawley rats were randomized into a control group(n=6)and a model group(n=6).The control group was fed routinely,whereas the model group was injected intraperitoneally with streptozotocin to establish a model of type 1 diabetes mellitus,and the high-fat feed was fed for 8 weeks to establish a model of type 1 diabetic osteoporosis.After 8 weeks of feeding,the femurs of rats in the two groups were taken and subjected to hematoxylin-eosin staining and micro-CT assay.The mRNA expression of programmed cell death protein 1 and programmed death ligand 1 was detected.(2)Cell experiment:Passage 3 rat bone marrow mesenchymal stem cells were randomly divided into four groups:normal control group,high-glucose model group cultured in low glucose medium,programmed cell death protein 1-silenced group transfected with programmed cell death protein 1 siRNA,and programmed cell death protein 1-silenced null group transfected with siRNA-NC.After 48 hours of transfection,the normal control group was cultured in a new low-glucose medium,and the other three groups were cultured in a high-glucose medium for another 48 hours of culture followed by osteogenic induction.After 21 days of osteogenic induction,alizarin red staining,and qRT-PCR(programmed cell death protein 1 and RUNX2 mRNA expression)and western blot(β-catenin,GSK-3β,p-GSK-3β and Axin2 protein expression)were performed.RESULTS AND CONCLUSION:In the animal experiment,hematoxylin-eosin staining and micro-CT assay showed successful modeling of type 1 diabetic osteoporosis in the model group.qRT-PCR assay showed that the mRNA expression of programmed cell death protein 1 and programmed cell death ligand 1 was higher in the model group than the control group(P<0.05).In the cell experiment,the results of alizarin red staining showed that the ability of mineralized nodule formation was lower in the high-glucose model group and the programmed cell death protein 1-silenced null group than in the control group and the programmed cell death protein 1-silenced group.Compared with the normal control group,the programmed cell death protein 1 mRNA expression and GSK3β and Axin2 protein expression were elevated in the high-glucose model group and the programmed cell death protein 1-silenced null group(P<0.05),and the RUNX2 mRNA expression and p-GSK3β and β-catenin protein expression were decreased(P<0.05).Compared with the high-glucose model group and the programmed cell death protein 1-silenced null group,programmed cell death protein 1 mRNA expression and GSK3β and Axin2 protein expression were decreased in the programmed cell death protein 1-silenced group(P<0.05),and RUNX2 mRNA expression and p-GSK3β and β-catenin protein expression were elevated(P<0.05).To conclude,programmed cell death protein 1 silencing can activate the Wnt/β-catenin and improve the osteogenic differentiation of rat bone marrow mesenchymal stem cells under high-glucose conditions.

The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer.Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis(YTE-17),attributing these effects to the regu-lation of multiple signaling pathways.However,knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited.In this study,we conducted isobaric tags for relative and absolute quantification(iTRAQ)analysis on intestinal epithelial cells(IECs)exposed YTE-17,both in vitro and in vivo,revealing a significant inhibition of the Wnt family member 5a(Wnt5a)/c-Jun N-terminal kinase(JNK)signaling pathway.Subsequently,we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment(TME),specifically focusing on macrophage-mediated T helper 17(Th17)cell induction in a colitis-associated cancer(CAC)model with Wnt5a deletion.Additionally,we performed the single-cell RNA sequencing(scRNA-seq)on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition,lineage,and functional status of immune mesenchymal cells during different stages of colorectal cancer(CRC)progression.Remarkably,our findings demon-strate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17,leading to the restoration of regulatory T(Treg)/Th17 cell balance in azoxymethane(AOM)/dextran sodium sulfate(DSS)model.Furthermore,we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages.Notably,our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical β-catenin oncogenic pathway in vivo.Specifically,we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with β-catenin activity within the TME,involving macrophages and T cells.In summary,our study undergoes the po-tential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment,thereby mitigating the risk of malignancies.

Objective Exploring the predictive value of amplitude integrated electroencephalography(aEEG)and brainstem auditory evoked potentials(BAEP)in cognitive and affective disorders related to cerebral small vessel disease(CSVD).Methods Retrospectively,100 patients with CSVD who visited the Department of Neurology at the Fourth Affiliated Hospital of Soochow University from January 2021 to February 2024 were included in the CSVD group.From January 2021 to February 2024,100 healthy people who underwent physical examination in the Physical Examination Center of the Fourth Affiliated Hospital of Soochow University and matched with the CSVD group for age and sex were prospectively included as the control group.Basic and clinical data were collected and compared between the CSVD group and the control group,including age,sex,years of education,hypertension,diabetes,smoking,drinking,total cholesterol,triglycerides,low-density lipoprotein cholesterol(LDL-C),C-reactive protein(CRP),galactin-3(Gal-3),cystatin C,homocysteine(Hcy),blood Tau protein,and glial fibrillary acidic protein(GFAP).Cognitive function was assessed using the mini-mental state examination(MMSE)and the Montreal cognitive assessment(MoCA)scale,with a MMSE score＜24 and a MoCA score＜25 indicating cognitive impairment.affective disorders were assessed using the Hamilton anxiety scale(HAMA)and the Hamilton depression scale(HAMD),with a HAMA score ≥ 14 or a HAMD score ≥20 indicating the presence of affective disorders.The scores of the above four scales were compared between the CSVD group and the control group.aEEG and BAEP data were collected and compared between the CSVD group and the control group.aEEG results were evaluated based on a composite score of background activity stability,sleep-wake cycle,lower boundary amplitude,and narrowband width,with a score of 0-3 indicating aEEG abnormalities.In the BAEP waveform,the Ⅰ,Ⅲ,and Ⅴ waves and the inter-wave intervals of Ⅰ-Ⅲ,Ⅲ-Ⅴ and Ⅰ-Ⅴ were observed and recorded,along with their peak latencies and inter-peak latencies.If the latency of each wave is prolonged＞mean+3 standard deviations and/or the interwave period is prolonged＞mean+3 standard deviations,it was considered a BAEP abnormality.CSVD patients were divided into cognitive impairment and non-cognitive impairment based on MMSE scale score and MoCA scale score,and all CSVD patients were divided into affective disorder and non-affective disorder based on HAMA score and HAMD score.The independent variables with statistically significant differences and no collinearity in the univariate analysis of cognitive and affective disorders in CSVD patients were included in the multivariate Logistic regression analysis,and the statistically significant factors were used to form the multivariate model.The area under the receiver operating characteristic(ROC)curve was used to analyze the predictive value of the multi-factor model for CSVD-related cognitive and affective disorders.Results(1)The proportion of hypertension patients,the levels of CRP,Gal-3,cystatin C,Hcy,Tau protein,GFAP,HAMA and HAMD scores in the CSVD group were higher than those in the control group(all P＜0.05),and the MMSE and MoCA scale were lower than those in the control group(both P＜0.05).The scores of continuity,sleep-wake cycle,lower boundary amplitude and narrow band width of aEEG in the CSVD group were lower than those in the control group(all P＜0.05).The peak latency and interpeak latency of BAEP in the CSVD group were higher than those in the control group(all P＜0.05).(2)There were 52 patients with cognitive impairment and 48 patients with non-cognitive impairment in CSVD patients.There were 36 patients with affective disorder and 64 patients with non-affective disorder.There were 17patients with both cognitive and affective disorders.The age,Tau protein,GFAP,the proportion of patients with abnormal aEEG and the proportion of patients with abnormal BAEP in patients with cognitive impairment were higher than those in patients without cognitive impairment(all P＜0.05).The age of patients with affective disorder,the proportion of patients with abnormal aEEG and the proportion of patients with abnormal BAEP were higher than those of patients without affective disorder(all P＜0.05).(3)Multivariate Logistic regression analysis showed that the risk of cognitive impairment in patients with abnormal aEEG CSVD was 4.364 times higher than that in patients with normal aEEG CSVD(OR,4.364,95％CI 1.554-12.252,P=0.005).The risk of cognitive impairment in patients with abnormal BAEP CSVD was 3.218 times higher than that in patients with normal BAEP CSVD(OR,3.218,95％CI 1.218-8.503,P=0.018).The ROC curve was used to analyze the predictive value of the multi-factor model jointly constructed by aEEG abnormalities and BAEP abnormalities for CSVD cognitive impairment.The results showed that the area under the ROC curve was 0.732,the sensitivity was 76.38％,and the specificity was 82.59％.(4)Multivariate Logistic regression analysis showed that the risk of affective disorder in patients with abnormal aEEG CSVD was 3.203 times higher than that in patients with normal aEEG CSVD(OR,3.203,95％CI 1.288-7.966,P=0.012).The risk of affective disorder in patients with abnormal BAEP CSVD was 2.553 times higher than that in patients with normal BAEP CSVD(OR,2.553,95％CI 1.011-6.446,P=0.047).The ROC curve was used to analyze the predictive value of the multi-factor model jointly constructed by aEEG abnormalities and BAEP abnormalities for CSVD affective disorders.The results showed that the area under the ROC curve was 0.700,the sensitivity was 74.21％,and the specificity was 83.49％.Conclusions The abnormality of aEEG and BAEP are important factors in constructing the prediction model of cognitive and affective disorders in CSVD patients.The multi-factor model constructed by aEEG and BAEP has certain value in predicting CSVD-related cognitive and affective disorders.

Objective Exploring the predictive value of amplitude integrated electroencephalography(aEEG)and brainstem auditory evoked potentials(BAEP)in cognitive and affective disorders related to cerebral small vessel disease(CSVD).Methods Retrospectively,100 patients with CSVD who visited the Department of Neurology at the Fourth Affiliated Hospital of Soochow University from January 2021 to February 2024 were included in the CSVD group.From January 2021 to February 2024,100 healthy people who underwent physical examination in the Physical Examination Center of the Fourth Affiliated Hospital of Soochow University and matched with the CSVD group for age and sex were prospectively included as the control group.Basic and clinical data were collected and compared between the CSVD group and the control group,including age,sex,years of education,hypertension,diabetes,smoking,drinking,total cholesterol,triglycerides,low-density lipoprotein cholesterol(LDL-C),C-reactive protein(CRP),galactin-3(Gal-3),cystatin C,homocysteine(Hcy),blood Tau protein,and glial fibrillary acidic protein(GFAP).Cognitive function was assessed using the mini-mental state examination(MMSE)and the Montreal cognitive assessment(MoCA)scale,with a MMSE score＜24 and a MoCA score＜25 indicating cognitive impairment.affective disorders were assessed using the Hamilton anxiety scale(HAMA)and the Hamilton depression scale(HAMD),with a HAMA score ≥ 14 or a HAMD score ≥20 indicating the presence of affective disorders.The scores of the above four scales were compared between the CSVD group and the control group.aEEG and BAEP data were collected and compared between the CSVD group and the control group.aEEG results were evaluated based on a composite score of background activity stability,sleep-wake cycle,lower boundary amplitude,and narrowband width,with a score of 0-3 indicating aEEG abnormalities.In the BAEP waveform,the Ⅰ,Ⅲ,and Ⅴ waves and the inter-wave intervals of Ⅰ-Ⅲ,Ⅲ-Ⅴ and Ⅰ-Ⅴ were observed and recorded,along with their peak latencies and inter-peak latencies.If the latency of each wave is prolonged＞mean+3 standard deviations and/or the interwave period is prolonged＞mean+3 standard deviations,it was considered a BAEP abnormality.CSVD patients were divided into cognitive impairment and non-cognitive impairment based on MMSE scale score and MoCA scale score,and all CSVD patients were divided into affective disorder and non-affective disorder based on HAMA score and HAMD score.The independent variables with statistically significant differences and no collinearity in the univariate analysis of cognitive and affective disorders in CSVD patients were included in the multivariate Logistic regression analysis,and the statistically significant factors were used to form the multivariate model.The area under the receiver operating characteristic(ROC)curve was used to analyze the predictive value of the multi-factor model for CSVD-related cognitive and affective disorders.Results(1)The proportion of hypertension patients,the levels of CRP,Gal-3,cystatin C,Hcy,Tau protein,GFAP,HAMA and HAMD scores in the CSVD group were higher than those in the control group(all P＜0.05),and the MMSE and MoCA scale were lower than those in the control group(both P＜0.05).The scores of continuity,sleep-wake cycle,lower boundary amplitude and narrow band width of aEEG in the CSVD group were lower than those in the control group(all P＜0.05).The peak latency and interpeak latency of BAEP in the CSVD group were higher than those in the control group(all P＜0.05).(2)There were 52 patients with cognitive impairment and 48 patients with non-cognitive impairment in CSVD patients.There were 36 patients with affective disorder and 64 patients with non-affective disorder.There were 17patients with both cognitive and affective disorders.The age,Tau protein,GFAP,the proportion of patients with abnormal aEEG and the proportion of patients with abnormal BAEP in patients with cognitive impairment were higher than those in patients without cognitive impairment(all P＜0.05).The age of patients with affective disorder,the proportion of patients with abnormal aEEG and the proportion of patients with abnormal BAEP were higher than those of patients without affective disorder(all P＜0.05).(3)Multivariate Logistic regression analysis showed that the risk of cognitive impairment in patients with abnormal aEEG CSVD was 4.364 times higher than that in patients with normal aEEG CSVD(OR,4.364,95％CI 1.554-12.252,P=0.005).The risk of cognitive impairment in patients with abnormal BAEP CSVD was 3.218 times higher than that in patients with normal BAEP CSVD(OR,3.218,95％CI 1.218-8.503,P=0.018).The ROC curve was used to analyze the predictive value of the multi-factor model jointly constructed by aEEG abnormalities and BAEP abnormalities for CSVD cognitive impairment.The results showed that the area under the ROC curve was 0.732,the sensitivity was 76.38％,and the specificity was 82.59％.(4)Multivariate Logistic regression analysis showed that the risk of affective disorder in patients with abnormal aEEG CSVD was 3.203 times higher than that in patients with normal aEEG CSVD(OR,3.203,95％CI 1.288-7.966,P=0.012).The risk of affective disorder in patients with abnormal BAEP CSVD was 2.553 times higher than that in patients with normal BAEP CSVD(OR,2.553,95％CI 1.011-6.446,P=0.047).The ROC curve was used to analyze the predictive value of the multi-factor model jointly constructed by aEEG abnormalities and BAEP abnormalities for CSVD affective disorders.The results showed that the area under the ROC curve was 0.700,the sensitivity was 74.21％,and the specificity was 83.49％.Conclusions The abnormality of aEEG and BAEP are important factors in constructing the prediction model of cognitive and affective disorders in CSVD patients.The multi-factor model constructed by aEEG and BAEP has certain value in predicting CSVD-related cognitive and affective disorders.

OBJECTIVE: To explore the therapeutic mechanism of Liushen Wan (LSW) against colitis-associated colorectal cancer (CAC) by network pharmacology. METHODS: TCMSP, BATMAN-TCM, CNKI, PubMed, Genecards, OMIM, and TTD databases were used to obtain the related targets of LSW and CAC. The common targets of LSW and CAC were obtained using Venny online website. The PPI network was constructed using Cytoscape 3.8.2 to screen the core targets of LSW in the treatment of CAC. GO and KEGG enrichment analysis were conducted using DAVID database. The therapeutic effect of LSW on CAC was evaluated in a C57BL/6J mouse model of AOM/DSS-induced CAC by observing the changes in body weight, disease activity index, colon length, and size and number of the tumor. HE staining and RT-qPCR were used to analyze the effect of LSW on inflammatory mediators. Immunohistochemistry and TUNEL staining were used to evaluate the effect of LSW on the proliferation and apoptosis of AOM/DSS-treated colon tumor cells. Immunohistochemistry and Western blotting were used to detect the effects of LSW on the expression of TLR4 proteins in CAC mice. RESULTS: Network pharmacology analysis identified 69 common targets of LSW and CAC, and 33 hub targets were screened in the PPI network. KEGG pathway enrichment analysis suggested that the effect of LSW on CAC was mediated by the Toll-like receptor signaling pathway. In the mouse model of AOM/DSS-induced CAC, LSW significantly inhibited colitis-associated tumorigenesis, reduced tumor number and tumor load (P < 0.05), obviously improved histopathological changes in the colon, downregulated the mRNA levels of proinflammatory cytokines, and inhibited the proliferation (P < 0.01) and promoted apoptosis of colon tumor cells (P < 0.001). LSW also significantly decreased TLR4 protein expression in the colon tissue (P < 0.05). CONCLUSION LSW can inhibit CAC in mice possibly by regulating the expression of TLR4 to reduce intestinal inflammation, inhibit colon tumor cell proliferation and promote their apoptosis.
Mice ; Animals ; Toll-Like Receptor 4 ; Colitis-Associated Neoplasms ; Network Pharmacology ; Mice, Inbred C57BL ; Colonic Neoplasms/pathology*

Seed quality plays an important role in the agricultural and animal husbandry production, the effective utilization of genetic resources, the conservation of biodiversity and the restoration and reconstruction of plant communities. Seed aging is a common physiological phenomenon during storage. It is a natural irreversible process that occurs and develops along with the extension of seed storage time. It is not only related to the growth, yield and quality of seed and seedling establishment, but also has an important effect on the conservation, utilization and development of plant germplasm resources. The physiological mechanisms of seed aging are complex and diverse. Most studies focus on conventional physiological characterization, while systematic and comprehensive in-depth studies are lacking. Here we review the recent advances in understanding the physiology of seed aging process, including the methods of seed aging, the effect of aging on seed germination, and the physiological and molecular mechanisms of seed aging. The change of multiple physiological parameters, including seed vigor, electrical conductivity, malondialdehyde content and storage material in the seed, antioxidant enzyme activity and mitochondrial structure, were summarized. Moreover, insights into the mechanism of seed aging from the aspects of transcriptome, proteome and aging related gene function were summarized. This study may facilitate the research of seed biology and the conservation and utilization of germplasm resources.
Germination ; Plants ; Proteome ; Seedlings ; Seeds/genetics*

Enzalutamide (ENZ) is a second-generation androgen receptor (AR) antagonist used for the treatment of castration-resistant prostate cancer (CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance (ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR (ARfl) or dominantly active androgen receptor splice variant 7 (ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.

Objective: To investigate the effect and safety of intensive hyperthermia combined with low-dose cisplatin plus radiotherapy in the treatment of patients with locally advanced NSCLC. Methods: From January 2012 to December 2015, 104 patients with locally advanced NSCLC were chosen in the Second People's Hospital of Weifang and randomly divided into two groups according to the digital table, with 52 patients in each group.The control group was given low-dose cisplatin plus radiotherapy, and the observation group was given intensive hyperthermia on the basis of control group.The ORR, DCR, median OS, median PFS, KPS score, the levels of coagulation function index and tumor markers before and after treatment and incidence of side effects in the two groups were compared. Results: The DCR of the observation group was significantly higher than that of the control group(86.54% vs.69.23%, χ²=8.24, P<0.05). The median OS and median PFS of the observation group were significantly longer than those of the control group(11.9 months vs.8.3 months; 7.5 months vs.4.7 months, t=2.56, 3.01, P<0.05). The KPS scores after treatment of the observation group were significantly higher than those of the control group and before treatment[(75.49±8.94)points vs.(68.65±7.06)points; (75.49±8.94)points vs.(62.23±6.34)points, t=2.78, 5.11, all P<0.05]. The levels of coagulation function index and tumor markers after treatment of the observation group were significantly lower than those of the control group and before treatment(t=3.14, 2.67, 3.59, 7.31; 4.89, 4.02, 4.70, 9.21; 2.44, 2.60, 3.20; 3.15, 3.78, 4.06; all P<0.05). There was no statistically significant difference in the incidence of side effects between the two groups(P>0.05). Conclusion Intensive hyperthermia combined with low-dose cisplatin plus radiotherapy in the treatment of patients with locally advanced NSCLC can efficiently control disease progress, increase survival benefits, higher quality of life, improve coagulation function, reduce the levels of tumor markers and possess satisfactory safety.