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.

Through the addition of discussion course associated with judicial expertise during the pre medical education, integration of true and typical forensic pathological cases into basic medical theory and experimental education, further addition of optional course of forensic medicine,and guiding the medical students applying the scientifically training projects about forensic pathology, students may improve their learning interesting and clinical thought, and are made early warning and increase the abilities of preventing and dealing with the suddenly medical tangles in the future, at the same time, the medical teachers also increase their professional levels and teaching qualities.These benefit the growing up of high quality medical doctors, decrease and even prevent the happening of medical tangles.

Bone Neoplasms ; pathology ; Cerebellum ; pathology ; Humans ; Neurocytoma ; pathology ; Petrous Bone ; pathology

Objective:To explore the effects of lanthanum nitrate low-dose on 2 type diabetic rat pancreas INSR ,IRS1 and apoptosis of cells.Methods:The 50 male Wistar rats were randomly divided into normal control group (10) and model group(40),and were given normal diet and high-fat high-sugar diet.After 8 weeks,making the module intraperitoneal injection of streptozotocin (STZ,30 mg/kg) rats to induce type 2 diabetes model ,after a successful modeling experimental animals were divided into three groups namely the control group,diabetic model group and La(NO3)3 treatment group,three groups of rats were given daily saline,saline,lanthanum (0.2 mg/kg) nitrate administered a month ,then were sacrificed blood and pancreas.By radioimmunoassay to detect glucose ,insulin levels(in rat serum);by ELISA to detect the protein content of INSR and IRS 1(in rat serum);by immunohistochemistry to detect the protein expression levels of INSR and IRS1(in rat pancreas tissue);TUNEL apoptosis detection kit was used to detect pancreatic tissue percentage of apoptosis;HE staining was used to detect pathological changes of the pancreas.Results: Compared with the normal control group,diabetic model rats blood glucose and pancreatic tissue apoptosis rate were significantly increased ,blood insulin,INSR and IRS1 protein content and pancreatic tissue the protein expression levels of INSR and IRS 1 were significantly reduced ,difference was statistically significant ( P<0.01 );La( NO3 ) 3 treatment group blood glucose and pancreatic tissue apoptosis rate were slightly elevated ,blood insulin , INSR and IRS1 protein content and pancreatic tissue the protein expression levels of INSR and IRS 1 were slightly reduced significantly(P<0.05);Light microscopy showed pancreatic tissue in the control group closely arranged ,plump,large volume islet pancreatic tissue of diabetic rats in groups evacuate more smaller islet volume ,pancreatic tissue lanthanum nitrate basic set tight,plump,slightly islet volume small.Conclusion:Oral lanthanum nitrate can be lowered blood sugar levels and inhibiting apoptosis of pancreatic tissue ,increased insulin levels and the protein expression levels of INSR and IRS 1 in pancreatic tissue ,have a protective effect on diabetic rat pancreas .

Objective:Guanxinshutong on cerebral ischemia reperfusion ( I/R) in rats learning and memory ability and brain Bcl-2,Bax protein expression to explore the protection mechanisms of Guanxinshutong on cerebral I /R injury in brain tissue.Methods:Healthy Wistar rats for the study were randomly divided into sham operation group ,I/R model group,high dose Guanxinshutong (1 g/kg) and low dose Guanxinshutong (0.5 g/kg) group,n=15.cerebral I/R model was estabhished by using the left commom cartid artery ligation method,modeling each group were fed daily before saline ,saline,Guanxinshutong (1 g/kg) and Guanxinshutong (0.5 g/kg), continuous 7 days;3 d after water maze training while continuing administration ,continuous 7 d,the eight day ,Morris water maze test;after the test,the rats were sacrificed blood and brain tissue ,serum by ELISA of Bcl-2 and Bax protein levels change;using HE staining of rat brain pathology;using immunohistochemistry assay in rat brain organization of Bcl-2 and Bax protein levels changes.Results:Compared with the sham group ,Guanxinshutong high-dose group test latency slightly longer timers after platform and platform quadrant dwell decreased slightly ,serum and brain tissue slightly elevated levels of Bax protein ,Bcl-2 protein levels decreased slightly but not significantly different ( P>0.05 ) ,low-dose group Guanxinshutong through latency test in rats ,after the number of platforms and platform quadrant dwell time decreased , serum and brain tissue elevated levels of Bax protein , Bcl-2 protein content decreased significantly different(P<0.01),cerebral I/R model group was significantly prolonged latency test ,after the number of platforms and platform quadrant dwell time significantly reduced serum and brain tissue was significantly increased Bax protein ,Bcl-2 protein content decreased with significant differences ( P<0.01 ).Conclusion: Guanxinshutong can significantly improve spatial memory , and by reducing Bax protein content and increased Bcl-2 protein,inhibition of cerebral I/R injury of apoptosis,and thus the brain tissue I/R has a protective effect.

To investigate the effect of treasure pill pretreatment on hypoxic brain injury Fas and Fas L protein expression.Methods:Newborn 7d Wistar rats 200,male or female,were randomly divided into 5 groups(n=40):normal control group, model group 1h hypoxia(Ⅰm-12h,Ⅰm-24h,Ⅰm-48h,Ⅰm-72h),model group 4h hypoxia(Ⅳm-12h,Ⅳm-24h,Ⅳm-48h,Ⅳm-72h), hypoxic 1h treasure pill treatment group(ⅠT-14h,ⅠT-24h,ⅠT-48h,ⅠT-72h),hypoxic 4h treasure pill treatment group(ⅣT-14h,ⅣT-24 h ,ⅣT-48 h ,ⅣT-72 h ).The newborn Wistar rats were placed in hypoxia chamber of 8%O2+92%N2 ( V/V) for establishment the model of neonatal rats with hypoxia.Before modeling continuous 7 d once-daily oral administration of saline and treasure pill , during hypoxia also dose ,after hypoxia 12 h,24 h,48 h,72 h animals were sacrificed blood and brain tissues tested.By ELISA to detect the protein levels of Fas and Fas L in serum and brain tissue;by immunohistochemistry method to detect the expression of Fas and Fas L in rat brain tissue.Results:Compared with normal control group ,other four groups the protein content and protein expression of Fas and Fas L are in the 12h time points after hypoxic significantly increased ,and 24 h time point that pealed at statistically significant ( P<0.01 ) ,model group was significantly higher than the treatment group at each time point ;model groups in 48 h,72 h time point the protein expression and protein content of Fas and Fas L was less than 12 h time point but still significantly higher than the control group ( P<0.01 );treasure pill groups in 48 h,72 h time point the protein expression and protein content of Fas and Fas L was less than 12 h time point ,and slightly higher than the normal control group ( P<0.05 ).Conclusion: Treasures pill can cut hypoxic brain damage in rats,the positive expression of Fas and Fas L protein content and protein ,and thus the hypoxic brain injury has a protective effect.

Objective:To detect the expressions of survivin, galectin-3 and thyroid peroxidase in papillary thyroid microcarcinoma ( PTMC) and cancer adjacent normal tissue to explore the clinical significant.The correlations between the expressions of survivin,Gal-3 and TPO with BRAFV600E gene mutation in PTMC were analyzed.Methods: The expressions of survivin,Gal-3 and TPO were measured by immunohistochemical ( IHC ) method in 56 cases of PTMC tissue and adjacent normal tissue; BRAFV600E mutation was detected by PCR amplification and subsequently sequencing.Chi square test was used to analyse the relation in the expression rates of survivin,Gal-3 and TPO and BRAFV600E gene mutation.Results:The survivin and Gal-3 were strongly expressed but TPO was negatively expressed.The survivin and Gal-3 were negative in adjacent normal tissues but TPO was expressed.There were sig-nificant differences in the expression rates of survivin, Gal-3 and TPO between PTMC tissue and adjacent normal tissue (all P<0.001).The BRAFV600E mutation rate (32.1%) and the expression rates of survivin,Gal-3 and TPO in PTMC tissue were found to be positively related to lymph node metastases (P=0.009,P=0.025,P=0.007,P=0.008),and negatively related to gender and age (all P>0.05).There were no correlation was found between the expressions of survivin,Gal-3,TPO and the BRAFV600E gene mutation in PTMC(all P>0.05).Conclusion: The strong expressions of survivin and Gal-3,the mild expression of TPO and BRAF mutation may be important in the development of PTMC,and the detection of BRAFV600E gene mutation and the expressions of survivin, Gal-3 and TPO could be used to the judgment of pathogenetic condition and prognostic outcomes.

Objective To investigate the expressions of inflammatory factors in papillary thyroid carcinoma tissue and their relationships with the clinical pathological characteristics,and to provide an experimental basis for guiding clinical treatment and prognosis.Methods 74 patients with papillary thyroid carcinoma dignosed by puncture were selected as experimental group,and 26 cases of healthy people were used as normal control group.The fasting venous blood samples from the subjects in two groups were collected,and the postoperative specimens from cancer tissue,adjacent normal tissue and the fasting venous blood 7 d after operation of the patients in experimental group were collected again.The interleukin 1α(IL-1α),interleukin 1β(IL-1β)and cyclooxygenase-2 (COX-2)protein expression levels in serum,cancer adjacent normal tissue and cancer tissue were detected by ELISA;the gene and protein expression levels of IL-1α,IL-1βand COX-2 were examined by real-time fluorescent quantitative method and immunohistochemistry;the relationships between their expressions and clinical stages, pathological types,lymph node metastasis of thyroid papillary carcinoma were analyzed.Results The expression levels of serum IL-1α,IL-1βand COX-2 protein of the patients in experimental group were significantly higher than those in normal control group (P<0.01);the gene and protein expression levels of IL-1α,IL-1βand COX-2 in thyroid papillary carcinoma tissue were significantly higher than those in adjacent tissue (P<0.01).There were positive correlations between the expressions of IL-1αand IL-1β,IL-1αand COX-2,IL-1βand COX-2 in thyroid papillary carcinoma tissue (r=0.64,P=0.035;r=0.71,P=0.042;r=0.69,P=0.038).Conclusion The expression levels of IL-1α, IL-1βand COX-2 in thyroid papillary carcinoma tissue are increased, suggesting that inflammation is involved in metastasis and invasion of thyroid papillary carcinoma,its application is expected to become a new means of cancer treatment strategies.

Aim To investigate the influence of Shen-mai injection ( SMI ) on the expression of cytochrome P450(CYP450) system in rat′s hearts. Methods Rat hearts were prepared after a fourteen-day continuous administration of SMI. The expression of several CYP genes, ANP, BNP and EPHX2 were measured by qPCR. Results SMI induced the increase in the ex-pression of other CYP genes except CYP2 B1、CYP4 A3 and CYP4 F6;HSI caused an induction of CYP2 E1 , CYP4A3,CYP4F1 and EHPX2 as compared with the control. In addition, there was a significant induction of ANP, BNP and EHPX2 and a significant inhibition of CYP2B1 and CYP2C11 after treated with MDI. Conclusion Although there is no significant change in the gene expression of CYP2 B1 after the treatment with SMI, but there is a general trend of induction, and MDI shows a significant inhibition of CYP2 B1 , therefore HSI has greater effect on CYP 2 B 1 than MDI . SMI causes a significant induction of CYP2 E1 , CYP4F1 and EHPX2 , similarly there is an induction of CYP2E1,CYP4F1 and EHPX2 by HSI and MDI, indi-cating that Hongshen and Maidong are both involved in the induction. MDI has a greater inductive effect than HSI on ANP and BNP. SMI is widely used for the treatment of cardiovascular diseases due to its regula-tion of CYP2J3、ANP and BNP mRNA expression.

Objective:To explore the effects of different types of music on Caspase-3 and Livin expression levels of the hippocampus of brain tissue of aged rats.Methods: Healthly elderly male Wistar rats 40 were randomly divided into :control group , Mozart music group ,Liangzhu music group and rock music group ,n=10;water maze training every morning while music intervention 2 h,afternoon pure music intervention 2 h,continuous 7 d,the eighth days ,the rats were sacrificed and taking blood and brain tissue ,by ELISA in serum and brain tissue Caspase-3 and Livin protein contents change;using immunohistochemistry assay in rat brain tissue Caspase-3 and Livin protein levels;real-time PCR detection of rat brain tissue changes in gene level of Caspase-3 and Livin.Results:Compared with the control group ,Mozart music group ,Liangzhu music rats the protein content ,protein level and gene level of Caspase-3 of serum and brain tissue were lower statistically significant ( P<0.01 ) , Livin was increased there was statistically significant ( P<0.01 ) ,Mozart music group and Liangzhu music group were no significant difference ( P>0.05 );while rock music group the protein content,protein level and gene level of Caspase-3 and Livin of brain tissue were not significantly difference (P>0.05).Conclusion:Mozart music group and Liangzhu music group by reducing serum and brain tissue Caspase -3 and increased Livin , to inhibit the apoptosis of the body′s nerve cells,which play a neuroprotective effect;the rock music group in the present study ineffective.