Construction and Validation of a Prognostic Model Based on Mitochondrial Genes in Prostate Cancer.

This study attempted to build a prostate cancer (PC) prognostic risk model with mitochondrial feature genes. PC-related MTGs were screened for Cox regression analyses, followed by establishing a prognostic model. Model validity was analyzed via survival analysis and receiver operating characteristic (ROC) curves, and model accuracy was validated in the GEO dataset. Combining risk score with clinical factors, the independence of the risk score was verified by using Cox analysis, followed by generating a nomogram. The Gleason score, microsatellite instability (MSI), immune microenvironment, and tumor mutation burden were analyzed in two risk groups. Finally, the prognostic feature genes were verified through a q-PCR test. Ten PC-associated MTGs were screened, and a prognostic model was built. Survival analysis and ROC curves illustrated that the model was a good predictor for the risk of PC. Cox regression analysis revealed that risk score acted as an independent prognostic factor. The Gleason score and MSI in the high-risk group were substantially higher than in the low-risk group. Levels of ESTIMATE Score, Immune Score, Stromal Score, immune cells, immune function, immune checkpoint, and immunopheno score of partial immune checkpoints in the high-risk group were significantly lower than in the low-risk group. Genes with the highest mutation frequencies in the two groups were SPOP, TTN, and TP53. The q-PCR results of the feature genes were consistent with the gene expression results in the database. The 10-gene model based on MTGs could accurately predict the prognosis of PC patients and their responses to immunotherapy.

Spinetoram-Induced Potential Neurotoxicity through Autophagy Mediated by Mitochondrial Damage.

Spinetoram is an important semi-synthetic insecticide extensively applied in agriculture. It is neurotoxic to insects, primarily by acting on acetylcholine receptors (nAChRs). However, few studies have examined the neurotoxicity of spinetoram in human beings. In this study, various concentrations (5, 10, 15, and 20 µM) of spinetoram were employed to expose SH-SY5Y cells in order to study the neurotoxic effects of spinetoram. The results showed that spinetoram exposure markedly inhibited cell viability and induced oxidative stress. It also induced mitochondrial membrane potential collapse (ΔΨm), and then caused a massive opening of the mitochondrial permeability transition pore (mPTP), a decrease in ATP synthesis, and Ca2+ overloading. Furthermore, spinetoram exposure induced cellular autophagy, as evidenced by the formation of autophagosomes, the conversion of LC3-I into LC3-II, down-regulation of p62, and up-regulation of beclin-1. In addition, we observed that p-mTOR expression decreased, while p-AMPK expression increased when exposed to spinetoram, indicating spinetoram triggered AMPK/mTOR-mediated autophagy. Complementarily, the effect of spinetoram on neurobehavior was studied using the zebrafish model. After being exposed to different concentrations (5, 10, and 20 µg/mL) of spinetoram, zebrafish showed neurobehavioral irregularities, such as reduced frequency of tail swings and spontaneous movements. Similarly, autophagy was also observed in zebrafish. In conclusion, spinetoram exposure produced potential neurotoxicity through autophagy mediated by mitochondrial damage. The experimental data and results of the neurotoxicity study of spinetoram provided above are intended to serve as reference for its safety assessment.

Correlation between age and curative effects of selective dorsal neurectomy for primary premature ejaculation.

BACKGROUND: The use of selective dorsal neurectomy (SDN) as a surgical treatment of premature ejaculation (PE) has increased for many years in Asian countries. OBJECTIVES: To investigate the correlation between age and curative effects of SDN in primary premature ejaculation (PPE) in mainland China. MATERIAL AND METHODS: From September 2016 to September 2020, 65 patients with PPE treated with SDN were selected for study. All of the patients were followed up from 12 to 56 (30.07 ±13.48) months. They were divided into 3 groups according to age: group A (22-30 years, n = 23), group B (31-37 years, n = 20) and group C (38-45 years, n = 22). The 5-item version of the International Index of Erectile Function (IIEF-5) and Premature Ejaculation Diagnostic Tool (PEDT) results, erectile rigidity grade, intravaginal ejaculation latency time (IELT), ejaculation control abilities (ECA) scores, and sexual intercourse satisfaction (SIS) scores were assessed in the 3 groups before and after operation to evaluate the clinical efficacy of surgery. RESULTS: Fifty-nine patients were finally followed up. The IIEF-5 scores and erectile rigidity grade of group A was significantly higher than that of groups B and C, both before and after surgery. The change of PEDT scores in group A was significantly higher than in groups B and C; the difference was statistically significant (p < 0.05). The IELT, ECA and SIS scores in group A were significantly higher than in groups B and C (p < 0.05). Operational efficiency ratio in groups B and C (65%, 70%) was significantly lower than in group A (95.24%). CONCLUSIONS: The SDN as a treatment of PPE in different age groups allowed to achieve certain results. The highest surgical efficiency (95.24%) was observed in the 22-30 years age group and the lowest (65%) in the 38-45 years age group. Therefore, we believe that the best time for surgery is between 22 and 30 years of age.

BCL2L12A localizes to the cell nucleus and induces growth inhibition through G2/M arrest in CHO cells.

BCL2L12, a newly identified member of Bcl-2 family, and its transcript variant BCL2L12A have been found to be associated with favorable prognosis in breast cancer patients while correlated with tumorigenesis of glioblastoma and colon cancer. However, the biological functions of BCL2L12 and especially those of BCL2L12A are largely unknown. Here, we report that, unlike other Bcl-2 family proteins, BCL2L12 and its transcript variant BCL2L12A are nuclear proteins. Interestingly, BCL2L12 forms speckle patterns in the nuclei and potently induces apoptosis in CHO cells. BCL2L12A had a diffuse distribution in the nuclei and inhibits cell growth by inducing cell cycle arrested at G2/M transition in CHO cells. More importantly, BCL2L12A-induced G2/M arrest was associated with a slight up-regulation of cyclin B1 and significant down-regulation of an active form of cyclin B1 phosphorylated at Ser147. Taken together, our study suggests that both BCL2L12 and BCL2L12A have negative effects on CHO cell growths, and that BCL2L12A is a potential cell cycle regulator that interferes with G2-M transition.

Knockdown of BCL2L12 leads to cisplatin resistance in MDA-MB-231 breast cancer cells.

BCL2L12, a newly identified member of Bcl-2 family, contains a BH2 domain and a putative BH3 domain. It was found to be highly expressed in normal breast tissues, and was associated with favorable prognosis in breast cancer patients. Here, we reported that the mRNA levels of BCL2L12 and its transcript variant BCL2L12A could be upregulated upon cisplatin treatment in MDA-MB-231 breast cancer cells. Knockdown of BCL2L12 and BCL2L12A dramatically inhibited cisplatin-induced apoptosis. In contrast, ectopic expressions of each of the proteins promoted cisplatin-induced apoptosis. These results indicated that decreased expressions or loss of BCL2L12 and BCL2L12A may contribute to the cisplatin resistance in breast cancer patients. Furthermore, we found that cisplatin-induced downregulation of beta-catenin was partially suppressed in BCL2L12- and BCL2L12A-knocked down MDA-MB-231 cells, which indicated that knockdown of these two proteins may stabilize beta-catenin in cisplatin-induced apoptosis. In short, we proposed that BCL2L12 and BCL2L12A may play an important role in cisplatin-induced apoptosis in MDA-MB-231 breast cancer cells.

CDK11p58 represses vitamin D receptor-mediated transcriptional activation through promoting its ubiquitin-proteasome degradation.

Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and regulates transcription of target genes. In this study, we identified CDK11(p58) as a novel protein involved in the regulation of VDR. CDK11(p58), a member of the large family of p34cdc2-related kinases, is associated with cell cycle progression, tumorigenesis, and apoptotic signaling. Our study demonstrated that CDK11(p58) interacted with VDR and repressed VDR-dependent transcriptional activation. Furthermore, overexpression of CDK11(p58) decreased the stability of VDR through promoting its ubiquitin-proteasome-mediated degradation. Taken together, these results suggest that CDK11(p58) is involved in the negative regulation of VDR.

Spontaneous rupture of hepatic epithelioid hemangioendothelioma: A case report.

Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor of vascular endothelial origin. Spontaneous rupture of HEH is a life-threatening complication and is extremely rare. HEH has variable malignant potential, and the clinical diagnosis remains challenging. Here we report a case of HEH with spontaneous rupture. A 44-year-old man presented with constant cutting pains over the right upper abdomen after eating. He had hemoptysis 11 d previously. Diagnostic abdominal puncture demonstrated active bleeding. Chest and abdominal computer tomography scan showed multiple ground-glass nodules over the lungs, multiple low-density intrahepatic nodules and massive hemorrhage. Transcatheter arterial embolization and exploratory laparotomy were performed and subsequent immunohistochemical examination confirmed a diagnosis of HEH.

Outcomes of preoperative endoscopic nasobiliary drainage and endoscopic retrograde biliary drainage for malignant distal biliary obstruction prior to pancreaticoduodenectomy.

AIM: To compare the outcomes of preoperative endoscopic nasobiliary drainage (ENBD) and endoscopic retrograde biliary drainage (ERBD) in patients with malignant distal biliary obstruction prior to pancreaticoduodenectomy (PD). METHODS: Data from 153 consecutive patients who underwent preoperative endoscopic biliary drainage prior to PD between January 2009 and July 2016 were analyzed. We compared the clinical data, procedure-related complications of endoscopic biliary drainage (EBD) and postoperative complications of PD between the ENBD and ERBD groups. Univariate and multivariate analyses with odds ratios (ORs) and 95% confidence intervals (95%CIs) were used to identify the risk factors for deep abdominal infection after PD. RESULTS: One hundred and two (66.7%) patients underwent ENBD, and 51 (33.3%) patients underwent ERBD. Endoscopic sphincterotomy was less frequently performed in the ENBD group than in the ERBD group (P = 0.039); the EBD duration in the ENBD group was shorter than that in the ERBD group (P = 0.036). After EBD, the levels of total bilirubin (TB) and alanine aminotransferase (ALT) were obviously decreased in both groups, and the decreases of TB and ALT in the ERBD group were greater than those in the ENBD group (P = 0.004 and P = 0.000, respectively). However, the rate of EBD procedure-related cholangitis was significantly higher in the ERBD group than in the ENBD group (P = 0.007). The postoperative complications of PD as graded by the Clavien-Dindo classification system were not significantly different between the two groups (P = 0.864). However, the incidence of deep abdominal infection after PD was significantly lower in the ENBD group than in the ERBD group (P = 0.019). Male gender (OR = 3.92; 95%CI: 1.63-9.47; P = 0.002), soft pancreas texture (OR = 3.60; 95%CI: 1.37-9.49; P = 0.009), length of biliary stricture (≥ 1.5 cm) (OR = 5.20; 95%CI: 2.23-12.16; P = 0.000) and ERBD method (OR = 4.08; 95%CI: 1.69-9.87; P = 0.002) were independent risk factors for deep abdominal infection after PD. CONCLUSION: ENBD is an optimal method for patients with malignant distal biliary obstruction prior to PD. ERBD is superior to ENBD in terms of patient tolerance and the effect of biliary drainage but is associated with an increased risk of EBD procedure-related cholangitis and deep abdominal infection after PD.

Primary splenic angiosarcoma with liver metastasis: A case report and literature review.

Primary splenic angiosarcoma (PSA) is an unusual and highly malignant vascular tumour with a high rate of metastatic. Moreover, the research on prognosis of the disease is poor. The epidemiology, etiology, clinical diagnosis and treatment of the disease remain challenging, because case reports of the disease are few in number. In accordance with other malignant tumors, PSA is very aggressive, and the majority of patients in which this disease is found are at an advanced stage. Almost all patients die within 12 mo of diagnosis irrespective of treatment. We report here a woman who had complained of upper bellyache and anorexia for 10 d. Magnetic resonance imaging showed enlargement of the spleen with multiple heterogeneous masses in the lower pole of the spleen. A hand-assisted laparoscopic splenectomy was performed which allowed histopathologic diagnosis. The patient was diagnosed with PSA and liver metastasis, and succumbed to the disease 35 d after surgery. The literature was finished combined with the clinical features, diagnosis and management of PSA.

Estrogen receptor α (ERα) mediates 17ß-estradiol (E2)-activated expression of HBO1.

BACKGROUND: HBO1 (histone acetyltransferase binding to ORC1) is a histone acetyltransferase (HAT) which could exert oncogenic function in breast cancer. However, the biological role and underlying mechanism of HBO1 in breast cancer remains largely unknown. In the current study, we aimed to investigate the role of HBO1 in breast cancer and uncover the underlying molecular mechanism. METHODS: Immunohistochemistry was applied to detect HBO1 protein expression in breast cancer specimens (n=112). The expression of protein level was scored by integral optical density (IOD) for further statistical analyses using SPSS. Real-time PCR was used to simultaneously measure mRNA levels of HBO1. The HBO1 protein expression in breast cancer cells was confirmed by western blot. RESULTS: HBO1 was highly expressed in breast cancer tissues and significantly correlated with estrogen receptor α (ERα) (p<0.001) and progestational hormone (PR) (p=0.002). HBO1 protein level also correlated positively with histology grade in ERα positive tumors (p=0.016) rather than ERα negative tumors. 17ß-estradiol (E2) could upregulate HBO1 gene expression which was significantly inhibited by ICI 182,780 or ERα RNAi. E2-increased HBO1 protein expression was significantly suppressed by treatment with inhibitor of MEK1/2 (U0126) in T47 D and MCF-7 cells. CONCLUSIONS: HBO1 was an important downstream molecule of ERα, and ERK1/2 signaling pathway may involved in the expression of HBO1 increased by E2.

Trihydrophobin 1 Interacts with PAK1 and Regulates ERK/MAPK Activation and Cell Migration.

The Rac1/Cdc42 effector, p21-activated kinase (PAK), is activated by various signaling cascades, including receptor-tyrosine kinases and integrins, and regulates a number of processes such as cell proliferation and motility. PAK activity has been shown to be required for maximal activation of the canonical RAF-MEK-MAPK signaling cascade, possibly because of PAK co-activation of RAF and MEK. Here we have shown that trihydrophobin 1 (TH1), originally identified as a negative regulator of A-RAF kinase, also interacted with PAK1 in cultured cells. Confocal microscopy assay indicated that TH1 colocalized with PAK1 in both the cytoplasm and nucleus, which is consistent with our previous results. GST pulldown and coimmunoprecipitation experiments demonstrated that TH1 interacted directly with PAK1 and bound selectively to the carboxyl-terminal kinase domain of PAK1, and the ability of the binding was enhanced along with activation of PAK1. The binding pattern of PAK1 implies that this interaction was mediated in part by PAK1 kinase activity. As indicated by in vitro kinase activity assays and Western blot detections, TH1 inhibited PAK1 kinase activity and negatively regulated MAPK signal transduction. Interestingly, TH1 bound with MEK1/ERK in cells and in vitro without directly suppressing their kinase activity. Furthermore, we observed that TH1 localized to focal adhesions and filopodia in the leading edge of cells, where TH1 reduced cell migration through affecting actin and adhesion dynamics. Based on these observations, we propose a model in which TH1 interacts with PAK1 and specifically restricts the activation of MAPK modules through the upstream region of the MAPK pathway, thereby influencing cell migration.

HSP70 protects BCL2L12 and BCL2L12A from N-terminal ubiquitination-mediated proteasomal degradation.

BCL2L12 has been found to be associated with favorable prognosis in breast cancer patients while correlated with tumorigenesis of glioblastoma and colon cancer. Here, we report that BCL2L12 and its transcript variant BCL2L12A are degraded through ubiquitin-proteasome system (UPS). Interestingly, the ubiquitinations and degradations of BCL2L12 and BCL2L12A are independent of the internal lysine residues but the first N-terminal residues. In addition, HSP70 was identified to interact with BCL2L12 and BCL2L12A and protected them from ubiquitinations and degradations in mammalian cells. In summary, HSP70 protects BCL2L12 and BCL2L12A from N-terminal ubiquitination-mediated proteasomal degradation.

CDK11p58 phosphorylation of PAK1 Ser174 promotes DLC2 binding and roles on cell cycle progression.

CDK11(p58), a CDK11 family Ser/Thr kinase, is a G2/M specific protein and contributed to regulation of cell cycle, transcription and apoptotic signal transduction. Recently, CDK11(p58) has been reported to exert important functions in mitotic process, such as the regulation of bipolar spindle formation and sister chromatid cohesion. Here, we identified p21 activated kinase 1 (PAK1) as a new CDK11(p58) substrate and we mapped a new phosphorylation site of Ser174 on PAK1. By mutagenesis, we created PAK1(174A) and PAK1(174E), which mimic the dephosphorylated and phosphorylated form of PAK1; further analysis showed PAK1(174E) could be recruited to myosin V motor complex through binding to dynein light chain 2 (DLC2). PAK1(174E) could accelerate the mitosis progression in a nocodazole blocked cell model, while PAK1(174A) exhibited an opposite role. Our results indicated PAK1 may serve as a downstream effector of CDK11(p58) during mitosis progression.

CDK11(p58) protein kinase activity is associated with Bcl-2 down-regulation in pro-apoptosis pathway.

CDK11(p58), a G2/M-specific protein kinase, has been shown to be associated with apoptosis in many cell lines, with largely unknown mechanisms. Our previous study proved that CDK11(p58)-enhanced cycloheximide (CHX)-induced apoptosis in SMMC-7721 hepatocarcinoma cells. Here we report for the first time that ectopic expression of CDK11(p58) down-regulates Bcl-2 expression and its Ser70, Ser87 phosphorylation in CHX-induced apoptosis in SMMC-7721 cells. Overexpression of Bcl-2 counteracts the pro-apoptotic activity of CDK11(p58). Furthermore, we confirm that the kinase activity of CDK11(p58) is essential to the down-regulation of Bcl-2 as well as apoptosis. Taken together, these results demonstrate that CDK11(p58) down-regulates Bcl-2 in pro-apoptosis pathway depending on its kinase activity, which elicits survival signal in hepatocarcinoma cells.

Down-regulation of the expression of beta1,4-galactosyltransferase V promotes integrin beta1 maturation.

In previous study, we have shown that beta1,4-galactosyltransferase V (GalT V) functions as a positive growth regulator in glioma. Here, we reported that down-regulation of the expression of GalT V in SHG44 cells by transfection with antisense cDNA specifically up-regulated the expression of cell surface integrin beta1 without the change of its mRNA, and with integrin beta1 125 kDa mature form increased and 105 kDa precursor form decreased. It is well known that the N-glycans of integrins modulate the location and functions of integrins. The SHG44 cells transfected with antisense cDNA of GalT V demonstrated decreased Golgi localization of integrin beta1, strengthened the interaction between integrin alpha5 and beta1 subunit, and enhanced the adhesion ability to fibronectin and the level of focal adhesion kinase phosphorylation. Our results suggested that the down-regulation of the expression of GalT V could promote the expression of cell surface integrin beta1 and subsequently inhibit glioma malignant phenotype.

Beta1,4-galactosyltransferase V functions as a positive growth regulator in glioma.

beta1,4-galactosyltransferase V (GalT V; EC 2.4.1.38) can effectively galactosylate the GlcNAcbeta1-->6Man arm of the highly branched N-glycans that are characteristic of glioma. Previously, we have reported that the expression of GalT V is increased in the process of glioma. However, currently little is known about the role of GalT V in this process. In this study, the ectopic expression of GalT V could promote the invasion and survival of glioma cells and transformed astrocytes. Furthermore, decreasing the expression of GalT V in glioma cells promoted apoptosis, inhibited the invasion and migration and the ability of tumor formation in vivo, and reduced the activation of AKT. In addition, the activity of GalT V promoter could be induced by epidermal growth factor, dominant active Ras, ERK1, JNK1, and constitutively active AKT. Taken together, our results suggest that GalT V functioned as a novel glioma growth activator and might represent a novel target in glioma therapy.