Traditional Chinese herbal medicine in treating amenorrhea caused by antipsychotic drugs: Meta-analysis and systematic review.

ETHNOPHARMACOLOGICAL RELEVANCE: Amenorrhea caused by antipsychotic drugs is not uncommon in clinical practice, and various treatment strategies are used to treat the condition. Chinese herbal medicine has its own theory for amenorrhea caused by antipsychotic drugs and has developed its own medication methods. AIM OF THE STUDY: To review and conduct meta-analysis of the use of traditional Chinese herbal medicine in treatment of amenorrhea caused by antipsychotic drugs. MATERIALS AND METHODS: A search was conducted across seven Chinese electronic databases (the China National Knowledge Infrastructure (CNKI) database, the China Science and Technology Journal Database, the Wanfang Database, the SinoMed, the Foreign Medical Literature Retrieval Service(FMRS), the Chinese University of Hong Kong Library, the Airiti Library), and the following English databases: MEDLINE, PreMEDLINE, OLD MEDLINE、Publisher Supplied Citation in pubmed; JBI EBP Database, EBM Reviews, Embase, OVID Emcare, Ovid MEDLINE(R), Maternity & Infant Care Database(MIDIRS), APA PsycInfo in OVID, and Cochrane Database of Systematic Reviews (Cochrane Reviews), Database of Abstracts of Reviews of Effects (Other Reviews), Cochrane Central Register of Controlled Trials (Clinical Trials),The Cochrane Methodology Register (Method Studies), Health Technology Assessment Database (Technology Assessments), NHS Economic Evaluation Database (Economic Evaluations) in Cochrane Library; and four databases (Science Direct, ProQuest, Web of Science, and Scopus) in official website using common standards and inclusion/exclusion criteria. The remaining reports were used for preliminary studies. Due to inconsistencies in control groups, randomized controlled trials and articles that combined with other drugs were also excluded. This study is a META analysis of a single rate. RESULTS: Initial screening returned 912 potentially relevant publications in all databases. After subsequent filtering, a total of 18 articles were included in the analysis. The overall effectiveness for treatment amenorrhea caused by antipsychotic drugs using traditional Chinese herbal medicine was 0.91, with 95% confidence interval of 0.89-0.93. Notably in most studies, the time needed to achieve this level of effectiveness was relatively long, usually in excess of three months. Although a satisfactory verification of an improvement in menstrual cycling takes time, the long treatment duration is a downside. Our analysis revealed that the following Chinese herbal remedies were most common: Danggui (Angelica sinensis (Oliv.) Diels), Chuanxiong (Ligusticum striatum DC.), Taoren (Prunus persica (L.) Batsch), Honghua (Carthamus tinctorius L.), Gancao (Glycyrrhiza uralensis Fisch.), Fuling ((Fungus) Poria cocos (Schw.) Wolf), Baizhu (Atractylodes macrocephala Koidz.), Xiangfu (Cyperus rotundus L.), Chaihu (Bupleurum chinense DC.), Shudihuang (Rehmannia glutinosa (Gaertn.) DC.(Processed), Baishao (Cynanchum otophyllum C.K.Schneid.) CONCLUSIONS: Chinese herbal medicine can effectively treat amenorrhea caused by psychiatric drugs, although it takes a long time to achieve satisfactory effectiveness. More research is needed to better understand different aspects of Chinese herbal medicine use in treatment of this particular medical condition.

TRIM37 overexpression is associated with chemoresistance in hepatocellular carcinoma via activating the AKT signaling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer in the worldwide. Sorafenib is approved for first-line therapy against advanced HCC, but chemo-resistance is still a leading cause of tumor relapse and treatment failure in HCC. Thus, there is a significant clinical need to identify effective strategies to overcome drug resistance on the disease. METHODS: The protein and mRNA expression of TRIM37 in HCC cell lines and patient tissues were determined using Real-time PCR and Western blot, respectively. HCC tissue samples were analyzed by IHC to investigate the association between TRIM37expression and the clinicopathological characteristics of HCC patients. Functional assays, such as MTT, FACS, and Tunel assay, are used to determine the oncogenic role of TRIM37 in human HCC progression. Furthermore, western blotting and luciferase assay were used to determine the mechanism of TRIM37promotes chemoresistance in HCC. RESULTS: We found that both the mRNA and protein expression of TRIM37 was markedly upregulated in HCC cell lines and tissues, especially in Sorafenib-resistance HCC tissues. Moreover, high TRIM37 expression was associated with poor prognosis with HCC patients. TRIM37 overexpression confers Sorafenib resistance on HCC cells; however, inhibition of TRIM37 sensitized HCC cell lines to Sorafenib cytotoxicity. Additionally, TRIM37 upregulated the levels of AKT activity and phosphorylated AKT, thereby activating canonical AKT signaling. CONCLUSION: Our findings suggest that targeting TRIM37 signaling may represent a promising strategy to enhance Sorafenib response in HCC patients with chemoresistant.

Predictive factors for the benefit of triple-drug transarterial chemoembolization for patients with unresectable hepatocellular carcinoma.

BACKGROUND: Compared with single-drug TACE, our previous phase III study demonstrated that triple-drug transarterial chemoembolization (TACE) prolonged overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). The aim of this study was to find which patients can benefit from the triple drugs TACE compared with single-drug TACE. METHODS: Patients in the triple-drug TACE arm received sponge embolization and emulsions composed of 50 mg epirubicin, 50 mg lobaplatin, 6 mg mitomycin C, and lipiodol, while patients in the single-drug TACE arm received sponge embolization and emulsions composed of 50 mg epirubicin and lipiodol. From July 2007 to November 2009, 244 patients (224 men and 20 women; age ranged from 21 to 75 years) from our phase III study formed the initial cohort. From January 2010 to June 2015, external validation cohort was composed of 449 patients (411 men and 38 women; age ranged from 18 to 75 years) from another institution. The validation cohort after propensity score matching (PSM) (n = 374) was analyzed. Cox proportional hazard model was used to evaluate the interaction term between treatments for each subgroup. This retrospective study was approved by the institutional review board at each center. RESULTS: No difference was observed in the baseline characteristic of three cohorts. This exploratory analysis showed that triple-drug TACE brought a survival benefit in the initial cohort, validation cohort (before PSM), and validation cohort (after PSM) compared with single-drug TACE. The outcomes of three cohorts all showed that a significantly greater OS triple-drug chemotherapy benefit versus single-drug chemotherapy was seen in patients with large tumors (larger than 10 cm) while no survival difference was seen in patients with small tumors (10 cm or smaller). CONCLUSIONS: Triple-drug TACE seems to benefit patients with HCC larger than 10 cm in particular compared with single-drug TACE.

Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin vs Sorafenib Alone for Hepatocellular Carcinoma With Portal Vein Invasion: A Randomized Clinical Trial.

Importance: Sorafenib is the first-line treatment for hepatocellular carcinoma with portal vein invasion; however, it has shown unsatisfactory survival benefit. Sorafenib plus hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown promising results for these patients in a previous phase 2 study. Objective: To investigate the efficacy and safety of sorafenib plus HAIC compared with sorafenib for hepatocellular carcinoma with portal vein invasion. Design, Setting, and Participants: This randomized, open-label clinical trial enrolled 818 screened patients. Of the 818 participants, 247 with hepatocellular carcinoma and portal vein invasion were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib plus HAIC or sorafenib. This trial was conducted at 5 hospitals in China and enrolled patients from April 1, 2016, to October 10, 2017, with a follow-up period of 10 months. Interventions: Randomization to receive 400 mg sorafenib twice daily (sorafenib group) or 400 mg sorafenib twice daily plus HAIC (SoraHAIC group) (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks). Main Outcomes and Measures: The primary endpoint was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment. Results: For 247 patients (median age, 49 years; range, 18-75 years; 223 men and 24 women), median overall survival was 13.37 months (95% CI, 10.27-16.46) in the SoraHAIC group vs 7.13 months (95% CI, 6.28-7.98) in the sorafenib group (hazard ratio [HR], 0.35; 95% CI, 0.26-0.48; P < .001). The SoraHAIC group showed a higher response rate than the sorafenib group (51 [40.8%] vs 3 [2.46%]; P < .001), and a longer median progression-free survival (7.03 [95% CI, 6.05-8.02] vs 2.6 [95% CI, 2.15-3.05] months; P < .001). Grade 3/4 adverse events that were more frequent in the SoraHAIC group than in the sorafenib group included neutropenia (12 [9.68%] vs 3 [2.48%]), thrombocytopenia (16 [12.9%] vs 6 [4.96%]), and vomiting (8 [6.45%] vs 1 [0.83%]). Conclusions and Relevance: Sorafenib plus HAIC of FOLFOX improved overall survival and had acceptable toxic effects compared with sorafenib in patients with hepatocellular carcinoma and portal vein invasion. Trial Registration: ClinicalTrials.gov identifier: NCT02774187.

Is Emergency Transcatheter Hepatic Arterial Embolization Suitable for Spontaneously Ruptured Hepatocellular Carcinoma in Child-Pugh C Cirrhosis?

PURPOSE: To evaluate the utility of emergent transcatheter arterial embolization for spontaneously ruptured hepatocellular carcinoma (HCC) in patients with Child-Pugh class C (CPC) liver cirrhosis presenting hemorrhagic shock. MATERIALS AND METHODS: A study of all 94 patients was retrospectively conducted from January 2006 to January 2016. Sixty patients underwent conservative treatment (control group) and 34 underwent embolization. RESULTS: Embolization provided better stabilization of hemodynamic status than conservative treatment (91.2% vs 61.7%), with greater overall survival (OS) rates at 30, 60, and 120 days (73.5%, 52.9%, and 29.4% vs 33.3%, 13.3%, and 0%, respectively). Mean follow-up duration was 51.07 days (range, 3-237 d). Median survival time was longer for the embolization group than the control group, specifically for patients with a shock index (SI) of ≥ 0.6 to < 1 (106.0 d ± 39.4 vs 34.0 d ± 4.7) or ≥ 1 (18.0 d ± 7.5 vs 11.0 d ± 3.2), those with CPC scores 10 or 11 (88.0 d ± 29.4 vs 28.0 d ± 4.5), and those with segmental (165.0 d ± 20.6 vs 34.0 d ± 9.7) or lobar (54.0 d ± 7.9 vs 26.0 d ± 3.4) portal vein tumor thrombus (PVTT). SI ≥ 1, Child-Pugh score of 12/13, tumor size ≥ 10 cm, and PVTT were independent factors in poor prognosis for OS. CONCLUSIONS: Emergent transcatheter arterial embolization is an effective intervention for ruptured HCC in patients with CPC liver function in hemorrhagic shock, particularly those with a SI ≥ 1, Child-Pugh scores of 10/11, and first- or lower-order PVTT.

High brain acid soluble protein 1(BASP1) is a poor prognostic factor for cervical cancer and promotes tumor growth.

BACKGROUND: The aim of this study was to determine whether brain abundant membrane attached signal protein 1 (BASP1) is a valuable prognostic biomarker for cervical cancer and whether BASP1 regulates the progression of cervical cancer. METHODS: Quantitative real-time PCR, western blotting, and immunohistochemistry were used to determined BASP1 levels. Statistical analyses were used to examine whether BASP1 was a prognostic factor for patients with cervical cancer. The MTT assay, colony formation assay, cell cycle assay, anchorage-independent growth assay, and a tumor xenograft model were used to determine the role of BASP1 in the proliferation and tumorigenicity of cervical cancer. RESULTS: Brain abundant membrane attached signal protein 1 was upregulated in cervical cancer tissues and cells, and BASP1 expression levels were higher in patients that had died during follow-up compared with those that survived. There was a positive correlation between BASP1 expression and clinical stage (p < 0.001), T classification (p < 0.001), N classification (p < 0.05), and survival or mortality (p < 0.05). Patients with higher BASP1 expression had a shorter overall survival time. Cox regression analysis shown BSAP1 was an unfavorable prognostic factor for patients with cervical cancer. Overexpression of BASP1 promoted the proliferation of cervical cancer and its colony formation ability, accelerated cell cycle progression, and enhanced tumorgenicity. BASP1 knockdown inhibited the proliferation of cervical cancer and its colony formation ability, suppressed cell cycle progression, and decreased tumorgenicity. CONCLUSIONS: The results showed that BASP1 not only is a novel prognostic factor for patients with cervical cancer, but also promotes the proliferation and tumorigenicity of cervical cancer.

Efficacy of Preoperative Transcatheter Arterial Embolization for Nasopharyngeal Angiofibroma: A Comparative Study.

OBJECTIVE: This study aimed to retrospectively evaluate the efficacy and safety of preoperative transcatheter arterial embolization (pTAE) for treating nasopharyngeal angiofibroma (NPAF). METHODS: Seventy-four NPAF patients were hospitalized for elective surgical treatment with pTAE (pTAE group, n = 32) or surgical treatment alone (non-pTAE group, n = 42) between January 1990 and December 2013. The following outcome measures were retrospectively analyzed and compared: intraoperative bleeding volume, surgery time (ST), duration of postoperative hospital stay (PHS), and disease recurrence. RESULTS: Among Radkowski stage I patients, those in pTAE group had a slightly higher but not significant bleeding volume than patients in non-pTAE group (344 ± 407 vs. 248 ± 219 mL, P = 0.899); among stage II/III patients, however, patients in pTAE group showed a significantly lower bleeding volume than patients in non-pTAE group (stage II, 829 ± 519 vs. 1339 ± 767 mL, P = 0.035; stage III, 1267 ± 592 vs. 2125  ± 479 mL, P = 0.024). The two groups presented comparable OTs, PHSs, and rates of frontal recurrence (all P>0.05). CONCLUSIONS: pTAE significantly reduces intraoperative bleeding in NPAF patients with Radkowski stage II/III disease, but offers no additional benefits regarding ST, PHS, or recurrence.

The feasibility and safety of a through-and-through wire technique for central venous occlusion in dialysis patients.

BACKGROUND: To retrospectively compare the operation time, success rate and efficacy between unidirectional and bidirectional procedures in the treatment of central venous occlusion diseases (CVOD), assess the advantages of the bidirectional approach, and determine the characteristics of CVOD appropriate for the bidirectional approach treatment. METHODS: A total of 49 patients who underwent endovascular interventions with all relevant data between January 2011 and December 2015 at the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, were included in this retrospective study, and were categorized into two groups: the 19 patients in group 1 had undergone percutaneous transluminal venoplasty (PTV) via a conventional technique (unidirectional procedure from the vein distal or proximal to the obstructive lesion), and the 30 in group 2 had undergone flossing wire technique (bidirectional procedure from femoral vein and the vein distal to obstructive lesion and using a flossing wire technique). The technical success rate, the fluoroscopy time in the procedure, perioperative complications, and patency were evaluated retrospectively. RESULTS: Compared with group 1, group 2 had a higher initial technical success rate (83.33% vs. 47.36%, p = 0.012) but a shorter fluoroscopy time (82.6 ± 26.1 vs. 116.1 ± 42.1, p = 0.048). Receiver operating characteristic (ROC) analysis indicated that a lesion with a length of 6.5 cm was the best predictor of technique success (p = 0.02) in group 1, but no cut-off value was identified for group 2. There were no significant differences in perioperative complications between these two groups. The complication rates were 31.58% (6/19) in group 1 and 6.67% (2/30) in group 2, (p = 0.043), respectively. No significant difference was observed between these two groups with respect to the stent patency rate. CONCLUSION: Compared with the conventional technique, the flossing wire technique has a higher success rate, shorter fluoroscopy time, fewer complications and similar patency rate. It is a feasible treatment for CVOD, especially for long obstructive lesions.

Initial Experience: Alleviation of Pain with Percutaneous CT-Guided Cryoablation for Recurrent Retroperitoneal Soft-Tissue Sarcoma.

PURPOSE: To evaluate the pain-alleviating effect of computed tomography (CT)-guided percutaneous cryoablation for recurrent retroperitoneal soft-tissue sarcomas (RPSs). MATERIALS AND METHODS: Data from 19 men and 20 women (median age, 50.3 y) with recurrent malignant RPS who underwent percutaneous cryoablation were reviewed retrospectively. A total of 50 tumors were treated by cryoablation, including a single tumor in 29 patients, 2 tumors in 9, and 3 tumors in 1. Adverse events and analgesic outcomes were compared as a function of tumor size (< 10 cm and ≥ 10 cm). Efficacy was assessed based on modified Response Evaluation Criteria In Solid Tumors and progression-free survival (PFS). RESULTS: Grade 1/2 adverse events included fever (n = 17), emesis (n = 7), frostbite (n = 5), and local pain (n = 4). The median follow-up period and PFS were 18.5 months (range, 12-42 mo) and 13.4 months ± 6.2, respectively. At the end of follow-up, 13 patients had died and 26 were living. The mean severe local pain scores on pretreatment day 1 and posttreatment days 1, 5, 10, 15, 20, and 25 were 7.49, 7.40, 6.51, 5.81, 5.35, 5.04, and 5.44, respectively, and significant differences versus pretreatment (P < .001) were reported for posttreatment days 5-25. Immediate relief occurred more frequently in the small-tumor group (4 of 7; 57.1%; P = .018), whereas delayed relief occurred more frequently in the large-tumor group (17 of 22; 77.3%; P = .030). CONCLUSIONS: Minimally invasive percutaneous cryoablation improves local pain and is a feasible treatment for recurrent RPSs.

Percutaneous computed tomography-guided cryoablation for recurrent retroperitoneal soft tissue sarcoma: a study of safety and efficacy.

AIMS: To evaluate the use of computed tomography image-guided percutaneous cryoablation for recurrent retroperitoneal soft tissue sarcomas (RPSs). RESULTS: Adverse events were limited to grades 1 and 2, included fever (n = 19), local pain (n = 11), emesis (n = 10), frostbite (n = 6), and nerve injury (n = 1). Fever was more frequent in the large tumor group (15.8%) than in small tumor group (1.9%) (P = 0.008). Median PFS and OS were 37.0 ± 7.7 months (range, 4-39 months) and 43.0 ± 5.9 months (range, 6-54 months), respectively. PFS and OS were significantly longer in the small tumor group than in the large tumor group (P = 0.011 and P = 0.015, respectively), but the response rate (82.7% vs. 72.8%, P = 0.240) did not differ significantly. On univariate analysis, tumor size, tumor invasion grade, and distant metastasis were significant prognostic factors for PFS and OS. On multivariate analysis, a tumor size ≥10 cm was an independent negative prognostic factor for PFS and OS after cryoablation (HR: 3.98, 95% CI: 1.27-12.50, P = 0.018 and HR: 4.33, 95% CI: 1.41-13.26, P = 0.010, respectively). MATERIALS AND METHODS: Data from 72 patients with recurrent RPSs who underwent percutaneous cryoablation were reviewed retrospectively. The prognostic factors for progression-free survival (PFS), overall survival (OS), and efficacy based on mRECIST criteria were analysis. Adverse events were compared according to tumor size (<10 and ≥10 cm). CONCLUSION: Minimally invasive percutaneous cryoablation was safe and efficacious for recurrent RPSs.

Mir-765 promotes cell proliferation by downregulating INPP4B expression in human hepatocellular carcinoma.

microRNAs (miRNAs) dysregulation is widely involved in cancer progression and contributed to sustained cell proliferation by directly targeting multiple targets. Therefore, better understanding the underlying mechanism of miRNA in carcinogenesis may improve diagnostic and therapeutic strategies for malignancy. In our study, we found that mir-765 is upregulated in both hepatocellular carcinoma (HCC) cell lines and tissues, compared to human normal liver cell line and adjacent non-cancerous tissues, respectively. Overexpression of mir-765 increased HCC cells proliferation and tumorigenicity, whereas inhibition of mir-765 reverses this effect. Furthermore, we demonstrated that INPP4B as a direct target of mir-765 and ectopic expression of mir-765 repressed INPP4B expression, resulting in upregulation of p-AKT, Cyclin D1, and downregulation of p-FOXO3a, p21 expression in HCC. Strikingly, we found that silencing the expression of INPP4B is the essential biological function of miR-765 during HCC cell proliferation. Collectively, our findings reveal that miR-765 is a potential onco-miR that participates in carcinogenesis of human HCC by suppressing INPP4B expression, and might represent a potential therapeutic target for HCC patients.

Target lesion response predicts survival of patients with hepatocellular carcinoma retreated with transarterial chemoembolization.

BACKGROUND & AIMS: The discontinuation rules of transarterial chemoembolization (TACE) for patients who were assessed as progressive disease (PD) but stage progression-free (SP-free: still belongs to Barcelona Clinic Liver Cancer B) after TACE are unclear. We aimed to evaluate the impact of the PD-pattern on the survival of these patients retreated with TACE. METHODS: In total, 115 consecutive patients who were assessed as PD but SP-free after TACE and then underwent at least one subsequent TACE session were included. Sixty patients were assessed as PD with target lesion progression (TP), and 55 patients were assessed as PD with target lesion non-progression (TNP). Survival and treatment-related adverse events were compared between the two groups. Additional external validation was performed using a data set (n = 103) from another institution. RESULTS: Patients with TNP had significantly longer median post-progression survival (PPS) than those with TP (21.0 vs. 11.9 months, P = 0.004). After TACE retreatment, the incidence of liver dysfunction was significantly higher for patients with TP than for patients with TNP (45% vs. 20%, P = 0.031). In the multivariate analysis, the target lesion response was one of the most significant prognostic factors for PPS (HR = 2.01; 95% confidence interval: 1.23-3.27; P = 0.005). The findings were supported by an independent external cohort. CONCLUSIONS: Compared to patients with TNP, patients with TP might exhibit no improvement in survival and even present damaged liver function after retreatment with TACE. Target lesion response is useful as a clinical decision for repeated TACE in these patients.

MiR-1180 promotes apoptotic resistance to human hepatocellular carcinoma via activation of NF-κB signaling pathway.

Apoptosis resistance in human hepatocellular carcinoma (HCC) is a significant factor in carcinogenesis. Therefore, understanding the molecular mechanisms involved in apoptosis resistance is crucial for developing anticancer therapies. Importantly, small non-coding microRNAs (miRNAs) have been reported as key biomarkers for detecting tumour onset and progression. In the present study, we demonstrate that miR-1180 is upregulated in HCC. Ectopic expression of miR-1180 has an anti-apoptotic effect in HCC, while miR-1180 inhibition increases cell apoptosis, both in vitro and in vivo. Moreover, our results show that miR-1180 directly targets key inhibitors of the nuclear factor (NF)-κB signaling pathway (i.e., OTUD7B and TNIP2) and the pro-apoptotic Bcl-2 associated death promoter (BAD) protein by post-transcriptional downregulation. Therefore, the anti-apoptotic function of miR-1180 in HCC may occur through NF-κB pathway activation via downregulation of its negative regulators. In conclusion, our study reveals the critical role of miR-1180 during apoptosis resistance in HCC.

DDR2 facilitates hepatocellular carcinoma invasion and metastasis via activating ERK signaling and stabilizing SNAIL1.

BACKGROUND: Several studies have found that DDR2 is up-regulated in many tumor types and facilitates tumor progression. However, the role of DDR2 in hepatocellular carcinoma (HCC) progression and its downstream signaling pathways remain unclear. METHODS: DDR2 expression was assessed in several cell lines and 112 pairs of HCC and matched adjacent noncancerous liver tissues. Clinical significance of DDR2 in HCC was analyzed. Phosphorylated DDR2 (p-DDR2) expression was detected by immunoblotting to evaluate its correlation with DDR2. The effect of DDR2 on HCC cell migration and invasion were examined. Cycloheximide chase experiments were performed to detect the half-life of SNAIL1. Moreover, DDR2 expression was detected by immunohistochemistry to evaluate its correlation with SNAIL1. The regulatory effect of DDR2 on ERK signaling, SNAIL1, EMT, MT1-MMP and MMP2 was confirmed by immunoblotting. The effect of type I collagen on DDR2/ERK2/SNAIL1 signaling was assessed. RESULTS: DDR2 was more highly expressed in HCC than in non-HCC tissues. DDR2 overexpression was correlated with clinicopathological features of poor prognosis. Clinical analysis revealed that DDR2 is an independent prognostic marker for predicting overall survival and disease free survival of HCC patients. Overexpression of DDR2 is associated with p-DDR2 amplification. In vitro studies showed that DDR2 facilitates HCC cell invasion, migration and EMT via activating ERK2 and stabilizing SNAIL1. DDR2 can up-regulate MT1-MMP and MMP2 expression through ERK2/SNAIL1 signaling in HCC. Additionally, collagen I can induce DDR2/ERK2/SNAIL1 signaling activation in HCC cells. CONCLUSIONS: Our findings suggest that DDR2 plays an important role in promoting HCC cell invasion and migration, and may serve as a novel therapeutic target in HCC.

Establishment of a new animal model for ischemic lumbar vertebrae.

Degeneration and ischemia of lumbar intervertebral disc has become a more and more important issue for elder people. However the mechanism for this is still known, largely due to a lack of a suitable animal model. In this study, we constructed a new animal model for the study of ischemic lumbar vertebrae. 42 New Zealand white rabbits were chosen for the study. For each rabbit, two vertebrae were used. L5 was set as the experimental group and L4 was set as the control group. Percutaneous lumbar puncture needles were applied in vertebrae adjacent to endplate for L5 and L4. For L4 1 ml saline was injected and for L5 1 ml pingyangmycin (2 mg/mL) was used. 1, 2, 3, 4, 5 weeks; 2 and 3 months after surgery, 6 rabbits at each time point were randomly chosen and underwent MRI, pathological test. The results in L5 and L4 were compared. Another 6 rabbits were used for DSA (Digital Subtraction Angiography) and vascular cast to study the length and diameters of the branches of lumbar artery. It was identified that since the third week, slightly hyperintense signal on T2-weighted image (T2WI) and fat-suppression T2-weighted image (FS T2WI) were detected. Lumbar vertebrae damage could be identified since the fourth week. Results of MRI and the size of pathological area were positively related (r=0.965, P<0.05). DSA and vascular cast could both clearly show the third level branches of lumbar artery. Our study suggested that injection of pingyangmycin via percutaneous lumbar needle could successfully induce ischemia in lumbar endplate. This method had little trauma, required a simple operation process and is highly repetitive. Besides, by vascular cast, the most important source of blood supply is the media branch of the lumbar artery. This branch could be a new therapy pathway for the degeneration of lumbar vertebrae.

PSCA s2294008 C>T and rs2976392 G>A polymorphisms contribute to cancer susceptibility: evidence from published studies.

PSCA gene plays an important role in cell adhesion, proliferation and survival. Increasing studies have focused on the association of PSCA gene rs2294008 C>T and rs2976392 G>A with cancer risk. However, the conclusions were inconsistent. Therefore, we performed a meta-analysis to elucidate whether there is a true association, or artifact. We systematically searched eligible studies from MEDLINE, EMBASE and CBM database. Odds ratios and 95% confidence intervals were used to evaluate the strength of the association. The final analysis included 32 studies consisting of 30028 cases and 38765 controls for the rs2294008 C>T polymorphism, and 14 studies with 8190 cases and 7176 controls for the rs2976392 G>A polymorphism. Consequently, the PSCA rs2294008 C>T polymorphism was significantly associated with increased overall cancer risk. Further stratifications indicated the increased risk was more pronounced for gastric (diffused type and non-gastric cardia adenocarcinoma) and bladder cancer. A similar association was observed for the rs2976392 G>A polymorphism. This meta-analysis demonstrated that both of the PSCA rs2294008 C>T and rs2976392 G>A polymorphisms are associated with increased cancer risk, especially for gastric cancer and bladder cancer. Further large-scale studies with different ethnicities and subtypes of gastric cancer are required to confirm the results from this meta-analysis.

A novel role for microRNA-129-5p in inhibiting ovarian cancer cell proliferation and survival via direct suppression of transcriptional co-activators YAP and TAZ.

Transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key oncogenes in mammalian cells. Activities of YAP and TAZ are largely restricted by the Hippo tumor suppressor pathway through phosphorylation-ubiquitination mechanisms. The involvement of microRNA in cancer progression has recently been reported, though whether they have a role in activating YAP and TAZ in human cancer cells remains unclear. Here, we report a microRNA, miR-129-5p, directly represses YAP and TAZ expression, leading to the inactivation of TEA domain (TEAD) transcription, and the downregulation of Hippo downstream genes, connective tissue growth factor (CTGF) and Cyclin A. Furthermore, we reveal miR-129-5p inhibits ovarian cancer cell proliferation, survival and tumorigenicity, and that downregulation of miR-129-5p in ovarian cancer cells highly correlates with malignant progression and poor survival. Hence, we demonstrate a novel mechanism for YAP and TAZ activation in cancers, indicating not only a potentially pivotal role for miR-129-5p in the progression of ovarian cancer, but also offering new therapeutic strategies to circumvent the disease.

[Expression of SOX2 in cervical intraepithelial neoplasia and cervical cancer and its clinical significance].

OBJECTIVE: To investigate the expression of SOX2 in cervical intraepithelial neoplasia (CIN) and cervical cancer and explore its association with the clinical features. METHODS: SOX2 expressions were examined using immunohistochemical method in 10 normal cervical tissue specimens, 36 cervical intraepithelial neoplasia specimens (including 10 cases of grade I, 12 of grade II, and 14 grade III) and 40 cervical cancer specimens (including 21 cases of stage I and 19 of stage II). The correlation between the immunohistochemical results and the clinical features of the patients was analyzed. RESULTS: SOX2 expression was negative in normal cervical tissues, and was positive in 41.6% of CIN specimens (10.0% in CIN I, 41.7% in CIN II, and 64.3% in CIN III) in 82.5% of cervical cancer specimens (78.2% in stage I and 88.2% in stage II). The patients with cervical cancer had a significantly higher positivity rate of SOX2 than normal control group (P<0.05). The positivity rate of SOX2 increased with the evolution of cervical disease. SOX2 protein expression was significantly correlated with the histological grade and lymph node metastasis (P<0.05), but not with the age or clinical stage of the patients (P<0.05). CONCLUSION: SOX2 expression may serve as a useful indicator for evaluating metastasis and malignancy of cervical cancer.

Clinical significance of microRNA expressions in diagnosing uterine cancer and predicting lymph node metastasis.

Recently, accumulating lines of evidence have demonstrated the association between microRNA (miRNAs) expression and uterine cancer, indicating that they may serve as promising novel biomarkers for uterine cancer. Therefore, we conducted this study to systematically evaluate the diagnostic accuracy of miRNAs in discriminating the uterine cancer patients from controls and further to determine their diagnostic values in lymph node metastasis (LNM) prediction. The pooled sensitivity, specificity, and other parameters, together with summary receiver operating characteristic (SROC) curve were used to assess the overall test performance. All statistical analyses were conducted using STATA 12.0 software. A total of nine articles were included in this meta-analysis. As for the accuracy of miRNAs in differentiating uterine cancer from controls, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under curve (AUC) were 0.84, 0.83, 4.8, 0.19, 25, and 0.90, respectively. As for the diagnostic accuracy of miRNAs in differentiating patients with LNM from those without LNM, the pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.75, 0.78, 3.5, 0.32, 011, and 0.83, respectively. In addition, subgroup analyses based on miRNA profiles suggested that multiple-miRNA assay displayed much better accuracy than single-miRNA assay, with an excellent AUC of 0.98 (92% sensitivity and 96% specificity). The high accuracy of multiple-miRNA assay, together with the application of miRNAs in LNM prediction, suggested that miRNAs may serve as non-invasive diagnostic markers of uterine cancer and further improve the comprehensive management of patients with uterine cancer. However, further larger studies are needed to confirm our findings.

miR-451 inhibits cell proliferation in human hepatocellular carcinoma through direct suppression of IKK-ß.

It has been demonstrated that nuclear factor-kappa B (NF-κB), which is overactivated in hepatocellular carcinoma (HCC), plays important roles in the development of HCC. Recently, a group of dysregulated micro RNAs were reported to be involved in HCC progression. Further understanding of micro RNA-mediated regulation of NF-κB pathway may provide novel therapeutic targets for HCC. In this study, we found that miR-451 expression was markedly downregulated in HCC cells and tissues compared with immortalized normal liver epithelial cells and adjacent non- cancerous tissues, respectively. Upregulation of miR-451 inhibited, while downregulation of miR-451 promoted, the tumorigenicity of HCC cells both in vitro and in vivo. These changes in the properties of HCC cells were associated with deregulation of two well-known cellular G1/S transitional regulators, cyclin D1 and c-Myc, which are downstream targets of NF-κB pathway. Furthermore, we demonstrated that miR-451 upregulation led to downregulation of cyclin D1 and c-Myc through inhibition of NF-κB pathway initiated by direct targeting of the IKBKB 3'-untranslated region. Therefore, these results suggest that miR-451 downregulation plays an important role in promoting proliferation of HCC cells and may provide the basis for the development of novel anti-HCC therapies.