Early diagnosis of caesarean scar pregnancy by ultrasound - a novel, simple and rapid clinical classification scoring system.

AIM: In the recent years, with the increase in the caesarean section rate, the incidence of caesarean scar pregnancy (CSP) has shown a significant upwards trend. We propose a novel, simple and rapid clinical and ultrasound (US) classification scoring system to assist in the early diagnosis of CSP. MATERIAL AND METHODS: A total of 385 patients with CSP were included in the study. All patients were given a comprehensive score, iincluding clinical data (whether HCG is consistent with gestational age and vaginal bleeding) and US findings (linea a and b, gestational sac morphology, the presence of primitive cardiac tube beat, and color Doppler aspect). The scores were analysed by ROC curve analysis, and sensitivity and specificity were calculated. RESULTS: A score of 4 has a specificity of 91.7% and a sensitivity of 95.6% in diagnose CSP. The area under the ROC curve was 0.973. CONCLUSION: This scoring system may be a reliable tool for the early diagnosis of CSP and has the characteristics of being simple and rapid. For patients with a total score of ≥4 points, CSP is suggested, and early clinical treatment can be carried out, while patients with a score of less than 4 points can temporarily retain pregnancy and be closely followed up.

Salicylic acid regulates phenolic acid biosynthesis via SmNPR1-SmTGA2/SmNPR4 modules in Salvia miltiorrhiza.

Phenolic acids are the main active ingredients in Salvia miltiorrhiza, which can be used for the treatment of many diseases, particularly cardiovascular diseases. It is known that salicylic acid (SA) can enhance phenolic acid content, but the molecular mechanism of its regulation is still unclear. Nonexpresser of PR genes 1 (NPR1) plays a positive role in the SA signaling pathway. In this study, we identified a SmNPR1 gene that responds to SA induction and systematically investigated its function. We found that SmNPR1 positively affected phenolic acid biosynthesis. Then, we identified a novel TGA transcription factor, SmTGA2, which interacts with SmNPR1. SmTGA2 positively regulates phenolic acid biosynthesis by directly up-regulating SmCYP98A14 expression. After double-gene transgenic analysis and other biochemical assays, it was found that SmNPR1 and SmTGA2 work synergistically to regulate phenolic acid biosynthesis. In addition, SmNPR4 forms a heterodimer with SmNPR1 to inhibit the function of SmNPR1, and SA can alleviate this effect. Collectively, these findings elucidate the molecular mechanism underlying the regulation of phenolic acid biosynthesis by SmNPR1-SmTGA2/SmNPR4 modules and provide novel insights into the SA signaling pathway regulating plant secondary metabolism.

Efficacy of apatinib+radiotherapy vs radiotherapy alone in patients with advanced multiline therapy failure for non small cell lung cancer with brain metastasis.

OBJECTIVE: Lung cancer is the leading cause of cancer-associated mortality worldwide. Central nervous system (CNS) metastasis is a prevalent and serious complication. The most common treatment for brain metastasis (BM) is still radiation therapy (RT). An increasing number of drugs have been shown to have intracranial activity or to sensitize tumours to radiotherapy. METHODS: Consecutive advanced multiline therapy failure in patients with non-small-cell lung cancer (NSCLC) with BM at the authors' hospital were retrospectively reviewed. Eligible patients were divided into two groups: Apatinib+RT group and RT group. Intracranial progression-free survival (PFS) and overall survival (OS) were analysed using the Kaplan-Meier method. RESULTS: The median intracranial PFS for the RT group and Apatinib+RT group was 5.83 months and 11.81 months (p = 0.034). The median OS for the RT group and Apatinib+RT group was 9.02 months and 13.62 months (p = 0.311). The Apatinib+RT group had a better intracranial PFS, but there were no significant differences between the two arms in OS. The Apatinib+RT group had significantly reduced symptoms caused by BM. CONCLUSION: RT combined with apatinib could help to control intracranial metastases. The Apatinib+RT group had significantly reduced symptoms caused by BM and improved quality of life for patients, the safety of the two treatments was similar. ADVANCES IN KNOWLEDGE: Here, we propose that RT combined with apatinib can significantly relieve brain symptoms and tolerate side-effects without affecting OS in patients with BM following failure of multiline therapy for NSCLC. Of course, this paper is a retrospective origin study, and more powerful evidence is needed to demonstrate.

LIMS2 is Downregulated in Osteosarcoma and Inhibits Cell Growth and Migration.

Methods: GEO, GEPIA, and UALCAN databases were used to assess LIMS2 expression in OS. UALCAN and CCLE databases were applied to assess the methylation levels of LIMS2 in OS tissues and cells, which was verified in OS cells using the methylation specific PCR. The effects of LIMS2 on regulating OS cell growth, migration and invasion were determined by CCK-8, Edu staining, and transwell chambers, respectively. The role of LIMS2 in the activation of MAPK signaling was assessed using western blotting assay in OS cells. Results: LIMS2 expression was declined in OS tissues and cells, while its methylation level was increased. The low expression of LIMS2 was associated with shorter overall survival and disease-free survival. Overexpression of LIMS2 inhibited cell growth, migration, and invasion and decreased the levels of p-ERK/ERK, p-P38/P38, and p-JNK/JNK. Conclusion: LIMS2 expression was decreased in OS, which was associated with hypermethylation level and poor prognosis. LIMS2 overexpression inhibited OS cell growth and migration, which may be caused by the suppression of MAPK signaling.

Lipopolysaccharide Enhances Tanshinone Biosynthesis via a Ca2+-Dependent Manner in Salvia miltiorrhiza Hairy Roots.

Tanshinones, the major bioactive components in Salvia miltiorrhiza Bunge (Danshen), are synthesized via the mevalonic acid (MVA) pathway or the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway and the downstream biosynthesis pathway. In this study, the bacterial component lipopolysaccharide (LPS) was utilized as a novel elicitor to induce the wild type hairy roots of S. miltiorrhiza. HPLC analysis revealed that LPS treatment resulted in a significant accumulation of cryptotanshinone (CT) and dihydrotanshinone I (DTI). qRT-PCR analysis confirmed that biosynthesis genes such as SmAACT and SmHMGS from the MVA pathway, SmDXS and SmHDR from the MEP pathway, and SmCPS, SmKSL and SmCYP76AH1 from the downstream pathway were markedly upregulated by LPS in a time-dependent manner. Furthermore, transcription factors SmWRKY1 and SmWRKY2, which can activate the expression of SmDXR, SmDXS and SmCPS, were also increased by LPS. Since Ca2+ signaling is essential for the LPS-triggered immune response, Ca2+ channel blocker LaCl3 and CaM antagonist W-7 were used to investigate the role of Ca2+ signaling in tanshinone biosynthesis. HPLC analysis demonstrated that both LaCl3 and W-7 diminished LPS-induced tanshinone accumulation. The downstream biosynthesis genes including SmCPS and SmCYP76AH1 were especially regulated by Ca2+ signaling. To summarize, LPS enhances tanshinone biosynthesis through SmWRKY1- and SmWRKY2-regulated pathways relying on Ca2+ signaling. Ca2+ signal transduction plays a key role in regulating tanshinone biosynthesis in S. miltiorrhiza.

Clinical Value Of Apatinib As A Salvage Treatment In Patients With Chemo-Refractory Advanced Cervical Cancer.

PURPOSE: Apatinib is effective and safe for several advanced or metastatic cancers, but its therapeutic value in cervical cancer is still unknown. The aim of the study was to assess the therapeutic value of apatinib in patients with chemo-refractory advanced cervical cancer. PATIENTS AND METHODS: This was a retrospective study of patients with advanced cervical cancer treated with apatinib between April 2015 and December 2018 at the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Patients had to have failed at least 2 lines of chemotherapy prior to receiving apatinib. The clinical tumor response was evaluated after 4 weeks of apatinib treatment, and then every 8 weeks (two cycles). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events were evaluated. RESULTS: Twenty-five patients were included in this study. The median PFS was 5.8 months (95% CI, 4.65-6.95), and the median OS was 12.2 months (95% CI, 8.99-15.41). ORR was 48% and DCR was 96%. Complete response was not observed. The most common adverse events in this study (all grades) were hand-foot syndrome (48%), hypertension (20%), and mouth mucositis (20%). CONCLUSION: Apatinib monotherapy showed good therapeutic value with tolerable adverse events for patients with chemo-refractory advanced cervical cancer.

Therapeutic effect of whole brain radiotherapy on advanced NSCLC between EGFR TKI-naïve and TKI-resistant.

BACKGROUND: The development of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has dramatically improved the prognosis of patients with EGFR-mutant non-small-cell lung cancer (NSCLC). The purpose of this study is to investigate the clinical outcome with or without EGFR-TKI resistance before WBRT and the sequence between EGFT-TKIs and whole brain radiotherapy (WBRT) of EGFR-mutant NSCLC patients who developed multiple brain metastases (BMs). PATIENTS AND METHODS: Three hundred forty-four EGFR-mutant NSCLC patients with multiple BMs were reviewed. Enrolled patients were divided into TKI-naïve group and TKI-resistant group. The intracranial progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan-Meier method. RESULTS: For patients with multiple BMs treated by WBRT, the median intracranial PFS and OS were longer in the TKI-naïve group than those in the TKI-resistant group, but there were no statistically significant between two groups (Intracranial PFS: 7.7 vs. 5.4 months, p = 0.052; OS: 11.2 vs. 9.2 months, p = 0.106). For patients with Lung-molGPA 0-2, no significant differences in median intracranial PFS (6.2 vs. 5.2 months, p = 0.123) and OS (7.8 vs. 6.7 months, p = 0.514) between TKI-naïve and TKI-resistant groups. For patients with Lung-molGPA 2.5-4, intracranial PFS: 12.8 vs. 10.1 months; OS: 23.3 vs. 15.3 months. CONCLUSIONS: Our study found that there were no difference in intracranial PFS and OS in all patients between the two groups of TKI-naïve and TKI-resistant. But for patients in subgroup of Lung-molGPA 2.5-4, there were a better intracranial PFS and OS in TKI-naïve group.

The effect of the primary tumor location on the survival of colorectal cancer patients after radical surgery.

Background and Objectives: Colorectal cancer is one of the most common cancers and the leading cause of cancer-related death worldwide. The impact of the primary tumor location on the prognosis of patients with colorectal cancer has long been a concern, but studies have led to conflicting conclusions. Methods: In total, 465 colorectal cancer patients who received radical surgery were reviewed in this study. Enrolled patients were divided into two groups according to the tumor location. Disease-free survival (DFS) and overall survival (OS) were analyzed via the Kaplan-Meier method. A Cox regression model was employed to evaluate the independent prognostic factors for DFS and OS. Results: The right colorectal cancer (RCC) and left colorectal cancer (LCC) groups comprised 202 and 140 patients, respectively. Univariate and multivariate analyses revealed that the tumor location and TNM stage were independent predictors of DFS and OS. Subgroup analyses by stage demonstrated that there were significant differences in DFS and OS between patients with stage II and III RCC and LCC, but not for those with stage I colorectal cancer. Conclusions: Patients with stage II and III LCC had better survival than those with RCC. However, this improvement in DFS and OS was not observed in patients with stage I colorectal cancer.

Effects of renal denervation on blood-pressure response to hemorrhagic shock in spontaneously hypertensive rats.

PURPOSE: Renal denervation (RD) has been demonstrated to be an effective approach to reduce blood pressure for those with resistant hypertension. Yet, we aimed to explore the effect and possible mechanism of RD on blood-pressure response to hemorrhagic shock in spontaneously hypertensive rats. METHODS: A total of 48 male spontaneously hypertensive rats were randomized to three groups: study group, sham-operation group and control group. RD was achieved by cutting off renal nerves and swabbing phenol on it. Ten weeks after RD, 8 rats in each group were sacrificed to collect the kidney and heart tissues. The remaining rats were subjected to an operation to induce hemorrhagic shock which would lead to 40% loss of total blood volume, and observed for 120 min. The serum concentration of norepinephrine was measured before and three weeks after RD. RESULTS: The blood-pressure and norepinephrine levels were reduced significantly after RD (p < 0.05). Systolic blood pressure and diastolic blood pressure of the surgery group were higher than those in the sham and control groups at 15, 30 and 45 min after hemorrhagic shock (p < 0.05), while no significant difference was observed at 60, 90 and 120 min (p > 0.05). Additionally, the beta-1 adrenergic receptor (ß1-AR) in the study group was significantly higher than those in the other two groups (p < 0.05) after hemorrhagic shock. CONCLUSION: This study demonstrated that RD could to some extent improve blood-pressure response to hemorrhagic shock in an established model of severe hemorrhagic shock in spontaneously hypertensive rats. The mechanism might be associated with up-regulation of ß1-AR.

Induction chemotherapy plus concurrent chemoradiotherapy versus induction chemotherapy plus volumetric modulated arc therapy alone in the treatment of stage II-IVB nasopharyngeal carcinoma patients: a retrospective controlled study.

BACKGROUND: In the era of intensity-modulated radiotherapy (IMRT), the role of additional concurrent chemotherapy (CC) to radiotherapy (RT) after induction chemotherapy (IC) compared to IC followed by RT alone remains unclear for stage II-IVB nasopharyngeal carcinoma (NPC) patients. The aim of this study was to evaluate the efficacy and toxicities of IC/RT and IC/CCRT in the treatment of NPC with volumetric modulated arc therapy (VMAT). METHODS: From January 2012 to March 2016, a total of 217 NPC patients were retrospectively assessed. Of the 217 patients, 139 patients received IC followed by VMAT alone and 78 patients received IC plus CCRT. Overall survival (OS), progression-free survival (PFS) and toxicities were assessed. RESULTS: The 5-year OS, PFS rates were 57.5%, 41.8% and 47.8%, 38.4% for the IC/RT and IC/CCRT arms, respectively, without significant difference in survival between the two groups (both p > 0.05). Multivariate analysis indicated that treatment modality (IC/RT vs. IC/CCRT) was not an independent prognostic factor for OS or PFS. Grade 3-4 leukopenia/neutropenia (3.60% vs. 20.51%, p < 0.001), gastrointestinal disorder (nausea/vomiting/diarrhea, 2.16% vs. 41.03%, p < 0.001), mucositis (29.50% vs. 47.44%, p = 0.01) and xerostomia (34.53% vs. 48.72%, p = 0.04) were more frequent in the IC/ CCRT arm than in the IC/RT arm during VMAT. CONCLUSIONS: No significant difference in OS and PFS was observed between IC plus VMAT alone and IC/CCRT in the treatment of stage II-IVB NPC patients, however, more side effects were observed in the IC/CCRT arm.

DR1 activation reduces the proliferation of vascular smooth muscle cells by JNK/c-Jun dependent increasing of Prx3.

Vascular smooth muscle cells (VSMCs) proliferation is a key process in atherosclerosis. However, little is known about the underlying mechanisms, leading to a lack of effective therapy. This study was to investigate whether dopamine receptor 1 (DR1) is involved in the VSMCs proliferation and related mechanisms. A7r5 cells were treated with oxidized low-density lipoprotein (ox-LDL, 10, 20, 50, 100, 200 µg/mL) in the presence or absence of the SKF38393 (DR1agonist), SCH23390 (DR1antiagonist), SP600125 (JNK inhibitor), PD98059(ERK1/2 inhibitor) or NAC (ROS inhibitor). Cell proliferation and related signaling pathway were evaluated. The expression of DR1 was negatively correlated with increasing of cell proliferation caused by ox-LDL. Cell proliferation and ROS generation in response to ox-LDL were prevented by DR1 agonist or over-expression. The peroxiredoxins protein (Prx1, 2, 3, 5, 6) were increased in A7r5 cells treated with ox-LDL; however, only Prx3 dramatically increased after activation of DR1 compared with ox-LDL group, which is related to activation of JNK/c-Jun pathway. In addition, ERK is associated with the restraining effects of DR1 activation. DR1 activation inhibits VSMCs proliferation primarily by JNK/c-Jun dependent increasing of Prx3, suggesting DR1 a potential target for the prevention of vascular proliferation disease.

Evaluation of Tumor-Derived Exosomal miRNA as Potential Diagnostic Biomarkers for Early-Stage Non-Small Cell Lung Cancer Using Next-Generation Sequencing.

Purpose: To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non-small cell lung cancer (NSCLC).Experimental Design: Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals.Results: There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively.Conclusions: Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis. Clin Cancer Res; 23(17); 5311-9. ©2017 AACR.

Sulfiredoxin involved in the protection of peroxiredoxins against hyperoxidation in the early hyperglycaemia.

As a direct consequence of hyperglycaemia, the excessive generation of ROS is central to the pathogenesis of diabetic cardiomyopathy. We hypothesize that stimulation of high glucose (HG) results in an increased sulfiredoxin (Srx) expression, which regulates ROS signaling through reducing the hyperoxidized peroxiredoxins (Prxs). We show that hyperoxidized Prxs were initially reduced in the preliminary stage but then dramatically increased in advanced stage and these changes corresponded to a significant increase of Srx expression in the heart of diabetic rats. These time-dependent changes were also confirmed in neonatal cardiomyocytes and H9c2 cells treated with HG. Moreover, the reduction rate of hyperoxidized Prxs was greatly improved in the HG 24h group, which had an elevated expression of Srx. Our data also show that HG-induced AP1 activation and Srx expression were almost abolished by JNK inhibitor and N-acetylcysteine (NAC). In addition, siRNA-Srx suppressed HG-induced ANP and ß-MHC gene expression. These observations suggest that activation of AP1 induced by HG is important for the expression of Srx and the reduction of hyperoxidized Prxs in cardiomyocytes. This Srx induction maybe is the pivotal compensatory protection mechanism against oxidative stress in diabetes or hyperglycaemia. Most interestingly, hyperoxidized Prxs/Srx pathway may be involved in the cardiac hypertrophy signaling of diabetes.

[Effects and mechanisms of low concentration dopamine on hydrogen peroxide-induced apoptosis in cultured neonatal rat cardiomyocytes].

OBJECTIVE: To study the effects of low concentration dopamine(DA) on hydrogen peroxide-induced apoptosis in cultured rat cardiomyocytes as well as the possible molecular mechanisms. METHODS: Cultured neonatal rat cardiomyocytes were randomly divided into the following groups: control group (control), hydrogen peroxide group (H2O2), pretreated with low concentration dopamine ( DA + H2O2), dopamine receptor l(DR1) antagonist group (DR1 + DA + H2O2), dopamine receptor 2(DR2) antagonist group (DR2 + DA + H2O2). The cell apoptosis was then assessed by MTT and flow cytometry. The cellular ultrastructure changes were observed by transmission electron micro- scope. The activity of lactate dehydrogenase(LDH )and superoxide dismutase (SOD) in cell medium was analyzed by colorimetry. The protein expressions of Cytochrone c, Caspase 3 and Caspase 9 were obtained by Western blot. RESULTS: Compared with hydrogen peroxide group, low concentration dopamine(10 µmol/L) decreased the apoptosis rate and the expression of protein of apoptosis related protein, enhanced SOD activity, decreased LDH activity. DR1 antagonist SCH-23390 treatment inhibited dopamine induced cardiac protective effect. DR2 antagonist haloperido treatment had no changes compared with dopamine group. CONCLUSION: Above findings indicate that low concentration dopanine inhibits apoptosis induced by hydrogen peroxide in neonatal rat cardiomyocytes, which is partly associated with the activation of DR1.