M6A-modified lncRNA FAM83H-AS1 promotes colorectal cancer progression through PTBP1.

LncRNA plays a crucial role in cancer progression and targeting, but it has been difficult to identify the critical lncRNAs involved in colorectal cancer (CRC) progression. We identified FAM83H-AS1 as a tumor-promoting associated lncRNA using 21 pairs of stage IV CRC tissues and adjacent normal tissues. In vitro and in vivo experiments revealed that knockdown of FAM83H-AS1 in CRC cells inhibited tumor proliferation and metastasis, and vice versa. M6A modification is critical for FAM83H-AS1 RNA stability through the writer METTL3 and the readers IGF2BP2/IGFBP3. PTBP1-an RNA binding protein-is responsible for the FAM83H-AS1 function in CRC. T4 (1770-2440 nt) and T5 (2440-2743 nt) on exon 4 of FAM83H-AS1 provide a platform for PTBP1 RRM2 interactions. Our results demonstrated that m6A modification dysregulated the FAM83H-AS1 oncogenic role by phosphorylated PTBP1 on its RNA splicing effect. In patient-derived xenograft models, ASO-FAM83H-AS1 significantly suppressed the growth of gastrointestinal (GI) tumors, not only CRC but also GC and ESCC. The combination of ASO-FAM83H-AS1 and oxaliplatin/cisplatin significantly suppressed tumor growth compared with treatment with either agent alone. Notably, there was pathological complete response in all these three GI cancers. Our findings suggest that FAM83H-AS1 targeted therapy would benefit patients primarily receiving platinum-based therapy in GI cancers.

Epstein-Barr virus-based prognostic model in nodular sclerosis classic Hodgkin lymphoma.

The role of Epstein-Barr virus (EBV) in lymphoma cells of nodular sclerosis classic Hodgkin lymphoma (NScHL) is controversial. Our aim was to explore this and establish a clinically feasible model for risk stratification. We interrogated data from 542 consecutive subjects with NScHL receiving ABVD therapy and demonstrated EBV-infection in their lymphoma cells with EBV-encoded small RNAs (EBERs) in situ hybridization. Subjects were divided into training and validation datasets. As data from the training dataset suggested EBERs-positivity was the only independent prognostic factor for both progression-free survival (PFS) and overall survival (OS), we developed corresponding prognostic models based on it. Our models showed excellent performance in both training and validation cohort. These data indicate the close association of EBV infection and the outcomes of persons with NScHL receiving ABVD. Additionally, our newly developed models should help physicians estimate prognosis and select individualized therapy.

MYC-Activated LncRNA MNX1-AS1 Promotes the Progression of Colorectal Cancer by Stabilizing YB1.

Long noncoding RNAs (lncRNA) are involved in tumorigenesis and drug resistance. However, the roles and underlying mechanisms of lncRNAs in colorectal cancer are still unknown. In this work, through transcriptomic profiling analysis of 21 paired tumor and normal samples, we identified a novel colorectal cancer-related lncRNA, MNX1-AS1. MNX1-AS1 expression was significantly upregulated in colorectal cancer and associated with poor prognosis. In vitro and in vivo gain- and loss-of-function experiments showed that MNX1-AS1 promotes the proliferation of colorectal cancer cells. MNX1-AS1 bound to and activated Y-box-binding protein 1 (YB1), a multifunctional RNA/DNA-binding protein, and prevented its ubiquitination and degradation. A marked overlap between genes that are differentially expressed in MNX1-AS1 knockdown cells and transcriptional targets of YB1 was observed. YB1 knockdown mimicked the loss of viability phenotype observed upon depletion of MNX1-AS1. In addition, MYC bound the promoter of the MNX1-AS1 locus and activated its transcription. In vivo experiments showed that ASO inhibited MNX1-AS1, which suppressed the proliferation of colorectal cancer cells in both cell-based and patient-derived xenograft models. Collectively, these findings suggest that the MYC-MNX1-AS1-YB1 axis might serve as a potential biomarker and therapeutic target in colorectal cancer. SIGNIFICANCE: This study highlights the discovery of a novel colorectal cancer biomarker and therapeutic target, MNX1-AS1, a long noncoding RNA that drives proliferation via a MYC/MNX1-AS1/YB1 signaling pathway. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2636/F1.large.jpg.

Trimethylamine N-Oxide increases soluble fms-like tyrosine Kinase-1 in human placenta via NADPH oxidase dependent ROS accumulation.

BACKGROUNDS: Preeclampsia (PE) is characterized as placental vascular disturbance and excessive secretion of soluble fms-like tyrosine kinase 1 (sFlt-1) into the maternal circulation. Trimethylamine N-oxide (TMAO, a gut microbe-derived metabolite) is strongly associated with various cardiovascular and cerebrovascular diseases. Recently, we observe that higher maternal circulating TMAO and sFlt-1 in patients with PE. The aims of the present study are to explore the effects of TMAO on placental sFlt-1 production and the underlying mechanism in human placenta. METHODS: Human placental explants, human placental primary trophoblasts and the extravillous trophoblasts (EVT) cell line (HRT-8/SVneo) were exposured to various concentrations of TMAO (100, 150, 300, and 600 µM). The mRNA expression and protein secretion of sFlt-1 in placental explants, primary trophoblasts and HRT-8/SVneo cells were determined with qPCR and ELISA, respectively. The levels of intracellular reactive oxygen species (ROS) production in primary trophoblasts and HRT-8/SVneo cells were measured by peroxide-sensitive fluorescent probe dichlorofluorescein diacetate. RESULTS: Exposure of placental explants, primary trophoblasts and HRT-8/SVneo cells to TMAO significantly enhanced sFlt-1 at both mRNA and protein levels in a dose dependent manner. Moreover, inhibition of NADPH oxidase with apocynin significantly attenuated TMAO-induced ROS production in primary trophoblasts and HRT-8/SVneo, and suppressed sFlt-1 secretion in placental explants, primary trophoblasts and HRT-8/SVneo. CONCLUSIONS: Our findings indicated the NADPH oxidase dependent ROS pathway played a critical role in mediating TMAO-induced sFlt-1 generation in human placenta. TMAO may become a potential novel target for pharmacological or dietary interventions to reduce the risk of developing PE.

Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes.

We performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes. Integrative comparison of cHCC-ICC with hepatocellular carcinoma and intrahepatic cholangiocarcinoma revealed that combined and mixed type cHCC-ICCs are distinct subtypes with different clinical and molecular features. Integrating laser microdissection, cancer cell fraction analysis, and single nucleus sequencing, we revealed both mono- and multiclonal origins in the separate type cHCC-ICCs, whereas combined and mixed type cHCC-ICCs were all monoclonal origin. Notably, cHCC-ICCs showed significantly higher expression of Nestin, suggesting Nestin may serve as a biomarker for diagnosing cHCC-ICC. Our results provide important biological and clinical insights into cHCC-ICC.

Prognostic Value of Lymphocyte Activation Gene-3 (LAG-3) Expression in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor with a high incidence in East Asia and the Middle East. The outcomes for ESCC patients are usually not optimal due to the recurrence and metastasis. This study is aim to examine the expression and the prognostic value of LAG-3 in ESCC. We applied immunohistochemistry analysis to examine the expression of LAG-3, CD4 and CD8 in 287 ESCC cohorts. Our study demonstrated that the decreased LAG-3 expression was significantly associated with CD4 tumor-infiltrated lymphocytes (TILs) (p=0.000), CD8 TILs (p=0.000), and the advanced clinical stages (p=0.041) by Chi-square analysis. Kaplan-Meier survival analysis revealed that higher LAG-3 expression were positively correlated with a better overall survival (OS) (p=0.010) and better progression free survival (PFS) (p=0.006), especially in the patients at stages T1-2 status (p=0.001, OS; p=0.001, PFS), N0 status (p=0.036, OS; p=0.050, PFS), and early stages (I-II) (p=0.006, OS; p=0.008, PFS). Both high of CD4 TIL /CD8 TIL ratio and LAG-3 expression were correlated with longer OS and PFS. Cox proportional hazards regression analysis showed that LAG-3 is an independent biomarker of survival (HR, 0.724; 95% CI 0.526-0.995; p = 0.047) (p=0.036). Taken together, we found that high expression of LAG-3 was correlated with an improved survival and LAG-3 is an independent predictor of survival, suggesting that LAG-3 may serve as a useful immune marker for the prognosis of ESCC.

RIT1 suppresses esophageal squamous cell carcinoma growth and metastasis and predicts good prognosis.

Ras-like without CAAX1 (RIT1) protein is a member of Ras family, which plays critical roles in signaling pathways and cellular process regulation. However, the role of RIT1 in esophageal squamous cell carcinoma (ESCC) is unclear. In this study, we found that the expression of RIT1 is downregulated in ESCC compared to corresponding non-tumor tissues. The low-level expression of RIT1 was correlated with poorer prognosis. Then we showed that RIT1 inhibited proliferation, invasion, and migration of ESCC cells, and silencing RIT1 by shRNA promoted tumorigenicity and metastasis in nude mice. We further demonstrated that RIT1 inhibited the malignant behaviors of ESCC through inhibiting the PI3K/AKT and MAPK pathway and epithelial-mesenchymal transition in ESCC cells. Our study also revealed that RIT1 increased drug sensitivity to cisplatin (CDDP), and this function could be carried out through downregulating stemness of ESCC. In conclusion, our study indicates for the first time that RIT1 displays tumor-suppressing functions in ESCC, and these functions were carried out by inhibiting MAPK and PI3K/AKT signaling pathway, inhibiting EMT, and downregulating cancer stemness of ESCC cells.

Pharmacological inhibition of DUSP6 suppresses gastric cancer growth and metastasis and overcomes cisplatin resistance.

Gastric cancer (GC) is the second cause of cancer-related death. Cisplatin (CDDP) is widely used as the standard GC treatment, but relapse and metastasis are common because of intrinsic or acquired drug resistance. The mitogen-activated protein kinase phosphatases (MAPK)-extracellular signal regulated kinases (ERK) pathway contributes to GC progression and drug resistance, but targeting the MAPK-ERK pathway is challenging in GC therapy. Here, we demonstrated that dual-specificity phosphatases 6 (DUSP6) was overexpressed in GC and predicted poor overall survival and progression-free survival. Knockdown DUSP6 inhibited GC proliferation, migration, invasion and induced apoptosis. (E/Z)-BCI hydrochloride (BCI), a DUSP6 small molecule inhibitor, increased the activity of ERK but interestingly decreased the expression of ERK response genes in BGC823, SGC7901 and CDDP-resistant SGC7901/DDP cells. BCI also caused cell death through the DNA damage response (DDR) pathway. Moreover, BCI inhibited cell proliferation, migration and invasion in a receptor-independent manner and enhanced CDDP cytotoxicity at pharmacological concentrations in the GC cells. In vivo experiments further showed that BCI enhances the antitumor effects of CDDP in cell-based xenografts and PDX models. In summary, our findings indicated that disruption of DUSP6 by BCI enhanced CDDP-induced cell death and apoptosis in GC may partly through ERK and DDR pathways. Thus, this study suggests that DUSP6 is a potential prognostic biomarker and a promising target for GC therapy.

Genomic comparison of esophageal squamous cell carcinoma and its precursor lesions by multi-region whole-exome sequencing.

Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC); however, the genetic evolution from dysplasia to ESCC remains poorly understood. Here, we applied multi-region whole-exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported in ESCC. Moreover, dysplasia is polyclonal, and remarkable heterogeneity is often observed between tumors and their neighboring dysplasia samples. Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma. The sharp contrast in the prevalence of the 'two-hit' event on TP53 between the two cohorts suggests that the complete inactivation of TP53 is essential in promoting the development of ESCC.The pathogenesis of oesophageal squamous cell carcinoma is a multi-step process but the genetic determinants behind this progression are unknown. Here the authors use multi-region exome sequencing to comprehensively investigate the genetic evolution of precursor dysplastic lesions and untransformed oesophagus.

[Expectant therapy versus curettage for retained products of conception after second trimester termination of pregnancy: analysis of outcomes and complications].

OBJECTIVE: To evaluate the prognosis and complications of expectant therapy and curettage for retained product of conception (RPOC) after second trimester termination of pregnancy (TOP). METHODS: A total of 270 patients with RPOC following second trimester TOP in Nanfang Hospital between January, 2014 and December, 2015 were included in this study. The duration of vaginal bleeding time and menstruation recovery interval were compared between patients receiving expectant therapy and curettage for RPOC, and binary logistic regression was used to assess the risk factors for complications in bivariate and multivariate analyses. RESULTS: The duration of vaginal bleeding time was significantly longer in expectant therapy group than in curettage group (P=0.005), while the menstruation recovery interval did not differ significantly between the two groups. The incidence of vaginal bleeding time for over 42 days was significantly higher in curettage group than in expectant therapy group (P=0.040), and the incidence of a menstruation recovery interval beyond 60 days was comparable between them. The incidence of complications was significantly higher in curettage group than in expectant therapy group either with adjustment of age, gravidity, parity, history of uterine surgery status, gestational age, type of indications, regimens for TOP and induction-abortion interval (OR=18.26 [95% CI: 3.57-93.42], P<0.001) or without adjustment (OR=10.60, [95% CI: 2.36-47.66], P=0.002). CONCLUSION: Expectant therapy and curettage for RPOC after second trimester TOP have comparable prognosis, but curettage is associated with a significantly higher rate of complications.

Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Ovarian Cancer: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND AND AIMS: Published data on the prognostic role of neutrophil-to-lymphocyte ratio (NLR) in ovarian cancer are controversial. We conducted this meta-analysis to obtain a more accurate assessment of prognostic significance of NLR in ovarian cancer. MATERIALS AND METHODS: We conducted a systematic literature search using the electronic databases PubMed, Web of Science, and Embase up to May 2016. Hazard ratio (HR) and odd ratio (OR) with 95% confidence interval (95% CI) were calculated. Subgroup analyses were carried out to explore the source of heterogeneity. Statistical analysis was performed using Stata 10.0. RESULTS: A total of 12 studies, consisting of 3,854 patients, which met our criterion were selected in this meta-analysis. Our pooled results showed that high pre-treatment NLR level was significantly associated with poorer overall survival (OS) (HR: 1.69, 95% CI 1.29-2.22) and shorter progression free survival (PFS) (HR 1.63, 95% CI 1.27-2.09). Additionally, increased NLR was also significantly correlated with advanced FIGO stage (OR 2.32, 95% CI1.79-3.00), higher serum level of CA-125 (OR 3.33, 95% CI 2.43-4.58), more extensive ascites (OR 3.54, 95% CI 2.31-5.42) as well as less chemotheraputic response (OR 0.53, 95% CI 0.40-0.70). The findings from most of subgroup meta-analyses were consistent with those from the overall meta-analyses. CONCLUSIONS: Elevated pre-treatment NLR could served as a predicative factor of poor prognosis for ovarian cancer patients.

Prognostic significance of neutrophil-to-lymphocyte ratio in cervical cancer: A systematic review and meta-analysis of observational studies.

BACKGROUND AND AIMS: The prognostic role of neutrophil-to-lymphocyte ratio (NLR) in cervical cancer are controversial. We conducted this meta-analysis to obtain a more accurate assessment of prognostic significance of NLR in cervical cancer. RESULTS: A total of 9 studies, consisting of 2,804 patients, were selected in this meta-analysis. Our pooled results showed that high pre-treatment NLR level was significantly associated with poorer overall survival (HR: 1.88, 95% CI 1.30-2.73) and shorter progression free survival (HR 1.65, 95% CI 1.18-2.29). Additionally, increased NLR was also significantly correlated with tumor size (OR 2.05, 95% CI 1.14-3.65), advanced FIGO stage (OR 2.12, 95% CI1.28-3.49) and lymph node involvement (OR 2.24, 95% CI 1.65-3.04). MATERIALS AND METHODS: We conducted a systematic literature search using the electronic databases PubMed, Web of Science, and Embase up to May 2016.Statistical analysis was performed using Stata 10.0. CONCLUSIONS: Elevated pretreatment NLR could serve as a predicative factor of poor prognosis for cervical cancer patients.

Responses to Crizotinib therapy in five patients with non-small-cell lung cancer who tested FISH negative and Ventana immunohistochemistry positive for ALK fusions.

AIM: Although immunohistochemistry (IHC) and reverse transcription-PCR can detect ALK rearrangements, the ALK break-apart FISH assay is currently considered the standard method. MATERIALS & METHODS: Five patients with advanced non-small-cell lung cancer, who had an ALK-negative FISH result that was later confirmed as positive by the Ventana IHC assay, were studied. Four had previously received chemotherapy or radiotherapy. All five were subsequently treated with Crizoitinib 250 mg twice daily. RESULTS & CONCLUSION: Four patients had a partial response to Crizotinib and one had stable disease. IHC is an efficient technique for diagnosing ALK rearrangements in patients with non-small-cell lung cancer, and may serve as an alternative to FISH in clinical practice.

Preterm Birth and Subsequent Risk of Acute Childhood Leukemia: a Meta-Analysis of Observational Studies.

BACKGROUND: Preterm birth (PTB) has been recognized as a crucial long term risk factor for multiple non-communicable diseases. However, studies between the relationship of PTB and the risk of acute childhood leukemia have yielded inconclusive results. Therefore, we performed a meta-analysis to systematically review the current literature to investigate whether PTB is associated with increased risk of acute childhood leukemia. METHODS: Three electronic databases (PubMed, Web of Science, and EMBASE) were searched up to December 1st, 2015. Relevant studies reporting the association between PTB and subsequent risk of acute childhood leukemia were included for further evaluation. Statistical analysis was performed using Revmen 5.3 and Stata 10.0. RESULTS: A total of 12 studies for acute childhood leukemia, eight studies for acute lymphoblastic leukemia (ALL), and seven studies for acute myeloid leukemia (AML) were included in the current meta-analyses. We calculated pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate the relationship between PTB and acute childhood leukemia as well as its two subtypes: ALL and AML. Our results suggested that PTB was significantly associated with increased risk of acute childhood leukemia (OR = 1.09, 95% CI = 1.02-1.17, P = 0.01) and AML (OR = 1.42, 95% CI = 1.21-1.67, P < 0.01). However, PTB was not significantly associated with an increased risk of ALL (OR = 1.04, 95% CI = 0.96-1.13, P = 0.29). CONCLUSION: Our data showed that PTB increased the risk of AML. Further studies are required to explore causality and dissect the biological mechanisms involved.

Maternal HCV infection is associated with intrauterine fetal growth disturbance: A meta-analysis of observational studies.

Since the evidence regarding the association between maternal hepatitis C virus (HCV) infection and impaired intrauterine fetal growth had not been conclusive, the aim of the present study was to evaluate the risk of maternal HCV infection in association with intrauterine fetal growth restriction (IUGR) and/or low birth weight infants (LBW). We performed an extensive literature search of PubMed, MEDLINE, and EMBASE through December 1, 2015. The odds ratios (ORs) of HCV infection and IUGR/LBW were calculated and reported with 95% confidence intervals (95% CIs). Statistical analysis was performed using RevMen 5.3 and Stata 10.0. Seven studies involving 4,185,414 participants and 5094 HCV infection cases were included. Significant associations between HCV infection and IUGR (OR = 1.53, 95% CI: 1.40-1.68, fixed effect model) as well as LBW were observed (OR = 1.97, 95% CI: 1.43-2.71, random effect model). The results still indicated consistencies after adjusting for multiple risk factors which could affect fetal growth, including maternal age, parity, maternal smoking, alcohol abuse, drugs abuse, coinfected with HBV/HIV and preeclampsia. Our findings suggested that maternal HCV infection was significantly associated with an increased risk of impaired intrauterine fetal growth. In clinical practice, a closer monitoring of intrauterine fetal growth by a series of ultrasound might be necessary for HCV-infected pregnant population.

[MiR-135b promotes proliferation of endometrial carcinoma cells by targeting FOXO1].

OBJECTIVE: To explore the expression of miR-135b in endometrial carcinoma and the mechanism by which miR-135b promotes the proliferation of endometrial cancer cells. METHODS: The expressions of miR-135b and FOXO1 were using RT-PCR detected in 22 fresh endometrial cancer tissues and paired adjacent tissues and also in endometrial cancer cell lines JEC, Ishikawa, HEC-1-B, and RL-952. The RL-952 and Ishikawa cell lines were transfected with miR-135b mimics or inhibitors, and the changes in their proliferative activity were detected with MTT assay; the expressions of FOXO1 mRNA and protein were detected by RT-PCR and Western blotting, respectively. RESULTS: The expression of miRNA135b was significantly up-regulated and FOXO1 expression was down-regulated in endometrial carcinoma tissues as compared with the adjacent tissues (P<0.05). The mRNA expression of miR-135b was negatively correlated with the expression of FOXO1 in endometrial carcinoma. In RL-952 and Ishikawa cell lines, transfection with miR-135b mimics obviously promoted the cell proliferation (P<0.05). Up-regulation of miR-135b significantly decreased the expressions of FOXO1 protein and mRNA (P<0.05), and down- regulation of miR-135b increased FOXO1 expressions (P<0.05). CONCLUSIONS: MiR-135b plays an important role in the occurrence and development of endometrial carcinoma partially by regulating its target gene FOXO1.

Activation of PAR-1/NADPH oxidase/ROS signaling pathways is crucial for the thrombin-induced sFlt-1 production in extravillous trophoblasts: possible involvement in the pathogenesis of preeclampsia.

BACKGROUNDS/AIMS: Preeclampsia was characterized by excessive thrombin generation in placentas and previous researches showed that thrombin could enhance soluble Fms-like tyrosine kinase 1 (sFlt-1) expression in first trimester trophoblasts. However, the detailed mechanism for the sFlt-1 over-production induced by thrombin was largely unknown. The purpose of this study was to explore the possible signaling pathway of thrombin-induced sFlt-1 production in extravillous trophoblasts (EVT). METHODS: An EVT cell line (HRT-8/SVneo) was treated with various concentrations of thrombin. The mRNA expression and protein secretion of sFlt-1 in EVT were detected with real-time polymerase chain reaction and ELISA, respectively. The levels of intracellular reactive oxygen species (ROS) production were determined by DCFH-DA. RESULTS: Exposure of EVT to thrombin induced increased intracellular ROS generation and overexpression of sFlt-1 at both mRNA and protein levels in a dose dependent manner. Short interfering RNA (siRNA) directed against PAR-1 or apocynin (an inhibitor of NADPH oxidase) could decrease the intracellular ROS generation and subsequently suppressed the production of sFlt-1 at mRNA and protein levels. CONCLUSIONS: Our results suggested that thrombin increased sFlt-1 production in EVT via the PAR-1 /NADPH oxidase /ROS signaling pathway. This also highlights the PAR-1 / NADPH oxidase / ROS pathway might be a potential therapeutic target for the prevention of preeclampsia in the future.

AOPPs (advanced oxidation protein products) promote apoptosis in trophoblastic cells through interference with NADPH oxidase signaling: implications for preeclampsia.

PURPOSE: To investigate the role of placental advanced oxidation protein products (AOPPs) in the pathogenesis of preeclampsia (PE). METHODS: Expression of AOPPs in human placental tissues collected from women with or without PE was examined by immunohistochemistry. The effect of AOPPs on in vitro trophoblast cell function was also examined. Specifically, we exposed trophoblastic cells to AOPPs and measured the production of human chorionic gonadotropin (hCG) as well as their invasion capacity using an in vitro Transwell invasion assay. We also investigated the effect of AOPPs on trophoblastic apoptosis and whether this effect could be mediated through interference in NADPH oxidase signaling. RESULTS: AOPPs were expressed in placental tissues, and were significantly increased in placentas from women with PE versus normotensive controls. AOPPs also affected trophoblast cell function in vitro by significantly reducing ß-HCG production and inhibiting trophoblas cell invasive capacity. Exposure to AOPPs significantly increased apoptosis in trophoblastic cells, which was mediated through the NADPH oxidase pathway. CONCLUSIONS: AOPPs expression is increased in PE placentas and exposure to AOPPs adversely affects trophoblast cell function, which may contribute to the shallow trophoblast invasion that characterizes this disorder. Additional studies are needed to investigate further to determine whether AOPPs can be used as a biomarker for PE.

Can HPV vaccine have other health benefits more than cancer prevention? A systematic review of association between cervical HPV infection and preterm birth.

Although the association between high-risk human papillomavirus (HPV) infection and cervical dysplasia as well as cervical cancer is well established, studies on the relationship between HPV infection and risk of preterm birth (PTB) have yielded inconclusive and inconsistent results. Therefore, we conducted a meta-analysis to investigate the association between HPV infection and PTB. The electronic database was searched until July 1, 2014. Relevant studies reporting the association between HPV infection and the risk of PTB were included and for further evaluation. Statistical analysis was performed using Revmen 5.3 and Stata 10.0. Six observational cohort studies and 2 case-control studies were included. A significant association between HPV infection and PTB was observed (odds ratio=2.12, 95% CI 1.51-2.98, P<0.001, random effect model). Stratification according to diagnostic methods indicated that both positive HPV DNA status and abnormal cervical cytology were associated with increased risk of PTB. Moreover, our data suggested a higher risk of PTB in Caucasian HPV-infected population, while no significant association was observed in the Asian population. Although the causality remains unclear, findings from our meta-analysis indicate that HPV infection might increase the risk of PTB. In the future, prospective cohorts with larger samples sizes are warranted to ascertain the causality and pathophysiological studies are required to explore the possible biological mechanisms involved.

Higher plasma AOPP is associated with increased proteinuria excretion and decreased glomerular filtration rate in pre-eclamptic women.

BACKGROUND: Advanced oxidation protein products (AOPP) as a novel biomarker of oxidative stress has been demonstrated in chronic kidney disease (CKD) patients. The research was to investigate the plasma AOPP level in pre-eclamptic pregnant women and its correlation with 24-h proteinuria collection, cystatin C(CC), uric acid(UA) and creatinine(Cr). METHODS: Fifty pre-eclamptic women, including 22 mild and 28 severe preeclampsia were enrolled. Twentyfive healthy singleton pregnant women were selected as control. Blood samples were obtained from all groups to measure the levels of AOPP, CC, UA, Cr and other biochemical parameters at admission. Total protein in the 24h urine collection was measured. Pearson correlation was performed to evaluate the associations between plasma AOPP level and 24-h proteinuria collection, plasma cystatin C, uric acid and creatinine. RESULTS: The means of AOPP levels were significantly different among severe, mild pre-eclampsia and normotensive pregnant women (88.6±10.0µmmol/L, 72.1±11.1µmmol/L and 48.7±11.3µmmol/L). The means of cystatin C levels were significantly different among severe, mild pre-eclampsia and normotensive pregnant women (1.8±0.6µmmol/L, 1.2±0.3µmmol/L and 1.0±0.2µmmol/L). Mild, severe pre-eclampsia and control groups did not differ significantly from each other with respect to uric acid and creatinine. Significant positive correlation between AOPP and 24-h proteinuria excretion in preeclamptic pregnant women was found in mild and severe preeclamptic pregnant women (r=0.792). Significant positive correlation between AOPP and cystatin C was found in normal and preeclamptic pregnant women (r=0.521). CONCLUSION: Plasma AOPP level had a significant positive correlation with 24-h proteinuria excretion and cystatin C. Further research about the relevance between the level of AOPP and the onset of preeclampsia was needed in order to have a profound prospective in oxidative stress and preeclampsia.