Association between maternal gestation weight gain and preterm birth according to pre-pregnancy body mass index and HbA1c.

BACKGROUND: To investigate the association between gestational weight gain (GWG) and preterm birth (PTB) according to pre-pregnancy body mass index (pp-BMI) and glycated haemoglobin (HbA1c) within the normal range. METHODS: We conducted a population-based retrospective cohort study between July 2017 and January 2020 at Women's Hospital, Zhejiang University School of Medicine. Women were classified into three groups (inadequate GWG, appropriate GWG, and excessive GWG). In addition, women were divided into different subgroups according to pp-BMI and HbA1c. We estimated the odds ratios (OR) with 95% confidence intervals (CI) to assess the associations between GWG and the risk of PTB. Meanwhile, we adjusted for possible confounding factors, including maternal age, infant sex, family history of diabetes, education, pregnancy mode, delivery mode, parity, and gravidity. RESULTS: The study involved 23,699 pregnant women, of which 1124 (4.70%) were PTB. Women who had inadequate GWG were found to have a significantly higher risk of PTB compared to women with appropriate GWG. In contrast, women with excessive GWG had a reduced risk of PTB. Similarly, GWG and PTB had similar risk associations in the HbA1c and pp-BMI subgroups. Among women with pp-BMI <18.5 kg/m2, women with inadequate GWG had a significantly increased risk of PTB compared with women in the control group (HbA1c 4.6-5.0%, appropriate GWG), and the risk increased with increasing HbA1c levels. Similar results were observed in women with normal pp-BMI. CONCLUSIONS: There was a significant association between GWG and the risk of PTB, but the risk varied by pp-BMI and HbA1c levels. Reasonable weight gain during pregnancy is essential to prevent PTB. Furthermore, while HbA1c is within the normal range, the higher levels should be noticed.

Preterm birth (PTB) rates have recently increased in China, drawing increased attention from physicians and society. Even though various risk factors for PTB have been well known, risk factors for PTB still need to be explored. This study aimed to investigate the association between gestational weight gain (GWG) and preterm birth (PTB) according to pre-pregnancy body mass index (pp-BMI) and glycated haemoglobin (HbA1c) within the normal range. Our research revealed that the underweight (pp-BMI <18.5 kg/m²) and normal weight (pp-BMI 18.5­24.9 kg/m²) groups' risk of preterm birth increased with rising HbA1c levels when GWG was inadequate. Despite HbA1c within the normal range, higher levels of HbA1c should be considered. As a result, among women with inadequate GWG, high levels of HbA1c confer a higher risk of PTB, which could alert clinicians to carry out early intervention to prevent PTB.

Triglyceride-glucose index: A promising biomarker for predicting risks of adverse pregnancy outcomes in Hangzhou, China.

Introduction: The triglyceride-glucose (TyG) index has been recommended as an alternative indicator of insulin resistance (IR). However, the association between the TyG index and adverse pregnancy outcomes remains to be elucidated. Methods: The present retrospective study was conducted at Women's Hospital, Zhejiang University School of Medicine and involved a total of 8,514 participants. Maternal fasting lipid profiles and glucose concentrations were measured. Based on the TyG index, the participants were categorized into quartiles. Logistic regression analysis was used to calculate odds ratios (ORs) for each quartile with reference to the first quartile, while receiver operating characteristic (ROC) curve analysis, Hosmer-Lemeshow test, and calibration curve analysis were employed to evaluate the predictive ability of the TyG index for adverse pregnancy outcomes. Results: The TyG index was higher in patients with preeclampsia, preterm birth, and macrosomia. On univariate analysis, there was an increased risk of developing adverse pregnancy outcomes with increasing quartiles of the TyG. After adjusting for potential confounders in multivariable logistic regression analysis, a positive independent correlation was found between the TyG index and preeclampsia, preterm birth, and macrosomia. In ROC curve analysis for predicting the risks of preeclampsia, preterm birth, and macrosomia, the area under the curve (AUC) could reach 0.665, 0.588, and 0.606, respectively. These predictive models demonstrated good calibration (all P > 0.05). Conclusions: The TyG index showed a good predictive capacity for assessing the risk of adverse pregnancy outcomes, and it should receive sufficient clinical attention.

Predictive value of maternal serum placental growth factor levels for discordant fetal growth in twins: a retrospective cohort study.

BACKGROUND: Accurate prenatal recognition of discordant fetal growth in twins is critical for deciding suitable management strategies. We explored the predictive value of the level of maternal second-trimester placental growth factor (PLGF) as a novel indicator of discordant fetal growth. METHODS: A total of 860 women pregnant with twins were enrolled, including 168 women with monochorionic twins (31 cases of discordant fetal growth and 137 without) and 692 with dichorionic twins (79 cases of discordant fetal growth and 613 without). Maternal second-trimester PLGF concentrations were measured via immunofluorescence. RESULTS: Maternal second-trimester PLGF levels were significantly lower in women pregnant with twins who subsequently developed discordant fetal growth than in those who did not (monochorionic twin pregnancy: P < 0.001; dichorionic twin pregnancy: P < 0.001). A 3-4 fold difference in median PLGF concentrations was detected between the two groups with both monochorionic and dichorionic twin pregnancies. Maternal second-trimester PLGF levels were significantly correlated with birth weight differences (monochorionic twin pregnancy: r = - 0.331, P < 0.001; dichorionic twin pregnancy: r = - 0.234, P < 0.001). A receiver operating characteristic curve was used to evaluate the predictive efficiency. In monochorionic twin pregnancies, the area under the curve (AUC) was 0.751 (95% confidence interval [CI]: 0.649-0.852), and the cutoff value was 187.5 pg/mL with a sensitivity of 77.4% and specificity of 71.0%. In dichorionic twin pregnancies, the AUC was 0.716 (95% CI; 0.655-0.777), and the cutoff value was 252.5 pg/mL with a sensitivity of 65.1% and specificity of 69.6%. Based on the above cutoff values, univariate and multivariate logistic regression analyses were performed to calculate the odds ratios (OR) for the PLGF levels. After adjustment for potential confounding factors, low PLGF concentrations still significantly increased the risk of discordant fetal growth (monochorionic twin pregnancy: adjusted OR: 7.039, 95% CI: 2.798-17.710, P < 0.001; dichorionic twin pregnancy: adjusted OR: 4.279, 95% CI: 2.572-7.120, P < 0.001). CONCLUSIONS: A low maternal second-trimester PLGF level is considered a remarkable risk factor and potential predictor of discordant fetal growth. This finding provides a complementary screening strategy for the prediction of discordant fetal growth and offers a unique perspective for the subsequent research in this field.

Triglyceride-glucose index is a risk factor for breast cancer in China: a cross-sectional study.

BACKGROUND: This research delved into the association between the risk of the Chinese population suffering from breast cancer (BC) and the triglyceride-glucose (TyG) index. METHODS: A total of 2,111 sufferers with benign breast disease (BBD) and 477 sufferers with BC were enrolled, and their TyG index was measured. Participants with varying TyG index values were categorized into quartiles. Logistic regression analysis was employed to assess the relationship between the TyG index and BC risk. The diagnostic performance of the TyG index for different stages of BC was measured using the receiver operating characteristic (ROC) curve. RESULTS: The TyG index of BC sufferers exceeded that of BBD (P < 0.001). A continuous increase in the risk of BC was found to be positively correlated with an ever-increasing TyG index. In the unadjusted model, the risk of getting BC mounted with quartiles of the TyG index growing (P < 0.001). In a logistic regression analysis that included all confounders, the highest quartile of the TyG index was strongly linked to BC risk [1.43 (1.01, 2.02), P < 0.05]. Moreover, with the adjustment of potential confounders, a high TyG index was found to result in a 2.53-fold higher risk of being diagnosed with advanced BC. CONCLUSIONS: The risen TyG index was positively correlated to the heightening risk of BC and had the potential to serve as a promising biomarker for BC. Individuals with a high TyG index ought to be mindful of the heightened risk of BC onset and progression.

Maternal gestational weight gain and adverse pregnancy outcomes in non-diabetic women.

OBJECTIVE: This study investigated the relationship between maternal gestational weight gain (GWG) and the risk of adverse pregnancy outcomes in gestational diabetes mellitus (GDM)-negative pregnant women. METHODS: We did a retrospective cohort study between 1 July 2017, and 1 January 2020, at Women's Hospital, Zhejiang University School of Medicine. Firstly, pregnant women were divided into subgroups according to the entire GWG (inadequate GWG, adequate GWG, and excessive GWG) and GDM status (positive and negative) during pregnancy. Secondly, the whole population of pregnant women with GDM was used as a reference to evaluate the relationship between GWG and adverse pregnancy outcomes in GDM-negative pregnant women. Lastly, subgroup analysis was conducted based on pre-pregnancy body mass index (pp-BMI). RESULTS: A total of 30,910 pregnant women were analysed. Included pregnancy women were divided into three groups based on GWG: 7569 (24.49%) pregnancy women had inadequate GWG, 13088 (42.34%) had adequate GWG, and 10,253 (33.17%) had excessive GWG. In addition to preterm birth and small for gestational age (SGA), the incidence of macrosomia and large for gestational age (LGA) continues to increase from inadequate GWG to excessive GWG groups. Pregnant women without GDM who have excessive GWG are at higher risk of macrosomia and LGA than pregnant women with GDM. Moreover, this risk increased with increasing pp-BMI. Pregnant women without GDM with inadequate GWG were at risk of preterm birth regardless of pp-BMI. Only those with inadequate GWG and pp-BMI < 18.5 kg/m2 had an increased risk of SGA. CONCLUSIONS: In conclusion, inappropriate GWG is strongly associated with adverse pregnancy outcomes, even if they do not have GDM. Therefore, this population should receive attention and management before and during pregnancy.Impact StatementWhat is already known on this subject? Several studies have focused on the GDM population and the risk of adverse pregnancy outcomes, but few have focused on GDM-negative populations. This is because GDM-negative women are perceived to be "safe," leading to less focus on themselves, which can lead to subsequent excessive weight gain during pregnancy. Whether this factor increases the risk of adverse pregnancy outcomes in this population remains unknown.What do the results of this study add? Our study found an inverse relationship between GWG and GDM. Therefore, our study focuses on this group of GDM-negative pregnant women. Their excessive weight gain increases the risk of adverse pregnancy outcomes, even higher than GDM pregnant women.What are the implications of these findings for clinical practice and/or further research? GWG is associated with adverse pregnancy outcomes. Therefore, pregnant women without GDM also need increased attention and management of their weight before and during pregnancy. Prenatal care providers can utilise tools such as diet, exercise counselling, weight tracking, and setting weight gain goals to reduce inappropriate weight gain and mitigate its adverse effects on pregnancy outcomes.

Combining HbA1c and insulin resistance to assess the risk of gestational diabetes mellitus: A prospective cohort study.

OBJECTIVE: To investigate the association of glycated hemoglobin (HbA1c) and homeostasis model assessment insulin resistance (HOMA-IR) with gestational diabetes mellitus (GDM) risk. METHODS: Data for this study were from a prospective cohort in Hangzhou, China. We included pregnant women with HbA1c, fasting insulin, and fasting glucose (FG) measured at 15-20 weeks of gestation and underwent oral glucose tolerance test (OGTT) at 24-28 weeks. Based on HbA1c and HOMA-IR, participants were divided into four groups. We estimated the odds ratios (OR) with 95% confidence intervals (CI) to assess the associations of HbA1c and HOMA-IR with GDM occurrence. Finally, we the potential additive interaction between HbA1c and HOMA-IR by calculating relative excess risk due to interaction (RERI) and the attributable proportion due to interaction (AP). RESULT: 462 pregnant women were included, of whom 136 (29.44%) developed GDM. Based on HbA1c and HOMA-IR, the study population was divided into four groups, with the percentages of each group being 51.30%, 15.58%, 20.56%, and 12.55%, respectively. The incidence of GDM increased with the increase of HOMA-IR and HbA1c, respectively, and the risk of GDM was significantly increased when both HOMA-IR and HbA1c were elevated. However, no such risk was observed in pregnant women < 35 years. Finally, we found significantly higher FG at 24-28 weeks in the high HOMA-IR and HbA1c group among GDM-positive pregnant women. CONCLUSIONS: The incidence of GDM increased with increasing HbA1c and HOMA-IR, and the risk of GDM was significantly increased when both HbA1c and HOMA-IR were elevated. This finding may help to identify high-risk women for GDM early in pregnancy and provide timely interventions.

Effect of maternal body mass index on the steroid profile in women with gestational diabetes mellitus.

Objective: To explore the effect of maternal body mass index (BMI) on steroid hormone profiles in women with gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT). Methods: We enrolled 79 women with NGT and 80 women with GDM who had a gestational age of 24-28 weeks. The participants were grouped according to their BMI. We quantified 11 steroid hormones profiles by liquid chromatography-tandem mass spectrometry and calculated the product-to-precursor ratios in the steroidogenic pathway. Results: Women with GDM and BMI<25kg/m2 showed higher concentrations of dehydroepiandrosterone (DHEA) (p<0.001), testosterone (T) (p=0.020), estrone (E1) (p=0.010) and estradiol (E2) (p=0.040) and lower Matsuda index and HOMA-ß than women with NGT and BMI<25kg/m2. In women with GDM, concentrations of E1 (p=0.006) and E2 (p=0.009) declined, accompanied by reduced E2/T (p=0.008) and E1/androstenedione (A4) (p=0.010) in the BMI>25 kg/m2 group, when compared to that in the BMI<25 kg/m2 group. The values of E2/T and E1/A4 were used to evaluate the cytochrome P450 aromatase enzyme activity in the steroidogenic pathway. Both aromatase activities negatively correlated with the maternal BMI and positively correlated with the Matsuda index in women with GDM. Conclusions: NGT women and GDM women with normal weight presented with different steroid hormone profiles. Steroidogenic pathway profiling of sex hormones synthesis showed a significant increase in the production of DHEA, T, E1, and E2 in GDM women with normal weight. Additionally, the alteration of steroid hormone metabolism was related to maternal BMI in women with GDM, and GDM women with overweight showed reduced estrogen production and decreased insulin sensitivity compared with GDM women with normal weight.

Gestational diabetes mellitus in the COVID-19 pandemic: A retrospective study from Hangzhou, China.

AIMS: Our study aimed to investigate changes in the prevalence of gestational diabetes mellitus (GDM) in the COVID-19 pandemic and postpandemic era and the risk of adverse pregnancy outcomes in pregnant women diagnosed with GDM during the blockade period. METHODS: First, we investigated changes in the prevalence of GDM and the population undergoing oral glucose tolerance tests (OGTT) after the COVID-19 pandemic. We then collected clinical information from pregnant women diagnosed with GDM to explore the risk of adverse pregnancy outcomes in pregnant women with GDM during the COVID-19 pandemic. RESULTS: After the COVID-19 pandemic, the proportion of pregnant women in the total number of outpatient OGTT tests decreased yearly. The ratio was 81.30%, 79.71%, and 75.48% from 2019 to 2021, respectively, with the highest proportion of pregnant women in February 2020 (92.03%). The prevalence of GDM was higher in March 2020 compared to the same period in 2019. However, from 2019 to 2021, the prevalence decreased year by year with 21.46%, 19.81%, and 18.48%, respectively. The risk of adverse pregnancy outcomes for pregnant women diagnosed with GDM during the most severe period of the COVID-19 pandemic did not differ from before the COVID-19 pandemic. CONCLUSIONS: After the COVID-19 pandemic, the prevalence of GDM increased during the most severe period of the epidemic, but the overall prevalence of GDM decreased year by year. In addition, the pandemic did not change the risk of adverse pregnancy outcomes in pregnant women with GDM.

[Corrigendum] RON and c­Met facilitate metastasis through the ERK signaling pathway in prostate cancer cells.

Subsequently to the publication of the above article, the authors have discovered that the version of Fig. 5 included in the paper was an incorrect version, and that two pairs of data panels were inadvertently included in Fig. 6D (the data panels for the NC+migration and NC+HGF+U0126+invasion experiments for the PC3 cells, and the data panels for the NC+invasion and NC+HGF+U0126+invasion experiments for the DU145 cells) that contained overlapping data derived from the same source. These data were intended to represent the results obtained under different experimental conditions. Furthermore, the GAPDH control bands in Fig. 4A (DU145 cells) and the p­ERK1/2 bands in Fig. 6A (PC3 cells) were incorrectly chosen for these figures. After having consulted the original data, the authors discovered that unintended errors were made in assembling the data for these graphs. In uploading the corrected version of Fig. 5, Fig. 3C and D and Fig. 4C and D were adjusted accordingly. The corrected versions of Figs. 3, 4, 5, and 6 are shown on the subsequent pages. The authors regret the errors that were made during the preparation of the published figures, and confirm that these errors did not affect the conclusions reported in the study. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree to this Corrigendum. Furthermore, they apologize to the readership for any inconvenience caused. [Oncology Reports 37: 3209­3218, 2017; DOI: 10.3892/or.2017.5585].

Unique Biomarker Characteristics in Gestational Diabetes Mellitus Identified by LC-MS-Based Metabolic Profiling.

BACKGROUND: Gestational diabetes mellitus (GDM) is a type of glucose intolerance disorder that first occurs during women's pregnancy. The main diagnostic method for GDM is based on the midpregnancy oral glucose tolerance test. The rise of metabolomics has expanded the opportunity to better identify early diagnostic biomarkers and explore possible pathogenesis. METHODS: We collected blood serum from 34 GDM patients and 34 normal controls for a LC-MS-based metabolomics study. RESULTS: 184 metabolites were increased and 86 metabolites were decreased in the positive ion mode, and 65 metabolites were increased and 71 were decreased in the negative ion mode. Also, it was found that the unsaturated fatty acid metabolism was disordered in GDM. Ten metabolites with the most significant differences were selected for follow-up studies. Since the diagnostic specificity and sensitivity of a single differential metabolite are not definitive, we combined these metabolites to prepare a ROC curve. We found a set of metabolite combination with the highest sensitivity and specificity, which included eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, arachidonic acid, citric acid, α-ketoglutaric acid, and genistein. The area under the curves (AUC) value of those metabolites was 0.984 between the GDM and control group. CONCLUSIONS: Our results provide a direction for the mechanism of GDM research and demonstrate the feasibility of developing a diagnostic test that can distinguish between GDM and normal controls clearly. Our findings were helpful to develop novel biomarkers for precision or personalized diagnosis for GDM. In addition, we provide a critical insight into the pathological and biological mechanisms for GDM.

Association of higher HbA1c within the normal range with adverse pregnancy outcomes: a cross-sectional study.

OBJECTIVE: The aim of this study was to investigate the association between a relatively high HbA1c level within the normal range and the risk of adverse pregnancy outcomes. METHODS: This retrospective cohort study was conducted between March 2018 and March 2019 at Women's Hospital, School of Medicine, Zhejiang University. Multiple logistic regression models after adjusting for plausible confounders were implemented to assess the relationships between the level of HbA1c and adverse pregnancy outcomes. RESULTS: A total of 8585 women were included in our study. The rates of preterm birth, macrosomia and preeclampsia were 4.4% (380/8585), 5.3% (457/8585) and 1.7% (149/8585), respectively. After adjusting for potential confounding variables, an HbA1c range of 5.5-5.9% (37-41 mmol/mol) remained significantly associated with an increased risk of preterm delivery (a-OR 2.27; 95% CI, 1.50-3.43), macrosomia (a-OR 1.97; 95% CI, 1.32-2.94) and preeclampsia (a-OR 3.70; 95% CI, 2.07-6.60). GDM-negative pregnant women with an HbA1c level in the range of 5.5-5.9% (37-41 mmol/mol) had an increased risk of preterm delivery (a-OR 2.84; 95% CI, 1.71-4.71) and preeclampsia (a-OR 3.82; 95% CI, 1.81-8.04). However, GDM-positive pregnant women had an increased risk of macrosomia (a-OR 2.12; 95% CI, 1.13-3.97) and preeclampsia (a-OR 2.62; 95% CI, 1.01-6.81). CONCLUSION: A higher HbA1c level within the normal range is an independent risk factor for preterm delivery and preeclampsia, especially among GDM-negative women. Therefore, relevant medical staff should enhance the awareness of risk and prevention to strengthen pregnancy monitoring.

The prognosis value of EphA3 and the androgen receptor in prostate cancer treated with radical prostatectomy.

BACKGROUND: This study aimed to preliminarily assess the relationship between erythropoietin-producing hepatocellular carcinoma receptor A3 (EphA3) and androgen receptor (AR) protein expression levels and prognosis in prostate cancer (PCa) to better understand the role of EphA3 in the prognosis and progression of PCa. MATERIALS: We investigated the expression of EphA3 and AR in human PCa by immunohistochemistry. RESULTS: EphA3 and AR were both significantly upregulated in PCa, with expression mainly localized to the nucleus. A high level of AR expression was found in 48.4% of 64 tumor samples, which was significantly more than in the adjacent tissue samples (15.6%) (P < 0.01). The percentage of samples expressing a high level of EphA3 was significantly greater in the PCa samples (54.7%) than in the adjacent tissue samples (20.3%) for the 64 tumors (P < 0.01). The high levels of EphA3 and AR expression in the PCa tissue samples were both correlated with the pathological stage, bladder and rectal invasion, distant metastasis, and preoperative PSA level (both P < 0.05). The survival time was significantly shorter in high levels of AR expression of patients. (P < 0.01). A high level of EphA3 in PCa patients suggests a poor prognosis (P < 0.05). Biochemical recurrence, distant metastasis, and the final scores of EphA3 and AR expression were significantly correlated with the prognosis of PCa (P < 0.05). CONCLUSIONS: Increased EphA3 expression is an independent prognostic factor for a poor outcome and decreased survival in PCa.

SGK1 inhibition-induced autophagy impairs prostate cancer metastasis by reversing EMT.

BACKGROUND: Despite SGK1 has been identified and characterized as a tumor-promoting gene, the functions and underlying mechanisms of SGK1 involved in metastasis regulation have not yet been investigated in cancer. METHODS: We investigated the cellular responses to GSK650394 treatment and SGK1 silencing (or overexpression) in human prostate cancer (PCa) cell lines and PC3 xenografts by wound healing assay, migration and invasion assay, western blotting, immunofluorescence and immunohistochemistry. RESULTS: In the present study, we found that SGK1 expression positively correlates with human prostate cancer (PCa) progression and metastasis. We show that SGK1 inhibition significantly attenuates EMT and metastasis both in vitro and in vivo, whereas overexpression of SGK1 dramaticlly promoted the invasion and migration of PCa cells. Our further results suggest that SGK1 inhibition induced antimetastatic effects, at least partially via autophagy-mediated repression of EMT through the downregulation of Snail. Moreover, ectopic expression of SGK1 obviously attenuated the GSK650394-induced autophagy and antimetastatic effects. What's more, dual inhibition of mTOR and SGK1 enhances autophagy and leads to synergistic antimetastatic effects on PCa cells. CONCLUSIONS: Taken together, this study unveils a novel mechanism in which SGK1 functions as a tumor metastasis-promoting gene and highlights how co-targeting SGK1 and autophagy restrains cancer progression due to the amplified antimetastatic effects.

SGK1 inhibition induces autophagy-dependent apoptosis via the mTOR-Foxo3a pathway.

BACKGROUND: Although inhibition of SGK1 has been shown to delay cancer progression, the underlying mechanisms have not yet been elucidated. METHODS: We investigated the cellular responses to GSK650394 treatment and SGK1 silencing (or overexpression) in human prostate cancer (PCa) cell lines and PC3 xenografts by flow cytometry, western blotting, immunofluorescence, transmission electron microscopy and immunohistochemistry. RESULTS: In the present study, we demonstrated that SGK1 inhibition, mediated by either GSK650394 or SGK1 shRNA, induced G2/M arrest, apoptosis and autophagy. Furthermore, 3MA-mediated autophagy inhibition attenuated SGK1 inhibition-induced apoptosis, suggesting that induction of autophagy precedes apoptosis. Moreover, ectopic expression of SGK1 significantly attenuated the GSK650394-induced effects. Suppression of mTOR and Foxo3a phosphorylation is critical for blockade of SGK1-induced autophagy and apoptosis, at least partially via pFoxo3a (S253)-LC3 and pFoxo3a (S253)-p27 interactions. Dual inhibition of mTOR and SGK1 enhances autophagy activation and leads to synergistic cytocidal effects in PCa cells. CONCLUSIONS: In summary, our findings show that SGK1 inhibition exhibits significant antitumour effects against PCa in vitro and in vivo. This study uncovered a novel mechanism of SGK1 inhibition in PCa, which is mediated, at least in part, by inducing autophagy-dependent apoptosis via the mTOR-Foxo3a pathway.

Androgen-independent LNCaP cells are a subline of LNCaP cells with a more aggressive phenotype and androgen suppresses their growth by inducing cell cycle arrest at the G1 phase.

Androgen deprivation therapy (ADT, surgical or chemical castration) is the mainstay treatment for metastatic prostate cancer (PCa); however, patients ineluctably relapse despite extremely low androgen levels. This evolution of PCa indicates its lethal progression. In this study, to mimic the traits of clinical PCa progression in vitro, we investigated the alterations in the cell biological characteristics in androgen-independent LNCaP cells (LNCaP-AI cells) compared with LNCaP cells. We also examined the effects of androgen on LNCaP and LNCaP-AI cell proliferation, androgen receptor (AR) expression and prostate-specific antigen (PSA) secretion. Furthermore, AR was silenced in the LNCaP and LNCaP-AI cells to detect the roles taht AR plays in cell growth, apoptosis and PSA secretion. We found that prolonged androgen ablation increased the LNCaP-AI cell growth rate and cell invasiveness, and induced epithelial-mesenchymal transition in the LNCaP-AI cells. Moreover, despite the fact that the LNCaP and LNCaP-AI cells expressed equal amounts of AR protein, androgen induced a greater secretion of PSA in the LNCaP-AI cells than in the LNCaP cells. The proliferation of the LNCaP-AI cells was not dependent on, but was suppressed by androgen, which led to arrest at the G1 phase. Conversely, androgen significantly increased LNCaP cell proliferation by promoting the G1-S transition. Moreover, the silencing of AR suppressed LNCaP and LNCaP-AI cell growth by inducing cell cycle arrest at the G1 phase rather than promoting apoptosis, and reduced PSA secretion. On the whole, our data suggest that LNCaP-AI cells have a more more aggressive phenotype compared with the LNCaP cells; AR remains a critical factor in the LNCaP-AI cells, and androgen suppresses LNCaP-AI cell growth by blocking the cell cycle at the G1 phase.

Circulating tumor cells in prostate cancer: Precision diagnosis and therapy.

The primary cause of tumor-associated mortality in prostate cancer (PCa) remains distant metastasis. The dissemination of tumor cells from the primary tumor to distant sites through the bloodstream cannot be detected early by standard imaging methods. Circulating tumor cells (CTCs) represent an effective prognostic and predictive biomarker, which are able to monitor efficacy of adjuvant therapies, detect early development of metastases, and finally, assess therapeutic responses of advanced disease earlier than traditional diagnostic methods. In addition, since repeated tissue biopsies are invasive, costly and not always feasible, the assessment of tumor characteristics on CTCs, by a peripheral blood sample as a liquid biopsy, represents an attractive opportunity. The implementation of molecular and genomic characterization of CTCs may contribute to improve the treatment selection and thus, to move toward more precise diagnosis and therapy in PCa. The present study summarizes the current advances in CTC enrichment and detection strategies and reviews how CTCs may contribute to significant insights in the metastatic process, as well as how they may be utilized in clinical application in PCa. Although it is proposed that CTCs may offer insights into the prognosis and management of PCa, there are a number of challenges in the study of circulating tumor cells, and their clinical utility remains under investigation.

Association between human papillomavirus and prostate cancer: A meta-analysis.

Observational studies have suggested an association between human papillomavirus (HPV) infection and the risk of prostate cancer (PCa). However, the association between HPV infection and the risk of PCa remains unclear. The aim of the present meta-analysis study was to investigate whether HPV serves a role in increasing the risk of PCa. Relevant previous studies up to May 2015 were searched in PubMed, Web of Science, Cochrane library, Chinese National Knowledge Infrastructure, China Wan Fang database and China Biomedical Literature Database. A random-effects model or fixed-effects model was employed to determine odds ratios (ORs) with 95% confidence intervals (CIs), when appropriate. Heterogeneity was evaluated using Q and I2 statistical analysis. A total of 24 case-control studies involving 971 patients and 1,085 controls were investigated to estimate the association between HPV infection and PCa risk. The pooled estimate for OR was 2.27 (95% CI, 1.40-3.69). Stratified pooled analyses were subsequently performed according to the HPV detection methods, geographical regions, publication years and types of tissue. Sensitivity analysis based on various exclusion criteria maintained the significance with respect to PCa individually. Little evidence of publication bias was observed. The meta-analysis suggested that HPV infection is associated with increasing risk of PCa, which indicated a potential pathogenetic link between HPV and PCa.

RON and c-Met facilitate metastasis through the ERK signaling pathway in prostate cancer cells.

Prostate cancer (PCa) is a metastatic malignant cancer driven by complex pathological mechanisms and characterized by poor long-term prognosis. Metastasis is the main cause of death of PCa patients, yet the molecular mechanisms of this process are poorly understood. In the present study, positive co-expression of RON and c-Met was observed in human clinical PCa tissues (biopsy material), as detected by immunohistochemical staining and quantitative real-time PCR. We investigated this further in PCa cells, demonstrating that the inhibition of RON and c-Met with foretinib (GSK1363089) suppressed metastasis and promoted the reversal of the epithelial-to-mesenchymal transition (EMT) in PCa cells. Furthermore, the invasion and migration of PCa cells were enhanced by the exogenous activation of RON with MSP and c-Met with HGF, whereas silencing of RON and c-Met attenuated the invasion and metastasis of the PCa cells. Our data also demonstrated that HGF/c-Met, but not the MSP-RON signaling pathway may be the dominant mechanism for PCa EMT. We further revealed that RON and c-Met facilitate metastasis via ERK1/2 signaling. These findings indicate that RON and c-Met facilitate metastasis through ERK1/2 signaling and that targeting RON and c-Met with foretinib may be an attractive therapeutic option for suppressing PCa metastasis.

Colorimetric detection of gene transcript by target-induced three-way junction formation.

Gene transcript often varies by alternative splicing, which plays different biological role that results in diversity of gene expression. Therefore, a simple and accurate identification of targeted transcript variant is of prime importance to achieve a precise molecular diagnosis. In this work, we presented a three-way junction based system where two split G-quadruplex forming sequences were coupled into two probes. Only upon the introduction of target gene transcript that offering a specific recognizable splicing site did the two probes assembled into three way junction conformation in a devised process, thus providing a functional G-quadruplex conformation that greatly enhanced hemin peroxidation. A notable resolution for gene splicing site detection was achieved. The detection limitation by colorimetric assay was 0.063µM, and this system has been proved to discriminate even in a single base false level around splicing site (about 3 times of single mismatched analyte to gain an equal signal by perfect analyte ). Furthermore, recoveries of 78.1%, 88.1%, 104.6% were obtained with 0.75µM, 0.25µM, 0.083µM of target, respectively, showing a capacity to further exploit a simple equipped device for gene transcript detection.