Uncertainty quantification for the random HIV dynamical model driven by drug adherence.

In HIV drug therapy, the high variability of CD4+ T cells and viral loads brings uncertainty to the determination of treatment options and the ultimate treatment efficacy, which may be the result of poor drug adherence. We develop a dynamical HIV model coupled with pharmacokinetics, driven by drug adherence as a random variable, and systematically study the uncertainty quantification, aiming to construct the relationship between drug adherence and therapeutic effect. Using adaptive generalized polynomial chaos, stochastic solutions are approximated as polynomials of input random parameters. Numerical simulations show that results obtained by this method are in good agreement, compared with results obtained through Monte Carlo sampling, which helps to verify the accuracy of approximation. Based on these expansions, we calculate the time-dependent probability density functions of this system theoretically and numerically. To verify the applicability of this model, we fit clinical data of four HIV patients, and the goodness of fit results demonstrate that the proposed random model depicts the dynamics of HIV well. Sensitivity analyses based on the Sobol index indicate that the randomness of drug effect has the greatest impact on both CD4+ T cells and viral loads, compared to random initial values, which further highlights the significance of drug adherence. The proposed models and qualitative analysis results, along with monitoring CD4+ T cells counts and viral loads, evaluate the influence of drug adherence on HIV treatment, which helps to better interpret clinical data with fluctuations and makes several contributions to the design of individual-based optimal antiretroviral strategies.

Vaginal microbial profile of cervical cancer patients receiving chemoradiotherapy: the potential involvement of Lactobacillus iners in recurrence.

The vaginal microbiome is an immune defense against reproductive diseases and can serve as an important biomarker for cervical cancer. However, the intrinsic relationship between the recurrence and the vaginal microbiome in patients with cervical cancer before and after concurrent chemoradiotherapy is poorly understood. Here, we analyzed 125 vaginal microbial profiles from a patient cohort of stage IB-IVB cervical cancer using 16S metagenomic sequencing and deciphered the microbial composition and functional characteristics of the recurrent and non-recurrent both before and after chemoradiotherapy. We demonstrated that the abundance of beneficial bacteria and stability of the microbial community in the vagina decreased in the recurrence group, implying the unique characteristics of the vaginal microbiome for recurrent cervical cancer. Moreover, using machine learning, we identified Lactobacillus iners as the most important biomarker, combined with age and other biomarkers (such as Ndongobacter massiliensis, Corynebacterium pyruviciproducens ATCC BAA-1742, and Prevotella buccalis), and could predict cancer recurrence phenotype before chemoradiotherapy. This study prospectively employed rigorous bioinformatics analysis and highlights the critical role of vaginal microbiota in post-treatment cervical cancer recurrence, identifying promising biomarkers with prognostic significance in the context of concurrent chemoradiotherapy for cervical cancer. The role of L. iners in determining chemoradiation resistance in cervical cancer warrants further detailed investigation. Our results expand our understanding of cervical cancer recurrence and help develop better strategies for prognosis prediction and personalized therapy.

Randomness accelerates the dynamic clearing process of the COVID-19 outbreaks in China.

During the implementation of strong non-pharmaceutical interventions (NPIs), more than one hundred COVID-19 outbreaks induced by different strains in China were dynamically cleared in about 40 days, which presented the characteristics of small scale clustered outbreaks with low peak levels. To address how did randomness affect the dynamic clearing process, we derived an iterative stochastic difference equation for the number of newly reported cases based on the classical stochastic SIR model and calculate the stochastic control reproduction number (SCRN). Further, by employing the Bayesian technique, the change points of SCRNs have been estimated, which is an important prerequisite for determining the lengths of the exponential growth and decline phases. To reveal the influence of randomness on the dynamic zeroing process, we calculated the explicit expression of the mean first passage time (MFPT) during the decreasing phase using the relevant theory of first passage time (FPT), and the main results indicate that random noise can accelerate the dynamic zeroing process. This demonstrates that powerful NPI measures can rapidly reduce the number of infected people during the exponential decline phase, and enhanced randomness is conducive to dynamic zeroing, i.e. the greater the random noise, the shorter the average clearing time is. To confirm this, we chose 26 COVID-19 outbreaks in various provinces in China and fitted the data by estimating the parameters and change points. We then calculated the MFPTs, which were consistent with the actual duration of dynamic zeroing interventions.

Threshold conditions for curbing COVID-19 with a dynamic zero-case policy derived from 101 outbreaks in China.

By 31 May 2022, original/Alpha, Delta and Omicron strains induced 101 outbreaks of COVID-19 in mainland China. Most outbreaks were cleared by combining non-pharmaceutical interventions (NPIs) with vaccines, but continuous virus variations challenged the dynamic zero-case policy (DZCP), posing questions of what are the prerequisites and threshold levels for success? And what are the independent effects of vaccination in each outbreak? Using a modified classic infectious disease dynamic model and an iterative relationship for new infections per day, the effectiveness of vaccines and NPIs was deduced, from which the independent effectiveness of vaccines was derived. There was a negative correlation between vaccination coverage rates and virus transmission. For the Delta strain, a 61.8% increase in the vaccination rate (VR) reduced the control reproduction number (CRN) by about 27%. For the Omicron strain, a 20.43% increase in VR, including booster shots, reduced the CRN by 42.16%. The implementation speed of NPIs against the original/Alpha strain was faster than the virus's transmission speed, and vaccines significantly accelerated the DZCP against the Delta strain. The CRN ([Formula: see text]) during the exponential growth phase and the peak time and intensity of NPIs were key factors affecting a comprehensive theoretical threshold condition for DZCP success, illustrated by contour diagrams for the CRN under different conditions. The DZCP maintained the [Formula: see text] of 101 outbreaks below the safe threshold level, but the strength of NPIs was close to saturation especially for Omicron, and there was little room for improvement. Only by curbing the rise in the early stage and shortening the exponential growth period could clearing be achieved quickly. Strengthening China's vaccine immune barrier can improve China's ability to prevent and control epidemics and provide greater scope for the selection and adjustment of NPIs. Otherwise, there will be rapid rises in infection rates and an extremely high peak and huge pressure on the healthcare system, and a potential increase in excess mortality.

Statistical Analysis of Two-Compartment Pharmacokinetic Models with Drug Non-adherence.

Poor drug adherence is considered one of major barriers to achieving the clinical and public health benefits of many pharmacotherapies. In the current paper, we aim to investigate the impact of dose omission on the plasma concentrations of two-compartment pharmacokinetic models with two typical routes of drug administration, namely the intravenous bolus and extravascular first-order absorption. First, we reformulate the classical two-compartment pharmacokinetic models with a new stochastic feature, where a binomial random model of dose intake is integrated. Then, we formalize the explicit expressions of expectation and variance for trough concentrations and limit concentrations, with the latter proved of the existence and uniqueness for steady-state distribution. Moreover, we mathematically demonstrate the strict stationarity and ergodicity of trough concentrations as a Markov chain. In addition, we numerically simulate the impact of drug non-adherence to different extents on the variability and regularity of drug concentration and compare the drug pharmacokinetic preference between one and two compartment pharmacokinetic models. The results of sensitivity analysis also suggest the drug non-adherence as one of the most sensitive model parameters to the expectation of limit concentration. Our modelling and analytical approach can be integrated into the chronic disease models to estimate or quantitatively predict the therapy efficacy with drug pharmacokinetics presumably affected by random dose omissions.

Statistical analysis of one-compartment pharmacokinetic models with drug adherence.

Pharmacokinetics is a scientific branch of pharmacology that describes the time course of drug concentration within a living organism and helps the scientific decision-making of potential drug candidates. However, the classical pharmacokinetic models with the eliminations of zero-order, first-order and saturated Michaelis-Menten processes, assume that patients perfectly follow drug regimens during drug treatment, and the significant factor of patients' drug adherence is not taken into account. In this study, therefore, considering the random change of dosage at the fixed dosing time interval, we reformulate the classical deterministic one-compartment pharmacokinetic models to the framework of stochastic, and analyze their qualitative properties including the expectation and variance of the drug concentration, existence of limit drug distribution, and the stochastic properties such as transience and recurrence. In addition, we carry out sensitivity analysis of drug adherence-related parameters to the key values like expectation and variance, especially for the impact on the lowest and highest steady state drug concentrations (i.e. the therapeutic window). Our findings can provide an important theoretical guidance for the variability of drug concentration and help the optimal design of medication regimens. Moreover, The developed models in this paper can support for the potential study of the impact of drug adherence on long-term treatment for chronic diseases like HIV, by integrating disease models and the stochastic PK models.

The risk of future waves of COVID-19: modeling and data analysis.

After a major outbreak of the coronavirus disease (COVID-19) starting in late December 2019, there were no new cases reported in mainland China for the first time on March 18, 2020, and no new cases reported in Hong Kong Special Administrative Region on April 20, 2020. However, these places had reported new cases and experienced a second wave since June 11, 2020. Here we develop a stochastic discrete-time epidemic model to evaluate the risk of COVID-19 resurgence by analyzing the data from the beginning of the outbreak to the second wave in these three places. In the model, we use an input parameter to represent a few potential risks that may cause a second wave, including asymptomatic infection, imported cases from other places, and virus from the environment such as frozen food packages. The effect of physical distancing restrictions imposed at different stages of the outbreak is also included in the model. Model simulations show that the magnitude of the input and the time between the initial entry and subsequent case confirmation significantly affect the probability of the second wave occurrence. Although the susceptible population size does not change the probability of resurgence, it can influence the severity of the outbreak when a second wave occurs. Therefore, to prevent the occurrence of a future wave, timely screening and detection are needed to identify infected cases in the early stage of infection. When infected cases appear, various measures such as contact tracing and quarantine should be followed to reduce the size of susceptible population in order to mitigate the COVID-19 outbreak.

Impact of media reports on the early spread of COVID-19 epidemic.

Media reports can modify people's knowledge of emerging infectious diseases, and thus changing the public attitudes and behaviors. However, how the media reports affect the development of COVID-19 epidemic is a key public health issue. Here the Pearson correlation and cross-correlation analyses are conducted to find the statistically significant correlations between the number of new hospital notifications for COVID-19 and the number of daily news items for twelve major websites in China from January 11th to February 6th 2020. To examine the implication for transmission dynamics of these correlations, we proposed a novel model, which embeds the function of individual behaviour change (media impact) into the intensity of infection. The nonlinear least squares estimation is used to identify the best-fit parameter values in the model from the observed data. To determine impact of key parameters with media impact and control measures for the later outcome of the outbreak, we also carried out the uncertainty and sensitivity analyses. These findings confirm the importance of the responses of individuals to the media reports, and the crucial role of experts and governments in promoting the public under self-quarantine. Therefore, for mitigating epidemic COVID-19, the media publicity should be focused on how to guide people's behavioral changes by experts, and the management departments and designated hospitals of the COVID-19 should take effective quarantined measures, which are critical for the control of the disease.

Prognostic factors affecting survival and recurrence in patients with early cervical squamous cell cancer following radical hysterectomy.

OBJECTIVE: This study aimed to investigate the clinical and histological features affecting the survival of patients with early cervical squamous cell cancer treated with radical hysterectomy. METHODS: We retrospectively analyzed clinical and histological data for patients with stage IB-IIA cervical cancer treated by radical hysterectomy at Zhejiang Cancer Hospital from August 2008 to January 2013. RESULTS: A total of 1435 patients were included in the study. Cox regression analysis identified tumor size >4 cm, lymphovascular space involvement (LVSI), lymph node ratio (LNR), and squamous cell carcinoma antigen (SCC-Ag) >2.65 ng/mL as independent prognostic risk factors. Among 1096 patients without high pathological risk factors, the 5-year local recurrence rates for SCC-Ag ≤2.65 and >2.65 ng/mL were 6.6% and 25.7%, respectively. Among 332 patients with lymph node positivity, the overall survival rates for LNR ≤0.19 and >0.19 were 87.8% and 55.6%, respectively. CONCLUSIONS: LVSI, tumor size >4 cm, LNR >0.19, and SCC-Ag >2.65 ng/mL may predict a poor prognosis in patients with early cervical squamous cell cancer treated with radical hysterectomy. SCC-Ag >2.65 ng/mL may be a useful prognostic factor guiding the use of postoperative radiotherapy in patients without pathologic risk factors.

Association between the location of transposed ovary and ovarian dose in patients with cervical cancer treated with postoperative pelvic radiotherapy.

BACKGROUND AND PURPOSE: How to protect the ovarian function during radiotherapy is uncertain. The purpose of this study was to explore the association between the location of the transposed ovary and the ovarian dose in patients with cervical cancer received radical hysterectomy, ovarian transposition, and postoperative pelvic radiotherapy. METHODS: A retrospective analysis was conducted of 150 young patients with cervical cancer who received radical hysterectomy, intraoperative ovarian transposition, and postoperative adjuvant radiotherapy in Zhejiang Cancer Hospital. Association between location of the transposed ovaries and ovarian dose was evaluated. The transposed position of ovaries with a satisfactory dose was explored using a receiver operator characteristic curve (ROC) analysis. Patients' ovarian function was followed up 3 months and 1 year after radiotherapy. RESULTS: A total of 32/214 (15%) transposed ovaries were higher than the upper boundary of the planning target volume (PTV). The optimum cutoff value of > 1.12 cm above the iliac crest plane was significantly associated with ovaries above the upper PTV boundary. When the ovaries were below the upper boundary of PTV, the optimum cutoff value of transverse distance > 3.265 cm between the ovary and PTV was significantly associated with ovarian max dose (Dmax) ≤ 4Gy, and the optimum cutoff value of transverse distance > 2.391 cm was significantly associated with ovarian Dmax≤5Gy. A total of 77 patients had received complete follow-up, and 56 patients (72.7%) showed preserved ovarian function 1 year after radiotherapy, which was significantly increased compared with 3 months (44.2%) after radiotherapy. CONCLUSIONS: The location of transposed ovaries in patients with cervical cancer is significantly correlated with ovarian dose in adjuvant radiotherapy. We recommend transposition of ovaries > 1.12 cm higher than the iliac crest plane to obtain ovarian location above PTV. When the transposed ovary is below the upper boundary of PTV, ovarian Dmax ≤4Gy may be obtained when the transverse distance between the ovary and PTV was > 3.265 cm, and the ovarian Dmax≤5Gy may be obtained when the transverse distance was > 2.391 cm.

Increased frequency of regulatory T cells in the peripheral blood of patients with endometrioid adenocarcinoma.

The aim of the present study was to investigate the frequency of cluster of differentiation (CD)4+CD25+CD127- regulatory T cells (Tregs) in the peripheral blood mononuclear cells (PBMCs) of patients with endometrioid adenocarcinoma (EA). A total of 82 female patients with EA were recruited. The PBMCs were flow cytometrically analyzed to determine the percentage of CD4+CD25+CD127- Tregs within the CD4+ T cell population. The associations between the prevalence of Tregs in PBMCs and defined clinical prognostic parameters were evaluated. To study the immunoregulatory capacity of Tregs, the level of specific cytokines were detected by ELISA, and the proliferation of cells was analyzed by incorporation of 3H-thymidine. It was revealed that Treg/CD4+ ratio in the peripheral blood of patients with EA was 4.89±1.42%, significantly higher than Treg/CD4+ ratio in healthy women. No correlation was observed between Treg frequency and stage, grade of differentiation, menopausal status or age. CD4+CD25+CD127- Tregs secreted large amounts of IL-10 but not IFN-γ. The level of IL-10 secreted by Tregs from patients with EA and healthy controls was not significantly different. In addition, there was no significant difference in the suppressive activity of Tregs in patients with EA compared with that of the healthy controls. These findings demonstrate that the increased frequency of immunosuppressive Tregs in patients with EA may be responsible for immune tolerance in endometrial cancer.

Prognostic value of the 2018 FIGO staging system for cervical cancer patients with surgical risk factors.

Objective: To determine the predictive value of the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer patients with surgical risk factors. Methods: Data of 662 cervical cancer patients (stages IB and IIA) with surgical risk factors treated at Zhejiang Cancer Hospital between 2008 and 2011 were retrospectively reviewed. Univariate log-rank test and multivariate Cox regression models were adopted to evaluate the relationship between 2018 FIGO stage and survival. Results: On re-staging of patients, 17.3%, 44.5%, 25.4%, and 37.1% of the patients with FIGO 2009 stage IB1, IB2, IIA1, and IIA2, respectively, were upgraded to FIGO 2018 IIIC1P stage, and 2.1%, 3.0%, 3.1%, and 2.1% patients, respectively, were upgraded to IIIC2P stage. The 5-year overall survival (OS) rates of patients with FIGO 2018 stage IB1, IB2, IB3, IIA1, IIA2, IIIC1P, and IIIC2P were 95.3%, 95.1%, 90.4%, 92.4%, 86.4%, 81.9%, and 56.3%, respectively. The 5-year progression-free survival (PFS) rates were 94.0%, 91.0%, 88.5%, 91.4%, 86.4%, 79.5%, and 43.8%, respectively. The 5-year OS rates of patients with 1-2 positive pelvic lymph nodes (PLNs) and those with >2 positive PLNs were 86.0% and 73.7%, respectively, and the 5-year PFS rates were 84.2% and 70.2%, respectively. OS and PFS of patients with 1-2 positive PLNs in stage IIIC1P were similar to those of patients in stage IIA2 without lymph node metastasis, but significantly better than those of patients with >2 positive PLNs. Multivariate analysis showed FIGO 2018 stage to be an independent prognostic factor for OS and PFS. Conclusion: The 2018 FIGO staging system for cervical cancer appears to be useful for predicting prognosis of patients with risk factors after radical surgery. Survival of stage IIA1 patients is better than that of stage IB3 patients. Stage IIIC1 is not homogenous; survival in stage IIIC1P depends on the number of positive PLNs.

A comprehensive analysis of the factors of positive pelvic lymph nodes on survival of cervical cancer patients with 2018 FIGO stage IIIC1p.

Objective: To evaluate the factors associated with positive pelvic lymph nodes (LNs) on the survival of patients with 2018 FIGO stage IIIC1p cervical cancer. Methods: We retrospectively analyzed 155 patients with pelvic lymph node metastasis (LNM) confirmed by pathology after radical resection of cervical cancer treated at Zhejiang Cancer Hospital, China, between March 2008 and October 2011. We analyzed the influence of the factors associated with positive pelvic LNs on the survival of patients. Results: The 5-year progress-free survival (PFS) and overall survival (OS) of patients were 78.1% and 81.9%, respectively. The 5-year PFS and OS of patients with more than 2 LNM were worse compared with patients with 1 or 2 LNM (68.4% vs 83.7%, p=0.013; 72.4% vs 87.6%, p=0.017, respectively). The 5-year PFS and OS of patients with more than 2 LNM sites were worse than that of patients with 1 or 2 LNM sites (60.0% vs 82.4%, p=0.008; 70.0% vs 84.8%, p=0.045, respectively). The 5-year PFS and OS of patients with common iliac LNM was poorer than that of patients without common iliac LNM (60.7% vs 81.9%, p=0.008; 67.9% vs 85.0%, p=0.020, respectively). Compared with other patients, the survival of patients with these three factors (more than 2 LNM, more than 2 LNM sites, and common iliac LNM) was the worst (p<0.05). Conclusion: More than 2 LNM, more than 2 LNM sites, and common iliac LNM were predictive factors of poor survival in stage IIIC1p cervical cancer patients. Survival of patients with stage IIIC1p cervical cancer declined with increasing presence of such factors. The combined evaluation of the factors associated with positive pelvic LNs is a more comprehensive and pragmatic approach in evaluating the prognosis of cervical cancer.

Management Of Synchronous Krukenberg Tumors From Gastric Cancer: a Single-center Experience.

Background: Whether metastasectomy improves prognosis of gastric cancer patients with ovarian metastases (Krukenberg tumors) is not clear. In this study, we examined the survival benefit of metastasectomy combined with chemotherapy for treatment of synchronous Krukenberg tumors from gastric cancer and identified the prognostic factors. Methods: The subjects of this study were patients diagnosed as synchronous Krukenberg tumors of gastric origin in the period between December 2004 and December 2015. Patients were classified in accordance with treatment modality: metastasectomy group (metastasectomy combined with chemotherapy) and non-metastasectomy group (chemotherapy alone). Clinicopathological characteristics together with treatment records were investigated in detail and their relationship with survival outcomes was examined. Results: Out of a total of 103 patients, 54 (52.4%) underwent metastasectomy of Krukenberg tumors while 49 (47.6%) patients had chemotherapy alone. Overall survival (OS) in the metastasectomy group was significantly longer than that in the non-metastasectomy group (18.9 months vs. 12.4 months, respectively; P<0.001). Metastasectomy (hazard ratio [HR] 0.486; 95% confidence interval [CI] 0.323-0.729; P<0.001), signet ring cells (HR 1.938; 95% CI 1.182-3.175; P=0.009), peritoneal carcinomatosis (HR 1.934; 95% CI 1.230-3.049; P=0.004), expression of estrogen receptor-ß (ER-ß) (HR 0.404; 95% CI 0.251-0.648; P<0.001), and progesterone receptor (PR) (HR 0.496; 95% CI 0.301-0.817; P<0.001) were independent predictors of OS. Conclusion: Metastasectomy combined with chemotherapy showed an association with survival benefit in patients with synchronous Krukenberg tumors from gastric cancer. Metastasectomy, expression of ER-ß and PR, peritoneal carcinomatosis, and signet ring cells were independent predictors of survival. Further prospective studies are warranted.

Cisplatin concurrent chemoradiotherapy vs adjuvant radiation in stage IB/IIA cervical cancer with intermediate risk factors, treated with radical surgery: a retrospective study.

PURPOSE: To determine if postoperative cisplatin concurrent chemoradiotherapy (CCRT) improves the outcome in stage IA/IIB cervical cancer patients with intermediate risk factors, when compared with radiation therapy (RT) alone, and identify the potential eligible populations for this treatment. PATIENTS AND METHODS: We reviewed medical records of 1,240 patients with stage IA/IIB cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy in our hospital between January 2008 and December 2011. Of the 1,240 patients, 436 displayed 1 or more intermediate risk factors. Of these, we screened 306 patients who underwent RT only or CCRT. We analyzed the effects of CCRT on survival and prognosis. RESULTS: The 5-year progress-free survival (PFS) in the CCRT group was superior to that in the RT-only group (96.0% vs 89.0%, respectively; P=0.031). The 5-year overall survivals (OSs) were not different between the 2 groups (P=0.141). Compared with RT-only group, CCRT did not improve PFS or OS in patients with 1 risk factor, large tumor size, or deep stromal invasion (P>0.05). Compared with RT-only group, CCRT improved PFS (97.9% vs 82.8%; P=0.017) but did not increase OS (97.9% vs 89.7%; P=0.109) in patients with lymphovascular space invasion plus deep stromal invasion/large tumor size. OS (92.3% vs 70.6%; P=0.048) and PFS (92.3% vs 64.7%; P=0.020) in the CCRT group were superior to those in the RT-only group with 3 risk factors. Compared with RT-only group, CCRT was an independent prognostic factor for favorable PFS (hazard ratio [HR] =0.238; 95% CI =0.0827-0.697, P=0.009) and OS (HR =0.192; 95% CI =0.069-0.533, P=0.002). CONCLUSION: Postoperative CCRT improved survival in stage IA/IIB cervical cancer patients with intermediate risk factors. Patients with 2 or more intermediate risk factors, including lymphovascular space invasion, may benefit from CCRT.

Postoperative clinicopathological factors affecting cervical adenocarcinoma: Stages I-IIB.

Currently, cervical adenocarcinoma (ADC) receives the same standard treatment as squamous cell carcinoma, but this treatment regimen is not wholly suited for ADC. The present study was conducted to assess the prognostic role of postoperative clinicopathological factors in patients with stage I-IIB cervical ADC.The study examined 312 patients with stage I-IIB cervical ADC who underwent radical hysterectomy, including pelvic lymphadenectomy, at our institutions between October 2006 and September 2014. Overall survival (OS) and relapse-free survival (RFS) was analyzed by the Kaplan-Meier method. Sites of recurrence were classified as local and distant locations.The 5-year OS and RFS rates were 88.2% and 83.8%, respectively. The 5-year OS rates for patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA, IB, IIA, and IIB were 100.0%, 90.7%, 82.8%, and 55.6%, respectively. The Cox model identified number of positive pelvic nodes and age at surgery as independent prognostic factors for survival, and number of positive pelvic nodes and postoperative tumor diameter (≥4 cm) as independent prognostic factors for relapse. Cancer recurrence developed in 35 women. The top three recurrence sites were pelvis, vaginal stump, and lung.A more aggressive therapeutic strategy different from current practice in cervical cancer is urgently required for cervical ADC. As a new prognostic factor, postoperative tumor diameter should receive special attention in ADC treatment.

LncRNA-MEG3 inhibits cell proliferation of endometrial carcinoma by repressing Notch signaling.

BACKGROUND: The long non-coding RNA MEG3 has shown functional role as a tumor suppressor in many cancer types, excluding endometrial carcinoma (EC). Thus, this study tried to reveal the MEG3 dysregulation in EC samples and potential functional mechanism due to its regulation on Notch signaling pathway. METHODS: The expression profiles of MEG3 and two Notch signaling molecules, Notch1 and Hes1, were detected in both EC tissues and cell lines through real time PCR and western blot analysis. Lentiviral vector carrying whole MEG3 transcript or shRNA targeting MEG3 (shMEG3) was transfected for MEG3 dysfunction studies, and cell proliferation was analyzed through MTT and colony-formation assays. Xenograft models were also established by subcutaneous implantation and tumor growth was compared under MEG3 dysregulation. RESULTS: Significant downregulation of MEG3 was observed in EC samples compared to control, while the protein levels of Notch1 and Hes1 were both upregulated. Cell proliferation was obviously inhibited by MEG3 overexpression, while opposite improved result was obtained in MEG3 knockout cells. Interestingly, MEG3-induced changes could be reversed by Notch1 regulators. Moreover, MEG3 overexpressing tumors showed strongly repressed growth in vivo, along with Notch signaling inhibition. CONCLUSION: Downregulated MEG3 exhibited an anti-proliferative role in EC by repressing Notch signaling pathway.

MicroRNA-130a promotes the metastasis and epithelial-mesenchymal transition of osteosarcoma by targeting PTEN.

MicroRNAs, which serve as post-transcriptional modulators of numerous genes, have been found to be important regulators during the pathogenesis of osteosarcoma. This study demonstrates for the first time that microRNA-130a (miR-130a) is significantly upregulated in osteosarcoma, and associated with the metastasis of osteosarcoma. Elevated level of miR-130a was closely correlated with poor clinical features and prognosis of osteosarcoma patients. In vitro assays revealed that miR-130a could potentiate the migration, invasion and the epithelial-mesenchymal transtion (EMT) of osteosarcoma cells. Moreover, phosphatase and tensin homolog (PTEN) was confirmed as not only a direct downstream target but also a functional mediator of miR-130a. MiR-130a exerted promoting effects on metastatic behavior and EMT of osteosarcoma cells through suppressing PTEN expression. Based on these findings, we conclude that miR-130a is a promising prognostic biomarker for osteosarcoma patients, and targeting miR-130a may be a potential treatment option for osteosarcoma patients with metastasis.

Circulating MicroRNA-21 Is Involved in Lymph Node Metastasis in Cervical Cancer by Targeting RASA1.

OBJECTIVE: The aims of this study were to discover if increased circulating microRNA-21 (miR-21) expression in serum is associated with lymph node metastasis in patients with cervical cancer and look further into the molecular mechanism of these. Whole-blood samples from 89 patients who have been histopathologically confirmed as having cervical cancer and 20 control subjects were collected, and then the association between lymph node metastasis and the level of circulating miR-21 was compared. Then cervical cancer cell lines HeLa (HPV-18 DNA, E6/E7RNA) and HT-3 (HPV DNA, E6/E7RNA) were used to confirm the interaction between miR-21 and RASA1. The role of RASA1 in cervical cancer cell migration was also studied in HeLa. Increased circulating miR-21 expression in serum is associated with lymph node metastasis in patients with cervical cancer. MicroRNA-21 reduces RASA1 expression in cervical cancer cell lines and promotes cervical cancer cell migration via RASA1. Furthermore, Ras-induced epithelial-mesenchymal transition contributes to miR-21/RASA1 axis promoting cervical cancer cell migration. Circulating miR-21 in serum could be a promising biomarker in auxiliary diagnosis of lymph node metastasis in cervical cancer, and inhibition of miR-21/RASA1 axis could be a possible strategy to restrain migration of cervical cancer.

Intra-operative frozen section analysis of common iliac lymph nodes in patients with stage IB1 and IIA1 cervical cancer.

INTRODUCTION: To evaluate frozen section analysis of common iliac lymph nodes for developing the accuracy of para-aortic lymphadenectomy and detection of para-aortic lymph node metastasis in patients with stage IB1 and IIA1 cervical cancer treated by surgical intent. METHODS: Three hundred and ninety-two patients with stage IB1 and IIA1 cervical cancer who underwent radical hysterectomy with pelvic and/or para-aortic lymphadenectomy were retrospectively analyzed. Among those patients, 183 (group A) underwent para-aortic lymphadenectomy when para-aortic lymph nodes were identified as suspicious by visualization and palpation. Other 209 patients (group B, underwent intra-operative frozen section analysis of common iliac lymph nodes) underwent para-aortic lymphadenectomy when frozen section analysis was positive, or para-aortic lymph nodes were identified as suspicious metastases by visualization and palpation. RESULTS: We found 21 positive cases (10.0%) of 209 patients by frozen section examination, represented by 1 false negative (4.5%) and 0 false positive case. The specificity and the positive predictive value of frozen section examination were 100%; the negative predictive value was 99.5% (187/188). Overall, the metastasis rates of pelvic lymph node, common iliac lymph node, and para-aortic lymph node were 35.7, 10.2, and 3.3%, respectively. We found the dissection and metastasis rates of para-aortic lymph node in group B statistically significantly higher than group A (14.4% vs. 7.1%, for dissection rates of group B vs. group A, P = 0.022) (5.3% vs. 1.1%, for metastasis rates of group B vs. group A, P = 0.021). CONCLUSION: The frozen section analysis of common iliac lymph nodes can develop the accuracy of the para-aortic lymphadenectomy and metastasis rate of para-aortic lymph node in patients with stage IB1 and IIA1 cervical cancer.