Prospective validation of the role of PET/CT in detecting disease after neoadjuvant chemotherapy in advanced ovarian cancer.

OBJECTIVES: The study aimed to compare the diagnostic accuracies of 2-[18F]FDG PET/CT and contrast-enhanced CT (ceCT) after neoadjuvant chemotherapy (NACT) in advanced ovarian cancer (OC). MATERIALS AND METHODS: This study consisted historical observational cohort and prospective validation cohort. Patients with newly diagnosed stage III-IV OC scheduled for NACT were recruited, with imaging performed after three to six cycles of NACT before interval debulking surgery. Nineteen regions in the abdominopelvic cavity were scored for the presence and absence of disease, referenced to the intra-operative findings or histological specimens. Diagnostic metrics were compared using McNemar's test. RESULTS: In the historical cohort (23 patients, age 58 ± 13), 2-[18F]FDG PET had an overall accuracy (Acc) 82%, sensitivity (Sen) 38%, specificity (Spe) 97%, positive predictive value (PPV) 79% and negative predictive value (NPV) 82%; ceCT had an overall Acc 86%, Sen 64%, Spe 93%, PPV 75% and NPV 89%. In the prospective cohort (46 patients, age 59 ± 9), 2-[18F] FDG PET had an overall Acc 87%, Sen 48%, Spe 98%, PPV 84% and NPV 88%; ceCT had an overall Acc 89%, Sen 66%, Spe 95%, PPV 77% and NPV 91%. No significant difference was demonstrated between the two imaging modalities (p > 0.05). High false-negative rates were observed in the right subdiaphragmatic space, omentum, bowel mesentery and serosa. High omental metabolic uptake after NACT was associated with histological non-responders (p < 0.05). CONCLUSION: 2-[18F]FDG PET/CT had no additional value over ceCT with comparable diagnostic accuracy in detecting disease after NACT in advanced OC. CLINICAL RELEVANCE STATEMENT: 2-[18F]FDG PET/CT is not superior to contrast-enhanced CT in determining disease after neoadjuvant chemotherapy in advanced ovarian cancer; contrast-enhanced CT should be suffice for surgical planning before interval debulking surgery. KEY POINTS: • Additional value of 2-[18F]FDG PET/CT over contrast-enhanced CT is undefined in detecting disease after neoadjuvant chemotherapy. • 2-[18F]FDG PET/CT has comparable diagnostic accuracy compared to contrast-enhanced CT. • Contrast-enhanced CT will be suffice for surgical planning after neoadjuvant chemotherapy.

Acceptability of self-collected vaginal samples for human papillomavirus testing for primary cervical cancer screening: comparison of face-to-face and online recruitment modes.

BACKGROUND: This study aimed to assess the acceptability and attitudes of women towards human papillomavirus (HPV) self-sampling and compare the effectiveness of two delivery modes utilising face-to-face and online website for cervical cancer screening in Hong Kong. METHODS: Women aged 30-65 years were invited to participate by distributing the study information pamphlets at the specialist clinics of a regional acute hospital. Those who were interested in participating were given the option to join directly face-to-face or through an online website. All participants provided informed consent and received self-sampling kits and acceptability questionnaires either immediately (face-to-face) or through the post after registering at the website (online). All participants were requested to collect their own vaginal samples using a swab which was then brushed on a DNA sample storage card and returned to the hospital either in person or by post. The self-collected samples were tested for high-risk HPV using the Sentis™ HPV assay, a validated isothermal nucleic acid amplification real-time fluorescent detection assay. The primary outcome was the uptake rate of HPV self-sampling. RESULTS: Of the 1998 women recruited (1200 face-to-face, 798 online), 1377 returned their samples, giving an overall uptake rate of 68.9%. The uptake rate was significantly greater in the face-to-face mode than in the online mode (74.6% vs. 60.4%, p < 0.001). The median age of the participants was 49 years, 43.7% were never or under-screened, and 7.1% had high-risk HPV detected. Overall, 82.1% of the participants reported self-sampling convenient, and 79.3% were not embarrassed when collecting self-samples. However, only 49.8% were confident that they had collected the self-samples correctly. Most (91.1%) of the participants expressed willingness to perform self-sampling again, mostly because it was simple (79.2%) and quick (56.3%). CONCLUSIONS: HPV self-sampling can serve as an alternative primary screening method for cervical cancer in Hong Kong, especially for individuals who have not been adequately screened in the past. Both face-to-face and online website recruitment were associated with high acceptability, emphasising the potential benefits of utilising different platforms and strategies for reaching diverse populations.

Building a baby-friendly community: Development, strategy, implementation and evaluation of a BFCI program.

AIM: The aim of the study was to investigate the impact of the use of baby-friendly community initiative (BFCI) model on various stakeholders in the community. DESIGN: Quasi-experimental research design. METHOD: The study was conducted in public premises and online workshops from April 2019 to September 2022. Participants were followed up for a period of 1 month, except for those employed at public premises. The program involved training based on an accredited BFCI framework to cultivate a breastfeeding-friendly attitude and knowledge. A paired sample t-test was used to examine breastfeeding attitude and knowledge scores before and after BFCI training among staff employed from public premises. An analysis of variance was conducted to examine the breastfeeding self-efficacy and attitude scores, measured repeatedly at different timepoints over 1-month timepoint (T0, T1 and T2) among pregnant and postpartum women. RESULTS: A total of 2340 perinatal women and 1339 staff from public premises were recruited. For staff, there was an increase in the mean score of breastfeeding knowledge and attitude by 5.8 and 6.1, respectively, at T1. Similarly, for perinatal women, there was an increase in the mean score of breastfeeding self-efficacy and attitude by 6.6 and 3.3, respectively, at T1. CONCLUSION: In summary, a BFCI model, with active community participation, accreditation and an award system, has been effective in promoting breastfeeding. Adapting the baby-friendly hospital initiative to local contexts and employing a social theory model can enhance breastfeeding promotion and improve infant health outcomes. Prioritizing culturally sensitive breastfeeding education is crucial for successful BFCI implementation. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Healthcare professionals should consider clients' culture and socio-economic backgrounds when providing breastfeeding education to maximize effectiveness. The target audience for breastfeeding education should be expanded to include various community stakeholders beyond families. IMPACT: What problem did the study address? This study addressed the problem of knowledge gaps among stakeholders in building a breastfeeding-friendly community, particularly in implementing a baby-friendly community initiative (BFCI) as part of a baby-friendly hospital initiative (BFHI). The research filled a service gap by providing effective interventions targeting community stakeholders and assessing the impact of a BFCI program on their knowledge and attitudes towards breastfeeding. What were the main findings? The findings highlighted the effectiveness of a BFCI program in enhancing breastfeeding knowledge and attitudes among frontline staff and increasing breastfeeding confidence among mothers. These findings contribute to the understanding of the program's impact on different stakeholders in the community. Where and on whom will the research have an impact? It impacts on global policymakers by providing insights for developing comprehensive guidelines for future BFCI implementations. It also contributes to the creation of a more baby-friendly community, benefiting breastfeeding families and their infants by promoting and supporting breastfeeding families. REPORTING METHOD: This study has adhered to relevant EQUATOR guidelines using the TREND reporting guideline. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. WHAT DOES THIS PAPER CONTRIBUTE TO THE WIDER GLOBAL CLINICAL COMMUNITY?: This study provides an overview of the establishment of a localized BFCI program. It also opens up a new direction for the community to investigate BFCI strategies for community stakeholders. It also provides evidence to support other countries in following a similar process, as each country approaches becoming breastfeeding-friendly in its own unique way. TRIAL AND PROTOCOL REGISTRATION: No protocol.

Tumor-secreted exosomal miR-141 activates tumor-stroma interactions and controls premetastatic niche formation in ovarian cancer metastasis.

BACKGROUND: Metastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the mechanistic underpinnings remain incompletely understood. METHODS: PCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations. RESULTS: Hsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers. CONCLUSIONS: This study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases.

Validating the use of the revised childbirth experience questionnaire in Hong Kong.

OBJECTIVE: To evaluate the psychometric properties of the traditional Chinese version of the Childbirth Experience Questionnaire (CEQ 2.0) and assess the childbirth experiences of Chinese women. METHODS: A cross-sectional survey was conducted in Hong Kong from July 2020 to February 2021. In total, 975 mothers, who could read traditional Chinese and gave birth in 2020 or 2021, were included in the analysis. Data were fitted into the model proposed by the original developers using the confirmatory factor analysis. The data were then randomly split into training and validation sets for exploratory and confirmatory factor analyses. Childbirth experiences were assessed. Factor structure, internal construct validity, internal consistency, and known-group validity were assessed. RESULTS: The originally proposed CEQ2.0 model showed a poor fit. An exploratory factor analysis identified a revised four-factor model (CEQ2.0-R) on a randomly split sample, which showed a satisfactory fit (CFI=0.912; TLI=0.884; SRMR=.053; RMSEA=0.072) on the other split sample. The revised scale comprised 13 items and four domains: (1)"Own capacity" (6 items), (2) "General support" (3 items), (3) "Perceived safety" (2 items), and (4) "Professional support" (2 items). CEQ2.0-R showed high internal construct validity and reliability. It can differentiate between participants with different characteristics, including parity, oxytocin augmentation, and companionship during labour. The childbirth experiences of the participants were merely positive, and participants reported that more support from midwives is needed. CONCLUSIONS: CEQ2.0-R can adequately describe the childbirth experiences of women in Hong Kong. The questionnaire is easy to be administer and can be used to assess several domains of the childbirth experiences. It may be useful to evaluate the aspects of support needed during childbirth.

Robotic Natural Orifice Transluminal Endoscopic Surgery Hysterectomy and Salpingo-Oophorectomy in a Porcine Model.

Purpose. The emergence of robotic-assisted surgical techniques has gained significant indications in terms of reduced trauma, shortened recovery, and higher patients' satisfaction. However, limitations by present surgical robotic systems used in natural orifice transluminal endoscopic surgery (NOTES) gynecology still exists, such as arm collisions, countertraction, instrument dexterity, and, in particular, space confinement due to the narrow pelvic anatomy. The current study evaluated the use of a miniaturized single-site surgical robotic system and its feasibility in performing robotic NOTES gynecological procedures using a live porcine animal model. Methods. Using a transrectal approach, the fully internalized robotic arms were deployed in a reverse configuration to access the lower pelvic cavity of the animals to perform NOTES gynecological procedures. Results. Robotic-assisted transrectal gynecological procedures were successfully performed using the new robotic system. A hemi-hysterectomy with unilateral salpingo-oophorectomy was completed in the first animal and a total hysterectomy with bilateral salpingo-oophorectomy in the second animal with an average docking time of 22.5 minutes and console time of 63 minutes and 58 minutes, respectively. The overall blood loss for each procedure was estimated to be <20 mL per animal with no intraoperative complications. Conclusions. The reverse configuration of the miniaturized surgical robotic system has demonstrated its capability to provide a potential solution to maintain clear visualization of the surgical field, optimal triangulation, and dexterity robotic NOTES gynecological procedures within the deep confined space of the pelvic cavity.

Molecular Biomarkers for the Early Detection of Ovarian Cancer.

Ovarian cancer is the deadliest gynecological cancer, leading to over 152,000 deaths each year. A late diagnosis is the primary factor causing a poor prognosis of ovarian cancer and often occurs due to a lack of specific symptoms and effective biomarkers for an early detection. Currently, cancer antigen 125 (CA125) is the most widely used biomarker for ovarian cancer detection, but this approach is limited by a low specificity. In recent years, multimarker panels have been developed by combining molecular biomarkers such as human epididymis secretory protein 4 (HE4), ultrasound results, or menopausal status to improve the diagnostic efficacy. The risk of ovarian malignancy algorithm (ROMA), the risk of malignancy index (RMI), and OVA1 assays have also been clinically used with improved sensitivity and specificity. Ongoing investigations into novel biomarkers such as autoantibodies, ctDNAs, miRNAs, and DNA methylation signatures continue to aim to provide earlier detection methods for ovarian cancer. This paper reviews recent advancements in molecular biomarkers for the early detection of ovarian cancer.

Orchestrated Action of AMPK Activation and Combined VEGF/PD-1 Blockade with Lipid Metabolic Tunning as Multi-Target Therapeutics against Ovarian Cancers.

Ovarian cancer is one of the most lethal gynecological malignancies worldwide, and chemoresistance is a critical obstacle in the clinical management of the disease. Recent studies have suggested that exploiting cancer cell metabolism by applying AMP-activated protein kinase (AMPK)-activating agents and distinctive adjuvant targeted therapies can be a plausible alternative approach in cancer treatment. Therefore, the perspectives about the combination of AMPK activators together with VEGF/PD-1 blockade as a dual-targeted therapy against ovarian cancer were discussed herein. Additionally, ferroptosis, a non-apoptotic regulated cell death triggered by the availability of redox-active iron, have been proposed to be governed by multiple layers of metabolic signalings and can be synergized with immunotherapies. To this end, ferroptosis initiating therapies (FITs) and metabolic rewiring and immunotherapeutic approaches may have substantial clinical potential in combating ovarian cancer development and progression. It is hoped that the viewpoints deliberated in this review would accelerate the translation of remedial concepts into clinical trials and improve the effectiveness of ovarian cancer treatment.

New Insights into Ferroptosis Initiating Therapies (FIT) by Targeting the Rewired Lipid Metabolism in Ovarian Cancer Peritoneal Metastases.

Ovarian cancer is one of the most lethal gynecological cancers worldwide. The poor prognosis of this malignancy is substantially attributed to the inadequate symptomatic biomarkers for early diagnosis and effective remedies to cure the disease against chemoresistance and metastasis. Ovarian cancer metastasis is often relatively passive, and the single clusters of ovarian cancer cells detached from the primary ovarian tumor are transcoelomic spread by the peritoneal fluid throughout the peritoneum cavity and omentum. Our earlier studies revealed that lipid-enriched ascitic/omental microenvironment enforced metastatic ovarian cancer cells to undertake metabolic reprogramming and utilize free fatty acids as the main energy source for tumor progression and aggression. Intriguingly, cell susceptibility to ferroptosis has been tightly correlated with the dysregulated fatty acid metabolism (FAM), and enhanced iron uptake as the prominent features of ferroptosis are attributed to the strengthened lipid peroxidation and aberrant iron accumulation, suggesting that ferroptosis induction is a targetable vulnerability to prevent cancer metastasis. Therefore, the standpoints about tackling altered FAM in combination with ferroptosis initiation as a dual-targeted therapy against advanced ovarian cancer were highlighted herein. Furthermore, a discussion on the prospect and challenge of inducing ferroptosis as an innovative therapeutic approach for reversing remedial resistance in cancer interventions was included. It is hoped this proof-of-concept review will indicate appropriate directions for speeding up the translational application of ferroptosis-inducing compounds (FINs) to improve the efficacy of ovarian cancer treatment.

COVID-19 related fear and depression of pregnant women and new mothers.

OBJECTIVE: To explore factors associated with depression and COVID-19 related fear among pregnant women and new mothers. DESIGN: A cross-sectional survey was conducted in China from July 2020 to July 2021. SAMPLE: A total of 3027 pregnant and new mothers were recruited. MEASUREMENT: Sociodemographic characteristics and the perceptions of the COVID-19 pandemic were collected. The Patient Health Questionnaire-9 (PHQ-9) and the Fear Scale was used to assess the depressive and fear level towards the COVID-19 pandemic, respectively. RESULTS: Approximately 17.2% of the participants had depression (PHQ-9 ≥10). In Hong Kong, participants who perceived that they have increased knowledge to prevent infection were less likely to have depression (adjusted odds ratio [aOR] = 0.83; 95% confidence interval [CI] = 0.74-0.94). There was no association between perceived severity if infected and severity of spread and the depression level in our sample. An inverse relationship was found between the COVID-19 related fear level and perceived knowledge to prevent infection (Beta-coefficient [ß] = -0.20; 95% CI = -0.38 to -0.02). CONCLUSION: Public health nurses need to promote accurate and up to date COVID-19 related information at clinical and community settings and implement effective screening for depression and fear symptoms to identify these high-risk groups to improve women's psychological well-being.

Association between MRI histogram features and treatment response in locally advanced cervical cancer treated by chemoradiotherapy.

OBJECTIVE: To examine the associations of histogram features of T2-weighted (T2W) images and apparent diffusion coefficient (ADC) with treatment response in locally advanced cervical cancer (LACC) following concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: Fifty-eight patients who underwent a 4-week CCRT regimen with MRI prior to treatment (pre-CCRT) and after treatment (post-CCRT) were retrospectively analysed. Histogram features were calculated from volumes of interest (VOIs) from one radiologist on T2W images and ADC maps. VOIs from two radiologists were used to assess observer repeatability in delineation and feature values at both time-points with the Dice similarity coefficient (DSC) and intraclass correlation coefficient (ICC). Treatment response was defined as a 90% reduction in tumour volume. Paired Mann-Whitney U tests were used to determine if features changed significantly between examinations. Two-sample Mann-Whitney U tests were used to identify features that were significantly different between response groups. Receiver operating characteristic (ROC) analysis was done on significantly different MRI features between treatment response groups. RESULTS: Pre-CCRT delineation and feature repeatability were generally good (DSC > 0.700; ICC > 0.750). Post-CCRT repeatability was low (DSC < 0.700; ICC < 0.750), but ADC mean and percentiles retained good ICC scores. All features, except for T2WKurtosis, significantly changed between examinations. Post-CCRT ADC50 was the only feature that demonstrated both good observer variability and significant differences between treatment response groups (p = 0.036) and had an AUC of 0.701 with a cut-off of 1.357 × 10-6 mm2/s. CONCLUSION: ADC and T2W histogram features could be used to track changes in LACC tumours undergoing CCRT. Post-CCRT ADC50 was associated with treatment response with good observer repeatability. KEY POINTS: • Pre-treatment tumour delineation and histogram feature values had good observer repeatability, while these were less repeatable at post-treatment. • MRI histogram analysis could be used to track changes in the tumour as it undergoes concurrent chemoradiotherapy. • Post-treatment median ADC was associated with treatment response and had good repeatability.

An Interactive Web-Based Sexual Health Literacy Program for Safe Sex Practice for Female Chinese University Students: Multicenter Randomized Controlled Trial.

BACKGROUND: Sexual health concerns among young adults worldwide help to motivate preventative practices against sexually transmitted infections. To foster better sexual health, sexual health literacy must be enhanced. Little research has been conducted on the impact of gender power dynamics on sexual health, such as sexual coercion, even though the prevalence of sexual coercion remains high in China. OBJECTIVE: This study describes the development and systematic evaluation of a web-based sexual health literacy intervention called "Smart Girlfriend" for female Chinese university students. METHODS: A multicenter randomized controlled trial was conducted with 781 female university students at 5 universities with dormitories in Hong Kong. Inclusion criteria were used to select unmarried, female, Chinese university students who were ≥18 years old and had not received a sexual health intervention in the past 12 months. Participants were randomly assigned to 2 groups: one group received an interactive web-based sexual health literacy intervention and the other group received a single webpage of online information about condom use. The intervention content was based on the Health Belief Model and the Continuum of Conflict and Control theory. The primary outcome was self-reported consistency of condom use with every partner at 3-month and 6-month follow-up assessments, analyzed using zero/one inflated beta (ZOIB) regression. The secondary outcome was an appraisal of the knowledge, attitudes, norms, and self-efficacy of condom use using the 25-item Multidimensional Condom Attitudes Scale (MCAS). The intention to treat was applied in analyses. RESULTS: Of 1503 individuals that were screened, 781 (52%) were randomized into 2 groups. The retention rates at the 3-month and 6-month follow-ups were 92% and 91%, respectively. Most participants were born locally (536/746, 72%), and 18% (134/746) self-reported as a sexual minority. ZOIB results regarding the consistency of condom use were not significant [model 1: odds ratio (OR) 2.25 with a 95% credible interval (CrI) of 0.84-6.36; model 2: OR 8.03 (95% CrI 0.22-330.31); model 3: OR 1.21 (95% CrI 0.78-1.86)]. Consistency in the intervention group was 5% higher (95% CI -1.90 to 11.63) than the control group at the 3-month follow-up, and 1% higher (95% CI -5.81 to 8·02) at the 6-month follow-up. MCAS scores at the 3-month follow-up were significantly higher in the intervention group (mean 122.51, SD 15.97) than the control group (mean 119.86, SD 15.85; P=.02). CONCLUSIONS: An interactive web-based sexual health literacy program did not significantly increase the consistency of condom use compared to a single webpage of condom use information; however, it did temporarily improve knowledge, attitudes, norms, and self-efficacy regarding condom use. Future revisions of this intervention should be personalized and delivered with a proactive approach. TRIAL REGISTRATION: ClinicalTrials.gov NCT03695679; https://clinicaltrials.gov/ct2/show/NCT03695679.

The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression.

Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's "Seed and Soil" hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor ß (TGFß), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.

MicroRNA-135a-induced formation of CD133+ subpopulation with cancer stem cell properties in cervical cancer.

Cancer stem cells (CSCs) play significant roles in tumor initiation. MicroRNA-135a (miR-135a) induced the formation of a CD133+ subpopulation from a human papillomavirus-immortalized cervical epithelial cell line. Compared with the CD133- cells, the CD133+ cells expressed higher levels of miR-135a and OCT4, exhibited significantly higher tumorsphere forming capacity and the time required for tumorsphere formation was shortened in the second generation. Serum induction suppressed the expression of CD133, OCT4 and miR-135a, but increased expression of involucrin in the miR-135a-induced CD133+ cells. The miR-135a-induced CD133+ cells were tumorigenic in a limiting dilution approach in vivo. The cells expressed significantly higher level of active ß-catenin and OCT4 than the CD133- counterpart. Wnt3a enhanced the expression of OCT4 and CD133 in cervical cancer cells but failed to enhance CD133 transcription in normal cervical cells. Wnt3a stimulation also increased tumorsphere size and self-renewal of miR-135a-induced CD133+ subpopulation. Wnt/ß-catenin inhibition suppressed tumorsphere formation while Wnt3a partially nullified the inhibitory effect. Taken together, miR-135a induced the formation of a subpopulation of cells with CSC properties both in vitro and in vivo and the Wnt/ß-catenin signaling pathway is essential to maintain its tumorigenicity.

Primary HPV testing with cytology versus cytology alone in cervical screening-A prospective randomized controlled trial with two rounds of screening in a Chinese population.

We conducted a prospective randomized controlled trial with two screening rounds to evaluate the effectiveness of combining HPV testing with liquid-based cytology (LBC) as a co-test, compared to LBC only in cervical cancer screening of a Chinese population. First, 15,955 women aged 30-60 were randomized at a 1:1 ratio into an intervention group (Digene Hybrid Capture 2 HPV test with LBC) and a control group (LBC alone). Women in the intervention group would be referred for colposcopy and biopsy immediately if they were found to have high-risk HPV regardless of cytology results. The detection of cervical intraepithelial neoplasia grade 2 or above (CIN2+) lesions was significantly higher in the intervention group compared to the control (0.95% vs. 0.38%, OR 2.50, 95% CI 1.65-3.88). At the subsequent round of screening approximately 36 months later, CIN2+ detection was significantly lower in the intervention group (0.08% vs. 0.35%, OR 0.23, 95% CI 0.08-0.57). Over the two rounds of screening, the total detection of CIN2+ was higher in the intervention group (1.01% vs. 0.66%, OR 1.53, 95% CI 1.09-2.19). There was a fourfold increase (10.6% vs. 2.4%, p < 0.001) in the number of colposcopies performed in the intervention arm. Adding a high-risk HPV test to cytology for primary cervical screening led to earlier detection of clinically significant preinvasive lesions, resulting in a reduced detection of CIN2+ lesions in subsequent rounds and an increased rate of colposcopy.

Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastasis and metabolic switch via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling in ovarian cancer.

BACKGROUND: Ovarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs). Here, we identify and characterise tumour subsets from ascites-derived tumour cells with stemness, metastasis and metabolic switch properties and to delineate the involvement of pyruvate dehydrogenase kinase 4 (PDK4) in such process. METHODS: Ovarian cancer cells/cell lines derived from ascites were used for tumourspheres/ALDH+CD44+ subset isolation. The functional roles and downstream signalling of PDK4 were explored. Its association with clinical outcome of ovarian cancer was analysed. RESULTS: We demonstrated enhanced CSC characteristics of tumour cells derived from ovarian cancer ascites, concomitant with ALDH and CD44 subset enrichment and high PDK4 expression, compared to primary tumours. We further showed tumourspheres/ALDH+CD44+ subsets from ascites-derived tumour cells/cell lines with CSC properties and enhanced glycolysis. Clinically, PDK4 expression was correlated with aggressive features. Notably, blockade of PDK4 in tumourspheres/ALDH+CD44+ subsets led to inhibition of CSC characteristics, glycolysis and activation of STAT3/AKT/NF-κB/IL-8 (signal transducer and activator of transcription 3/protein kinases B/nuclear factor-κB/interleukin-8) signalling. Conversely, overexpression of PDK4 in ALDH-CD44- subsets exerted the opposite effects. CONCLUSION: Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastatic and metabolic switch properties via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling, suggesting PDK4 as a viable therapeutic molecular target for ovarian cancer management.

CD109 mediates tumorigenicity and cancer aggressiveness via regulation of EGFR and STAT3 signalling in cervical squamous cell carcinoma.

BACKGROUND: CD109 was involved in the tumorigenesis and progression of various cancers via TGF-ß1 signalling and STAT3 activation. As CD109 is strongly expressed in cervical squamous cell carcinoma, this study was conducted to investigate its functional characteristics in cervical cancer. METHODS: CD109 expression was examined by immunohistochemistry (IHC) with cervical tissue microarray. The effects of CD109 expression were examined on migration, cell proliferation, spheroid formation and soft-agar colony-formation assay. Meanwhile, cervical cancer cell lines with high CD109 expression were chosen for the functional study using siRNA knockdown and CRISPR/Cas9 knockout. RESULTS: IHC demonstrated an upregulation of CD109 in the cell membrane of cervical squamous cell carcinoma. CD109( + ) cells isolated by flow-cytometric sorting displayed enhanced migration, cell proliferation, sphere-forming and anchorage-independent cell growth ability. In contrast, silencing of CD109 expression could reverse the in vitro and in vivo tumorigenic and aggressive properties. Furthermore, CD109 induced EGFR-mediated STAT3 phosphorylation known to be responsible for cell migration, proliferation and maintenance of CSC phenotype. CONCLUSION: Abundant CD109( + ) populations in cervical cancer cells potentially contributed to carcinogenesis and aggressiveness, whereas silencing of CD109 expression could reverse those properties. CD109 mediates cervical tumorigenicity and aggressiveness via CD109/EGFR/STAT3 signalling.

Infiltration of T cells promotes the metastasis of ovarian cancer cells via the modulation of metastasis-related genes and PD-L1 expression.

Due to its high ability to disseminate, ovarian cancer remains one of the largest threats to women's health, worldwide. Evidence showed that the immune cells infiltrating the tumor microenvironment are crucial in mediating metastasis. Therefore, it is necessary to understand which types of immune cells are involved in metastasis, and to determine the mechanisms by which they influence the process. By immunohistochemistry, we found that higher concentrations of intratumoral CD8+ T cells were found to be correlated with an advanced grade and stage of ovarian cancer. Additionally, the infiltration of stromal CD8+ T cells was also significantly higher in tissues with advanced stages and metastatic tumors. A positive correlation between the infiltration of FoxP3+ Treg cells and histological grade was also observed, regardless of location. PD-L1 expression in metastatic tumors was also higher than that in paired primary ovarian tumors. Transwell migration and invasion assays revealed the increased migration and invasion of ovarian cancer cell lines (A2780CP and ES2) and ascites-derived ovarian cancer cells following co-culturing with CD8+ T cells. Enhanced expression of MMP-9, uPA, VEGF, bFGF, IL-8, IL-10, and PD-L1 by cancer cells following co-culturing with CD8+ T cells were also detected by qPCR, ELISA or flow cytometry. In conclusion, our findings suggest that the infiltrated T cells could promote the development of ovarian cancer, and provide another mechanism of immune evasion mediated by T cells.

Predictive biomarkers and tumor microenvironment in female genital melanomas: a multi-institutional study of 55 cases.

Female genital melanomas are rare. At diagnosis, most affected patients have advanced disease. Surgery remains the primary treatment, and adjuvant therapy is largely ineffective. Recently, immune checkpoints and the mitogen-activated protein kinase pathway have been explored as treatment targets. However, evaluation of these biomarkers in genital melanomas is limited. We evaluated the clinicopathological features of 20 vulvar, 32 vaginal, and three cervical melanomas and assessed programmed cell death ligand 1 (PD-L1) expression, CD8 tumor-infiltrating lymphocyte density, mismatch repair proteins, VE1 immunohistochemistry, and KIT and BRAF mutations. The median age of the patients was 66 years, and median tumor sizes were 25, 30, and 20 mm for vulvar, vaginal, and cervical tumors, respectively. Mean mitotic figures were 18, 19, and 30 per mm2. Thirty-seven patients (67%) had operable tumors. After a median follow-up of 15 months, only nine patients (16%) were alive. Eight of the nine survivors did not have lymph node metastasis. Using 5% as the threshold, PD-L1 expression was observed in 55%, 50%, and 33% of vulvar, vaginal, and cervical tumors, respectively, when the Roche SP263 antibody was used and 20%, 53%, and 0%, respectively, when the Dako 28-8 antibody was used. The median CD8 tumor-infiltrating lymphocyte density was significantly higher in vulvar/vaginal than cervical melanomas and correlated with PD-L1 expression. No cases exhibited loss of mismatch repair proteins. Five cases harbored KIT mutations, three of which were hotspots. BRAF V600E mutation was not detected. Univariable analysis showed that tumor size greater than or equal to 33 mm, mitotic figures of greater than or equal to 10 per mm2, lymph node metastasis, and low CD8+ tumor-infiltrating lymphocyte density were adverse prognostic factors. Thus, patients with genital melanomas have a poor prognosis, and evaluation of multiple biomarkers is necessary to identify patients who may benefit from immunotherapy or targeted therapy.

MAP30 protein from Momordica charantia is therapeutic and has synergic activity with cisplatin against ovarian cancer in vivo by altering metabolism and inducing ferroptosis.

Increasing evidence shows that Traditional Chinese Medicine (TCM) has an obvious appeal for cancer treatment, but there is still a lack of scientific investigation of its underlying molecular mechanisms. Bitter melon or bitter gourd (Momordica charantia) is an edible fruit that is commonly consumed, and it is used to cure different diseases in various ancient folk medical practices. We report that a bioactive protein, MAP30, isolated from bitter melon seeds exhibited potent anticancer and anti-chemoresistant effects on ovarian cancer cells. Functional studies revealed that MAP30 inhibited cancer cell migration, cell invasion, and cell proliferation in various ovarian cancer cells but not normal immortalized ovarian epithelial cells. When administered with cisplatin, MAP30 produced a synergistic effect on cisplatin-induced cell cytotoxicity in ovarian cancer cells. When low doses of cisplatin and MAP30 were co-injected intraperitoneally, a remarkable reduction of tumor dissemination and tumor growth was observed in an ovarian cancer ascites mouse model. Notably, blood tests confirmed that MAP30 did not cause any adverse effects on liver and kidney functions in the treated mice. MAP30 activated AMP-activated protein kinase (AMPK) signaling via CaMKKß and induced cell cycle arrest in the S-phase. MAP30 modulated cell metabolism of ovarian cancer cells via suppression of GLUT-1/-3-mediated glucose uptake, adipogenesis, and lipid droplet formation in tumor development and progression. MAP30 also induced an increase in intracellular Ca2+ ion concentration, which triggered ROS-mediated cancer cell death via apoptosis and ferroptosis. Collectively, these findings suggest that natural MAP30 is a non-toxic supplement that may enhance chemotherapeutic outcomes and benefit ovarian cancer patients with peritoneal metastases.