Respective prevalence of high-risk HPVgenotypes in cervical neoplasia in Senegal.

OBJECTIVES: With the perspective of prophylactic vaccination against high-risk human papillomavirus (HPV), we analyzed the viral epidemiology of cervical neoplasia in Senegal. METHODS: All patients were treated at the Institut Joliot Curie du Cancer in Dakar. HPV genotypes were characterized using a real-time polymerase chain reaction-based approach and sequencing. RESULTS: Histologically, there were 224 invasive carcinomas, 17 high-grade intraepithelial neoplasia (CIN), and five undetermined histologies. Molecular analysis was conclusive in 241 cases. HPV DNA was found in 207/241 (85.9%) cases while 34/241 (14.1%) remained HPV negative. There was one single genotype in 127/207 (61.4%) cases and several in 80/207 (38.6%) corresponding to 308 genotypes identified. Viral genotyping found HPV16 in 175 (56.8%) cases, HPV18 in 45 (14.6%), HPV45 in 40 (13.0%), HPV58 in 35 (11.4%), HPV33 in 6 (2.0%), HPV35 in 3 (1.0%), HPV31 in 2 (0.6%), HPV39 and HPV56 in one (0.3% each). CONCLUSION: Our analysis showed that 98.4% of the HPV-positive cases were associated with viral genotypes covered by the 9-valent HPV vaccine. However, 14.1% of cases remained HPV negative. Therefore, prophylactic vaccination using a 9-valent vaccine should dramatically reduce the incidence of HPV-associated neoplasia but the detection and treatment of CIN remain necessary for the optimal prevention of cervical cancer.

Evaluation of variation of interfraction doses to organs at risk during brachytherapy of cervical cancer.

BACKGROUND: Two-dimensional treatment planning using radiographs or simulator films was the standard in planning brachytherapy for patients with cervical cancer. Three-dimensional (3D) treatment planning has improved treatment efficacy. This retrospective study compares conventional and 3D treatment planning of brachytherapy in patients with cervical cancer and interfraction dose variation to bladder and rectum (D2cc). METHODS: The mean doses to bladder and rectum (D2cc) were computed by computed tomography (CT)-based planning during 100 sessions of intracavitary brachytherapy for carcinoma cervix with the same source configuration as generated for conventional planning, and these estimates were compared with the doses at International Commission on Radiation Units and measurements (ICRU) rectal, bladder points and point A. Interfraction variation of doses to bladder and rectum during various sessions was also analysed. RESULT: The mean ICRU bladder dose and D2cc of the bladder for all patients was 3.7 Gy and 7.4 Gy, respectively (p < 0.001). The mean ICRU rectal dose from conventional plan was 4.3Gy and with CT planning, 4.45 Gy (p = 0.04). Interfraction dose variations for D2cc of the bladder were min -5.3 Gy and max 4.8 Gy and those of the rectum were min -1.8 Gy and max 1.72Gy. CONCLUSION: Dosimetric evaluation of conventional and 3D CT-based treatment planning for the same brachytherapy sessions demonstrated underestimation of ICRU bladder dose points (p < 0.001) and the rectal ICRU point dose and D2cc (p=0.04). The doses to organs at risk did not show a statistically significant variation between the fractions. However, large variation was noted between the interfractional maximum and minimum doses to bladder and rectum.

The Impact of Human Papillomavirus Catch-Up Vaccination in Australia: Implications for Introduction of Multiple Age Cohort Vaccination and Postvaccination Data Interpretation.

We used transmission-dynamic modeling to estimate the added effectiveness of vaccinating multiple cohorts of females (12-26 years) in Australia compared with the theoretical introduction of routine-only (12-13 years) vaccination. Our results suggest that vaccinating multiple cohorts produced markedly faster direct/herd effects, and it added benefits that last for 20-70 years. Furthermore, the number needed to vaccinate to prevent 1 anogential warts (AGW) case or cervical cancer (CC) was similar for routine + catch-up (AGW = 9.9, CC = 678) and routine-only vaccination (AGW = 9.9, CC = 677), thus providing similar levels of efficiency per person vaccinated.

Transforming growth factor-ß1 in carcinogenesis, progression, and therapy in cervical cancer.

Transforming growth factor ß1 (TGF-ß1) is a multifunctional cytokine that plays important roles in cervical tumor formation, invasion, progression, and metastasis. TGF-ß1 functions as a tumor inhibitor in precancerous lesions and early stage cancers of cervix whereas as a tumor promoter in later stage. This switch from a tumor inhibitor to a tumor promoter might be due to various alterations in TGF-ß signaling pathway, such as mutations or loss of expression of TGF-ß receptors and SMAD proteins. Additionally, the oncoproteins of human papillomaviruses have been shown to stimulate TGF-ß1 expression, which in turn suppresses host immune surveillance. Thus, in addition to driving tumor cell migration and metastasis, TGF-ß1 is believed to play a key role in promoting human papillomavirus infection by weakening host immune defense. In this article, we will discuss the role of TGF-ß1 in the expression, carcinogenesis, progression, and therapy in cervical cancers. A better understanding of this cytokine in cervical carcinogenesis is essential for critical evaluation of this cytokine as a potential prognostic marker and therapeutic target.

HMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells.

Acquisition of an impaired functionality by plasmacytoid dendritic cells (pDCs) contributing to cancer progression has been documented in different types of cancers. In the present study, we postulate that molecules secreted by (pre)neoplastic epithelial cells of the genital tract (cervix/vulva) might attract pDCs but also modify their proper functionality, allowing these cells to initiate a tolerogenic response interfering with antitumor immunity. We demonstrated that pDCs are recruited during the cervical metaplasia-dysplasia-cancer sequence, through the action of their chemoattractant, chemerin. We showed that stimulated-pDCs exposed to cervical/vulvar tumor microenvironment display an altered phenotype. We also demonstrated that cervical/vulvar neoplastic keratinocytes inhibit the proper function of pDCs by decreasing their IFNα secretion in response to CpG oligonucleotides. In parallel, we observed that (pre)neoplastic areas of the cervix are infiltrated by FoxP3(+) Treg cells which colocalize with pDCs. Accordingly, pDCs cocultured with cervical/vulvar neoplastic keratinocytes have the capacity to induce a Treg cell differentiation from naïve CD4(+) T cells, which is in agreement with the development of a tolerogenic response. We identified HMGB1 as a soluble factor produced by neoplastic keratinocytes from the genital tract involved in pDCs functional alteration. Indeed, this molecule inhibited pDC maturation, decreased IFNα secretion following TLR9 stimulation and forced these cells to become tolerogenic. In contrast, inhibition of HMGB1 restored pDC phenotype. Our findings indicate that the use of inhibitory molecules notably directed against HMGB1 in cervical/vulvar (pre)neoplastic lesions might prevent alterations of pDCs functionality and represent an attractive therapeutic strategy to overcome immune tolerance in cancers.

N-Benzylcinnamide induces apoptosis in HPV16 and HPV18 cervical cancer cells via suppression of E6 and E7 protein expression.

Seventy percent of all cervical cancers are caused by human papillomavirus (HPV) infections. Natural products are being extensively explored for their potential ability to prevent and treat cervical cancers. N-benzylcinnamide (PT-3) is a natural product purified from Piper submultinerve. Whether or not PT-3 has an effect on cervical cancer cells is as yet unknown. Therefore, we set out to explore the mechanism of action behind PT-3 and how it affects cells that either contain or lack HPV DNA. Our results demonstrate that PT-3 slows the growth kinetics of CaSki (HPV-16 positive) and HeLa (HPV-18 positive) cells in a dose-dependent manner, but does not slows HPV-negative cells. Importantly, we also found that PT-3 induces apoptosis by suppressing expression of E6 and E7 viral oncogenes in HPV-infected cervical cancer CaSki and HeLa cells. Moreover, we found that suppression of E6 and E7 expression leads to modulations in p53 and protein retinoblastomas, which are not changed in HPV-negative cervical cancer C33A cells. These findings demonstrate that PT-3 can effectively promote apoptosis by downregulating expression of E6 and E7.

PIAS3, SHP2 and SOCS3 Expression patterns in Cervical Cancers: Relevance with activation and resveratrol-caused inactivation of STAT3 signaling.

OBJECTIVE: Resveratrol inhibits cervical cancer (CC) cells by blocking STAT3 signaling. However, the mechanism of resveratrol-induced STAT3 inactivation remains largely unknown. SHP2, PIAS3, and SOCS3 are STAT3 negative regulators; therefore, their statuses in cervical adenocarcinoma (HeLa) and squamous cell carcinoma (SiHa and C33A) cell lines without and with resveratrol treatment and their correlation with STAT3 activation in CC specimens were investigated. METHODS: MTT and TUNEL assays were used to check the resveratrol sensitivity of CC cells, and immunocytochemical staining, Western blotting, and RT-PCR were used to analyze SHP2, PIAS3, and SOCS3 expression and the intracellular distribution of STAT3. Tissue microarray based immunohistochemical staining was performed to investigate potential correlations between SHP2, PIAS3, and SOCS3 expression and STAT3 activation. RESULTS: PIAS3 and SOCS3 were found to be weakly expressed in CC cells and upregulated by resveratrol; this was accompanied by inhibition of STAT3 signaling. The SHP2 level remained unchanged in all three cell lines after resveratrol treatment. STAT3 nuclear translocation was more frequent in adenocarcinomas and squamous cell carcinomas than that of their noncancerous counterparts. The SOCS3 level and detection rate were higher in noncancerous squamous cells (but not in glandular epithelia) compared with their cancerous counterparts. The phospho-SHP2 detection rate was similar in noncancerous and tumor tissues of squamous and glandular origins; however, PIAS3 levels were distinct. CONCLUSIONS: Of the three STAT3 negative regulators, PIAS3 correlated most negatively with STAT3 nuclear translocation and may inhibit STAT3 signaling in both histological CC subtypes. PIAS3 responsiveness may reflect greater resveratrol sensitivity and improved therapeutic outcome in CCs.

Utilization of cervical cancer screening and determinant factors among female nurses in selected public hospitals in Addis Ababa, Ethiopia.

BACKGROUND: Cervical cancer is one of the top cause of death among childbearing women globally and public health issue for underdeveloped nations.It is the world's second most prevalent cancer among women. In 2018, 311,000 women died due to cervical cancer.Approximately 80 % of these deaths occurred in developing countries.However, there has been insufficient research on cervical cancer screening utilisation among Ethiopian nurses, despite the fact that nurses promote women's health and play a key role in cervical cancer education. As a result, evaluating utilization of cervical cancer screening among nurses is critical for program effectiveness. OBJECTIVE: To assess the magnitude of utilization of cervical cancer screening and determinant factors among female Nurses in selected public hospitals in Addis Ababa, Ethiopia. METHODOLOGY: An institutional-based cross-sectional study design was employed from October 1 to November 30, 2022. Data was collected using an interviewer-administered questionnaire. The data was entered into Epi data version 3.1 and then exported to SPSS version 22 for data management and analysis. Bivariate and multi-variable logistic regressions were employed to identify the predictor variables. Statistical significance was considered at P < 0.05 with adjusted odds ratio calculated at 95 % CI. RESULT: The magnitude of utilization of cervical cancer screening among nurses working in selected public hospitals in Addis Ababa was 18.5 % (95 % CI: 14.2, 23.1). Having work experience > 8 years (AOR = 16.78; 95 % CI: 4.82, 58.44), history of STI (AOR = 53.72; 95 % CI: 14.18, 203.45) and having multiple sexual partners (AOR = 12.74; 95 % CI: 4.15, 39.11) were significantly associated with utilization of cervical cancer screening among female nurses. CONCLUSION: The overall cervical cancer screening rate among female nurses was low compared to the WHO strategy for cervical cancer elimination, which asks for 70 % of women worldwide to be checked for cervical illnesses regularly by 2030. According to the study findings, respondents' work experience, STI history, and having multiple sexual partners influenced their utilization of cervical cancer screening among nurses. To boost the utilization of screening services, female nurses should place a strong emphasis on maintaining screening awareness through education and knowledge sharing.Finally, we recommend future researchers to do comparative study design to draw any scientific and credible conclusions.

Assessing the impact of lubricant on liquid-based Pap smear test outcomes: a randomized clinical trial.

Background: Since today cervical cancers are growing, there is an increasing need to use screening and examination methods. Meanwhile, liquid-based Pap smear test is a common screening method for women, which is widely applied today. Studies have found that use of lubricant gel in this test can affect the pathology and cytology results. Accordingly, the authors intended to evaluate the effect of use of lubricant gel on the Pap smear test results. Methods: This study was of single-blind clinical trial, the study population consisted of candidate patients for screening in terms of cervical pathology, for whom liquid-based Pap smear was done. In this study, 506 patients participated, divided into two groups of 253. One group used lubricant gel during the Pap smear, while the other group underwent this test without lubricant. The data were analyzed by SPSS 21. Results: The study results indicated that once the two groups were compared in terms of age, interval of menstruation time and intercourse time from the sampling, no significant relationship was found between the two groups (P>0.05). It was also found that use of lubricant did not affect the cytology and pathology results of patients (P>0.05). Conclusion: The use of lubricant gel in patients can reduce pain in patients during examination and testing, but does not affect the cytological and pathological results of patients.

Therapeutic Vaccines for HPV-Associated Cervical Malignancies: A Systematic Review.

IMPORTANCE: Despite widespread prophylactic vaccination, cervical cancer continues to be a major health problem with considerable mortality. Currently, therapeutic vaccines for HPV-associated cervical malignancies are being evaluated as a potential complement to the standard treatment. OBJECTIVE: The present systematic review was conducted on randomized controlled trials (RCTs) to investigate the effects of therapeutic vaccines on the treatment of patients with cervical cancer and cervical intraepithelial neoplasia (CIN) of Grades 2 and 3. EVIDENCE REVIEW: The PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched. Only articles in English published up until 31 January 2024 were selected. Also, reference lists of the selected original papers and recent review articles were manually searched for additional sources. Data on study characteristics were extracted from the selected articles. Data on outcomes of interest were synthesized, and vaccine efficacy endpoints (histological lesion regression, clinical response, and overall survival) were selected as the basis for grouping the studies. FINDINGS: After screening 831 articles, nine RCTs with 800 participants were included, of which seven studies with 677 participants involved CIN2 and CIN3 and examined lesion regression to ≤CIN1 as the efficacy endpoint. Results of two of these studies were deemed to have a high risk of bias, and another one did not contain statistical analyses. Results of the other four studies were quantitively synthesized, and the pooling of p-values revealed a significant difference between the vaccine and placebo groups in terms of lesion regression (p-values of 0.135, 0.049, and 0.034 in RCTs, yielding a combined p-value of 0.010). The certainty of the evidence was rated as moderate. Patients with advanced cervical cancers were studied in two RCTs with 123 participants. Clinical response and overall survival were taken as endpoints, and the results were reported as not significant. The certainty of the evidence of these results was rated as very low, mainly due to the very small number of events. All studies reported good tolerance for the vaccines. CONCLUSIONS AND RELEVANCE: The results indicate the potential for therapeutic vaccines in the regression of CIN2 and CIN3 lesions. Moreover, a potential gap in evidence is identified regarding the very low number of RCTs in patients with advanced cervical cancer.

Immune Environment and Immunotherapy in Endometrial Carcinoma and Cervical Tumors.

Endometrial cancer (EC) is the seventh most common tumor in women, and prognosis of recurrent and metastatic disease is poor. Cervical cancer (CC) represents the fifth most common gynecological cancer. While ECs are more common in developed countries, the incidence of CC has decreased due to the recent implementation of large screening and vaccination programs. Until very recently, patients with advanced or unresectable EC or CC had very limited treatment options and were receiving in first line setting platinum/taxane-based chemotherapy (CT). Significant progress in the treatment of gynecological cancers has occurred in the last few years, with the use of innovative targeted therapies and immunotherapy. However, targeting the immune system in patients with gynecological tumors remains challenging and is not always successful. In ovarian cancer, several immunotherapy treatment regimens have been investigated (as monotherapy and combination therapy in first and subsequent lines of treatment) and showed poor responses. Therefore, we specifically focused our review on EC and CC for their specific immune-related features and therapeutic results demonstrated with immunotherapy. We report recent and current immunotherapy-based clinical trials and provide a review of emerging data that are likely to impact immunotherapy development based on increased biomarkers' identification to monitor response and overcome resistance.

HPV pathogenesis, various types of vaccines, safety concern, prophylactic and therapeutic applications to control cervical cancer, and future perspective.

Over 98% of cervical cancers (CC) are caused by regular infections with "high risk" genotype of the human papilloma virus (HPV). However, this is not always the causative factor. Therefore, production of HPV vaccinations represents a significant chance to minimize the risk of CC. Phase III studies for a number of preventative HPV vaccines based on L1-virus-like particle (VLPs) have just been completed and the preliminary results are very convincing. However, there are a lot of practical concerns that need to be resolved before the use of these vaccinations. These vaccines were challenged with obvious queries such as protection time, subject receiving vaccines, time of vaccination, and how to include them into ongoing screening programs. Although these vaccines were 90% effective at preventing HPV infection as these offered only modest advantages for the removal of pre-existing infections. New advancements in the creation of therapeutic vaccinations have been explored for further improvement and post-vaccination surveillance. Therapeutic vaccines attempted to boost cell-mediated immunities and these are detrimental to the infected cell as opposed to neutralizing antibodies (different from prophylactic vaccines).

A Review of Commonly used Health-Related Quality of Life instruments in Gynecological Cancer Survivors.

The number of cancer survivors is increasing steadily due to an aging population, continuing improvement in early detection, and treatment. Comparative effectiveness studies and clinical trials are being done to assess late effects of treatment and health-related quality of life. This is in addition to long-term follow-up to assess survival. The aim of the review was to summarize the literature on commonly used quality of life instruments for patients with gynecological cancers with special focus on patient reported outcomes. A literature review was done to summarize the commonly used health-related quality of life instruments in gynecological cancer survivors. Most items assess general quality of life, sexual function, and/or treatment-related toxicity. The commonly reported instruments are the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) with disease specific modules for cervix, ovary, and endometrium. Another tool is the Functional Assessment of Cancer Therapy (FACT) questionnaire with similar disease specific modules. The questionnaires were accessed with permission from these organizations. These instruments typically have about 10-30 questions that assess treatment related bowel and bladder toxicity. This is connected to the patients' self-reported quality of life, generally ranked using a 5-point scale. Length and emphasis vary in different questionnaires. The validated tools in cancer populations allow better quantification and assessment of quality of life. However, there may be limitations. Some of the general instruments may be too broad to assess treatment-related long-term side effects. Others may be too narrow to generalize closely related patient groups. Also, some questions may not be culturally appropriate in certain situations.

Th17 cells target the metabolic miR-142-5p-succinate dehydrogenase subunit C/D (SDHC/SDHD) axis, promoting invasiveness and progression of cervical cancers.

During cervical carcinogenesis, T-helper (Th)-17 cells accumulate in the peripheral blood and tumor tissues of cancer patients. We previously demonstrated that Th17 cells are associated with therapy resistance as well as cervical cancer metastases and relapse; however, the underlying Th17-driven mechanisms are not fully understood. Here, using microarrays, we found that Th17 cells induced an epithelial-to-mesenchymal transition (EMT) phenotype of cervical cancer cells and promoted migration and invasion of 2D cultures and 3D spheroids via induction of microRNA miR-142-5p. As the responsible mechanism, we identified the subunits C and D of the succinate dehydrogenase (SDH) complex as new targets of miR-142-5p and provided evidence that Th17-miR-142-5p-dependent reduced expression of SDHC and SDHD mediated enhanced migration and invasion of cancer cells using small interfering RNAs (siRNAs) for SDHC and SDHD, and miR-142-5p inhibitors. Consistently, patients exhibited high levels of succinate in their serum associated with lymph node metastases and diminished expression of SDHD in patient biopsies correlated with increased numbers of Th17 cells. Correspondingly, a combination of weak or negative SDHD expression and a ratio of Th17/CD4+ T cells > 43.90% in situ was associated with reduced recurrence-free survival. In summary, we unraveled a previously unknown molecular mechanism by which Th17 cells promote cervical cancer progression and suggest evaluation of Th17 cells as a potential target for immunotherapy in cervical cancer.

Machine learning based evaluation of clinical and pretreatment 18F-FDG-PET/CT radiomic features to predict prognosis of cervical cancer patients.

PURPOSE: To examine the usefulness of machine learning to predict prognosis in cervical cancer using clinical and radiomic features of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (CT) (18F-FDG-PET/CT). METHODS: This retrospective study included 50 cervical cancer patients who underwent 18F-FDG-PET/CT before treatment. Four clinical (age, histology, stage, and treatment) and 41 18F-FDG-PET-based radiomic features were ranked and a subset of useful features for association with disease progression was selected based on decrease of the Gini impurity. Six machine learning algorithms (random forest, neural network, k-nearest neighbors, naive Bayes, logistic regression, and support vector machine) were compared using the areas under the receiver operating characteristic curve (AUC). Progression-free survival (PFS) was assessed using Cox regression analysis. RESULTS: The five top predictors of disease progression were: stage, surface area, metabolic tumor volume, gray-level run length non-uniformity (GLRLM_RLNU), and gray-level non-uniformity for run (GLRLM_GLNU). The naive Bayes model was the best-performing classifier for predicting disease progression (AUC = 0.872, accuracy = 0.780, F1 score = 0.781, precision = 0.788, and recall = 0.780). In the naive Bayes model, 5-year PFS was significantly higher in predicted non-progression than predicted progression (80.1% vs. 9.1%, p < 0.001) and was only the independent factor for PFS in multivariate analysis (HR, 6.89; 95% CI, 1.92-24.69; p = 0.003). CONCLUSION: A machine learning approach based on clinical and pretreatment 18F-FDG PET-based radiomic features may be useful for predicting tumor progression in cervical cancer patients.

The effect of Wnt/ß-catenin signaling on PD-1/PDL-1 axis in HPV-related cervical cancer.

Infection with high-risk human papillomavirus (HPV), including HPV-16 and HPV-18, is the main cause of malignancies, such as cervical cancer. Viral oncoproteins encoded by HPV are expressed in HPV-positive cancers and associated with the early cancer stages and the transformation of normal cells. The signaling pathways involved in the transformation of normal cells to cancerous form and the subsequently expressed programmed cell death-ligand 1 (PD-L1) on the surface of the transformed cells lead to a disruption in recognition of tumor cells by the immune cell system, including T lymphocytes and dendritic cells which lead to the development of cervical cancer malignancy. These cells also produce modest levels of cytokines during exhaustion, tumor-infiltrating T CD4+ cells with high levels of PD-1 and CD39 release considerable quantities of cytokines. The Wnt/ß-catenin signaling pathway, which controls the expression of genes involved in the tumor cells' markers, is demonstrated to be one of the most potent cancer stimulants. It leads to the evasion of the tumor cells from immune cell detection and ultimately avoids being recognized by dendritic cells or T-cells. PD-L1, as an inhibitory immune checkpoint, is essential for controlling immune system activity by inhibiting T-cells' inflammatory function. In the present review, we looked into how Wnt/ß-catenin affects the expression of PD-L1 and related genes like c-MYC in cancer cells and its role in the development of HPV-induced malignancy. We hypothesized that blocking these pathways could be a potential immunotherapy and cancer prevention method.

HPV-Negative Cervical Cancer: A Narrative Review.

Cervical cancer (CC) is the fourth most frequent cancer in women worldwide. HPV infection is associated with the majority of CC cases, but a small proportion of CCs actually test negative for HPV. The prevalence of HPV among CC histotypes is very different. It has been suggested that HPV-negative CC may represent a biologically distinct subset of tumors, relying on a distinct pathogenetic pathway and carrying a poorer prognosis, than HPV-positive CCs. Although, the discordance in terms of sensitivity and specificity between different HPV tests as well as the potential errors in sampling and storing tissues may be considered as causes of false-negative results. The identification of HPV-negative CCs is essential for their correct management. The aim of this narrative review is to summarize the clinical and pathological features of this variant. We also discuss the pitfalls of different HPV tests possibly leading to classification errors.

CD59 receptor targeted delivery of miRNA-1284 and cisplatin-loaded liposomes for effective therapeutic efficacy against cervical cancer cells.

Co-delivery of two different therapeutics (miRNA-1284 and cisplatin (CDDP)) into the cancer cells in a single nanocarrier provides new dimension to the cancer treatment. In this study, we have designed the CD59sp-conjugated miRNA-1284/cisplatin(CDDP)-loaded liposomes for the enhanced therapeutic effect against cervical cancers. Compared with miRNA-1284/CDDP-loaded liposomes (LP-miCDDP), CD59 antibody-conjugated LP-miCDDP (CD/LP-miCDDP) showed a significantly higher cytotoxicity in HeLa cells. Notably, MiR-1284 showed a typical concentration-dependent cell killing effect in the cervical cancer cells owing to the downregulation of HMGB1. Flow cytometer analysis showed that CD/LP-miCDDP resulted in maximum apoptosis effect (~ 60%) compared to CDDP (~ 20%) or miR-1284 (~ 12%) treated cells indicating the superior anticancer effect in the cancer cells. Importantly, CD/LP-miCDDP significantly prolonged the blood circulation of encapsulated drug in rats with AUC(o-t) of CD/LP-miCDDP showed a 6.9 fold higher value than that of free CDDP. Similarly, CD/LP-miCDDP showed an eightfold decrease in the clearance (CL) and 3.6-fold higher t1/2 compared to that of free CDDP. Overall, results demonstrated that targeted and synergistic co-delivery of therapeutic components could be promising in cervical cancer therapy.

In Vitro Organotypic Systems to Model Tumor Microenvironment in Human Papillomavirus (HPV)-Related Cancers.

Despite the well-known role of chronic human papillomavirus (HPV) infections in causing tumors (i.e., all cervical cancers and other human malignancies from the mucosal squamous epithelia, including anogenital and oropharyngeal cavity), its persistence is not sufficient for cancer development. Other co-factors contribute to the carcinogenesis process. Recently, the critical role of the underlying stroma during the HPV life cycle and HPV-induced disease have been investigated. The tumor stroma is a key component of the tumor microenvironment (TME), which is a specialized entity. The TME is dynamic, interactive, and constantly changing-able to trigger, support, and drive tumor initiation, progression, and metastasis. In previous years, in vitro organotypic raft cultures and in vivo genetically engineered mouse models have provided researchers with important information on the interactions between HPVs and the epithelium. Further development for an in-depth understanding of the interaction between HPV-infected tissue and the surrounding microenvironment is strongly required. In this review, we critically describe the HPV-related cancers modeled in vitro from the simplified 'raft culture' to complex three-dimensional (3D) organotypic models, focusing on HPV-associated cervical cancer disease platforms. In addition, we review the latest knowledge in the field of in vitro culture systems of HPV-associated malignancies of other mucosal squamous epithelia (anogenital and oropharynx), as well as rare cutaneous non-melanoma associated cancer.

Molecular Profiling Reveals Common and Specific Development Processes in Different Types of Gynecologic Cancers.

BACKGROUND: Gynecologic cancers have become a major threat to women's health. The molecular biology of gynecologic cancers is not as well understood as that of breast cancer, and precision targeting is still new. Although viewed collectively as a group of cancers within the female reproductive system, they are more often studied separately. A comprehensive within-group comparison on molecular profiles is lacking. METHODS: We conducted a whole-exome sequencing study of cervical/endometrial/ovarian cancer samples from 209 Chinese patients. We combined our data with genomic and transcriptomic data from relevant TCGA cohorts to identify and verify common/exclusive molecular changes in cervical/endometrial/ovarian cancer. RESULTS: We identified shared molecular features including a COSMIC signature of deficient mismatch repair (dMMR), four recurrent copy-number variation (CNV) events, and extensive alterations in PI3K-Akt-mTOR signaling and cilium component genes; we also identified transcription factors and pathways that are exclusively altered in cervical/endometrial/ovarian cancer. The functions of the commonly/exclusively altered genomic circuits suggest (1) a common reprogramming process during early tumor initiation, which involves PI3K activation, defects in mismatch repair and cilium organization, as well as disruption in interferon signaling and immune recognition; (2) a cell-type specific program at late-stage tumor development that eventually lead to tumor proliferation and migration. CONCLUSION: This study describes, from a molecular point of view, how similar and how different gynecologic cancers are, and it provides a hypothesis about the causes of the observed similarities and differences.