The Science

In silico design of a multi-epitope vaccine against HPV16/18

Abstract Background Cervical cancer is the fourth most common cancer affecting women and is caused by human Papillomavirus (HPV) infections that are sexually transmitted. There are currently commercially available prophylactic vaccines that have been shown to protect vaccinated individuals against HPV infections, however, these vaccines have no therapeutic effects for those who are previously infected with the virus. The current study’s aim was to use immunoinformatics to develop a multi-epitope vaccine with therapeutic potential against cervical cancer. Results In this study, T-cell epitopes from E5 and E7 proteins of HPV16/18 were predicted. These epitopes were evaluated and chosen based on their antigenicity, allergenicity, toxicity, and induction of IFN-γ production (only in helper T lymphocytes). Then, the selected epitopes were sequentially linked by appropriate linkers. In addition, a C-terminal fragment of Mycobacterium tuberculosis heat shock protein 70 (HSP70) was used as an adjuvant for the vaccine construct. The physicochemical parameters of the vaccine construct were acceptable. Furthermore, the vaccine was soluble, highly antigenic, and non-allergenic. The vaccine’s 3D model was predicted, and the structural improvement after refinement was confirmed using the Ramachandran plot and ProSA-web. The vaccine’s B-cell epitopes were predicted. Molecular docking analysis showed that the vaccine's refined 3D model had a strong interaction with the Toll-like receptor 4. The structural stability of the vaccine construct was confirmed by molecular dynamics simulation. Codon adaptation was performed in order to achieve efficient vaccine expression in Escherichia coli strain K12 (E. coli). Subsequently, in silico cloning of the multi-epitope vaccine was conducted into pET-28a ( +) expression vector. Conclusions According to the results of bioinformatics analyses, the multi-epitope vaccine is structurally stable, as well as a non-allergic and non-toxic antigen. However, in vitro and in vivo studies are needed to validate the vaccine’s efficacy and safety. If satisfactory results are obtained from in vitro and in vivo studies, the vaccine designed in this study may be effective as a therapeutic vaccine against cervical cancer.

A Novel Prognostic Risk Model for Cervical Cancer Based on Immune Checkpoint HLA-G-Driven Differentially Expressed Genes

Human leukocyte antigen G (HLA-G) is a potential checkpoint molecule that plays a key role in cervical carcinogenesis. The purpose of this study was to construct and validate a prognostic risk model to predict the overall survival (OS) of cervical cancer patients, providing a reference for individualized clinical treatment that may lead to better clinical outcomes. HLA-G-driven differentially expressed genes (DEGs) were obtained from two cervical carcinoma cell lines, namely, SiHa and HeLa, with stable overexpression of HLA-G by RNA sequencing (RNA-seq). The biological functions of these HLA-G-driven DEGs were analysed by GO enrichment and KEGG pathway using the “clusterProfiler” package. The protein-protein interactions (PPIs) were assessed using the STRING database. The prognostic relevance of each DEG was evaluated by univariate Cox regression using the TCGA-CESC dataset. After the TCGA-CESC cohort was randomly divided into training set and testing set, and a prognostic risk model was constructed by LASSO and stepwise multivariate Cox regression analysis in training set and validated in testing set or in different types of cervical cancer set. The predictive ability of the prognostic risk model or nomogram was evaluated by a series of bioinformatics methods. A total of 1108 candidate HLA-G-driven DEGs, including 391 upregulated and 717 downregulated genes, were obtained and were enriched mostly in the ErbB pathway, steroid biosynthesis, and MAPK pathway. Then, an HLA-G-driven DEG signature consisting of the eight most important prognostic genes CD46, LGALS9, PGM1, SPRY4, CACNB3, PLIN2, MSMO1, and DAGLB was identified as a key predictor of cervical cancer. Multivariate Cox regression analysis showed that this signature is an independent risk factor for the overall survival of CESC patients. Kaplan-Meier survival analysis showed that the 5-year overall survival rate is 23.0% and 84.6% for the high-risk and low-risk patients, respectively (P<0.001). The receiver operating characteristic (ROC) curve of this prognostic model with an area under the curve (AUC) was 0.896 for 5 years, which was better than that of other clinical traits. This prognostic risk model was also successfully validated in different subtypes of cervical cancer, including the keratinizing squamous cell carcinoma, non-keratinizing squamous cell carcinoma, squamous cell neoplasms, non-squamous cell neoplasms set. Single-sample gene set enrichment (ssGSEA) algorithm and Tumor Immune Dysfunction and Exclusion (TIDE) analysis confirmed that this signature influence tumour microenvironment and immune checkpoint blockade. A nomogram that integrated risk score, age, clinical stage, histological grade, and pathological type was then built to predict the overall survival of CESC patients and evaluated by calibration curves, AUC, concordance index (C-index) and decision curve analysis (DCA). To summarize, we developed and validated a novel prognostic risk model for cervical cancer based on HLA-G-driven DEGs, and the prognostic signature showed great ability in predicting the overall survival of patients with cervical cancer.

Sociodemographic factors associated with HPV awareness/knowledge and cervical cancer screening behaviors among caregivers in the U.S

Abstract Background Family caregivers may be at a higher risk for several chronic diseases, including cancer. Cervical cancer is one of the most common causes of cancer death among women. Despite family caregivers’ vulnerability, the status of their HPV awareness, knowledge, and preventive health behaviors, including cervical cancer screening, has been understudied. Thus, this study aimed to examine the sociodemographic factors associated with HPV awareness and knowledge and adherence to the cervical cancer screening guidelines among caregivers in the U.S. Methods Nationally representative cross-sectional survey data were obtained from the Health Information National Trends Survey (HINTS 5, 2017–2020). Female caregivers aged 21–65 were included (N = 1190). Weighted multivariable logistic regression was performed to identify factors associated with HPV awareness (heard of HPV), knowledge (HPV can cause cervical cancer), and adherence to the United States Preventive Service Task Force 2018 cervical cancer screening guidelines by sociodemographic factors (age, race/ethnicity, education, household income, marital status,) and the intensity of caregiving. Results An estimated 79% of female caregivers were aware of HPV and 84% adhered to the cervical cancer screening guidelines. Caregivers who were older than 50 (OR = 3.62, 1.91–6.85, adherence of aged 21–50 vs. 51–65), Hispanics of race/ethnicity compared with Black/African Americans (OR = 3.14, 1.31–7.52, adherence of Black/African Americans vs. Hispanics), with a high school education or less (OR = 2.34, 1.14–4.82, adherence of Some college or more vs. High school education or less), and with intense caregiving duty (spending 35 h/week or more on caregiving) compared with light-duty (OR = 2.34, 1.10–5.00, adherence of 5–14 h vs. 35 h or more, weekly) had poor adherence to the cervical cancer screening guidelines. Caregivers who were older, racial minorities (Asian, Native Hawaiian/Pacific Islander, American Indian/Alaska Native, Multiple races), and less educated showed lower HPV awareness (Heard of HPV) than their counterparts. Conclusions There are caregiving populations whose HPV awareness and cervical cancer screening adherence are low. To improve their awareness and knowledge of HPV and support their cervical cancer screening behaviors, we need to consider interventions that target those specific populations.

High prevalence of and factors associated with human papillomavirus infection among women attending a tertiary hospital in Gauteng Province, South Africa

Abstract Background Persistent high-risk (hr) human papillomavirus (HPV) infection is a necessary cause of cervical cancer. Cervical cancer is a major public health problem in Sub-Saharan Africa including South Africa. This study investigated the prevalence of and factors associated with hr-HPV infection among women attending a tertiary hospital in Gauteng Province, South Africa. Methods Cervical samples were collected from 526 participants aged ≥ 18 years using a Cervex Brush® Combi and tested for hr-HPV types on the Abbott m2000 analyzer using the Abbott RealTime HR HPV assay. Samples that tested hr-HPV deoxyribonucleic acid (DNA)-positive were further tested for hr-HPV E6/E7 messenger ribonucleic acid (mRNA) using the APTIMA® HPV assay on the Panther system (Hologic, Inc.). Sociodemographic data were collected using a self-administered questionnaire. Binomial regression analysis was used to assess factors associated with hr-HPV infection. Results Overall hr-HPV DNA prevalence was 48.1% (95%CI: 43.8–52.4%). Of the hr-HPV DNA-positives, 24.5% (95%CI: 19.3–30.1) had HPV-16; 12.3% (95%CI: 8.5–16.9) had HPV-18 and 87.4% (95%CI: 82.6–91.2) had other 12 h-HPVs. Of the samples positive for hr-HPV DNA, 84.2% (95%CI: 79.1–88.5) (213/253) were positive for hr-HPV E6/E7 mRNA. Advanced age was an important factor linked to hr-HPV E6/E7 mRNA positivity. Based on multivariate binomial regression analysis, unemployment (PR: 1.50; 95%CI: 1.23–1.83) and being married (PR: 0.61; 95%CI: 0.47–0.81) were identified as statistically significant (p < 0.0001) predictive and protective factors, respectively, for hr-HPV infection. Conclusions The prevalence of hr-HPV infection was high. Furthermore, hr-HPV DNA-positive samples had a high hr-HPV E6/E7 mRNA prevalence. The presence of hr-HPV E6/E7mRNA indicates active infection and thus a greater risk of developing the cervical disease. Therefore, HPV mRNA testing could be a better test to monitor women who are positive with Pap smear before colposcopy is performed to reduce the burden of referrals.

MOCRA: A multi-algorithm clinical decision support system for the early detection of ovarian cancer

Early and accurate triage of adnexal masses remains challenging due to the heterogeneous presentation of ovarian cancer and the fragmented nature of existing diagnostic tools. While several validated algorithms exist-such as NICE NG12, HSE, IOTA Simple Rules, O-RADS v2022, RMI2, and ROMA-each evaluates different aspects of risk, and none provide an integrated, clinically actionable output. We developed MOCRA (Multivariate Ovarian Cancer Risk Assessment), a deterministic, rule-based clinical decision support system (CDSS) designed to harmonize these tools into a unified risk stratification. This retrospective, single-center diagnostic accuracy study included 68 analyzable patients with adnexal masses. MOCRA encoded six validated diagnostic algorithms using object-oriented architecture and combined their outputs through transparent precedence rules to produce a four-level risk classification (low, intermediate, high, indeterminate). Diagnostic performance was evaluated against physician-confirmed outcomes (histopathology or ≥ 6-month follow-up). Functional reliability was assessed using predefined test cases, and usability was evaluated by 15 gynecologic oncologists using the Post-Study System Usability Questionnaire (PSSUQ). Among 68 patients (7 malignant, 61 benign), MOCRA achieved an accuracy of 97.1%, sensitivity 100.0%, specificity 96.7%, F1-score 87.5%, and AUC 0.984. No malignancies occurred in the MOCRA low-risk category. Compared with single algorithms, MOCRA reduced false negatives while maintaining high specificity by cross-validating symptom, biomarker, and ultrasound signals. Functional testing confirmed deterministic and stable performance (mean reliability 4.8/5). Usability ratings were uniformly positive (overall PSSUQ score 4.6/5), with clinicians highlighting the interpretability of the four-tier risk level and the clarity provided by side-by-side algorithm outputs. MOCRA demonstrates strong diagnostic performance and high clinician usability in this pilot evaluation, suggesting that deterministic integration of multiple validated algorithms can improve consistency and reduce missed high-risk cases. However, the small, single-center dataset-particularly the limited number of malignant cases-warrants cautious interpretation. Larger multicenter and prospective studies with extended follow-up are needed to confirm generalizability and real-world clinical impact.

Cervical screening: the evolving landscape

Infiltration Patterns of Cervical Epithelial Microenvironment Cells During Carcinogenesis

BackgroundLocal cellular microenvironment plays a crucial role in the HPV-induced cervical malignant transformation. Characterization of the dynamic infiltration changes of microenvironment cells during cervical carcinogenesis would contribute to a better understanding of involved mechanisms.MethodsThree public gene expression datasets of cervical squamous epithelium samples were collected and combined. We applied seven up-to-date computational methods for infiltrating estimation and compared their results (CD4+ and CD8+ T cells) to the known fraction. After benchmarking the applied methods, the cell filtration patterns were determined and clustered through fuzzy c-means algorithm.ResultsMost methods displayed better performance in predicting the abundance of CD4+ T cell than that of CD8+ T cell. The infiltration patterns of 33 microenvironment cell types (including 31 immune cells and 2 non-immune cells) were determined, and five immune cell clusters with distinct features were then derived. Meanwhile, opposite changes in abundance were observed between the activated and resting state of some immune cells from the progression perspective.ConclusionsBased on characteristics and evaluation performance of different methods, as well as previous findings, for the first time we provide a comprehensive overview of the infiltration patterns of microenvironment cells throughout cervical cancer progression.

Perception and Practice of Cervical Cancer Screening Services and the Role of Social Workers in Facilitating Screening Uptake in Enugu State, Nigeria

We examined the perception and practice of cervical cancer screening among women in Enugu State, Nigeria. We employed mixed methods and conveniently sampled women aged >15 years. The quantitative data were subjected to chi-square and regression analysis while the qualitative data were analyzed using thematic analysis. The study findings show that over 57% of the respondents have a positive perception of cervical cancer screening while over 80% revealed that they practice cervical cancer screening. Factors such as education, income, and residence are significant in predicting the practice of cervical cancer screening. Therefore, social work strategies to leverage these modifiable predictors in facilitating cervical screening uptake are recommended.

Fine mapping of RNA isoform diversity using an innovative targeted long-read RNA sequencing protocol with novel dedicated bioinformatics pipeline

Solving the structure of mRNA transcripts is a major challenge for both research and molecular diagnostic purposes. Current approaches based on short-read RNA sequencing and RT-PCR techniques cannot fully explore the complexity of transcript structure. The emergence of third-generation long-read sequencing addresses this problem by solving this sequence directly. However, genes with low expression levels are difficult to study with the whole transcriptome sequencing approach. To fix this technical limitation, we propose a novel method to capture transcripts of a gene panel using a targeted enrichment approach suitable for Pacific Biosciences and Oxford Nanopore Technologies platforms. We designed a set of probes to capture transcripts of a panel of genes involved in hereditary breast and ovarian cancer syndrome. We present SOSTAR (iSofOrmS annoTAtoR), a versatile pipeline to assemble, quantify and annotate isoforms from long read sequencing using a new tool specially designed for this application. The significant enrichment of transcripts by our capture protocol, together with the SOSTAR annotation, allowed the identification of 1,231 unique transcripts within the gene panel from the eight patients sequenced. The structure of these transcripts was annotated with a resolution of one base relative to a reference transcript. All major alternative splicing events of the BRCA1 and BRCA2 genes described in the literature were found. Complex splicing events such as pseudoexons were correctly annotated. SOSTAR enabled the identification of abnormal transcripts in the positive controls. In addition, a case of unexplained inheritance in a family with a history of breast and ovarian cancer was solved by identifying an SVA retrotransposon in intron 13 of the BRCA1 gene. We have validated a new protocol for the enrichment of transcripts of interest using probes adapted to the ONT and PacBio platforms. This protocol allows a complete description of the alternative structures of transcripts, the estimation of their expression and the identification of aberrant transcripts in a single experiment. This proof-of-concept opens new possibilities for RNA structure exploration in both research and molecular diagnostics.

An exercise and nutrition intervention for ovarian cancer patients during and after first-line chemotherapy (BENITA study): a randomized controlled pilot trial

Data on the treatment-supporting effect of modifiable lifestyle factors such as nutrition and physical activity on survival or quality of life (QoL) are scarce in patients with ovarian cancer. Despite a strong rationale for evaluating the effect of a multimodal intervention and multiple studies targeting other cancer sites, randomized controlled trials (RCTs) on the effects of a combined nutrition and exercise intervention on survival and QoL in ovarian cancer patients are rare. No study has investigated the impact of an early intervention during first-line chemotherapy. To evaluate the study design, feasibility, safety, and acceptance of combined nutrition and exercise in patients diagnosed with ovarian cancer during and after first-line chemotherapy. Physical exercise and a cancer-specific nutrition intervention after ovarian cancer diagnosis is feasible, accepted, and safe for patients receiving first-line chemotherapy. A 1:1 RCT with an intervention group and a control group. The intervention group receives an exercise and nutrition program whereas the control group continues to follow the usual care. Inclusion: women ≥18 years of age; women diagnosed with ovarian cancer, tubal cancer, or peritoneal cancer and primary or interval debulking surgery. Exclusion: Eastern Cooperative Oncology Group (ECOG) status of 2 or worse. Recruitment rate, completion rate, side effects, and adherence. n=30 patients (15 per arm) will be recruited. Accrual completion is planned for the end of 2019. Results will be presented in the months following study completion 1 year after recruitment has been finalised. The pilot phase was approved by the ethics committee of the Medical Faculty of Hamburg on December 13, 2017 (PV5456). The study was registered on September 9, 2018 at the German Study Registry for Clinical Studies (DRKS00013231).

Topical 5-aminolevulinic acid photodynamic therapy for cervical high-grade squamous intraepithelial lesions

To evaluate the efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in the treatment of high-grade squamous intraepithelial lesions of the cervix (HSIL). This retrospective study included 22 female patients with histologically confirmed HSIL and high-risk human papillomavirus (HR-HPV) infections. Patients were treated with ALA-PDT once a week for a total of 6 times. All patients had a follow-up period of 3 months and 6 months. The assessment of effectiveness of ALA-PDT was performed by ThinPrep cytology test (TCT), HPV DNA assay, HPV E6/E7 mRNA examination, colposcopy, biopsy, and immunohistochemistry detection. Three months after 5-ALA PDT, the histologic disappearance rate was 81.82% (18/22), while the HPV clearance rate was 54.55% (12/22). At the 6 months checkpoint, the HSIL disappearance rate was 90.91% (20/22) and the HPV clearance rate was 86.36% (19/22). Before PDT, 68.18% of patients (15/22) were confirmed with TCT abnormalities, while only one patient (1/22, 4.55%) was abnormal in the TCT test at 6 months checkpoint. All participants were found HPV E6/E7 mRNA positive initially, while the HPV E6/E7 mRNA negative rate was 90.91% (20/22) at 6 months checkpoint. Additionally, we found a significant difference of the expression of CD4+ and CD8+ T cells and HPV E6 and E7 proteins before ALA-PDT and at 3 months follow-up (P < 0.01). No severe side effects were seen. Topical 5-ALA PDT is an effective treatment for cervical HSIL with HR-HPV infection.

Synergistic effects of thalidomide and cisplatin are mediated via the PI3K/AKT and JAK1/STAT3 signaling pathways in cervical cancer

Thalidomide (THD) has been found to synergize with cisplatin (DDP) in certain types of cancers; however, their combined use in the treatment of cervical cancer has not been reported to date, at least to the best of our knowledge. Thus, the present study aimed to explore the synergistic effects of THD and DDP and determine their regulatory effects on the phosphoinositide 3‑kinase (PI3K)/protein kinase B (AKT) and Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) pathways in cervical cancer. For this purpose, 0‑160 µM THD and 0‑64 µM DDP monotherapy or in combination were used to treat the HeLa and SiHa cervical cancer cell lines. This was followed by the calculation of the combination index (CI) and 160 µM THD and 16 µM DDP were then used to treat the cells. Relative cell viability and apoptosis, as well as the mRNA and protein levels of PI3K, AKT, JAK1 and STAT3 were evaluated. The results revealed that THD and DDP monotherapy suppressed the viability of the HeLa and SiHa cells in a concentration‑dependent manner. Moreover, THD and DDP treatment exerted a more prominent suppressive effect on the relative viability of HeLa and SiHa cells compared with DDP monotherapy at several concentration settings; further CI calculation revealed that the optimal synergistic concentrations were 160 µM for THD and 16 µM for DDP. Subsequently, combined treatment with THD and DDP suppressed relative cell viability, whereas it promoted cell apoptosis compared with THD or DPP monotherapy; it also inhibited the PI3K/AKT and JAK1/STAT3 signaling pathways compared with DPP or THD monotherapy in both HeLa and SiHa cells. On the whole, the present study demonstrated that THD synergizes with DDP to exert suppressive effects on cervical cancer cell lines. This synergistic action also inactivated the PI3K/AKT and JAK1/STAT3 pathways. Thus, these findings suggest that the combined use of THD and DPP may have potential for use in the treatment of cervical cancer.

Using HPV-meta for human papillomavirus RNA quality detection

AbstractIn the era of cervical cancer elimination, accurate and validated pipelines to detect human papillomavirus are essential to elucidate and understand HPV association with human cancers. We aimed to provide an open-source pipeline, “HPV-meta”, to detect HPV transcripts in RNA sequencing data, including several steps to warn operators for possible viral contamination. The “HPV-meta” pipeline automatically performs several steps, starting with quality trimming, human genome filtering, HPV detection (blastx), cut-off settlement (10 reads and 690 bp coverage to make an HPV call) and finishing with fasta sequence generation for HPV positive samples. Fasta sequences can then be aligned to assess sequence diversity among HPV positive samples. All RNA sequencing files (n = 10,908) present in the cancer genome atlas (TCGA) were analyzed. “HPV-meta” identified 25 different HPV types being present in 488/10,904 specimens. Validation of results showed 99.98% agreement (10,902/10,904). Multiple alignment from fasta files warned about high sequence identity between several HPV 18 and 38 positive samples, whose contamination had previously been reported. The “HPV-meta” pipeline is a robust and validated pipeline that detects HPV in RNA sequencing data. Obtaining the fasta files enables contamination investigation, a non very rare occurrence in next generation sequencing.

Maintaining the Partnership Between a Tribal Breast and Cervical Cancer Program and a University-Based Cancer Prevention Center During COVID-19 Lock-Down Restrictions-A Case Study

To inform women of the Navajo Nation of safety measures implemented to minimize COVID-19 virus exposure during screening and treatment procedures at Navajo Nation based health care facilities, the Navajo Nation Breast and Cervical Cancer Prevention Program (NNBCCPP) and the University-based Partnership for Native American Cancer Prevention Program (NACP) collaborated to develop a podcast to describe the continued availability of services. During the COVID-19 pandemic, women of all ages and ethnicities in the US needing breast and cervical cancer prevention screenings and treatment, have been hesitant to seek services given the advice to avoid crowded spaces and maintain physical distancing. Epidemiological trends indicate that proactive, intensive strategies are needed in Native American communities for early detection and treatment to support early cancer diagnosis and improve cancer survival. The NNBCCPP and Northern Arizona University (NAU) through the National Institute of Health's National Cancer Institute funded NACP had a nascent partnership prior to the onset of COVID-19 pandemic. This partnership relied on face-to-face interaction to allow for informal social interaction, facilitate clear communication and support continued trust building. To adhere to federal, state and tribal recommendations to minimize gatherings and to stay in-place to minimize the spread of the virus, the Navajo Nation and NAU restricted, and in most cases would not approve employee travel for partnership meetings. The plans to develop a podcast necessitated bringing additional members into the collaboration who were unfamiliar to the original partners and due to travel restrictions, required all interactions to be remote. This expanded group met virtually to develop a script, record and edit the podcast. More importantly, group members had to build and maintain trust over months of communicating via a teleconference video platform. This collaborative addressed challenges related to unstable Internet connections and periodic stay-at-home policies; thus, these emerging partners had to modify social and professional communication to respect and accommodate the stress and uncertain circumstances created by the pandemic on the citizens and employees of Navajo Nation. This case study describes strategies used to maintain and respect all members of the partnership.

Single-cell RNA sequencing reveals key signaling pathways and biological functions in giant cell tumors of bone

Enhancement of Conventional and Photodynamic Therapy for Treatment of Cervical Cancer with Cannabidiol

Cervical cancer (CC) is the fourth most diagnosed cancer in women worldwide. Conventional treatments include surgery, chemo- and radiotherapy, however these are invasive and may cause severe side effects. Furthermore, approximately 70% of late-stage CC patients experience metastasis, due to treatment resistance and limitations. Thus, there is a dire need to investigate alternative therapeutic combination therapies. Photodynamic therapy (PDT) is an alternative CC treatment modality that has been clinically proven to treat primary CC, as well as to limit secondary metastasis. Since PDT is a non-invasive localized treatment, with fewer side effects and lessened resistance to dose repeats, it is considered far more advantageous. However, more clinical trials are required to refine its delivery and dosing, as well as improve its ability to activate specific immune responses to eradicate secondary CC spread. Cannabidiol (CBD) isolates have been shown to exert in vitro CC anticancer effects, causing apoptosis post treatment, as well as inducing specific immune responses, which obstruct tumor invasion and angiogenesis, and so hinder CC metastatic spread. This review paper discusses the current conventional and alternative PDT treatment modalities for CC, as well as their limitations over the last 10 years. It has a particular focus on the combinative administration of CBD with these treatments in order to prevent CC secondary migration and so possibly encourage future research studies to focus on this synergistic effect to eradicate CC.

Expression of CD44v6 and RCAS1 in Uterine Cervical Carcinoma Infected with Human Papillomavirus and Its Effect on Cell Proliferation and Differentiation

To investigate the expression of CD44v6 and RCAS1 and the presence of HPV in cervical cancer tissues, to determine serum RCAS1 levels, and to evaluate these components in correlation with clinicopathologic features and survival. A total of 52 patients consisting of 28 squamous cell carcinoma (SCC) and 24 adenocarcinoma cases, were studied. RCAS1 and CD44v6 expression was evaluated using immunohistochemical staining. HPV 16 and 18 E6 genes were detected using PCR, and serum RCAS1 concentrations were measured using ELISA. Associations between these factors and clinicopathologic features and survival were analyzed. CD44v6 expression was significantly higher in SCC compared with that in adenocarcinoma (P<0.001). It also showed a significant relation to histologic grade (P<0.001) and tumor size (P=0.03). RCAS1 expression was higher in adenocarcinoma than in SCC (P=0.001), and it showed a borderline relation with histological grade (P=0.057). Overall survival was not significantly different in both CD44v6 and RCAS1 expression; however, FIGO stage (P=0.025) and tumor size (P=0.042) resulted statistically different. The pre-surgical treatment serum RCAS1 levels were not associated with any clinicopathological variables. The presence of HPV 16 E6 was higher in SCC, while the presence of HPV 18 E6 was higher in adenocarcinoma (P<0.001). Detection of HPV 16 E6 was significantly associated with expression of CD44v6. The presence of HPV both HPV 16 E6 and HPV 18 E6 was found in cancer tissues with RCAS1 expression, but without any statistical significance. CD44v6 and RCAS1 expression seems to be involved in tumor proliferation and differentiation, but it is not implicated in the progression and invasion of cervical cancer infected by HPV. Pre-treatment levels of serum RCAS1 in cervical cancer are not a diagnostic and predictive biomarker.

Analysis of Rapid arc-based Radiation Therapy on Dosimetric Parameters in Cervical Cancer Patients with and without Bone Marrow Sparing

The standard treatment for cervical cancer is chemoradiation therapy. Pelvic radiation is associated with higher dose to bone marrow (BM) causing interrupted treatment due to haematologic toxicity with inferior outcomes. This study aims to evaluate rapid arc technique in sparing pelvic BM and dosimetric parameters for pelvis V5GY, V10GY, V20GY, V30GY, and V40GY dose. Twenty one cervical cancer patients were selected for the analysis. Planning target volume (PTV) contours, total pelvic BM and surrounding structures contours were standardised. Two rapid arc based procedures were designed for individual patient. One was done using bone marrow sparing (BMS) constraints while other was performed without BMS constraints. Data for both plans was calculated with regard to PTV, normal structures and pelvic BM. Difference in dose distribution in both groups was analysed using Wilcoxon and Friedman ANOVA test. In the presence of BM constraint a significant changes in pelvic BM dose for values of V10GY (p=0.002), V20GY (p=0.002) and V40GY (p=0.025) was observed. The coverage of PTV was found to be unaffected by adding BM constraint. The BM is radiosensitive structure so dosage is linked with haemtological toxicity. Increased dose is associated with higher grade of haematological toxicity in pelvic radiotherapy. The study suggests that adding BM constraint in plans reduced the pelvic BM dose while not affecting PTV coverage and dose to bowel, bladder and rectum. Bone marrow constraint in pelvic radiotherapy can be considered for better treatment toleration and to determine its role in decreasing haematological toxicity.

A unique Levey–Jennings control chart used for internal quality control in human papillomavirus detection

Abstract Objective The purpose of this study was to provide an updated estimate of the prevalences of different types of human papillomavirus (HPV) in females in Chaoshan District and to establish an internal quality control (IQC) method for excluding false-positive results in HPV detection by using the Levey–Jennings control chart. Method HPV types were detected in 23,762 cervical samples by using PCR membrane hybridization. The means and standard deviations (SDs) of the positive rates were calculated, the Levey–Jennings chart was plotted, and the rules for “out of control” and “warning” were established. A set of standardized IQC for HPV DNA tests was developed based on the values and Levey–Jennings charts. Result In 466 batches, the positive rate exceeded the 1 + 2SD rule 24 times, but there was no consecutive exceedance, which was considered “in control”. When the positive rate exceeded the 1 + 3SD rule 8 times with consecutive exceedance, it was considered “out of control”. Further examination revealed that detections showing “out of control” had an undesirable random error, indicating that contamination may occur due to improper operation. Conclusion This unique Levey–Jennings control chart is a practical method for eliminating false-positive results in HPV DNA detection and should be widely applicable in molecular diagnostic laboratories.

An accidentally-found metastatic cervical cancer for three years after loop electrosurgical excision procedure for cervical intraepithelial neoplasia 3

Extracellular vesicle and citrullination signatures are novel biomarkers in sturgeon (Acipenser gueldenstaedtii) during chronic stress due to seasonal temperature challenge.

Emerging Radiopharmaceuticals Beyond FDG for Ovarian Cancer: A Review of Advances in Nuclear Medicine

ABSTRACT Aims This review summarizes the role and future prospects of nuclear medicine in ovarian cancer, focusing on novel radiopharmaceuticals beyond FDG for diagnostic, predictive, and therapeutic applications within a theranostic framework. Materials and Methods A narrative literature review was conducted using major databases. Peer‐reviewed articles addressing non‐FDG radiopharmaceuticals in ovarian cancer were identified and assessed; FDG‐based studies were excluded due to the availability of prior comprehensive reviews. Results Novel radiopharmaceuticals show potential to enhance diagnostic accuracy, allow early evaluation of treatment response, predict chemotherapy resistance, and support stratification for targeted therapies. Several tracers are under investigation for theranostic use, offering combined diagnostic and therapeutic benefits. Discussion Incorporating novel radiopharmaceuticals into ovarian cancer management may help overcome limitations of conventional imaging and systemic therapy. Theranostic strategies, uniting molecular imaging with radionuclide therapy, represent a promising step toward personalized medicine and could significantly influence clinical outcomes. Conclusion Nuclear medicine, through innovative radiopharmaceuticals and theranostic approaches beyond FDG, is expected to expand its role in ovarian cancer care. Further research is needed to validate these applications and facilitate their integration into clinical practice.

Cervical cancer screening programmes and age-specific coverage estimates for 202 countries and territories worldwide: a review and synthetic analysis

Cervical cancer screening coverage is a key monitoring indicator of the WHO cervical cancer elimination plan. We present global, regional, and national cervical screening coverage estimates against the backdrop of the 70% coverage target set by WHO. In this review and synthetic analysis, we searched scientific literature, government websites, and official documentation to identify official national recommendations and coverage data for cervical cancer screening for the 194 WHO member states and eight associated countries and territories published from database inception until Oct 30, 2020, supplemented with a formal WHO country consultation from Nov 27, 2020, to Feb 12, 2021. We extracted data on the year of introduction of recommendations, the existence of individual invitation to participate, financing of screening tests, primary screening and triage tests used, recommended ages and screening intervals, use of self-sampling, and use of screen-and-treat approaches. We also collected coverage data, either administrative or survey-based, as disaggregated as possible by age and for any available screening interval. According to data completeness and representativeness, different statistical models were developed to produce national age-specific coverages by screening interval, which were transformed into single-age datapoints. Missing data were imputed. Estimates were applied to the 2019 population and aggregated by region and income level. We identified recommendations for cervical screening in 139 (69%) of 202 countries and territories. Cytology was the primary screening test in 109 (78%) of 139 countries. 48 (35%) of 139 countries recommended primary HPV-based screening. Visual inspection with acetic acid was the most recommended test in resource-limited settings. Estimated worldwide coverage in women aged 30-49 years in 2019 was 15% in the previous year, 28% in the previous 3 years, and 32% in the previous 5 years, and 36% ever in lifetime. An estimated 1·6 billion (67%) of 2·3 billion women aged 20-70 years, including 662 million (64%) of 1·0 billion women aged 30-49 years, had never been screened for cervical cancer. 133 million (84%) of 158 million women aged 30-49 years living in high-income countries had been screened ever in lifetime, compared with 194 million (48%) of 404 million women in upper-middle-income countries, 34 million (9%) of 397 million women in lower-middle-income countries, and 8 million (11%) of 74 million in low-income countries. Two in three women aged 30-49 years have never been screened for cervical cancer. Roll-out of screening is very low in low-income and middle-income countries, where the burden of disease is highest. The priority of the WHO elimination campaign should be to increase both screening coverage and treatment of detected lesions; however, expanding the efforts of surveillance systems in both coverage and quality control are major challenges to achieving the WHO elimination target. Instituto de Salud Carlos III, European Regional Development Fund, Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia, and Horizon 2020. For the French, Spanish translations of the abstract see Supplementary Materials section.

Prophylactic and Therapeutic HPV Vaccines: Current Scenario and Perspectives

Persistent human papillomavirus (HPV) infection is recognized as the main cause of cervical cancer and other malignant cancers. Although early detection and treatment can be achieved by effective HPV screening methods and surgical procedures, the disease load has not been adequately mitigated yet, especially in the underdeveloped areas. Vaccine, being regarded as a more effective solution, is expected to prevent virus infection and the consequent diseases in the phases of both prevention and treatment. Currently, there are three licensed prophylactic vaccines for L1-VLPs, namely bivalent, quadrivalent and nonavalent vaccine. About 90% of HPV infections have been effectively prevented with the implementation of vaccines worldwide. However, no significant therapeutic effect has been observed on the already existed infections and lesions. Therapeutic vaccine designed for oncoprotein E6/E7 activates cellular immunity rather than focuses on neutralizing antibodies, which is considered as an ideal immune method to eliminate infection. In this review, we elaborate on the classification, mechanism, and clinical effects of HPV vaccines for disease prevention and treatment, in order to make improvements to the current situation of HPV vaccines by provoking new ideas.

Dissecting the Single-Cell Transcriptome Network of Immune Environment Underlying Cervical Premalignant Lesion, Cervical Cancer and Metastatic Lymph Nodes

Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

Role of Immunity and Vaginal Microbiome in Clearance and Persistence of Human Papillomavirus Infection

Cervical cancer disproportionately affects women of reproductive age, with 80% of cases occurring in low- and middle-income countries. Persistent infection with high-risk human papillomavirus (HPV) genotypes has been described as the most common non-systemic biological risk factor for the development of cervical cancer. The mucosal immune system plays a significant role in controlling HPV infection by acting as the first line of host defense at the mucosal surface. However, the virus can evade host immunity using various mechanisms, including inhibition of the antiviral immune response necessary for HPV clearance. Pro-inflammatory cytokines and the vaginal microbiome coordinate cell-mediated immune responses and play a pivotal role in modulating immunity. Recently, diverse vaginal microbiome (associated with bacterial vaginosis) and genital inflammation have emerged as potential drivers of high-risk HPV positivity and disease severity in women. The potential role of these risk factors on HPV recurrence and persistence remains unclear. This article reviews the role of cellular or cytokine response and vaginal microbiome dysbiosis in the clearance, persistence, and recurrence of HPV infection.

Analyzing Stability, Binding Capability and Pharmacokinetic Properties of Allyl Sulfide Combined With Cytotoxic Evaluation in Breast Cancer Cells

Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis

The trade-off between comparative effectiveness and reproductive morbidity of different treatment methods for cervical intraepithelial neoplasia (CIN) remains unclear. We aimed to determine the risks of treatment failure and preterm birth associated with various treatment techniques. In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials database for randomised and non-randomised studies reporting on oncological or reproductive outcomes after CIN treatments from database inception until March 9, 2022, without language restrictions. We included studies of women with CIN, glandular intraepithelial neoplasia, or stage IA1 cervical cancer treated with excision (cold knife conisation [CKC], laser conisation, and large loop excision of the transformation zone [LLETZ]) or ablation (radical diathermy, laser ablation, cold coagulation, and cryotherapy). We excluded women treated with hysterectomy. The primary outcomes were any treatment failure (defined as any abnormal histology or cytology) and preterm birth (<37 weeks of gestation). The network for preterm birth also included women with untreated CIN (untreated colposcopy group). The main reference group was LLETZ for treatment failure and the untreated colposcopy group for preterm birth. For randomised controlled trials, we extracted group-level summary data, and for observational studies, we extracted relative treatment effect estimates adjusted for potential confounders, when available, and we did random-effects network meta-analyses to obtain odds ratios (ORs) with 95% CIs. We assessed within-study and across-study risk of bias using Cochrane tools. This systematic review is registered with PROSPERO, CRD42018115495 and CRD42018115508. 7880 potential citations were identified for the outcome of treatment failure and 4107 for the outcome of preterm birth. After screening and removal of duplicates, the network for treatment failure included 19 240 participants across 71 studies (25 randomised) and the network for preterm birth included 68 817 participants across 29 studies (two randomised). Compared with LLETZ, risk of treatment failure was reduced for other excisional methods (laser conisation: OR 0·59 [95% CI 0·44-0·79] and CKC: 0·63 [0·50-0·81]) and increased for laser ablation (1·69 [1·27-2·24]) and cryotherapy (1·84 [1·33-2·56]). No differences were found for the comparison of cold coagulation versus LLETZ (1·09 [0·68-1·74]) but direct data were based on two small studies only. Compared with the untreated colposcopy group, risk of preterm birth was increased for all excisional techniques (CKC: 2·27 [1·70-3·02]; laser conisation: 1·77 [1·29-2·43]; and LLETZ: 1·37 [1·16-1·62]), whereas no differences were found for ablative methods (laser ablation: 1·05 [0·78-1·41]; cryotherapy: 1·01 [0·35-2·92]; and cold coagulation: 0·67 [0·02-29·15]). The evidence was based mostly on observational studies with their inherent risks of bias, and the credibility of many comparisons was low. More radical excisional techniques reduce the risk of treatment failure but increase the risk of subsequent preterm birth. Although there is uncertainty, ablative treatments probably do not increase risk of preterm birth, but are associated with higher failure rates than excisional techniques. Although we found LLETZ to have balanced effectiveness and reproductive morbidity, treatment choice should rely on a woman's age, size and location of lesion, and future family planning. National Institute for Health and Care Research: Research for Patient Benefit.

National Burden and Trend of Cancer in Ethiopia, 2010–2019: a systemic analysis for Global burden of disease study

AbstractOver the last two decades, we have tracked the national burden of cancer and its trends in Ethiopia, providing estimates of incidence, death, and disability adjusted life years. In Ethiopia, there were an estimated 53,560 (95% UI 52,480–55,540) new incident cases, 39,480 deaths (95% UI 32,640–46,440), and 1.42 million (95% UI 1.16–1.68) DALYs of cancer 2019. Cancer incidence, death, and DALYs counts increased by 32% (95% UI 11–55%), 29% (95% UI 12–44%), and 19% (95% UI − 2 to 44%) between 2010 to 2019, respectively, while age-standardised incidence, death, and DALYs rates increased by 5% (95% UI − 7 to 18%), 2% (95% UI − 9 to 14%), and − 2% (95% UI − 15 to 12%) respectively. In 2019, the leading incidence cases were leukemia, cervical cancer, breast cancer, colon and rectum cancer, and stomach cancer, while leukemia, breast cancer, cervical cancer, and stomach cancer were the most common killer cancers in Ethiopia. According to the findings of this study, tobacco-related cancers such as pancreatic, kidney, and lung cancer have increased in Ethiopian females over the last decade, while genitourinary cancer has increased in Ethiopian males. Another significant finding was that infection-related cancers, such as stomach cancer and Hodgkin lymphoma, have been rapidly declining over the last decade.

Explaining socioeconomic inequality in cervical cancer screening uptake in Malawi

Abstract Background Cervical cancer is a prevalent public health concern and is among the leading causes of death among women globally. Malawi has the second highest cervical cancer prevalence and burden in the world. Due to the cervical cancer burden, the Malawi government scaled up national cancer screening services in 2011, which are free for all women. This paper is the first study to examine the socioeconomic inequality in cervical cancer screening uptake using concentration indices, in Malawi. Furthermore, it decomposes the concentration index to examine how each factor contributes to the level of inequality in the uptake of cervical cancer screening. Methods The data used in this paper were obtained from the nationally representative Malawi Population HIV Impact Assessment (MPHIA) household survey, which was conducted in 2015. Concentration curves were constructed to explore whether there was any socioeconomic inequality in cervical cancer screening and, if so, its extent. This was complemented by concentration indices that were computed to quantify the magnitude of socioeconomic inequality. A decomposition analysis was then conducted to examine the factors that explained/were associated with greater socioeconomic inequality in cervical cancer screening. The methodology in this paper followed that of previous studies found in the literature and used the wealth index to measure socioeconomic status. Results The results showed that the concentration curves lay above the line of equality, implying a pro-rich inequality in cervical cancer screening services. Confirming the results from the concentration curves, the overall concentration index was positive and significant (0.142; %95 CI = 0.127, 0.156; p &lt; 0.01). The magnitude was lower in rural areas (0.075; %95CI = 0.059, 0.090; p &lt; 0.01) than in urban areas (0.195; %95CI = 0.162, 0.228 p &lt; 0.001). After undertaking a decomposition of the concentration index, we found that age, education, rural or urban location, and wealth status account for more than 95% of the socioeconomic inequality in cervical cancer uptake. Conclusion Despite the national scale-up of free cancer care at the point of use, cervical cancer screening uptake in Malawi remains pro rich. There is a need to implement parallel demand-side approaches to encourage uptake among poorer groups. These may include self-testing and mobile screening centres, among others.