Human papillomavirus (HPV) is a leading cause of cervical cancer and other malignancies, necessitating the development of highly sensitive and specific detection tools. This review explores recent advancements in fluorescent nanobiosensors (FNBS) for HPV detection, focusing on the integration of nanomaterials and DNA nanotechnology, highlighting their contributions to improving sensitivity, specificity, and point-of-care (POC) usability. The review critically evaluates a range of nanomaterial-based FNBS, including those employing quantum and carbon dots, nanoclusters, nanosheets, and nanoparticles, discussing their underlying signal amplification mechanisms, target recognition strategies, and limitations related to toxicity, stability, and reproducibility. Furthermore, it examines the application of diverse DNA nanotechnology, such as DNA origami, DNAzyme, catalytic hairpin assembly (CHA), hybridization chain reaction (HCR), and DNA hydrogel in improving FNBS performance. It also addresses the current challenges in clinical translation, emphasizing the necessity for large-scale production methods and thorough clinical validation to ensure biosafety. It also outlines the potential of innovative technologies, such as CRISPR-Cas-based diagnostics and artificial intelligence, to further revolutionize HPV detection and enable accessible, cost-effective screening, particularly in resource-limited settings. This review provides a valuable resource for researchers and clinicians seeking to develop next-generation FNBS for improved HPV diagnostics and cervical cancer prevention.

Limited data are available about the distribution of human papillomavirus (HPV) among women undergoing cervical cancer screening in Mozambique. We describe the prevalence of high-risk HPV risk groups detected in women who participated in the MULHER Study, a prospective trial of Mozambican women undergoing cervical cancer screening with HPV testing.

From January 2020 to January 2023, 9,014 women aged 30-49 years in Maputo City and Gaza Province, Mozambique underwent cervical cancer screening. Cervicovaginal samples were self-collected (97.5%) or provider-collected (2.5%) and primary HPV testing was performed using the GeneXpert HPV testing platform (Cepheid Inc, USA) which provided data on HR-HPV risk groups: HPV16, HPV18/45 and 11 other HR-HPV types in aggregate. Women with a positive HR-HPV test underwent visual assessment using dilute acetic acid applied to the cervix for treatment decisions.

Of the 9,014 women enrolled in the MULHER Study, 8,954 (99.3%) had a valid HPV test result. Of those, 2,805 (31.3%) tested positive for at least one HR-HPV group: HPV16 (n = 475, 16.9%), HPV18/45 (n = 686, 24.6%) and other HR-HPV (n = 2,150, 77.1%). A total of 17.8% were positive for multiple HPV HR groups. HR-HPV infection prevalence was higher among women living with HIV (WLWH) than HIV-negative women (39.7% vs. 24.3% respectively; p < 0.001). WLWH were more likely to test positive for HPV18/45 (p = 0.03) and for two or more HR-HPV risk groups (P < 0.0001) compared with HIV-negative women. HPV16 was the most frequently detected HR-HPV group (56.7%) among women diagnosed with invasive cervical cancer.

HR-HPV prevalence was high among Mozambican women aged 30-49 years, especially among WLWH, consistent with the high burden of cervical cancer in this population. HPV16 was the most common HR-HPV group among women with cervical cancer. Further study is needed to determine the role of HR-HPV genotyping in follow-up and treatment in Mozambique.

The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing, with UV radiation being the main cause. Other risk factors are age, sex, skin type and immunosuppression. Human papillomaviruses (HPVs) are associated with benign and malignant skin tumours. In contrast to anogenital and oropharyngeal carcinomas, which are caused by alpha papillomaviruses, the HPV types associated with cSCC belong to the beta-HPV genus. These viruses infect the skin epithelium and are widespread in skin samples from healthy people. It is assumed that HPV amplifies the DNA damage caused by UV radiation and disrupts the repair mechanisms of the cells, without remaining permanently detectable in the tumour tissue, the so-called hit-and-run theory. The HPV status of tumours appears to have a positive influence on prognosis and response to therapy due to increased immune infiltration, in particular by tissue-resident memory T cells and activation of immune effector cells. This favours responses to immunotherapies such as PD-1/PD-L1 inhibitors, whereas immunosuppression may promote a pro-carcinogenic effect. In conclusion, the role of beta HPV in the development of cSCC appears to be closely associated with the immune status of the host. Depending on the immune status, beta HPV can play either a protective or a tumour-promoting role, and in view of the increasing incidence of skin cancer worldwide, enhancing the immune response against virus-infected keratinocytes, e.g., through HPV vaccination, could represent a promising approach for the prevention and therapy of squamous cell carcinomas.

Background and Objectives: Human papillomavirus (HPV) is one of the most prevalent sexually transmitted illnesses. HPV is responsible for genital condyloma lesions. A durable and effective systemic treatment regimen has not been established for HPV-related infections. In the present study, our purpose was to evaluate the role of active hexose correlated compound (AHCC) in preventing relapse in patients who underwent cauterization for condyloma accuminata. Materials and Methods: A total of 244 individuals admitted to our hospital between January 2019 and June 2022 were diagnosed as having condyloma acuminata, and those who underwent condyloma cauterization were evaluated retrospectively. We included 133 individuals who met the criteria. Patients who received AHCC were scheduled for follow-up examinations at regular intervals every three months. Patients were divided into two groups and analyzed based on whether they did or did not use AHCC. Results: The average age of AHCC non-users was significantly greater than that of AHCC users (p < 0.01). The number of condylomas and the maximum condyloma diameter of AHCC users before treatment were found to be significantly higher than in AHCC non-users (p = 0.006 and p = 0.004, respectively). Among participants with recurrence, the number and diameter of condylomas in AHCC users were significantly lower than in AHCC non-users (p = 0.019 and p = 0.042, respectively). Conclusions: Although the usage of AHCC is not expected to help prevent recurrence after the cauterization of condylomata acuminate in all patients, physicians may consider AHCC as a nutritional supplement and supportive therapy in the absence of other systemic treatments. Consequently, the duration of AHCC support necessary to optimize the effect of AHCC use on relapse prevention requires further evaluation on the basis of both target IFN-β levels and HPV infection status.

Background/Objective: Condyloma acuminatum, also known as genital warts, results from infections of the basal epithelium or mucous membranes by human papillomavirus (HPV). These lesions can significantly impact patients' quality of life. Recent advances in laser technology, particularly ablative lasers such as CO2 and Erbium-YAG (Er:YAG), have introduced new treatment opportunities. The Er:YAG laser has gained recognition as a safe and effective treatment for viral warts. This study aimed to evaluate the efficacy of Er:YAG laser treatment of male genital warts and to identify risk factors that might influence its effectiveness. Methods: A retrospective chart review of 102 patients who underwent Er:YAG laser wart removal between January 2019 and April 2024 was conducted. Results: Of the 102 patients, 61 (60%) achieved complete response by the 12-month follow-up visit. The response rates were significantly lower when there was a high number of sessions required for complete response, long duration between wart onset and laser treatment, high number of warts treated, positive smoking status, concurrent immunosuppressed state, or active metabolic disease. Conclusions: The Er:YAG laser is an effective method for treating recalcitrant warts. Various factors were shown to influence its efficacy.

An increasing number of studies indicate that the gut, cervical, and vaginal microbiota may play crucial roles in the development of cervical cancer (CC). However, the interactions between the microbiota and the host are yet unknown. To address this gap, a systematic review and meta-analysis were conducted to assess the microbiota alterations in a variety of body locations, including the gut and genital tract.

Electronic searches of PubMed, Embase, Web of Science, and the Cochrane Library were conducted to retrieve eligible papers published from January 1, 2014, to January 1, 2024 (PROSPERO: CRD42024554433). This study was restricted to English-language studies reporting on alpha diversity, beta diversity, and relative abundance, as well as on patients with CC whose microbiota had been analyzed via next-generation sequencing technologies. To assess the risk of bias (RoB), we utilized the Newcastle‒Ottawa Quality Assessment Scale (NOS) and the ROBINS-I tool. For the meta-analysis, we employed Review Manager 5.4.

Thirty-six eligible studies were included in this review. The Chao1 index (SMD = 0.96, [95% CI: 0.71, 1.21], I2 = 0%) and the Shannon index (SMD = 1.02, [95% CI: 0.53, 1.50], I2 = 85%) values from vaginal samples were significantly greater in patients than in the controls. In the cervical samples, the Shannon index value (SMD = 1.29, [95% CI: 0.61, 1.97], I2 = 93%) significantly increased, whereas the Chao1 index value did not significantly differ (SMD = 0.50, [95% CI: -0.46, 1.46], I2 = 89%). The Shannon index value (SMD = 0.25, [95% CI: -0.22, 0.72], I2 = 38%) did not significantly differ across the gut samples. The majority of studies (19/25) indicated that the patients and noncancer controls differed significantly in terms of beta diversity. Cancer-associated changes were observed, with a dramatic decrease in the Lactobacillus genus and significant increases in pathogenic bacteria, including the Anaerococcus, Peptostreptococcus, Porphyromonas, Prevotella, and Sneathia genera. Additionally, the impact of antineoplastic therapies on microbial diversity was inconsistently reported across several studies.

This systematic review elucidates the microbiota alterations associated with the prevalence of CC and its response to anti-tumor therapies, aiming to provide insights for future research directions and precision medicine strategies to enhance women's quality of life.

CRD42024554433.

The aim of this systematic review and meta-analysis was to qualitatively and quantitatively evaluate the current evidence on the significance of the loss of early stages of oral carcinogenesis in lesions diagnosed according to clinical and/or histopathological criteria and their evolution to oral cancer.

We searched MEDLINE (through PubMed), Embase, Scopus and Web of Science for primary-level studies published before November 2024, designed as prospective or retrospective longitudinal cohorts, and not restricted by language or publication date. The risk of bias was critically assessed using the QUIPS tool. Meta-analyses, heterogeneity exploration, sensitivity and small-study effect analyses were conducted.

The inclusion criteria were met by six primary-level studies, which recruited 330 patients with OPMDs with follow-up data. The loss of pRb expression, assessed through immunohistochemistry, was significantly associated with a higher malignant transformation risk of OPMDs (RR = 1.92, 95%CI = 1.25-2.94, p = 0.003). The leukoplakia subgroup retained this significant association (p = 0.006), being the OPMD where the loss of pRb expression showed the best predictive value for malignant transformation (RR = 2.00, 95%CI = 1.22-3.29). Regarding the immunohistochemical technique and scoring methods, better performance and results were achieved by applying a cutoff point > 10% pRb-positive cells with nuclear staining (RR = 2.10, 95%CI = 1.30-3.38, 95%CI = 0.002).

The present systematic review and meta-analysis supports that the loss of expression of the tumor suppressor pRb, assessed through immunohistochemistry, is a predictor of the malignant transformation risk of oral leukoplakias. Future studies are needed in other OPMDs following the recommendations provided based on current evidence gaps.

Cervical cancer, primarily caused by HPV infection, remains a global health concern. Current treatments face challenges including drug resistance and toxicity. This study investigates combining E5-siRNA with chemotherapy drugs, Oxaliplatin and Ifosfamide, to enhance treatment efficacy in HPV-16 positive cervical cancer cells, targeting E5 oncoprotein to overcome limitations of existing therapies.

The CaSki cervical cancer cell line was transfected with E5-siRNA, and subsequently treated with Oxaliplatin/Ifosfamide. Quantitative real-time PCR was employed to assess the expression of related genes including p53, MMP2, Nanog, and Caspases. Cell apoptosis, cell cycle progression, and cell viability were evaluated using Annexin V/PI staining, DAPI staining, and MTT test, respectively. Furthermore, stemness ability was determined through a colony formation assay, and cell motility was assessed by wound healing assay.

E5-siRNA transfection significantly reduced E5 mRNA expression in CaSki cells compared to the control group. The MTT assay revealed that monotherapy with E5-siRNA, Oxaliplatin, or Ifosfamide had moderate effects on cell viability. However, combination therapy showed synergistic effects, reducing the IC50 of Oxaliplatin from 11.42 × 10-8 M (45.36 μg/ml) to 6.71 × 10-8 M (26.66 μg/ml) and Ifosfamide from 12.52 × 10-5 M (32.7 μg/ml) to 8.206 × 10-5 M (21.43 μg/ml). Flow cytometry analysis demonstrated a significant increase in apoptosis for combination treatments, with apoptosis rates rising from 11.02 % (Oxaliplatin alone) and 16.98 % (Ifosfamide alone) to 24.8 % (Oxaliplatin + E5-siRNA) and 34.9 % (Ifosfamide + E5-siRNA). The sub-G1 cell population increased from 15.7 % (Oxaliplatin alone) and 18 % (Ifosfamide alone) to 21.9 % (Oxaliplatin + E5-siRNA) and 27.1 % (Ifosfamide + E5-siRNA), indicating cell cycle arrest. The colony formation assay revealed a substantial decrease in the number of colonies following combination treatment. qRT-PCR analysis showed decreased expression of stemness-related genes CD44 and Nanog, and migration-related genes MMP2 and CXCL8 in the combination groups. Apoptosis-related genes Casp-3, Casp-9, and pP53 showed increased expression following combination therapy, while BAX expression increased and BCL2 expression decreased relative to the control.

The study demonstrates that combining E5-siRNA with Oxaliplatin or Ifosfamide enhances the efficacy of chemotherapy in HPV-16 positive cervical cancer cells. This synergistic approach effectively targets multiple aspects of cancer cell behavior, including proliferation, apoptosis, migration, and stemness. The findings suggest that this combination strategy could potentially allow for lower chemotherapy doses, thereby reducing toxicity while maintaining therapeutic efficacy. This research provides valuable insights into targeting HPV E5 as a complementary approach to existing therapies focused on E6 and E7 oncoproteins, opening new avenues for combination therapies in cervical cancer treatment.

In 2012, the Department of Visceral Surgery of the Lausanne University Hospital CHUV implemented a dedicated high-resolution anoscopy (HRA) outpatient clinic for surveillance and follow-up purposes. This 10-year longitudinal study analyzed 537 patients (2214 visits) using a structured screening protocol. Dysplastic lesions were detected in 49% of patients, predominantly low-grade squamous intraepithelial lesions (LSILs, 74%). Among LSIL cases, 6% progressed to high-grade squamous intraepithelial lesions (HSILs) within 24 months, reaching 25% cumulative progression at 36 months. Of HSIL patients, 3% developed carcinoma in situ after 48 months. Notably, no invasive carcinoma was observed during the follow-up. Four patients diagnosed with squamous cell carcinoma at initial screening were treated with chemoradiotherapy, and one required salvage surgery. Independent risk factors for the presence of higher-stage precancerous lesions (≥HSILs) were the presence of high-risk HPV genotypes (OR 14.5, 95% CI 5-42.2, p < 0.001), detectable HIV viral load (OR 5.4, 95% CI 1.8-16.7, p = 0.003), and symptoms at the first screening visit (OR 3.2, 95% CI 1.1-9.9, p = 0.04). HIV-positive status was associated with a trend towards an increased risk of progression (OR 2.79, p = 0.073). These findings highlight the importance of systematic follow-up and early intervention in high-risk populations to prevent anal cancer progression.

BackgroundIn the global scenario of public health, cervical cancer poses a major threat with high mortality rates, especially in women. New incidence cases and prevalence vary across different regions, as recently shown by GLOBOCAN data. The development of cervical cancer is primarily due to persistent infection by high-risk genotypes of human papillomavirus (HPV), which is a multifaceted process that is influenced by genetic, environmental, and lifestyle factors.PurposeThe goal of this study is to thoroughly investigate cervical cancer, including its etiology, molecular mechanisms, progression, diagnosis strategies, and current therapies. This review further highlights the transformative power of HPV vaccination and screening programs in curbing the disease's burden and potentially promising novel approaches like immunotherapy and targeted therapy.Research DesignThis is a narrative review article that summarizes previous literatures regarding cervical cancer in terms of molecular mechanism, etiology, clinical developments, and prevention.Study SampleThe review encompassed studies from diverse sources, including experimental, observational, and clinical research published between 1992 and 2025.Data Collection and/or AnalysisData were collected through comprehensive literature searches using databases such as PubMed, Scopus, and the Cochrane Library with defined inclusion and exclusion criteria.ResultsNonetheless, there are gaps in research and controversies regarding vaccine coverage, screening practices, and treatment accessibility for poor populations. Precision medicine trends are emerging along with new biomarkers for early detection and personalized treatment, which also form part of this discussion. Key findings include the critical role of prevention measures in controlling the global impact of cervical cancer.ConclusionsThe paper synthesizes the existing knowledge and identifies gaps that require further research, which is significant in augmenting prevention, diagnosis, and treatment of cervical cancer towards addressing its public health implications worldwide.

HER-2/neu, a membrane-bound receptor encoded on chromosome 17q21, is involved in carcinogenesis across several cancers, including breast, stomach, and cervical cancer. This study evaluates HER-2/neu expression in premalignant and malignant cervical lesions and correlates it with histological types and grades.

This prospective hospital-based study, conducted at the Department of Pathology of a tertiary care teaching hospital in Eastern India, included 74 cases (11 premalignant, 63 malignant) from January 2023 to October 2024. HER-2/neu expression was analyzed using immunohistochemistry (IHC), and scoring was based on the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) 2013 guidelines. Statistical analysis was performed to determine correlations.

HER-2/neu positivity was observed in 8 (10.8%) out of 74 cases. Among squamous cell carcinomas (SCC), poorly differentiated cases showed maximum positivity in 4 (66.7%) cases, followed by moderately differentiated SCC in 2 (33.3%) cases, with no positivity in well-differentiated SCC. Among adenocarcinomas (a total of 10 (13.5%) among 74 in number), only 1 (12.5%) out of 8 cases were found to be Her-2/neu positive. Premalignant lesions demonstrated positivity in one (9.1%) case only. There was no statistically significant correlation between HER-2/neu expression and histological grade or presence of malignancy.

HER-2/neu expression is higher in malignant cervical lesions compared to premalignant ones, suggesting its role in tumor progression. Further studies with larger sample sizes and additional variables like human papillomavirus (HPV) status are recommended to explore its prognostic potential.

Cancer is a significant global health concern associated with multiple distinct factors, including microbial and viral infections. Numerous studies have elucidated the role of microorganisms, such as Helicobacter pylori (H. pylori), as well as viruses for example human papillomavirus (HPV), hepatitis B virus (HBV), and hepatitis C virus (HCV), in the development of human malignancies. Substantial attention has been focused on the treatment of these microorganism- and virus-associated cancers, with promising outcomes observed in studies employing peptide-based therapies. The current paper provides an overview of microbe- and virus-induced cancers and their underlying molecular mechanisms. We discuss an assortment of peptide-based therapies which are currently being developed, including tumor-targeting peptides and microbial/viral peptide-based vaccines. We describe the major technological advancements that have been made in the design, screening, and delivery of peptides as anticancer agents. The primary focus of the current review is to provide insight into the latest research and development in this field and to provide a realistic glimpse into the future of peptide-based therapies for microbe- and virus-induced neoplasms.

Human papillomavirus (HPV) is involved in virtually all cases of cervical cancer. However, HPV alone is not sufficient to cause malignant development. The effects of chronic inflammation and the interaction of immune components with the microenvironment infected with the high-risk HPV type (HR) may contribute to cancer development. Transforming growth factor β (TGFB) appears to play an important role in cervical carcinogenesis. Protein and mRNA levels of this cytokine gradually increase as normal tissue develops into malignant tissue and are closely related to the severity of HPV infection. At the onset of infection, TGFB can inhibit the proliferation of infected cells and viral amplification by inhibiting cell growth and downregulating the transcriptional activity of the long control region (LCR) of HPV, thereby reducing the expression of early genes. When infected cells progress to a malignant phenotype, the response to the cell growth inhibitory effect of TGFB1 is lost and the suppression of E6 and E7 expression decreases. Subsequently, TGFB1 expression is upregulated by high levels of E6 and E7 oncoproteins, leading to an increase in TGFB1 in the tumor microenvironment, where this molecule promotes epithelial-to-mesenchymal transition (EMT), cell motility, angiogenesis, and immunosuppression. This interaction between HPV oncoproteins and TGFB1 is an important mechanism promoting the development and progression of cervical cancer.

Cervical cancer (CaCx) is a major public health issue, with over 600,000 women diagnosed annually. CaCx kills someone every 90 s, mostly in low- and middle-income countries. There are effective yet imperfect mechanisms to prevent CaCx. Since human papillomavirus (HPV) infections cause most CaCx, they can be prevented by vaccination. Screening methodologies can identify premalignant lesions and allow interventions before a CaCx develops. However, these tools are less feasible in resource-poor environments. Additionally, current screening modalities cannot triage lesions based on their relative risk of progression, which results in overtreatment. CaCx care relies heavily on genotoxic agents that cause severe side effects. This review discusses ways that recent technological advancements could be leveraged to improve CaCx care and prevention.

Human papillomavirus (HPV) infection plays an important role in cervical cancer. HPV is classified within the Papillomaviridae family and is a non-enveloped, small DNA virus. HPV infection can be classified into two distinct scenarios: i) With or without integration into the host chromosomes. Detection of its infection can be useful in the study of cervical lesions. In the present review, the structural and functional features of HPV, HPV typing, infection and transmission mode, the risk factors for cervical susceptibility to infection and HPV detection methods are described in detail. The development of HPV detection methods may have far-reaching significance in the prevention and treatment of cervical disease. This review summarizes the advantages and limitations of each HPV detection method.

High-risk human papillomavirus (HPV) infections are responsible for cervical cancer. However, little is known about the differences between HPV types and risk categories regarding their genetic diversity and particularly APOBEC3-induced mutations - which contribute to the innate immune response to HPV. Using a capture-based next-generation sequencing, 156 HPV whole genome sequences covering 43 HPV types were generated from paired cervical and anal swabs of 30 Togolese female sex workers (FSWs) sampled in 2017. Genetic diversity and APOBEC3-induced mutations were assessed at the viral whole genome and gene levels. Thirty-four pairwise sequence comparisons covering 24 HPV types in cervical and anal swabs revealed identical infections in the two anatomical sites. Differences in genetic diversity among HPV types was observed between patients. The E6 gene was significantly less conserved in low-risk HPVs (lrHPVs) compared to high-risk HPVs (hrHPVs) (p = 0.009). APOBEC3-induced mutations were found to be more common in lrHPVs than in hrHPVs (p = 0.005), supported by our data and by using large HPV sequence collections from the GenBank database. Focusing on the most common lrHPVs 6 and 11 and hrHPVs 16 and 18, APOBEC3-induced mutations were predominantly found in the E4 and E6 genes in lrHPVs, but were almost absent in these genes in hrHPVs. The variable APOBEC3 mutational signatures could contribute to the different oncogenic potentials between HPVs. Further studies are needed to conclusively determine whether APOBEC3 editing levels are associated to the carcinogenic potential of HPVs at the type and sublineage scales.

The Lower Anogenital Squamous Terminology (LAST) Project recommended unified classification for HPV-associated squamous lesions of the lower anogenital tract, using a 2-tiered nomenclature in 2013. Adherence to the new nomenclature worldwide is unknown. This study aims to assess the trend of the use of the two-tiered High Squamous Intraepithelial Lesion and Low Squamous Intraepithelial Lesion (HSIL/LSIL) as opposed to the traditional three-tiered Anal Intraepithelial Neoplasia (AIN I/II/III) classification as suggested by the LAST Project.

A literature search on full-text English language studies of premalignant anal lesion was performed on PubMed from 2002-2022. The studies were categorized by continent, and the prevalence of HSIL/LSIL classification vs AIN I/II/III was calculated.

546 studies and 251 studies were identified using the AIN I/II/II and the HSIL/LSIL classification respectively. Global trend suggested a statistically significant downward trend in the use of the two-tiered nomenclature system in publications globally. Regional trend including North America, Europe, and other (Asia and Latin America) showed variance in adoption of the two-tiered nomenclature system.

Despite multidisciplinary collaborative effort, adherence to the recommendations to use the two-tiered system for HPV-associated premalignant anal lesions continues to be suboptimal. Further efforts are needed to identify the cause of poor adherence to be able to create strategies that reinforces unification of terminology and integration of LAST the recommendations.

Human papillomaviruses (HPV), most commonly HPV16, are associated with a subset of head and neck squamous cell carcinoma (HNSCC) tumors, primarily oropharyngeal carcinomas, with integration of viral genomes into host chromosomes associated with worse survival outcomes. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. The role of BET protein-mediated transcription of viral-cellular genes in the viral-HNSCC genomes needs to be better understood. Using a combination of TAME-Seq, qRT-PCR, and immunoblot analyses, we show that BET inhibition downregulates E6 and E7 significantly, with heterogeneity in the downregulation of viral transcription across different HPV+ HNSCC cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4, mirroring the downregulation of viral E6 and E7 expression. We found that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A (p21) expression, leading to a G1-cell cycle arrest with apoptotic activity. Overall, our studies demonstrate that BET inhibition regulates both E6 and E7 viral and key cellular cell cycle regulator E2F gene expression and cellular gene expression in HPV-associated HNSCC and highlight the potential of BET inhibitors as a therapeutic strategy for this disease while also underscoring the importance of considering the heterogeneity in cellular responses to BET inhibition.

Replication-defective viral vector vaccines have several advantages over conventional subunit vaccines, including potent antibody responses, cellular responses critical for eliminating pathogen-infected cells, and the induction of highly immunogenic and durable immune responses without adjuvants. The Human papillomavirus (HPV), a microorganism with over 200 genotypes, plays a crucial role in inducing human tumors, with the majority of HPV-related malignancies expressing HPV proteins. Tumors associated with HPV infection, most of which result from HPV16 infection, include those affecting the cervix, anus, vagina, penis, vulva, and oropharynx. In recent years, the development of therapeutic HPV vaccines utilizing viral vectors for the treatment of premalignant lesions or tumors caused by HPV infection has experienced rapid growth, with numerous research pipelines currently underway. Simultaneously, screening for optimal antigens requires more basic research and more optimized methods. In terms of preclinical research, we present the various models used to assess vaccine efficacy, highlighting their respective advantages and disadvantages. Further, we present current research status of therapeutic vaccines using HPV viral vectors, especially the indications, initial efficacy, combination drugs, etc. In general, this paper summarizes current viral vector therapeutic HPV vaccines in terms of HPV infection, antigen selection, vectors, efficacy evaluation, and progress in clinical trials.

Human papillomavirus (HPV) is a major cause of cervical cancer. As the natural history of HPV-associated cervical lesions is HPV genotype-dependent, it is important to understand the characteristics of these genotypes and to manage them accordingly. Among high-risk HPVs, HPV16 and 18 are particularly aggressive, together accounting for 70% of HPV genotypes detected in cervical cancer. Other than HPV16 and 18, HPV31, 33, 35, 45, 52, and 58 are also at a high risk of progression to cervical intraepithelial neoplasia (CIN)3 or higher. Recent studies have shown that the natural history of HPV16, 18, 52, and 58, which are frequently detected in Japan, depends on the HPV genotype. For example, HPV16 tends to progress in a stepwise fashion from CIN1 to CIN3, while HPV52 and 58 are more likely to persist in the CIN1 to CIN2 state. Among the high-risk HPVs, HPV18 has some peculiar characteristics different from those of other high-risk HPV types; the detection rate in precancerous lesions is much lower than those of other high-risk HPVs, and it is frequently detected in highly malignant adenocarcinoma and small cell carcinoma. Recent findings demonstrate that HPV18 may be characterized by latent infection and carcinogenesis in stem cell-like cells. In this context, this review outlines the natural history of HPV-infected cervical lesions and the characteristics of each HPV genotype.

The purpose of this research was to evaluate, in a tertiary care context, the effects of human papillomavirus (HPV) infection on the incidence and prognosis of oral malignancies.

At a tertiary care hospital, 100 patients who received an oral cancer diagnosis between 2020 and 2022 were the subject of a retrospective analysis. Medical records were used to gather clinicopathological data, and histopathological specimens' molecular analyses were used to ascertain the HPV infection status. To assess the variations in overall and disease-free survival between HPV-positive [HPV+] and HPV-negative [HPV-] patients, survival analysis was done.

Of the oral malignancies that tested positive for HPV, 25% were caused by strains HPV-16 and HPV-18. Patients who tested positive for HPV had unique clinicopathological characteristics, such as a decreased prevalence of lymph node involvement, nonkeratinizing histology, and younger age at diagnosis. When compared to HPV- patients, HPV+ patients had substantially better overall survival (P = 0.032) and disease-free survival (P = 0.047) according to survival analysis.

The incidence and prognosis of oral malignancies are significantly impacted by HPV infection, as demonstrated by current data. When compared to HPV- cancers, HPV+ tumors have different clinicopathological characteristics and improved survival rates. These findings have implications for therapy selection and prognostication, and they highlight the significance of HPV testing in the therapeutic management of oral malignancies. To understand the underlying molecular pathways and provide tailored therapeutics for oral malignancies that are HPV+, more research is required.

There are high incidence and mortality rates of cervical cancer among females in East Africa. This is exacerbated by limited up-to-date data on premalignant lesions and associated factors in this setting. In this study, we determined the prevalence of cervical intraepithelial lesions and associated factors among women attending the Mbarara Regional Referral Hospital cervical cancer clinic in Southwestern Uganda.

In this cross-sectional study, 364 participants were recruited from among women attending the Mbarara Regional Referral Hospital cervical cancer clinic from 1 April to 30 June 2023. On consent, the study nurse collected demographic data and Pap smears, which were microscopically examined and reported by a laboratory scientist and a pathologist following the Bethesda grading system (2014). Statistical analyses were done in STATA version 17, using proportions, Chi-square, bivariate, and multivariate logistic regression analysis to determine associated factors at ⩽0.05 significance level.

The mean age of participants was 41.9 years. A third of all study participants (37.6%, 132/351) were contraceptive users, mostly hormonal contraceptives (87.1%, 115/132). Almost 88% (307/351) had an unknown Human Papilloma Virus status. The prevalence of cervical intraepithelial lesions among our study participants was 6.6% (23/351), of which 73.9% (17/23) were low-grade squamous intraepithelial lesions. More than half (9/17, 52.9%) of low-grade squamous intraepithelial lesions were active hormonal contraceptive users. Use of hormonal contraceptives (OR: 3.032, p: 0.0253), use of intrauterine devices (OR: 6.284, p: 0.039), and any family history of cervical cancer (OR: 4.144, p: 0.049) were significantly associated with cervical intraepithelial lesions.

The prevalence of cervical intraepithelial lesions was 6.6%, lower than global estimates. Use of hormonal and intrauterine device contraceptives, as well as family history of cervical cancer, were significantly associated with cervical intraepithelial lesions among our study population. Prospective studies are recommended to further understand associations between different types of intrauterine devices and hormonal contraceptives, and cervical lesions.

Cervical cancer (CaCx) ranks as the fourth most prevalent cancer among women globally. Persistent infection of high-risk human papillomaviruses (HR-HPVs) is major etiological factor associated with CaCx. Signal Transducer and Activator of Transcription 3 (STAT3), a prominent member of the STAT family, has emerged as independent oncogenic driver. It is a target of many oncogenic viruses including HPV. How STAT3 influences HPV viral gene expression or gets affected by HPV is an area of active investigation. A better understanding of host-virus interaction will provide a prognostic and therapeutic window for CaCx control and management. In this comprehensive review, we delve into carcinogenic role of STAT3 in development of HPV-induced CaCx. With an emphasis on fascinating interplay between STAT3 and HPV genome, the review explores the diverse array of opportunities and challenges associated with this field to harness the prognostic and therapeutic potential of STAT3 in CaCx.

Human genital papilloma virus infection is the most prevalent sexually transmitted infection in the world. It is estimated that more than 75% of sexually active women contract this infection in their lifetime. In 80% of young women, there is the clearance of the virus within 18-24 months. In developed countries, oral squamous cell carcinoma (OSCC) is now the most frequent human papilloma virus (HPV)-related cancer, having surpassed cervical cancer, and it is predicted that by 2030 most squamous cell carcinomas will be the HPV-related rather than non-HPV-related form. However, there are currently no screening programs for oral cavity infection. While the natural history of HPV infection in the cervix is well known, in the oropharynx, it is not entirely clear. Furthermore, the prevalence of HPV in the oropharynx is unknown. Published studies have found wide-ranging prevalence estimates of 2.6% to 50%. There are also conflicting results regarding the percentage of women presenting the same type of HPV at two mucosal sites, ranging from 0 to 60%. Additionally, the question arises as to whether oral infection can develop from genital HPV infection, through oral and genital contact or by self-inoculation, or whether it should be considered an independent event. However, there is still no consensus on these topics, nor on the relationship between genital and oral HPV infections. Therefore, this literature review aims to evaluate whether there is evidence of a connection between oral and cervical HPV, while also endorsing the usefulness of the screening of oral infection in patients with high-risk cervical HPV as a means of facilitating the diagnosis and early management of HPV-related oral lesions. Finally, this review emphasizes the recommendation for the use of the HPV vaccines in primary prevention in the male and female population as the most effective means of successfully counteracting the increasing incidence of OSCC to date.

Nearly all cervical cancer cases are caused by infection with high-risk human papillomavirus (HR-HPV) types. The mechanism of cervical cell transformation is related to the powerful action of viral oncoproteins and cellular gene alterations. Transcriptomic data from cervical cancer and normal cervical cells were utilized to identify upregulated genes and their associated pathways. The laminin subunit beta-3 (LAMB3) mRNAwas overexpressed in cervical cancer and was chosen for functional analysis. The LAMB3 was predominantly expressed in the extracellular region and the plasma membrane, which play a role in protein binding and cell adhesion molecule binding, leading to cell migration and tissue development. LAMB3 was found to be implicated in the pathway in cancer and the PI3K-AKT signaling pathway. LAMB3 knockdown decreased cell migration, invasion, anchorage-dependent and anchorage-independent cell growth and increased the number of apoptotic cells. These effects were linked to a decrease in protein levels involved in the PI3K-AKT signaling pathway and an increase in p53 protein. This study demonstrated that LAMB3 could promote cervical cancer cell migration, invasion and survival.

Cervical cancer (CC) causes more than 311,000 deaths annually worldwide. The integration of human papillomavirus (HPV) is a crucial genetic event that contributes to cervical carcinogenesis. Despite HPV DNA integration is known to disrupt the genomic architecture of both the host and viral genomes in CC, the complexity of this process remains largely unexplored.

In this study, we conducted whole-genome sequencing (WGS) at 55-65X coverage utilizing the PacBio long-read sequencing platform in SiHa and HeLa cells, followed by comprehensive analyses of the sequence data to elucidate the complexity of HPV integration. Firstly, our results demonstrated that PacBio long-read sequencing effectively identifies HPV integration breakpoints with comparable accuracy to targeted-capture Next-generation sequencing (NGS) methods. Secondly, we constructed detailed models of complex integrated genome structures that included both the HPV genome and nearby regions of the human genome by utilizing PacBio long-read WGS. Thirdly, our sequencing results revealed the occurrence of a wide variety of genome-wide structural variations (SVs) in SiHa and HeLa cells. Additionally, our analysis further revealed a potential correlation between changes in gene expression levels and SVs on chromosome 13 in the genome of SiHa cells.

Using PacBio long-read sequencing, we have successfully constructed complex models illustrating HPV integrated genome structures in SiHa and HeLa cells. This accomplishment serves as a compelling demonstration of the valuable capabilities of long-read sequencing in detecting and characterizing HPV genomic integration structures within human cells. Furthermore, these findings offer critical insights into the complex process of HPV16 and HPV18 integration and their potential contribution to the development of cervical cancer.

Human papillomaviruses (HPVs) infect keratinocytes of stratified squamous epithelia, and persistent infection with high-risk HPV types, such as HPV16, may lead to the development of malignancies. HPV evades host immunity in part by linking its gene expression to the host differentiation program, and therefore relies on differentiation to complete its life cycle. Based on previous reports indicating that the HPV16 protein E5 is important in the late stages of the differentiation-dependent life cycle, we found that organotypic cultures harboring HPV16 genomes lacking E5 showed reduced markers of terminal differentiation compared to wild type HPV16-containing cultures. We found that epidermal growth factor receptor (EGFR) levels and activation were increased in an E5-depdendent manner in these tissues, and that EGFR promoted terminal differentiation and expression of the HPV16 L1 gene. These findings suggest a function for E5 in preserving the ability of HPV16 containing keratinocytes to differentiate, thus facilitating the production of new virus progeny.

High-risk HPV infection accounts for 99.7% of cervical cancer, over 90% of anal cancer, 50% of head and neck cancers, 40% of vulvar cancer, and some cases of vaginal and penile cancer, contributing to approximately 5% of cancers worldwide. The development of cancer is a complex, multi-step process characterized by dysregulation of signaling pathways and alterations in metabolic pathways. Extensive research has demonstrated that metabolic reprogramming plays a key role in the progression of various cancers, such as cervical, head and neck, bladder, and prostate cancers, providing the material and energy foundation for rapid proliferation and migration of cancer cells. Metabolic reprogramming of tumor cells allows for the rapid generation of ATP, aiding in meeting the high energy demands of HPV-related cancer cell proliferation. The interaction between Human Papillomavirus (HPV) and its associated cancers has become a recent focus of investigation. The impact of HPV on cellular metabolism has emerged as an emerging research topic. A significant body of research has shown that HPV influences relevant metabolic signaling pathways, leading to cellular metabolic alterations. Exploring the underlying mechanisms may facilitate the discovery of biomarkers for diagnosis and treatment of HPV-associated diseases. In this review, we introduced the molecular structure of HPV and its replication process, discussed the diseases associated with HPV infection, described the energy metabolism of normal cells, highlighted the metabolic features of tumor cells, and provided an overview of recent advances in potential therapeutic targets that act on cellular metabolism. We discussed the potential mechanisms underlying these changes. This article aims to elucidate the role of Human Papillomavirus (HPV) in reshaping cellular metabolism and the application of metabolic changes in the research of related diseases. Targeting cancer metabolism may serve as an effective strategy to support traditional cancer treatments, as metabolic reprogramming is crucial for malignant transformation in cancer.

Cervical cancer accounts for a high number of deaths worldwide. Risk factors are extensive for cervix cancer but Human papillomavirus (HPV) plays a prime role in its development. Different strains of HPV are prevalent globally, which show different grades of mortality and morbidity among women. This study is planned to evaluate the molecular mechanism of different strains of HPV infection and progression leading to cervix cancer.

This review includes different research articles on cervix cancer progression reported from India and all over the world.

HPV 16 and 18 are prevalent strains using heparan sulfate-independent and dependent pathways for viral replication inside the cell. It also uses transcription mechanisms through NF-kappa B, FOXA-1, and AP-1 genes while strains like HPV-35, 45, and 52 are also predominant in India, which showed a very slow mechanism of progression due to which mortality rate is low after their infection with these strains.

HPV uses E6 and E7 proteins which activate NF-kappa B and AP-1 pathway which suppresses the tumor suppressor gene and activates cytokine production, causing inflammation and leading to a decrease in apoptosis due to Caspase-3 activation. In contrast, the E7 protein involves HOXA genes and decreases apoptotic factors due to which mortality and incidence rates are low in viruses that use E7 motifs. Some HPV strains employ the cap-dependent pathway, which is also associated with lower mortality and infection rates.

The Mus musculus papillomavirus 1 (MmuPV1) E6 and E7 proteins are required for MmuPV1-induced disease. Our understanding of the activities of MmuPV1 E6 has been based on affinity purification/mass spectrometry studies where cellular interacting partners of MmuPV1 E6 were identified, and these studies revealed that MmuPV1 E6 can inhibit keratinocyte differentiation through multiple mechanisms. We report that MmuPV1 E6 encodes additional activities including the induction of proliferation, resistance to density-mediated growth arrest, and decreased dependence on exogenous growth factors. Proteomic and transcriptomic analyses provided evidence that MmuPV1 E6 increases the expression and steady state levels of a number of cellular proteins that promote cellular proliferation and other hallmarks of cancer. These results indicate that MmuPV1 E6 is a major driver of MmuPV1-induced pathogenesis.

Cancer is a multi-factorial disease, and the etiology of breast cancer (BC) is due to a combination of both genetic and environmental factors. Breast tissue shows a unique microbiota, Proteobacteria and Firmicutes are the most abundant bacteria in breast tissue, and several studies have shown that the microbiota of healthy breast differs from that of BC. Breast microbiota appears to be correlated with different characteristics of the tumor, and prognostic clinicopathologic features. It also appears that there are subtle differences between the microbial profiles of the healthy control and high-risk patients. Genetic predisposition is an extremely important risk factor for BC. BRCA1/2 germline mutations and Li-Fraumeni syndrome are DNA repair deficiency syndromes inherited as autosomal dominant characters that substantially increase the risk of BC. These syndromes exhibit incomplete penetrance of BC expression in carrier subjects. The action of breast microbiota on carcinogenesis might explain why women with a mutation develop cancer and others do not. Among the potential biological pathways through which the breast microbiota may affect tumorigenesis, the most relevant appear to be DNA damage caused by colibactin and other bacterial-derived genotoxins, β-glucuronidase-mediated estrogen deconjugation and reactivation, and HPV-mediated cancer susceptibility. In conclusion, in patients with a genetic predisposition, an unfavorable breast microbiota may be co-responsible for the onset of BC. Prospectively, the ability to modulate the microbiota may have an impact on disease onset and progression in patients at high risk for BC.

The phenomenon of cell death is a vital aspect in the regulation of aberrant cells such as cancer cells. Anoikis is a kind of cell death that occurs when cells get separated from the extracellular matrix. Some cancer cells can inhibit anoikis in order to progress metastasis. One of the key variables that might be implicated in anoikis resistance (AR) is viral infections. The most important viruses involved in this process are Epstein-Barr virus, human papillomavirus, hepatitis B virus, human herpes virus 8, human T-cell lymphotropic virus type 1, and hepatitis C virus. A better understanding of how carcinogenic viruses suppress anoikis might be helpful in developing an effective treatment for virus-associated cancers. In the current study, we review the role of the mentioned viruses and their gene products in anoikis inhibition.

Human papillomavirus (HPV) is implicated in over 90% of cervical cancer cases, with factors like regional variability, HPV genotype, the population studied, HPV vaccination status, and anatomical sample collection location influencing the prevalence and pathology of HPV-induced cancer. HPV-16 and -18 are mainly responsible for the progression of several cancers, including cervix, anus, vagina, penis, vulva, and oropharynx. The oncogenic ability of HPV is not only sufficient for the progression of malignancy, but also for other tumor-generating steps required for the production of invasive cancer, such as coinfection with other viruses, lifestyle factors such as high parity, smoking, tobacco chewing, use of contraceptives for a long time, and immune responses such as stimulation of chronic stromal inflammation and immune deviation in the tumor microenvironment. Viral evasion from immunosurveillance also supports viral persistence, and virus-like particle-based prophylactic vaccines have been licensed, which are effective against high-risk HPV types. In addition, vaccination awareness programs and preventive strategies could help reduce the rate and incidence of HPV infection. In this review, we emphasize HPV infection and its role in cancer progression, molecular and immunopathogenesis, host immune response, immune evasion by HPV, vaccination, and preventive schemes battling HPV infection and HPV-related cancers.

To detect the HPV genotype and integration sites in patients with high-risk HPV infection at different stages of photodynamic therapy using nanopore technology and to evaluate the treatment effect.

Four patients with HPV infection were selected and subjected to photodynamic therapy, and cervical exfoliated cell was sampled at before treatment, after three courses of treatment and six courses of treatment, their viral abundance and insertion sites were analyzed by nanopore technology, and pathological examinations were performed before and after treatment. In this study, we developed a novel assay that combined viral sequence enrichment and Nanopore sequencing for identification of HPV genotype and integration sites at once. The assay has obvious advantages over qPCR or NGS-based methods, as it has better sensitivity after viral sequences enrichment and can generate long-reads (kb to Mb) for better detection rate of structure variations, moreover, fast turn-around time for real-time viral sequencing and analysis.

The pathological grade was reduced in all four patients after photodynamic therapy. Virus has been cleared in two cases after treatment, the virus amount reduced after treatment but not completely cleared in one case, and two type viruses were cleared and one type virus persisted after treatment in the last patient with multiple infection. Viral abundance and the number of integration sites were positively correlated. Gene enrichment analysis showed complete viral clearance in 1 patient and 3 patients required follow-up.

Nanopore sequencing can effectively monitor the abundance of HPV viruses and integration sites to show the presence status of viruses, and combined with the results of gene enrichment analysis, the treatment effect can be dynamically assessed.

High-risk human papillomavirus (HR-HPV) infection is a major cause of infection-related cancer worldwide. 3101 HR-HPV-positive females were retrospectively analyzed and grouped using the cervical cytological screening (ThinPrep cytological test, TCT) evaluations combined with colposcopy. The HPV16 infection rate is the highest in all groups. HPV16 was the most frequent in each group, with significant differences between the four groups (χ2 = 23.41, P = 0.0001). The distribution of HPV16 and HPV33 correlated with the pathologic stage in each group. The mixed infection rate of mRNA testing differs significantly between groups (P < 0.01, χ2 = 17.44, P = 0.002). HR-HPV infection duration of less than six months accounted for 87.65%, 6 and 12 months of persistent infection (28.28%), and more than one year of continuous infection accounted for only 16.48%. The top three HPV types in a group with a duration of more than 12 months were HPV52 (3.03%), HPV16 (2.55%), and HPV39 (1.58%). The least clearance types were HPV39 (63.48%), 56 (69.54%), and 52 (71.44%) more than 12 months. This study revealed the region's primary pathogenic subtypes on different cervical lesions and provided the basis for diagnosing and treating HPV infection.

The recognition that persistent infection with carcinogenic human papillomavirus (HPV) is a necessary cause of cervical precancer and cancer has led to the introduction of HPV testing into cervical cancer screening, either as a primary screening test or in conjunction with cervical cytology (i.e., co-testing). HPV testing has much higher sensitivity for detection of cervical precancer and provides greater long-term reassurance if negative compared to cytology. However, most HPV infections are transient, and do not progress to invasive cancer, thus triage tests are required to identify individuals who should be referred to colposcopy for diagnostic evaluation. This chapter begins with a description of the biology, natural history, and epidemiology of HPV as a foundation for understanding the role of HPV in cervical carcinogenesis. This section is followed by a detailed discussion regarding the introduction of HPV-based testing and triage into cervical cancer screening and management. Summarized triage tests include cervical cytology, HPV genotyping, p16/Ki-67 dual stain, and HPV and cellular methylation markers. The final section of this chapter includes an important discussion on cervical cancer disparities, particularly within the United States, followed by concluding remarks.

Human viral oncogenesis is a complex phenomenon and a major contributor to the global cancer burden. Several recent findings revealed cellular and molecular pathways that promote the development and initiation of malignancy when viruses cause an infection. Even, antiviral treatment has become an approach to eliminate the viral infections and prevent the activation of oncogenesis. Therefore, for a better understanding, the molecular pathogenesis of various oncogenic viruses like, hepatitis virus, human immunodeficiency viral (HIV), human papillomavirus (HPV), herpes simplex virus (HSV), and Epstein-Barr virus (EBV), could be explored, especially, to expand many potent antivirals that may escalate the apoptosis of infected malignant cells while sparing normal and healthy ones. Moreover, contemporary therapies, such as engineered antibodies antiviral agents targeting signaling pathways and cell biomarkers, could inhibit viral oncogenesis. This review elaborates the recent advancements in both natural and synthetic antivirals to control viral oncogenesis. The study also highlights the challenges and future perspectives of using antivirals in viral oncogenesis.

WD repeat and HMG-box DNA binding protein 1 (WDHD1) is a highly conserved gene from yeast to humans. It actively participates in DNA replication, playing a crucial role in DNA damage repair and the cell cycle, contributing to centromere formation and sister chromosome segregation. Notably, several studies have implicated WDHD1 in the development and progression of diverse tumor types, including esophageal carcinoma, pulmonary carcinoma, and breast carcinoma. Additionally, the inhibitor of WDHD1 has been found to enhance radiation sensitivity, improve drug resistance, and significantly decrease tumor cell proliferation. This comprehensive review aims to provide an overview of the molecular structure, biological functions, and regulatory mechanisms of WDHD1 in tumors, thereby establishing a foundation for future investigations and potential clinical applications of WDHD1.

HPV (Human papillomavirus) affects 600,000 people worldwide each year. Almost all cervical cancers are associated with a past HPV infection. In particular, the positivity to the high-risk type HPV16 is detected in most of the invasive cervical cancers. FDA has approved prophylactic vaccines that protect against new HPV16 infections, but do not induce immunity in those patients with established infections or neoplasms. To date, no therapeutic vaccine targeting HPV16-associated lesions has been authorized. We have developed an mRNA-based vaccine against the HPV16 late oncoproteins E6 and E7, which are abundantly and exclusively expressed in high-grade squamous intraepithelial lesions (HSILs), a stage of the cervical disease that precedes the progression to carcinoma. Our in vitro and in vivo studies demonstrated that the translated mRNA is functional and elicits an antigen-specific adaptive immune response. Upon immunization with the vaccine, mice with HPV16+ lesions exhibited tumor growth inhibition, extension of lifespan, and development of a protective immune memory. In light of these results and the remarkable clinical success of mRNA vaccines against SARS-CoV2, we believe that our mRNA-based therapeutic vaccine has the potential to offer a non-invasive treatment alternative to the current standard of care for HPV16+ HSILs.

Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+).

To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+ METHODS: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models.

The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08-1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77-4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33-2.27) were also risk factors for CIN2+ detection.

Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted.