Search Results (439)

Lactobacillus species play a fundamental role in maintaining a healthy vaginal microbiota and have been increasingly recognized for their protective effects against high-risk human papillomavirus (HR-HPV) infection and the progression of cervical intraepithelial neoplasia (CIN). These beneficial bacteria contribute to host defense through multiple mechanisms, including the production of lactic acid that sustains a low vaginal pH, enhancement of epithelial barrier integrity via E-cadherin regulation, and modulation of immune signaling pathways such as interferon responses and NF-κB activity. Lactobacillus strains exert anti-inflammatory effects by downregulating pro-inflammatory cytokines and interfering with oncogenic pathways including Wnt/β-catenin and the expression of HPV E6 and E7 proteins. Additionally, they may regulate tumor-suppressor microRNAs and modulate dendritic cell and macrophage activity, supporting antiviral immunity. Recent studies have explored their potential influence on CIN regression and HR-HPV clearance, particularly the strains Lactobacillus crispatus and L. gasseri, which are associated with favorable microbial community states. This review explores the potential mechanisms through which Lactobacillus species contribute to HR-HPV clearance and the regression of cervical dysplasia, integrating evidence from molecular studies, in vivo models, and clinical trials. The emerging role of probiotic interventions as adjunctive strategies in HPV management is also discussed, highlighting their possible synergy with conventional treatments and prophylactic vaccination. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) ranks sixth in the world in terms of incidence. Small proline-rich proteins (SPRRs) are precursors of the keratinocyte envelope and act as substrates of transglutaminase. A change in SPRR expression is characteristic in a few types of cancer. Our aim was to determine the concentration of SPRR1A and SPRR2A in tumours samples obtained from 61 patients with HNSCC (OSCC, OPSCC, LSCC, HPSCC, NCSCC, and SSCC). Also, we aimed to determine the relationship between protein concentration and other clinical and/or demographic variables. Methods: An ELISA test was used to determine the concentrations of SPRR in the tumour tissue homogenates. Results: In margin samples, we found a statistically significant association between SPRR1A levels and nodal status (N) and between SPRR1A levels in tumours and margins with G2 histological grade. When we analysed the effect of tobacco and alcohol habits, we found a statistically significant difference between the SPRR1A and SPRR2A amount in smokers and non-smokers in margin samples. Also, we found a statistically significant difference between the SPRR1A and SPRR2A levels in tumour and margin samples obtained from patients that either abstain and occasionally or regularly consume alcohol. Furthermore, we found in tumour and margin samples from patients with concomitant diseases an association between SPRR1A and SPRR2A levels. Our results showed altered concentrations of SPRR1A at margins, depending on HPV status. Conclusions: These results suggest that differences in SPRR proteins are determined by disease status and unhealthy behaviours, which, in a wider perspective, can influence carcinogenesis. Full article

Background/Objectives: Human papillomavirus (HPV) is a prevalent sexually transmitted infection globally and is linked to the development of various cancers. While several international studies have investigated the incidence of high-risk HPV (HR-HPV) in bladder cancers, no such research has been conducted within the UK. Conflicting results in previous studies leave uncertainty regarding the role of HR-HPV in bladder cancer. This study aimed to assess the presence of HR-HPV DNA in bladder cancer specimens from the UK. Methods: A total of 55 fresh bladder specimens, including 4 benign and 51 malignant samples, were analysed using polymerase chain reaction (PCR) and Sanger sequencing to detect 12 HR-HPV types. Immunohistochemistry (IHC) was used to confirm the expression of the HPV E7 protein in HR-HPV-positive samples. Results: HR-HPV DNA was detected in 33% of bladder cancer specimens, with HPV16, HPV35, and HPV52 being the most prevalent types. None of the benign samples tested positive for HR-HPV. IHC confirmed HPV E7 protein expression in 81% of HR-HPV DNA-positive cancer samples. Conclusions: The findings suggest that HR-HPV may play a role in a subset of bladder cancers in the UK. The absence of HR-HPV in benign bladder specimens supports its potential involvement in cancer progression. Further research is needed to clarify the mechanistic role of HR-HPV in bladder cancer development. Full article

Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare thrombotic disorder first identified in 2021 as a catastrophic syndrome associated with anti-SARS-CoV-2 adenoviral vector (AdV)-vaccine administration. It is characterized by the presence of oligo- or monoclonal anti-PF4 antibodies able to induce in vitro platelet activation in the presence of PF4. In addition to this immune-based pathomechanism, random splicing events of the Adv-vector DNA encoding for SARS-CoV-2 spike protein resulting in the secretion of soluble spike variants have been postulated as a possible pathophysiological mechanism. More recently, some novel clinical-pathological anti-PF4-associated entities also characterized by thrombosis, thrombocytopenia, and VITT-like antibodies but independent from heparin or AdV-vaccine administration have been identified. To date, these VITT-like disorders have been reported following the administration of vaccines different from anti-SARS-CoV-2 AdV-vaccines, like human papillomavirus (HPV) and mRNA-based COVID-19 vaccines, following a bacterial or viral respiratory infection, and in patients with a monoclonal gammopathy of undetermined significance. The purpose of this review is to provide an update on the knowledge on VITT pathogenesis, focusing on recent findings on anti-PF4 antibodies, on a possible genetic predisposition to VITT, on VITT-antibody intracellular activated pathways, on lipid metabolism alterations, and on new VITT-like disorders. Full article

Cutaneous warts caused by human papillomavirus (HPV) are among the most common dermatological conditions, affecting the quality of life of numerous people. Although they are widespread, effective and reliable treatment alternatives are limited, emphasizing the necessity for novel treatment options. Intralesional immunotherapy has emerged as a promising alternative, aiming to stimulate the host immune response to achieve the clearance of both treated and distant lesions. This review explores the immunopathogenesis of cutaneous warts and provides an in-depth analysis of intralesional therapies including measles–mumps–rubella (MMR) vaccine, purified protein derivative (PPD), Bacillus Calmette–Guérin (BCG), Candida antigen, Mycobacterium w vaccine (MWV), vitamin D3, and autoinoculation. We provide a comprehensive analysis of the most promising modalities, highlighting their mechanism of action, outcomes, advantages, and limitations. Although initial data indicate that intralesional immunotherapy offers advantageous efficacy and tolerability, there is a lack of standardized treatment protocols and randomized controlled trials to endorse its broad application. Nevertheless, considering its potential to address local and distant lesions with minimal adverse effects, intralesional immunotherapy may represent a transformative approach to managing cutaneous warts. Full article

Background: Head and neck squamous cell carcinoma (HNSCC) exhibit considerable heterogeneity, complicating the prediction of disease progression and treatment response. Consequently, researchers are actively investigating reliable biomarkers to forecast disease trajectories and inform therapeutic decisions. This study examines the role of BAG3, a protein involved in cell survival and stress response, as a potential predictive marker in HNSCC. The objective is to analyze BAG3 expression across various HNSCC types and correlate it with disease-free survival (DFS), aiming to elucidate the influence of BAG3 positivity on cancer progression. Methods: A multi-institutional retrospective study was conducted by analyzing BAG3 expression by immunohistochemistry in 104 tissue samples from patients with head and neck squamous cell carcinoma (HNSCC). The data were then correlated with DFS to assess the impact of BAG3 positivity on prognosis. Results: Immunohistochemical analysis of primary tumor samples collected from therapy-naive patients showed that BAG3 positivity was widespread across different head and neck cancer sites, with no significant correlation to sex, smoking status, HPV infection, tumor location, grade, or TNM parameters. However, BAG3 high positive patients had shorter DFS (median 23.2 months) compared to BAG3-negative patients (median 31.3 months). Cox analysis revealed that BAG3 high expression by IHC was associated with a more than 3-fold increased risk of disease recurrence. Conclusions: This study is the first to explore BAG3 as a biomarker for HNSCC recurrence. While preliminary findings suggest a link between BAG3 positivity and increased recurrence risk, further research is needed to validate these results. Prospective studies could help establish BAG3’s prognostic value and potentially lead to more personalized treatment approaches for HNSCC. Full article

Background/Objectives: Cervical cancer (CC) is a significant global health challenge, particularly in low- and middle-income countries (LMICs), where limited access to human papillomavirus (HPV) vaccination and effective CC screening results in a majority of cases and fatalities among women. Moreover, existing vaccines do not target HPV-independent cancers. Current screening methods are expensive and time-consuming, with a limited emphasis on CC protein biomarkers. Therefore, we aimed to validate critical markers that allow the development of affordable point-of-care screening tests for resource-limited settings. Methods: This study first optimized a cell lysis and protein extraction protocol for CC cell lines and clinical cervical swabs. Subsequently, four proteins—topoisomerase II alpha (TOP2A), minichromosome maintenance complex component 2 (MCM2), valosin-containing protein (VCP), and cyclin-dependent kinase inhibitor 2A (p16INK4a)—were quantified in the resulting lysates using enzyme-linked immunosorbent assays, as well as in cervical tumors and squamous intraepithelial lesions (SILs) using immunohistochemistry for further validation. Results: Acetone precipitation allowed for efficient cell isolation, and radioimmunoprecipitation assay buffer yielded the highest protein recovery. VCP and p16INK4a were overexpressed across all cancer cell lines compared to primary cells. All four biomarkers were overexpressed in high-grade SIL (HSIL) swab specimens and tumor samples, including CC subtypes, G1–G3 tumor grades, and HSILs. Lastly, we showed that the proteins could accurately classify swabs and tissue specimens into clinically relevant groups. Conclusions: The quantitative analysis of these biomarkers, along with the subsequent sensitive and specific clinical classification, highlights their potential application in SIL early detection and CC prevention, particularly in LMICs. Full article

Cervical cancer ranks as the fourth most prevalent cancer and cause of cancer-related mortality among women globally. It exhibits a recurrence/metastasis rate of approximately 30% and a dismal 5-year survival of only 17% in metastatic cases. Despite significant advancements in surgical techniques, chemoradiotherapy, and targeted therapies, effective treatment options for metastatic cervical cancer remain limited. This study explored Polyphyllin I (PPI), which is a monomeric compound derived from the Rhizoma of Paris Polyphyllin, as a potential inhibitor of cervical cancer metastasis. Mechanistically, PPI directly interacted with β-catenin at the Ser552 site, inhibiting its phosphorylation and subsequent nuclear translocation, thereby suppressing TCF/LEF transcriptional activity and downstream EMT transcription factors (ZEB1, Slug, Snail, and Twist). Notably, PPI promoted β-catenin degradation via the autophagy–lysosomal pathway, as confirmed by CHX chase assays and the detection of the p62 and LC3 proteins, without altering the mRNA levels of β-catenin. In vitro experiments demonstrated that PPI effectively suppressed the migration and invasion of HO-8910PM cells by reversing the process of EMT. Additionally, PPI effectively inhibited TCF/LEF signaling, leading to a reduction in the transcription levels of EMT-associated transcription factors (EMT-TFs), which was mediated by the TCF/LEF family downstream of β-catenin. Furthermore, PPI exhibited inhibitory effects on proliferation, migration, and invasion in both HPV-positive (SiHa) and HPV-negative (C33A) cervical cancer cells. In vivo, PPI significantly suppressed peritoneal metastasis in a luciferase-labeled HO-8910PM xenograft mouse model. These findings reveal the dual role of PPI in blocking β-catenin signaling and inducing β-catenin depletion, thereby effectively restraining metastatic progression. This study underscores the potential of PPI as a promising therapeutic candidate for targeting cervical cancer metastasis through autophagy-mediated β-catenin regulation, offering a novel strategy to address current treatment limitations. Full article

Human papillomavirus (HPV) infection is a major risk factor for cervical cancer, demanding improved diagnostic strategies to distinguish between transient infections and those requiring intervention. Background: This systematic review and meta-analysis evaluated the diagnostic accuracy of HPV L1 immunocytochemistry (ICC) in detecting high-grade cervical intraepithelial neoplasia (CIN2+). Methods: We systematically analyzed data from 15 studies (PROSPERO 2022 CRD42022375916) comprising 3804 cervical smears with varying cytological findings (NILM to ≥ASC-US). Results: The pooled sensitivity for detecting CIN2+ was 80.7% (95% CI: 76.2–84.4%); however, substantial heterogeneity was present (I² = 65.97%, p < 0.001). Similarly, the pooled specificity was 56.9% (95% CI: 49.6–64%), with even higher heterogeneity (I² = 90.46%, p < 0.001). This considerable heterogeneity, which may be attributable to methodological variations or regional differences in HPV prevalence and genotyping, limits the generalizability of these findings. Furthermore, the moderate specificity suggests a high rate of false positives, limiting the clinical utility of HPV L1 ICC as a standalone diagnostic test. Conclusions: In conclusion, although HPV L1 ICC exhibits acceptable sensitivity for detecting CIN2+, its limitations, including low specificity and substantial heterogeneity, necessitate its use as an adjunct to other established diagnostic methods, alongside further research to enhance its diagnostic performance, and necessitate its use as a supplementary test alongside established diagnostic methods, pending further research to refine its clinical utility. Full article

Background/Objectives: Laryngeal cancer (LC), predominantly squamous cell carcinoma (SCC), represents a considerable health burden worldwide. Tumour subsite heterogeneity (supraglottic, glottic, subglottic) influences clinical behavior and outcomes. This review synthesizes current knowledge on epidemiology, risk factors, diagnostics, histological variants, biomarkers, treatment modalities, and survival. Results: This narrative review synthesizes current literature on the epidemiology, risk factors, diagnosis, histological variants, biomarkers, and prognosis of LC. The review highlights the critical influence of tumour sites (supraglottic, glottic, subglottic) on metastatic patterns and survival. Key risk factors of LC include tobacco and alcohol use, human papillomavirus (HPV) infection, and occupational exposures. The diagnostic process encompasses clinical examination, endoscopy, biopsy, and imaging. Several biomarkers that aid in diagnosis, treatment plan determination, and prognosis prediction have been established. These biomarkers include long noncoding RNAs, cell cycle regulators, apoptosis regulators, oncogenes, tumour suppressor genes, growth factor pathway components, angiogenic factors, structural proteins, sex hormone receptors, and immunological markers. Current treatment modalities range from organ-preserving surgery and radiotherapy to combined chemoradiotherapy and total laryngectomy. Finally, survival data are presented and stratified by stage and subsite. Conclusions: The review underscores the need for a multidisciplinary approach to LC management, integrating clinical, pathological, and molecular information to optimize patient outcomes. Full article

A 67-year-old male with metastatic human papillomavirus (HPV)-positive oropharyngeal cancer receiving pembrolizumab (anti-programmed cell death protein 1 [PD-1] immune checkpoint inhibitor) presented with bilateral ocular dryness. It is important to note that these symptoms appeared eight months after the initiation of the pembrolizumab therapy. Ophthalmologic evaluation revealed keratoconjunctivitis sicca with characteristic bulbar fluorescein staining and the Schirmer test showed 0 mm bilaterally. Serological testing demonstrated positive antinuclear and anti-SSb/La antibodies, consistent with Sjögren’s syndrome as an immune-related adverse event (irAE). Treatment with topical fluorometholone 0.1% and diquafosol 3% led to complete symptom resolution within one year while maintaining cancer immunotherapy. Long-term follow-up over 3.5 years demonstrated sustained ocular improvement and a favorable oncologic response without development of systemic autoimmune manifestations. This case highlights that Sjögren’s syndrome as an irAE may present with isolated ocular manifestations, which could be overlooked in clinical practice. Full article

Human papillomaviruses (HPVs) are small double-stranded DNA viruses that infect epithelial cells and cause cervical, anogenital, and oropharyngeal cancers. HPV genome replication relies on the viral E1 and E2 proteins to initiate DNA replication. The first step is the assembly of the E1-E2 complex at the origin of replication. We have examined the role of full-length HPV E1 helicase and its interaction with E2 in pre-initiation complex formation. Electrophoretic mobility shift assays (EMSAs) with purified E1 and E2 proteins revealed that the HPV genome does not have a specific E1 binding site, or such a sequence is not required for pre-initiation complex formation. E1 alone did not show any binding to the origin DNA sequences, while E2 facilitated E1 recruitment to the origin, forming the E1-E2-DNA ternary complex. Formation of such a complex required at least two E2 binding sites. These findings led us to propose a novel mechanism in which E2 dimers serve as the primary recruiters of E1 to form the pre-initiation complex. This study provides new insights into the mechanistic role of E2 in the recruitment of E1 at the origin of HPV DNA replication, enhancing our understanding of HPV biology and potentially informing future therapeutic strategies. Full article

Cervical cancer ranks third in mortality and fourth in incidence among women worldwide as one of the leading causes of death from cancer in females. The main reason behind cervical carcinogenesis is long-term infection with high-risk human papillomavirus (HPV) genotypes, particularly HPV16 and HPV18. This review investigates HPV distribution across the world, along with cervical cancer molecular development mechanisms and current treatment strategies. Epidemiological data show that disease patterns vary significantly between different geographic regions because underdeveloped nations bear a higher disease burden. The molecular mechanisms of oncogenes E6 and E7 disrupt tumor suppressor pathways, while epigenetic modifications through DNA methylation and miRNA dysregulation promote malignant cell transformation. The reduction in HPV infection through prophylactic vaccination has shown promise, yet barriers related to accessibility and coverage still exist. The therapeutic technologies of gene expression inhibitors together with immunotherapies and epigenetic targeting agents show promise but require optimization to achieve specific targeting while minimizing off-target effects. A combined approach that integrates HPV vaccination with early diagnosis and molecular-specific therapies represents the most effective method to manage cervical cancer impact. The future care of patients will require increased translational research along with better immunization programs to drive prevention and therapeutic outcomes. Full article

Human papillomavirus (HPV) 16 is transported in a retrograde fashion from the cell surface to the Golgi apparatus. Prior to mitosis, the virus loses association with the Golgi and, following nuclear envelope breakdown, is found associated with the condensed mitotic chromatin. The intervening steps have not been well defined. It was previously demonstrated that the virus is transported to the mitotic chromosomes in vesicles. Here, we describe the role of the endoplasmic reticulum (ER) in the post-Golgi trafficking and the importance of the ER-generated coat protein complex II (COPII) anterograde trafficking pathway in HPV infection. HPV pseudovirus (PsV) colocalized with COPII components and silencing of this pathway inhibited HPV infection. Additionally, the inner COPII coat protein, Sec24b, could be biochemically isolated in association with HPV capsid proteins. This study provides insight into the mechanism of post-Golgi HPV trafficking. Full article

Human papillomavirus (HPV) infection is the most prevalent sexually transmitted disease, and a primary cause of persistent infection leading to cervical cancer (CC). CC remains one of the most common malignancies among women worldwide, with approximately 660,000 new cases and 350,000 deaths annually. In Mexico, this cancer accounts for 13.9% of female deaths. Currently, no antiviral treatment exists for HPV infection. Available therapies for dysplasia and CC focus on the destruction or surgical removal of infected tissue using cytotoxic agents. While the prophylactic HPV vaccine effectively prevents new infections, it does not benefit the millions already infected, underscoring the urgent need for novel therapeutic strategies. This study aimed to identify potential antagonists for the interaction between the HPV16 E2 and E1 proteins through in silico screening. A virtual screening was performed targeting the TAD of the HPV16 E2 protein (PDB ID: 1DTO) using the Maybridge HitFinder™ small molecule library. Six molecules with the best binding energies were identified: 11419, 11829, 10756, 10708, 10632, and 10726. Among these, molecules 10756, 10708, 10632, and 10726 demonstrated promising potential as antagonists, interacting with Tyr19 and/or Glu39 residues. These findings highlight potent therapeutic candidates against HPV-related diseases. Full article