Targeted inhibition of BET proteins in HPV16-positive head and neck squamous cell carcinoma reveals heterogeneous transcriptional responses.

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.

Age-specific performance of human papillomavirus E6/E7 mRNA assay versus cytology for primary cervical cancer screening and triage: community-based screening in China.

Background: In the general population, primary human papillomavirus (HPV) testing is advocated for cervical cancer (CC) screening. HPV E6/E7 mRNA (Aptima HPV, AHPV) assays have garnered considerable traction due to their higher specificity when compared with HPV DNA assays. Here, we investigated age-specific primary AHPV screening assays and different triage strategies versus cytology to identify the best approach. Methods: Between April 2018 and December 2021, we recruited female participants from 34 communities across Liaoning province and Qingdao City, China. Primary cervical screening protocols included liquid-based cytology (LBC) and AHPV assays, with females positive for any assays undergoing colposcopy. Genotyping (AHPV-GT) was conducted on all HPV-positive samples. Our primary outcomes were the identification of age-specific detection rates, colposcopy referral rates, and sensitivity and specificity values for high-grade squamous intraepithelial lesions or worse (HSIL+). AHPV and different triage strategy performances were also examined across different age cohorts. Results: Our investigation included 9911 eligible females. Age-specific abnormal cytology rates were in the 6.1%-8.0% range, and were highest in 45-54-year olds. When compared with 35-44-or 45-54-year olds, HPV prevalence was highest in 55-64-year olds (12.2% or 11.6% vs.14.1%, P = 0.048 and P = 0.002, respectively). In 35-44-year olds, AHPV sensitivity for detecting HSIL+ was 96.6 (95% confidence interval [CI]: 89.7-100) - significantly higher than LBC sensitivity (65.5 [95% CI: 48.3-82.8], P < 0.001). When compared with LBC, HSIL+ detection rates by AHPV-GT using reflex LBC triage increased by 31.5% (9.6‰ vs. 7.3‰), and colposcopy referral rates decreased by 16.4% (5.1% vs. 6.1%). In 45-54-year olds, HSIL+ detection rates for AHPV-GT using reflex LBC triage were lower than LBC rates (6.2‰ vs. 6.6‰). In 55-64-year olds, AHPV sensitivity (97.2 [95% CI: 91.7-100.0]) was higher than LBC sensitivity (66.7 [95% CI: 50.0-80.6], P = 0.003). The area under the curve (AUC) value was not significantly different between AHPV-GT with reflex LBC triage and LBC (0.845 [95% CI: 0.771-0.920] vs. 0.812 [95% CI: 0.734-0.891], P = 0.236). Conclusions: Primary AHPV screening using different triage strategies were different across different age cohorts. Thus, AHPV may be an appropriate primary screening method for 35-44 and 55-64 year old females, while AHPV-GT with reflex LBC triage may be more apt for 35-44 year old females.

Analyzing nonlinear and asymmetric effects of green finance and renewable energy on energy efficiency amidst technological innovation in E7 countries.

The study aims to explore the relationship between green funding, green energy, and energy efficiency in E7 countries, guided by the SDG-7 guidelines recommended by the United Nations General Assembly. Methodologically, the study employs the Nonlinear Autoregressive Distributed Lag (NARDL) and Two-Stage Least Squares (2SLS) techniques on data collected between 1988 and 2022. The rationale for this approach lies in its ability to capture both short-term and long-term dynamics in the relationship between green funding, green energy, and energy efficiency. Analysis of the data reveals varying stages of green funding growth among E7 countries, with China (1.52), Brazil (1.44), India (1.35), Indonesia (1.94), Mexico (1.73), and Russia (1.93) exhibiting different levels of progress. Russia and Turkey are identified as having the highest Gini coefficients in 2019, indicating disparities in green funding distribution within these countries. The empirical findings underscore the critical role of investment in the energy sector by both corporations and the public sector to enhance access to electricity, bolster energy security, and foster environmentally sustainable economic development. However, the study identifies insufficient investment as a fundamental obstacle hindering progress in green energy efficiency in E7 nations. Despite the potential for implementing energy efficiency measures and renewable energy sources in E7 countries, the future remains uncertain due to existing obstacles in green financing and regulatory frameworks. Consequently, the paper emphasizes the imperative of addressing these obstacles to unlock the full funding potential for energy efficiency initiatives in E7 nations.

Epstein-Barr virus replication within differentiated epithelia requires pRb sequestration of activator E2F transcription factors.

Epstein-Barr virus (EBV) co-infections with human papillomavirus (HPV) have been observed in oropharyngeal squamous cell carcinoma. Modeling EBV/HPV co-infection in organotypic epithelial raft cultures revealed that HPV16 E7 inhibited EBV productive replication through the facilitated degradation of the retinoblastoma protein pRb/p105. To further understand how pRb is required for EBV productive replication, we generated CRISPR-Cas9 pRb knockout (KO) normal oral keratinocytes (NOKs) in the context of wild-type and mutant K120E p53. EBV replication was examined in organotypic rafts as a physiological correlate for epithelial differentiation. In pRb KO rafts, EBV DNA copy number was statistically decreased compared to vector controls, regardless of p53 context. Loss of pRb did not affect EBV binding or internalization of calcium-treated NOKs or early infection of rafts. Rather, the block in EBV replication correlated with impaired immediate early gene expression. An EBV infection time course in rafts with mutant p53 demonstrated that pRb-positive basal cells were initially infected with delayed replication occurring in differentiated layers. Loss of pRb showed increased S-phase progression makers and elevated activator E2F activity in raft tissues. Complementation with a panel of pRb/E2F binding mutants showed that wild type or pRb∆685 mutant capable of E2F binding reduced S-phase marker gene expression, rescued EBV DNA replication, and restored BZLF1 expression in pRb KO rafts. However, pRb KO complemented with pRb661W mutant, unable to bind E2Fs, failed to rescue EBV replication in raft culture. These findings suggest that EBV productive replication in differentiated epithelium requires pRb inhibition of activator E2Fs to restrict S-phase progression.IMPORTANCEA subset of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma is co-positive for Epstein-Barr virus (EBV). Potential oncogenic viral interactions revealed that HPV16 E7 inhibited productive EBV replication within the differentiated epithelium. As E7 mediates the degradation of pRb, we aimed to establish how pRb is involved in EBV replication. In the context of differentiated epithelium using organotypic raft culture, we evaluated how the loss of pRb affects EBV lytic replication to better comprehend EBV contributions to carcinogenesis. In this study, ablation of pRb interfered with EBV replication at the level of immediate early gene expression. Loss of pRb increased activator E2Fs and associated S-phase gene expression throughout the differentiated epithelium. Complementation studies showed that wild type and pRb mutant capable of binding to E2F rescued EBV replication, while pRb mutant lacking E2F binding did not. Altogether, these studies support that in differentiated tissues, HPV16 E7-mediated degradation of pRb inhibits EBV replication through unregulated E2F activity.

Pollen-Food Allergy Syndrome: From Food Avoidance to Deciphering the Potential Cross-Reactivity between Pru p 3 and Ole e 7.

BACKGROUND: Cross-reactivity between nonspecific lipid transfer proteins could cause anaphylaxis, further influencing food avoidance and nutrient deficiencies. The one affecting olive pollen (Ole e 7) and peach (Pru p 3) may underlie a variety of pollen-food syndromes, though a deep molecular analysis is necessary. METHODS: Three Ole e 7-monosensitised patients (MON_OLE), three Pru p 3-monosensitised patients (MON_PRU) and three bisensitised patients (BI) were selected. For epitope mapping, both digested proteins were incubated with patient sera, and the captured IgE-bound peptides were characterised by LC-MS. RESULTS: The analysis revealed two Ole e 7 epitopes and the three Pru p 3 epitopes previously described. Interestingly, the "KSALALVGNKV" Ole e 7 peptide was recognised by MON_OLE, BI and MON_PRU patients. Conversely, all patients recognised the "ISASTNCATVK" Pru p 3 peptide. Although complete sequence alignment between both proteins revealed 32.6% identity, local alignment considering seven residue fragments showed 50 and 57% identity when comparing "ISASTNCATVK" with Ole e 7 and "KSALALVGNKV" with Pru p 3. CONCLUSIONS: This study mapped sIgE-Ole e 7-binding epitopes, paving the way for more precise diagnostic tools. Assuming non-significant sequence similarity, structural homology and shared key residues may underlie the potential cross-reactivity between Ole e 7 and Pru p 3 nsLTPs.

The polymorphism analysis and therapy vaccine target epitopes screening of HPV-35 E6 E7 among the threaten α-9 HPV in Sichuan area.

High-risk human papilloma virus (HR-HPV) persistent infection is closely associated with the development of cervical cancer and squamous intraepithelial lesion (SIL).The α-9 HPVs, which is predominantly composed of HR-HPV types, account for 75% of HR-HPV infection in Sichuan. The oncoproteins E6 and E7 of HPV play a crucial role in tumor initiation and progression. Notably, HPV-35 is the only HR-HPV type within the α-9 genus that is not included in the nine-valent HPV prophylactic vaccine. Cervical cell samples obtained from Sichuan were collected for HPV detection and genotyping. Among the 406 HPV-positive samples, 31 HPV-35 were detected, 24 HPV-35 E6 and 26 E7 were successfully amplified and sequenced, five nucleotide mutations in E6 and three in E7 were detected, T232C, T434G of E6 (W78R, I145R) and C67T, G84T of E7 (H23Y, L28F) were non-synonymy mutation. PAML 4.8 server was used to detect positive selection sites of HPV-35 E6, E7, and E6 is W78R. Phyre2 were used to predict and analyze protein structures, W78R made influences on protein structure. IEDB were used to screen epitopes vaccine target for HPV-35 affection therapy, and 5 HPV-35 E6 and 3 HPV-35 E7 most potential epitopes were obtained, the most potential peptides for therapy vaccine design were 79-91YRYSVYGETLEKQ, 45-60FACYDLCIVREGQPY, 124-135RFHNIGGRWTGR of E6; 3-19GEITTLQDYVLDLEPEA, 38-47TIDGPAGQAK, 70-88VQSTHIDIRKLEDLLMGTF of E7 and W78R mainly decreased the epitopes affinity.Conclusions Amino acid substitution in the positive selection sites of HPV-35 E6 and E7 genes have been found to influence protein structure and to decrease the overall affinity of antigen epitopes. This observation aligns with the evolutionary significance of positive selection site, which may confer advantages to the virus by making infected cells more challenging for the immune system to detect, thereby enhancing HPV's adaptability to the host environment. The polymorphism analysis of HPV-35 E6, E7 contributes to the enrichment of α-9 HPV data in Sichuan China, which is instrumental in improving the effectiveness of clinical detection. Furthermore, these findings provide a relevant theoretical foundation for the prevention and treatment of HPV-related diseases.

HPV 16/18 E7 oncoprotein detection as a promising triage strategy for HPV 16/18-positive patients: A prospective multicenter study with a 2-year follow up.

OBJECTIVE: To explore the effectiveness of HPV 16/18 E7 oncoprotein in detecting high-grade cervical intraepithelial neoplasia (CIN) and predicting disease outcomes in HPV 16/18-positive patients. METHODS: The present study was a cross-sectional study with a 2-year follow up. We collected 915 cervical exfoliated cell samples from patients who tested positive for HPV 16/18 in gynecologic clinics of three tertiary hospitals in Beijing from March 2021 to October 2022 for HPV 16/18 E7 oncoprotein testing. Subsequently, 2-year follow up of 408 patients with baseline histologic CIN1 or below were used to investigate the predictive role of HPV 16/18 E7 oncoprotein in determining HPV persistent infection and disease progression. RESULTS: The positivity rate of the HPV 16/18 E7 oncoprotein assay was 42.06% (249/592) in the inflammation/CIN 1 group and 85.45% (277/324) in the CIN2+ group. For CIN2+ detection, using the HPV 16/18 E7 oncoprotein assay combined with HPV 16/18 testing, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 85.45%, 57.94%, 52.57%, and 87.95%, respectively. During the 2-year follow up, the sensitivity, specificity, PPV, and NPV for predicting persistent HPV infection were 48.44%, 58.21%, 34.64%, and 71.18% in the baseline inflammation and CIN1 group. CONCLUSIONS: As a triage method for high-grade CIN screening in HPV 16/18-positive patients, HPV 16/18 E7 oncoprotein demonstrated a relatively high NPV, making it suitable for clinical use in triaging HPV 16/18-positive cases and potentially reducing the colposcopic referral rate. HPV 16/18 E7 oncoprotein exhibited a preferably predictive value in determining HPV infection outcomes and disease progression.

Towards sustainable development: Examining renewable energy consumption in E-7 countries.

In the contemporary landscape, sustainable development became major challenge for the economy which is tackled if environmental issues are resolved. In this regard, this study investigate renewable energy, institutional quality, foreign direct investment (FDI), economic growth on environmental pollution in E-7 countries (Brazil, Russia, China, Indonesia, India, Mexico, and Turkey). Utilizing annual data from 2002 to 2023, selected the panel Nonlinear Autoregressive Distributed Lag (NARDL) after applying stationary process. The results depict that there is short and long run relationship among the selected variables, CO2 emissions exhibit an asymmetrical response to positive and negative shocks in exogenous variables. A one-percent change in FDI, GDP, IQ and EC reduce the carbon emission. Our research concludes with policy recommendation that prioritize priorities economic growth and environmental sustainability. To achieve a healthy environment and sustainable growth in the E7 countries, it is essential to strengthen institutional frameworks, encourage green investments, and foster technical innovation.

HPV18 E6/E7 activates Ca2+ influx to promote the malignant progression of cervical cancer by inhibiting Ca2+ binding protein 1 expression.

Mounting studies have shown that the oncoproteins E6 and E7 encoded by the human papillomavirus (HPV) genome are essential in HPV-induced cervical cancer (CC). Ca2+ binding protein 1 (CABP1), a downstream target of HPV18-positive HeLa cells that interferes with E6/E7 expression, was identified through screening the GEO Database (GSE6926). It was confirmed to be down-regulated in CC through TCGA prediction and in vitro detection. Subsequent in vitro experiments revealed that knocking down E6/E7 inhibited cell proliferation, migration, and invasion, whereas knocking down CABP1 promoted these processes. Simultaneously knocking down CABP1 reversed these effects. Additionally, the results were validated in vivo. Previous studies have indicated that CABP1 can regulate Ca2+ channels, influencing Ca2+ influx and tumor progression. In this study, it was observed that knocking down CABP1 enhanced Ca2+ inflow, as demonstrated by flow cytometry and confocal microscopy. Knocking down E6/E7 inhibited these processes, whereas simultaneously knocking down E6/E7 and CABP1 restored the inhibitory effect of knocking down E6/E7 on Ca2+ inflow. To further elucidate that E6/E7 promotes CC progression by inhibiting CABP1 expression and activating Ca2+ influx, BAPTA/AM treatment was administered during CABP1 knockdown. It was discovered that Ca2+ chelation could reverse the effect of CABP1 knockdown on CC cells. In conclusion, our results offer a novel target for the diagnosis and treatment of HPV-induced CC.

Genome composition-based deep learning predicts oncogenic potential of HPVs.

Human papillomaviruses (HPVs) account for more than 30% of cancer cases, with definite identification of the oncogenic role of viral E6 and E7 genes. However, the identification of high-risk HPV genotypes has largely relied on lagged biological exploration and clinical observation, with types unclassified and oncogenicity unknown for many HPVs. In the present study, we retrieved and cleaned HPV sequence records with high quality and analyzed their genomic compositional traits of dinucleotide (DNT) and DNT representation (DCR) to overview the distribution difference among various types of HPVs. Then, a deep learning model was built to predict the oncogenic potential of all HPVs based on E6 and E7 genes. Our results showed that the main three groups of Alpha, Beta, and Gamma HPVs were clearly separated between/among types in the DCR trait for either E6 or E7 coding sequence (CDS) and were clustered within the same group. Moreover, the DCR data of either E6 or E7 were learnable with a convolutional neural network (CNN) model. Either CNN classifier predicted accurately the oncogenicity label of high and low oncogenic HPVs. In summary, the compositional traits of HPV oncogenicity-related genes E6 and E7 were much different between the high and low oncogenic HPVs, and the compositional trait of the DCR-based deep learning classifier predicted the oncogenic phenotype accurately of HPVs. The trained predictor in this study will facilitate the identification of HPV oncogenicity, particularly for those HPVs without clear genotype or phenotype.

Microfluid biosensor for detection of hpv in patient scraping samples: Determining E6 and E7 oncogenes.

E6 and E7 oncogenes are pivotal in the carcinogenic transformation in HPV infections and efficient diagnostic methods can ensure the detection and differentiation of HPV genotype. This study describes the development and validation of an electrochemical, label-free genosensor coupled with a microfluidic system for detecting the E6 and E7 oncogenes in cervical scraping samples. The nanostructuring employed was based on a cysteine and graphene quantum dots layer that provides functional groups, surface area, and interesting electrochemical properties. Biorecognition tests with cervical scraping samples showed differentiation in the voltammetric response. Low-risk HPV exhibited a lower biorecognition response, reflected in ΔI% values of 82.33 % ± 0.29 for HPV06 and 80.65 % ± 0.68 for HPV11 at a dilution of 1:100. Meanwhile, high-risk, HPV16 and HPV18, demonstrated ΔI% values of 96.65 % ± 1.27 and 93 % ± 0.026, respectively, at the same dilution. Therefore, the biorecognition intensity followed the order: HPV16 >HPV18 >HPV06 >HPV11. The limit of detection and the limit of quantification of E6E7 microfluidic LOC-Genosensor was 26 fM, and 79.6 fM. Consequently, the E6E7 biosensor is a valuable alternative for clinical HPV diagnosis, capable of detecting the potential for oncogenic progression even in the early stages of infection.

Novel Gammapapillomavirus type in the nasal cavity of a wild red colobus (Piliocolobus tephrosceles).

Papillomaviruses (PVs) are double-stranded, circular, epitheliotropic DNA viruses causing benign warts (papillomas) or inducing dysplasia that can progress to cancer. Although they have been identified in all vertebrate taxa, most classified types are human PVs (HPVs); relatively little is known about PVs in other species. Here we characterize a novel Gammapapillomavirus type, PtepPV1, from a nasal swab of a wild red colobus (Piliocolobus tephrosceles) in Kibale National Park, Uganda. The virus has a genome of 6576 bases, encoding the seven canonical early (E) ORFs (E6, E7, E1, E2, E4, E1^E4 and E8^E2) and two late (L) ORFs (L1 and L2) of the gammapapillomaviruses, and is 81.0% similar to HPV-mSK_118, detected in a cutaneous wart from an immunocompromised human patient, in the L1 gene at the amino acid level. Alphapapillomaviruses (genus Alphapapillomavirus) cause anogenital carcinomas such as cervical cancer and have been described previously in several nonhuman primates. However, the first gammapapillomavirus (genus Gammapapillomavirus), which cause transient cutaneous infections, was not described until 2019 in a healthy rhesus macaque (Macaca mulatta) genital swab. The new virus from red colobus, PtepPV1, has many genomic features encoded by high-risk oncogenic PVs, such as the E7 gene LXSXE and CXXC motifs, suggesting potential for pRb and zinc-finger binding, respectively. To our knowledge, PtepPV1 is also the first reported nonhuman primate PV found in the nasal cavity. PtepPV1 expands the known host range, geographical distribution, tissue tropism and biological characteristics of nonhuman primate PVs.

Correlation analysis of human papillomavirus E6/E7 mRNA detection with diagnosis, prognosis and recurrence risk in patients with cervical epithelioma.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) is an important precursor of cervical cancer. Early detection and treatment can reduce the incidence of cervical cancer. AIM: To investigate the detection rate of human papillomavirus (HPV) E6/E7 mRNA in cervical tissue of patients with different types of epithelial cell neoplasia (CIN) and its relationship with CIN progression and diagnosis. METHODS: One hundred women with HPV infection detected by cervical exfoliation cytology between January 2022 and January 2023 were retrospectively selected. These patients were graded CIN based on colposcopy and cervical pathology. The positive expression rates of HPV E6/E7 mRNA and HPV [polymerase chain reaction (PCR)-reverse dot crossing] were compared among all groups. Patients with HPV E6/E7 mRNA expression in the grade 1 CIN group were followed up for 1 yr. The relationship between atypical squamous epithelium and high malignant epithelial neoplasia was investigated by univariate and multivariate analysis. RESULTS: The diagnostic sensitivity, specificity, and sensitivity of PCR-reverse point hybridization technology for secondary CIN were 70.41%, 70.66%, and 0.714, respectively. Sensitivity and specificity for secondary CIN were 752% and 7853%, respectively, the area under the curve value was 0.789. Logistic Multifactorial model analysis revealed that the HPV positive rates and the HPV E6/E7 mRNA positive rates were independent risk factors of CIN grade I (P < 0.05). In CIN grade I patients with positive for HPV E6/E7 mRNA, in its orientation to grade CIN patients, in its orientation to grade CIN patients, at 69.2%, compared with patients negative for HPV E6/E7 mRNA (30.8%), significant difference (P < 0.05). CONCLUSION: HPV E6/E7 mRNA and HPV (PCR-reverse dot hybrid) positive expression have a close relationship with CIN-grade disease progression and is an independent risk factor for high-grade CIN lesions.

Genetic variability of human papillomavirus type 18 based on E6, E7 and L1 genes in central China.

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection is an important factor for the development of cervical cancer. HPV18 is the second most common HR-HPV after HPV16. METHODS: In this study, MEGA11 software was used to analyze the variation and phylogenetic tree of HPV18 E6-E7 and L1 genes. The selective pressure to E6, E7 and L1 genes was estimated using pamlX. In addition, the B cell epitopes of L1 amino acid sequences and T cell epitopes of E6-E7 amino acid sequences in HPV18 were predicted by ABCpred server and IEDB website, respectively. RESULTS: A total of 9 single nucleotide variants were found in E6-E7 sequences, of which 2 were nonsynonymous variants and 7 were synonymous variants. Twenty single nucleotide variants were identified in L1 sequence, including 11 nonsynonymous variants and 9 synonymous variants. Phylogenetic analysis showed that E6-E7 and L1 sequences were all distributed in A lineage. In HPV18 E6, E7 and L1 sequences, no positively selected site was found. The nonconservative substitution R545C in L1 affected hypothetical B cell epitope. Two nonconservative substitutions, S82A in E6, and R53Q in E7, impacted multiple hypothetical T cell epitopes. CONCLUSION: The sequence variation data of HPV18 may lay a foundation for the virus diagnosis, further study of cervical cancer and vaccine design in central China.

Comparison of preclinical efficacy of immunotherapies against HPV-induced cancers.

INTRODUCTION: Persistent infections with the human papilloma viruses, HPV16 and HPV18, are associated with multiple cancers. Although prophylactic vaccines that induce HPV-neutralizing antibodies are effective against primary infections, they have no effect on HPV-mediated malignancies against which there is no approved immuno-therapy. Active research is ongoing on immunotherapy of these cancers. AREAS COVERED: In this review, we compared the preclinical efficacy of vaccine platforms used to treat HPV-induced tumors in the standard model of mice grafted with TC-1 cells, which express the HPV16 E6 and E7 oncoproteins. We searched for the key words, 'HPV,' 'vaccine,' 'therapy,' 'E7,' 'tumor,' 'T cells' and 'mice' for the period from 2005 to 2023 in PubMed and found 330 publications. Among them, we selected the most relevant to extract preclinical antitumor results to enable cross-sectional comparison of their efficacy. EXPERT OPINION SECTION: We compared these studies for HPV antigen design, immunization regimen, immunogenicity, and antitumor effect, considering their drawbacks and advantages. Among all strategies used in murine models, certain adjuvanted proteins and viral vectors showed the strongest antitumor effects, with the use of lentiviral vectors being the only approach to result in complete tumor eradication in 100% of experimental individuals while providing the longest-lasting memory.

Persistent infections with the human papilloma virus HPV16 and HPV18 gentoypes can cause multiple cancers.Prophylactic anti-HPV vaccines show no efficacy against persistent HPV infections or already malignant tissues.No immunotherapy against HPV-induced cancers has been thus far approved for use in humans.Active research is ongoing on immunotherapy of HPV-induced malignancies.We compared the efficacy of the immunotherapy strategies developed against HPV-induced cancers in the standard murine TC-1 tumor model since 2005.Certain adjuvanted proteins and viral vectors induce the strongest effects against HPV-induced tumors.Lentiviral vectors, able to induce the longest-lasting T-cell immune memory, give rise to full eradication of large solid tumors in 100% of mice.

Enhancing Cervical Cancer Screening with 7-Type HPV mRNA E6/E7 Testing on Self-Collected Samples: Multicentric Insights from Mexico.

Cervical cancer remains a significant public health issue, particularly in regions with low screening uptake. This study evaluates the effectiveness of self-sampling and the 7-type HPV mRNA E6/E7 test in improving cervical cancer screening outcomes among a referral population in Mexico. A cohort of 418 Mexican women aged 25 to 65, referred for colposcopy and biopsy due to abnormal cytology results (ASC-US+), participated in this study. Self-samples were analyzed using both the 14-type HPV DNA test and the 7-type HPV mRNA E6/E7 test. The study assessed the sensitivity, specificity, positive predictive value (PPV), and the necessity of colposcopies to detect CIN3+ lesions. Participant acceptability of self-sampling was also evaluated through a questionnaire. The 7-type HPV mRNA E6/E7 test demonstrated equivalent sensitivity but significantly higher specificity (77.0%) and PPV for CIN3+ detection compared to the 14-type HPV DNA test (specificity: 45.8%, p < 0.001). The use of the HPV mRNA test as a triage tool reduced the number of colposcopies needed per CIN3+ case detected from 16.6 to 7.6 (p < 0.001). Self-sampling was highly accepted among participants, with the majority reporting confidence in performing the procedure, minimal discomfort, and willingness to undertake self-sampling at home. Self-sampling combined with the 7-type HPV mRNA E6/E7 testing offers a promising strategy to enhance cervical cancer screening by improving accessibility and ensuring precise diagnostics. Implementing these app roaches could lead to a significant reduction in cervical cancer morbidity and mortality, especially in underserved populations. Future research should focus on the long-term impact of integrating these methods into national screening programs and explore the cost-effectiveness of widespread implementation.

The association between human papillomavirus and lung cancer: A Mendelian randomization study.

BACKGROUND: To investigate the causal relationship between human papillomavirus (HPV) and lung cancer, we conducted a study using the two-sample Mendelian randomization (TSMR). METHOD: Data from genome-wide association studies (GWAS) were analyzed with HPV E7 Type 16 and HPV E7 Type 18 as exposure factors. The outcome variables included lung cancer, small cell lung cancer, adenocarcinoma and squamous cell lung cancer. Causality was estimated using inverse variance weighted (IVW), MR-Egger and weighted median methods. Heterogeneity testing, sensitivity analysis, and multiple validity analysis were also performed.. RESULTS: The results showed that HPV E7 Type 16 infection was associated with a higher risk of squamous cell lung cancer (OR = 7.69; 95% CI:1.98-29.85; p = 0.0149). HPV E7 Type 18 infection significantly increased the risk of lung adenocarcinoma (OR = 0.71; 95% CI: 0.38-1.31; p = 0.0079) and lung cancer (OR = 7.69; 95% CI:1.98-29.85; p = 0.0292). No significant causal relationship was found between HPV E7 Type 16 and lung adenocarcinoma, lung cancer, or small cell lung carcinoma, and between HPV E7 Type 18 and squamous cell lung cancer or small cell lung carcinoma. CONCLUSIONS: This study has revealed a causal relationship between HPV and lung cancers. Our findings provide valuable insights for further mechanistic and clinical studies on HPV-mediated cancer.

The RP11-417E7.1/THBS2 signaling pathway promotes colorectal cancer metastasis by activating the Wnt/ß-catenin pathway and facilitating exosome-mediated M2 macrophage polarization.

BACKGROUND: Metastasis is the major cause of colorectal cancer (CRC) mortality. Emerging evidence suggests that long noncoding RNAs (lncRNAs) drive cancer metastasis and that their regulatory pathways could be targeted for preventing metastasis. However, the underlying mechanisms of lncRNAs in CRC metastasis remain poorly understood. METHODS: Microarray analysis was used to screen for differentially expressed lncRNAs. Transwell assays, fibronectin cell adhesion assays, and mouse metastasis models were utilized to evaluate the metastatic capacities of CRC in vitro and in vivo. Chromatin isolation by RNA purification, chromatin immunoprecipitation and chromosome conformation capture were applied to investigate the underlying mechanism involved. qRT‒PCR and transmission electron microscopy were performed to confirm macrophage polarization and the presence of cancer-derived exosomes. RESULTS: The lncRNA RP11-417E7.1 was screened and identified as a novel metastasis-associated lncRNA that was correlated with a poor prognosis. RP11-417E7.1 enhances the metastatic capacity of CRC cells in vivo and in vitro. Mechanistically, RP11-417E7.1 binding with High mobility group A1 (HMGA1) promotes neighboring thrombospondin 2 (THBS2) transcription via chromatin loop formation between its promoter and enhancer, which activates the Wnt/ß-catenin signaling pathway and facilitates CRC metastasis. Furthermore, exosomes derived from CRC cells transport THBS2 into macrophages, thereby inducing the M2 polarization of macrophages to sustain the prometastatic microenvironment. Notably, netropsin, a DNA-binding drug, suppresses chromatin loop formation mediated by RP11-417E7.1 at the THBS2 locus and significantly inhibits CRC metastasis in vitro and in vivo. CONCLUSIONS: This study revealed the novel prometastatic function and mechanism of the lncRNA RP11-417E7.1, which provides a potential prognostic indicator and therapeutic target in CRC.

Time to take HPV infection in colorectal cancer patients more seriously.

Background: The association between viral infections and colorectal cancer (CRC) remains an enigma in cancer research. Certain types of Human Papillomaviruses (hr-HPVs), known for their oncogenic properties, have been observed in particular CRC biopsies, further adding to the enigma surrounding this association. Materials and methods: This cross-sectional study was conducted on 40 confirmed cases of CRC adenocarcinoma. The presence and genotyping of HPV DNA in colorectal fresh tissue and urine samples was assessed using an HPV DNA hybridization kit. A subset of serum samples from both CRC cases and healthy volunteers was randomly chosen and subjected to western blot to investigate the presence of HPV16 E6/E7 oncoproteins carried by exosomes. Results: It was observed that 26/40 HPV-positive CRC patients demonstrated 7 times more chance to develop colorectal cancer when compared to those 8/40 normal tissue (odds ratio [OR] = 7.4; confidence interval [CI] 95% = 0.483156-0.793718; p < 0.001). Of 26 HPV-positive CRC patients, 14 urine samples were also showed HPV DNA positivity (p = 0.013). High-risk HPV16 was the most prevalent genotype detected in both 24/40 tumor and 12/40 urine samples (p < 0.001). The tumor sample of a male was HPV45, while another male's urine sample was HPV31. A female CRC patient had HPV83 in tumor and HPV56 in urine. Here, was the first detection of HPV83 in a CRC patient. Notably among 20 randomly selected serum exosome samples, one serum sample concurrently tested positive for both HPV16 E6 and E7 oncoproteins, and one sample tested positive for HPV16 E7 oncoprotein. Conclusion: High risk HPV DNA detection in CRC urine samples supports non-invasive screening tools. Detection of HPV16 E6 and E7 oncoproteins in exosomes from serum samples shows potential for non-invasive diagnostics. HPV's potential role in CRC development is also underscored. HPV vaccination should be implemented in low- and middle-income countries to prevent cancer.

Bioinformatics Analysis Reveals E6 and E7 of HPV 16 Regulate Metabolic Reprogramming in Cervical Cancer, Head and Neck Cancer, and Colorectal Cancer through the PHD2-VHL-CUL2-ELOC-HIF-1α Axis.

Human papillomavirus 16 (HPV 16) infection is associated with several types of cancer, such as head and neck, cervical, anal, and penile cancer. Its oncogenic potential is due to the ability of the E6 and E7 oncoproteins to promote alterations associated with cell transformation. HPV 16 E6 and E7 oncoproteins increase metabolic reprogramming, one of the hallmarks of cancer, by increasing the stability of hypoxia-induced factor 1 α (HIF-1α) and consequently increasing the expression levels of their target genes. In this report, by bioinformatic analysis, we show the possible effect of HPV 16 oncoproteins E6 and E7 on metabolic reprogramming in cancer through the E6-E7-PHD2-VHL-CUL2-ELOC-HIF-1α axis. We proposed that E6 and E7 interact with VHL, CUL2, and ELOC in forming the E3 ubiquitin ligase complex that ubiquitinates HIF-1α for degradation via the proteasome. Based on the information found in the databases, it is proposed that E6 interacts with VHL by blocking its interaction with HIF-1α. On the other hand, E7 interacts with CUL2 and ELOC, preventing their binding to VHL and RBX1, respectively. Consequently, HIF-1α is stabilized and binds with HIF-1ß to form the active HIF1 complex that binds to hypoxia response elements (HREs), allowing the expression of genes related to energy metabolism. In addition, we suggest an effect of E6 and E7 at the level of PHD2, VHL, CUL2, and ELOC gene expression. Here, we propose some miRNAs targeting PHD2, VHL, CUL2, and ELOC mRNAs. The effect of E6 and E7 may be the non-hydroxylation and non-ubiquitination of HIF-1α, which may regulate metabolic processes involved in metabolic reprogramming in cancer upon stabilization, non-degradation, and translocation to the nucleus.