The distribution of human papillomaviruses (HPVs) must be understood for the control and prevention of cervical cancer. Community-based Papanicolaou and HPV DNA tests were performed on 41 578 women. The prevalences of HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 were assessed. In total, 10% women were infected/co-infected by these HPVs. The infection rate increased from 7.1% in women aged ⩽30 years to 10.4% in those aged 50–60 years, and then decreased slightly to 9.9% in those aged >60 years. The HPV 16 and 58 positivity rates were significantly higher among women with high-grade squamous intraepithelial lesions (HSILs) than among those with cervicitis/negativity for intraepithelial lesion or malignancy (NILM) or low-grade SILs (LSILs). The HPV 18, 52 and 68 infection rates were significantly lower in women with HSILs than in those with NILM or LSILs. The proportion of women infected by multiple HPV strains was higher among those with HSILs. The proportions of the five most common genotypes, HPV 16, 18, 33, 52 and 58, increased with the number of co-infecting strains. HPV 16 and 58 were the high-risk HPVs in the Shanghai community and should be the focus in HPV screening and vaccination. The International Agency for Research on Cancer has classified 12 human papillomavirus (HPV) genotypes  as group 1 carcinogens because of their association with cervical cancer . This paCurrently, many prophylactic vaccines are now available worldwide . These vThe most prevalent HPV genotypes, HPV infection rates, and the demographic and sociological characteristics of HPV infection vary widely by region , 12. ChiTo ensure early detection and management of breast and cervical cancer, and to standardise screening and referral, the Shanghai Minhang District Health and Family Planning Commission has implemented community-based screening in Minhang District, which, based on the latest census data, has a population of 2.43 million in nine towns. Commencing in 2014, screening was implemented in four towns; more than 10 000 women are screened annually via initial Papanicolaou (Pap) and hrHPV co-testing. The follow-up for those with abnormal test results is that recommended by the American College of Obstetricians and Gynecologists 2012 Updated Consensus Guidelines for the Management of Abnormal Cervical Cancer Screening Tests and Cancer Precursors . Women wThe study was conducted in accordance with all relevant tenets of the World Medical Association's Declaration of Helsinki. The Review Board of the Ethics Committee of Medical Research at Minhang Hospital, Fudan University  approved the study protocol . Written informed consent was obtained from all participants according to the guidelines of the Chinese National Ethics Regulation Committee. All participants were informed of their right to withdraw consent personally or via relatives, caregivers or guardians. The authors assert that all procedures complied with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.in situ; SCC; and adenocarcinoma [For Pap test, a speculum is gently inserted to expose the cervix; then, a sterile cytobrush was inserted into the cervical os and gently rotated in the cervical canal and the portion of the cervix extending into the vagina to collect squamous and glandular cells. The cells were then evaluated as recommended by the manufacturer of the BD SurePath liquid-based Pap test , and the results were reported using the Bethesda System for Reporting Cervical Cytology; Definitions, Criteria, and Explanatory Notes; Third Edition . The resarcinoma , 16.At the time of Pap testing, cervical specimens for HPV testing were collected using a sterile cytobrush simultaneously as described above, and viral DNA was extracted using QIAamp DNA Mini Kits . HPV DNA evaluation and genotyping were performed using a kit provided by Huada Biotech Co. Ltd . The kit detects 12 hrHPVs , two possibly carcinogenic genotypes (66 and 68) and two low-risk strains (6 and 11). The kit employs polymerase chain reaction followed by HPV genotype-specific DNA microarray analysis. It has been approved by the Chinese Food and Drug Administration. All procedures followed the manufacturer's protocols.t test, χ2 test or Fisher's exact probability test, as appropriate. All statistical analyses were performed with the aid of SPSS software , and the significance level was set to α = 0.05.Continuous variables are presented as means ± standard deviations and categorical data are presented as frequencies (percentages). Differences between groups were evaluated using the Between 2014 and 2017, a total of 41 578 women were screened using the Pap and HPV DNA tests. Of these, 4156 (10.0%) women were infected or co-infected by HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and/or 68. In 2014, 2015, 2016 and 2017, 7514, 11 130, 12 335 and 10 473 women, respectively, were co-tested. The HPV 16 and 18 positivity rates ranged from 1.3% to 1.8% and from 0.7% to 1.0%, respectively, over the 4 years. The positivity rates for serotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 ranged from 6.5% to 8.0% over the 4 years . When thOf all 4156 HPV-positive females, 2000 underwent colposcopy in our hospital; complete cytological and HPV data were available for 1481 of these women. Their average age was 56.3 ± 8.8 years; the numbers of women aged 21–29, 30–65 and >65 years were 11 (0.7%), 1276 (86.1%) and 194 (13.2%), respectively . The PapAll HPV genotypes were common in women with cervicitis/NILM; the lowest infection rate (2.4%) was that of HPV 59 and the highest (23.9%) was that of HPV 52 . HPV 16,n = 58), LSIL (n = 112) and HSIL (n = 75) underwent colposcopy and biopsy. Ninety-four histological examinations were completed. When determining the prevalences of hrHPVs by CIN status, we grouped women with CIN II, CIN II–III and SCC as CIN II+. Fifty-two and 42 women were of CIN I and CIN II+ status, respectively (+ status (61.9%) than among those with cervicitis (18.0%) and those of CIN I status (21.2%); HPV 68 was not detected in the 42 women of CIN II+ status. Although the rates of infection with genotypes 52 and 58 were thus similar to those revealed by SIL grouping, positivity did not differ significantly among the cervicitis/NILM, CIN I and CIN II+ groups.Women with ASC-US (ectively . As was In total, 1144, 278 and 60 women were infected by one, two and three or more strains of HPV, respectively . The proWe present community-based HPV and Pap co-test baseline data. The overall prevalence of all 14 HPV genotypes was 10.0%, consistent with other data from eastern Asia , 4. We fet al. [The HPV 18, 52 and 68 infection rates were significantly lower in women with HSILs than in those with NILM and LSILs. HPV 18 is more strongly linked to adenocarcinoma than is SCC ; thus, Het al.  showed tThe clinical sensitivity of hrHPV DNA testing in terms of the detection of CIN II+ status is approximately 95% in screening populations , 24, encMost HPV infections are cleared/suppressed by host cell-mediated immune processes within 1–2 years . The mosMore and more studies confirm that vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities –30. CurrIn conclusion, HPV 16 and 58, but not 16 and 18, are associated with local women with HSIL; the HPV 18, 52 and 68 infection rates were significantly lower in local women with HSIL; and the proportion of women infected by multiple HPV strains was higher in local women with HSIL.


Uterine cervical cancer is the fourth most common cancer in women, and its etiology has been recognized. High-risk human papilloma virus (HR-HPV) infection induces an opportunity for malignant transformation. This paper discusses the current issues based on a review of the literature and compares the impact of the dietary and nutrient intake to the impact of tobacco smoking on cervical cancer development. The important roles of diet/nutrition in cervical cancer are as prophylaxis against HR-HPV infection. Antioxidant vitamins can inhibit the proliferation of cancer cells, stabilize the p53 protein, prevent DNA damage, and reduce immunosuppression. In contrast, tobacco smoking not only causes DNA adducts and strand breaks, but it independently causes an increased viral load in HR-HPV-infected cells. Tobacco smoking induces the heightened expression of E6 and E7 and can inhibit the immune system response to HPV. What happens when two materials, which have opposite effects on cervical cells, are taken in at the same time? The negative effects of tobacco smoking may be stronger than the positive effects of vitamins, vegetables, and fruits on the regression of cervical disease such as cervical intraepithelial neoplasia (CIN). A relatively low intake of vitamins, vegetables, and fruits in combination with tobacco smoking was most associated with a high incidence of cervical neoplasia. Cervical cancer is the fourth most frequent cancer in women with an estimated 570,000 new cases in 2018 [Exposure to tobacco smoke is associated with the development of multiple cancers ,4. In 20In contrast, the important role of antioxidant nutrients/diets, such as vitamins, fruits, and vegetables, in preventing the development of cervical cancer has received a lot of attention during recent decades . The impThis paper reviews the current issues in the relevant literature and the effects of the antioxidant diets/nutrients and smoking on cervical cancer, and it discusses the points to be noted.HPV types 6, 11, and 42 are associated with benign genital warts and low-grade cervical intraepithelial neoplasia (CIN), while HR-HPV such as HPV types 16, 18, and (less frequently) 31, 33, and 35 have been identified as an infectious agent to cause high-grade precursor lesions and the majority of cervical cancers ,10. PersExposure at a young age also increases the risk of persistent HR-HPV . Thus, HA close link between chronic inflammation, oxidative stress, and carcinogenesis has been reported ,19. InflHR-HPV integration is facilitated by the generation of DNA damage/double strand breaks (DSBs) , which cAntioxidants can act as efficient scavengers of free radicals and oxidants to prevent DNA damage . If antiAntioxidant vitamins  can inhibit the proliferation of cancers ,30, stabMost recently, we reviewed the recent clinical studies of dietary oxidants on development of cervical cancer . The folWei et al. suggested that in HR-HPV-infected cells, tobacco smoking not only causes DNA adducts and strand breaks , but it p < 0.05) [p < 0.05). In a population-based case-control study of 137 women with CIN 2–3 and 253 healthy aged-matched women, smoking was found to be associated with CIN 2–3  [p = 0.002). In a case-control study of 480 patients with cervical cancer and 797 population controls in the United States, a two-fold increase in risk was observed in patients who smoked 40 or more cigarettes per day and those who had smoked for ≥ 40 years [In a clinical study of 1007 women, the risk of HPV infection in smoking women was reported to be 1.905 times greater than that in nonsmoking women (odds ratio (OR) 1.905,  < 0.05) . Further40 years . The dat40 years . p < 0.001, and adjusted OR 3.15, p = 0.001) [Passive smoking is also associated with a risk of developing cervical cancer. In a case-control study with 177 cervical cancer cases and 177 controls, females with sexual partners who were smokers showed an increased risk of developing cervical cancer  . In a me= 0.001) . During HR-HPV infection, E6 has the ability to inhibit the function of p53 ,16, and In contrast, in HR-HPV-infected cells, tobacco smoke not only causes DNA adducts and strand breaks , but it p = 0.024). However, this benefit was abolished in smokers. Tomita et al. also reported that a low intake (≤ 39 g) of dark-green and deep-yellow vegetables and fruits without tobacco smoking was associated with a lower incidence of CIN 3 development (OR 1.14) in comparison to smokers with higher intakes of dark-green and deep-yellow vegetables and fruits  [p < 0.001), compared with nonsmokers, with a higher rate of HR-HPV-infected cells. In patients with cervical disease, the negative effects of tobacco smoking may be stronger than the positive effects of vitamins, vegetables, and fruits. A relatively low intake of vitamins, vegetables, and fruits in combination with tobacco smoking was most associated with a high incidence of cervical neoplasia. In particular, young patients with cervical disease should, therefore, both stop any active smoking and increase their intake of dietary/nutrient antioxidants, while also being careful to avoid passive smoking.Individuals can easily be exposed to tobacco smoke through passive smoking and consume dietary/nutrient antioxidants such as vitamins, vegetables, and fruits in the environment. What happens when two materials, which have opposite effects on cervical cells, are taken in at the same time? Fujii et al. reported some very interesting findings . In nonsOR 1.83) . In addiIn patients with cervical disease, the negative effects of tobacco smoking may have a greater impact than the beneficial effects of dietary antioxidant intake on cervical cancer development. Therefore, patients, in particular young patients with cervical disease, should stop any active smoking, and avoid passive smoking, while also increasing their intake of vitamins, vegetables, and fruits.


Cervical cancer is a critical public health issue in sub-Saharan Africa (SSA), where it is the second leading cause of cancer among women and the leading cause of female cancer deaths. Incidence and mortality rates are substantially higher than in high-income countries with population-based screening programs, yet implementing screening programs in SSA has so far proven to be challenging due to financial, logistical, and sociocultural factors. Human Papillomavirus (HPV) vaccination is an effective approach for primary prevention of cervical cancer and presents an opportunity to reduce the burden from cervical cancer in SSA. With a number of SSA countries now eligible for Global Alliance for Vaccines and Immunization (GAVI) support for vaccine introduction, it is timely to consider the factors that impede and facilitate implementation of vaccine programs in SSA. This article describes epidemiological features of cervical cancer in SSA and the current status of HPV vaccine implementation in SSA countries. Rwanda’s experience of achieving high vaccination coverage in their national HPV immunization program is used as a case study to explore effective approaches to the design and implementation of HPV vaccination programs in SSA. Key factors in Rwanda’s successful implementation included government ownership and support for the program, school-based delivery, social mobilization, and strategies for reaching out-of-school girls. These findings might usefully be applied to other SSA countries planning for HPV vaccination. Cervical cancer is a major cause of morbidity and mortality in sub-Saharan Africa (SSA), where the burden from noncommunicable diseases is increasing due in large part to improved control of communicable diseases and an ageing population . IncidenCervical cancer is the second most frequent cause of female cancer in women aged 15–44 years in SSA . The mosCountry-specific data on time trends are limited but where available demonstrate an increasing burden from cervical cancer. In Uganda, cervical cancer prevalence has increased by 1.8% per annum over the previous two decades to 2018 , and theCervical cancer is usually preceded by a long phase of precancerous changes, which can be detected by screening before progression to invasive disease, allowing for early intervention and treatment . In highScreening methods used vary between countries in SSA. The most frequent method used is Pap smears with cytological analysis , but SSAThe high prevalence of HPV infection in SSA points to a great need for improving access to effective cervical cancer screening. While alternative screening types suitable for LMICs now exist, challenges to implementation have meant they are still not widely available and uptake of screening remains low . PrimaryInfection with the Human Papillomavirus (HPV) is the main cause of cervical cancer, with some estimates that it is responsible for greater than 99% of cases , and theHPV vaccination holds great potential for reducing the burden from cervical cancer in LMICs. It has been demonstrated to be cost-effective, for example Bray and colleagues 2015) estimated that the cost of averting one disability-adjusted life-year (DALY) with HPV vaccination is less than the per capita gross domestic product (GDP) . There i5 estimatOver the past decade, HPV vaccination efforts have gained momentum in SSA, in large part due to inclusion of the HPV vaccine in the GAVI portfolio ,5,19,20.As of June 2018, there are eight countries in SSA with a national HPV immunization program see , and neaNumerous barriers to implementation of national vaccination programs in SSA exist, including inadequate infrastructure and finances, limited health worker training, vaccine cost, and cold chain capacity constraints ,24. As yRwanda was the first low-income country to implement a national HPV vaccination program ,26. RwanMerck, an HPV vaccine manufacturer. Merck provided free vaccines to Rwanda for three years, with an understanding that future doses would be supplied at a concessional fee [The Rwandan Ministry of Health (MOH) received support from onal fee . Rwanda’onal fee ,23 (see onal fee . Schoolsonal fee . The taronal fee . The strategies used by Rwanda have been utilized successfully in other LMICs introducing national HPV vaccination programs. Gallagher and colleagues  undertooWith eight SSA countries having now introduced national HPV vaccination programs, and at least twice that number with current pilot projects, it is important to learn from countries like Rwanda that have had successful experiences with implementation. In order to achieve high vaccine coverage sustained over time, the following lessons from Rwanda’s experience could be useful for other SSA countries. High levels of commitment at the national governmental level with demonstrated leadership are important for successful HPV introduction . A recenDelivery through schools is effective in countries with high levels of school attendance ,29. In HHigh levels of school attendance facilitated Rwanda’s success with school-based delivery, and community health workers were able to identify and vaccinate out-of-school girls at health centres. In countries with lower school attendance, reaching out-of-school girls may be more challenging, and many SSA countries have indicated difficulties in achieving this . There iEarly community involvement and social mobilization was a cornerstone of Rwanda’s HPV vaccination program ,26. A seThe burden of cervical cancer in SSA is substantial, and there is a great need for improved prevention in order to reduce morbidity and mortality from this disease. While secondary prevention through national screening programs has contributed significantly to reducing incidence and mortality from cervical cancer in high-income countries, constraints to implementing and sustaining similar programs in SSA have limited the effectiveness of screening in SSA. Primary prevention of cervical cancer through HPV vaccination is a cost-effective preventive measure that is currently being implemented in numerous SSA countries. Although challenges exist, examples of high vaccine coverage and sustainable programs demonstrate that high vaccine coverage and sustainable programs can be delivered with strong commitment from government, comprehensive planning with ministries of health as well as education, and early community sensitisation. These lessons might usefully be applied in SSA countries with current HPV vaccine demonstration projects, as well as those beginning to plan for vaccine introduction.


Rural Veterans often lack access to health care. Veterans Affairs (VA) supports telehealth technologies to provide services remotely that are comparable to onsite in-person care. We piloted VA Video Connect (VVC), to deliver an interactive exercise program for Veterans modeled on the VA Gerofit Program, a successful facility-based exercise program. VVC connects an exercise physiologist directly to the home with smart devices. Invitations to join Gerofit were mailed to 216 rural Veterans. Of 17 respondents, 7 (mean age 68) agreed to VVC tele-exercise 1x week for 12 weeks. Two Veterans were lost to follow-up prior to enrollment. Baseline VVC assessments (N=5) were indicative of high functional impairment in comparison to age-based norms: 2-minute step test , 30-second chair stands , and 30-second arm curls . Feasibility, barriers, and program impact will be discussed. Functional impairment indicates need for telehealth to reach Rural Veterans.


RNA binding proteins (RBPs) are strongly linked to the pathophysiology of motor neuron diseases. Recent studies show that RBPs, such as TIA1, also contribute to the pathophysiology of tauopathy. RBPs co-localize with tau pathology, and reduction of TIA1 protects against tau-mediated neurodegeneration. The mechanism through which TIA1 reduction protects against tauopathy, and whether TIA1 modulates the propagation of tau, are unknown. Previous studies indicate that the protective effect of TIA1 depletion correlates with both the reduction of oligomeric tau and the reduction of pathological TIA1 positive tau inclusions. In the current report, we used a novel tau propagation approach to test whether TIA1 is required for producing toxic tau oligomers and whether TIA1 reduction would provide protection against the spread of these oligomers. The approach used young PS19 P301S tau mice at an age at which neurodegeneration would normally not yet occur and seeding oligomeric or fibrillar tau by injection into hippocampal CA1 region. We find that propagation of exogenous tau oligomers (but not fibrils) across the brain drives neurodegeneration in this model. We demonstrate that TIA1 reduction essentially brackets the pathophysiology of tau, being required for the production of tau oligomers, as well as regulating the response of neurons to propagated toxic tau oligomers. These results indicate that RNA binding proteins modulate the pathophysiology of tau at multiple levels and provide insights into possible therapeutic approaches to reduce the spread of neurodegeneration in tauopathy.The online version of this article (10.1007/s00401-018-1937-5) contains supplementary material, which is available to authorized users. RNA binding proteins (RBPs) are strongly implicated in neurodegeneration. Mutations in RBPs are associated with motor neuron diseases and form a strong component of the pathology of these diseases. Recent studies demonstrate that RBPs, stress granules (SGs) and the translational stress response are also key pathways mediating the pathophysiology of tauopathy , 9, 43. The current study uses tau seeding and propagation models to investigate the mechanisms through which TIA1 impacts on tauopathy. In tauopathies, misfolding or aggregated tau forms oligomers and fibrils . EmerginThe current study investigates the activities of tau species in propagating tau pathology and neurodegeneration and demonstrates a key role for TIA1 and SGs in neurodegeneration mediated by extracellular, propagated tau oligomers. The critical role of TIA1 enabled further investigation into the pathophysiological mechanisms through which TIA1 contributes to tauopathy. This study begins by comparing the effects in vivo and in vitro of different tau species extracted from P301S tau mouse brains and demonstrates that tau oligomer and fibrillar fractions both propagate tau pathology in vitro and in vivo, but exhibit striking differences in the neurodegenerative outcomes. The oligomeric tau fraction induced tau pathology in neuronal soma that co-localized with SG markers and elicited profound neurodegeneration. In contrast, over the 3-month period of this study, the fibrillar tau fractions induced tau inclusions predominantly in synapses and dendrites, but showed no association with SG markers, nor did they elicit neurodegeneration. Next, we further use this model for mechanistic studies. We show that TIA1 reduction elicited neuroprotection through both cell autonomous and cell non-autonomous mechanisms. Mice with reduced TIA1 produce less toxic tau oligomers and also exhibit reduced vulnerability to toxic tau oligomers generated from elderly P301S MAPT mice. These results demonstrate that oligomeric tau propagates toxic tau pathology through a mechanism mediated by TIA1 and pathological SGs, suggesting a broad role for SGs in the mechanisms of tau-mediated neurodegeneration.Tia1−/− mice (B6.129S2(C)-Tia1tm1Andp/J) were generated in and obtained from Anderson lab in Harvard University, Dana Farber Cancer Institute . . 7]. OurTo further confirm the existence of oligomeric and fibrillar forms of tau in S1p or P3 injected mice brain, tau oligomer marker TOMA2 and fibrillar tau marker thioflavin S were used to detect tau inclusions in CA3 and LEnt, respectively. The data indicate that the S1p fraction primarily induced oligomeric tau aggregation, while the P3 fraction primarily induced fibrillar tau aggregation . We also examined a cohort of injected PS19 mice that were killed at 15 days after injection. In both cohorts, the fractions containing tau aggregates exhibited only modest diffusion into CA3 and no diffusion into distant LEnt region . The limited diffusion of the tagged tau suggests that the tau aggregation present in CA3 and LEnt over both short- and long-term models resulted predominantly from the templating of human tau synthesized in the recipient neurons.The mechanism of propagation and toxicity in neurons is largely unknown. The localization of propagated tau oligomers to neuronal soma raised the possibility that they might interact with the TIA1/SG pathway, which also localizes to the neuronal soma. To test for co-localization of tau oligomers with TIA1 positive SGs, brain tissue sections from mice treated with the S1p or P3 fractions were probed with anti-TIA1 antibody and the oligomeric tau-specific antibody TOMA2  tau than fibrillar tau (P3 fraction). Neurodegeneration associated with propagation of the oligomeric or fibrillar tau was assessed by immunohistochemical labeling with neuronal marker NeuN in CA3 and LEnt regions Fig. a. The reWe hypothesized that the neurodegeneration induced by the propagated oligomeric tau might elicit a stress reaction in the affected neurons and that this stress response might be associated with cytoplasmic translocation of TIA1 and SG formation. This is important because recent studies indicate that tau pathology associates with TIA1 positive SG responses in neurons , 43, 44.Tia1/++ and PS19::Tia1/−+ mice and harvested at 6 months. The TOMA2 staining data showed that TIA1 reduction greatly reduced the basal level of TOMA2 oligomeric tau in PS19::TIA+/− mice, as well as blocking the propagation of oligomeric tau in S1p-injected mice  via AAV9-mediated transduction in hippocampal neurons over-expressing human WT or P301L tau. The efficiency of TIA1 knock down was greater than 50% of TIA1 as detected in cell lysate by immunoblot . We documented propagation of S1p-induced tauopathy (CP13 staining) in these cultures . We proceeded to test whether the S1p fraction from PS19::Tia1/−+ mice was less toxic than the equivalent fraction from PS19::Tia1/++ mice. We exposed DIV14 cultures of hippocampal neurons to samples of S1p fraction isolated from PS19::Tia1/++, PS19::Tia1/−+ and WT C57BL/6 mice. Medium was collected after 24 h. Analysis of LDH levels from the medium of the neurons demonstrated a 30% decrease in LDH from cultures exposed to PS19::Tia1/−+ S1p compared to PS19::Tia1/++ , TIA1 and SGs. Indeed, binding of TIA1 to tau oligomers generated by templating of extracellularly propagated tau could promote their stabilization and accumulation . This suTia1/−+ mice were highly resistant to neurodegeneration mediated by the S1p oligomeric fractions from PS19 mice, and S1p oligomeric fractions from PS19::Tia1/−+ mice exhibited reduced toxicity in cultures of hippocampal neuron over-expressing tau. Although the relative contributions to neurodegeneration from cell synthesized tau and intercellular propagated tau are not well understood for PS19 P301S tau mice aging normally, the current study used templated tau fractions to greatly accelerate production of tau pathology, which means that most of the tau pathology studied resulted from tau propagation. The neuroprotection provided by TIA1 reduction demonstrates its requirement in neurodegeneration mediated by propagated, templated tau oligomers. Thus, the current study demonstrates for the first time that TIA1 regulates neurodegeneration mediated by both intrinsic and extrinsic tau, with TIA1 regulating toxicity by determining the amount of toxic tau oligomers and the response of neurons to the toxic tau oligomers. The discovery that these neurodegenerative pathways share a unified mechanism mediated by tau oligomers, TIA1 and SG biology, suggests that therapeutic approaches targeting this pathological mechanism will be able to inhibit both the cell synthesized (intrinsic) and intercellular propagated tau pathways in tauopathy, leading to increased therapeutic efficacy. We suggest that inhibiting the interaction of TIA1 with tau might be one such approach.The direct role of TIA1 in the mechanism of toxicity mediated by propagated tau was proven by showing that TIA1 reduction decreased degeneration associated with propagated tau. PS19::Supplementary material 1 (DOCX 11731 kb)Below is the link to the electronic supplementary material.


Cervical cancer screening with assays detecting DNA of high-risk human papillomavirus (hrHPV) types is more effective than cytology-based screening. This study completes the diagnostic accuracy assessment conducted previously within the framework of VALGENT-2  and aims to determine whether the reproducibility of Xpert HPV is in line with international validation criteria.Validation of new hrHPV DNA assays requires demonstration of good reproducibility and non-inferior clinical accuracy for cervical precancer compared to a standard comparator assay. The international reproducibility criteria are: lower bound of 95% confidence interval of the intra- and inter-laboratory agreement regarding detection of high-risk HPV DNA exceeding 87% with kappa ≥0.5.The Xpert HPV assay showed high intra-laboratory reproducibility with an overall positivity/negativity agreement of 96.9% and a kappa of 0.925. Inter-laboratory testing showed an agreement of 97.8% with a kappa of 0.948.The Xpert HPV assay fulfills the HPV test reproducibility criterion requirement for use in cervical cancer screening. High level of evidence from large randomized trials currently exists which indicates that human papillomavirus (HPV) based assays are more effective than cytology screening to reduce the burden of severe cervical dysplasia and cancer . Two HPVInternational guidelines have been widely adopted for the clinical validation of novel HPV tests. In a population of screened women of at least 30 years of age, the novel HPV test should demonstrate non-inferior sensitivity and specificity for cervical intraepithelial neoplasia grade 2+ (CIN2+) compared to the standard comparator tests (Hybrid Capture 2 (HC2) HPV DNA test or GP5+/6+ PCR EIA)  = 0.019) and 1.006 , respectively, among screened women aged 30 or older [Our data confirm that the intra-laboratory reproducibility and inter-laboratory agreement of Xpert HPV largely exceeds the requirements formulated in the international guidelines for the validation of a novel hrHPV test with respect to its use in primary cervical cancer screening. Our study completes the VALGENT-2 clinical validation study which demonstrated a relative sensitivity and relative specificity of hrHPV testing with Xpert HPV compared to GP5+/6+ PCR of 0.984 (95% CI 0.931–1.040, p


Most endocervical adenocarcinomas are human papillomavirus (HPV)-related cancers associated with p16 immunostaining. Ovarian metastasis from cervical cancer is a rare phenomenon, the mechanism of dissemination remains unclear. The diagnosis of metastasis may be difficult to establish when the ovarian neoplasm presents features consistent with primary tumor. Immunohistochemical expression of p16 in ovarian tumors can guide the diagnosis of metastasis from HPV-related cervical cancer, but p16 positivity is nonspecific. Identical HPV genotype in the paired endocervical and ovarian tumors is a better marker for cervical origin, which may also be confirmed by identical HPV integration site.Two women presented with HPV18 cervical adenocarcinoma. No signs of disease were visible on MRI after treatment. After several years of follow-up, mucinous ovarian tumors were discovered in both patients. Molecular analyses showed that the ovarian lesions were HPV18-positive; indicating a primary cervical origin. A third woman was diagnosed with grade 1 ovarian endometrioid carcinoma with no peritoneal carcinomatosis. Final histological examination and HPV genotyping revealed HPV18-related in situ endometrioid adenocarcinoma in the endocervix and HPV18-related invasive endometrioid adenocarcinoma in the endometrium and both ovaries. Additional molecular analyses performed in two patients identified the same HPV integration sites in both the ovarian and cervical tumors, confirming that the ovarian mass was a metastasis from the cervical adenocarcinoma.We report three new cases of ovarian neoplasia in which the diagnosis of metastasis from cervical cancer was supported by the same HPV genotype and the same integration site in the paired cervical and ovarian tumors. To our knowledge, this is the first report of molecular evidence of the cervical origin of an ovarian metastasis. HPV screening should be performed in ovarian tumors for all patients with history of cervical neoplasia. Endocervical adenocarcinomas are high-risk human papillomavirus (HPV)-related cancers. HPV16 or HPV18 are the genotypes most frequently observed . TypicalOnly a few cases of HPV-related ovarian metastasis from endocervical adenocarcinoma have been reported in the literature over the last decade , 4. In tIn the present report, we describe our experience of three cases and provide proof of the cervical origin of the metastasis, based on identification of the same integration site of the HPV genome in the paired endocervical and ovarian tumor DNAs. To our knowledge, this is the first time that tumor spread from endocervix to ovary has been demonstrated by molecular evidence.2) were administered. The patient was reevaluated by MRI at the end of treatment, showing less than 50% size response with persistent parametrial involvement. Adjuvant brachytherapy (25 Gy) and external beam pelvic radiation (8 Gy in 3 daily fractions) was therefore decided. Two months later, the lesion had completely resolved on MRI. After 3 years of follow-up, MRI revealed a pelvic mass with no increased uptake on PET-CT. Bilateral salpingo-oophorectomy was performed based on a diagnosis of right ovarian mass without peritoneal carcinomatosis or other distant disease. Histological examination concluded on invasive mucinous adenocarcinoma.A 55-year-old nulliparous postmenopausal woman with no medical history was managed for FIGO  stage IIIB cervical cancer. Cervical biopsies showed HPV18-related moderately differentiated invasive adenocarcinoma. Magnetic resonance imaging (MRI) revealed a 4 cm anterior mass extending to the uterine isthmus, uterine corpus, left parametrium and superior third of the vagina. No other lesion was visualized on abdominal computed tomography (CT) and positron emission tomography (PET-CT). Concomitant external beam pelvic radiation (45 Gray (Gy) in 1.8 Gy daily fractions) and six cycles of chemotherapy . The patient is still on treatment.To determine the origin of the ovarian lesion and in view of the synchronous HPV18-positive cervical carcinoma, molecular analyses were performed, showing that the ovarian tumor was HPV18-positive, strongly suggesting a primary cervical origin. As previous analyses of the cervical tumor identified the HPV integration site in chromosome 13, the ovarian tumor was screened to determine whether the ovarian metastasis presented the same HPV integration site. The same HPV integration site at locus 13q22.1 was demonstrated in ovarian tumor DNA, clearly confirming that the ovarian mass was a metastasis from the cervical adenocarcinoma  with negative surgical margins. No obvious infiltration was observed on the examined slides. Nine years later, after several failures of in vitro fertilization, the patient experienced abdominal pain. Ultrasound imaging revealed a 9.5 cm complex left adnexal mass. Examination of the laparoscopic left salpingo-oophorectomy revealed mucinous cystadenoma of the intestinal type with borderline character traits and extensive foci of intraepithelial carcinoma. Seventeen months later, after being lost to follow-up, a 10 cm right ovarian mass was discovered. Total hysterectomy, right salpingo-oophorectomy, appendectomy, omentectomy were performed, revealing a 2.5 cm HPV18-related cervical cancer extending to the uterine isthmus with mucinous proliferation of intestinal type involving the cervix and right ovary. The HPV insertion site could not be determined due to insufficient tumor tissue. One month later, the patient was referred to our oncologic surgery department, where complementary laparoscopic pelvic and para-aortic lymphadenectomies were performed. Carcinomatous metastasis and intestinal involvement were discovered during laparoscopy. The patient was treated with FOLFOX chemotherapy for 3 months and then underwent complete cytoreductive surgery with peritonectomy, multiple bowel resections and intraperitoneal hyperthermic chemotherapy due to a partial response to chemotherapy. Examination of the resected tissues showed carcinomatous cells partly modified by chemotherapy and a high mitotic index (Ki 67: 70%). The patient is currently on follow-up.Total DNA, isolated from formalin-fixed tissue blocks, was used for HPV typing. Real-time PCR using Sybr®Green PCR Master mix at a final concentration of 1X, specific primers for HPV16, HPV18 and HPV33  at a finhttps://blast.ncbi.nlm.nih.gov/Blast.cgi) and human genome (hg19 reference) using the blat tool (https://genome.ucsc.edu).For the identification of HPV integrations sites in patient 1 and patient 2, the DIPS-PCR method was performed on total DNA isolated from cryopreserved tumor tissue . BrieflyPresence of HPV of the same integration site in both cervical and ovarian tumors were confirmed by PCR using specific primers followed by Sanger sequencing, as shown by Figs. Immunohistochemistry was performed for p16 on formalin-fixed, paraffin-embedded tissue sections using the prediluted E6H4 antibody  on a Leica Bond automated instrument  with standard antigen retrieval and incubation times. Both nuclear and cytoplasmic staining was required for a cell to be considered “positive”.We describe, for the first time, the molecular signature of an HPV18-positive ovarian metastasis from cervical carcinoma based on identification of the same HPV DNA integration site in both cervical and ovarian cancer cells.Ovarian metastasis from cervical adenocarcinoma is a rare phenomenon, as cervical adenocarcinoma usually gives rise to metastases in contiguous structures and pelvic lymph nodes. The differential diagnosis with primary mucinous ovarian carcinoma is challenging . SimilarHPV-related cervical adenocarcinomas typically express P16 , a surroThese case reports demonstrate the very specific molecular signature of the HPV integration site and the filiation between the cervical carcinoma and the ovarian secondaries. Three hypotheses have been proposed to explain dissemination of cervical adenocarcinoma to the ovary , 11, 15:As the same genetic alteration was identified in both cervical and ovarian tumors, we can rule out the hypothesis proposed by Reichert et al. based on ascending spread of HPV infection , as HPV HPV genotyping, performed with commercial kits or in-house assay, is a fast method which works on tumor DNA from FFPE samples and may be good enough to diagnose metastasis of HPV-related tumor. Identification of the same HPV integration site by DIPS-PCR assay in two different tumors clearly demonstrates the filiation between these tumors and rules out the hypothesis of occurrence of different tumors harboring the same HPV type. However, this method has been validated for HPV16 and HPV18 types only, with tumor DNA from cryopreserved tissue samples . A new NWhen an ovarian tumor is diagnosed in a patient with a history of cervical cancer, clinicians should eliminate the diagnosis of cervical cancer metastasis. P16 expression is a good marker to suggest ovarian metastasis from HPV-related cervical cancer, but is not sufficiently specific, as it can also be expressed in primary ovarian cancer. Therefore, in a clinical setting of a history of HPV-related cervical cancer, the HPV type and HPV integration site should be assessed in the ovarian tumor and compared to those of the primary cervical cancer whenever possible. The same HPV viral DNA integration site or the same HPV genotype in both tumors confirms the cervical origin of the ovarian metastasis.


Incidence of anal and oral infections with Human Papillomavirus (HPV) is increasing, particularly among Human Immunodeficiency Virus-positive (HIV+) men. HPV type 16 has exhibited the highest incidence and only limited data is available on other prevalent types, variants of HPV16, as well as associated factors. We were interested in identifying prevalent HPV types, variants of type 16, as well as factors associated with HPV16 infections in the oral cavity of HIV+ men who have sex with men (MSM).2 test, and p values equal to or less than 0.05 were considered significant. SPSS ver. Twenty-four statistical software (IBM Corp) was used.A cross-sectional study of oral cavity samples from HIV+ MSM, that in a previous study were identified as positive for HPV16 in the anal canal. Cells from the oral cavity  were used to extract DNA and detect HPV infections using INNO-LiPA HPV Genotyping Extra II, and PCR. From these, 80 samples  were used to identify variants of type 16 by sequencing. Statistical differences were estimated by the XWe found a high prevalence of High-Risk HPV (HR-HPV) and Low-Risk HPV (LR-HPV). Patients were positive in the oral cavity for HR types; 16, 39 and 18  and LR types 11 and 6 (53.9 and 34.3% respectively). Surprisingly, only European variants of type 16 were found in the oral cavity, although American Asian (22.5%) and African (2.5%) variants were identified in the anal canal. The analysis showed that CD4 counts could be the most important risk factor associated with HR-HPV infections in the oral cavity, anal canal or both anatomical regions. The risk of infection of the oral cavity with type 18 increased in men diagnosed with HIV for more than 6 years.Prevalence of both HR and LR HPV’s in the oral cavity of Mexican HIV+ MSM is very high. The fact that only European variants of HPV16 were found in the oral cavity suggest a possible tropism not previously described. HPV’s are recognized as one of the major causes of sexually transmitted infections related to cancer worldwide, and have been detected in cervical, anal and oral high-grade intraepithelial lesions –3. AmongInfection with human immunodeficiency virus (HIV) affects 36.9 million people worldwide with more than 1.7 million persons in Latin America , 14. HIVThe prevalence of oral HR-HPV infection is relatively low among the general population, accounting for 3.5%,  while a Variants of HPV types reflect an evolutionary history of viral genomes associated with the rapid expansion of the human populations they infect and that can be used for epidemiological and etiologic studies to investigate to transmission of this virus within and among populations, as well as their presence on different anatomical regions. HPV16 variants have been grouped on five main groups: European (E), Asian (As), Asian American (AA), African-1 (Af1), African-2 (Af2), that show a particular geographic distribution, often clustering at specific parts of the world, such as Africa East Asia, North and Latin-America , 32. SevPreviously our group determined that HIV+ MSM exhibited a multiplicity of associated viral types, in addition to HPV16 in anal canal and among HPV16-positive patients, European variants were the most prevalent . We now Three hundred twenty-four patients were recruited in the HIV Clinic at Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán” located in Mexico City. Selected samples have the characteristic of being positive for type 16, determined in a previous study of the prevalence of HPV in the anal canal of HIV+ MSM .In this cross-sectional study, we analysed 204 samples  to detect simultaneous co-infections of other HPV types. From these, only 80 with an enough sample quantity,  were obtained and used to identify variants of type 16. Samples were obtained and processed as previously described by Mendez et al., 2014 .3) levels, and viral suppression (defined as HIV-RNA <200 copies/ml), were evaluated.Socio-demographic, clinical and sexual behaviour information was collected using a self-applied written questionnaire. Clinical information was verified and completed with information available in the clinic records. The age of participants, education, employment, time since HIV diagnosis, time with anti-retroviral therapy treatment (time with ART), regimen of ART initiation , were asked. CD4 . For identification of viral types present in the samples, we used the INNO-LiPA® HPV Genotyping Extra II kit (INNOGENETICS Heiden Germany), which detects 32 different HPVs. HR-HPV  and LR-HPV  and the additional types; 26, 53, 70, 73 and 82.The HPV16+ samples were subjected to a polymerase chain reaction (PCR) to identify variants within E6 and the long control region (LCR) with specific primers for HPV16 . The PCR products were sequenced using the Big Dye terminator kit and equipment Applied Biosystems 3500/3500xL Genetic Analyzer. Analysis of the sequences was done with the Chromas Program and the alignment of them program Multiple Sequence Alignment-Clustalw.2 test) and multivariate analysis (bivariate logistic regression) of risk factors , regimen of ART initiation, CD4 levels and viral suppression) were performed specifically for each type of HPV and as group: LR HPV , and HR HPV , HPV 16–18 and “Other HR HPV” . From the multivariate analysis adjusted for the risk factors, above mentioned, for infection by type of HPV , in the anatomical regions studied, those that had statistical significance for each logistic regression model were represented. For each variable, the alpha level used for the statistical analyses’ significance was p < 0.05. SPSS ver. Twenty-four statistical software (IBM Corp) was used.A descriptive statistical analysis was performed to summarize the sociodemographic characteristics of the selected population. The quantitative variables with normal distribution, were expressed as mean and standard deviations (SD). For data with free distribution, the median and Interquartile Ranges (IQR) were used. Qualitative variables were categorized and expressed by frequency and percentage. The prevalence of HPV was reported as the proportion of anal, oral and anal-oral samples positive for each identified viral type. (the positivity of the high risk and low risk HPV was considered when the proportion of positive cases of HPV in which the specific HPV was detected). The bivariate , while median of ART was 2.16 years ; 59.8% of participants have an ART with a regimen based Non-Nucleotide Reverse Transcriptase Inhibition (NNRTIs). On average, the CD4 count was 428.76 ± 236.23, and nearly 80% of the participants reported viral suppression  in the anal canal and 53.9% (55 patients) in the oral cavity, while 37.3% (38 patients) exhibited type 11 in both regions.Regarding HR HPV, HPV16 was the most prevalent type of HR-HPV type in the oral cavity with 80.4% (82 patients). HPV39 was the second most prevalent HR type; 58.8% (60 patients) in the anal canal and 61.8% (63 patients) in the oral cavity, while 33.3% (34 patients) exhibited it in both regions.HPV52 type was the third; 56.9% (58 patients) in the anal canal and 49% (50 patients) in the oral cavity, while 26.5% (27 patients) in both regions. The rest of HR-HPV types  were less prevalent in anal canal, oral cavity or both anatomical regions.Considering LR types, while 80.4% 82/102) of the anal samples were positive, only 66.7% (68/102) of the oral samples contained LR HPV. The positivity for LR in both anatomical regions was 55.9% (57/102)  and in 21.6% in both anatomical sites. The group of “Other HR HPV”  showed high prevalence in the samples from the anal canal, oral cavity and simultaneously in both anatomical regions  (Table 3) levels, and viral suppression (defined as HIV-RNA <200 copies/ml). Only those risk factors that had statistical significance for each logistic regression model are shown in Table To evaluate the possible association of several risk factors with or without probability of HPV infection, we performed a logistic regression adjusted by age of participants, education, employment, time since HIV diagnosis, time with anti-retroviral therapy treatment (time with ART), regimen of ART initiation , CD4 cells/mm levels, Concerning HR HPV types, in oral infection with HPV 68 type was associated with time under ART treatment , while HPV 68 infection in the same anatomical region was less associated in patients older than 42 years.In general, the risk of infection of the oral cavity with 66 and 51 types increases with CD4 counts between 201 and 499. Whereas oral infection with 66 type correlates with age (36–41 years). We found that the risk of infection of the oral cavity with type 18 increased in men diagnosed with HIV for more than 6 years. HPV 52 infection at both anatomical regions in men with CD4 (201–499) and without viral suppression was associated. The “Other HR types” infection risk was high associated in patients with CD4 counts between 201 and 499. On the contrary, HPV 39 infection in both anatomical sites  in patients with CD4 < 200 was low associated. Regarding HPV 6 infection was related in the anal region among men with lower education (fewer than 12 years), while oral infection with this same viral type was low linked in patients with a CD4 count < 200. The HPV 70 infection in the anal region was less probable in patients under NNRTIs treatment regimen. The LR-HPV infection (as a group) were correlated in the oral-anal region of men who had work , only 80 with enough sample quantity,  were obtained and used to identify variants of type 16. Sequence analysis of PCR products from the E6 and LCR regions of type 16-positive samples showed three types of variants  were present in the anal samples. The most frequent variant was European (75%/30 patients), followed by Asian- American (22.5%/9 patients), and African (2.5%/1 patient). Surprisingly, in the oral cavity only European variants were detected  was the most prevalent variant of HPV16 13 patients), followed by EA176G (six patients), EC188G (five patients), EA178T (three patients), and EG131G (two patients). Regarding non-European variants, the American-Asian AA-a (six patients) and AA-c (three patients) and the African Af1-a (one patient) were the most prevalent ones. In the oral cavity, the most prevalent variant of type 16 was the European 350G (18 patients), followed by the European Prototype (EP) (15 patients), EA176G (three patients), and EA178G and EC161G  count could be the most important risk factor associated with infection of oncogenic HPV types, in the oral cavity, anal region or both anatomical regions, , we found that anal and oral infection with oncogenic HPV types were significantly associated with decreased CD4 counts and short HAART durations. HPV infection can cause significant pathology in all men, but MSM are at particularly susceptible.On other hand it has been widely reported that variants of viral types determined among human populations correlate with geographic regions, and associated with different pathologic risks for the development of cancerous lesions , 35, 37.In this study we found a high prevalence of HR and LR types of HPV, in addition to type 16 in the anal canal and the oral cavity of HIV+ MSM. Importantly, the fact that non-European variants of HPV16 were only found in the oral cavity suggests a tropism for different anatomical regions. In addition, the information on HPV prevalence and genotypes in asymptomatic Mexican HIV+ patients are necessary for HPV related anal and oral neoplasia prevention.This finding supporting the importance of early prophylactic vaccination in this population to achieve maximum benefit. It is important to mention that the use of quadrivalent HPV  vaccine in HPV + MSM prevented 95% of persistence anal HPV infections in young HIV-uninfected MSM . BecauseOur data also support the need for establishing anal and oral screening systems for early detection of cancer among these patients and regular follow-up strategies, especially in HIV+ patients with high-risk HPV. Priority should be given to the identification and treatment of anal or oral lesions in MSM with HIV/AIDS.


Laryngeal cancer has the second highest incidence of head and neck malignant tumors worldwide. In recent years, studies have shown that human papillomavirus (HPV) infection may be a high-risk factor for laryngeal cancer and closely related to the development and prognosis of laryngeal cancer. The mechanism of the occurrence and development of laryngeal cancer caused by HPV infection needs investigation, as does a rapid and effective HPV detection method for effectively preventing the occurrence of laryngeal cancer and controlling its development. Many studies have explored the relation between HPV infection and laryngeal cancer. Here we review the research progress in investigating HPV infection in terms of DNA, mRNA and protein levels in the occurrence and development of laryngeal cancer and routine HPV detection methods. Laryngeal cancer is the most common head and neck malignant tumor in the northern areas of China and its main pathological type is laryngeal squamous cell carcinoma (LSCC) These differences in findings may be due to a variety of factors such as differences in population geographical distribution, test sample quality, and sensitivity and specificity of test methods used. However, they are mainly attributed to the unclear molecular mechanism of laryngeal cancer caused by HPV infection and different detection methods. This paper reviews the effects of HPV infection on the development of laryngeal cancer and the advantages and disadvantages of routine HPV detection methods in terms of DNA, mRNA and protein levels.As early as 1982, Syrijanen et al.The occurrence and development of human cancer is closely related to the selective expression of genes in time or space . HPV infection mainly affects the occurrence and development of laryngeal cancer by integrating in the host cell genome, activating the expression of proto-oncogenes and inhibiting the expression of tumor suppressor genes. Its DNA enters the nucleus in a free state, and then integrates into the genome of the host cells as soon as HPV infects via the damaged laryngeal mucosa epithelial cells to the host cells. The integration of the HPV DNA can lead to genetic mutation and expression disorder of host cells, which leads to cell metabolic disorder and malignant proliferation.When HPV infects the larynx, it can promote the development of laryngeal cancer by activating the expression of various proto-oncogenes. For instance, in the larynx, HPV infection may cause excessive expression or mutation of the proto-oncogene RAS, which may lead to a cell-membrane signal transduction disorder mediated by its protein product p21, thereby resulting in malignant cell proliferation and laryngeal carcinoma. HPV infection can also activate the expression of epidermal growth factor receptor and Myc genes, promoting cells moving from the G1 to S phase, thus accelerating the cell cycle and leading to laryngeal cancer.HPV infection causes laryngeal cancer, which is also associated with tumor suppressor gene mutation and inactivation. p53, Rb and p16 genes are all important tumor suppressor genes in the body and participate in regulating cell proliferation cycle. After HPV infects the larynx, early E6 gene expression can cause p53 inactivation and E7 expression can cause Rb inactivation HPV infection can also be carcinogenic by interacting with the apoptotic inhibiting gene, survivin, cyclin D1 and human telomere reverse transcriptase, thus accelerating cell cycle progression, inhibiting cell senescence, and promoting tumorigenesis After HPV enters laryngeal mucosa epithelial cells, HPV DNA integrates in the host cell genome to cause gene mutation and expression disorder and transcribes and expresses the viral oncoprotein to cause cancer. Fusconi et al.The mRNA expression of HPV is increased with the development of laryngeal lesions , and the mRNA expression of HPV is also increased Poltronieri et al. found that HR-HPV genome transcribes viral miRNAs in the HPV infection and cancer development process, and miRNA silencing could be a valuable approach to support pharmaceutical interventions in HPV-dependent cancers HPV infection induces laryngeal cancer mainly because of excessive expression of HR-HPV E6 and E7 proteins. When HPV infects laryngeal tissues, it can cause excessive expression of HPV E6 and E7 proteins and directly or indirectly affect the stability and activity of proto-oncogenes and tumor suppressor genes. For example, HPV16 E7 protein can activate the cell cycle regulation protein D1 (cyclin D1), thereby accelerating the G1-to-S phase in cells and leading to the occurrence and development of laryngeal cancer Studies have shown that after HR-HPV16 and 18 infect the larynx, the early gene product E6 protein can bind with p53 protein and form a complex resulting in p53 inactivation and thus hindering the role of p53 protein in tumor inhibition in cells. The HR-HPV16 E7 protein can bind to the Rb gene product, thus degrading the Rb protein so it loses its function of inhibiting cell proliferation Highly expressed cyclin D1 and high-risk p53 mutations were found associated with poor disease-specific survival rate in patients with laryngeal cancer. The functional classification of p53 mutants based on EAp53 can predict the disease-specific survival rate with advanced laryngeal cancer and p53 mutation. The model of Bcl-xL and cyclin D1 staining, p53 mutation classification and HPV status is of great significance for predicting disease-specific survival For regulating the cell cycle, p16 protein is an inhibitory protein of the cell cycle-dependent kinase CDK4, which can prevent cell proliferation, also known as a negative regulation protein of the cell cycle. The latest National Comprehensive Cancer Network (NCCN) guidelines for 2018 (v2.2018 Head and Neck Cancers) distinguishes treatments for oropharyngeal cancer between p16 (HPV)-positive and p16-negative cancers. Therefore, the association between p16 protein and HPV-related laryngeal cancers is also worth investigating. The expression of p16 protein is slightly lower in laryngeal carcinoma than benign laryngeal lesions and significantly lower than in vocal polyps in vtro, the diagnosis and typing of HPV cannot be performed by simple serological detection. Currently, the detection and typing of HPV mainly relies on molecular biological methods, including cytological methods, immunohistochemistry (IHC), in situ hybridization (ISH), western blot analysis of protein, and polymerase chain reaction (PCR). Table The pathogenicity of HPV is closely related to its type, so detection and classification of HPV has important clinical significance in screening, prevention and treatment of tumors and determining prognosis. Because HPV cannot be cultured PCR can detect expression in many samples with its advantages of being simple to perform, rapid, sensitive and low cost. In addition to using specific typing primers to detect a single type of HPV gene, general primers such as MY11 and MY09 can identify the conserved sequences of most HPV L1 genes. Nevertheless, cross contamination between samples easily occurs and high false-positive rates are possible. In addition, PCR is not a reliable method for HPV genotyping. RT-PCR can detect the mRNA level of HPV E6/E7 and accurately reflect the transcription activity of viral oncogenes. It can avoid the defect that the presence of HPV DNA detected by conventional PCR does not mean that viral genes are expressed or are in the state of transcription. As compared with other methods, RT-PCR, with its high sensitivity and specificity, can be used as the “gold standard” for HPV-related tumors to some extent Nucleic acid hybridization, which has good specificity and sensitivity, can also be used for HPV typing, so it plays a certain role in studying the impact of different HPV types on the occurrence and development of diseases. As compared with DNA ISH based on DNA level, RNA ISH is more sensitive and specific. The sensitivity of DNA ISH is limited, especially for tumor samples with low viral copy numbers. Moreover, results of DNA ISH can be difficult to interpret in cases when hybridization signals are limited  Development and application of the RNAscope technology solved some technical problems of RNA ISH As compared with conventional RNA ISH, RNAscope has obvious advantages for detecting HPV infection in laryngeal cancer because of its high sensitivity and specificity, the visualization and quantitative analysis of single molecules, and being able to detect partially degraded RNA For protein level detection, tumor suppressor protein p16 immunohistochemical staining is the main marker to evaluate the status of HPV infection. Positivity for p16 is a good prognostic marker of HPV-associated oropharyngeal squamous cell carcinoma Emerging studies indicated that HPV infection may plays an important role in the initiation and progression of laryngeal cancer, but the clinical data for HPV infection in laryngeal cancer are largely inconsistent. In addition to genotypes of HPV infection being different, the infection rate varies among regions. Particularly, studies from China show high variation in HPV prevalence, from 2.4% to 76.42% Table . GeneticIn this study, we reviewed recent advances about the correlation between HPV and laryngeal cancer, and summarized the potential carcinogenic mechanism of HPV infection from the levels of DNA, mRNA and protein: 1) the integration of the HPV DNA or genes into host cells; 2) carcinogenesis via activation of proto-oncogenes and inactivation of tumor suppressor genes; and 3) HPV viral proteins being indirectly carcinogenic via other biological progresses . We also summarized the common methods of HPV detection and analyzed their advantages and disadvantages.As one of the most common malignant tumors in head and neck, laryngeal cancer seriously affects patients' quality of life and survival. HR-HPV infection is closely related to the occurrence and development of laryngeal cancer, but the carcinogenesis of HPV for laryngeal cancer has not been fully explained. Therefore, we must deeply study the molecular mechanism of laryngeal cancer caused by HPV infection. At the same time, rapidly detecting the type and degree of HPV infection by convenient and sensitive testing methods is crucial for preventing and treating laryngeal cancer.Up to now, most studies at the DNA level have focused on the abnormal expression of various proto-oncogenes and tumor suppressor genes caused by HPV infection when explaining the role of oncogenic viruses in the development of laryngeal cancer. They rarely analyzed the possible interaction between two or more types of viruses. Some studies have shown that the incidence of laryngeal cancer is closely related to Epstein Barr virus (EBV) infection and pointed out that HR-HPV infection plays a certain role in inducing laryngeal cancer The mRNA level of HPV is correlated with the occurrence and development of laryngeal cancer, but we have relatively few studies at this level. In comparison, in recent years, many reports have described the effects of non-coding RNA on the development and prognosis of laryngeal cancer. The microRNAs miR-497, miR-181a, and miR-155 and long noncoding RNA HOXAll-AS can affect the occurrence, development and prognosis of laryngeal cancer by changing the biological behaviors of laryngeal cancer cells, such as invasion, migration, proliferation and apoptosis In recent years, studies have shown that factors such as smoking may be a contributing factor to cancer-caused HPV infection. Patients who smoked frequently showed increased carcinogenicity of HPV in their bodies, which promoted the development of head and neck tumors