Background: Overexpression of aspartate β-hydroxylase (ASPH) in human tumors contributes to their progression by stimulating cell proliferation, migration, and invasion. Several signaling pathways affected by ASPH have been identified, but the high number of potential targets of ASPH hydroxylation suggests that additional mechanisms may be involved. This study was performed to reveal new targets of ASPH signaling. Methods: The effect of ASPH on the oncogenicity of three mouse tumor cell lines was tested using proliferation assays, transwell assays, and spheroid invasion assays after inhibition of ASPH with the small molecule inhibitor MO-I-1151. ASPH was also deactivated with the CRISPR/Cas9 system. A transcriptomic analysis was then performed with bulk RNA sequencing and differential gene expression was evaluated. Expression data were verified by quantitative PCR and immunoblotting. Results: Inhibition or abrogation of ASPH reduced proliferation of the cell lines and their migration and invasiveness. Among the genes with differential expression in more than one cell line, two members of the lymphocyte antigen 6 (Ly6) family, Ly6a and Ly6c1, were found. Their downregulation was confirmed at the protein level by immunoblotting, which also showed their reduction after ASPH inhibition in other mouse cell lines. Reduced production of the Ly6D and Ly6K proteins was shown after ASPH inhibition in human tumor cell lines. Conclusions: Since increased expression of Ly6 genes is associated with the development and progression of both mouse and human tumors, these results suggest a novel mechanism of ASPH oncogenicity and support the utility of ASPH as a target for cancer therapy.
- Publikační typ
- časopisecké články MeSH
Metylační umlčení některých buněčných genů je známkou progrese karcinogeneze a proto testy, které metylaci detekují, by mohly být využívány v diagnostice či „stagingu“ maligních onemocnění. V diagnostice dlaždicobuněčných karcinomů děložního hrdla (DH), které jsou téměř ve 100 % způsobeny dlouhodobou infekcí vysoce rizikovými lidskými papilomaviry (HR-HPV), je metylační umlčení určitých buněčných genů vysoce specifickým markerem pokročilé dysplastické léze a zřejmě vzniká důsledkem aberantní aktivace metyltransferázy DNMT1 virovými onkoproteiny E6 a E7. Metylační test provedený ze vzorku cervikovaginální cytologie umožňuje zvýšit výpovědní hodnotu tohoto neinvazivního vyšetření a selektovat pacientky s biologicky závažnou dlaždicobuněčnou lézí pro následné vyšetření. Pomocí cytologického vyšetření lze odhalit také méně časté anogenitální malignity, které jsou indukované HR-HPV v nižší míře – žlázové léze různého původu, nejčastěji adenokarcinomy DH a endometria a anální karcinom. Cílem naší pilotní studie bylo ohodnotit přínos metylačního testu pro diagnostiku těchto malignit na souboru 50 tekutých cervikovaginálních cytologií s nálezem žlázové léze a 74 tekutých análních cytologií HIV-pozitivních homosexuálů, kteří jsou ve vysokém riziku vzniku karcinomu anu.
Methylation silencing of certain cellular genes is a sign of carcinogenesis progression and therefore tests that detect methylation could be used in the diagnosis or staging of malignant diseases. In the diagnosis of squamous cell carcinomas of the cervix which are almost 100% caused by long-term infection with highrisk human papillomavirus (HR-HPV), methylation silencing of certain cellular genes is a highly specific marker of advanced dysplastic lesions and appears to result from aberrant activation of the methyltransferase DNMT1 by viral oncoproteins E6 and E7. A methylation test performed on a cervicovaginal cytology specimen allows to increase the diagnostic value of this non-invasive test and to select patients with severe squamous cell lesions for follow-up. Other less frequent anogenital malignancies that are induced by HR-HPV to a lesser extent can also be detected by cytological examination - glandular lesions of various origins, most commonly cervical and endometrial adenocarcinomas and anal carcinoma. The aim of our pilot study was to evaluate the utility of a methylation test for the diagnosis of these malignancies in a cohort of 50 liquid-based cervicovaginal cytologies with glandular lesion and 74 liquid-based anal cytologies from HIV-positive men having sex with men who are at high risk for anal cancer development.
- MeSH
- cytodiagnostika metody MeSH
- HIV séropozitivita komplikace MeSH
- infekce papilomavirem diagnóza komplikace patologie MeSH
- lidé MeSH
- metylace DNA * MeSH
- nádory anu diagnóza patologie prevence a kontrola MeSH
- nádory děložního čípku diagnóza patologie prevence a kontrola MeSH
- onkogenní proteiny virové genetika MeSH
- pilotní projekty MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
BACKGROUND: HIV-positive men who have sex with men (MSM) are more likely to experience human papillomavirus (HPV) infection. The persistent HPV infection is the major factor in the development of anal and oropharyngeal neoplasms. Data on the prevalence of anal and oral HPV in MSM are almost absent from the countries of Central and Eastern Europe. We conducted a cross-sectional study focused on the prevalence of oral and anal HPV infections and the relationship between current anal and oral HPV intrapersonal infection in a Czech population of predominantly HIV-positive MSM. METHODS: Oral gargle and anal swab samples from 205 predominantly HIV-positive MSM from the Czech Republic were analysed for HPV infection using PCR. Selected sociodemographic and clinical data were correlated with HPV detection using generalized linear models and multivariate analysis. RESULTS: HPV infection was detected in 183 (96.8%) anal and 48 (23.6%) oral samples. The most common type of HR-HPV was HPV16 in both anal (25.4%) and oral (2.5%) samples. Multiple anal HPV infections and the presence of vaccine-targeted HR-HPV types were significantly correlated with abnormal anal cytology and HIV status. CONCLUSION: The prevalence of anal HPV infection in Czech predominantly HIV-positive MSM ranks among the highest reported, while oral HPV prevalence is consistent with MSM populations. Minimal overlap of oral and anal HPV types within a patient was observed.
- MeSH
- anální kanál MeSH
- HIV infekce * komplikace epidemiologie diagnóza MeSH
- HIV séropozitivita * epidemiologie MeSH
- homosexualita mužská MeSH
- infekce papilomavirem * diagnóza MeSH
- lidé MeSH
- Papillomaviridae genetika MeSH
- prevalence MeSH
- průřezové studie MeSH
- rizikové faktory MeSH
- sexuální a genderové menšiny * MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Current knowledge about human papillomavirus (HPV) infection in psoriasis patients treated with biologics is limited. In this study we evaluated the prevalence of oral and genital HPV infection in psoriasis patients treated with biologics or topical therapy for at least 6 months. The presence of HPV DNA in oral rinse and genital smears was evaluated. In total, 267 patients who met the inclusion criteria and agreed to participate were enrolled: 110 (41.2%) on topical therapy, 84 (31.5%) on anti-TNF-alpha therapy, 31 (11.6%) on anti-IL-12/23 therapy and 42 (15.7%) on anti-IL-17 therapy. The presence of genital HPV infection was detected in 34.6% of men receiving anti-TNF-α treatment, in 25.0% of patients on anti-IL-12/23 and 18.8% of patients on anti-IL-17 therapy. The difference in prevalence was not statistically different from men on topical treatment (26.3%). Prevalence of oral HPV infection was higher across all of the biologic groups (11.9% for anti-TNF-α, 12.9% for anti-IL-12/23 and 19.0% for anti-IL-17) compared to patients on topical therapy (7.3%), but statistically significant only for anti-IL-17 (p < 0.05). The presence of oral HPV infection in patients treated with biologics was significantly higher (44.0%) in patients on long-term biologic treatment (>8 years) compared to patients taking biologics for a shorter period (9.1%; p < 0.01). Our results suggest that patients on biologics for psoriasis have a higher prevalence of oral HPV infection compared to patients on topical treatment. Long-term treatment with biologics seems to be associated with a higher prevalence of oral HPV infection, independent of previous conventional immunosuppressive therapy.
- MeSH
- biologická terapie MeSH
- biologické přípravky * škodlivé účinky MeSH
- infekce papilomavirem * diagnóza epidemiologie MeSH
- inhibitory TNF MeSH
- lidé MeSH
- Papillomaviridae MeSH
- pohlavní orgány MeSH
- psoriáza * farmakoterapie epidemiologie MeSH
- sexuálně přenosné nemoci * MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Anální karcinom je nádor s nízkou prevalencí, ale vysokou morbiditou. Díky vzácnosti tohoto nádoru proto nebylo donedávna ani uvažováno o jeho screeningu. V posledních dekádách však dochází k nárůstu počtu případů hlavně v populaci HIV pozitivních mužů majících sex s muži. Vzhledem k tomu, že většina případů análního karcinomu jsou dlaždicobuněčné karcinomy asociované s infekcí lidskými papilomaviry (HPV), máme obdobně jako v případě karcinomu děložního hrdla i v případě análního karcinomu možnost sekundární prevence pomocí vhodného screeningu. Základem současných screeningových vyšetření je digitální anorektální vyšetření, cytologické vyšetření a anoskopie. Včasné zachycení léčitelných forem je důležité i vzhledem k tomu, že díky kulturním změnám a prevalenci rizikových faktorů lze v budoucnu předpokládat nadále zvyšování incidence tohoto nádoru. Ke zvýšení efektivity screeningu je však nutná taktéž edukace a motivace rizikových skupin pacientů, hlavně rozšiřováním povědomí o análním karcinomu a roli rizikového sexuálního chování a HPV infekce.
Anal cancer is a tumour with a low prevalence but high morbidity. Due to the rarity of this tumour, therefore, its screening has not been considered until recently. However, in recent decades there has been an increase in the number of cases, especially in the population of HIV-positive men having sex with men. Since the most cases of anal cancer are squamous cell carcinomas associated with human papillomavirus (HPV) infection, as in the case of cervical cancer, there is the possibility of secondary prevention through appropriate screening. The basis of current screening examinations are digital anorectal examination, cytological examination and anoscopy. Early detection of treatable forms is important, also based on the fact that due to cultural changes and the prevalence of risk factors, an increase in the incidence of this tumour can be expected. However, education and motivation of at-risk groups of patients are necessary to increase the effectiveness of the screening, mainly by raising awareness of anal cancer and the role of risky sexual behavior and HPV infection.
- MeSH
- časná detekce nádoru metody MeSH
- karcinom diagnóza terapie MeSH
- lidé MeSH
- nádory anu * diagnóza klasifikace terapie MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Importance: Recurrent respiratory papillomatosis (RRP) is a rare benign chronic disease of the larynx etiologically linked with the infection of low-risk human papillomavirus (HPV). Combination of surgical and immunomodulatory therapy has limited success. Possible use of prophylactic HPV vaccine that includes HPV-6 and HPV-11 antigens has been studied. Objective: To evaluate if the HPV vaccination is associated with a lower number of recurrences requiring surgical intervention in patients with new and recurrent RRP. Design, Setting, and Participants: This was a non-placebo-controlled intervention study. Enrollment data were collected from October 2011 to August 2013. The patients were followed up at 1 month, 12 months, and 5 years after the third dose of the vaccine and clinically monitored until December 31, 2018. Data were analyzed from 2019 to 2021. Altogether, 50 adults with active RRP were enrolled and followed up in referral centers. For the final outcome, follow-up data for 42 patients were available. Eight patients who did not fulfill the protocol were excluded. Interventions: All patients received HPV vaccine as an adjuvant treatment and were clinically followed up. When RRP progression or a significant recurrent lesion was detected, surgical removal via direct laryngoscopy was indicated. No adjuvant therapy with antiviral or biological agents was used. Main Outcomes and Measures: This study compared the prevaccination and postvaccination positivity for HPV-specific antibodies. The main outcome was the difference in the frequency of RRP recurrences in the prevaccination and postvaccination period. Results: A total of 50 patients with RRP were enrolled (median [SD] age, 41.5 [12.3] years [range, 21-73 years]; 39 [78%] men and 11 [22%] women). After HPV vaccination, patients with previously no HPV-specific antibodies showed seroconversion, and all patients developed 100-fold higher levels of HPV vaccine type-specific antibodies compared with the prevaccination period. In patients with recurrent RRP, decreased frequency of recurrences requiring surgical treatment was present after vaccination (from 0.85 to 0.36 recurrences/y). No difference in postvaccination recurrences was found between patients with newly diagnosed and recurrent RRP. Conclusions and Relevance: In this nonrandomized clinical trial, the frequency of RRP recurrences was significantly lower after HPV vaccination, and patients with RRP thus had a reduced burden of disease. Because no difference was detected in the frequency of recurrent postvaccination lesions in patients with new and recurrent disease, it appears that both groups showed equal benefit following HPV vaccination. These findings suggest that the earlier that patients with RRP receive HPV vaccine, the sooner they may show reduced burden of disease. Trial Registration: EudraCT Identifier: 2011-002667-14; ClinicalTrials.gov Identifier: NCT01375868.
- MeSH
- Alphapapillomavirus * MeSH
- dospělí MeSH
- infekce dýchací soustavy * prevence a kontrola MeSH
- infekce papilomavirem * prevence a kontrola MeSH
- lidé MeSH
- vakcinace MeSH
- vakcíny proti papilomavirům * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
- MeSH
- DNA testy na papilomavirus metody MeSH
- klinické laboratorní techniky MeSH
- lidé MeSH
- lidské papilomaviry * izolace a purifikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Lidské papilomaviry (HPV) vyvolávají ve většině případů bezpříznakové infekce, ale také řadu benigních onemocnění s vysokou morbiditou a řadu dalších premaligních onemocnění a karcinomů žen i mužů. K promoření populace dochází ihned po zahájení pohlavního života, ale důsledky perzistující infekce se mohou projevit až po dlouhé době. Proti infekci typu HPV, které vyvolávají 90 % benigních lézí a nádorových onemocnění, máme v rukou nástroj primární prevence, velmi účinné vakcíny. Řada studií ukázala účelnost těchto vakcín v prevenci snižování HPV-asociovaných onemocnění nejen u vakcinovaných jedinců, ale v dostatečně proočkovaných kohortách, i u jedinců věkově odpovídajících skupin. Jednoznačně nejvyšší účelnost vakcín je při jejich pohlavně neutrální plošné aplikaci. V klinické zkoušce bylo prokázáno, že 70% pohlavně neutrální vakcinace vede k eradikaci vakcinálních typů HPV, včetně nejvíce prevalentního typu HPV 16, který má nejvyšší reprodukční číslo. V České republice je situace z tohoto pohledu nadějná, ale zamezení snižování proočkovanosti dívek a další navyšování proočkovanosti chlapců jsou důležité a může k tomu přispět objasňování důležitosti vakcinace v dětském věku a zdůrazňování bezpečnosti těchto vakcín.
Although causing mostly asymptomatic infections, human papillomaviruses (HPV) can also be responsible for a number of benign diseases with high morbidity and other premalignant diseases and carcinomas in both women and men. The population comes into contact with HPV soon after sexual debut, and persistent infection can have late sequelae. Highly effective HPV vaccines are available as a primary prevention tool against HPV types responsible for 90 % of benign lesions and cancers. A number of studies have shown these vaccines to be effective in reducing HPV-associated diseases not only in the vaccinated individuals but also in other age-matched individuals from cohorts with high vaccine coverage. The highest protection is achieved by mass, gender neutral HPV vaccination campaigns. A clinical trial has found that a 70% gender neutral HPV vaccine coverage results in eradication of vaccine HPV types including the most prevalent HPV 16, which has the highest reproduction number. In the Czech Republic, the situation is promising from this perspective; however, it is vital to prevent vaccine coverage reduction in girls and to further increase the vaccine coverage in boys. Underlining the importance of childhood vaccination and the safety of HPV vaccines can be helpful in this regard.
