Implications of viral infections and oncogenesis in uterine cervical carcinoma etiology and pathogenesis.

Background: Uterine Cervical Carcinoma (UCC) is the most prevalent gynecological malignancy globally, with a rising incidence in recent years. Accumulating evidence indicates that specific viral infections, including human papillomavirus (HPV), Epstein-Barr virus (EBV), Hepatitis B and C viruses (HBV and HCV), and human herpesvirus (HHV), may contribute to UCC development and progression. Understanding the complex interplay between viral infections and UCC risk is crucial for developing novel preventative and therapeutic interventions. Methods: This comprehensive review investigates the association between viral infections and UCC risk by examining the roles of various viral pathogens in UCC etiology and pathogenesis, and possible molecular mechanisms. Additionally, we evaluate current diagnostic methods and potential therapeutic strategies targeting viral infections for UCC prevention or treatment. Results: The prevention of UCC has been significantly advanced by the emergence of self-sampling for HPV testing as a crucial tool, allowing for early detection and intervention. However, an essential challenge in UCC prevention lies in understanding how HPV and other viral coinfections, including EBV, HBV, HCV, HHV, HIV, or their concurrent presence, may potentially contribute to UCC development. The molecular mechanisms implicated in the association between viral infections and cervical cancer development include: (1) interference of viral oncogenes with cellular regulatory proteins, resulting in uncontrolled cell proliferation and malignant transformation; (2) inactivation of tumor suppressor genes by viral proteins; (3) evasion of host immune responses by viruses; (4) induction of a persistent inflammatory response, contributing to a tumor-promoting microenvironment; (5) epigenetic modifications that lead to aberrant gene expression; (6) stimulation of angiogenesis by viruses; and (7) activation of telomerase by viral proteins, leading to cellular immortalization. Additionally, viral coinfections can also enhance oncogenic potential through synergistic interactions between viral oncoproteins, employ immune evasion strategies, contribute to chronic inflammation, modulate host cellular signaling pathways, and induce epigenetic alterations, ultimately leading to cervical carcinogenesis. Conclusion: Recognizing the implications of viral oncogenes in UCC etiology and pathogenesis is vital for addressing the escalating burden of UCC. Developing innovative preventative and therapeutic interventions requires a thorough understanding of the intricate relationship between viral infections and UCC risk.

Challenge of managing hepatitis B virus and hepatitis C virus infections in resource-limited settings.

The global burden of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and coinfection represents a major public health concern, particularly in resource-limited settings. Elimination of HCV by 2030 has become foreseeable, with effective direct-acting antiviral oral therapies and the availability of affordable generics in low-and-middle-income countries (LMICs). However, access to oral nucleos(t)ide therapy for HBV remains critical and is limited outside the existing global HIV program platforms despite affordable prices. Prevention of mother-to-child transmission of HBV through scaling up of birth dose implementation in LMICs is essential to achieve the 2030 elimination goal. Most individuals living with HBV and/or HCV in resource-limited settings are unaware of their infection, and with improved access to medications, the most significant barrier remains access to affordable diagnostics and preventive strategies. The coronavirus disease 2019 pandemic interrupted hepatitis elimination programs, albeit offered opportunities for improved diagnostic capacities and raised political awareness of the critical need for strengthening health care services and universal health coverage. This review underpins the HBV and HCV management challenges in resource-limited settings, highlighting the current status and suggested future elimination strategies in some of these countries. Global efforts should continue to improve awareness and political commitment. Financial resources should be secured to access and implement comprehensive strategies for diagnosis and linkage to care in resource-constrained settings to fulfill the 2030 elimination goal.

Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development.

About 20% of total cancer cases are associated to infections. To date, seven human viruses have been directly linked to cancer development: high-risk human papillomaviruses (hrHPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus 1 (HTLV-1). These viruses impact on several molecular mechanisms in the host cells, often resulting in chronic inflammation, uncontrolled proliferation, and cell death inhibition, and mechanisms, which favor viral life cycle but may indirectly promote tumorigenesis. Recently, the ability of oncogenic viruses to alter autophagy, a catabolic process activated during the innate immune response to infections, is emerging as a key event for the onset of human cancers. Here, we summarize the current understanding of the molecular mechanisms by which human oncogenic viruses regulate autophagy and how this negative regulation impacts on cancer development. Finally, we highlight novel autophagy-related candidates for the treatment of virus-related cancers.

Maternal hepatitis B virus and hepatitis C virus carrier status during pregnancy and long-term respiratory complications in the offspring.

OBJECTIVE: Maternal HBV or HCV carrier status is a cause for concern regarding both the course of pregnancy and the short-term perinatal outcomes. Our main aim was to evaluate whether offspring born to carrier mothers during pregnancy, also suffer from long-term pediatric respiratory morbidity (until 18 years of age). METHOD OF STUDY: A population-based cohort analysis was conducted at a single tertiary medical center. The study included all singleton deliveries between the years 1991-2014, comparing incidence of respiratory-related hospitalization of offspring born to mothers who were carrier of HBV or HCV during their pregnancy to those born to nonexposed mothers. Respiratory morbidities were based on a predefined set of ICD-9 codes. A Kaplan-Meier survival curve was used to compare cumulative hospitalization incidence between the groups and a Cox regression model was used to adjust for confounding variables. RESULTS: During the study period, 242,342 deliveries met the inclusion criteria. Of them, 771 (0.31%) were to HBV or HCV mother carriers during pregnancy. A Kaplan-Meier curve demonstrated that children born to HBV or HCV carriers had higher cumulative incidence of respiratory morbidity (Log rank test p = 0.007). In the Cox regression model, while controlling for maternal age, diabetes mellitus, hypertensive disorders, caesarian section and gestational age at birth, maternal HBV or HCV carrier status was noted as an independent risk factor for long-term respiratory morbidity in the offspring (adjusted HR = 1.43, 95% CI 1.07-1.90, p = 0.015). CONCLUSIONS: Maternal HBV or HCV carrier status in pregnancy may increase offspring susceptibility to long-term respiratory morbidity.

Bardoxolone methyl as a novel potent antiviral agent against hepatitis B and C viruses in human hepatocyte cell culture systems.

Antiviral drugs against hepatitis B virus (HBV) relieve symptoms experienced by patients with hepatitis; however, these drugs cannot eliminate HBV infection from all patients completely. On the other hand, direct antiviral agents (DAAs) against hepatitis C virus (HCV) can achieve near-complete elimination of HCV infection. However, recent reports have claimed that DAAs pose a risk for HBV reactivation among patients with HBV and HCV co-infection. This suggests that an effective anti-viral strategy for both HBV and HCV would be extremely useful. We hypothesized that an activator of nuclear factor-erythroid factor 2 (Nrf2) could be a candidate, because heme oxygenase-1 (HO-1), a product of the Nrf2-target gene, was shown to be related to suppression of genome replication in both HBV and HCV. In this study, the potential of bardoxolone methyl (BARD), an Nrf2 activator, was examined in cell culture systems against HBV and HCV. We investigated that BARD had a suppressive effect on the production of extracellular HBV DNA in several HBV culture systems. In addition, BARD treatment reduced the levels of intracellular HBV pregenome RNA (pgRNA), a transcript from the HBV genome and a template of HBV genome replication. HCV genome replication was also suppressed in HCV subgenomic replicon-bearing cells by BARD treatment. BARD might be a novel treatment for patients with HBV and HCV co-infection.

Prevalência de infecção pelos vírus linfotrópicos de células T humanas dos tipos 1 e 2 (HTLV-1 e HTLV-2) e vírus da imunodificiência humana do tipo 1 (HIV-1) em população infectada pelos vírus da hepatite B (HBV) e hepatite C (HCV)

Os vírus linfotrópicos de células T humanas dos tipos 1 (HTLV-1) e 2 (HTLV2),assim como o vírus da imunodeficiência humana (HIV) e os vírus dashepatites B (HBV) e C (HCV) compartilham vias de transmissão, portantocoinfecções por estes vírus podem acontecer e alterar o curso das doençasa eles relacionadas. O presente estudo avaliou a prevalência de infecção porHTLV-1/2 em população com hepatite B e C, infectada ou não pelo HIV, e oimpacto das coinfecções na viremia HBV e HCV. O estudo foi realizado em1.244 amostras de plasma/soro enviadas ao Instituto Adolfo Lutz de SãoPaulo para determinação de carga viral (CV) de HBV e HCV: 622 depacientes com HBV (G1, 327 homens e 295 mulheres, média de idade 45,8anos) e 622 de pacientes com HCV (G2, 343 homens e 279 mulheres, médiade idade de 50,8 anos). A triagem de HTLV-1/2 foi realizada por ensaioimunoenzimático (EIA HTLV-I/II, Gold ELISA, REM) e confirmadas porWestern Blot (HTLV BLOT 2.4, MP Biomedicals) e imunoensaio de linha(INNO-LIA HTLV-I/II, Fujirebio). A pesquisa de infecção por HIV foi realizadapor teste imunocromatográfico (kit Rapid Check HIV 1 e 2, NDI, UniversidadeFederal do Espírito Santo, Brasil) seguido do EIA (GS HIV-1/HIV-2 Plus OEIA, Bio-Rad). A infecção por HTLV-1 foi confirmada em 25 amostras (cincono G1 e 20 no G2)...

The human T-cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2) aswell as the human immunodeficiency virus (HIV) and the hepatitis B virus(HBV) and hepatitis C virus (HCV) share routes of virus transmission; thusco-infections with such viruses can occur and alter the course of subsequentdiseases. The present study aimed at evaluating the prevalence of HTLV-1/-2 in blood samples of individuals with hepatitis B and C, infected or not byHIV, and the impact of co-infections on the HBV and HCV viremia. The studywas conducted with 1,244 plasma/serum samples sent to Instituto AdolfoLutz of São Paulo for measuring HCV and HBV viral load (VL): 622 fromHBV-infected patients (G1, 327 male and 295 female, median age 45.8years), and 622 from HCV-infected patients (G2, 343 male and 279 female,median age 50.8 years). HTLV-1/-2 antibodies were screened by enzymeimmunoassay (EIA, HTLV-I/II, Gold ELISA, REM), and confirmed by Westernblot (HTLV BLOT 2.4, MP Biomedicals), and line immunoassay (INNO-LIAHTLV-I/II, Fujirebio). The HIV infection was detected byimmunochromatographic assay (Rapid Check HIV 1 e 2, NDI, UniversidadeFederal do Espírito Santo, Brasil) and by EIA (GS HIV-1/HIV-2 Plus O EIA,Bio-Rad). HTLV-1 was confirmed in 25 samples (5 in G1 and 20 in G2)...

HBV or HCV and pregnancy

Despite effective anti-HBV prophylaxis, cases of acute and chronic inflammation are still occurring, including among pregnant women. Studies in Asia suggest considering antiviral treatment among pregnant women with viremia above 10 log6 copies / ml. Current guidelines exclude the use of caesarean section as a method to reduce the likelihood of neonatal infection. At the same time, there are no grounds to ban the breastfeeding of a baby born to an HBV-infected mother. HCV infection can adversely affect the course of pregnancy. As with HBV infection, caesarean section does not reduce the risk of infection. Also breastfeeding among these patients is not contraindicated. The inability to use appropriate prophylaxis in newborns is one of the reasons for the targeted treatment of HCV-infected women at the procreation age in the first place.

Active co-infection with HBV and/or HCV in South African HIV positive patients due for cancer therapy.

Human immunodeficiency virus (HIV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV) share routes of transmission. There is limited data on the incidence of active co-infection with HBV and/or HCV in cancer patients infected with HIV in Africa. This was a prospective study based on 34 patients with varied cancer diagnosis, infected with HIV and awaiting cancer therapy in South Africa. HIV viral load, CD4+ cell counts, Alanine-aminotransferase and aspartate aminotransferase levels were tested. Exposure to HBV and HCV was assessed serologically using commercial kits. Active HBV and/or HCV co-infection was detected using viral specific nested PCR assays. HCV 5'-UTR PCR products were sequenced to confirm active HCV infection. Active viral infection was detected in 64.7% of patients for HBV, 38.2% for HCV, and 29.4% for both HBV and HCV. Occult HBV infection was observed in 63.6% of the patients, while seronegative HCV infection was found in 30.8% of patients. In addition, CD4+ cell count < 350 cells/µl was not a risk factor for increased active HBV, HCV or both HBV and HCV co-infections. A total of 72.7%, 18.2% and 9.1% of the HCV sequences were assigned genotype 5, 1 and 4 respectively.The study revealed for the first time a high active HBV and/or HCV co-infection rate in cancer patients infected with HIV. The findings call for HBV and HCV testing in such patients, and where feasible, appropriate antiviral treatment be indicated, as chemotherapy or radiotherapy has been associated with reactivation of viral hepatitis and termination of cancer therapy.

Surveillance programmes for early detection of hepatocellular carcinoma.

Primary hepatocellular carcinoma (HCC) is the most commonly diagnosed primary malignancy of the liver. The number of new diagnosed cases of HCC seems to be on a rise worldwide. HCC is typically diagnosed in patients with underlying liver cirrhosis (> 90% cases) regardless of aetiology; over a five-year follow-up period HCC develops in 15-20% of patients with cirrhosis. Patients who are at a high risk of HCC development (i.e. individuals with liver cirrhosis, especially/or chronically infected with HBV or HCV) should undergo regular screening for HCC; the current screening standard comprises liver ultrasonography and determination of α-fetoprotein (AFP) concentration in blood serum at ca. 6 months' intervals (now has been excluded from current diagnostic standards). Only such diagnostic methods are capable of detecting HCC early, and thus make it possible to treat the cancer effectively.

Increasing incidence in liver cancer in Canada, 1972-2006: Age-period-cohort analysis.

BACKGROUND/AIMS: Our study aimed to assess 1) the temporal trends in incidence and mortality of liver cancer and 2) age-period-cohort effects on the incidence in Canada. METHODS: We analyzed data obtained from the Canadian Cancer Registry Database and Canadian Vital Statistics Death Database. We first examined temporal trends by sex, age group, and birth cohort between 1972 and 2006. Three-year period rates and annual percentage change (APC) were calculated to compare the changes over the study period. We used age-period-cohort modelling to estimate underlying effects on the observed trends in incidence. RESULTS: The overall age-adjusted incidence rates increased from 2.6 and 1.5 per 100 000 in 1972-74 to 6.5 (APC: 2.9) and 2.2 (APC: 1.2) per 100 000 in 2004-06 among males and females, respectively. The age-adjusted mortality rates increased from 3.3 and 2.0 per 100 000 in 1972-74 to 6.0 (APC: 2.3) and 2.6 (APC: 1.2) per 100 000 in 2004-06 among males and females, respectively. The incidence increased most rapidly in men aged 45-54 years (APC: 4.1) and women aged 65-74 years (APC: 1.7) over the period of study. CONCLUSIONS: The age-period-cohort analysis suggests that birth-cohort effect is underlying the increase in incidence. While the exact reason for the increased incidence of liver cancer remains unknown, reported increase in HBV and HCV infections, and immigration from high-risk regions of the world may be important factors.

The Evaluation for Hepatitis B and Hepatitis C Virus Infection in Aplastic Anemia / 대한내과학회지

OBJECTIVE: Aplastic anemia is a rare but serious complication of viral hepatitis. Both aplastic anemia and viral hepatitis are more common in Korea than in the Western countries. It is necessary to study about the relationship between them. METHODS: Twenty-three patients with aplastic anemia visiting Chonnam University Hospital from 1995 to 1996 were studied for positivity of hepatitis B virus (HBV) and hepatitis C virus (HCV) to investigate the association of hepatitis virus infection with aplastic anemia. The surface antigen of HBV (HBsAg) and anti-HCV in sera were tested by EIA(enzyme immunoassay), and the presence of HBV-DNA and HCV-RNA in both sera and bone marrow cells was examined by the polymerase chain reaction (PCR). RESULTS: The positivities of HBsAg and anti-HCV in 23 patients with aplastic anemia were 4.3% (1 patient) and 8.7% (2 patients), respectively. The positivity of HBsAg is similar to that of HBsAg in general population of Korea. The positivity of anti-HCV is higher than that of anti-HCV in general population of Korea. One patient had HBV DNA and 3 patients had HCV RNA in their sera. All of the 3 hepatitis C viremic patients received 11 to 15 units of blood products in the past. None of the patients showed the evidence of recent viral hepatitis infection. HBV DNA and HCV RNA were not detected by the PCR in bone marrow cells in any of the patients. CONCLUSION: This study suggests that the HBV or HCV might not be a causative agent of aplastic anemia. The higher positivity of anti-HCV in the patients might be due to passive transmission of HCV after transfusion of blood products.