Development of biomarker panel to predict, prevent and create treatments tailored to the persons with human papillomavirus-induced cervical precancerous lesions

Abstract

IntroductionHuman papillomavirus (HPV) induce many cancer conditions and cause cervical cancer, second in frequency of malignant disease in women.The aim was to develop biomarker panel for HPV-induced cervical precancerous diseases in patients infected with herpes simplex virus (HSV).Material and methodsThe study involved 71 women with cervical precancerous diseases (mean age 26 ± 5 years) revealed by colposcopic, cytomorphological, and ultrasound signs which were assessed according to the following: first group, 44 patients infected with HPV; second group, 27 HPV-negative patients; and third group, 30 healthy patients (controls). In cervical specimen, we identified HPV DNA of different oncogenic risk types by polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) kits (JSC SPC ‘DiaprofMed’) were used for detecting antibodies to HSV1 and/or HSV2 and for determining the avidity index. The production of pro-inflammatory cytokines, interferon-γ (IFN-γ), IFN-α, TNF-α, and interleukin-1β (IL-1β), and anti-inflammatory cytokines, IL-4, IL-10, and transforming growth factor-β1 (TGF-β1), were studied by ELISA.ResultsIn HPV-induced cervix precancerous diseases, we identified low-avidity IgG antibodies to HSV serum of 20 patients; in the serum of 17 patients, we identified average-avidity antibodies, and high-avidity antibodies were found in 2 patients only. In 14 HPV-negative patients, we found low-avidity IgG antibodies to HSV; in 10 patients, medium avidity. Patients with low-avidity IgG antibodies to herpes virus showed high and medium oncogenic risk HPV types and a decrease of IFN-γ compared to patients with medium-avidity IgG antibodies. Production of IFN-γ was suppressed also in HPV-negative patients with cervical precancers, but we found low- and medium-avidity IgG antibodies to herpes virus. In patients with low-avidity antibodies, we observed increased level of IL-10. Level of IFN-α, IL-1β, IL-2, and IL-4 did not change in patients of all groups, but TGF-β1 increased.ConclusionsIn HPV-positive patients, those with low-avidity IgG antibodies to HSV had immunosuppression, confirmed by increased TGF-β1 and violation of IFN-γ production. Therefore, in pro- and anti-inflammatory cytokines and IgG antibodies to HSV, their avidity is an important diagnostic biomarker of HPV-induced precancerous cervical diseases. Low-avidity IgG antibodies may be an indication for treatment with immunomodulators and antiviral drugs.

The efficacy of probiotics for monosodium glutamate-induced obesity: dietology concerns and opportunities for prevention

“…There were illustrated extensive interrelations among virus action, cellular oxidative stress, gene damage, multiple immune pathways and proteomic changes in diabetes mellitus, cancer and many chronic disorders development; many of them are also related to HPV infection [96,97]. On the other hand, the obesity may induce the T cell response in virus infection [98].…”

Role of Cytokines in Genesis, Progression and Prognosis of Cervical Cancer

“…Treg cytokine profile showed progressive increase with progressing disease indicating a poor cell mediated immunity with high grade lesions. Lazarenko et al (2014) have recently evaluated a panel of biomarkers for assessment of progression from healthy cervices to HPV infected, CIN and cancer. These included several cytokines (PBMC), HPV status, HSV antibodies, and newer biophysical techniques like cervical sonocervicography using ultrasonography which has shown a high specificity, sensitivity, positive predictive value and negative predictive value.…”

“…However biopsy is an invasive procedure and is particularly non-desirable in the younger women desirous of conserving menstrual and childbearing functions. Hence further studies were carried out by authors who have observed that the higher local or circulatory peripheral concentrations of some cytokines are indicative of a higher risk of progression from CIN 1 to CIN 2 or 3 and further to invasive cancer and metastasis (Adam et al, 1999;Fugimoto et al, 2000;Pardo-Govea et al, 2005;Bais et al, 2007;Sharma et al, 2007;Hong et al, 2010;Kemp et al, 2010;Ali et al, 2012;Mhatre et al, 2012;Peghini et al, 2012;Lazarenko et al, 2014). Souza et al (2013) recently demonstrated higher serum concentrations of IL-17, mean-pg/ml: 22.50 in HSIL vs 12.20 in LSIL, and of IL-22, mean pg/ml 168.2 vs 61.48, p<0.05 respectively.…”

Antioxidant-Vitamin C: Lung Function; Lung Cancer

“…Of these, 25 [86, were not reviewed further because they were a republication or reanalysis of data that were already used to evaluate the health claim and/or because they had scientific deficiencies that prevented FDA from drawing scientific conclusions from the study (Table 1). For example, studies that measured biomarkers that had not been previously validated for the specific cancer under study (e.g., serum level of insulin-like growth factor and cervical dysplasia) [110,111] were excluded because they did not provide reliable evidence for risk reduction, and therefore, no scientific conclusions could be drawn from them for the evaluation of a qualified health claim about cancer. Studies for which no information was provided about the validation of the food frequency questionnaire used were also excluded because failure to validate a food-frequency questionnaire may lead to false conclusions about associations between dietary factors and disease risk [112,113].…”