• Journal of Microbiology and Biotechnology
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• v.29 no.9
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• pp.1444-1452
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• 2019

The conventional prophylactic vaccines for human papillomavirus (HPV) efficiently prevent infection with high-risk HPV types, but they do not promote therapeutic effects against cervical cancer. Previously, we developed HPV16 E7-expressing Lactobacillus casei (L. casei-E7) as a therapeutic vaccine candidate for cervical cancer, which induces antitumor therapeutic effects in a TC-1 murine cancer model. To improve the therapeutic effect of L. casei-E7, we performed co-treatment with poly-gamma-glutamic acid (${\gamma}-PGA$), a safe and edible biomaterial naturally secreted by Bacillus subtilis. We investigated their synergistic effect to improve antitumor efficacy in a murine cancer model. The treatment with ${\gamma}-PGA$ did not show in vitro cytotoxicity against TC-1 tumor cells; however, an enhanced innate immune response including activation of dendritic cells was observed. Mice co-administered with ${\gamma}-PGA$ and L. casei-E7 showed significantly suppressed growth of TC-1 tumor cells and an increased survival rate in TC-1 mouse models compared to those of mice vaccinated with L. casei-E7 alone. The administration of ${\gamma}-PGA$ markedly enhanced the activation of natural killer (NK) cells but did not increase the E7-specific cytolytic activity of $CD8^+$ T lymphocytes in mice vaccinated with L. casei-E7. Overall, our results suggest that oral administration of ${\gamma}-PGA$ induces a synergistic antitumor effect in combination with L. casei-E7.

• Korean Journal of Head & Neck Oncology
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• v.33 no.2
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• pp.9-15
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• 2017

The recently released the $8^{th}$ edition of the American Joint Committee on Cancer (AJCC) Staging Manual introduces significant modifications from the prior $7^{th}$ edition. In this paper, the contents of the new changes in the decision of cancer of the head and neck is summarized except changes in staging of skin and thyroid cancer. In addition to the 8th edition, 1) Addition of extracapsular involvement in metastatic lymph nodes (N category) 2) Oral cancer T classification change, 3) Staging of the pharyngeal cancer was divided into 3 chapters: high-risk human papilloma virus (HR-HPV) associated oropharyngeal cancer (OPC), non HR-HPV associated OPC and hypopharynx cancer (HPC), and nasopharynx cancer (NPC) 4) Changes in T and N classification in NPC, 5) In the case of cancer of unknown primary, P16-positive case is defined as HR-HPV related OPC, and EBV-positive case is defined as NPC. The process that led to these changes highlights the need to collect high-fidelity cancer registry-level data that can be used to confirm prognostic observations identified in institutional data sets. Clinicians will continue to use the latest information for patient care, including scientific content of the 8th Edition Manual. All newly diagnosed cases through December $31^{st}$ 2017 should be staged with the 7th edition. The time extension will allow all partners to develop and update protocols and guidelines and for software vendors to develop, test, and deploy their products in time for the data collection and implementation of the 8th edition in 2018. The 8th edition strikes a balance between a personalized, complex system and a more general, simpler one that maintains the user-friendliness and worldwide acceptability of the traditional TNM staging paradigm.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.3
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• pp.1151-1157
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• 2015

Human papillomavirus (HPV) is responsible for one of the most frequent sexually transmitted infections. The first phylogenetic analysis was based on a LCR region fragment. Nowadays, 4 variants are known: African (Af-1, Af-2), Asian-American (AA) and European (E). However the existence of sub-lineages of the European variant havs been proposed, specific mutations in the E6 and LCR sequences being possibly related to persistent viral infections. The aim of this study was a phylogenetic study of HPV16 sequences of endocervical samples from C${\acute{o}}$rdoba, in order to detect the circulating lineages and analyze the presence of mutations that could be correlated with malignant disease. The phylogenetic analysis determined that 86% of the samples belonged to the E variant, 7% to AF-1 and the remaining 7% to AF-2. The most frequent mutation in LCR sequences was G7521A, in 80% of the analyzed samples; it affects the binding site of a transcription factor that could contribute to carcinogenesis. In the E6 sequences, the most common mutation was T350G (L83V), detected in 67% of the samples, associated with increased risk of persistent infection. The high detection rate of the European lineage correlated with patterns of human migration. This study emphasizes the importance of recognizing circulating lineages, as well as the detection of mutations associated with high-grade neoplastic lesions that could be correlated to the development of carcinogenic lesions.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6145-6150
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• 2014

Toll-like receptors (TLRs) are expressed in immune and tumor cells and recognize pathogen-associated molecular patterns. Cervical cancer (CC) is directly linked to a persistent infection with high risk human papillomaviruses (HR-HPVs) and could be associated with alteration of TLRs expression. TLR9 plays a key role in the recognition of DNA viruses and better understanding of this signaling pathway in CC could lead to the development of novel immunotherapeutic approaches. The present study was undertaken to determine the level of TLR9 expression in cervical neoplasias from Tunisian women with 53 formalin-fixed and paraffin-embedded specimens, including 22 samples of invasive cervical carcinoma (ICC), 18 of cervical intraepithelial neoplasia (CIN), 7 of condyloma and 6 normal cervical tissues as control cases. Quantification of TLR9 expression was based on scoring four degrees of extent and intensity of immunostaining in squamous epithelial cells. TLR9 expression gradually increased from CIN1 (80% weak intensity) to CIN2 (83.3% moderate), CIN3 (57.1% strong) and ICC (100% very strong). It was absent in normal cervical tissue and weak in 71.4% of condyloma. The mean scores of TLR9 expression were compared using the Kruskall-Wallis test and there was a statistical significance between normal tissue and condyloma as well as between condyloma, CINs and ICC. These results suggest that TLR9 may play a role in progression of cervical neoplasia in Tunisian patients and could represent a useful biomarker for malignant transformation of cervical squamous cells.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6405-6409
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• 2014

Background: To study the prevalence of abnormal anal cytology by Papanicolaou (Pap) technique in HIV-infected women who attended a HIV clinic at Prapokklao Hospital, Chanthaburi, Thailand. Materials and Methods: HIV-infected women who attended a HIV clinic at Prapokklao Hospital from March 2013 to February 2014 were recruited for anal Pap smears. Participants who had abnormal results of equally or over "abnormal squamous/glandular cells of undetermined significance" (ASC-US) were classified as abnormal anal cytology. Results: A total of 590 anal Pap smears were performed at HIV clinic of Prapokklao Hospital during the study period. There were only 13 patients who had abnormal Pap tests, which were: 11 ASC-US and 2 HSIL (high grade squamous intraepithelial lesion). The prevalence of abnormal anal Pap smears in HIV-infected women who attended HIV clinic at Prapokklao Hospital was 2.2 percent. Percentage of high risk HPV in patients who had abnormal Pap test was 88.9 (8/9). Conclusions: The prevalence of abnormal anal Papanicolaou smears in HIV-infected women who attended the HIV clinic at Prapokklao hospital was quite low in comparison to the earlier literature.

• Bulletin of the Korean Chemical Society
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• v.30 no.12
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• pp.2999-3005
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• 2009

Among the more than 120 different types of human papillomavirus (HPV), types 16 and 18 have been known to be high risk agents that cause cervical cancer. We examined, in an immuno-chromatographic analysis, the potential of using the early gene product, E7 protein, as a diagnostic marker of cervical cancer caused by HPV. We developed monoclonal antibodies specific to HPV-16 and 18 E7 proteins that were produced from bacterial cells using gene recombinant technology. For each E7 protein, the optimal antibody pair was selected using the immuno-chromatographic sandwichtype binding system based on the lateral flow through membrane pores. Under these conditions, this rapid testing assay had a detection capability as low as 2 ng/mL of E7 protein. Furthermore, since viral analysis required the host cell to be lysed using chemicals such as detergents, it was possible that the E7 protein was structurally damaged during this process, which would result in a decrease in detection sensitivity. Therefore, we examined the detrimental effects caused by different detergents on the E7 protein using HeLa cells as the host. In these experiments, we found that the damage caused by the detergent, nonylphenylpolyethylene glycol (NP-40), was minimal relative to Triton X-100 commonly used for the cell lysis. Temperature also affected the stability of the E7 protein, and we found that the E7 protein was stabilized at 4$^{\circ}C$ for about 2 h, which was 4 times longer than at room temperature. Finally, a HPV-infected cervical cancer cell line, which was used as a real sample model, was treated using the optimized conditions and the presence of E7 proteins were analyzed by immuno-chromatography. The results of this experiment demonstrated that this rapid test could specifically detect HPV-infected samples.

• BMB Reports
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• v.51 no.11
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• pp.584-589
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• 2018

Secondary prevention via earlier detection would afford the greatest chance for a cure in premalignant lesions. We investigated the exomic profiles of non-malignant and malignant changes in head and neck squamous cell carcinoma (HNSCC) and the genomic blueprint of human papillomavirus (HPV)-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC). Whole-exome (WES) and whole-genome (WGS) sequencing were performed on peripheral blood and adjacent non-tumor and tumor specimens obtained from eight Korean HNSCC patients from 2013 to 2015. Next-generation sequencing yielded an average coverage of $94.3{\times}$ for WES and $35.3{\times}$ for WGS. In comparative genomic analysis of non-tumor and tumor tissue pairs, we were unable to identify common cancer-associated early mutations and copy number alterations (CNA) except in one pair. Interestingly, in this case, we observed that non-tumor tonsillar crypts adjacent to HPV-positive OPSCC appeared normal under a microscope; however, this tissue also showed weak p16 expression. WGS revealed the infection and integration of high-risk type HPV16 in this tissue as well as in the matched tumor. Furthermore, WES identified shared and tumor-specific genomic alterations for this pair. Clonal analysis enabled us to infer the process by which this transitional crypt epithelium (TrCE) evolved into a tumor; this evolution was accompanied by the subsequent accumulation of genomic alterations, including an ERBB3 mutation and large-scale CNAs, such as 3q27-qter amplification and 9p deletion. We suggest that HPV16-driven OPSCC carcinogenesis is a stepwise evolutionary process that is consistent with a multistep carcinogenesis model. Our results highlight the carcinogenic changes driven by HPV16 infection and provide a basis for the secondary prevention of OPSCC.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5621-5624
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• 2013

Mucosal head and neck cancers are squamous cell carcinomas that develop in the upper-aero digestive epithelium. Together they constitute the sixth most common cancer with an estimated 900,000 new cases and 350,000 deaths each year reported worldwide. The risk factors are tobacco, alcohol and human papillomavirus (HPV). Our research team initially reported a high incidence rate of HNC in the indigenous population of the Northern Territory. Mortality rates also vary in the Australian States and Territories, with particularly high mortality observed in the Northern Territory. There is a paucity of incidence studies of HNC for the Australian States and Territories. Therefore this review primarily focuses on variation in incidence and mortality iacross the country and highlights specifically the high incidence and mortality in the Northern Territory. Attention is also given to sex-specific incidence and mortality rates.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5567-5577
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• 2013

The prevalence of oral cancers (OC) is high in Asian countries, especially in South and Southeast Asia. Asian distinct cultural practices such as betel-quid chewing, and varying patterns of tobacco and alcohol use are important risk factors that predispose to cancer of the oral cavity. The aim of this review is to provide an update on epidemiology of OC between 2000 and 2012. A literature search for this review was conducted on Medline for articles on OC from Asian countries. Some of the articles were also hand searched using Google. High incidence rates were reported from developing nations like India, Pakistan, Bangladesh, Taiwan and Sri Lanka. While an increasing trend has been observed in Pakistan, Taiwan and Thailand, a decreasing trend is seen in Philippines and Sri Lanka. The mean age of occurrence of cancer in different parts of oral cavity is usually between 51-55 years in most countries. The tongue is the leading site among oral cancers in India. The next most common sites in Asian countries include the buccal mucosa and gingiva. The 5 year survival rate has been low for OC, despite improvements in diagnosis and treatment. Tobacco chewing, smoking and alcohol are the main reasons for the increasing incidence rates. Low socioeconomic status and diet low in nutritional value lacking vegetables and fruits contribute towards the risk. In addition, viral infections, such as HPV and poor oral hygiene, are other important risk factors. Hence, it is important to control OC by screening for early diagnosis and controlling tobacco and alcohol use. It is also necessary to have cancer surveillance at the national-level to collect and utilise data for cancer prevention and control programs.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.9
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• pp.3851-3864
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• 2014

Cytokine research is currently at the forefront in cancer research. Deciphering the functions of these multiple small molecules, discovered within the cell and in intercellular spaces, with their abundance and pleotrophism, was initially a great challenge. Advances in analytical chemistry and molecular biology have made it possible to unravel the pathophysiological functions of these polypeptides/proteins which are called interleukins, chemokines, monokines, lymphokines and growth factors. With more than 5 million women contracting cervical cancer every year this cancer is a major cause of mortality and morbidity the world over, particularly in the developing countries. In more than 95% of cases it is associated with human papilloma virus (HPV) infection which is persistent, particularly in those with a defective immune system. Although preventable, the mere magnitude of prevalence of HPV in the world population makes it a dominating current health hazard. The discovery of cytokine dysregulation in cervical cancer has spurted investigation into the possibility of using them as biomarkers in the early diagnosis of cases at high risk of developing cancer. Their critical role in carcinogenesis and progression of cervical cancer is now being revealed to a great extent. From diagnostics to prognosis, and now with a possible role in therapeutics and prevention of cervical cancer, the cytokines are being evaluated in all anticancer approaches. This review endeavours to capture the essence of the astonishing journey of cytokine research in cervical neoplasia.