Recent Results in Cancer Research最新文献

Persistent infection with hepatitis C virus (HCV) is a major risk factor for hepatocellular carcinoma (HCC). Accumulating evidence suggests that not only inflammation and subsequent fibrosis but also HCV itself are associated with hepatocarcinogenesis. To date, studies using transgenic mouse and cell-culture models, in which HCV proteins are expressed, indicate the direct pathogenicity of HCV, including oncogenic activity. In particular, the core protein of HCV induces excessive oxidative stress by impairing the mitochondrial electron transfer system by disrupting the function of the molecular chaperone, prohibitin. HCV also modulates intracellular signaling pathways, including mitogen-activated protein kinase, promoting the proliferation of hepatocytes. In addition, HCV induces disorders in lipid and glucose metabolism, thereby accelerating the progression of liver fibrosis and the development of HCC. Due to the development of direct-acting antivirals, which was made possible by basic research, HCV can be eradicated from almost all infected patients. However, such patients can develop HCC long after eradication of HCV, suggesting the genetic and/or epigenetic changes induced by HCV may be persistent. These results enhance our understanding of the role of HCV in hepatocarcinogenesis and will facilitate the development of therapeutic and preventive strategies for HCV-induced HCC.

Human papillomavirus (HPV) is the most common sexually transmitted infection, currently affecting close to 80 million Americans. Importantly, HPV infection is recognized as the etiologic factor for numerous cancers, including cervical, vulval, vaginal, penile, anal, and a subset of oropharyngeal cancers. The prevalence of HPV infection and its associated diseases are a significant problem, affecting millions of individuals worldwide. Likewise, the incidence of HPV infection poses a significant burden on individuals and the broader healthcare system. Between 2011 and 2015, there were an estimated 42,700 new cases of HPV-associated cancers each year in the United States alone. Similarly, the global burden of HPV is high, with around 630,000 new cases of HPV-associated cancer occurring each year. In the last decade, a total of three preventive major capsid protein (L1) virus-like particle-based HPV vaccines have been licensed and brought to market as a means to prevent the spread of HPV infection. These prophylactic vaccines have been demonstrated to be safe and efficacious in preventing HPV infection. The most recent iteration of the preventive HPV vaccine, a nanovalent, L1-VLP vaccine, protects against a total of nine HPV types (seven high-risk and two low-risk HPV types), including the high-risk types HPV16 and HPV18, which are responsible for causing the majority of HPV-associated cancers. Although current prophylactic HPV vaccines have demonstrated huge success in preventing infection, existing barriers to vaccine acquisition have limited their widespread use, especially in low- and middle-income countries, where the burden of HPV-associated diseases is highest. Prophylactic vaccines are unable to provide protection to individuals with existing HPV infections or HPV-associated diseases. Instead, therapeutic HPV vaccines capable of generating T cell-mediated immunity against HPV infection and associated diseases are needed to ameliorate the burden of disease in individuals with existing HPV infection. To generate a cell-mediated immune response against HPV, most therapeutic vaccines target HPV oncoproteins E6 and E7. Several types of therapeutic HPV vaccine candidates have been developed including live-vector, protein, peptide, dendritic cell, and DNA-based vaccines. This chapter will review the commercially available prophylactic HPV vaccines and discuss the recent progress in the development of therapeutic HPV vaccines.

Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in nearly 1 million deaths every year. Many of these patients die from severe liver diseases, including HCC. HBV may induce HCC through the induction of chronic liver inflammation, which can cause oxidative stress and DNA damage. However, many studies also indicated that HBV could induce HCC via the alteration of hepatocellular physiology that may involve genetic and epigenetic changes of the host DNA, the alteration of cellular signaling pathways, and the inhibition of DNA repair mechanisms. This alteration of cellular physiology can lead to the accumulation of DNA damages and the promotion of cell cycles and predispose hepatocytes to oncogenic transformation.

Human and animal cell cultures are indispensable model systems for the biomedical research and pharmaceutical industry and already represent one of the most important alternatives to animal experiments. The development of mammalian cell culture started in the first half of the last century when fundamental questions of genetics were unresolved and the pioneers of cell culture did not care about individual personality rights of donors of biomaterials. However, cultivation of primary and continuous cell cultures was and still is usually associated with the use of FBS, which-almost universally applicable-is questionable in terms of extraction and quality variations measurably affecting reproducibility of results. The history of the cell line HeLa is a prime example for the development of biomedical research with its great successes in the fight against cancer and development of Polio Virus vaccinia, but also for limitations in the public and scientific applications of cell lines in the age of digitization and bioinformatics. HeLa leads from the establishment of the first human continuous cell line to initial cancer research using tumor cells, from disastrous cross-contaminations by HeLa cell cultures to legal and ethical controversy by reading out the individual genome and the commercial use that continues to this day.

Human T-cell leukemia virus type 1 (HTLV-1) was discovered in 1980 as the first, and to date, the only retrovirus that causes human cancer. While HTLV-1 infection is generally asymptomatic, 3-5% of infected individuals develop a T cell neoplasm known as adult T cell leukemia/lymphoma (ATL) decades after infection. Since its discovery, HTLV-1 has served as a model for understanding retroviral oncogenesis, transcriptional regulation, cellular signal transduction, and cell-associated viral infection and spread. Much of the initial research was focused on the viral trans-activator/oncoprotein, Tax. Over the past decade, the study of HTLV-1 has entered the genomic era. With the development of new systems for studying HTLV-1 infection and pathogenesis, the completion of the whole genome, exome and transcriptome sequencing analyses of ATL, and the discovery of HBZ as another HTLV-1 oncogene, many established concepts about how HTLV-1 infects, persists and causes disease have undergone substantial revision. This chapter seeks to integrate our current understanding of the mechanisms of action of Tax and HBZ with the comprehensive genomic information of ATL to provide an overview of how HTLV-1 infects, replicates and causes leukemia.

Terminal chaperonage embedded in palliative care deeply resonates with human needs and has undergone significant advances in the past decades. At the same time, it is in jeopardy due to austerity measures in healthcare. Its comprehensive translation in philanthropic end-of-life practice necessitates reflection on underlying ethical issues. This chapter addresses ethical aspects arising in pain and terminal chaperonage and deduces important ethical imperatives in the wake of the palliative mandate. The imperatives affect the deployment of resources necessary for a humane pain and terminal chaperonage, one that is to be comprehensive and flexible in design and implementation at the same time. Furthermore, they are concerned with critical implications for dying clients emerging from the idiosyncratic properties of opioids with respect to their potential to induce mental status alterations. Given that living and dying are profoundly mental by nature, the human mind plays a fundamental role in the command of both. Based on this, this chapter also outlines the essentials of terminal thought plasticity and affect catharsis en route to a mindful, decent death. It identifies and advocates eight most fundamental affective, respectively cognitive fields of the human mind, the "Ensemble of the essential eight iridescent fields of relinquishment", whose adaptable, culturally sensitive facilitation in mental management prior to death may have to be considered the core ethical imperative in terminal chaperonage - in true congruence with philanthropic end-of-life care.

Approximately, 1.4 million virus-induced cancers occur annually, representing roughly 10% of the worldwide cancer burden, with the majority (> 85%) occurring in the lower- and middle-income countries. The viruses associated with the greatest number of cancer cases are human papillomaviruses (HPVs), which cause cervical cancer and several other epithelial malignancies, and hepatitis viruses HBV and HCV, which are responsible for the majority of hepatocellular cancer. Other oncoviruses include Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), human T-cell leukemia virus (HTLV-I), and Merkel cell polyoma virus (MCPyV). These oncoviruses include various classes of DNA and RNA viruses and induce cancer by a variety of mechanisms. However, cancers develop in a minority of infected individuals and almost always after chronic infection of many year's duration. Identification of the oncoviruses has provided critical insights in human carcinogenesis and led to several interventions that may reduce the risk of developing the tumors they induce. These interventions include preventive vaccines against HBV and HPV, screening for persistent HPV and HCV infections, antivirals for the treatment of chronic HBV and HCV infection, and screening the blood supply for the presence of HBV and HCV. Further efforts to identify additional oncogenic viruses in human cancers and new insights into etiology and pathogenesis of virally induced cancers would likely lead to new approaches for prophylactic and therapeutic interventions.

Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer-related death worldwide.

LDLT covers all standard indications for liver transplantation, and the results are similar or even better than for standard DDLT. Due to the donor shortage and long waiting time, LDLT has become a relevant option for patients with liver tumors, provided the expected five-year survival rate is comparable to that of patients receiving a DDLT. Nowadays, LDLT offers the possibility to extend the standard morphometric selection by considering the biological parameters. In the setting of LDLT, we are not only faced with surgical morbidity in the donor, but long-term non-medical problems like psychological complications and financial burden also have to be considered. On the other hand, the benefits to the donor are mainly social and psychological. In LDLT, the donor's altruism is the fundamental ethical principle and it is based on the principles of (1) beneficence (doing good), (2) non-maleficence (avoiding harm), (3) respect for autonomy, and (4) respect for justice (promoting fairness). On top of that, the concept of double equipoise of living organ donation evaluates the relationship between the recipient's need, the donor's risk, and the recipient's outcome. It considers each donor-recipient pair as a unit, analyzing whether the specific recipient's benefit justifies the specific donor's risk in particular oncologic indications. In this light, it is essential to seek adequate informed consent focused on risk, benefits and outcome benefits of both donor and recipient supported by an independent living donor advocate. Finally, the transplant team must protect donors from donation if harm does not justify the expected benefit to the recipient.

Human papillomavirus (HPV) vaccination of young adolescent girls as a part of primary prevention of cervical cancer is now a routine practice in many countries. Bangladesh, a lower-middle income country, observed a successful HPV vaccination demonstration program recently. As much as the benefits of the vaccination programs are well-recorded, the ethics of administration of it is not focused highly; rather the focus tends to be on the most efficient method to get it done. In countries like Bangladesh, vaccination-related ethical issues are often overlooked. Thus, addition of HPV vaccination to the existing immunization programs calls for logical discussion and consideration to preserve the highest ethical standard in administering this vaccine to a sensitive age group of adolescence. This chapter summarizes some ethical concerns related to the HPV vaccination implementation in Bangladesh.