The year 2011 marks the centenary of Francis Peyton Rous's landmark experiments on an avian cancer virus. Since then, seven human viruses have been found to cause 10-15% of human cancers worldwide. ...Viruses have been central to modern cancer research and provide profound insights into both infectious and non-infectious cancer causes. This diverse group of viruses reveals unexpected connections between innate immunity, immune sensors and tumour suppressor signalling that control both viral infection and cancer. This Timeline article describes common features of human tumour viruses and discusses how new technologies can be used to identify infectious causes of cancer.
Merkel cell carcinoma (MCC) is a rare but aggressive human skin cancer that typically affects elderly and immunosuppressed individuals, a feature suggestive of an infectious origin. We studied MCC ...samples by digital transcriptome subtraction and detected a fusion transcript between a previously undescribed virus T antigen and a human receptor tyrosine phosphatase. Further investigation led to identification and sequence analysis of the 5387-base-pair genome of a previously unknown polyomavirus that we call Merkel cell polyomavirus (MCV or MCPyV). MCV sequences were detected in 8 of 10 (80%) MCC tumors but only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues. In six of eight MCV-positive MCCs, viral DNA was integrated within the tumor genome in a clonal pattern, suggesting that MCV infection and integration preceded clonal expansion of the tumor cells. Thus, MCV may be a contributing factor in the pathogenesis of MCC.
Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for the CFTR anion channel. In the absence of ...functional CFTR, the epithelial Na
channel is also dysregulated. Airway surface liquid (ASL) hydration is maintained by a balance between epithelial sodium channel (ENaC)-led Na
absorption and CFTR-dependent anion secretion. This finely tuned homeostatic mechanism is required to maintain sufficient airway hydration to permit the efficient mucus clearance necessary for a sterile lung environment. In CF airways, the lack of CFTR and increased ENaC activity lead to ASL/mucus dehydration that causes mucus obstruction, neutrophilic infiltration, and chronic bacterial infection. Rehydration of ASL/mucus in CF airways can be achieved by inhibiting Na
absorption with pharmacological inhibitors of ENaC. Areas covered: In this review, we discuss ENaC structure and function and its role in CF lung disease and focus on ENaC inhibition as a potential therapeutic target to rehydrate CF mucus. We also discuss the failure of the first generation of pharmacological inhibitors of ENaC and recent alternate strategies to attenuate ENaC activity in the CF lung. Expert opinion: ENaC is an attractive therapeutic target to rehydrate CF ASL that may serve as a monotherapy or function in parallel with other treatments. Given the increased number of strategies being employed to inhibit ENaC, this is an exciting and optimistic time to be in this field.
Merkel cell polyomavirus (MCV) is the recently discovered cause of most Merkel cell carcinomas (MCCs), an aggressive form of nonmelanoma skin cancer. Although MCV is known to integrate into the tumor ...cell genome and to undergo mutation, the molecular mechanisms used by this virus to cause cancer are unknown. Here, we show that MCV small T (sT) antigen is expressed in most MCC tumors, where it is required for tumor cell growth. Unlike the closely related SV40 sT, MCV sT transformed rodent fibroblasts to anchorage- and contact-independent growth and promoted serum-free proliferation of human cells. These effects did not involve protein phosphatase 2A (PP2A) inhibition. MCV sT was found to act downstream in the mammalian target of rapamycin (mTOR) signaling pathway to preserve eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation, resulting in dysregulated cap-dependent translation. MCV sT-associated 4E-BP1 serine 65 hyperphosphorylation was resistant to mTOR complex (mTORC1) and mTORC2 inhibitors. Steady-state phosphorylation of other downstream Akt-mTOR targets, including S6K and 4E-BP2, was also increased by MCV sT. Expression of a constitutively active 4E-BP1 that could not be phosphorylated antagonized the cell transformation activity of MCV sT. Taken together, these experiments showed that 4E-BP1 inhibition is required for MCV transformation. Thus, MCV sT is an oncoprotein, and its effects on dysregulated cap-dependent translation have clinical implications for the prevention, diagnosis, and treatment of MCV-related cancers.
Common Commensal Cancer Viruses Moore, Patrick S; Chang, Yuan
PLoS pathogens,
01/2017, Letnik:
13, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Determining causality requires measuring the virus infection in the context of these factors rather than infection alone. ...EBV infection alone does not cause cancer but EBV infection of a ...post-germinal B cell having a c-Myc rearrangement does. An analogous pathway is shown for the genesis of Burkitt lymphoma, in which EBV is responsible for a portion of tumors, but also only in the biological context of other factors, such as cMYC translocations. Since EBV is nearly ubiquitous, teasing out its contribution to a rare cancer like Burkitt lymphoma is supremely difficult using standard epidemiologic methods, but is readily evident using molecular biologic information that has been available for decades.
Human oncogenic viruses: nature and discovery Chang, Yuan; Moore, Patrick S.; Weiss, Robin A.
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
10/2017, Letnik:
372, Številka:
1732
Journal Article
Recenzirano
Odprti dostop
Seven kinds of virus collectively comprise an important cause of cancer, particularly in less developed countries and for people with damaged immune systems. Discovered over the past 54 years, most ...of these viruses are common infections of humankind for which malignancy is a rare consequence. Various cofactors affect the complex interaction between virus and host and the likelihood of cancer emerging. Although individual human tumour viruses exert their malignant effects in different ways, there are common features that illuminate mechanisms of oncogenesis more generally, whether or not there is a viral aetiology.
This article is part of the themed issue ‘Human oncogenic viruses’.
Financial stress has been proposed as an economic determinant of depression. However, there is little systematic analysis of different dimensions of financial stress and their association with ...depression. This paper reports a systematic review of 40 observational studies quantifying the relationship between various measures of financial stress and depression outcomes in adults. Most of the reviewed studies show that financial stress is positively associated with depression. A positive association between financial stress and depression is found in both high-income and low-and middle-income countries, but is generally stronger among populations with low income or wealth. In addition to the "social causation" pathway, other pathways such as "psychological stress" and "social selection" can also explain the effects of financial stress on depression. More longitudinal research would be useful to investigate the causal relationship and mechanisms linking different dimensions of financial stress and depression. Furthermore, exploration of effects in subgroups could help target interventions to break the cycle of financial stress and depression.
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. Over the past decade, an association has been discovered between MCC and either ...integration of the Merkel cell polyomavirus, which likely drives tumorigenesis, or somatic mutations owing to ultraviolet-induced DNA damage. Both virus-positive and virus-negative MCCs are immunogenic, and inhibition of the programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) immune checkpoint has proved to be highly effective in treating patients with metastatic MCC; however, not all patients have a durable response to immunotherapy. Despite these rapid advances in the understanding and management of patients with MCC, many basic, translational and clinical research questions remain unanswered. In March 2018, an International Workshop on Merkel Cell Carcinoma Research was held at the US National Cancer Institute, at which academic, government and industry experts met to identify the highest-priority research questions. Here, we review the biology and treatment of MCC and report the consensus-based recommendations agreed upon during the workshop.
The objective is to understand what really drives prescription expenditure at the end of life in order to inform future expenditure projections and service planning. To achieve this objective an ...empirical analysis of public medication expenditure on the older population (individuals ≥ 70 years of age) in Ireland (n = 231,780) was undertaken. A two part model is used to analysis the individual effects of age, proximity to death (PTD) and morbidity using individual patient-level data from administrative pharmacy records for 2006–2009 covering the population of community medication users. Decedents (n = 14,084) consistently use more medications and incur larger expenditures than similar survivors, especially in the last 6 months of life. The data show a positive and statistically significant impact of PTD on prescribing expenditures with minimal effect for age alone even accounting for patient morbidities. Nevertheless improved measures of morbidity are required to fully test the hypothesis that age and PTD are proxies for morbidity. The evidence presented refutes age as a driver of prescription expenditure and highlights the importance of accounting for mortality in future expenditure projections.
•Prescription medication expenditures have significantly increased in the last two decades.•Proximity to death is a more important driver of prescription expenditure than age.•But proximity to death may itself be a proxy for morbidity, disability or senescence.•Accounting for chronic conditions reduced the observed proximity to death effect.•Projections of prescription expenditure need to consider mortality and morbidity.
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