The role of cancer metabolism in defining the success of oncolytic viro-immunotherapy

Oncolytic viruses infect, replicate in, and kill cancer cells selectively without harming normal cells. The rapidly expanding clinical development of oncolytic virotherapy is an exciting interdisciplinary field that provides insights into virology, oncology, and immunotherapy. Recent years have seen greater focus on rational design of cancer-selective viruses together with strategies to exploit their immunostimulatory capabilities, ultimately to develop powerful oncolytic cancer vaccines. However, despite great interest in the field, many important experiments are still conducted under optimum conditions in vitro, with many nutrients present in excess and with cellular stress kept to a minimum. Whilst this provides a convenient platform for cell culture, it bears little relation to the typical conditions found within a tumour in vivo, where cells are often subject to a range of metabolic and environmental stresses. Viral infection and cancer will both lead to production of metabolites that are also not present in media in vitro. Understanding how oncolytic viruses interact with cells exposed to more representative metabolic conditions in vitro represents an under-explored area of study that could provide valuable insight into the intelligent design of superior oncolytic viruses and help bridge the gap between bench and bedside. This review summarises the major metabolic pathways altered in cancer cells, during viral infection and highlights possible targets for future studies.     

Isocitrate dehydrogenase variants in cancer — Cellular consequences and therapeutic opportunities

Abnormal metabolism is common in cancer cells and often correlates with mutations in genes encoding for enzymes involved in small-molecule metabolism. Isocitrate dehydrogenase 1 (IDH1) is the most frequently mutated metabolic gene in cancer. Cancer-associated substitutions in IDH1 and IDH2 impair wild-type production of 2-oxoglutarate and reduced nicotinamide adenine dinucleotide phosphate (NADPH) from isocitrate and oxidised nicotinamide adenine dinucleotide phosphate (NADP⁺ ), and substantially promote the IDH variant catalysed conversion of 2-oxoglutarate to d-2-hydroxyglutarate (d-2HG). Elevated d-2HG is a biomarker for some cancers, and inhibition of IDH1 and IDH2 variants is being pursued as a medicinal chemistry target. We provide an overview of the types of cancer-associated IDH variants, discuss some of the proposed consequences of altered metabolism as a result of elevated d-2HG, summarise therapeutic efforts targeting IDH variants and identify areas for future research.     

An inducible morphological defence is a passive by-product of behaviour in a marine snail

Many organisms have evolved inducible defences in response to spatial and temporal variability in predation risk. These defences are assumed to incur large costs to prey; however, few studies have investigated the mechanisms and costs underlying these adaptive responses. I examined the proximate cause of predator-induced shell thickening in a marine snail (Nucella lamellosa) and tested whether induced thickening leads to an increase in structural strength. Results indicate that although predators (crabs) induce thicker shells, the response is a passive by-product of reduced feeding and somatic growth rather than an active physiological response to predation risk. Physical tests indicate that although the shells of predator-induced snails are significantly stronger, the increase in performance is no different than that of snails with limited access to food. Increased shell strength is attributable to an increase in the energetically inexpensive microstructural layer rather than to material property changes in the shell. This mechanism suggests that predator-induced shell defences may be neither energetically nor developmentally costly. Positive correlations between antipredator behaviour and morphological defences may explain commonly observed associations between growth reduction and defence production in other systems and could have implications for the evolutionary potential of these plastic traits.     

The role of estrogen receptor β (ERβ) in malignant diseases—A new potential target for antiproliferative drugs in prevention and treatment of cancer

The discovery of ERβ in the middle of the 1990s represents a paradigm shift in our understanding of estrogen signaling. It has turned out that estrogen action is not mediated by one receptor, ERα, but by two balancing factors, ERα and ERβ, which are often antagonistic to one another. Excitingly, ERβ has been shown to be widespread in the body and to be involved in a multitude of physiological and pathophysiological events. This has led to a strong interest of the pharmaceutical industry to target ERβ by drugs against various diseases. In this review, focus is on the role of ERβ in malignant diseases where the anti proliferative activity of ERβ gives hope of new therapeutic approaches.     

In vitro growth of murine T cells. IV. Use of T-cell growth factor to clone lymphoid cells

Murine bone marrow cells can suppress the in vitro primary antibody response of normal spleen cells without apparent cytotoxicity. The bone marrow cells suppress the response to both T-dependent (SRBC) and T-independent (DNP-Ficoll) antigens. When bone marrow cells are fractionated on a sucrose density gradient, the suppressive activity is found in the residue rather than the lymphocyte fraction. The suppressive activity is either unaffected or enhanced by treatment with anti-T- and anti-B-cell serums. Pretreatment of mice with phenylhydrazine which reduces the number of pre-B cells did not reduce the suppressive activity of their bone marrow cells. Suppressive activity is abolished by irradiation of the marrow cells in vitro with 1000 R prior to assay. The activity is present in the marrow of thymus deficient (nude) mice, infant mice, and mice which have been made polycythemic by transfusion. Furthermore, the suppressor cell can phagocytize iron carbonyl particles, is slightly adherent to plastic and Sephadex G-10, and can bind to EA monolayers. We conclude that the suppressor cell is not a mature lymphocyte or granulocyte nor a member of the erythrocytic series, but is likely to be an immature cell possibly of the myeloid series. We speculate on the physiologic role of this cell.     

Analysis of the effects of cesium ions on potassium channel currents in biological membranes

Cesium ions block potassium channels in biological membranes in a voltage dependent manner. For example, external cesium blocks inward current with little or no effect on outward current. Consequently, it produces a characteristic N-shaped current-voltage relationship. We have modeled this result by single file diffusion of ions in a narrow channel spanning the membrane with a special blocking site in the channel for cesium ions. The model enables us to make detailed comparisons of the effects of cesium on potassium channels in different types of biological membranes.     

Evaluation of disparities in maintaining healthy lifestyle behaviors among female cancer survivors by race/ethnicity and US nativity

BackgroundThere are well-known racial/ethnic disparities in maintaining healthy lifestyle behaviors throughout cancer survivorship among US-born women. Less is known about these associations among women born outside the US, as these women may experience disparities in survivorship care due to the lack of access to culturally appropriate health services. We evaluated disparities in the associations between race/ethnicity and US nativity and the likelihood of meeting recommendations for maintaining a healthy lifestyle during cancer survivorship.Methods2044 female cancer survivors contributed data from the National Health and Nutrition Examination Survey (NHANES) (1999–2018). Adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) were calculated with multivariable logistic regression models to measure the association between independent variables (race/ethnicity, US nativity, length of time in the US) and outcomes (obesity, meeting weekly physical activity (PA) recommendations, smoking history, alcoholic drinks/day) overall and by comorbidity.ResultsMost survivors were breast cancer survivors (27.6 %), non-Hispanic white (64.2 %), and US native (84.5 %). Compared to US native survivors, foreign-born survivors were less likely (aOR, 0.30, 95 % CI, 0.10–0.87) to not meet PA recommendations, while foreign-born survivors living in the US ≥ 15 years were 2.30 times more likely (95 % CI, 1.12–4.73) to not meet PA recommendations. Having at least one comorbidity modified (p-interaction< 0.05) the relationships between US nativity and length of time in the US.ConclusionOur findings provide new evidence for disparities in maintaining healthy lifestyle behaviors among female cancer survivors and can help inform lifestyle interventions for female cancer survivors from different racial/ethnic backgrounds.     

Burden of disease due to cancer in a Southern Brazilian state

Background: Despite the considerable epidemiological relevance of cancer in developing countries, there are very few studies of the burden related to cancer. The aim of this study was to present and discuss data from a burden-of-cancer study performed in a Southern Brazilian state. Methods: An epidemiological study of ecological design was performed to calculate the disability-adjusted life year (DALY) index. The study was based on records of individuals admitted and treated for cancer in the Brazilian National Health System Hospitals, or individuals who had died of cancer while residing in the state of Santa Catarina in 2008. Results: A total of 73,872.9 DALYs were estimated, which generated a rate of 1220.5 DALYs/100,000 inhabitants. The highest DALYs were those for cancer of the trachea, bronchus and lung with 179.0/100,000 inhabitants, gastric cancer with 101.7/100,000 inhabitants, and breast cancer with 99.7/100,000 inhabitants. The percentage contribution of the DALY component varied according to cancer type; however, mortality was the major component in all types. The highest rates were observed in 60–69-year-olds with 6071.3/100,000 inhabitants, in 70–79-year-olds with 5095.4/100,000 inhabitants, and in 45–59-year-olds with 3189.0 DALY/100,000 inhabitants; 53.7% of DALYs occurred in males. Conclusions: The greatest burden of disease due to cancer in Santa Catarina was attributed to cancer of the trachea, bronchus and lung, followed by gastric and breast cancers. The mortality component was responsible for the greatest burden.     

CpG methylation recruits sequence specific transcription factors essential for tissue specific gene expression

CG methylation is an epigenetically inherited chemical modification of DNA found in plants and animals. In mammals it is essential for accurate regulation of gene expression and normal development. Mammalian genomes are depleted for the CG dinucleotide, a result of the chemical deamination of methyl-cytosine in CG resulting in TpG. Most CG dinucleotides are methylated, but ~ 15% are unmethylated. Five percent of CGs cluster into ~ 20,000 regions termed CG islands (CGI) which are generally unmethylated. About half of CGIs are associated with housekeeping genes. In contrast, the gene body, repeats and transposable elements in which CGs are generally methylated. Unraveling the epigenetic machinery operating in normal cells is important for understanding the epigenetic aberrations that are involved in human diseases including cancer. With the advent of high-throughput sequencing technologies, it is possible to identify the CG methylation status of all 30 million unique CGs in the human genome, and monitor differences in distinct cell types during differentiation and development. Here we summarize the present understanding of DNA methylation in normal cells and discuss recent observations that CG methylation can have an effect on tissue specific gene expression. We also discuss how aberrant CG methylation can lead to cancer. This article is part of a Special Issue entitled: Chromatin in time and space.     

Agaricus Bisporus: An assessment of its carcinogenic potency

This assessment focuses on the concentrations of some chemicals present in theAgaricus bisporus mushroom, the cancer-inducing doses of these chemicals or mushroom used in the animal experiments, the total amounts of these chemicals or mushroom needed to induce cancer in these mice, and the estimated total amounts of these chemicals or mushroom needed to induce cancer in humans. By adding the estimated amounts of chemicals needed to induce cancer and by comparing it with the amount of raw mushroom needed to induce the same effect, it becomes obvious that we have accounted for less than 2% of the carcinogenic components of theAgaricus bisporus mushroom. Since some unavailable data handicapped this assessment, it should be regarded as tentative and subject to further adjustment.