The incidence of liver cancer has increased in recent years. Worldwide, liver cancer is common: more than 600000 related deaths are estimated each year. In the USA, about 27170 deaths due to liver cancer are estimated for 2016. Liver cancer is highly resistant to conventional chemotherapy and radiotherapy. For all stages combined, the 5-year survival rate is 15-17%, leaving much to be desired for liver cancer prevention and therapy. Heterogeneity, which can originate from genomic instability, is one reason for poor outcome. About 80-90% of liver cancers are hepatocellular carcinoma (HCC), and recent cancer genome sequencing studies have revealed frequently mutated genes in HCC. In this review, we discuss the cause of the tumor heterogeneity based on the functions of genes that are frequently mutated in HCC. We overview the functions of the genes that are most frequently mutated (e.g. TP53, CTNNB1, AXIN1, ARID1A and WWP1) that portray major pathways leading to HCC and identify the roles of these genes in preventing genomic instability. Notably, the pathway analysis suggested that oxidative stress management may be critical to prevent accumulation of DNA damage and further mutations. We propose that both chromosome instability (CIN) and microsatellite instability (MIN) are integral to the hepatic carcinogenesis process leading to heterogeneity in HCC and that the pathways leading to heterogeneity may be targeted for prognosis, prevention and treatment.

Biological effects and epidemiological consequences of arsenic exposure, and reagents that can ameliorate arsenic damage in vivo Biological effects and epidemiological consequences of arsenic exposure, and reagents that can ameliorate arsenic damage in vivo

Colon cancer is the second most lethal cancer; approximately 600,000 people die of it annually in the world. Colon carcinogenesis generally follows a slow and stepwise process of accumulation of mutations under the influence of environmental and epigenetic factors. To adopt a personalized (tailored) cancer therapy approach and to improve current strategies for prevention, diagnosis, prognosis, and therapy overall, advanced understanding of molecular events associated with colon carcinogenesis is necessary. A contemporary approach that combines genetics, epigenomics, and signaling pathways has revealed many genetic/genomic alterations associated with colon cancer progression and their relationships to a genomic instability phenotype prevalent in colon cancer. In this review, we describe the relationship between gene mutations associated with colon carcinogenesis and a genomic instability phenotype, and we discuss possible clinical applications of genomic instability studies. Colon carcinogenesis is associated with frequent mutations in several pathways that include phosphatidylinositol 3-kinase, adenomatous polyposis coli, p53 (TP53), F-box and WD repeat domain containing 7, transforming growth factor-β, chromosome cohesion, and K-RAS. These genes frequently mutated in pathways affecting colon cancer were designated colon cancer (CAN) genes. Aberrations in major colon CAN genes have a causal relationship to genomic instability. Conversely, genomic instability itself plays a role in colon carcinogenesis in experimental settings, as demonstrated in transgenic mouse models with high genomic instability. Thus, there is a feedback-type relationship between CAN gene mutations and genomic instability. These genetic/genomic studies have led to emerging efforts to apply the knowledge to colon cancer prognosis and to targeted therapy.

The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

Survival rate of metastatic colorectal cancers is less than 5%. A major reason is that those cancers respond poorly to chemotherapy drugs. However, factors contributing to chemoresistance in colorectal cancers are barely known, thus isolation of factors involved is the critical first step for mechanistic understanding and therapy improvement. With expression cloning, we isolated human BRD8 (bromodomain 8) as an influential factor for spindle poison sensitivity. BRD8 is an accessory subunit of human NuA4-HAT (histone acetyl transferase) complex (also known as TRRAP/TIP60 complex), but its role in cancer and drug resistance is unknown. Here, we report that BRD8 is involved in cellular survival and in sensitivity to spindle poisons and proteasome inhibitor in aggressive colorectal cancers. BRD8 protein expression level is several-fold higher in human metastatic colorectal cancer cell lines (DLD-1, HCA-7 and HCT-116) than in other cell lines tested. Normal-appearing rat colonic mucosa and azoxymethane (AOM)-induced colorectal adenocarcinoma tissue expressed a barely detectable amount of BRD8 protein, but aggressive colon tumors induced with AOM and dextran sodium sulfate expressed BRD8 at a significantly higher level, suggesting that BRD8 expression is associated with tumor progression toward advanced stages and may aid to gain growth advantage. Supporting the notion, siRNA-mediated knockdown of BRD8 induced cell death or growth delay in colorectal cancer cell lines, and surviving BRD8-knockdown cells were particularly sensitive to spindle poisons and a proteasome inhibitor MG132. Conversely, at least one isoform of BRD8 gave growth advantage and resistance to taxol when stably overexpressed in HeLa cells. Targeting BRD8 would improve therapy outcome against aggressive/metastatic colorectal cancers.

The cerebral amyloid‐β accumulation that begins in middle age is considered the critical triggering event in the pathogenesis of late‐onset Alzheimer's disease (LOAD). However, the molecular mechanism remains elusive. The Shugoshin 1 (Sgo1^−/+) mouse model, a model for mitotic cohesinopathy‐genomic instability that is observed in human AD at a higher rate, showed spontaneous accumulation of amyloid‐β in the brain at old age. With the model, novel insights into the molecular mechanism of LOAD development are anticipated. In this study, the initial appearance of cerebral amyloid‐β accumulation was determined as 15‐18 months of age (late middle age) in the Sgo1^−/+ model. The amyloid‐β accumulation was associated with unexpected GSK3α/β inactivation, Wnt signaling activation, and ARC/Arg3.1 accumulation, suggesting involvement of both the GSK3‐Arc/Arg3.1 axis and the GSK3‐Wnt axis. As observed in human AD brains, neuroinflammation with IFN‐γ expression occurred with amyloid‐β accumulation and was pronounced in the aged (24‐month‐old) Sgo1^−/+ model mice. AD‐relevant protein panels (oxidative stress defense, mitochondrial energy metabolism, and β‐oxidation and peroxisome) analysis indicated (a) early increases in Pdk1 and Phb in middle‐aged Sgo1^−/+ brains, and (b) misregulations in 32 proteins among 130 proteins tested in old age. Thus, initial amyloid‐β accumulation in the Sgo1^−/+ model is suggested to be triggered by GSK3 inactivation and the resulting Wnt activation and ARC/Arg3.1 accumulation. The model displayed characteristics and affected pathways similar to those of human LOAD including neuroinflammation, demonstrating its potential as a study tool for the LOAD development mechanism and for preclinical AD drug research and development.