Progression of Hepatic Adenoma to Carcinoma in Ogg1

The carcinogenic potential of phenobarbital (PB) was assessed in a mouse line carrying a mutant Mmh allele of the Mmh/Ogg1 gene encoding the enzyme oxoguanine DNA glycosylase (Ogg1) responsible for the repair of 8-hydroxy-2′-deoxyguanosine (8-OHdG). Mmh homozygous mutant (Ogg1−/−) and wild-type (Ogg1+/+) male and female, 10-week-old, mice were treated with 500 ppm PB in diet for 78 weeks. Hepatocellular carcinomas (HCCs) were found in PB-treated Ogg1−/− mice, while Ogg1+/+ animals developed only hepatocellular adenomas (HCAs) at the same rate. This was coordinated with PB-induced significant elevation of 8-OHdG formation in DNA and cell proliferation in adjacent liver of Ogg1−/− mice. Proteome analysis predicted activation of transcriptional factor Nrf2 in the livers and HCAs of PB-administered Ogg1+/+ mice; however, its activation was insufficient or absent in the livers and HCCs of Ogg1−/− mice, respectively. Significant elevation of phase I and II metabolizing enzymes was demonstrated in both Ogg1−/− and Ogg1+/+ animals. Treatment of Ogg1−/− mice with PB resulted in significant elevation of cell proliferation in the liver. These results indicate that PB induced progression from HCA to HCC in Ogg1−/− mice, due to persistent accumulation of DNA oxidative base modifications and suppression of Nrf2-mediated oxidative stress response, resulting in significant elevation of cell proliferation

Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n = 152) and 3, 311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P = 1.42 x 10(-12)),8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472;P = 3.41 x 10(-8)),and 2p22 at SOS1 (rs963731;P = 1.76 x 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22;rs1768208;P = 2.07 x 10(-7)) and MAPT H1c (17q21;rs242557;P = 7.91 x 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein)

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Harnessing The Power Of Cruciferous Vegetables: Developing A Biomarker For Brassica Vegetable Consumption Using Urinary 3,3´-Diindolylmethane

University of Minnesota M.S. thesis.April 2016. Major: Clinical Research. Advisor: Robert Kratzke. 1 computer file (PDF); iii, 21 pages.Glucobrassicin gives rise to indole-3-carbinol (I3C), a compound with potent anti-cancer effects in preclinical models. We previously showed that urinary 3,3´-diindolylmethane (DIM, the predominate metabolite of I3C), can discriminate between consumption of high and low doses of glucobrassicin-containing vegetables. However, the quantitative relationship between glucobrassicin exposure and urinary DIM level is unclear. We hypothesized that a range of glucobrassicin exposure from Brassica vegetables is reflected in urinary DIM and that this effect plateaus. Forty-five subjects consumed vegetables at 1 of 7 discrete dose levels (25 to 500 umol) of glucobrassicin for 2 days. Urine was collected for 24 hours afterward, and DIM was measured by LC/ESI-MS/MS-SRM. Urinary DIM excretion increased predictably with increasing glucobrassicin dose, plateauing between 200 and 300 umol of glucobrassicin. Glucobrassicin dose and urinary DIM correlated (R=0.82). The positive and strong correlation between glucobrassicin dose and urinary DIM supports its use as a biomarker of glucobrassicin exposure and I3C uptake.Fujioka, Naomi. (2016). Harnessing The Power Of Cruciferous Vegetables: Developing A Biomarker For Brassica Vegetable Consumption Using Urinary 3,3´-Diindolylmethane. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/181790

Mortality from COVID-19 in patients with lung cancer

The World Health Organization declared coronavirus infectious disease-2019 (COVID-19) linked to the severe acute respiratory syndrome (SARS-CoV-2), a global pandemic in March 2020. The pandemic outbreak has led to the most unprecedented and catastrophic loss of human life in the recent history. As of January 2021, there were more than 100 million cases of COVID-19 and more than two million deaths worldwide. Compared to the general population, patients with cancer are at a higher risk of poor outcomes from COVID-19. In large cohort studies, mortality from COVID-19 in patients with cancer can be as high as 40%. In addition to clinical variables (older age, male sex, and co-morbidities) that are associated with mortality in general population, cancer patients are uniquely vulnerable to severe COVID-19 due to immunosuppression from cancer and its therapy, and disruption of routine clinical care. Among patients with cancer, the lung cancer population is at a higher risk of poor outcomes and mortality from COVID-19 for several reasons. For instance, lung is the main target organ in COVID-19 that can lead to respiratory failure, patients with lung cancer have baseline poor lung function from chronic obstructive pulmonary disorder and smoking. In addition, some of the lung cancer treatment side-effects like pneumonitis, may obscure the diagnosis of COVID-19. In this article, we systematically review the most impactful cohort studies published to date in patients with cancer and COVID-19. We describe the rates of mortality in patients with cancer and COVID-19 with a special focus on the lung cancer population. We also summarize the factors associated with poor outcomes and mortality in patients with lung cancer and COVID-19

Enhanced Susceptibility of Ogg1 Mutant Mice to Multiorgan Carcinogenesis

The role of deficiency of oxoguanine glycosylase 1 (Ogg1) Mmh homolog, a repair enzyme of the 8-hydroxy-2’-deoxyguanosine (8-OHdG) residue in DNA, was investigated using the multiorgan carcinogenesis bioassay in mice. A total of 80 male and female six-week-old mice of C57BL/6J background carrying a mutant Mmh allele of the Mmh/Ogg1 gene (Ogg1−/−) and wild type (Ogg1+/+) mice were administered N-diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), N-bis (2-hydroxypropyl) nitrosamine (DHPN) and 1,2-dimethylhydrazine dihydrochloride (DMH) (DMBDD) to induce carcinogenesis in multiple organs, and observed up to 34 weeks. Significant increase of lung adenocarcinomas incidence was observed in DMBDD-treated Ogg1−/− male mice, but not in DMBDD-administered Ogg1+/+ animals. Furthermore, incidences of lung adenomas were significantly elevated in both Ogg1−/− males and females as compared with respective Ogg1−/− control and DMBDD-treated Ogg1+/+ groups. Incidence of total liver tumors (hepatocellular adenomas, hemangiomas and hemangiosarcomas) was significantly higher in the DMBDD-administered Ogg1−/− males and females. In addition, in DMBDD-treated male Ogg1−/− mice, incidences of colon adenomas and total colon tumors showed a trend and a significant increase, respectively, along with significant rise in incidence of simple hyperplasia of the urinary bladder, and a trend to increase for renal tubules hyperplasia in the kidney. Furthermore, incidence of squamous cell hyperplasia in the forestomach of DMBDD-treated Ogg1−/− male mice was significantly higher than that of Ogg1+/+ males. Incidence of small intestine adenomas in DMBDD Ogg1−/− groups showed a trend for increase, as compared to the wild type mice. The current results demonstrated increased susceptibility of Ogg1 mutant mice to the multiorgan carcinogenesis induced by DMBDD. The present bioassay could become a useful tool to examine the influence of various targets on mouse carcinogenesis

mTOR Activation in Liver Tumors Is Associated with Metabolic Syndrome and Non-Alcoholic Steatohepatitis in Both Mouse Models and Humans

Non-alcoholic steatohepatitis (NASH) can cause liver fibrosis and cirrhosis, with final progression to hepatocellular carcinoma (HCC) in some cases. Various factors have been suggested to be involved in the development of NASH. Considering the many possible contributing factors, we postulated that mechanisms of progression from NASH to HCC could differ depending on the risk factors. In the present study, we applied two mouse models of NASH–HCC and performed histopathological and proteome analyses of mouse liver tumors. Furthermore, to compare the mechanisms of NASH–HCC progression in mice and humans, we investigated HCCs in humans with a background of metabolic syndrome and NASH, as well as HCCs associated with hepatitis virus infection by immunohistochemistry. It was demonstrated that upstream regulators associated with the mammalian target of rapamycin (mTOR) pathway were altered in liver tumors of mice with metabolic syndrome characteristics (TSOD mice) using proteome analysis. Immunohistochemical analysis showed that mTOR was characteristically phosphorylated in liver tumors of TSOD mice and HCCs from metabolic syndrome cases in humans. These results indicated that the mTOR pathway is characteristically activated in liver tumors with metabolic syndrome and NASH, unlike liver tumors with other etiologies