Correlation-based and feature-driven mutation signature analyses to identify genetic features associated with DNA mutagenic processes in cancer genomes

Mutation signatures represent unique sequence footprints of somatic mutations resulting from specific DNA mutagenic and repair processes. However, their causal associations and the potential utility for genome research remain largely unknown. In this study, we performed PanCancer-scale correlative analyses to identify the genomic features associated with tumor mutation burdens (TMB) and individual mutation signatures. We observed that TMB was correlated with tumor purity, ploidy, and the level of aneuploidy, as well as with the expression of cell proliferation-related genes representing genomic covariates in evaluating TMB. Correlative analyses of mutation signature levels with genes belonging to specific DNA damage-repair processes revealed that deficiencies of NHEJ1 and ALKBH3 may contribute to mutations in the settings of APOBEC cytidine deaminase activation and DNA mismatch repair deficiency, respectively. We further employed a strategy to identify feature-driven, de novo mutation signatures and demonstrated that mutation signatures can be reconstructed using known causal features. Using the strategy, we further identified tumor hypoxia-related mutation signatures similar to the APOBEC-related mutation signatures, suggesting that APOBEC activity mediates hypoxia-related mutational consequences in cancer genomes. Our study advances the mechanistic insights into the TMB and signature-based DNA mutagenic and repair processes in cancer genomes. We also propose that feature-driven mutation signature analysis can further extend the categories of cancer-relevant mutation signatures and their causal relationships.

Monitoring Insecticide Resistance and Target Site Mutations of L1014 Kdr And G119 Ace Alleles in Five Mosquito Populations in Korea

Mosquitoes are globally distributed and important vectors for the transmission of many human diseases. Mosquito control is a difficult task and the cost of preventing mosquito-borne diseases is much lower than that for curing the associated diseases. Thus, chemical control remains the most effective tool for mosquito. Due to the long-term intensive use of insecticides to control mosquito vectors, resistance to most chemical insecticides has been reported. This study aimed to investigate the relationship between insecticide resistance and target site mutation of L1014 kdr and G119 ace alleles in 5 species/species group of mosquitoes (Aedes vexans, Ae. albopictus, Anopheles spp., Culex pipiens complex, and Cx. tritaeniorhynchus) obtained from 6 collection sites. For Anopheles spp., the proportion of mosquitoes with mutated alleles in L1014 was 88.4%, homozygous resistant genotypes were observed in 46.7%, and heterozygous resistant genotypes were observed in 41.8%. For the Cx. pipiens complex and Cx. tritaeniorhynchus species, homozygous resistant genotypes were found in 25.9% and 9.8%, respectively. However, target site mutation of L1014 in the Ae. vexans nipponii and Ae. albopictus species was not observed. Anopheles spp., Cx. pipiens complex, and Cx. tritaeniorhynchus mosquitoes were resistant to deltamethrin and chlorpyriphos, whereas Ae. vexans nipponii and Ae. albopictus were clearly susceptible. We also found a correlation between the resistance phenotype and the presence of the L1014 kdr and G119 ace mutations only in the Anopheles spp. population. In this study, we suggest that insecticide resistance poses a growing threat and resistance management must be integrated into all mosquito control programs.

Mushrooms: An Important Source of Natural Bioactive Compounds

Mushrooms are known for their various attributes in the fields of nutrition and therapeutics. With exceptional taste, aroma, and nutritional value, they are considered ‘functional food’-improving health and providing nutritional benefits to the body. Mushrooms have also been widely applied therapeutically as they possess diverse bioactive compounds known as secondary metabolites. These secondary metabolites demonstrated diverse biological properties such as anticancer, anti-diabetic, immunomodulatory, antimicrobial, anti-inflammatory, antiviral, anti-allergic, and antioxidative activities. This review presents bioactive compounds from the field of mushroom metabolite research and discusses important findings regarding bioactive compounds identified during the last five years (2015 – 2019).

A Pilot Project of Systematic Tuberculosis Screening in the Elderly in a South Korean Province / 결핵및호흡기질환

BACKGROUND@#Tuberculosis (TB) is a major infectious disease in South Korea causing substantial disease burden, particularly in the elderly. This study aimed to identify the case detection rate of mobile TB screening for the elderly conducted in the Jeollanam-do region and to analyze risk factors of active TB.@*METHODS@#We screened the elderly population (≥65 years old) in Jeollanam-do from August to December 2017. Chest radiography was performed for all participants. Participants with TB presumptive signs were asked to submit sputum specimen(s). Sputum smear, culture, and polymerase chain reaction analyses were performed. Cascade analysis, chi-squared tests, and Fisher exact tests were used to evaluate screening performance.@*RESULTS@#In total, 12,402 participants were screened, and 211 (1.7%) were suspected to have active TB; 181 of the suspected patients (85.8%) underwent sputum smear test, and 16 (8.8%) patients were confirmed to have TB. The TB prevalence among the elderly was bacteriologically confirmed to be 129 per 100,000 individuals, which was similar to national TB notification data for the same age groups. The proportion of active TB cases increased with age, and differed based on sex and past TB history. However, TB-related symptoms, comorbidity status, and TB screening history within 12 months were not predictive of active TB.@*CONCLUSION@#This study identified that the prevalence rate was similar to national TB notification data from the same age groups. Periodic, community-based, systematic TB screening among the elderly population is recommended.

A Pilot Project of Systematic Tuberculosis Screening in the Elderly in a South Korean Province / 결핵

BACKGROUND: Tuberculosis (TB) is a major infectious disease in South Korea causing substantial disease burden, particularly in the elderly. This study aimed to identify the case detection rate of mobile TB screening for the elderly conducted in the Jeollanam-do region and to analyze risk factors of active TB. METHODS: We screened the elderly population (≥65 years old) in Jeollanam-do from August to December 2017. Chest radiography was performed for all participants. Participants with TB presumptive signs were asked to submit sputum specimen(s). Sputum smear, culture, and polymerase chain reaction analyses were performed. Cascade analysis, chi-squared tests, and Fisher exact tests were used to evaluate screening performance. RESULTS: In total, 12,402 participants were screened, and 211 (1.7%) were suspected to have active TB; 181 of the suspected patients (85.8%) underwent sputum smear test, and 16 (8.8%) patients were confirmed to have TB. The TB prevalence among the elderly was bacteriologically confirmed to be 129 per 100,000 individuals, which was similar to national TB notification data for the same age groups. The proportion of active TB cases increased with age, and differed based on sex and past TB history. However, TB-related symptoms, comorbidity status, and TB screening history within 12 months were not predictive of active TB. CONCLUSION: This study identified that the prevalence rate was similar to national TB notification data from the same age groups. Periodic, community-based, systematic TB screening among the elderly population is recommended.

Effects of irradiation and leukoreduction on down-regulation of CXCL-8 and storage lesion in stored canine whole blood

White blood cells (WBCs) and storage period are the main factors of transfusion reactions. In the present study, cytokine/chemokine concentrations after leukoreduction (LR) and irradiation (IR) in stored canine whole blood were measured. Red blood cell storage lesion caused by IR and LR were also compared. Blood samples from 10 healthy Beagles were divided into four groups (no treatment, LR-, IR-, and LR + IR-treated). Leukocytes were removed by filtration in the LR group and gamma radiation (25 Gy) was applied in the IR group. Immunologic factors (WBCs, interleukin-6 [IL-6], C-X-C motif chemokine ligand 8 [CXCL-8], and tumor necrosis factor-alpha) and storage lesion factors (blood pH, potassium, and hemolysis) were evaluated on storage days 0, 7, 14, 21, and 28. Compared to the treated groups, IL-6 and CXCL-8 concentrations during storage were significantly higher in the control (no treatment) group. LR did not show changes in cytokine/chemokine concentrations, and storage lesion presence was relatively mild. IR significantly increased CXCL-8 after 14 days of storage, but IR of leukoreduced blood did not increase CXCL-8 during 28 days of storage. Storage lesions such as hemolysis, increased potassium, and low pH were observed 7 days after IR and storage of blood, regardless of LR. IR of leukoreduced blood is beneficial to avoid immune reactions; however, storage lesions should be considered upon storage.

L1 Recombinant Proteins of HPV Tested for Antibody Forming Using Sera of HPV Quadrivalent Vaccine

Virus-like particles (VLPs) derived from human papillomavirus (HPV) L1 capsid proteins were used for HPV quadrivalent recombinant vaccine. The HPV quadrivalent vaccine is administrated in a 3-dose regimen of initial injection followed by subsequent doses at 2 and 6 months to prevent cervical cancer, vulvar, and vaginal cancers. The type 6, 11, 16, or 18 of HPV infection is associated with precancerous lesions and genital warts in adolescents and young women. The HPV vaccine is composed of viral L1 capsid proteins are produced in eukaryotic expression systems and purified in the form of VLPs. Four different the L1 protein of 3 different subtypes of HPV: HPV11, HPV16, and HPV18 were expressed in Escherichia coli divided into 2 fragments as N- and C-terminal of each protein in order to examine the efficacy of HPV vaccine. Vaccinated sera failed to recognize N-terminal L1 HPV type 16 and type 18 by western blot while they detected N-terminal L1 protein of HPV type 11. Moreover, the recombinant C-terminal L1 proteins of type 16 was non-specifically recognized by the secondary antibody conjugated with horseradish peroxidase. This expression and purification system may provide simple method to obtain robust recombinant L1 protein of HPV subtypes to improve biochemical analysis of antigens with immunized sera.

IL-32-induced Inflammatory Cytokines Are Selectively Suppressed by α1-antitrypsin in Mouse Bone Marrow Cells

The induction of interleukin (IL)-32 in bone marrow (BM) inflammation is crucial in graft versus host disease (GvHD) that is a common side effect of allogeneic BM transplantation. Clinical trials on α-1 antitrypsin (AAT) in patients with GvHD are based on the preliminary human and mouse studies on AAT reducing the severity of GvHD. Proteinase 3 (PR3) is an IL-32-binding protein that was isolated from human urine. IL-32 primarily induces inflammatory cytokines in myeloid cells, probably due to PR3 expression on the membrane of the myeloid lineage cells. The inhibitory activity of AAT on serine proteinases may explain the anti-inflammatory effect of AAT on GvHD. However, the anti-inflammatory activity of AAT on BM cells remains unclear. Mouse BM cells were treated with IL-32γ and different inflammatory stimuli to investigate the anti-inflammatory activity of AAT. Recombinant AAT-Fc fusion protein inhibited IL-32γ-induced IL-6 expression in BM cells, but failed to suppress that induced by other stimuli. In addition, the binding of IL-32γ to PR3 was abrogated by AAT-Fc. The data suggest that the specific anti-inflammatory effect of AAT in mouse BM cells is due to the blocking of IL-32 binding to membrane PR3.

Diagnosis of Lymphoid Malignancy by PCR for Analysis of Antigen Receptor Rearrangement after Blood Transfusion in a Dog with Acute Lymphocytic Leukemia

Acute lymphocytic leukemia (ALL) is uncommon lymphoid malignancy in dogs, and its diagnosis is challenging. A 14-year-old spayed female mixed breed dog was transferred to a veterinary medical teaching hospital for an immediate blood transfusion. The dog showed lethargy, pale mucous membranes, and a weak femoral pulse. Complete blood count revealed non-regenerative anemia and severe leukopenia with thrombocytopenia. ALL was tentatively diagnosed based on the predominance of immature lymphoblasts on blood film examination. For confirmation of lymphoid malignancy, PCR for antigen receptor rearrangement (PARR) on a peripheral blood sample and flow cytometry analysis were performed after blood transfusion. Flow cytometry analysis revealed that lymphocyte subsets were of normal composition, but PARR detected a T-cell malignancy. The dog was diagnosed with ALL and survived 1 wk after diagnosis. In conclusion, after blood transfusion, flow cytometry was not a reliable diagnostic method for an ALL dog, whereas PARR could detect lymphoid malignancy. Our results suggest that PARR should be the first-line diagnostic tool to detect canine lymphoid malignancy after a blood transfusion.

Dendritic Cell Dysfunction in Patients with End-stage Renal Disease

End-stage renal disease (ESRD) with immune disorder involves complex interactions between the innate and adaptive immune responses. ESRD is associated with various alterations in immune function such as a reduction in polymorphonuclear leukocyte bactericidal activity, a suppression of lymphocyte proliferative response to stimuli, and a malfunction of cell-mediated immunity at the molecular level. ESRD also increases patients' propensity for infections and malignancies as well as causing a diminished response to vaccination. Several factors influence the immunodeficiency in patients with ESRD, including uremic toxins, malnutrition, chronic inflammation, and the therapeutic dialysis modality. The alteration of T-cell function in ESRD has been considered to be a major factor underlying the impaired adaptive cellular immunity in these patients. However, cumulative evidence has suggested that the immune defect in ESRD can be caused by an Ag-presenting dendritic cell (DC) dysfunction in addition to a T-cell defect. It has been reported that ESRD has a deleterious effect on DCs both in terms of their number and function, although the precise mechanism by which DC function becomes altered in these patients is unclear. In this review, we discuss the effects of ESRD on the number and function of DCs and propose a possible molecular mechanism for DC dysfunction. We also address therapeutic approaches to improve immune function by optimally activating DCs in patients with ESRD.

Cytokine-like Activity of Liver Type Fatty Acid Binding Protein (L-FABP) Inducing Inflammatory Cytokine Interleukin-6

It has been reported that fatty acid binding proteins (FABPs) do not act only as intracellular mediators of lipid responses but also have extracellular functions. This study aimed to investigate whether extracellular liver type (L)-FABP has a biological activity and to determined serum L-FABP levels in patients with end-stage renal disease (ESRD). We isolated L-FABP complementary deoxyribonucleic acid (cDNA) from the Huh7 human hepatocarcinoma cell line and expressed the recombinant L-FABP protein in Escherichia coli. A549 lung carcinoma and THP-1 monocytic cells were stimulated with the human recombinant L-FABP. Human whole blood cells were also treated with the human recombinant L-FABP or interleukin (IL)-1α. IL-6 levels were measured in cell culture supernatants using IL-6 enzyme-linked immunosorbent assay (ELISA). Human recombinant L-FABP induced IL-6 in a dose-dependent manner in A549, THP-1 cells, and whole blood cells. The blood samples of healthy volunteers and patients with ESRD were taken after an overnight fast. The serum levels of L-FABP in healthy volunteers and ESRD patients were quantified with L-FABP ELISA. The values of L-FABP in patients with ESRD were significantly lower than those in the control group. Our results demonstrated the biological activity of L-FABP in human cells suggesting L-FABP can be a mediator of inflammation.

A Case of True Renal Lupus Vasculitis Combined with Pauci-immune Glomerulonephritis in a Patient with Systemic Lupus Erythematosus

Renal lupus vasculitis is a rare vascular lesion complicated with systemic lupus erythematosus (SLE). We report an unusual case of true renal lupus vasculitis with antineutrophil cytoplasmic antibodies (ANCA)-negative pauci-immune glomerulonephritis in a patient with SLE. A 32-year-old woman presenting with hematuria and overt proteinuria was admitted to the hospital. She had been diagnosed with SLE at 16 years of age and treated with prednisolone, hydroxychloroquine, and methotraxate. A kidney biopsy revealed 42 glomeruli with ischemic wrinkling, and segmental loop necrosis with fibrin deposition. Prominent inflammatory cell infiltration of interlobular arteries and afferent arterioles with severe necrosis was demonstrated. No electron-dense and immune deposits in the glomeruli were observed by immunofluorescent and electron microscopy; in contrast, those in the renal vascular wall showed a full-house pattern. Antiphospholipid antibodies and ANCA were negative. The patient was treated with monthly intravenous cyclophosphamide pulses and high dose steroid, and showed good response on further follow-up.

Bowen Disease Arising from Unilateral Systematized Linear Porokeratosis / 대한피부과학회지

No abstract available.

Fibroadenoma Arising in the Accessory Breast Tissue of Axilla / 대한피부과학회지

No abstract available.