Rosmarinic Acid Inhibits Ultraviolet B-Mediated Oxidative Damage via the AKT/ERK-NRF2-GSH Pathway In Vitro and In Vivo.

Rosmarinic acid (RA) is a phenolic ester that protects human keratinocytes against oxidative damage induced by ultraviolet B (UVB) exposure, however, the mechanisms underlying its effects remain unclear. This study aimed to elucidate the cell signaling mechanisms that regulate the antioxidant activity of RA and confirm its cyto-protective role. To explore the signaling mechanisms, we used the human keratinocyte cell line HaCaT and SKH1 hairless mouse skin. RA enhanced glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS) expression in HaCaT cells in a dose- and time-dependent manner. Moreover, RA induced nuclear factor erythroid-2-related factor 2 (NRF2) nuclear translocation and activated the signaling kinases protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, the ERK inhibitor U0126, and small interfering RNA (siRNA) gene silencing suppressed RA-enhanced GCLC, GSS, and NRF2 expression, respectively. Cell viability tests showed that RA significantly prevented UVB-induced cell viability decrease, whereas the glutathione (GSH) inhibitors buthionine sulfoximine, LY294002, and U0126 significantly reduced this effect. Moreover, RA protected against DNA damage and protein carbonylation, lipid peroxidation, and apoptosis caused by UVB-induced oxidative stress in a concentration-dependent manner in SKH1 hairless mouse skin tissues. These results suggest that RA protects against UVB-induced oxidative damage by activating AKT and ERK signaling to regulate NRF2 signaling and enhance GSH biosynthesis. Thus, RA treatment may be a promising approach to protect the skin from UVB-induced oxidative damage.

Emergence of NDM-1-producing Pseudomonas aeruginosa Sequence Type 773 Clone: Shift of Carbapenemase Molecular Epidemiology and Spread of 16S rRNA Methylase Genes in Korea.

Imipenemase (IMP)-6-producing Pseudomonas aeruginosa sequence type (ST) 235 is a dominant clone of carbapenemase-producing P. aeruginosa (CPPAE) in Korea. As part of the Antimicrobial Resistance Surveillance System in Korea, we found an increase in the carbapenem resistance rate of P. aeruginosa isolates from blood cultures and a shift in the molecular epidemiology of CPPAE. A total of 212 non-duplicated P. aeruginosa blood isolates were obtained from nine general hospitals and two nursing homes. Twenty-four isolates were identified as CPPAE. We observed the emergence of the NDM-1 P. aeruginosa ST 773 clone (N=10), mostly from Gyeongsang Province. The IMP-6 ST 235 clone (N=11) was detected in all provinces. CPPAE isolates showed very high resistance rates to amikacin, and all NDM-1 P. aeruginosa strains carried rmtB. This is the first nationwide surveillance of the recently emerged NDM-1-producing P. aeruginosa ST773 clone in Korea. Continuous surveillance is necessary to prevent the infection and transmission of carbapenem- and amikacin-resistant P. aeruginosa in Korea.

Characteristics of Escherichia coli Urine Isolates and Risk Factors for Secondary Bloodstream Infections in Patients with Urinary Tract Infections.

Escherichia coli is responsible for more than 80% of all incidences of urinary tract infections (UTIs). We assessed a total of 636 cases of patients with E. coli UTIs occurring in June 2019 in eight tertiary hospitals in South Korea for the traits of patients with E. coli UTIs, UTI-causative E. coli isolates, and risk factors associated with bloodstream infections (BSIs) secondary to UTIs. Antimicrobial susceptibility testing was conducted using the disc diffusion method, and the genes for extended-spectrum beta-lactamases (ESBLs) and plasmid-mediated ampC genes were screened by using PCR and sequencing. Multilocus sequence typing and virulence pheno-/genotyping were carried out. A total of 49 cases developed BSIs. The E. coli urine isolates primarily comprised sequence type 131 (ST131) (30.0%), followed by ST1193, ST95, ST73, and ST69. Three-quarters of the ST131 H30Rx isolates possessed the blaCTX-M-15-like gene, whereas 66% of H30R and 50% of H41 isolates possessed the blaCTX-M-14-like gene. All the ST1193 isolates showed biofilm formation ability, and three-quarters of the ST73 isolates exhibited hemolytic activity with high proportions of papC, focG, and cnf1 positivity. The prevalence of the ST131 H41 sublineage and its abundant CTX-M possession among the E. coli urine isolates were noteworthy; however, no specific STs were associated with bloodstream invasion. For BSIs secondary to UTIs, the papC gene was likely identified as a UTI-causative E. coli-related risk factor and urogenital cancer (odds ratio [OR], 12.328), indwelling catheter (OR, 3.218), and costovertebral angle tenderness (OR, 2.779) were patient-related risk factors. IMPORTANCE Approximately half of the BSIs caused by E. coli are secondary to E. coli UTIs. Since the uropathogenic E. coli causing most of the UTIs is genetically diverse, understanding the risk factors in the E. coli urine isolates causing the BSI is important for pathophysiology. Although the UTIs are some of the most common bacterial infectious diseases, and the BSIs secondary to the UTIs are commonly caused by E. coli, the assessments to find the risk factors are mostly focused on the condition of patients, not on the bacterial pathogens. Molecular epidemiology of the UTI-causative E. coli pathogens, together with the characterization of the E. coli urine isolates associated with the BSI secondary to UTI, was carried out, suggesting treatment options for the prevalent antimicrobial-resistant organisms.

Pathogenic NOTCH3 Variants Are Frequent Among the Korean General Population.

OBJECTIVE: This study aimed to determine the frequency of pathogenic NOTCH3 variants among Koreans. METHODS: In this cross-sectional study, we queried for pathogenic NOTCH3 variants in 2 Korean public genome databases: the Korean Reference Genome Database (KRGDB) and the Korean Genome Project (Korea1K). In addition, we screened the 3 most common pathogenic NOTCH3 variants (p.Arg75Pro, p.Arg544Cys, and p.Arg578Cys) for 1,000 individuals on Jeju Island, where the largest number of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been reported in Korea. RESULTS: The pathogenic NOTCH3 variant (p.Arg544Cys) was found in 0.12% of sequences in the KRGDB, and 3 pathogenic variants (p.Arg75Pro, p.Arg182Cys, and p.Arg544Cys) were present in 0.44% of the Korea1K database. Of the 1,000 individuals on Jeju Island, we found 2 cysteine-altering NOTCH3 variants (p.Arg544Cys variant in 9 and p.Arg578Cys in 1 individual) in 1.00% of the participants (95% confidence interval: 0.48%-1.83%). The presence of cysteine-altering NOTCH3 variants was significantly associated with a history of stroke (p < 0.001). DISCUSSION: Pathogenic NOTCH3 variants are frequently found in the general Korean population. Such a high prevalence of pathogenic variants could threaten the brain health of tens of thousands to hundreds of thousands of older adults in Korea.

The first case of abdominal mycotic aneurysm caused by K1 hypervirulent Klebsiella pneumoniae in a healthy adult.

Incidence of hypervirulent Klebsiella pneumoniae (hvKp) infection has been steadily increasing in the Asia-Pacific rim. The characteristic of hvKp infection is its ability to cause multiple site infections and unpredictable metastatic spread in the community. We describe the first case of mycotic aneurysm caused by hvKp serotype K1 in a previously healthy man and review the literature. Of a total of 13 cases, including our case, three cases were related to hvKp. Among patients with hvKp, the level of mycotic aneurysm in most patients was the infrarenal aorta, and they underwent an aortic graft or coil embolization. All strains were susceptible to most antimicrobial agents, except ampicillin. Early detection of hvKp can help to prevent the metastatic spread of pathogens and be useful for optimal patient care and epidemiologic research.

L-Ascorbic Acid Inhibits Breast Cancer Growth by Inducing IRE/JNK/CHOP-Related Endoplasmic Reticulum Stress-Mediated p62/SQSTM1 Accumulation in the Nucleus.

Anticancer effects of L-ascorbic acid (Vitamin C, L-AA) have been reported in various types of cancers. L-AA intake reduces breast cancer recurrence and mortality; however, the role of L-AA in the treatment of breast cancer remains poorly understood. In this study, we investigated the effect and mechanism action of L-AA on breast cancer growth. L-AA inhibited the growth of breast cancer cells by inducing apoptotic cell death at the evaluated treatment concentrations without affecting normal cells. Moreover, L-AA induces autophagosome formation via regulation of mammalian target of rapamycin (mTOR), Beclin1, and autophagy-related genes (ATGs) and increased autophagic flux. Notably, we observed that L-AA increased p62/SQSTM1 (sequestosome 1) protein levels. Accumulation of p62 protein in cancer cells in response to stress has been reported, but its role in cancer regulation remains controversial. Here, we demonstrated that L-AA-induced p62 accumulation is related to L-AA-induced breast cancer growth inhibition. Furthermore, L-AA induced endoplasmic reticulum (ER) stress via the IRE-JNK-CHOP (inositol-requiring endonuclease-c-Jun N-terminal kinase-C/EBP homologous protein) signaling pathways, which increased the nuclear levels of p62/SQSTM1. These findings provide evidence that L-AA-induced ER stress could be crucial for p62 accumulation-dependent cell death, and L-AA can be useful in breast cancer treatment.

Over-activation of AKT signaling leading to 5-Fluorouracil resistance in SNU-C5/5-FU cells.

Here, we investigated whether over-activation of AKT pathway is important in the resistance to 5-fluorouracil (5-FU) in SNU-C5/5-FU cells, 5-FU-resistant human colon cancer cells. When compared to wild type SNU-C5 cells (WT), SNU-C5/5-FU cells showed over-activation of PI3K/AKT pathway, like increased phosphorylation of AKT, mTOR, and GSK-3ß, nuclear localization of ß-catenin, and decreased E-cadherin. Moreover, E-cadherin level was down-regulated in recurrent colon cancer tissues compared to primary colon cancer tissues. Gene silencing of AKT1 or treatment of LY294002 (PI3 kinase inhibitor) increased E-cadherin, whereas decreased phospho-GSK-3ß. LY294002 also reduced protein level of ß-catenin with no influence on mRNA level. PTEN level was higher in SNU-C5/WT than SNU-C5/5-FU cells, whereas the loss of PETN in SNU-C5/WT cells induced characteristics of SNU-C5/5-FU cells. In SNU-C5/5-FU cells, NF-κB signaling was activated, along with the overexpression of COX-2 and stabilization of survivin. However, increased COX-2 contributed to the stabilization of survivin, which directly interacts with cytoplasmic procaspase-3, while the inhibition of AKT reduced this cascade. We finally confirmed that combination treatment with 5-FU and LY294002 or Vioxx could induce apoptosis in SNU-C5/5-FU cells. These data suggest that inhibition of AKT activation may overcome 5-FU-resistance in SNU-C5/5-FU cells. These findings provide evidence that over-activation of AKT is crucial for the acquisition of resistance to anticancer drugs and AKT pathway could be a therapeutic target for cancer treatment.

Associations of MicroRNA Polymorphisms (miR-146a, miR-196a2, and miR-499) with the Risk of Hypertension in the Korean Population.

AIMS: Polymorphisms in microRNA (miR) genes are thought to be associated with various cancers and vascular diseases. To date, however, the effects of the miR gene polymorphisms on susceptibility to hypertension have rarely been investigated. In this study, we investigated the associations of three miR gene polymorphisms (miR-146aC>G/rs2910164, miR-196a2T>C/rs11614913, and miR-499A>G/rs3746444) with the risk of hypertension in Korean patients. METHODS: A total of 855 study subjects (340 patients with hypertension and 515 healthy normotensive subjects) were included in this study. Genotyping of the three miR gene polymorphisms was accomplished by polymerase chain reaction-restriction fragment length polymorphism analyses. RESULTS: Significant differences were observed in the genotype distributions of the miR-146aC>G polymorphism between the hypertensive patients and controls with the GG genotype, in both model-independent analyses, as well as in dominant (CC vs. CG+GG) and recessive (CC+CG vs. GG) models, being highly significantly associated with disease (AOR = 2.293, 95% CI: 1.466-3.586, p = 0.001; AOR = 1.727, 95% CI: 1.182-2.522, p = 0.015; AOR = 1.782, 95% CI: 1.267-2.506, p = 0.001, respectively). Neither the miR-196a2T>C nor the miR-499A>G polymorphisms were distributed significantly differently between hypertensive patients and control subjects. Several allelic combinations of the three miR polymorphisms were also associated with susceptibility to hypertension. Stratified analysis revealed that the miR-146aC>G and miR-499A>G polymorphisms are associated with a greater risk of hypertension. CONCLUSION: This study suggests that the variant of miR-146aC>G polymorphism and allelic combinations, at least in Koreans, affect susceptibility to hypertension.

An Assay of Measuring Platelet Reactivity Using Monoclonal Antibody against Activated Platelet Glycoprotein IIb/IIIa in Patients Taking Clopidogrel.

BACKGROUND AND OBJECTIVES: Residual platelet reactivity in patients who are taking clopidogrel is commonly measured with VerifyNow assay, which is based on the principle of light transmission aggregometry. However, to evaluate the residual platelet reactivity, it would be more accurate if the reactivity of platelet glycoprotein (GP) IIb/IIIa is directly monitored. In this study, PAC1, a monoclonal antibody against activated platelet GP IIb/IIIa, was used to measure the residual platelet reactivity. SUBJECTS AND METHODS: Twenty seven patients with coronary artery disease taking clopidogrel were enrolled. Platelets in whole blood were stained with fluorescein isothiocyanate (FITC)-conjugated PAC1. Mean fluorescence intensity (MFI) and % positive platelets (PP) were measured with flow cytometry, and the binding index (BI; MFI × %PP/100) was calculated. P2Y12 reaction unit (PRU) and % inhibition of VerifyNow assay were also measured in the usual manner. RESULTS: PRU of VerifyNow assay correlated significantly with MFI, %PP, and BI at 10 µM (r=0.59, 0.73, and 0.60, respectively, all p<0.005) and 20 µM of adenosine diphosphate (ADP; r=0.61, 0.75, and 0.63, respectively, all p<0.005). The % inhibition also correlated significantly with MFI, %PP, and BI at 10 µM (r=-0.60, -0.69, and -0.59, respectively, all p<0.005) and 20 µM of ADP (r=-0.63, -0.71, and -0.62, respectively, all p<0.005). CONCLUSION: Direct measurements of the reactivity of platelet GP IIb/IIIa were feasible using PAC1 and flow cytometry in patients taking clopidogrel. Further clinical studies are required to determine the cut-off values which would define high residual platelet reactivity in patients on this treatment protocol.

The Protective Effects of the VEGF -2578C>A and -1154G>A Polymorphisms Against Hypertension Susceptibility.

AIMS: It has been reported that plasma vascular endothelial growth factor (VEGF) levels are elevated in hypertensive patients. The aim of this study was to investigate the association of -2578C>A and -1154G>A polymorphisms in the VEGF gene with susceptibility to hypertension. METHODS: A total of 640 subjects (320 hypertensive patients and 320 healthy normotensive subjects) were enrolled in the study. Genotyping of the -2578C>A and -1154G>A polymorphisms was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: The CA and AA genotypes and dominant and recessive models of the -2578C>A polymorphism were protective against MetS susceptibility (p<0.0001, p=0.001, p<0.0001, and p=0.015, respectively). The GA genotype and dominant model (GG vs. GA+AA) of the -1154G >A polymorphism were found less frequently in patients with hypertension compared to the controls (p=0.0001, p<0.0001, respectively). Haplotypes of the -2578C>A and -1154G>A polymorphisms were also different between the patients and controls. CONCLUSIONS: The A allele of the -2578C>A polymorphism and haplotypes of the -2578C>A and -1154G>A polymorphisms in the promoter region of the VEGF gene might be protective against the development of hypertension in Koreans. Further studies examining these associations in other populations are warranted.

Three cases of postoperative septic arthritis caused by Mycobacterium conceptionense in the shoulder joints of immunocompetent patients.

Mycobacterium conceptionense is a species member of Mycobacterium fortuitum complex, a potential pathogen of increasing clinical importance among opportunistic infections. This species causes a wide spectrum of cutaneous and extracutaneous diseases. In this report, we describe three patients who underwent shoulder surgery with postoperative joint infection by M. conceptionense.

Skin and Soft Tissue Infection due to Rapidly Growing Mycobacteria: Case Series and Literature Review.

BACKGROUND: Nontuberculous mycobacteria (NTM) are ubiquitous in soil and water. Most NTM cause disease in humans only rarely unless some aspect of host defense is impaired. Recently, rapidly growing mycobacteria (RGM) is not uncommon, and the prevalence of RGM infection has been increasing. RGM causes a wide spectrum of pulmonary and extrapulmonary diseases and has been shown as an important source for opportunistic infection. MATERIALS AND METHODS: We report 5 patients of skin and soft tissue infection due to RGM in tertiary medical center in Jeju Island and analyzed 21 patients of skin and soft tissue infection due to RGM in Republic of Korea. Clinical, microbiological and epidemiological data were collected from each patient. NTM isolates were identified using conventional and molecular methods including 16S rDNA gene sequencing. RESULTS: The mean age of the RGM patients (n=26) was 54.9 ± 15.9 years and 73% were women. Mycobacterium fortuitum complex was the most common (12/26). Antimicrobial resistance for clarithromycin and quinolone were 12% and 60%, respectively. Clarithromycin based therapy was done in 46%. The mean duration of treatment was 21.2 ± 8.7 weeks. CONCLUSIONS: Many cases can be cured after therapy for 4-7 month with at least 2 or 3 antibiotics according to in vitro susceptibility. Recent increasing of NTM cases suggests that species and subspecies identification is epidemiologically important, especially related to medical procedure, and surgery.

CD26/DPP4 levels in peripheral blood and T cells in patients with type 2 diabetes mellitus.

CONTEXT: Dipeptidyl peptidase 4 (CD26/DPP4) is expressed on blood T cells and also circulates in a soluble form (sCD26/DPP4). OBJECTIVE: We aimed to evaluate blood T cell and circulating CD26/DPP4 and its association with metabolic parameters in patients with type 2 diabetes mellitus (T2DM). DESIGNS: We measured CD26/DPP4 expression (percentage of CD26(+) cells using flow cytometry) on CD4(+) and CD8(+) T cells, serum CD26/DPP4 level and activity, and various metabolic parameters in T2DM patients not on DPP4 inhibitor therapy (n = 148). Nondiabetic subjects (n = 50) were included as a control group. RESULTS: Compared with the healthy controls, CD26/DPP4 expression on CD4(+) T cells and CD8(+) T cells was higher in T2DM patients. Serum CD26/DPP4 levels and enzymatic activities were also higher in patients with T2DM than in the control group only when metformin and/or thiazolidinedione-treated T2DM patients were excluded; metformin and/or thiazolidinedione-treated T2DM patients had lower values compared with other T2DM patients. Various parameters in T2DM patients were related to CD26/DPP4 expression on the T cells (hemoglobin A1c), serum sCD26/DPP4 (hemoglobin A1c and insulin resistance assessed by updated homeostasis model assessment), and serum CD26/DPP4 activity (insulin resistance assessed by updated homeostasis model assessment, γ-glutamyl transferase, and alanine aminotransferase) by multivariate analyses. After active glucose control for 12 weeks in drug-naive T2DM patients (n = 50), CD26/DPP4 expression on blood T cells was significantly decreased. CONCLUSIONS: Our results suggest that the CD26/DPP4 level on blood T cells was associated with glucose control status in patients with T2DM.

(1S,2S,3E,7E,11E)-3,7,11,15-Cembratetraen-17,2-olide, a cembrenolide diterpene from soft coral Lobophytum sp., inhibits growth and induces apoptosis in human colon cancer cells through reactive oxygen species generation.

We observed that (1S,2S,3E,7E,11E)-3,7,11,15-Cembratetraen-17,2-olide (LS-1), marine cembrenolide diterpene, inhibited growth and induced apoptosis in colon cancer cells via a reactive oxygen species (ROS) dependent mechanism. Treatment of HT-29 cells with LS-1 resulted in ROS generation, which was accompanied by disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, sub-G1 peak accumulation, activation of Bid, caspase-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase (PARP) along with the suppressive expression of B cell lymphoma-2 (Bcl-2). All these effects were significantly blocked on pretreatment with the ROS inhibitor N-acetylcysteine (NAC), indicating the involvement of increased ROS in the proapoptotic activity of LS-1. Moreover, we showed that LS-1 induced the phosphorylation of c-Jun N-terminal kinase (JNK) and dephosphorylation of p38, extracellular signal-regulated kinase (ERK), Akt, Src and signal transducer and activator of transcription (STAT)3, which were effectively attenuated by NAC. In addition, the expressions of antioxidant catalase and glutathione peroxidase were abrogated by treatment using LS-1 with or without NAC. These findings reveal the novel anticancer efficacy of LS-1 mediated by the induction of apoptosis via ROS generation in human colon cancer cells.

Inhibitory effects of Carpinus tschonoskii leaves extract on CpG-stimulated pro-inflammatory cytokine production in murine bone marrow-derived macrophages and dendritic cells.

This report describes the anti-inflammatory effects of MeOH extract from leaves of Carpinus tschonoskii (CE) on primary bone marrow-derived macrophage (BMDMs) and dendritic cells (BMDCs). Primary BMDMs and BMDCs were used for pro-inflammatory cytokine production and Western blot analysis. Human embryonic kidney cell line 293 T (HEK293 T) was used to access NF-κB activity. In all cases, CpG DNA was used to stimulate the cells. The CE (0-150 µg/ml) was treated to BMDMs, BMDCs, and HEK293T cells. CE pre-treatment in CpG-stimulated BMDMs and BMDCs showed a dose-dependent inhibitory effect on pro-inflammatory cytokine (e.g., IL-12 p40, IL-6, and TNF-α) production as compared to non-treated controls. The CE pre-treatment had no significant inhibition on mitogen-activated protein kinases (MAPKs) phosphorylation but strongly inhibited IκBα degradation. In NF-κB reporter gene assay, the CE pre-treatment inhibited NF-κB-dependent luciferase activity in a dose-dependent manner. Taken together, these data suggest that CE has significant inhibitory effect on pro-inflammatory cytokine production and warrant further studies concerning potentials of CE for medicinal uses.

Involvement of heme oxygenase-1 in Korean colon cancer.

Heme oxygenase-1 (HO-1) catabolizes heme into carbon monoxide, biliverdin, and free iron which mediate its protective effect against oxidative stress. The aim of the present study was to determine the expression level and activity of HO-1 in Korean colon cancer tissues and cell lines. HO-1 protein expression was higher (>1.5-fold) in tumor tissues than in adjacent normal tissues in 14 of 20 colon cancer patients, and HO-1 protein expression was closely correlated with HO-1 enzyme activity in cancer tissues. Immunohistochemical data confirmed that HO-1 protein was expressed at a higher level in colon cancer tissues than in normal mucosa. Furthermore, HO-1 mRNA and protein expression and enzyme activity were higher in the colon cancer cell lines Caco-2, SNU-407, SNU-1033, HT-29, and SW-403 than in the normal fetal human colon cell line FHC. Treatment with the HO-1 inhibitor zinc protoporphyrin decreased the viability of colon cancer cell lines. These data indicate that HO-1 may serve as a clinically useful biomarker of colon cancer and as a target for anticolon cancer drugs.

Capsaicin sensitizes TRAIL-induced apoptosis through Sp1-mediated DR5 up-regulation: involvement of Ca(2+) influx.

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various malignant cells, several cancers including human hepatocellular carcinoma (HCC) exhibit potent resistance to TRAIL-induced cell death. The aim of this study is to evaluate the anti-cancer potential of capsaicin in TRAIL-induced cancer cell death. As indicated by assays that measure phosphatidylserine exposure, mitochondrial activity and activation of caspases, capsaicin potentiated TRAIL-resistant cells to lead to cell death. In addition, we found that capsaicin induces the cell surface expression of TRAIL receptor DR5, but not DR4 through the activation Sp1 on its promoter region. Furthermore, we investigated that capsaicin-induced DR5 expression and apoptosis are inhibited by calcium chelator or inhibitors for calmodulin-dependent protein kinase. Taken together, our data suggest that capsaicin sensitizes TRAIL-mediated HCC cell apoptosis by DR5 up-regulation via calcium influx-dependent Sp1 activation.

Identification of 13q deletion, trisomy 1q, and IgH rearrangement as the most frequent chromosomal changes found in Korean patients with multiple myeloma.

The most frequent genetic aberrations in multiple myeloma (MM) are 13q deletions and translocations involving the immunoglobulin heavy chain gene (IGH). There have been no reports on the cytogenetic abnormalities found in Korean patients with MM. We investigated the actual prevalence and prognostic value of cytogenetic changes using fluorescence in situ hybridization (FISH). FISH studies with 12 different specific probes for the regions containing the genes or chromosome regions (13q, 1q, IGH, p53, MLL, p16, CEP 7, CEP 11, and CEP 12) were performed in 128 patients. The most frequent change found was 13q deletion (48%), followed by trisomy 1q (45%), IGH translocation (37%), and trisomy 11 (26%). Among the three different probes used to detect 13q deletion, D13S25 (48/58) was the most sensitive probe compared to RB (43/58) and D13S319 (39/58). Among the patients showing one or more changes by FISH, 75% (82/110) had a 13q deletion, a trisomy 1q, or an IGH translocation. Azotemia, anemia, thrombocytopenia, intramedullary plasmacytosis, and stage were significantly associated with the 13q deletion; serum beta(2)-microglobulin, thrombocytopenia, and intramedullary plasmacytosis were also related to trisomy 1q. The pattern of molecular cytogenetic changes in Korean patients with MM is somewhat different from what has been observed in reported Caucasian populations: 37 versus 50-70% with regard to the IGH translocation. The prevalence of the 13q deletion was similar in Korean and Caucasian populations, 48 versus 30-50%. We suggest that the detection of at least these three genetic changes, 13q- trisomy 1q, and an IGH rearrangement, would be helpful for follow-up of Korean patients with MM.

Deletion of any part of the BCR or ABL gene on the derivative chromosome 9 is a poor prognostic marker in chronic myelogenous leukemia.

To evaluate the prognostic significance of submicroscopic deletions of the ABL or BCR gene associated with t(9;22) in chronic myelogenous leukemia (CML), we investigated the incidence of an ABL or BCR deletion on derivative chromosome 9 using fluorescence in situ hybridization (FISH). FISH was performed using the LSI BCR/ABL dual-fusion translocation probe on bone marrow cells of 86 patients with CML. Of 86 patients, ABL deletion was detected in 13 (15.1%) patients and BCR deletion in 8 patients (9.3%). Patients with ABL deletion showed shorter event-free survival time (EFS) than those without ABL deletion (P = 0.020). Patients with BCR deletion showed significantly short overall survival time (OS; P = 0.039). Patients with ABL and/or BCR deletion (14/86 patients, 16.3%) showed significantly short OS and EFS (median OS, 43.0 months; median EFS, 40.0 months), compared to the patients without any BCR or ABL gene deletions (median OS, 94.0 months; median EFS, 90.0 months; P = 0.041 for OS, P = 0.008 for EFS). All the patients with BCR deletion, except for one, had a concomitant ABL deletion, suggesting that BCR deletion occurs in conjunction with ABL deletion. In patients with ABL deletion only, BCR/ABL rearrangement with b2a2 mRNA type tended to be more frequent than in patients without any deletion of the two genes (P = 0.073). Deletion of any of the BCR or ABL genes on derivative chromosome 9 was associated with both short OS and EFS. We conclude that deletion of not only the ABL gene, but also of the BCR gene, is a poor prognostic marker that indicates rapid disease progression in CML.

Korean patients with chronic lymphocytic leukemia show the similar types of chromosomal aberrations as those in Europe and North America.

Chronic lymphocytic leukemia (CLL) is frequent in the West, but rare in Korea. In this study, the frequency of chromosome aberration in Korean CLL patients was examined by applying interphase fluorescence in situ hybridization (FISH). Conventional cytogenetic test and FISH were performed on bone marrow aspirates obtained from 16 CLL patients. By applying DNA probes (Vysis, Downers Grove, IL, USA), the deletion in 11q22-23, 13q14, 13q34, and 17p13, and trisomy 12 were examined. With FISH, molecular cytogenetic aberration was detected in 10 of 16 patients [63%, 95% confidence interval (CI) 39-86], whereas with conventional cytogenetic test, chromosomal aberration was detected only in 2 out of 13 cases (15%, 95% CI 0-35). In total, the cases with one or more chromosomal aberrations were 11 out of 16 cases (69%, 95% CI 46-92). The most frequently detected aberration was the 13q14 deletion (69%, 95% CI 44-94), followed by trisomy 12 (19%, 95% CI 0-38) and 11q22 deletion (14%, 95% CI 0-33). No deletion in 17p13 was observed. In conclusion, CLL in Korean is a heterogeneous genetic disorder, showing similar genetic changes in Europe and North America.