Gender difference in the impact of coexisting diabetes mellitus on long-term clinical outcome in people with heart failure: a report from the Korean Heart Failure Registry.

AIM: Few data are available on the gender-related differences in the prognostic impact of diabetes in people with heart failure. This study was performed to investigate whether there is a gender difference in the association between diabetes and long-term clinical outcomes in people hospitalized for heart failure. METHODS: A total of 3162 people hospitalized with heart failure (aged 67.4 ± 14.1 years, 50.4% females) from the data set of the nationwide registry were analysed. The primary endpoint was a composite of all-cause mortality and heart failure readmission. RESULTS: People with diabetes (30.5% for males vs. 31.1% for females, P = 0.740) were older and had more unfavourable risk factors and laboratory findings than those without diabetes in both genders. During a median follow-up period of 549 days, there were 1418 cases of composite events (44.8%). In univariable analysis, the coexistence of diabetes was significantly associated with a higher incidence of composite events in both genders (P < 0.05 each for males and females). In multivariable analysis, the prognostic impact of diabetes on the development of composite events remained significant in females even after controlling for potential confounders (hazard ratio 1.43, 95% confidence intervals 1.12-1.84; P = 0.004). However, an independent association between diabetes and composite events was not seen in males in the same multivariable analysis (P > 0.05). CONCLUSIONS: In people with heart failure, the impact of diabetes on long-term mortality and heart failure readmission seems to be stronger in females than in males. More careful and intensive management is needed especially in females with heart failure and diabetes.

Association between phthalates and externalizing behaviors and cortical thickness in children with attention deficit hyperactivity disorder.

BACKGROUND: Previous studies have implicated the relationship between environmental phthalate exposure and attention deficit hyperactivity disorder (ADHD) symptoms of childhood, but no studies have been conducted in children who have a confirmed diagnosis of ADHD obtained through meticulous diagnostic testing. We aimed to determine whether phthalate metabolites in urine would be higher in children with ADHD than in those without ADHD and would correlate with symptom severity and cortical thickness in ADHD children. METHOD: A cross-sectional examination of urine phthalate metabolite concentrations was performed; scores for ADHD symptoms, externalizing problems, and continuous performance tests were obtained from 180 children with ADHD, and brain-imaging data were obtained from 115 participants. For the control group, children without ADHD (N = 438) were recruited. Correlations between phthalate metabolite concentrations and clinical measures and brain cortical thickness were investigated. RESULTS: Concentrations of phthalate metabolites, particularly the di(2-ethylhexyl) phthalate (DEHP) metabolite, were significantly higher in boys with ADHD than in boys without ADHD. Concentrations of the di-n-butyl phthalate (DBP) metabolite were significantly higher in the combined or hyperactive-impulsive subtypes compared to the inattentive subtype, and the metabolite was positively correlated with the severity of externalizing symptoms. Concentrations of the DEHP metabolite were negatively correlated with cortical thickness in the right middle and superior temporal gyri. CONCLUSIONS: The results of this study suggest an association between phthalate concentrations and both the diagnosis and symptom severity of ADHD. Imaging findings suggest a negative impact of phthalates on regional cortical maturation in children with ADHD.

Peripheral artery questionnaire improves ankle brachial index screening in symptomatic patients with peripheral artery disease.

AIM: The peripheral artery questionnaire (PAQ) is a disease-specific health status measure of patients with peripheral artery disease (PAD). Whether the PAQ scores are associated with a PAD diagnosis among patients with symptoms suspicious for PAD is unknown and could help increase the pretest probability of ankle brachial index (ABI) screening among patients with suspicious symptoms. METHODS: The PAQ was completed by 567 patients evaluated for potential intermittent claudication at six tertiary centres. Demographics, medical history, physical examination findings and the PAQ domain scores were compared with ABI. A diagnostic threshold < 0.90 for a PAD diagnosis was assessed with a ROC of PAQ scores. The correlation between the PAQ Summary Score and ABI was also calculated. RESULTS: The PAQ Summary Score was significantly lower in patients with low ABI as compared with those having a normal ABI (37.6 ± 19.0 vs. 70.1 ± 22.7, p < 0.001). The PAQ Summary Score and ABI were highly correlated (r = 0.56, p < 0.001) and the optimal PAQ Summary Score for predicting low ABI was 50.3 (AUC = 0.86, sensitivity 80.3%, specificity 78.3%). CONCLUSIONS: The PAQ Summary Score was associated with an increased likelihood of PAD in patients with suspected PAD symptoms, and a low summary score (≤ 50.3) was an optimal threshold for predicting PAD among patients referred for ABI.

Association between urine cotinine levels, continuous performance test variables, and attention deficit hyperactivity disorder and learning disability symptoms in school-aged children.

BACKGROUND: We examined the cross-sectional relationship between environmental tobacco smoke exposure, continuous performance test (CPT) measures, and attention deficit hyperactivity disorder (ADHD) or learning disability symptoms in school-aged children. METHOD: In total, 989 children (526 boys, mean age 9.1 ± 0.7 years), recruited from five South Korean cities participated in this study. We used urine cotinine as a biomarker for environmental tobacco smoke exposure, and obtained the children's scores on a CPT. Parents completed the Korean versions of the ADHD rating scale-IV (ADHD-RS) and learning disability evaluation scale (LDES). Using generalized linear mixed model (GLMM), we assessed the associations between urine cotinine concentrations, neuropsychological variables, and symptoms of ADHD and learning disabilities. Additionally, we conducted structural equation models to explore the effects' pathways. RESULTS: After adjusting for a range of relevant covariates, GLMM showed urinary cotinine levels were significantly and positively associated with CPT scores on omission errors, commission errors, response time, and response time variability, and with parent- and teacher-rated ADHD-RS scores. In addition, urine cotinine levels were negatively associated with LDES scores on spelling and mathematical calculations. The structural equation model revealed that CPT variables mediated the association between urine cotinine levels and parental reports of symptoms of ADHD and learning disabilities. CONCLUSIONS: Our data indicate that environmental exposure to tobacco smoke is associated with ADHD and learning disabilities in children, and that impairments in attention and inhibitory control probably mediate the effect.

Enhanced carbohydrate craving in patients with poorly controlled Type 2 diabetes mellitus.

AIMS: Although hyperphagia is a common manifestation of diabetes mellitus, data on food craving in patients with diabetes are limited. This study compared food craving in patients with Type 2 diabetes mellitus and a control group without diabetes. METHODS: A total of 210 subjects (105 with Type 2 diabetes and 105 age-, sex- and BMI-matched control subjects) participated in two food craving surveys. The surveys were as follows: the General Food Cravings Questionnaire--Trait, which assesses the general trait of food craving; and the Food Cravings Questionnaire--State, which assesses the state of food craving or current desire for high-carbohydrate or high-fat foods in response to pictures of food. Follow-up Food Cravings Questionnaire--State surveys were administered approximately 3 months later to the subjects with diabetes. Survey results were analysed to assess relationships between food craving and glycaemic control. RESULTS: The General Food Cravings Questionnaire--Trait scores in the group with Type 2 diabetes and the control group were not significantly different. The group with Type 2 diabetes had higher carbohydrate craving scores, but lower fat craving scores, than the control group. Carbohydrate craving scores in subjects with diabetes were positively correlated with HbA(1c). In follow-up surveys, carbohydrate craving scores declined in patients with improved glycaemic control. CONCLUSIONS: The surveys showed that patients with Type 2 diabetes had higher carbohydrate cravings and lower fat cravings than the age-, sex- and BMI-matched control group. Carbohydrate craving in patients with diabetes was associated with poor glycaemic control.

Assessment of the fatty liver index as an indicator of hepatic steatosis for predicting incident diabetes independently of insulin resistance in a Korean population.

AIMS: Fatty liver disease, especially non-alcoholic fatty liver disease, is considered to be the hepatic manifestation of the metabolic syndrome, both closely associated with insulin resistance. Furthermore, fatty liver disease assessed by ultrasonography is known to be a predictor of the development of Type 2 diabetes mellitus. However, it remains unclear whether fatty liver disease plays a role in the pathogenesis of Type 2 diabetes independently of insulin resistance. In this study, we investigated whether fatty liver disease assessed by the fatty liver index can predict the development of Type 2 diabetes independently of systemic insulin resistance. METHODS: We examined the clinical and laboratory data of 7860 subjects without diabetes who underwent general routine health evaluations at the Asan Medical Center in 2007 and had returned for follow-up examinations in 2011. Fatty liver index was calculated using an equation that considers serum triglyceride levels, γ-glutamyltransferase, waist circumference and BMI. RESULTS: During a 4-year period, 457 incident diabetes cases (5.8%) were identified. The odds ratios for the development of Type 2 diabetes were significantly higher in the group with a fatty liver index ≥ 60 (fatty liver index-positive) than in the group with a fatty liver index < 20 (fatty liver index-negative) after adjusting for various confounding variables including homeostasis model assessment of insulin resistance. Odds ratios were significant regardless of the insulin resistance status at baseline. CONCLUSIONS: Our results suggest that fatty liver index as a simple surrogate indicator of hepatic steatosis is valuable in identifying subjects at high risk for Type 2 diabetes. In addition, fatty liver disease itself contributes to the development of Type 2 diabetes independently of systemic insulin resistance.

No significant association between the alpha-2A-adrenergic receptor gene and treatment response in combined or inattentive subtypes of attention-deficit hyperactivity disorder.

INTRODUCTION: Given the shortage of pharmacogenetic studies on treatment response according to subtype of attention-deficit hyperactivity disorder (ADHD), we investigated the associations between the MspI and DraI polymorphisms of the alpha-2 A-adrenergic receptor gene (ADRA2A) and treatment response to methylphenidate according to subtype of ADHD. METHODS: We enrolled 115 medication-naïve children with ADHD into an open label 8-week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical -Global Impression (CGI), ADHD rating scale, and Continuous Performance Test (CPT) pre- and post-treatment. RESULTS: There was no statistically significant association between the MspI or DraI genotypes and the relative frequency of CGI-improvement (CGI-I) 1 or 2 status among any of the groups (all types of ADHD, ADHD-C, or ADHD-I). However, among the children with ADHD-C, those subjects with the C/C genotype at the ADRA2A DraI polymorphism tended to have a CGI-I 1 or 2 status post-treatment (OR=4.45, p=0.045). DISCUSSION: The results of this study do not support the association between the the MspI or DraI genotypes and treatment response to methylphenidate in ADHD. However, our results -suggest that subtypes might influence pharmacogenetic results in ADHD.·available online at http://www.thieme-connect.de/ejournals/toc/pharmaco.

Parental perceived benefits of OROS-methylphenidate treatment for the child with attention-deficit/hyperactivity disorder and for parents themselves.

Given the shortage of studies on parental perceived benefits of OROS-methylphenidate treatment in Asian populations, we assessed parental response to OROS-methylphenidate treatment of Korean children with attention-deficit/hyperactivity disorder (ADHD), in relation to children's academic performance and behavioral symptoms as well as parental rearing stress and depressive symptoms.We enrolled 132 medication-naïve children with ADHD into a multicenter, open-label, 12-week trial of OROS-MPH. The outcome measures were the ADHD rating scale-IV (ADHD-RS), the comprehensive attention test and academic performance rating scale, and the clinical global impression (CGI)-severity/improvement instrument (for the children) and Beck depression inventory and parenting stress index (for their parents).We found parent-perceived improvements in children's ADHD-related behavioral symptoms and academic function and their parents' depressive symptoms and parenting stress. Investigator-rated ADHD symptoms and subjects' neuropsychological function were also improved (p<0.001).Parents of Korean children with ADHD perceive that OROS-methylphenidate treatment improves their children's academic function and behavior as well as their own child-rearing stress and emotional state. These findings must be interpreted with caution, due to a non-comparative open-label trial.

Change in cytokines in patients with warts after contact immunotherapy with squaric acid dibutylester.

BACKGROUND: A wart is a skin lesion caused by infection with human papillomavirus (HPV). Contact immunotherapy is one of the many therapeutic options that have been used to treat warts; however, the effectiveness of contact immunotherapy differs from patient to patient, and the cause of this variation in clinical response is unclear. AIM: To assess cytokine changes in patients after contact immunotherapy with squaric acid dibutylester (SADBE). METHODS: In total, 21 patients with warts and 9 healthy control subjects were enrolled in the study. The frequencies of CD3+ T cells expressing interleukin (IL)-4, IL-10, IL-12, tumour necrosis factor-α and interferon-γ were measured by flow cytometry analysis of peripheral blood at baseline in both patients and controls, and after SADBE treatment in patients. RESULTS: Lower expression of IL-4 and higher expression of IL-12 in CD3+ T cells were found in patients compared with controls. The percentage of CD3+/IL-4+ T cells significantly increased after contact immunotherapy in all responders, but was significantly higher in those with an excellent response, who also had a significantly higher percentage of CD3+/IL-10+ T cells. The patients with an excellent response also had a significant decrease in the percentage of CD3+/IL-12+ T cells, and the percentage of CD3+/IL-4+ T cells normalized. CONCLUSIONS: Response to contact immunotherapy can vary depending on the types of cytokine changes produced by treatment. An excessive shift to a Th2 pattern and increased IL-10 production after contact immunotherapy may hinder clearance of HPV.

Effect of vardenafil on nitric oxide synthase expression in the paraventricular nucleus of rats without sexual stimulation.

Vardenafil hydrochloride (HCl) is a potent and selective phosphodiesterase type-5 (PDE-5) inhibitor that enhances nitric oxide (NO)-mediated relaxation of human corpus cavernosum and NO-induced rabbit penile erection, and enhances erectile function in patients. In the present study, the effect of vardenafil on nitric oxide synthase (NOS) and neuronal NOS expressions in the paraventricular nucleus (PVN) of rats without sexual stimulation was investigated using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry and neuronal NOS (nNOS) immunohistochemistry and western blot analysis. The present results showed that NOS and nNOS expression in the PVN was increased by vardenafil treatment as the dose- and duration-dependently without sexual stimulation. The phosphodiesterase type-5 inhibitor, vardenafil, augmented NOS expression in the brain without sexual stimulation. The present study suggests that sexual behaviour can be directly modulated by neurotransmitters such as nitric oxide.

Severe Periodontal Disease Increases Acute Myocardial Infarction and Stroke: A 10-Year Retrospective Follow-up Study.

This study aimed to evaluate the causal association of periodontal disease with acute myocardial infarction (AMI) and stroke, after controlling for various confounders among the Korean population. A retrospective cohort study using the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) was performed during 2002 to 2015 (baseline: 2002 to 2005; follow-up: 2006 to 2015) in the Republic of Korea. A total of 298,128 participants with no history of AMI or stroke were followed up for 10 y. AMI and stroke were defined by a diagnosis using the International Classification of Diseases, 10th Revision (ICD-10) guideline. Periodontal condition was classified into 3 groups (healthy, moderate periodontal disease, severe periodontal disease [SPD]) using the combination of ICD codes, treatment codes in the NHIS, and recommendation of periodontal treatment by the dentists in HEALS. Various confounders, such as sociodemographic, behavioral, systemic, and oral health factors, including hypercholesterolemia, were considered. Multivariable Cox regression analysis was applied to estimate adjusted incidence rate ratio (adjusted hazard ratio [aHR]) based on person-year of periodontal condition for AMI, stroke, and nonfatal major adverse cardiovascular events (MACEs) encompassing AMI or stroke controlling for various confounders. Stratified analyses according to age group, sex, and toothbrushing frequency were also performed. After controlling for various confounders, participants with SPD compared with non-SPD participants had a higher incidence by 11% for AMI (aHR, 1.11; 95% confidence interval [CI], 1.02-1.20), by 3.5% for stroke (aHR, 1.035; 95% CI, 1.01-1.07), and by 4.1% for MACEs (aHR, 1.04; 95% CI, 1.01-1.07). The association of SPD with AMI and MACE was highly modified in females and adults aged 40 to 59 y. In the total Korean population, SPD increased total AMI events by 4.3%, total stroke events by 1.4%, and the total MACEs by 1.6%. Our data confirmed that SPD was causally associated with the new events of AMI and stroke.

Isolation and characterization of bacteriocin-producing bacteria from the gastrointestinal tract of broiler chickens for probiotic use.

AIMS: To isolate and characterize the bacteriocin-producing bacteria (BPB) from the gastrointestinal tract of broiler chickens for probiotic use. METHODS AND RESULTS: In total, 291 bacterial strains were isolated from broilers and screened for bacteriocin-producing ability. The bacteriocins produced by Enterococcus faecium SH 528, Ent. faecium SH 632 and Pediococcus pentosaceus SH 740 displayed inhibitory activity against pathogens including Clostridium perfringens and Listeria monocytogenes. Activity of the bacteriocins remained unchanged after 30 min of heat treatment at 60 degrees C or exposure to organic solvents, but diminished after treatment with proteolytic enzymes. PCR was used to detect the structural genes enterocin A and B in SH 528, enterocin L50 and P in SH 632, and pediocin PA-1 in SH 740. Most of them were resistant to 0.5% bile salts and remained viable after 2 h at pH 3.0. Ent. faecium SH 528 exhibited the highest amylase activity among the strains tested. CONCLUSIONS: We selected Ent. faecium SH 528 and SH 632 and Ped. pentosaceus SH 740 by probiotic selection criteria including inhibition activity against pathogens. SIGNIFICANCE AND IMPACT OF THE STUDY: The isolated BPB could potentially be used in the poultry industry as probiotics to control pathogens.

Isolation and partial characterization of a bacteriocin produced by Pediococcus pentosaceus K23-2 isolated from Kimchi.

AIMS: Screening and partial characterization of a bacteriocin produced by Pediococcus pentosaceus K23-2 isolated from Kimchi, a traditional Korean fermented vegetable. METHODS AND RESULTS: A total of 1000 lactic acid bacteria were isolated from various Kimchi samples and screened for the production of bacteriocin. Pediocin K23-2, a bacteriocin produced by the Pediococcus pentosaceus K23-2 strain, showed strong inhibitory activity against Listeria monocytogenes. The bacteriocin activity remained unchanged after 15 min of heat treatment at 121 degrees C or exposure to organic solvents; however, it diminished after treatment with proteolytic enzymes. The bacteriocin was maximally produced at 37 degrees C, when the pH of the culture broth was maintained at 5.0 during the fermentation, although the optimum pH for growth was 7.0. The molecular weight of the bacteriocin was about 5 kDa according to a tricine SDS-PAGE analysis. CONCLUSIONS: Pediococcus pentosaceus K23-2 isolated from Kimchi produces a bacteriocin, which shares similar characteristics to the Class IIa bacteriocins. The bacteriocin is heat stable and shows wide antimicrobial activity against Gram-positive bacteria, especially L. monocytogenes. SIGNIFICANCE AND IMPACT OF THE STUDY: Pediocin K23-2 and pediocin K23-2-producing P. pentosaceus K23-2 could potentially be used in the food and feed industries as natural biopreservatives, and for probiotic application to humans or livestock.

Dynamics of Xanthomonas oryzae pv. oryzae Populations in Korea and Their Relationship to Known Bacterial Blight Resistance Genes.

ABSTRACT Developing resistant cultivars requires an understanding of the dynamics of the pathogen populations as well as the genetics of host resistance. Bacterial leaf blight (BB), caused by the vascular pathogen Xanthomonas oryzae pv. oryzae, has become one of the most devastating diseases of rice. We demonstrate here the quantitative analyses of responses of near-isogenic lines carrying various BB resistance (R) genes and R-gene combinations against 16 X. oryzae pv. oryzae isolates representing Korean BB pathotypes. The estimated main effects of each R gene against the 16 isolates identified prominent differences in BB pathotypes between Korea and other countries. Three major aspects of our quantitative observations and statistical analysis are (i) strong and broad resistance of xa5; (ii) independent and additive genetic actions of Xa4, xa5, and Xa21 under digenic or trigenic status; and (iii) a strong quantitative complementation effect contributed by the functional alleles of Xa4 and Xa21. We conclude that the pyramid line containing genes Xa4, xa5, and Xa21 would be the most promising and valuable genotype for improving Korean japonica cultivars for BB resistance.

Indepth diagnosis of a secondary clarifier by the application of radiotracer technique and numerical modeling.

To make an indepth diagnosis of a full-scale rectangular secondary clarifier, an experimental and numerical study has been performed in a wastewater treatment facility. Calculation results by the numerical model with the adoption of the SIMPLE algorithm of Patankar are validated with radiotracer experiments. Emphasis is given to the prediction of residence time distribution (RTD) curves. The predicted RTD profiles are in good agreement with the experimental RTD curves at the upstream and center sections except for the withdrawal zone of the complex effluent weir structure. The simulation results predict successfully the well-known flow characteristics of each stage such as the waterfall phenomenon at the front of the clarifier, the bottom density current and the surface return flow in the settling zone, and the upward flow in the exit zone. The detailed effects of density current are thoroughly investigated in terms of high SS loading and temperature difference between influent and ambient fluid. The program developed in this study shows the high potential to assist in the design and determination of optimal operating conditions to improve effluent quality in a full-scale secondary clarifier.

A distinct region of chromosome 19p13.3 associated with the sporadic form of adenoma malignum of the uterine cervix.

Adenoma malignum (AM) is known to be one of the malignant tumors that is commonly associated with Peutz-Jeghers syndrome. Recently, the genetic locus of Peutz-Jeghers syndrome was mapped to the telomeric region of chromosome 19p. We analyzed nine sporadic cases of AM with high-density loss of heterozygosity to study the region of chromosome 19p13.2-13.3 using eight microsatellite markers. Our deletion mapping data revealed a distinct region with 100% loss of heterozygosity frequency at marker D19S216. This result indicates that a putative tumor suppressor gene for AM is located at D19S216 on chromosomal band 19p13.3 and plays an important role in AM tumorigenesis.

Frequent somatic mutations of the beta-catenin gene in intestinal-type gastric cancer.

The increased level of cytoplasmic beta-catenin through the mutations to either beta-catenin or adenomatous polyposis coli (APC) has been proposed as an important oncogenic step in various tumors. Gastric cancer showed frequent genetic alterations of the APC gene, and the risk for gastric cancer in familial adenomatosus polyposis patients is 10 times higher than that in the general population. These findings raise the possibility that mutations of beta-catenin may also be associated with the development of gastric cancer. We detected seven somatic mutations in a portion of exon 3 encoding for the glycogen synthase kinase 3beta phosphorylation consensus region of the beta-catenin gene in 43 gastric cancers. All of these mutations were missense mutations, of which five are in the highly conserved aspartic acid 32 and two are in serine 29; all of these seven mutations were detected exclusively in intestinal-type gastric cancers (7 of 26; 26.9%), but not in the diffuse-type (0 of 17). We concluded that disruption of the APC/beta-catenin/T cell factor-lymphoid enhancer binding factor pathway might play an important role especially in the development of intestinal-type gastric cancer.

Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers.

Several lines of evidence suggest that apoptosis dysregulation plays an important role in cancer metastasis. In this study, to explore the possibility that the mutations of death receptors are involved in the metastasis mechanism, we analyzed the death domains of Fas and tumor necrosis factor-related apoptosis-inducing ligand-receptor 1 and -2 (TRAIL-R1 and -R2) genes for the detection of somatic mutations in 57 breast cancers with (n = 34) or without (n = 23) metastasis to the regional lymph nodes. We found seven mutations (three TRAIL-R1 and four TRAIL-R2 mutations), and these mutations were detected only in the breast cancers with metastasis. Furthermore, we also analyzed the allelic losses of chromosome 8p21-22, where TRAIL-R1 and R2 reside in the same series of breast cancers, and found that the allelic losses were significantly higher in metastatic breast cancers. We expressed the tumor-derived TRAIL-R1 and TRAIL-R2 mutants in 293 cells and found that apoptosis was suppressed. These data suggest that TRAIL-R1 and R2 genes are relevant to the frequent loss of chromosome 8p21-22 in breast cancer and that the inactivating mutations of TRAIL-R1 and -R2 genes play a role in the metastasis of breast cancer.

A distinct tumor suppressor gene locus on chromosome 15q21.1 in sporadic form of colorectal cancer.

The SM1311 family is an Ashkenazi family with dominantly inherited predisposition to colorectal adenomas and carcinomas and has a high-penetrance locus in chromosome 15q, with a multipoint logarithm of the odds score of 3.06 at marker D15S118. In the present study, we performed a high-density loss of heterozygosity study with 13 polymorphic microsatellite markers, including D15S118, spanning 15q15.3-q22.1, on 70 cases of the sporadic form of colorectal tumors. Our deletion mapping data showed a locus at D15S968 in chromosomal sub-band 15q21.1 may harbor a tumor suppressor gene in an area <0.521 Mb in physical map distance defined by markers D15S514 and D15S222. THBS1, 0.185 Mb proximal to D15S968, is the nearest known gene to this specific narrow loss of heterozygosity region. Thus, we speculate that THBS1 might be the most probable candidate gene involved in colorectal cancer carcinogenesis.

Point mutations and deletions of the Bcl10 gene in solid tumors and malignant lymphomas.

The Bcl10 gene, which encodes a protein with proapoptotic activity, recently has been identified on chromosome 1p22. In this study, we analyzed somatic mutations and deletions of the Bcl10 gene in a series of 439 tumor tissues from various histological origins that are known to have frequent loss of heterozygosity at chromosome 1p22. According to the LOH study at intragenic polymorphic sites, deletion of Bcl10 in informative cases was detected in 50% of malignant mesotheliomas, 33% of gastric carcinomas, 23% of breast carcinomas, 20% of hepatocellular carcinomas, 17% of lymphomas, 15% of colorectal carcinomas, 13% of laryngeal carcinomas, and 10% of male germ cell tumors (GCTs). In contrast, we detected Bcl10 mutations in 4 of 120 lymphomas (3.3%) and 2 of 78 GCTs (2.6%), respectively, but no mutation was found in the remaining solid tumors analyzed. Taken together, these data imply that Bcl10 may occasionally be involved in the pathogenesis of lymphoma and GCTs. However, the absence or low frequency of the mutation suggests that either Bcl10 is inactivated by other mechanisms or it is not the only target of chromosome 1p22 deletion in human tumors.