Genetic abnormalities involved in t(12;21) TEL-AML1 acute lymphoblastic leukemia: analysis by means of array-based comparative genomic hybridization

The TEL (ETV6)-AML1 (RUNX1) chimeric gene fusion is the most common genetic abnormality in childhood acute lymphoblastic leukemias. Evidence suggests that this chimeric gene fusion constitutes an initiating mutation that is necessary but insufficient for the development of leukemia. In a search for additional genetic events that could be linked to the development of leukemia, we applied a genome-wide array-comparative genomic hybridization technique to 24 TEL-AML1 leukemia samples and two cell lines. It was found that at least two chromosomal imbalances were involved in all samples. Recurrent regions of chromosomal imbalance (>10% of cases) and representative involved genes were gain of chromosomes 10 (17%) and 21q (25%; RUNX1) and loss of 12p13.2 (87%; TEL), 9p21.3 (29%; p16INK4a/ARF), 9p13.2 (25%; PAX5), 12q21.3 (25%; BTG1), 3p21 (21%; LIMD1), 6q21 (17%; AIM1 and BLIMP1), 4q31.23 (17%; NR3C2), 11q22-q23 (13%; ATM) and 19q13.11-q13.12 (13%; PDCD5). Enforced expression of TEL and to a lesser extent BTG1, both single genes known to be located in their respective minimum common region of loss, inhibited proliferation of the TEL-AML1 cell line Reh. Together, these findings suggest that some of the genes identified as lost by array-comparative genomic hybridization may partly account for the development of leukemia.     

Radical repair of cor triatriatum with partially unroofed coronary sinus and persistent left superior vena cava 35 years after operation for tetralogy of Fallot

We report a rare case of simultaneous repair for Cor triatriatum (CT), partially unroofed coronary sinus (CS) with persistent left superior vena cava (PLSVC), moderately severe tricuspid regurgitation, and atrial flutter 35 years after radical operation for tetralogy of Fallot (TOF). A 40-year-old woman underwent patch closure of atrial septal defect as to drain blood from left SVC to right atrium (RA), excision of diaphragm in left atrium (LA), tricuspid annuloplasty, and cryoablation. Postoperative course was uneventful with successful anatomical correction.     

Angiotensin Ⅱ receptor blocker provides pancreatic β-cell protection independent of blood pressure lowering in diabetic db/db mice1

AIM: Several epidemiological studies have suggested that treatment with angiotensin II type 1 receptor blocker provided a risk reduction of developing type 2 diabetes. The aim of this study was to investigate whether and how chronic candesartan treatment can attenuate the deleterious influence of the hyperactive local intra-islet renin-angiotensin system in the diabetes state. METHODS: Eight-week-old db/db mice were randomized to candesartan 1 mg/kg, candesartan 10 mg/kg, manidipine 10 mg/kg, or placebo via gavage for 6 weeks. Their age-matched nondiabetic littermates db/m mice were treated with placebo and acted as nondiabetic controls. After 6 weeks' treatment, an intraperitoneal glucose tolerance test, immunohistochemical staining of oxidative stress markers, insulin, CD31, azan staining and an electron microscopy observation were performed. RESULTS: Chronic candesartan treatment provided an improvement of glucose tolerance, and greatly rescued islet beta-cell mass. Candesartan treatment also notably decreased staining intensity of oxidative stress markers, as well as attenuating intra-islet fibrosis and improving blood supply in the islet. In the electron microscopy observation, candesartan-treated animals exhibited improved granulation and less remarkable endoplasmic reticulum and Golgi bodies; furthermore, candesartan treatment greatly relieved the swelling of mitochondria to nearly normal. Both the benefits of reducing oxidative stress and ultrastructure protection were in a dose-dependent and blood pressure-independent manner. CONCLUSION: After diabetes was initiated, candesartan treatment could not reverse the state of diabetes, but it effectively improved glucose tolerance and protected beta-cell function by attenuating oxidative stress, islet fibrosis, sparsity of blood supply and ultrastructure disruption in a dose-dependent and blood pressure-independent manner.     

Effect of familial history and smoking on common cancer risks in Japan

BACKGROUND: Inherited genetic predispositions are important risk factors for the development of cancer in general. To determine genetic susceptibility for 14 common cancers, a case-control study of the impact of a family history of cancer in first-degree relatives was conducted. The authors further evaluated the effect modification by habitual smoking with adjustment for other confounding environmental factors. METHODS: In total, 18,836 cancer cases and 28,125 age-matched and sex-matched controls, confirmed as being free of cancer, were recruited. Odds ratios (ORs) and 95% confidence intervals were determined by multiple logistic regression analysis, including stratification by family history for 14 cancer sites and interactions with a smoking history. RESULTS: The associations between family history and risk of cancer were generally stronger at the same sites than across cancer sites. Risks to first-degree relatives at the same sites were found to be significantly elevated with 8 of 14 cancer sites; especially high ORs were found for prostate and thyroid cancers. Some across-site associations were observed; in particular, a reciprocal association between breast and prostate cancer was found. The interaction between family history and smoking history for breast cancer was found to be statistically significant. There was no statistical evidence for the interactions in other sites, but among subjects with a family history, the ORs were found to be higher in smokers compared with nonsmokers. CONCLUSIONS: The results of the current study support the hypothesis of a genetic susceptibility to cancers in family members. For breast cancer, the interaction between family history and smoking history was observed to be significant.     

Clinical significance of a blood eosinophilia in adult T-cell leukemia/lymphoma: a blood eosinophilia is a significant unfavorable prognostic factor

We investigated the clinical significance of a blood eosinophilia in a cohort of 158 consecutive patients with adult T-cell leukemia/lymphoma (ATLL), and multivariate analysis revealed that a blood eosinophilia was an independent and a significant unfavorable prognostic factor. Interestingly, a blood eosinophilia was independent of serum LDH level, which might reflect the tumor burden. The present study shows that measurement of the blood eosinophil count is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients.     

Phenotypic and genotypic characterization of 14 leukemia and lymphoma cell lines with 11q23 translocations

11q23 translocation is the most popular chromosomal abnormality in infant leukemia. In adults, it is often encountered in non-Hodgkin's lymphoma (NHL). In this study, we analyzed the phenotypic and genotypic characteristics of 9 acute leukemic cell lines with 11q23 translocations and one with deletion of the 11q23 locus, nine of which were established by researchers in this group, together with 4 NHL cell lines with 11q23 translocations. All lines were considered to belong to the B-cell lineage at different stages. All 10 leukemic lines showed clonal rearrangement of the immunoglobulin heavy chain (IgH) gene: two corresponded to the B-precursor stage (CD19⁺, cytoplasmic μ⁻), while the other 8 corresponded to the pre-B stage (cytoplasmic μ⁺). All 4 NHL lines showed rearrangements of both the IgH and Igκ genes with three expressing surface Ig; specifically, mature B-cell phenotype. As for myelocytic-monocytic markers, at least one out of 4 antigens examined were positive in 8 of the 10 leukemic cell lines, while only one of the 4 NHL lines was reactive. There were essentially no clear phenotypic or genotypic differences between t(4;11) and t(11;19) cell lines, supporting the view that both diseases have similar clinicopathological characteristics. These cell lines are also valuable for cloning genes at the chromosomal breakpoints.     

Foreign-body granuloma mimicking an extrahepatically growing liver tumor: Report of a case

We herein describe a 74-year-old woman with a foreign-body granuloma mimicking a liver tumor. Imaging studies revealed a pedunculated left lobe mass in the setting of chronic liver disease. She had a past history of a cholecystectomy as well as a previous gynecological operation. A left lateral segmentectomy was performed because of the possibility of a rupture. The dissected specimen showed a foreign-body granuloma caused by gauze. We believe this case to be a very unique granuloma, which should be kept in mind whenever making a diagnosis of a liver tumor particularly in a patient with chronic liver disease, who has a past history of abdominal surgery.     

Coronary artery disease and carotid artery intima-media thickness in Japanese type 2 diabetic patients

OBJECTIVE: To investigate the association between carotid atherosclerosis, measured as intima-media thickness (IMT), and cardiovascular morbidity in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We investigated the relationship between IMT and coronary artery disease (CAD) in 40 type 2 diabetic patients and 40 control subjects. Diabetic patients with CAD determined by coronary angiography were consecutively recruited, whereas the control subjects were recruited from among diabetic outpatients without CAD at the same institution. IMT was measured in both carotid arteries using B-mode ultrasonography. RESULTS: Carotid IMT was significantly greater in the diabetic patients than in the control subjects (1.27 +/- 0.07 vs. 1.03 +/- 0.04 mm, P < 0.05). IMT was associated with CAD by logistic regression analysis using all independent variables (P = 0.062). When the 40 patients with CAD were divided into a group of 20 patients with coronary artery bypass grafting (CABG) and another 20 patients without CABG, the IMT was significantly greater in the CABG group than in the non-CABG group (1.47 +/- 0.11 vs. 1.07 +/- 0.07 mm, P < 0.05). CONCLUSIONS: These results indicate that the presence of carotid atherosclerosis implies a high probability of coronary involvement in Japanese nonobese subjects with type 2 diabetes.     

Liver transplantation-associated de novo hepatitis B virus infection: application of molecular evolutionary analysis

OBJECTIVE: De novo hepatitis B virus (HBV) infection after liver transplantation has recently been reported to be associated with donors without serum hepatitis B surface antigen (HbsAg) but with hepatitis B core antigen (anti-HBc). We elucidate the source of de novo HBV infection after liver transplantation by molecular evolutionary analysis. METHODS: The serum sample was obtained from a recipient who underwent living related liver transplantation. He was negative for all HBV-related serum markers before the transplantation. The recipient became seropositive for HBsAg at 6 months after transplantation. The liver tissue was obtained from a donor who was seronegative for HBsAg, but positive for anti-HBs and anti-HBc. RESULTS: HBV DNA was detected from the serum and liver tissue in a recipient and donor, respectively. A total of 5 clones each of small-S gene of HBV from the donor and recipient were sequenced. A phylogenetic tree analysis based on small-S gene revealed that all isolates derived from the recipient and donor were clustered together within a close range of evolutionary distances. These results indicated that HBV was transmitted by the liver graft from the donor. CONCLUSIONS: Molecular evolutionary analysis can be adopted for the study of the transmission route of viral infection via organ transplantation.