Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement

The possible involvement of germline mutation of the ataxia telangiectasia mutated (ATM) gene in childhood acute leukemia with mixed lineage leukemia (MLL) gene rearrangement (MLL(+)) was investigated. Of the 7 patients studied, 1 showed a germline missense ATM mutation (8921C>T; Pro2974Leu), located in the phosphatidylinositol-3 (PI-3) kinase domain. In reconstitution assays, the ATM mutant 8921T could only partially rescue the radiosensitive phenotype of AT fibroblasts, and in an in vitro kinase assay, it showed a defective phosphorylation of p53-Ser15. Furthermore, the introduction of 8921T in U2OS cells, characterized by a normal ATM/p53 signal transduction, caused a significant reduction of in vivo p53-Ser15 phosphorylation, suggesting a dominant-negative effect of the mutant ATM over the wild-type protein. Our finding in this patient suggests that altered function of ATM plays some pathogenic roles in the development of MLL(+) leukemia.     

Transition of thyroid autoantibodies by rituximab treatment for thyroid MALT lymphoma

Thyroid MALT lymphoma is an extremely rare malignancy believed to arise against a background of Hashimoto's thyroiditis. Rituximab is a monoclonal antibody directed against B cell specific antigen CD20. Recently, there have been reports that rituximab is effective for autoimmune thyroid diseases such as Graves' disease as well as for treatment of B cell malignant lymphoma. We present the changes in thyroid autoantibodies in Hashimoto's thyroiditis after rituximab administration for 3 cases of thyroid MALT lymphoma. Case 1 had been taking levothyroxine and was diagnosed with thyroid MALT lymphoma. She was treated with rituximab monotherapy, and her thyroid enlargement improved. Anti-thyroid peroxidase antibody (TPOAb) turned negative after rituximab monotherapy, and TSH levels decreased with the same levothyroxine dosage. Case 2 was diagnosed with recurrent thyroid MALT lymphoma after chemotherapy (CHOP). He suffered from leg sensory disturbance because of vincristine sulfate. The patient was treated with rituximab. TPOAb decreased, but did not turn negative. TSH levels were within normal range during the disease course, but TSH levels were low in comparison with before rituximab therapy. Case 3 was diagnosed with thyroid MALT lymphoma after radiation therapy on the neck for laryngeal cancer. Thyroid enlargement improved after rituximab monotherapy, and thyroid autoantibody levels decreased. TSH increased transiently after radiation therapy, but TSH decreased gradually without levothyroxine after rituximab monotherapy. We report 3 cases in which thyroid autoantibody levels in Hashimoto's thyroiditis decreased after rituximab monotherapy for thyroid MALT lymphoma, but it is controversial whether thyroid dysfunction due to Hashimoto's thyroiditis is restored.     

Pneumococcal vertebral osteomyelitis and psoas abscess in a patient with systemic lupus erythematosus disclosing positivity of pneumococcal urinary antigen assay

A 53-year-old woman with systemic lupus erythematosus presented with a 3-day history of fever and coughing. Diagnosis of pneumococcal bronchitis was made based on symptoms and positivity of pneumococcal urinary antigen test. On day 3, severe low back pain acutely occurred. Pneumococcal vertebral osteomyelitis and psoas abscess was diagnosed 17 days later by yield of penicillin-susceptible S. pneumoniae strain in blood cultures and drainage fluid. Although pneumococcal urinary antigen test is a useful tool for the diagnosis of pneumococcal pneumonia, we should consider the possibility of pneumococcal infections other than pneumonia or overwhelming bacteremia in immunosuppressive patients when urinary antigen test is positive.     

Anti-oxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits

Studies in vitro reveal that fluvastatin, an HMG-CoA reductase inhibitor, has a strong DPPH radical scavenging activity and achieves concentration-dependent inhibition of copper- and cell-induced oxidation of low-density lipoprotein (LDL). To further examine the anti-oxidative activity of fluvastatin in vivo, we elucidated the effects of chronic treatment with fluvastatin at a dose insufficient to reduce plasma cholesterol levels (2 mg/kg per day) on vasomotion and vascular oxidative stress in thoracic aortas of 0.5% cholesterol-fed rabbits. After 12 weeks of dietary treatment, aortic segments from rabbits fed cholesterol alone showed impaired endothelium-dependent relaxation responses to acetylcholine and A23187 compared to normal chow-fed rabbits in association with a significant increase in plasma total cholesterol levels. In contrast, although plasma total cholesterol levels were not different from those in control cholesterol-fed rabbits, aortic segments from fluvastatin-treated rabbits showed normal relaxation. Compared with rabbits fed cholesterol alone, fluvastatin treatment decreased susceptibility of LDL to ex vivo copper-induced oxidation, reduced vascular superoxide generation, and atheromatous plaque formation. In conclusion, the potent anti-oxidative properties of fluvastatin in addition to its cholesterol-lowering activity appear to contribute to its anti-atherosclerotic effect in vivo.     

Comparison of Clinical Features Between Primary and Secondary Breast Diffuse Large B Cell Lymphoma: A Yokohama Cooperative Study Group for Hematology Multicenter Retrospective Study

We performed a retrospective analysis of DLBCL with breast involvement to compare the prognosis of primary breast lymphoma (PBL) to secondary breast lymphoma (SBL; especially in limited stage cases). We retrospectively reviewed records of 25 diffuse large B-cell lymphoma (DLBCL) patients with breast involvement who received chemotherapy between January 2000 and August 2012. We compared clinical features and prognosis among patients with PBL (n = 11), limited stage SBL (LSBL; n = 6), and advanced stage SBL (ASBL, n = 8). The PBL group had significantly lesser patients with breast tumours (BTs) > 5 cm than the SBL group (P = 0.02). After a median follow-up of 71.3 months, we observed significantly better 5-year overall survival (OS) in the PBL group (90.0%) than in the LSBL (33.3%, P = 0.01) group, but not for progression-free survival (PFS). Patients with BT > 5 cm had worse OS (P = 0.01) and PFS (P = 0.04) than those with BT ≤ 5 cm. PBL had a better prognosis than SBL among limited stage DLBCL.     

Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease

There are conflicting reports about the involvement of single nucleotide polymorphisms (SNPs) of the ataxia telangiectasia mutated (ATM) gene with cancer, and the consequences of these SNPs for ATM function remain unclear. We therefore sought to identify SNPs of the ATM gene in pediatric Hodgkin disease (HD) and to analyze ATM function in cells from patients with these SNPs. We have identified SNPs of the ATM gene in 5 of 14 children (S1455R, n = 1; H1380Y, n = 1; N1650S, n = 2; and I709I, n = 1). One patient had nonsense-associated altered splicing of the ATM gene. Lymphoblastoid cell lines expressing the S1455R and N1650S exhibited defective ATM-mediated p53 phosphorylation and Chk2 activation; cells expressing the H1380Y exhibited defective c-Abl activation after X-irradiation. Expression of the N1650S in ATM-null fibroblasts conferred only partial hyperradiosensitivity. Furthermore, the introduction of N1650S ATM into U2OS cells, which express wild-type ATM, showed reduced p53-Ser15 phosphorylation, suggesting a dominant-negative effect of the N1650S over the wild-type ATM protein. We conclude that the rare polymorphic variants of the ATM gene that we identified in children with HD encode functionally abnormal proteins, and we discuss the possible genetic risk factors for childhood HD.     

From the Cover: Intake and transformation to a glycoside of (Z)-3-hexenol from infested neighbors reveals a mode of plant odor reception and defense

Plants receive volatile compounds emitted by neighboring plants that are infested by herbivores, and consequently the receiver plants begin to defend against forthcoming herbivory. However, to date, how plants receive volatiles and, consequently, how they fortify their defenses, is largely unknown. In this study, we found that undamaged tomato plants exposed to volatiles emitted by conspecifics infested with common cutworms (exposed plants) became more defensive against the larvae than those exposed to volatiles from uninfested conspecifics (control plants) in a constant airflow system under laboratory conditions. Comprehensive metabolite analyses showed that only the amount of (Z)-3-hexenylvicianoside (HexVic) was higher in exposed than control plants. This compound negatively affected the performance of common cutworms when added to an artificial diet. The aglycon of HexVic, (Z)-3-hexenol, was obtained from neighboring infested plants via the air. The amount of jasmonates (JAs) was not higher in exposed plants, and HexVic biosynthesis was independent of JA signaling. The use of (Z)-3-hexenol from neighboring damaged conspecifics for HexVic biosynthesis in exposed plants was also observed in an experimental field, indicating that (Z)-3-hexenol intake occurred even under fluctuating environmental conditions. Specific use of airborne (Z)-3-hexenol to form HexVic in undamaged tomato plants reveals a previously unidentified mechanism of plant defense.In response to herbivory, plants emit specific blends of volatiles (1). When undamaged plants are exposed to volatiles from neighboring herbivore-infested plants, they begin to defend against the impending infestation of herbivores (2, 3). This so-called “plant–plant signaling” has been reported in several plant species (4). For example, a study on the expression profiles of defense-related genes when Arabidopsis was exposed to several volatiles, including green leaf volatiles and a monoterpene, showed that the manner of induction varied with the gene monitored or the volatile used, suggesting that the plant responses were specific to the individual volatile compound (5). Kost and Heil (6) reported that the secretion of extrafloral nectar (an alternative food for carnivores) in undamaged lima bean plants was enhanced by volatiles from infested conspecific plants; this reaction was specific to (Z)-3-hexenyl acetate. Recently, Kikuta et al. (7) showed that wound-induced volatile organic compounds from Chrysanthemum cinerariaefolium induced the biosynthesis of pyrethrins in volatile-exposed neighboring plants. In this plant–plant signaling system, a blend of five compounds at specific concentrations was essential for the pyrethrin biosynthesis in receiver plants.These previous studies on plant–plant signaling raise questions about how different airborne volatiles are received by undamaged neighboring plants. Tamogami et al. (8) reported that airborne (E)-nerolidol was metabolized by Achyranthes bidentata plants into (E)-4,8-dimethyl-1,3,7-nonatriene. However, the mechanisms involved in the reception of airborne (E)-nerolidol in plants remained unclear. To date, only the receptor for ethylene, ETR1, a typical histidine kinase involved in a two-component regulatory system, has been identified (9, 10); no information exists on receptors for other volatile compounds in plants. In this study, we conducted comprehensive analyses of metabolic changes in intact tomato plants (Solanum lycopersicum) exposed to volatiles emitted from conspecifics infested with common cutworm (CCW; Spodoptera litura) and also conducted bioassays and biochemical analyses. We report that (Z)-3-hexenol emitted from herbivore-infested tomato plants is used by undamaged plants to form a glycoside with defensive function against CCW.     

Significance of IA-2 antibody in Japanese type 1 diabetes: its association with GAD antibody

To investigate the presence and level of serum antibodies to IA-2 (IA-2A) in Japanese patients with adult type 1 diabetes in order to clarify its association with glutamic acid decarboxylase (GAD) antibody. Serum samples were obtained from 101 Japanese patients with type 1 diabetes, including 37 patients with slowly progressive form of type 1 diabetes. Serum levels of IA-2A and GADA were determined by radioimmunoassay. The study had a cross-sectional design. IA-2A and GADA were detected in 37 and 59% of these patients, respectively. Of the 37 slowly progressive form of patients, IA-2A and GADA were present in 49 and 86%, respectively (NS). GADA levels were significantly higher (P<0.05) in IA-2A positive than in IA-2A negative patients in slowly progressive form, but IA-2A levels did not differ significantly between GADA positive and GADA negative patients. Measuring IA-2A in combination with GADA is useful for the diagnosis and prognosis of type 1 diabetes in Japanese.     

Direct and indirect effects of pulsatile shear stress on the smooth muscle cell.

BACKGROUND: Anastomotic intimal hyperplasia is still an unsolved problem after small caliber prosthetic bypass grafting. Oscillatory turbulent flow occurs at the end to side anastomosis, and produces various effects on smooth muscle cells (SMCs) and endothelial cells (ECs), which compose intimal hyperplasia. We examined the influences of pulsatile oscillating shear stress on smooth muscle cells mitogenic activity induced by sheared endothelial cells. METHODS:1) Smooth muscle cells were cultured under three different pulsatile shear conditions (mean: 0, 6, and 60 dyne/cm2). 2) Endothelial cells were cultured under both static and sheared condition (mean: 60 dyne/cm2). Using the conditioned media from each well, SMCs were cultured under static and sheared conditions (60 dyne/cm2). Four groups of SMCs were devised by combining the two types of media and the two culture conditions. SMC colony spreading distances were measured as an index of combined migration and proliferation activity. An MTT assay and a cell counting assay were used to determine the proliferation activities of SMCs. RESULTS: 1) SMC spreading activity was suppressed by shear stress. SMC proliferative activity was stimulated by pulsatile turbulent shear stress. 2) SMC spreading activity was stimulated by mitogens derived from ECs under shear stress. However, this augmented SMC spreading activity was attenuated under sheared conditions. The mitogens derived from ECs under pulsatile shear stress had no effects on SMC proliferation activity. CONCLUSIONS: Pulsatile oscillating shear stress attenuates SMC migration activity induced by EC-denve mitogens and stimulates SMC proliferative activity.