GATA2 zinc finger 2 mutation found in acute myeloid leukemia impairs myeloid differentiation

AbstractWe identified two novel GATA2 mutations in acute myeloid leukemia (AML). One mutation (p.R308P-GATA2) was a R308P substitution within the zinc finger (ZF)-1 domain, and the other (p.A350_N351ins8-GATA2) was an eight-amino-acid insertion between A350 and N351 residues within the ZF-2 domain. p.R308P-GATA2 did not affect DNA-binding and transcriptional activities, while p.A350_N351ins8-GATA2 reduced them, and impaired G-CSF-induced granulocytic differentiation of 32D cells. Although p.A350_N351ins8-GATA2 did not show a dominant-negative effect over wild-type (Wt)–GATA2 by the reporter assay, it might be involved in the pathophysiology of AML by impairing myeloid differentiation because of little Wt-GATA2 expression in primary AML cells harboring the p.A350_N351ins8 mutation

Clinical significance of nuclear non-phosphorylated beta-catenin in acute myeloid leukaemia and myelodysplastic syndrome

Wnt signaling activates the canonical pathway and induces the accumulation of non-phosphorylated beta-catenin (NPBC) in the nucleus. Although this pathway plays an important role in the maintenance of haematopoietic stem cells as well as in oncogenesis, the significance of nuclear NPBC remains unclear in malignant haematopoiesis. This study examined the expression of nuclear NPBC in bone marrow specimens from 54 and 44 patients with de novo acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), respectively. On immunohistochemistry with an anti-NPBC antibody, the nuclei were positively stained in 22 and 18 of AML and MDS specimens, respectively. Staining of nuclear NPBC was associated with AML subtypes (M6 and M7), low complete remission (CR) rate, and poor prognosis. Nuclear NPBC was also associated with a high score when using the International Prognostic Scoring System (IPSS) for MDS and with −7/−7q and complex karyotypes. These findings suggest that in situ detection of nuclear NPBC by immunohistochemistry could provide new insights into the pathogenesis and prognosis of AML and MDS

A novel non-canonical Notch signaling regulates expression of synaptic vesicle proteins in excitatory neurons

Notch signaling plays crucial roles for cellular differentiation during development through γ-secretase-dependent intramembrane proteolysis followed by transcription of target genes. Although recent studies implicate that Notch regulates synaptic plasticity or cognitive performance, the molecular mechanism how Notch works in mature neurons remains uncertain. Here we demonstrate that a novel Notch signaling is involved in expression of synaptic proteins in postmitotic neurons. Levels of several synaptic vesicle proteins including synaptophysin 1 and VGLUT1 were increased when neurons were cocultured with Notch ligands-expressing NIH3T3 cells. Neuron-specific deletion of Notch genes decreased these proteins, suggesting that Notch signaling maintains the expression of synaptic vesicle proteins in a cell-autonomous manner. Unexpectedly, cGMP-dependent protein kinase (PKG) inhibitor, but not γ-secretase inhibitor, abolished the elevation of synaptic vesicle proteins, suggesting that generation of Notch intracellular domain is dispensable for this function. These data uncover a ligand-dependent, but γ-secretase-independent, non-canonical Notch signaling involved in presynaptic protein expression in postmitotic neurons

顎関節におけるHIF-1αの役割

Objective: Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease characterized by permanent cartilage loss. Articular cartilage is maintained in a low-oxygen environment. The chondrocyte response to hypoxic conditions involves expression of hypoxia inducible factor 1α (HIF-1α), which induces chondrocytes to increase expression of vascular endothelial growth factor (VEGF). Here, we investigated the role of HIF-1α in mechanical load effects on condylar cartilage and subchondral bone in heterozygous HIF-1α-deficient mice (HIF-1α+/-). Design: Mechanical stress was applied to the TMJ of C57BL/6NCr wild-type (WT) and HIF-1α+/- mice with a sliding plate for 10 days. Histological analysis was performed by HE staining, Safranin-O/Fast green staining, and immunostaining specific for articular cartilage homeostasis. Results: HIF-1α+/- mice had thinner cartilage and smaller areas of proteoglycan than WT controls, without and with mechanical stress. Mechanical stress resulted in prominent degenerative changes with increased expression of HIF-1α, VEGF, and the apoptosis factor cleaved Caspase-3 in condylar cartilage. Conclusion: Our results indicate that HIF-1a may be important for articular cartilage homeostasis and protective against articular cartilage degradation in the TMJ under mechanical stress condition, therefore HIF-1α could be an important new therapeutic target in TMJ-OA

Class II MHC Antigen Expression in Bronchial Lavage Cells in a Canine Lung Allograft Model using FK506 Immunosuppression

Footnotes: Katsunobu Kawahara, MD., The First Department of Surgery, Nagasaki University School Medicine, Sakamoto-machi 7-1 #852, Nagasaki, Japan, TEL 0958-47-2111, FAX 0958-47-5034 Abbreviations: MHC: Major histocompatibility antigens, CsA: Cyclosporine A, BAL: Bronchoalveolar lavage, APC: Antigen presenting cell To assess the effect of FK506 on class II MHC antigen expression on lymphocytes recovered from bronchoalveolar lavage (BAL) in dogs following left lung allotransplantation, flow cytometric anlysis with OKIa-1 monoclonal antibody was performed. Dogs were divided into two groups: Group 1 (n = 6), control group (dogs without surgery); Group 2 (n = 23), dogs recieving left lung allotransplantation and immunosuppression using FK506 (0.1mg/kg/day intramuscularly). No significant difference existed in the percentage of OKIa-1 positive lymphocytes recovered from control animals (31.2 ± 11.2%) vs. normal allografts in Group 2 (34.8 ± 8.5%, n = 16). With rejection, however, the percentage of OKIa-1 positive lymphocytes increases significantly in Group 2: 56.2 ± 10.3% in mild rejection (n = 6) and 91.4 ± 4.3% in moderate or severe rejection (n = 4) (p < 0.01). Chest radiographs appeared normal in allografted lungs with histologically mild rejection. The percentage of the OKIa-1 positive lymphocytes in BAL did not significantly change during the first, second, or third week following transplantation, ((32.2 ± 6.4 (n = 5), 36.4 ± 4.2 (n = 4), and 35.8 ± 12.3 (n = 7), respectively)) in the allografted lungs without rejection. FK506 does not affect the class II MHC antigen expression of lymphocytes recovered from BAL in canine allografted lungs without rejection. Furthermore, this compound does not change in class II antigen expression seen with allograft rejection

Results of Surgical Treatment for Small Cell Lung Cancers

We analyzed the data for patients with small cell lung cancer, especially as regards comparison of the results of surgical treatment before and after the introduction of multimodal chemotherapy treatments. Sixty cases with small cell lung cancer were admitted in our department between January, 1955 and December, 1993. Among them, 38 cases underwent pulmonary resection. To evaluate the efficacy of the multimodal treatment including cisplatin with surgical therapy, patients were devided whether pulmonary resection was performed before 1983 (Group A) or after 1984 (Group B). There were no differences in sex and stage between two groups, but ages and operative proceduress were significantly different (p <0.05). Ages were older in Group B (65.5 years) than in Group A (58.1 years) and operations were lesser in Group B (lobectomy or segmentectomy 87.0 %) than in Group A (pneumonectomy or bilobectomy 53.5 %). The operative mortality rates were 13.3 % (2/15) in Group A and 4.3 % (1/23) n Group B. Survival rate at 3 years of Group A was only 6.7 % and no patients survived more than 4 years. While, survival rates of Group B at 3 and 5 years were 24.2 %. The 5 years survival rate of patients with Stage I and II of Group B was 46.9 % and that of Stage III and IV was 8.5%. It is concluded that surgical resection of limited small cell lung cancer (Stage I and II) with intensive chemotherapy is an efficient therapeutic approach

MRマイクロイメージングとガドリニウム-デンドロン修飾ナノリポソーム造影剤を用いた3D微小血管およびナノ粒子分布の腫瘍内評価

The enhanced permeability and retention (EPR) effect is variable depending on nanoparticle properties and tumor/vessel conditions. Thus, intratumoral evaluations of the vasculature and nanoparticle distribution are important for predicting the therapeutic efficacy and the intractability of tumors. We aimed to develop a tumor vasculature evaluation method and high-resolution nanoparticle delivery imaging using magnetic resonance (MR) micro-imaging technology with a gadolinium (Gd)-dendron assembled liposomal contrast agent. Using the Gd-liposome and a cryogenic receiving coil, we achieved 50-μm isotropic MR angiography with clear visualization of tumor micro-vessel structure. The Gd-liposome-enhanced MR micro-imaging revealed differences in the vascular structures between Colon26- and SU-DHL6-grafted mice models. The vessel volumes and diameters measured for both tumors were significantly correlated with histological observations. The MR micro-imaging methods facilitate the evaluation of intratumoral vascularization patterns, the quantitative assessment of vascular-properties that alter tumor malignancy, particle retentivity, and the effects of treatment

CEA in Esophageal Cancer Tissues

The presence of carcinoembryonic antigen (CEA) was assessed in cancer tissues of 53 patients with esophageal carcinoma. Positive rates of CEA staining in tissues were 81.1%. Well differentiated carcinomas tended to be well stained. The survival time in positive tissue CEA patients was longer than that in negative one. The measurement of a presence of tissue CEA is of help to judge the prognosis

Activation of tumor suppressor protein PTEN and induction of apoptosis are involved in cAMP-mediated inhibition of cell number in B92 glial cells

金沢大学医薬保健研究域医学系During brain development, cAMP induces morphological changes and inhibits growth effects in several cell types. However, the molecular mechanisms underlying the growth inhibition remain unknown. Tumor suppressor protein phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid phosphatase that inhibits the phosphoinositide 3-kinase (PI3K) pathway. The phosphorylation of Akt, which is one of the key molecules downstream of PI3K, inhibits apoptosis. In this study, we investigated the role of PTEN in cAMP-mediated growth inhibition. B92 rat glial cells were treated with 2 different cAMP stimulatory agents, a phosphodiesterase (PDE) inhibitor and a β-adrenoceptor agonist. Both cAMP stimulatory agents induced marked morphological changes in the cells, decreased cell number, decreased Akt phosphorylation, activated PTEN, cleaved caspase-3, and induced the condensation and fragmentation of nuclei. These results indicate that the cAMP stimulatory agents induced apoptosis. Protein phosphatase inhibitor prevented cAMP-induced dephosphorylation of PTEN and Akt. In addition, cAMP analogs and Epac-selective agonists affected PTEN and Akt activities. These results suggested that cAMP-induced apoptosis may be mediated by PTEN activation and Akt inhibition through protein phosphatase in B92 cells. Our results provide new insight into the role of PTEN in cAMP-induced apoptosis in glial cells. © 2011 Elsevier Ireland Ltd