Tec protein-tyrosine kinase is involved in interleukin-3 signaling pathway

Among cytoplasmic protein-tyrosine kinases (PTKs) Tec now forms a novel subfamily with recently identified Tec-related PTKs (Btk and Itk/Tsk). Tec is known to be abundantly expressed in myeloid cells, and multiple forms of Tec protein can be generated via the mechanism of alternative splicing. In this report, we have investigated 5'-terminal diversity of the tec messages to demonstrate a predominant form of the Tec protein in mouse hematopoietic cell lines. Using anti-Tec serum, we could show that stimulation with interleukin-3 (IL-3) can induce tyrosine phosphorylation of Tec both in myeloid and pro-B-cell lines. IL-3 stimulation was also shown to induce kinase activity of Tec. Furthermore, we could demonstrate that Tec is constitutively associated with the Shc protein in vivo. Thus, we conclude that Tec is involved in the signaling pathway of IL-3.     

The pipeline of new anticancer agents for breast cancer treatment in 2003

In recent years, strategy in cancer therapy in general, and breast cancer in particular, has been the use of maximum tolerated doses of toxic non-specific agents as well as the investigation of a range of new agents that specifically target tumor-related molecules, in a variety of biological pathways. The trial of chemotherapy (CT) versus chemotherapy+trastuzumab (Herceptin) in HER-2-overexpressing metastatic breast cancer (MBC) was one of the first to use a biological agent in combination with chemotherapy with success and, together with some trials of taxanes in anthracycline-resistance patients one of the few to demonstrate an overall survival (OS) advantage in MBC. Five main molecular pathways are of particular interest in terms of new drug development in breast cancer: the estrogen receptor (ER) pathway, the tyrosine kinase signal transduction pathway, the cell cycle regulation pathway, the apoptosis pathway and the angiogenesis pathway. This review will focus on new agents, cytotoxic, hormonal and molecular-targeted, which are in advanced clinical stages of development for the treatment of MBC.     

Voxel-based analysis of age and gender effects on striatal [123I] FP-CIT binding in healthy Japanese adults

Annals of Nuclear Medicine - Although previous studies have investigated age and gender effects on striatal subregional dopamine transporter (DaT) binding, these studies were mostly based on a...     

The relative importance of nervous system and hormones to the 2-deoxy-D-glucose-induced hyperglycemia in fed rats

We examined the relative contributions of hormones and nervous system to the total 2-deoxy-D-glucose (2-DG)-induced central nervous system-mediated hyperglycemia. 2-DG was injected into the third cerebral ventricle in the following four groups of rats, and hepatic venous plasma glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine were measured: 1) intact rats; 2) intact rats receiving somatostatin with insulin infusion through the femoral vein to inhibit glucagon secretion and maintain the basal insulin level; 3) bilateral adrenalectomized (ADX) rats to prevent epinephrine secretion; and 4) ADX rats receiving somatostatin with insulin infusion. Comparing areas under glucose curves among the intact rats, those receiving somatostatin with insulin infusion, ADX rats, and ADX rats receiving somatostatin with insulin infusion, the area under the glucose curve was intact rats greater than intact rats receiving somatostatin with insulin infusion greater than ADX rats receiving somatostatin with insulin infusion greater than ADX rats. These results suggest that there are three distinct sympathetic nervous system responses to 2-DG-induced central nervous system-mediated hyperglycemia. 2-DG-induced hyperglycemia is not dependent on only one of those three systems, it is dependent on all of them. The relative potency of the factors to 2-DG-induced hyperglycemia increases in the following order: direct neural innervation of liver (including suppressive epinephrine action on insulin secretion), glucagon, and direct epinephrine action on liver.     

Cytokine-induced nitric oxide inhibits mitochondrial energy production and induces myocardial dysfunction in endotoxin-treated rat hearts

The mechanism responsible for cardiac depression in septic shock remains unknown. The present study examined whether nitric oxide (NO) overproduced by inducible NO synthase (iNOS) can inhibit aerobic energy metabolism and impair the myocardial function in endotoxin-treated rat hearts. Lipopolysaccharide (LPS) significantly decreased systolic blood pressure (BP) to 44% of control during the 48 h treatment. Hearts from control and LPS-treated rats were perfused in a Langendorff apparatus. After LPS injection, left ventricular (LV) developed pressure (LVDP) was significantly depressed, plasma NO2-/NO3- (NO(x)) concentration was markedly increased, and myocardial adenosine 5'-triphosphate (ATP), creatine phosphate (CrP), and the ratio of ATP/adenosine 5'-diphosphate were progressively decreased with time. Immunological examination showed a significant expression of iNOS protein in the LPS-treated myocytes. Aminoguanidine, an inhibitor of iNOS, significantly attenuated these LPS-induced functional and metabolic changes. Myocardial cyclic guanosine 3',5'-monophosphate (cGMP) content was significantly increased after LPS injection. Methylene blue, an inhibitor of soluble guanylate cyclase, blunted this increase in cGMP and significantly restored the LPS-induced contractile dysfunction 6 h after LPS injection. In addition, there was a significant negative correlation between LVDP and myocardial cGMP levels as well as a significant negative correlation between LVDP and plasma NO(x) levels. In contrast, 48 h after LPS injection, methylene blue no longer affected cardiac performance, and there was a significant positive correlation between LVDP and myocardial ATP content. Furthermore, the normalized activities (as a ratio of the citrate synthase activity) of mitochondrial NADH-CoQ reductase, succinate-CoQ reductase, and ATPase, were significantly inhibited, and the swelling or disruption of mitochondria cristae was seen in the 48 h LPS treatment. These LPS-induced functional and morphological disorders in the mitochondria were significantly improved by aminoguanidine. The findings suggest that sustained production of NO by iNOS leads to contractile dysfunction via cGMP in the early stage, but that it can directly impair the mitochondrial function, lower myocardial energy production, and contribute significantly to the myocardial dysfunction in the later stage of septic shock.     

Local neurohumoral regulation in the transition to isolated diastolic heart failure in hypertensive heart disease: absence of AT1 receptor downregulation and 'overdrive' of the endothelin system

OBJECTIVE: Although isolated diastolic heart failure with preserved left ventricular (LV) systolic function frequently occurs, regulation of local neurohumoral factors in the transition from diastolic dysfunction without signs of heart failure to diastolic failure, a target for therapeutic strategy, remains to be clarified, partly because of a lack of animal models. Our laboratory recently demonstrated that Dahl-Iwai salt-sensitive (Dahl-S) rats fed on a high-salt diet since 7 weeks of age develop hypertension followed by compensated LV hypertrophy at 13 weeks and transition to isolated diastolic heart failure at 19 weeks. METHODS: Gene expression of the components of the renin-angiotensin system, endothelin (ET) system and natriuretic peptide system in the left ventricle was investigated in the transition to isolated diastolic heart failure in this model. RESULTS: The compensated ventricular hypertrophy was associated with slight increases in angiotensin-converting enzyme (ACE) and angiotensin II type-1a (AT1a) receptor mRNA levels. Although preproET-1 (ppET-1) and ET-converting enzyme-1 (ECE-1) mRNA levels were not increased, mRNA levels of ET type-A (ETA) and ET type-B (ETB) receptors were increased. Atrial natriuretic peptide (ANP) mRNA level increased, but not brain natriuretic peptide (BNP) mRNA level. At the decompensated failing stage (at 19 weeks), ACE mRNA level further increased without downregulation of ATla receptor mRNA level. The mRNA levels of ppET-1 and ECE-1 increased with persistent upregulation of mRNA levels of ETA and ETB receptors, and immunohistochemical staining for ET-1 was found at endothelial cells and myocytes. BNP mRNA level increased with a further increase in ANP mRNA level. CONCLUSIONS: The transition to isolated diastolic heart failure in hypertrophied hearts was associated with preserved gene expression of the renin-angiotensin system and 'overdrive' of gene expression of the ET system. BNP gene expression is likely to be activated by the progression of diastolic failure rather than by LV hypertrophy alone.     

Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome

JAK3 mutations have been reported in transient myeloproliferative disorder (TMD) as well as in acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL). However, functional consequences of the JAK3 mutations in TMD patients remain undetermined. To further understand how JAK3 mutations are involved in the development and/or progression of leukaemia in Down syndrome, additional TMD patients and the DS-AMKL cell line MGS were screened for JAK3 mutations, and we examined whether each JAK3 mutation is an activating mutation. JAK3 mutations were not detected in 10 TMD samples that had not previously been studied. Together with our previous report we detected JAK3 mutations in one in 11 TMD patients. Furthermore, this study showed for the first time that a TMD patient-derived JAK3 mutation (JAK3(I87T)), as well as two novel JAK3 mutations (JAK3(Q501H) and JAK3(R657Q)) identified in an MGS cell line, were activating mutations. Treatment of MGS cells and Ba/F3 cells expressing the JAK3 mutants with JAK3 inhibitors significantly decreased their growth and viability. These results suggest that the JAK3 activating mutation is an early event during leukaemogenesis in Down syndrome, and they provide proof-of-principle evidence that JAK3 inhibitors would have therapeutic effects on TMD and DS-AMKL patients carrying activating JAK3 mutations.     

Effect of temporary school closure due to COVID-19 on musculoskeletal function in elementary school children

Objective: In 2020, coronavirus disease-2019 (COVID-19) became the cause of a pandemic. In response, the Japan Sports Agency issued warnings about secondary damage to health, such as the threat to physical and mental well-being due to the lack of exercise in this situation. In this study, we report on cross-sectional and longitudinal examinations of standing trunk flexion to evaluate how temporary long-term school closures affected musculoskeletal function in elementary school students.Patients and Methods: All children in one public elementary school in T-city during the school years 2019 and 2020 were included in this study. A digital forward flexion meter was used to measure standing trunk flexion.Results: In this study, 284 (284/289: 98.3%) and 266 (266/274: 97.1%) children in school years 2020 and 2019, respectively, were found to have valid data for cross-sectional analysis. The standing trunk flexion did not show significant differences between grades or sexes. In the longitudinal analysis, the results of the comparison of standing trunk flexion in children for two consecutive years revealed significant differences only between grades 3 and 4 (P<0.05) and between girls in grades 3 and 4 (P<0.01), but no significant differences in other grades or among boys or girls were observed.Conclusion: Initially, we expected that there would be a difference in the results of functional assessment using standing trunk flexion depending on the period of absence from school. However, the results of this study showed no significant changes in standing trunk flexion. Moreover, since children’s musculoskeletal functions may be affected by various factors during the COVID-19 pandemic, they should be carefully monitored in the future.