The role of the G20 economies in global health.

The Meetings of Health Ministers of the Group of Twenty (G20) that started at the G20 Summit in Berlin, Germany in 2017 have provided a platform for the discussion of global health matters such as antimicrobial resistance (AMR), public health emergencies, and universal health coverage. Similar issues are also discussed at meetings of the G7 and the World Health Assembly (WHA). This article will examine recent data to explore the characteristics of the G20 and its potential for improving health outcomes. G20 countries have a leading role to play in helping other countries improve global health outcomes because member countries have already faced many issues associated with aging society and increased prevalence of non-communicable diseases (NCDs). Indeed, 71% of the world's elderly population lives in the G20 countries and most of these countries have a high proportional mortality from NCDs of more than 70%. G20 countries are also responsible for a disproportionate share of global impacts. For instance, 72% of CO2 emissions are produced by G20 countries. Migration dynamics and its consequences also need to be considered from the perspective of optimizing health outcomes. Moreover, 78% of the world's top 50 pharmaceutical companies are located in the G20 countries. There is ample room for G20 countries to pursue collaborative and cooperative approaches that can complement the roles of the G7 and WHA in similar health issues. The G20 could, for example, share experiences on dealing with aging and NCDs, reduce their CO2 emissions, prohibit the production of low-quality medicines, and use standardized health check-up formats for migrants and refugees to transfer their own health information. As a group, the G20 countries have the potential to solve global health problems and other issues. The convening of high-level health meetings at G20 summits has the potential to facilitate such endeavors.

A functional single nucleotide polymorphism in the vitamin-K-dependent gamma-glutamyl carboxylase gene (Arg325Gln) is associated with bone mineral density in elderly Japanese women.

The vitamin-K-dependent gamma-glutamyl carboxylase (GGCX) carboxylates vitamin-K-dependent proteins including bone Gla protein (osteocalcin) and matrix Gla protein, which play important roles in bone metabolism. Therefore, GGCX polymorphism might explain in part individual susceptibility to osteoporosis. In the present study, polymorphisms in the exons of this gene were screened in Japanese elderly women and a non-synonymous single nucleotide polymorphisms (SNP) were found; c.8762 G>A; (Arg325Gln). When the kinetic parameters of GGCX325-Gln and GGCX325-Arg were compared in vitro, Vmax/Km was significantly higher for GGCX325-Gln (944.4+/-9.21 pmol/30 min/mg/mM FLEEL) than for GGCX325-Arg (671.9+10.79 pmol/30 min/mg/mM FLEEL) (p=0.018). Then, association study of this polymorphism with forearm bone mineral density (BMD) of Japanese postmenopausal women (n=500, age 73.6+/-5.74) was conducted. As a result, the body mass index (BMI)-adjusted Z score in the subpopulation older than 75 years (n=207) was higher in those with 325-Gln (0.650+/-0.883, mean+/-SD) than those with 325-Arg/Gln or 325-Arg (0.133+/-0.650) (p=0.0383). This is the first report to demonstrate the different activities of GGCX between the common genotypes and their association with BMD.

Functional analysis of the single nucleotide polymorphism (787T>C) in the tissue-nonspecific alkaline phosphatase gene associated with BMD.

UNLABELLED: Polymorphisms of the TNSALP gene have not previously been studied as a possible determinant for variations in BMD or as a predisposing genetic factor for osteoporosis. This study showed a significantly higher association between the 787T>C (Tyr246His) TNSALP gene and BMD among 501 postmenopausal women. Furthermore, the effects of amino acid substitution on the catalytic property of the protein translated from the 787T>C gene were examined. INTRODUCTION: Alkaline phosphatase (ALP) is present mainly on the cell membrane in various tissues and hydrolyzes a variety of monophosphate esters into inorganic phosphoric acid and alcohol. Human ALPs are classified into four types: tissue-nonspecific, intestinal, placental, and germ cell types. Based on studies of hypophosphatasia, which is a systemic skeletal disorder resulting from a tissue-nonspecific ALP (TNSALP) deficiency, TNSALP was suggested to be indispensable for bone mineralization. MATERIALS AND METHODS: We explored the possibility that the TNSALP gene may contribute to age-related bone loss in humans by examining the association between TNSALP gene polymorphisms and BMD in 501 Japanese postmenopausal women. To analyze the protein translated from the TNSALP gene associated with BMD, we constructed a TNSALP cDNA expression plasmid. RESULTS: We genotyped two single nucleotide polymorphisms (787T>C[Tyr246His] and 876A>G[Pro275Pro]), which proved to be in complete linkage disequilibrium. There was a significant difference in BMD and the BMD score adjusted for age and body weight (Z score) among haplotypes (p = 0.041), which was lowest among 787T/876A homozygotes, highest among 787T>C/876A>G homozygotes, and intermediate among heterozygotes. In subgroups divided by age, haplotypes were significantly associated with BMD in older postmenopausal women (>74 years; p = 0.001), but not in younger postmenopausal women (<74 years; p = 0.964). Expression of the 787T>C TNSALP gene using COS-1 cells showed that the protein translated from 787T>C had ALP-specific activity similar to that of 787T. Interestingly, the K(m) value for TNSALP in cells transfected with the 787T>C TNSALP gene was decreased significantly compared with that of cells bearing the 787T gene, reflecting the higher affinity. CONCLUSIONS: These results suggest that variation in TNSALP may be an important determinant of age-related bone loss in humans and that the phosphate metabolism pathway may provide a novel target for the prevention and treatment of osteoporosis.

The mutant (F310L and V365I) tissue-nonspecific alkaline phosphatase gene from hypophosphatasia.

Hypophosphatasia (HOPS) is a heritable disorder characterized by defective skeletal mineralization, deficiency of tissue-nonspecific alkaline phosphatase (TNSALP) activity and premature loss of deciduous teeth. In a previous study, we detected missense mutations in the TNSALP gene of a patient who inherited the F310L and the V365I mutation with severe periodontitis and childhood HOPS. Expression of the mutant V365I TNSALP gene using COS-1 cells demonstrated that the protein translated from the mutant had undetectable ALP activity. In the present study, we characterized another ALP enzyme translated from the mutant F310L and compared it with the ALP in the patient's serum. The COS-1 cells transfected with the F310L and co-transfected with F310L and V365I (F310L/V365I) exhibited levels of 67% and 31%, respectively, with the enzymatic activity of the wild-type taken as 100%. In the thermostability test, TNSALPs in the COS-1 cells transfected with the mutant F310L or F310L/V365I were significantly more heat labile compared with that of the wild-type. Moreover, ALP from the patient's serum was also more heat labile than normal ALP. These results suggest that the protein translated from the mutant F310L, in addition to the mutant V365I, may be responsible for the expression of symptoms of the childhood-type HOPS.

Selective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3).

The receptor tyrosine kinase FLT3 is constitutively activated by an internal tandem duplication (ITD) mutation within the juxtamembrane domain in 20-30% of patients with acute myeloid leukemia. In this study, we identified GTP-14564 as a specific kinase inhibitor for ITD-FLT3 and investigated the molecular basis of its specificity. GTP-14564 inhibited the growth of interleukin-3-independent Ba/F3 expressing ITD-FLT3 at 1 microM, whereas a 30-fold higher concentration of GTP-14564 was required to inhibit FLT3 ligand-dependent growth of Ba/F3 expressing wild type FLT3 (wt-FLT3). However, this inhibitor suppressed the kinase activities of wt-FLT3 and ITD-FLT3 equally, suggesting that the signaling pathways for proliferation differ between wt-FLT3 and ITD-FLT3. Analysis of downstream targets of FLT3 using GTP-14564 revealed STAT5 activation to be essential for growth signaling of ITD-FLT3. In contrast, wt-FLT3 appeared to mainly use the MAPK pathway rather than the STAT5 pathway to transmit a proliferative signal. Further analysis demonstrated that the first two tyrosines in an ITD were critical for STAT5 activation and growth induction but that all of the tyrosines in the juxtamembrane region were dispensable in terms of the proliferation signals of wt-FLT3. These results indicate that an ITD mutation in FLT3 elicits an aberrant STAT5 activation that results in increased sensitivity to GTP-14564. Thus, FLT3-targeted inhibition is an attractive approach, with the potential for selective cytotoxicity, to the treatment of ITD-FLT3-positive acute myeloid leukemia.