骨転移を有しない前立腺がん患者へのアンドロゲン除去療法による骨粗鬆症に対する経口ビスフォスフォネート製剤の予防効果について

We studied the short-term efficacy of alendronate, an oral bisphosphonates, on bone mineral density (BMD) during androgen deprivation therapy (ADT) in 45 nonmetastatic prostate cancer patients at the beginning of ADT (treatment group). All received alendronate five mg daily from the initiation of ADT. Lumber BMD was evaluated by dual energy X-ray absorptiometry, at baseline and after six months of treatment. Historical data on 24 patients with prostate cancer who received ADT without bisphosphonate administration were studied as controls (control group). BMD decreased in 13.9 and 45.8% of the patients in the treatment and control groups, respectively. Mean BMD changes in the lumber spine were +1.6 +/- 3.0% in the treatment group and -1.1 +/- 2.7% in the control group (p = 0.006). No pathological fractures occurred during the study period. No severe adverse effects were observed, but three patients could not continue alendronate treatment because of adverse events. Despite the short-term of this evaluation, our results showed that oral alendronate is an effective and safe treatment for preventing bone loss and increasing BMD in patients receiving ADT for prostate cancer.目的:アンドロゲン除去療法は骨塩減少とそれに伴う病的骨折の潜在的な危険因子である。点滴ビスフォスフォネート製剤はアンドロゲン除去療法を受けている前立腺がん患者に対する骨塩量の減少を予防することが示されているが経口ビスフォスフォネート製剤については評価されていない。今回, われわれは経口ビスフォスフォネート製剤の1つであるアレンドン酸を骨転移を有しない前立腺がん患者に投与して骨塩量を測定し短期間での効果を検討した。対象と方法:治療群として45人の骨転移を有しない前立腺がん患者について検討した。アレンドロン酸を1日5mg経口投与し治療前, 治療半年後に腰椎の骨塩量を測定し比較検討した。対照群として24人の骨転移を有しない前立腺がん患者についても同様に検討を行った。結果:骨塩量の減少は治療群で13.9%, 対照群で45.8%に見られた。腰椎における骨塩量の変化は治療群で平均1.6%, 対照群で-1.1%であった(p=0.006)。治療期間内において病的骨折は認められず, 有害事象として重篤なものは認めなかったが副作用のため3例が内服継続困難であった。結語:短期間の検討であるにもかかわらず経口ビスフォスフォネート製剤であるアレンドロン酸は前立腺がん患者に対するアンドロゲン除去療法による骨塩量減少を予防するのに有効で安全な治療法であることが示唆された。(著者抄録

The Effect on Intracytoplasmic Sperm Injection Outcome of Genotype, Male Germ Cell Stage and Freeze-Thawing in Mice

BACKGROUND: Intracytoplasmic sperm injection (ICSI) has been widely used to study the mechanisms of mammalian fertilization and to rescue male-factor infertility in humans and animals. However, very few systematic analyses have been conducted to define factors affecting the efficiency of ICSI. In this study, we undertook a large-scale series of ICSI experiments in mice to define the factors that might affect outcomes. METHODOLOGY/PRINCIPAL FINDINGS: We used a 5 x 3 x 2 factorial design with the following factors: mouse genotype (ICR, C57BL/6, DBA/2, C3H/He, and 129/Sv strains), type of male germ cells (epididymal sperm, elongated or round spermatids), and their freeze-thawing treatment. The efficiencies (parameters) of each developmental step were analyzed by three-way ANOVA (significance level P<0.01). The type of male germ cells affected all the four parameters observed: oocyte survival after injection, cleavage of oocytes, implantation, and birth of offspring. Genotype affected the oocyte survival, cleavage and birth rates, whereas freeze-thawing had no effects on any of the parameters. There were significant genotype/cell type interactions for oocyte survival and cleavage, indicating that they were determined by a combination of strain and germ cell maturity. Multiple comparisons revealed that spermatozoa and elongated spermatids gave better implantation and birth rates than did round spermatids, while spermatozoa and elongated spermatozoa were indistinguishable in their ability to support embryonic development. The best overall efficiency (birth rate per oocytes injected) was obtained with frozen-thawed DBA/2 strain elongated spermatids (23.2+/-4.2%). CONCLUSIONS/SIGNIFICANCE: The present study provides the first comprehensive information on ICSI using the mouse as a model and will contribute to the efficient use of materials, time, and efforts in biomedical research and clinics involving ICSI

Development of thiol-responsive amide bond cleavage device and its application for peptide nucleic acid-based DNA releasing system

To develop a thiol-responsive DNA releasing system, a thiol-responsive amino acid capable of inducing an amide bond cleavage in the presence of a thiol was developed. It was successfully combined with peptide nucleic acid (PNA), and thiol-induced release of DNA from the thiol-responsive PNA/DNA complex was observed

One-step generation of multiple transgenic mouse lines using an improved Pronuclear Injection-based Targeted Transgenesis (i-PITT)

Ohtsuka, M., Miura, H., Mochida, K. et al. One-step generation of multiple transgenic mouse lines using an improved Pronuclear Injection-based Targeted Transgenesis (i-PITT). BMC Genomics 16, 274 (2015). https://doi.org/10.1186/s12864-015-1432-

Macrophage migration inhibitory factor stimulated by Helicobacter pylori increases proliferation of gastric epithelial cells

AIM: Helicobacter pylori (H pylori) is associated with increased gastric inflammatory and epithelial expression of macrophage migration inhibitory factor (MIF) and gastric epithelial cell proliferation. This study aimed at determining whether H pylori directly stimulates release of MIF in monocytes, whether the cag pathogenicity island (PAI) is involved for this function, and whether MIF stimulated by H pylori increases gastric epithelial cell proliferation in vitro. METHODS: A cytotoxic wild-type H pylori strain (TN2)and its three isogenic mutants (TN2△cag, TN2△cagA and TN2△cagE) were co-cultured with cells of a human monocyte cell line, THP-1, for 24 h at different organism/cell ratios. MIF in the supernatants was measured by an ELISA. Cells of a human gastric cancer cell line, MKN45, were then co-cultured with the supernatants, with and without monoclonal anti-MIF antibody for 24 h. The cells were further incubated for 12 h after addition of (3)H-thymidine, and the levels of incorporation of (3)H-thymidine were measured with a liquid scintillation counter. RESULTS: The wild-type strain and the isogenic mutants, TN2△cagA and TN2△cagE, increased MIF release at organism/cell ratios of 200/1 and 400/1, but not at the ratios of 50/1 and 100/1. However, the mutant TN2△cag did not increase the release of MIF at any of the four ratios. (3)H-thymidine readings for MKN-45 cells were significantly increased with supernatants derived from the wild-type strain and the mutants TN2△cagA and TN2△cagE, but not from the mutant TN2△cag. Moreover, in the presence of monoclonal anti-MIF antibody, the stimulatory effects of the wild-type strain on cell proliferation disappeared. CONCLUSION: H pylori stimulates MIF release in monocytes, likely through its cag PAI, but not related to cagA or cagE. H pylori-stimulated monocyte culture supernatant increases gastric cell proliferation, which is blocked by anti-MIF antibody, suggesting that MIF plays an important role in H pylori-induced gastric epithelial cell proliferation

Development of a Reduction‐Responsive Amino Acid that Induces Peptide Bond Cleavage in Hypoxic Cells

Utilization of a hypoxia-responsive amino acid is indispensable in the preparation of hypoxic tumor-specific peptidyl prodrugs. Bioreduction of a nitro group is among the most attractive triggering reactions in the hypoxia-responsive prodrugs. In this paper, design and synthesis of a reduction-responsive amino acid that induces peptide bond cleavage after reduction of the nitro group are described. Application to hypoxia-responsive peptide bond cleavage system is also reported

Design and synthesis of caged ceramide : UV-responsive ceramide releasing system based on UV-induced amide bond cleavage followed by O–N acyl transfer

Sphingolipids, recognized as membrane constructs and as key signaling molecules, have been studied to examine intracellular function. Some caged sphingolipids that release parent sphingolipids after exposure to UV-irradiation have been previously developed, but caged ceramide has yet to be reported. In this study, we report the design and synthesis of a caged ceramide. Photo-irradiation experiment clarified that the caged ceramide can be successfully converted to the parent ceramide by UV-irradiation. Introduction of an alkyne-handle moiety for further modification of the caged ceramide is also reported