Peroxisome proliferator-activated receptor δ as a molecular target to regulate lung cancer cell growth

AbstractIt has been assumed that prostaglandin (PG)I2 signaling contributes to the negative growth control of lung cancer cells; however, the mechanism remains unresolved. PGI2 functions through a cell surface G protein-coupled receptor (prostaglandin I2-binding receptor, IP) and also exerts an effect by interacting with a nuclear hormone receptor, peroxisome proliferator-activated receptor δ (PPARδ). We found that PPARδ was a key molecule of PGI2 signaling to give negative growth control of lung cancer cells (A549), using carbarprostacyclin, a PGI2 agonist for IP and PPARδ, and L-165041, a PPARδ agonist. Furthermore, PPARδ-induced cell growth control was reinforced by the inhibition of cyclooxygenase. These results suggest that PPARδ activation under the suppression of PG synthesis is important to regulate lung cancer cell growth

Comparison of Hemorrhagic Risk between Prasugrel and Clopidogrel : a Retrospective Study using Adverse Drug Event Reporting Databases

Background: Prasugrel inhibits platelet aggregation more potently and exerts therapeutic action faster than clopidogrel. In the global phase III trial conducted in Western and South American countries that excluded Asian countries, prasugrel reduced ischemic events but increased hemorrhagic risk compared with clopidogrel in patients with acute coronary syndrome scheduled for percutaneous coronary intervention. In the Japanese phase III trial for similar patients, the efficacy of prasugrel compared with clopidogrel was comparable to the global trial, but the safety could not be confirmed because of an insufficient number of patients. Furthermore, given the strict enrollment criteria, the results of these trials may not be applicable to routine clinical practice. Accordingly, we compared the hemorrhagic risk of prasugrel and clopidogrel in real-world settings by analyzing adverse drug event reports in post-marketing stages provided by the Japanese regulatory authorities and the U.S. Food and Drug Administration (FDA). Methods: We analyzed a total of 3,970 reports for prasugrel (n = 518) or clopidogrel (n = 3,452) between 2014 and 2017 in the Japanese Adverse Drug Event Report (JADER) and a total of 91,914 reports for either prasugrel (n = 5,992) or clopidogrel (n = 85,922) between 2009 and 2019 in the FDA Adverse Event Reporting System (FAERS). Results: In JADER and FAERS, prasugrel was more frequently and significantly associated with hemorrhagic event reports than clopidogrel. After adjustment for known confounders including age, sex, and concomitant medications (aspirin, anticoagulants, and proton pump inhibitors), the hemorrhagic risk of prasugrel compared with clopidogrel remained significant (adjusted reporting odds ratios [95% CI] for total, intracranial, and gastrointestinal hemorrhagic events = 2.42 [1.97-2.96], 2.45 [1.85-3.24], and 2.27 [1.73-2.97] in JADER, and 2.21 [2.09-2.34], 1.21 [1.09-1.33], and 1.41 [1.29-1.54] in FAERS). Conclusions: The hemorrhagic risk was found to be greater with prasugrel than clopidogrel in real-world patients, including Japanese patients

4-Hydroxyderricin inhibits osteoclast formation and accelerates osteoblast differentiation

4-Hydroxyderricin (4-HD) is a major polyphenol of Angelica keiskei (Japanese name Ashitaba), exhibiting anti-allergic, anti-diabetic, anti-oxidant, and antitumor effects. The present study was designed to evaluate the effects of 4-HD on bone formation and maintenance by using cultured osteoclasts and osteoblasts. 4-HD did not affect cell proliferation of stromal ST2 cells and preosteoblast MC3T3-E1 cells at concentrations of 1–10 μM. This compound inhibited the formation of multinucleated osteoclasts from mouse splenic cells, and we identified a molecular pathway of osteoclast differentiation mediated by 4-HD, which led to inhibition of the expression of receptor activator of nuclear factor-κB ligand and macrophage-colony stimulating factor in ST2 cells. By contrast, 4-HD enhanced indices of osteoblast differentiation, such as alkaline phosphatase activity and calcium deposition by osteoblastic MC3T3-E1 cells, at concentrations of 1–10 μM. Furthermore, we found that 4-HD at 1 μM attenuated H2O2 levels in MC3T3-E1 cells. Our findings indicate that 4-HD may have critical effects on bone formation and maintenance

Drug Repositioning for Cardiac Arrest

The survival rate of cardiac arrest patients is less than 10%; therefore, development of a therapeutic strategy that improves their prognosis is necessary. Herein, we searched data collected from medical facilities throughout Japan for drugs that improve the survival rate of cardiac arrest patients. Candidate drugs, which could improve the prognosis of cardiac arrest patients, were extracted using “TargetMine,” a drug discovery tool. We investigated whether the candidate drugs were among the drugs administered within 1 month after cardiac arrest in data of cardiac arrest cases obtained from the Japan Medical Data Center. Logistic regression analysis was performed, with the explanatory variables being the presence or absence of the administration of those candidate drugs that were administered to ≥10 patients and the objective variable being the “survival discharge.” Adjusted odds ratios for survival discharge were calculated using propensity scores for drugs that significantly improved the proportion of survival discharge; the influence of covariates, such as patient background, medical history, and treatment factors, was excluded by the inverse probability-of-treatment weighted method. Using the search strategy, we extracted 165 drugs with vasodilator activity as candidate drugs. Drugs not approved in Japan, oral medicines, and external medicines were excluded. Then, we investigated whether the candidate drugs were administered to the 2,227 cardiac arrest patients included in this study. The results of the logistic regression analysis showed that three (isosorbide dinitrate, nitroglycerin, and nicardipine) of seven drugs that were administered to ≥10 patients showed significant association with improvement in the proportion of survival discharge. Further analyses using propensity scores revealed that the adjusted odds ratios for survival discharge for patients administered isosorbide dinitrate, nitroglycerin, and nicardipine were 3.35, 5.44, and 4.58, respectively. Thus, it can be suggested that isosorbide dinitrate, nitroglycerin, and nicardipine could be novel therapeutic agents for improving the prognosis of cardiac arrest patients

Prognosis of Elderly Japanese Patients Aged ≥80 Years Undergoing Hemodialysis

Although the number of elderly patients requiring dialysis has increased, data regarding the prognosis of elderly patients undergoing hemodialysis are limited. In the present study, prognosis in Japanese hemodialysis patients aged ≥80 years was evaluated. From January 1988 to July 2013, 1144 consecutive patients with end-stage renal disease required renal replacement therapy at our institution; of these, 141 were aged ≥80 years. These patients’ charts were retrospectively reviewed for relevant clinical variables and survival time. The life expectancies table from the National Vital Statistics database was used, and prognostic factors were assessed by multivariate analysis. In total, 107 deaths (76%) were recorded during the study period. The median survival time and estimated life-shortening period in the patients were 2.6 years and −5.3 years, respectively. Eastern Cooperative Oncology Group Performance Status and hemoglobin level were revealed as prognostic factors in the multivariate analysis. Estimates of prognosis and prognostic factors may provide useful information for physicians as well as elderly patients with end-stage kidney disease

Abnormal spermatogenesis and male infertility in testicular zinc finger protein Zfp318-knockout mice

Zfp318, a mouse gene with a Cys2/His2 zinc finger motif, is mainly expressed in germ cells in the testis. It encodes two alternative transcripts, which regulate androgen receptor-mediated transcriptional activation or repression by overexpression of them. However, the role of Zfp318 is still obscure in vivo, especially in spermatogenesis. To elucidate the role of Zfp318 during gamete production, we established a knockout mouse line. Zfp318-null male mice exhibited infertility, whereas Zfp318-null female mice displayed normal fertility. ZFP318 was expressed during multiple stages of spermatogenesis, from spermatocytes to round spermatids. The nuclei of secondary spermatocytes showed high levels of expression. Histological analysis and quantitative analysis of DNA content showed decreased numbers of both spermatids in the seminiferous tubules and mature spermatozoa in the epididymides of Zfp318-null mice. These results suggest that Zfp318 is expressed as a functional protein in testicular germ cells and plays an important role in meiosis during spermatogenesis

ナイチンゲール病棟の設計思想とプライバシー ―時代背景にみるプライバシーの捉え方－

【要旨】著者らは，看護学生を対象にナイチンゲールが考案したナイチンゲール病棟に関するイメージ調査を行った結果，患者のプライバシー確保に関して否定的な回答がみられた．そこでナイチンゲールがプライバシーをどのように捉えているかを，ナイチンゲール著作集で確認すると，看護師側のプライバシーについてのみ記述され，患者側のプライバシーを守ることについての記述はなかった．そこで，ナイチンゲール病棟が提唱された 1860 年代からの英国文学作品 6 作品を用い，羞恥心への認識と，質問紙により現代の看護学生が感じる羞恥心レベルについて調査し，ナイチンゲール病棟の設計 思想と現代におけるプライバシーの捉え方について検討した．文献検討では，その時代前後で，病院の患者の階級や求められる医療が変化し，プライバシーが必要になった．ナイチンゲール病棟を提唱した時期はちょうどその過渡期であり，プライバシーへの十分な配慮がなされていなかったことが示唆された．看護学生のアンケート調査では，患者が治療を受ける場合，特に身体の一部が露出されるときに羞恥心が あると答えていた．ナイチンゲール病棟については，看護者の目が行き届き安心感を与えるが，患者のプラ イバシーがないと捉えていた．Abstract: We administered a questionnaire survey of a hospital ward designed by Florence Nightingale called “Nightingale ward” to nursing students, and obtained negative responses regarding securing patient privacy. Given the results above, we reviewed Nightingale’s publications to learn her perspective on privacy. Our review showed that privacy was described only from the standpoint of nurses and there was no reference to patient privacy protection. In order to investigate privacy issues with the Nightingale ward, we reviewed six British literary works published during the 1860s, the period in which the Nightingale ward was proposed, to investigate how people at that time thought about embarrassment, and surveyed the extent of patients’ embarrassment that was perceived by the present-day nursing students. Literature review showed that the social classes of inpatients and required medical care changed around the period of time in which Nightingale lived, leading to increased significance of privacy protection. The time when the Nightingale ward was proposed was exactly in the transition stage, and privacy had not been given adequate attention. According to the survey results, the nursing students felt that patients were embarrassed during treatment, especially when parts of their body were exposed. Openness of the Nightingale ward may bring a sense of ease for patients but it also poses difficulty in securing their privacy. The results indicated that this issue may be a potential factor to make patients feel embarrassed, and the Nightingale ward was therefore considered to “lack privacy.