HFIGMI–VMAT for brain metastases

Volumetric-modulated arc therapy (VMAT) can be used to design hypofractionated radiotherapy treatment plans for multiple brain metastases. The purpose of this study was to evaluate treatment outcomes of hypofractionated image-guided multifocal irradiation using VMAT (HFIGMI–VMAT) for brain metastases. From July 2012 to December 2016, 67 consecutive patients with 601 brain metastases were treated with HFIGMI–VMAT at our institution. The prescribed dose was 50 Gy to a 95% volume of the planning target volume in 10 fractions. Fifty-five of the 67 patients had non-small-cell lung cancer, and the remaining 12 had other types of cancer. The median number of brain metastases was five, and the median maximum diameter was 1.2 cm. The median duration of follow-up was 12.0 months (range, 1.9–44.8 months), and the median survival time 18.7 months. Four patients with six lesions had local recurrences. The local control rate in the 64 assessed patients was 98.4% and 95.3% at 6 and 12 months, respectively (three died before assessment). The local control rate for the 572 assessed lesions was 99.8% and 99.3% at 6 and 12 months, respectively. Thirty-nine patients developed distant brain metastases, the distant brain control rate being 59.7% and 40.5% at 6 and 12 months, respectively. Acute toxicities were generally mild (Grade 1–2). Three patients (4.5%) developed radiation necrosis requiring corticosteroid therapy. The HFIGMI–VMAT technique with flat dose delivery was well tolerated and achieved excellent local control. This technique is a promising treatment option for patients with multiple and large brain metastases

Is the progression of treatment for patients with hemophilia leading to improvements in school or social life?: A questionnaire survey for mothers of children or adolescents who chiefly receive prophylactic treatment for hemophilia.

【背景】血友病患者の治療は進歩した。そこで治療の進歩による患者の学校・社会生活の詳細を明らかにするために，母親を対象に，若年世代の患者の学校・社会生活，母親の困り事について実態調査した。 【方法】血友病患者の母親を対象に，無記名自記式の質問紙調査を実施した。 【結果】母親27人の回答が得られ，息子である患者は30人だった。定期輸注実施は23人で，そのうち家庭で輸注を行う者は22人だった。通園経験のある者は27人だった。全ての行事に参加させた者が18人だった。宿泊行事中の定期輸注の実施について，中学生までは学校に支援依頼していた。患者８人は自己注射し，高校生以降の患者４人は，自室で一人の時に注射をしたという回答だった。母親の困り事は「血管確保の失敗と焦り」だった。 【結論】治療の進歩は患者の学校・社会生活を改善した。しかし継続的治療を支える家族の負担のもとに成立する。今後必要な医療支援として，患者の宿泊行事中の輸注において，患者が安心して注射できる場所についての助言が示された。Background: Hemostatic treatment for patients with hemophilia（ PWH） has improved. The aim of this study was to clarify school status and social life among young boys with hemophilia, as well as their mothers’ frustrations. Methods: A questionnaire survey was completed anonymously by mothers of hemophilic boys. Results: A total of 27 mothers of 30 PWHs completed the survey. Twenty-three PWHs had received prophylactic treatment, and 22 received home infusion therapy. Twenty-seven PWHs had attended preschool, and 18 had participated in all preschool/school events. When factor concentrates needed to be infused during overnight events, many mothers requested the assistance of medical staff until the PWHs were junior high school students. When they were high school students, eight PWHs were able to infuse themselves. Four PWHs were reported to infuse alone, hiding from the public eye. Mothers’ chief source of frustration was“ infusion failure on busy mornings.” Conclusion: This study indicates that the progress of treatment for PWHs may improve the school or social life of patients. However, these patients’ family support is also essential for the patients’ treatment. Medical support, such as advice about where to self-infuse during overnight events is needed for PWHs

ERRγ agonist under mechanical stretching manifests hypertrophic cardiomyopathy phenotypes of engineered cardiac tissue through maturation

iPS細胞から成熟した人工心筋組織の作製方法の開発 肥大型心筋症の治療法開発への利用に期待. 京都大学プレスリリース. 2023-10-06.Stretching and stimulating engineered heart tissues to accurately portray hypertrophic cardiomyopathy. 京都大学プレスリリース. 2023-10-17.Engineered cardiac tissue (ECT) using human induced pluripotent stem cell-derived cardiomyocytes is a promising tool for modeling heart disease. However, tissue immaturity makes robust disease modeling difficult. Here, we established a method for modeling hypertrophic cardiomyopathy (HCM) malignant (MYH7 R719Q) and nonmalignant (MYBPC3 G115∗) pathogenic sarcomere gene mutations by accelerating ECT maturation using an ERRγ agonist, T112, and mechanical stretching. ECTs treated with T112 under 10% elongation stimulation exhibited more organized and mature characteristics. Whereas matured ECTs with the MYH7 R719Q mutation showed broad HCM phenotypes, including hypertrophy, hypercontraction, diastolic dysfunction, myofibril misalignment, fibrotic change, and glycolytic activation, matured MYBPC3 G115∗ ECTs displayed limited phenotypes, which were primarily observed only under our new maturation protocol (i.e., hypertrophy). Altogether, ERRγ activation combined with mechanical stimulation enhanced ECT maturation, leading to a more accurate manifestation of HCM phenotypes, including non-cardiomyocyte activation, consistent with clinical observations

鉄存在下HepG2細胞におけるTNF-α/actinomycin D処理による肝障害モデルの構築

We examained the contribution of iron to the cytotoxicity of tumor necrosis factor (TNF)-a combined with actinomycin D (ActD) as a model of hepatocyte injury in Hep G2 cells. In general,hepatocytes are resistant to TNF-a. However,a transcriptional inhibitor such as ActD can sensitize then to TNF-a. In the present study, we show that low levels of ActD (0.5nM) sensitized HepG2 cells to the cytotoxic effects of TNF-a (20 ng/mL) for 48h. Iron plays a critical role in catalyxing the formation of potent oxidants. To acsses the toxicological significance of this TNF-a/ActD interaction,ferric-nitrilotriacetate (Fe-NTA,2uM) was added to the cells. Treatment with Fe-NTA significantly increased the sensitivity to the TNF-a/ActD-mediated cell death. TNF-a/ActD-mediated cell death in the presence of a lower concentration of iron did not result in DNA fragmentation. We suggest that iron increased the sensitivity to the cytotoxicity of TNF-a/ActD in HepG2 cells. It is likely that TNF-a/ActD/Fe-NTA-mediated cell death contributes to the non-apoptotic death of cells via oxidative stress caused by iron. Our experimental model may be useful for studying hepatic drug metabolism using TNF-a as a hepatocyte injury,especially in HepG2 cells

Effect of dietary components on renal inorganic phosphate (Pi) excretion induced by a Pi-depleted diet

Dietary inorganic phosphate (Pi) is the most important factor in the regulation of renal Pi excretion. Recent studies suggest the presence of an enteric-renal signaling axis for dietary Pi as well as the existence of a mechanism by which the intestine detects changes in luminal Pi concentrations. The mechanisms of intestinal Pi sensing, however, are unknown. In the present study, we focused on Pi depletion signals and investigated the effects of dietary components on intestinal Pi sensing. After feeding rats experimental diets for 3 days, we investigated urinary Pi excretion and plasma biochemical parameters. Renal Pi excretion was suppressed in rats fed a low-Pi diet (0.02% Pi). Elimination of dietary calcium (Ca) completely blocked the suppression of Pi excretion, suggesting that the presence of Ca is essential for the Pi depletion signal. Furthermore, a minimum Ca content of more than 0.02% was necessary for the Pi depletion signal. Magnesium, lanthanum, and strontium, which are agonists of calcium sensing receptor, instead of Ca, reduced Pi excretion.Therefore, dietary Ca appears to be important for the Pi depletion-sensing mechanism in the gastrointestinal tract. In addition, the calcium sensing receptor may be involved in the Pi depletion signal

Semaphorin 4D promotes bone invasion in head and neck squamous cell carcinoma

Head and neck squamous cell carcinomas (HNSCCs) frequently invade the bones of the facial skeleton. Semaphorin 4D (Sema4D) is an axon guidance molecule produced by oligodendrocytes. Sema4D was also identified in the bone microenvironment and many cancer tissues including HNSCC. To date, however, the role of Sema4D in cancer-associated bone disease is still unknown. This is the first study to demonstrate the role of Sema4D in bone invasion of cancer. In the clinical tissue samples of bone lesion of HNSCC, Sema4D was detected at high levels, and its expression was correlated with insulin-like growth factor-I (IGF-I) expression. In vitro experiments showed that IGF-I regulates Sema4D expression and Sema4D increased proliferation, migration and invasion in HNSCC cells. Sema4D also regulated the expression of receptor activator of nuclear factor κβ ligand (RANKL) in osteoblasts, and this stimulated osteoclastgenesis. Furthermore, knockdown of Sema4D in HNSCC cells inhibited tumor growth and decreased the number of osteoclasts in a mouse xenograft model. Taken together, IGF-I-driven production of Sema4D in HNSCCs promotes osteoclastogenesis and bone invasion