Disease modeling of pulmonary fibrosis using human pluripotent stem cell-derived alveolar organoids

iPS細胞を用いて作製した肺胞オルガノイドで間質性肺炎の病態再現に成功 --治療満足度の低い間質性肺炎の治療薬開発に向けて前進--. 京都大学プレスリリース. 2021-11-19.Although alveolar epithelial cells play a critical role in the pathogenesis of pulmonary fibrosis, few practical in vitro models exist to study them. Here, we established a novel in vitro pulmonary fibrosis model using alveolar organoids consisting of human pluripotent stem cell-derived alveolar epithelial cells and primary human lung fibroblasts. In this human model, bleomycin treatment induced phenotypes such as epithelial cell-mediated fibroblast activation, cellular senescence, and presence of alveolar epithelial cells in abnormal differentiation states. Chemical screening performed to target these abnormalities showed that inhibition of ALK5 or blocking of integrin αVβ6 ameliorated the fibrogenic changes in the alveolar organoids. Furthermore, organoid contraction and extracellular matrix accumulation in the model recapitulated the pathological changes observed in pulmonary fibrosis. This human model may therefore accelerate the development of highly effective therapeutic agents for otherwise incurable pulmonary fibrosis by targeting alveolar epithelial cells and epithelial-mesenchymal interactions

JASTRO IC/IS Guideline for Gynecologic Cancers

It has been postulated that the combination of intracavitary and interstitial brachytherapy (IC/IS) is effective and safe for large and irregularly shaped uterine cervical cancer patients. However, due to its invasiveness compared to conventional intracavitary brachytherapy (ICBT), it has to be said that the implementation speed of IC/IS is slow. Until now, there have been no guidelines for required equipment, human resources, and procedural guide focusing solely on IC/IS. The purpose of this guideline is to provide radiation oncologists and medical physicists who wish to start IC/IS with practical and comprehensive guidance for a safe IC/IS introduction and to help accelerate the spread of the utilization of IC/IS nationwide. This is the English translation of the Japanese IC/IS Guidelines, and it was created in an effort to share the Japanese approach to the management of locally advanced uterine cervical cancer worldwide

Challenge and Outcome for the Prostate Squamous Cell Carcinoma Which Developed 8 Years after Low-Dose-Rate Brachytherapy Approached by a Combined Multimodal Treatment with High-Dose-Rate Interstitial Brachytherapy, External Beam Radiation Therapy, and Chemotherapy

Prostate squamous cell carcinoma (pSCC) rarely develops as a secondary cancer after treatment with low-dose-rate brachytherapy (LDR-BT). There is no established effective treatment for the disease condition. Herein, we present a 78-year-old man who developed pSCC 8 years after LDR-BT. He was subsequently selected to receive a combined multimodal treatment with high-dose-rate interstitial brachytherapy (HDR-ISBT), external beam radiation therapy, and chemotherapy for his pSCC. Eleven months later, he displayed no biochemical failure nor clinical radiographic recurrence. However, MRI detected a newly developed prostatic-rectal fistula (grade 4), and a colostomy was performed to relieve pain and inflammation. To our knowledge, this is the first report to perform a combined multimodal treatment with HDR-ISBT for pSCC suspected as a secondary cancer due to LDR-BT

Brachytherapy in Japan

This study aimed to assess the current state of brachytherapy (BT) resources, practices and resident education in Japan. A nationwide survey was undertaken encompassing 177 establishments facilitating BT in 2022. Questionnaires were disseminated to each BT center, and feedback through online channels or postal correspondence was obtained. The questionnaire response rate was 90% (159/177), and every prefecture had a response in at least one center. The number of centers in each prefecture ranged from 0.6 to 3.6 (median: 1.3) per million population. The annual number of patients in each center ranged from 0 to 272 (median: 31). While most prefectures provided intracavitary (IC) BT for gynecological cancers and interstitial (IS) BT for prostate cancer, only one-third of the prefectures provided IS BT for cancer sites other than the prostate. The institutional image-guided BT implementation rate was 71%. IC and IS BT was performed for 15.4% of IC BT cases of gynecological cancer. Only 47% of the BT training centers answered that they could provide adequate training in BT for residents. The most common reason for this finding was the insufficient number of patients in each center. The results show that, although BT has achieved uniformity in terms of facility penetration, new technologies are not yet widespread enough. Furthermore, IS BT, which requires advanced skills, is limited to a few BT centers, and considerable number of BT training centers do not have sufficient caseloads to provide the necessary experience for their residents

Drug-Induced Hypersensitivity Syndrome Caused by Carbamazepine Used for the Treatment of Trigeminal Neuralgia

An 88-year-old man was diagnosed with trigeminal neuralgia, and treatment of carbamazepine 200 mg/day was initiated. About 6 weeks later, the patient developed a skin rash accompanied by fever. He was admitted to hospital and diagnosed with drug-induced hypersensitivity syndrome (DIHS) caused by carbamazepine. Oral carbamazepine treatment was stopped, but blood tests showed acute liver and acute renal failure. Drug-induced lymphocyte stimulation test (DLST) for carbamazepine, human herpes virus-6 (HHV-6) IgG, and CMV-HRP were negative. Oral prednisolone therapy was begun 18 days later. The titer of HHV-6 IgG antibodies was then detected (640 times). Following treatment, liver and renal function improved and the erythema disappeared

A dietary survey in patients with chronic pancreatitis

食事療法は慢性膵炎治療の基本として重要であるが，その具体的な内容についてはあまり明確にされていない。今回，筆者らは慢性膵炎例の食事に関する全国調査の一部を担当したので，その成績を報告し，問題点と対策について考察した。対象は慢性膵炎間欠期の患者56名（男44名，女12名）である。(1)エネルギー摂取量では1日1,400kcal以下が16名（29％）にみられ，肥満度80～90％が7名および80％以下が9名という栄養状態と考え合わせて，食事の回数を増やしてでも摂取エネルギーの改善をはかる必要がある。(2)蛋白質および脂質摂取量についても同様な成績であり，消化酵素剤を投与しながら量的，質的な改善をはかる必要がある。(3)糖質については質的改善をはかる必要がある。(4)ビタミンとミネラルも不足傾向にあった。野菜の摂取不足が顕著であった。(5)診断確定後も禁酒できない患者が男17名(39％)，女1名(8％)にみられ，その指導が重要な課題である。Importance of diet therapy has been emphasized in chronic pancreatitis. However, concrete measures and programs of the diet therapy have remained to be studied. Therefore, Intractable Pancreatic Disease Study Group recently carried out a nation-wide questionnaire survey on the diets in patients with chronic pancreatitis under the auspIces of the Ministry of Health and Welfare. Attendant physicians were requested to report the nutritional states of their patients and the kinds and amounts of foods taken by their patients on three consecutive days. The nutritional state was evaluated by a body weight index calculated by the following formula:Body Weight Index (%) = Present Body Weight / Ideal Body Weight X 100. Daily nutritional intake (calorie, protein, fat, carbohydrate, and others) was calculated by dieticians according to the Food Exchange Table published by the Japanese Association of Diabetes. The present study constitutes a part of the group study. Patients consisted of 44 men and 12 women who fulfilled the diagnostic criteria proposed by the Japanese Society of Gastroenterology;20 men and 3 women had secondary diabetes mellitus. Following results and conclusions were obtained. (1) Average daily calorie intake of the patients was 1,759kcal as compared with 2,057kcal in the general population in Japan. Sixteen patients (28.6%) showed daily calorie intake less than 1,400 kcal and consequently poor nutritional states (6 patients with body weight indices less than 80% and 10 with 80-90%). It is important, therefore, to try to improve the daily calorie intake by increasing the frequency of diets in these patients. (2) Average daily intake of protein was 72.1 g (animal protein 38.1 g), only slightly less than 79.2 g (animal protein 41.7 g) in the general population. However, as many as 16 patients (28.6%) showed daily protein intake of less than 60 g and poor nutritional states as described above. It is important, therfore, to encourage patients to maintain the daily protein intake of more than 60 g by increasing the frequency of diets with oral administration of digestive enzymes. (3) Average daily intake of fat was 39.9 g (animal fat 23.8 g), approximately 20 g less than 58.3 g (animal fat 28.0 g) in the general population. As many as 17 patients (30.4%) showed daily fat intake of less than 30 g , and 16 of the 17 patients showed poor nutritional states as described above. It is important, therefore, to encourage patients to maintain the daily fat intake of more than 30 g (especially by increasing the amounts of vegetable oil) by increasing the frequency of diets with oral administration of digestive enzymes. (4) Average daily intake of carbohydrate was 278 g, almost equal to 289 g in the general population. However, many patients took as much as 48 g of carbohydrate in the from of cakes, plain sugar and alcohol beverages. Seventeen men (39%) and one woman (8%) had continued drinking alcohol beverages even after the diagnosis was made. It is important, therefore, to encourage patients to improve the quality of carbohydrate intake, although it is admittedly difficult to realize the ideal. (5) Intake of vitamins and minerals (especially calcium) also tended to be insufficient. Green vegetables were especially insufficient. (6) In conclusion, it is utmost important in chronic pancreatitis to perform periodical evaluation of nutritional intake and feed back the information to the treatment through a close patient-dietician-doctor relationship

DNaseI hypersensitivity at gene-poor, FSH dystrophy-linked 4q35.2

A subtelomeric region, 4q35.2, is implicated in facioscapulohumeral muscular dystrophy (FSHD), a dominant disease thought to involve local pathogenic changes in chromatin. FSHD patients have too few copies of a tandem 3.3-kb repeat (D4Z4) at 4q35.2. No phenotype is associated with having few copies of an almost identical repeat at 10q26.3. Standard expression analyses have not given definitive answers as to the genes involved. To investigate the pathogenic effects of short D4Z4 arrays on gene expression in the very gene-poor 4q35.2 and to find chromatin landmarks there for transcription control, unannotated genes and chromatin structure, we mapped DNaseI-hypersensitive (DH) sites in FSHD and control myoblasts. Using custom tiling arrays (DNase-chip), we found unexpectedly many DH sites in the two large gene deserts in this 4-Mb region. One site was seen preferentially in FSHD myoblasts. Several others were mapped >0.7 Mb from genes known to be active in the muscle lineage and were also observed in cultured fibroblasts, but not in lymphoid, myeloid or hepatic cells. Their selective occurrence in cells derived from mesoderm suggests functionality. Our findings indicate that the gene desert regions of 4q35.2 may have functional significance, possibly also to FSHD, despite their paucity of known genes