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Yosuke Ota, Yukihiro Itoh, Takashi Kurohara, Ritesh Singh, Elghareeb E. Elboray, Chenliang Hu, Farzad Zamani, Anirban Mukherjee, Yuri Takada, Yasunobu Yamashita, Mie Morita, Mano Horinaka, Yoshihiro Sowa, Mitsuharu Masuda, Toshiyuki Sakai, and Takayoshi Suzuki. ACS Medicinal Chemistry Letters 2022 13 (10), 1568-1573. DOI: 10.1021/acsmedchemlett.2c00126. Copyright © 2022 American Chemical Society., Anticancer drug delivery by small molecules offers a number of advantages over conventional macromolecular drug delivery systems. We previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) as small-molecule-based drug delivery vehicles for targeting lysine-specific demethylase 1 (LSD1)-overexpressing cancers. In this study, we applied this PDC strategy to the HDAC-inhibitory anticancer agent vorinostat. Among three synthesized PCPA or arylcyclopropylamine (ACPA)-vorinostat conjugates 1, 9, and 32, conjugate 32 with a 4-oxybenzyl linker showed sufficient stability in buffer solutions, potent LSD1 inhibition, efficient LSD1-dependent vorinostat release, and potent and selective antiproliferative activity toward LSD1-expressing human breast cancer and small-cell lung cancer cell lines. These results indicate that the conjugate selectively releases vorinostat in cancer cells. A similar strategy may be applicable to other anticancer drugs.

Additional file 2. Supplementary Table 2.

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Additional file 3. Supplementary Table 3.

Supplementary Fig. 1. Homozygous gpt delta rat genotyping. Supplementary Fig. 2. Distribution map of read-pairs covering EG10 copy junctions in homozygous gpt delta rats.

Supplemental Digital Content is available in the text, Rationale: Foreign body (FB) ingestion is a relatively common clinical situation in the emergency department. However, multiple sharply pointed foreign bodies located in different organs are rare conditions and no definite treatment guidelines has been established. Patient concerns: A 31-year-old amateur magician visited the outpatient clinic with a chief complaint of epigastric discomfort. He might have accidentally swallowed some needles while practicing a magic trick 2 days before. Diagnosis: Imaging tests revealed 1 needle was stuck in the left liver lobe through the stomach wall, 1 was in the third portion of the duodenum, 3 were in the ascending colon, and 2 were in the transverse colon. Interventions: A needle in the duodenum and 5 in the colon were removed by endoscopy. The needle stuck in the liver from the stomach was not visible inside the stomach and was successfully removed by laparoscopy a few days later. Outcomes: The patient was able to tolerate an oral diet and was discharged on postoperative day 4 without any complications. Lessons: Developing a treatment plan in cases of multiple sharp FB may be difficult. A multidisciplinary team of endoscopists and surgeons is needed to determine the best possible treatment plan. This experience illustrates the importance of the planning of the sequence and method of removal of multiple foreign bodies from the gastrointestinal tract.

Atypical adenoma of the thyroid is a rare form of tumor, and its accurate diagnosis prior to surgical resection is difficult as the histological and pathological morphologies are very similar to those of anaplastic thyroid carcinoma (ATC), and its anaplastic transformation remains to be elucidated. We reported a case of a 75-year-old female with a thyroid isthmus nodule diagnosed repeatedly by FNAC as anaplastic carcinoma. Both the first and second FNAC specimen slides showed a large number of scattered or aggregated atypical cells consisting of large, pleomorphic nuclei with irregular membranes, chromatin clumps and prominent nucleoli. The morphology of the surgical specimen was similar to that of an anaplastic carcinoma and although it showed signs of transition from a normal follicular epithelium, there was no invasive growth or mitosis. This lesion was diagnosed as an atypical adenoma, and a papillary carcinoma was also present in the right lobe of the thyroid. Here we evaluate the molecular features of atypical adenomas in comparison with 9 ATC samples, and discuss whether or not atypical adenomas represent a form of premalignant lesion. Ki-67 expression was found to be very low in atypical adenomas whereas all ATC samples showed high levels of Ki-67 expression. Epithelial-mesenchymal transition (EMT) marker expression suggested that atypical adenomas maintain their epithelial phenotype to a higher degree than do ATCs. Differential diagnosis between ATC and atypical adenoma is difficult by cytological and histological methods alone, and Ki-67 and EMT marker expression may support the diagnosis.

The intermediate‐conductance Ca2+‐activated K+ channel KC a3.1 is involved in the promotion of tumor growth and metastasis, and is a potential therapeutic target and biomarker for cancer. Histone deacetylase inhibitors (HDACis) have considerable potential for cancer therapy, however, the effects of HDACis on ion channel expression have not yet been investigated in detail. The results of this study showed a significant decrease in KC a3.1 transcription by HDAC inhibition in the human breast cancer cell line YMB‐1, which functionally expresses KCa3.1. A treatment with the clinically available, class I, II, and IV HDAC inhibitor, vorinostat significantly downregulated KC a3.1 transcription in a concentration‐dependent manner, and the plasmalemmal expression of the KC a3.1 protein and its functional activity were correspondingly decreased. Pharmacological and siRNA‐based HDAC inhibition both revealed the involvement of HDAC2 and HDAC3 in KC a3.1 transcription through the same mechanism. The downregulation of KC a3.1 in YMB‐1 was not due to the upregulation of the repressor element‐1 silencing transcription factor, REST and the insulin‐like growth factor‐binding protein 5, IGFBP5. The significant decrease in KC a3.1 transcription by HDAC inhibition was also observed in the KC a3.1‐expressing human prostate cancer cell line, PC‐3. These results suggest that vorinostat and the selective HDACis for HDAC2 and/or HDAC3 are effective drug candidates for KC a3.1‐overexpressing cancers.

Additional file 3. Supplementary material for: Effective cleaning of rust stained marble.

The histone lysine demethylase KDM4 subfamily, comprised of four members (A, B, C, and D), play critical roles in controlling transcription, chromatin architecture and cellular differentiation. We previously demonstrated that KDM4C is significantly amplified and overexpressed in aggressive basal-like breast cancers and functions as a transforming oncogene. However, information regarding the genomic and transcriptomic alterations of the KDM4 subfamily in different subtypes of breast cancer remains largely incomplete. Here, we conducted a meta-analysis of KDM4A, B, C and D in breast cancer and identified associations among recurrent copy number alterations, gene expression and breast cancer subtypes. We demonstrated that KDM4A and D are also significantly overexpressed in basal-like breast cancer, whereas KDM4B overexpression is more dominant in estrogen-receptor-positive, luminal breast cancer. Next, we investigated the therapeutic potential of a novel histone demethylase inhibitor, NCDM-32B, in breast cancer. The treatment of basal breast cancer cell lines with NCDM-32B resulted in the decrease of cell viability and anchorage independent growth in soft agar. Furthermore, we found that NCDM-32B impaired several critical pathways that drive cellular proliferation and transformation in breast cancer. Our findings demonstrate genetic amplification and overexpression of the KDM4 demethylases in different subtypes of breast cancer. Furthermore, histone methylation is reversible and KDM4 demethylases are druggable targets. Thus, KDM4 inhibitors may serve as a novel therapeutic approach for a subset of aggressive breast cancer.

text, 紀要論文 / Departmental Bulletin Paper

Human lymphoblastoid cell line TK6 was used to investigate TK gene mutation frequency and the loss of heterozygosity (LOH) induced by cyclophosphamide (CP).Relative survival, mutation frequency at tk locus induced by CP (+S9) after 4 h treatment were detected. DNA isolated from mutants in the control culture and CP treatment group was analyzed for LOH.Exposure to CP for 4 h decreased relative survival, induced TK gene mutation in a dose-dependent manner. Doubling time of normally and slowly growing mutants was (14.6 +/- 1.74) h and (35.8 +/- 3.78) h respectively. The percentage of hemizygous LOH in CP-induced mutants (50%) was 2.4 times than that of the control (20.7%).Great damage to TK gene is the main cause of mutation induced by CPin TK6 cells.

Gravity is one of factors to maintain our living system to be active and healthy, because our biological system is constructed based on at least three important conditions under gravity on the earth as follows: (1) activity-dependent system at both levels of the cell and body, (2) morpho-dynamic system constituted of the cytoskeleton and extracellular matrix as, and (3) self organization to keep centering their mass at both levels of the cell and body. Such a system is organized by dynamically regulated protein filament system, such as actin, tubulin/MicroTubule (MT) and intermediate filament system. The use of filaments (the cytoskeleton, which is regulated with dynamic property) must be essential for maintaining shape responding own mobile activity intrinsic for especially animals under the gravity on the earth. Keeping such a morpho-dynamic system needs molecular chaperone, which takes care of free forms of proteins to keep equilibrium balancing free forms and filamentous forms, which has various functional properties of polarity, pushing ability, making various shapes and making fulcrum in the association with other protein complex at focal adhesion and extracellular matrix. Striated muscles are typical organized form that we can analyze a mechanism of two cytoskeleton systems of actin and tubulin/microtubule, because they work with balanced force each other under physiological condition against calcium oscillation per each beating. These organization of the cytoskeleton realizes autonomic beating like everlasting nonstop ping machine. It is interesting to study that what factors strongly relates to autonomous system, quantity of tension, and dynamic property. Studies to characterize tubulin/MT are rare in striated muscles. Beating heart expresses molecular chaperone alpha B-crystallin like as untigravitational muscle, which may support continuous beating keeping dynamic instability by taking care of chaperoning free forms of tubulin, actin and intermediate filament. Under space the expression levels of alpha B-crystallin may decrease because of the unloaded work performed by cardiac myocyte., 資料番号: AA0063706085

A number of N, N-dibenzylaminoacetaldehyde diakyl acetales (1) double-cyclized in 70% perchloric acid or triflic acid (trifluoromethanesulfonic acid) to give good yields of 7, 12-dihydro-5H-6, 12-methanodibenz[c, f]azocines (2) even when a powerful electron-withdrawing substituent, for example a nitro group, was present on the benzene ring. Triflic acid treatment of α-dibenzylaminoketones (3) caused double-cyclization to give 12-substituted derivatives of 2.

Vitamin D-sulfur dioxide adducts undergo regioselective methylation at C-6 with sodium hydride used as the base and at C-19 with lithium tetramethylpiperidide. The methylated adducts are converted to the corresponding vitamin D derivatives by extrusion of sulfur dioxide.

Leiomyoma is one of the most commonly observed esophageal submucosal tumors, often appearing as a smooth-surfaced and semicircular protruded lesion. It sometimes grows toward the esophageal lumen and may be pedunculated in rare cases. We encountered a case of a pedunculated esophageal submucosal tumor diagnosed before treatment as a leiomyoma originating in the muscularis mucosae of a 68-year-old man. As the tumor arose in the muscularis mucosae, it could be safely resected via an endoscopic procedure. Only one case of pedunculated leiomyoma has been reported to date, and we herein report the second case, which was successfully treated by a minimally invasive endoscopic technique.