前立腺癌において転写超保存領域Uc.63+はアンドロゲン受容体シグナルを介してドセタキセル抵抗性を促進させる

広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

Immobilization-induced hypersensitivity associated with spinal cord sensitization during cast immobilization and after cast removal in rats

This study examined mechanical and thermal hypersensitivity in the rat hind paw during cast immobilization of the hind limbs for 4 or 8 weeks and following cast removal. Blood flow, skin temperature, and volume of the rat hind paw were assessed in order to determine peripheral circulation of the hind limbs. Sensitization was analyzed by measuring the expression of the calcitonin gene-related peptide (CGRP) in the spinal dorsal horn following cast immobilization. Two weeks post immobilization, mechanical and thermal sensitivities increased significantly in all rats; however, peripheral circulation was not affected by immobilization. Cast immobilization for 8 weeks induced more serious hypersensitivity compared to cast immobilization for 4 weeks. Moreover, CGRP expression in the deeper lamina layer of the spinal dorsal horn increased in the rats immobilized for 8 weeks but not in those immobilized for 4 weeks. These findings suggest that immobilization-induced hypersensitivity develops during the immobilization period without affecting peripheral circulation. Our results also highlight the possibility that prolonged immobilization induces central sensitization in the spinal cord.The final publication is available at link.springer.co

Hyperalgesia in an immobilized rat hindlimb: Effect of treadmill exercise using non-immobilized limbs

Cast immobilization of limbs causes hyperalgesia, which is a decline of the threshold of mechanical and thermal mechanical stimuli. The immobilization-induced hyperalgesia (IIH) can disturb rehabilitation and activities of daily living in patients with orthopedic disorders. However, it is unclear what therapeutic and preventive approaches can be used to alleviate IIH. Exercise that activates the descending pain modulatory system may be effective for IIH. The purpose of this study was to investigate the effects of treadmill exercise during the immobilization period, using the non-immobilized limbs, on IIH. Thirty-six 8-week-old Wistar rats were randomly divided into (1) control, (2) immobilization (Im), and (3) immobilization and treadmill exercise (Im. +. Ex) groups. In the Im and Im. +. Ex groups, the right ankle joints of each rat were immobilized in full plantar flexion with a plaster cast for an 8-week period. In the Im. +. Ex group, treadmill exercise (15. m/min, 30. min/day, 5 days/week) was administered during the immobilization period while the right hindlimb was kept immobilized. Mechanical hyperalgesia was measured using von Frey filaments every week. To investigate possible activation of the descending pain modulatory system, beta-endorphin expression levels in hypothalamus and midbrain periaqueductal gray were analyzed. Although IIH clearly occurred in the Im group, the hyperalgesia was partially but significantly reduced in the Im. +. Ex group. Beta-endorphin, which is one of the endogenous opioids, was selectively increased in the hypothalamus and midbrain periaqueductal gray of the Im. +. Ex group. Our data suggest that treadmill running using the non-immobilized limbs reduces the amount of hyperalgesia induced in the immobilized limb even if it is not freed. This ameliorating effect might be due to the descending pain modulatory system being activated by upregulation of beta-endorphin in the brain

A randomized phase III study of short-course radiotherapy combined with Temozolomide in elderly patients with newly diagnosed glioblastoma; Japan clinical oncology group study JCOG1910 (AgedGlio-PIII)

BACKGROUND: The current standard treatment for elderly patients with newly diagnosed glioblastoma is surgery followed by short-course radiotherapy with temozolomide. In recent studies, 40 Gy in 15 fractions vs. 60 Gy in 30 fractions, 34 Gy in 10 fractions vs. 60 Gy in 30 fractions, and 40 Gy in 15 fractions vs. 25 Gy in 5 fractions have been reported as non-inferior. The addition of temozolomide increased the survival benefit of radiotherapy with 40 Gy in 15 fractions. However, the optimal regimen for radiotherapy plus concomitant temozolomide remains unresolved. METHODS: This multi-institutional randomized phase III trial was commenced to confirm the non-inferiority of radiotherapy comprising 25 Gy in 5 fractions with concomitant (150 mg/m2/day, 5 days) and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant (75 mg/m2/day, every day from first to last day of radiation) and adjuvant temozolomide in terms of overall survival (OS) in elderly patients with newly diagnosed glioblastoma. A total of 270 patients will be accrued from 51 Japanese institutions in 4 years and follow-up will last 2 years. Patients 71 years of age or older, or 71-75 years old with resection of less than 90% of the contrast-enhanced region, will be registered and randomly assigned to each group with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in April 2020. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in August 2020. DISCUSSION: If the primary endpoint is met, short-course radiotherapy comprising 25 Gy in 5 fractions with concomitant and adjuvant temozolomide will be a standard of care for elderly patients with newly diagnosed glioblastoma. TRIAL REGISTRATION: Registry number: jRCTs031200099 . Date of Registration: 27/Aug/2020. Date of First Participant Enrollment: 4/Sep/2020

Molecular mechanisms of docetaxel resistance in prostate cancer

Docetaxel (DTX) chemotherapy offers excellent initial response and confers significant survival benefit in patients with castration-resistant prostate cancer (CRPC). However, the clinical utility of DTX is compromised when primary and acquired resistance are encountered. Therefore, a more thorough understanding of DTX resistance mechanisms may potentially improve survival in patients with CRPC. This review focuses on DTX and discusses its mechanisms of resistance. We outline the involvement of tubulin alterations, androgen receptor (AR) signaling/AR variants, ERG rearrangements, drug efflux/influx, cancer stem cells, centrosome clustering, and phosphoinositide 3-kinase/AKT signaling in mediating DTX resistance. Furthermore, potential biomarkers for DTX treatment and therapeutic strategies to circumvent DTX resistance are reviewed

A 49-year-old woman presenting with hepatoid adenocarcinoma of the urinary bladder: a case report

Abstract Introduction Adenocarcinomas represent less than 2 percent of all urothelial neoplasms. Hepatoid adenocarcinoma is rare in the urinary bladder. Pathological diagnosis is based on a combination of histological features resembling hepatocellular carcinoma and positive immunostaining for α-fetoprotein. Case presentation We report a case of hepatoid adenocarcinoma of the urinary bladder. A 49-year-old Japanese woman underwent a total mastectomy, and post-operatively abdominal computed tomography revealed a tumor of the urinary bladder. Trans-urethral resection of the bladder tumor was performed, and pathological examination revealed a hepatoid adenocarcinoma of the urinary bladder. Our patient has had no evidence of recurrence 20 months after surgery to remove the tumor. Conclusions Hepatoid adenocarcinoma seems to be an aggressive malignant neoplasm that is rare in the urinary bladder. This case report is only the ninth case of hepatoid adenocarcinoma in the urinary bladder to appear in the literature. It is important to be aware of atypical cancer localizations in order to reach a correct diagnosis.</p

Non-coding RNAs are promising targets for stem cell-based cancer therapy

The term ânon-coding RNAâ (ncRNA) is generally used to indicate RNA that does not encode a protein and includes several classes of RNAs, such as microRNA and long non-coding RNA. Several lines of evidence suggest that ncRNAs appear to be involved in a hidden layer of biological procedures that control various levels of gene expression in physiology and development including stem cell biology. Stem cells have recently constituted a revolution in regenerative medicine by providing the possibility of generating suitable cell types for therapeutic use. Here, we review the recent progress that has been made in elaborating the interaction between ncRNAs and tissue/cancer stem cells, discuss related technical and biological challenges, and highlight plausible solutions to surmount these difficulties. This review particularly emphasises the involvement of ncRNAs in stem cell biology and in vivo modulation to treat and cure specific pathological disorders especially in cancer. We believe that a better understanding of the molecular machinery of ncRNAs as related to pluripotency, cellular reprogramming, and lineage-specific differentiation is essential for progress of cancer therapy. Keywords: Stem cell-based therapy, Non-coding RNA, Transcribed ultraconserved regio