Expression and Function of Androgen Receptor Coactivator p44/Mep50/WDR77 in Ovarian Cancer

Hormones, including estrogen and progesterone, and their receptors play an important role in the development and progression of ovarian carcinoma. Androgen, its receptor and coactivators have also been implicated in these processes. p44/Mep50/WDR77 was identified as a subunit of the methylosome complex and lately characterized as a steroid receptor coactivator that enhances androgen receptor as well as estrogen receptor-mediated transcriptional activity in a ligand-dependent manner. We previously described distinct expression and function of p44 in prostate, testis, and breast cancers. In this report, we examined the expression and function of p44 in ovarian cancer. In contrast to findings in prostate and testicular cancer and similar to breast cancer, p44 shows strong cytoplasmic localization in morphologically normal ovarian surface and fallopian tube epithelia, while nuclear p44 is observed in invasive ovarian carcinoma. We observed that p44 can serve as a coactivator of both androgen receptor (AR) and estrogen receptor (ER) in ovarian cells. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in ovarian cancer cells in the presence of estrogen or androgen. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during ovarian tumorigenesis

The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation

Purpose: In children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients. Methods: Data were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition. Results: Forty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5-17.7 and 0.05-14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07-0.35) vs. 0.09 (0.02-0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04-0.32) vs. 0.09 (0.01-0.18) mg/kg/12h, p

Risk Factors for COVID-19 Infection in Adult Patients: A Retrospective Observational Study in Japan

Akie Yoshida,1 Kazuhiro Furumachi,2 Etsuko Kumagai,2 Keiko Hosohata1 1Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka, Japan; 2Department of Nephrology, Kenwakai Hospital, Nagano, JapanCorrespondence: Keiko Hosohata, Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka, Japan, Tel +81-72-690-1271, Fax +81-72-690-1023, Email [email protected]: The aim of the study was to identify the characteristics of patients infected with coronavirus disease 2019 (COVID-19) and to determine risk factors for COVID-19 infection in Japanese patients.Patients and Methods: We conducted a single-center retrospective observational study in Japanese adult patients (≥ 20 years) who visited Kenwakai Hospital (Nagano Japan). We analyzed data of 378 patients (mean age, 75 ± 14 years; men, 54%) from the hospital’s electronic information system. COVID-19 was diagnosed by polymerase-chain reaction. Patients were divided into 2 groups based on diagnosis of COVID-19.Results: Patients infected with COVID-19 showed significantly higher rates of men (69.8 vs 51.6%, P = 0.025) than uninfected control patients. After adjustment for possible confounding factors, COVID-19 infection was significantly associated with BUN (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.01– 1.03) and serum creatinine (Scr) (OR, 1.14; 95% CI, 1.05– 1.24). This association was observed in men (BUN, P = 0.012; Scr, P = 0.012), but not in women (BUN, P = 0.43; Scr, P = 0.54).Conclusion: BUN and Scr are potential risk factors for infection of COVID-19 in Japanese patients, particularly in men. Our results suggest that renal parameters might be important in Japanese male patients for the early detection of COVID-19 infection.Keywords: adult patients, COVID-19, risk factors, kidney function, Japanes

Drug-induced tubulointerstitial nephritis in a retrospective study using spontaneous reporting system database

Saki Oyama, Keiko Hosohata, Ayaka Inada, Iku Niinomi, Yasuhiro Mori, Yuki Yamaguchi, Mayako Uchida, Kazunori Iwanaga Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan Introduction: Tubulointerstitial nephritis (TIN) is a problem in clinical settings because drug therapy is the cause in most cases. Patients often present with nonspecific symptoms, which can lead to delays in the diagnosis and treatment of the disease. The purpose of this study was to clarify the rank-order of the association of TIN with the causative drugs using a spontaneous reporting system database. Materials and methods: Data were extracted from the Japanese Adverse Drug Event Report database of the Pharmaceuticals and Medical Devices Agency (Japan). Based on 5,195,890 reports of all adverse reactions, we obtained 3,088 reports of TIN caused by all drugs and calculated the reporting odds ratio (ROR) and 95% CI for TIN. Results: The 5 drugs with the highest RORs were gliclazide (ROR, 30.5; 95% CI, 17.4&ndash;53.2), tosufloxacin tosilate hydrate (ROR, 29.5; 95% CI, 21.3&ndash;41.0), piperacillin&ndash;tazobactam (ROR, 24.3; 95% CI, 19.4&ndash;30.5), cefteram pivoxil (ROR, 23.5; 95% CI, 12.5&ndash;44.2), and mefenamic acid (ROR, 22.5; 95% CI, 13.4&ndash;37.7). No sex-related difference was observed in drug-induced TIN. Most of the reports about TIN onset following the administration of culprit drugs were recorded within 12 weeks. Conclusion: Based on the results, a comprehensive study using a pharmacovigilance database enabled us to identify the dugs that most frequently induced TIN, so these drugs should be used carefully in clinical practice to avoid TIN. Keywords: tubulointerstitial nephritis, pharmacovigilance, spontaneous reporting system, reporting odds ratio, Japanese Adverse Drug Event Report database, JADE

Evaluation of medication-related osteonecrosis of the jaw using the Japanese Adverse Drug Event Report database

Ayaka Inada, Keiko Hosohata, Saki Oyama, Iku Niinomi, Yasuhiro Mori, Yuki Yamaguchi, Mayako Uchida, Kazunori Iwanaga Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569-1094, Japan Background: Bisphosphonates (BPs) and denosumab are widely used to treat osteoporosis and complications associated with bone metastases. However, medication-related osteonecrosis of the jaw (MRONJ) is a serious problem. Objective: The objective of this study was to evaluate the frequency, outcome, and characteristics of patients with drug-induced MRONJ. Methods: Retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database from the Pharmaceuticals and Medical Devices Agency. Adverse event reports submitted to JADER between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) was calculated. Results: Among the BPs that cause MRONJ, zoledronate was the most common; therefore, we compared the characteristics of cases of MRONJ induced by zoledronate with those induced by denosumab. Among the 3,875 (68.1% women) cases of MRONJ, zoledronate-related MRONJ accounted for 1,283 (56.0% women) and denosumab-related MRONJ accounted for 322 (55.3% women). MRONJ was more frequent after 70 years of age regardless of the use of either zoledronate or denosumab; onset occurred after 1 year from the denosumab treatment, but it is unknown when onset occurred after zoledronate treatment. The outcomes for MRONJ were poor, with 406 reports on zoledronate (31.6%) and 152 reports on denosumab (47.2%) demonstrating nonrecovery. Zoledronate (ROR: 319.3, 95% CI: 296.0&ndash;344.4) had the highest ROR among BP agents. Denosumab had a high ROR (ROR: 155.2, 95% CI: 136.5&ndash;176.3). Zoledronate and denosumab were used in similar patient backgrounds, and their use resulted in a similar frequency of MRONJ. Conclusion: The findings of this comprehensive evaluation of MRONJ using the JADER database will be helpful for prescribing medications to elderly patients. Keywords: medication-related osteonecrosis of the jaw, pharmacovigilance, spontaneous reporting system, reporting odds ratio, Japanese Adverse Drug Event Report databas