Efficacy and Safety of Tofacitinib in Patients with Polymyalgia Rheumatica (EAST PMR): An open-label randomized controlled trial.

BACKGROUND: Polymyalgia rheumatica (PMR) is a common inflammatory disease in elderly persons whose mechanism of pathogenesis has not been elucidated. Glucocorticoids are the main first-line treatments but result in numerous side effects. Therefore, there is a need to explore pathogenetic factors and identify possible glucocorticoid-sparing agents. We aimed to study the pathogenetic features of the disease and assess the efficacy and safety of Janus tyrosine kinase (JAK)-inhibitor tofacitinib in patients with PMR. METHODS AND FINDINGS: We recruited treatment-naïve PMR patients from the First Affiliated Hospital, Zhejiang University School of Medicine, between September 2020 and September 2022. In the first cohort, we found that the gene expression patterns of peripheral blood mononuclear cells (PBMCs) in 11 patients (10 female, 1 male, age 68.0 ± 8.3) with newly diagnosed PMR were significantly different from 20 healthy controls (17 female, 3 male, age 63.7 ± 9.8) by RNA sequencing. Inflammatory response and cytokine-cytokine receptor interaction were the most notable pathways affected. We observed marked increases in expression of IL6R, IL1B, IL1R1, JAK2, TLR2, TLR4, TLR8, CCR1, CR1, S100A8, S100A12, and IL17RA, which could trigger JAK signaling. Furthermore, tofacitinib suppressed the IL-6R and JAK2 expression of CD4+T cells from patients with PMR in vitro. In the second cohort, patients with PMR were randomized and treated with tofacitinib or glucocorticoids (1/1) for 24 weeks. All PMR patients underwent clinical and laboratory examinations at 0, 4, 8, 12, 16, 20, and 24 weeks, and PMR activity disease scores (PMR-AS) were calculated. The primary endpoint was the proportion of patients with PMR-AS ≤10 at weeks 12 and 24. Secondary endpoints: PMR-AS score, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) at weeks 12 and 24. Thirty-nine patients with newly diagnosed PMR received tofacitinib, and 37 patients received glucocorticoid. Thirty-five patients (29 female, 6 male, age 64.4 ± 8.4) and 32 patients (23 female, 9 male, age 65.3 ± 8.7) patients completed the 24-week intervention, respectively. There were no statistically significant differences in primary or secondary outcomes. At weeks 12 and 24, all patients in both groups had PMR-AS <10. PMR-AS, CRP, and ESR were all significantly decreased in both groups. No severe adverse events were observed in either group. Study limitations included the single-center study design with a short observation period. CONCLUSIONS: We found that JAK signaling was involved in the pathogenesis of PMR. Tofacitinib effectively treated patients with PMR as glucocorticoid does in this randomized, monocenter, open-label, controlled trial (ChiCTR2000038253). TRIAL REGISTRATION: This investigator-initiated clinical trial (IIT) had been registered on the website (http://www.chictr.org.cn/, ChiCTR2000038253).

Association of abnormal glucose metabolism and insulin resistance in patients with atypical and typical endometrial cancer.

This study aimed to detect glucose metabolism indicators and insulin resistance index in patients with endometrial cancer, and to explore the clinical significance and correlation between them. A total of 65 patients with endometrial cancer (52 of typical endometrial and 13 cases of atypical endometrial cancer patients, 27 with diabetes mellitus, and 38 cases without diabetes mellitus) were selected at the People's Hospital of Rizhao from June, 2010 to June, 2016 to serve as the observation group. During the same period, 62 patients with endometrial benign lesions (24 with diabetes mellitus and 38 cases without diabetes mellitus) were selected as the control group. General information including height, body weight, body mass index (BMI), abdominal, waist and hip circumference, and waist-to-hip ratio (WHR) was compared between the two groups. Fasting blood glucose, glycosylated hemoglobin, fasting insulin level (FINS), insulin resistance index (HOMA-IR), follicle estrogen (FSH), luteinizing hormone and estradiol (estrogen) were detected and compared between the two groups. Multivariate logistic regression was used to analyze the risk factors for endometrial cancer. The results showed that there were no significant differences in the height and hip circumference among the typical, atypical and control groups. By contrast, weight, BMI, waist circumference, abdominal circumference and the WHR of the typical group were significantly higher than those of the atypical and control groups (P<0.05). No significant differences were found between the atypical and control groups (P>0.05). Levels of the FINS and HOMA-IR typical group were significantly higher than those in the atypical and control groups, and the incidence of hyperinsulinemia and insulin resistance was significantly higher in the observation than in the control group (P<0.05). Of the patients with diabetes, the levels of FINS, HOMA-IR and estrogen were significantly higher, but the level of FSH was significantly lower in the observation compared to the control group (P<0.05). For patients without diabetes, significant differences in the levels of FINS and HOMA-IR were found between the observation and control groups (P<0.05). There was no significant difference in the levels of FINS and HOMA-IR among endometrial cancer patients with different pathological features (P>0.05). HOMA-IR (OR=1.240), estrogen (OR=1.192) and FSH (OR=1.002) are risk factors for endometrial cancer. The results suggest that hyperinsulinemia and insulin resistance are risk factors of endometrial cancer. Insulin may therefore be involved in the development of endometrial cancer by affecting the level of sex hormones.

Knockdown of CIP2A sensitizes ovarian cancer cells to cisplatin: an in vitro study.

BACKGROUND: CIP2A is a recently characterized oncoprotein which involves in the progression of several human malignancies. CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis. This study was performed to investigate the role of CIP2A in ovarian cancer (OC) chemoresistance. METHODS: Using DDP-resistant SKOV3 cells (SKOV3(DDP)), we first determined the effect of CIP2A silencing by siRNA-mediated knockdown of CIP2A on chemosensitivity in vitro; we then determined the effect of pCDNA3.1-mediated overexpression of CIP2A on chemosensitivity in SKOV3 cells in vitro. To elucidate the molecular mechanisms underlying CIP2A-mediated chemoresistance, the activities of AKT signaling molecules associated with CIP2A were analyzed. RESULTS: Knockdown of endogenous CIP2A in SKOV3(DDP) cells resulted in the reduction in cell growth and increase in the chemosensitivity of SKOV3(DDP) cells to DDP in vitro, which may be caused by CIP2A-induced AKT activity inhibition. Notably, CIP2A overexpression could significantly decrease the sensitivities of SKOV3 cells to cisplatin, which might be ascribed to CIP2A-induced activation of the AKT pathway. CONCLUSIONS: Taken together, the results suggest that CIP2A contributes to cisplatin resistance in OC. Thus, CIP2A is a potential therapeutic target for OC.