Estrogen-related receptor (ERR)α presents structural similarities with estrogen receptor (ER)α. However, it is an orphan receptor not binding to naturally occurring estrogens. This study was designed to investigate the role of ERRα in endometrial cancer progression. Immunohistochemistry analysis on 50 specimens from patients with endometrial cancer showed that ERRα was expressed in all examined tissues and the elevated expression levels of ERRα were associated with advanced clinical stages and serous histological type (p < 0.01 for each). ERRα knockdown with siRNA suppressed angiogenesis via VEGF and cell proliferation in vitro (p < 0.01). Cell cycle and apoptosis assays using flow cytometry and western blot revealed that ERRα knockdown induced cell cycle arrest during the mitotic phase followed by apoptosis initiated by caspase-3. Additionally, ERRα knockdown sensitized cells to paclitaxel. A significant reduction of tumor growth and angiogenesis was also observed in ERRα knockdown xenografts (p < 0.01). These findings indicate that ERRα may serve as a novel molecular target for the treatment of endometrial cancer.

Estrogen-related receptor alpha (ERRα), which shares structural similarities with estrogen receptors, is associated with tumor progression in endometrial cancer, but little is known about the detailed underlying mechanism. We investigated whether ERRα, in cooperation with peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), could participate in epithelial-mesenchymal transition (EMT) in endometrial cancer through cancer-stromal interactions. Two endometrial cancer cell lines, Ishikawa and HEC-1A, transfected with ERRα/PGC-1α expression plasmids or silenced for ERRα expression, were co-cultured with telomerase-transformed human endometrial stromal cells (T-HESCs). We found that EMT-associated factors including vimentin, Snail, and zinc finger E-box binding homeobox 1 were upregulated in cancer cells overexpressing ERRα/PGC-1α and that transforming growth factor-beta (TGF-β) was induced in T-HESCs in the same conditions. In contrast, ERRα knockdown suppressed EMT-associated factors in cancer cells and TGF-β in T-HESCs. ERRα/PGC-1α overexpression increased the expression of EMT-associated factors after TGF-β exposure; however, it decreased E-cadherin at protein level. ERRα knockdown suppressed EMT-associated factors in the presence of TGF-β, whereas E-cadherin remained unchanged. Matrigel invasion assays revealed that ERRα knockdown attenuated the stimulation of migration and invasion by TGF-β. These findings suggest that ERRα is a potential target for inhibiting TGF-β-induced EMT through cancer-stromal interactions in endometrial cancer.

IntroductionRecombinant human soluble thrombomodulin (rhTM) is a novel anti-coagulant agent that regulates the imbalanced coagulation system by reducing the excessive activation of thrombin. rhTM potentially reduces the morbidity and mortality in patients with sepsis-induced disseminated intravascular coagulation (DIC). However, the efficacy of rhTM in obstetric DIC has not yet been established. We performed this study to examine whether the administration of rhTM was a potentially effective treatment for DIC induced by one or more underlying obstetric disorders.MethodsThis is a single-center, retrospective cohort study conducted between January 2007 and February 2015 using the records of the Department of Obstetrics at the Perinatal Medical Center of TOYOTA Memorial Hospital, Aichi, Japan. The eligibility criteria were known or suspected obstetric DIC documented on the basis of clinical and laboratory data and association with one or more major underlying obstetric disorders. Baseline imbalance between patients with and without treatment of rhTM was adjusted using an inverse probability of treatment weighting using propensity scores composed of the following independent variables: severe postpartum hemorrhage, placental abruption, and preeclampsia/eclampsia, including hemolysis, elevated liver enzymes, and low platelet syndrome, initial platelet counts, D-dimer levels, fibrinogen levels, and prothrombin time–international normalized ratio (PT–INR). We evaluated laboratory changes and clinical outcomes in the early phase of obstetric DIC.ResultsIn total, 66 of 4627 patients admitted to our department during the study period fulfilled the required criteria; of these, 37 and 29 patients were included in the rhTM and control group, respectively. After adjustment, treatment with rhTM was associated with significant improvements in platelet counts, D-dimer levels, fibrinogen levels, and PT–INR compared with the control group. The platelet concentrate transfusion volume was significantly lower in the rhTM treatment group (3.02 vs 6.03 units, P = 0.016). None of the adjusted group differences were statistically significant for all types of organ damage and failure.ConclusionrhTM administration was associated with clinical and laboratory improvement in patients with DIC caused by underlying obstetric conditions. Further clinical research is needed to clarify the optimal application of rhTM in each of the causative obstetric disorders.

This study aimed to evaluate the efficacy and safety of computed tomography-magnetic resonance imaging (CT-MRI)-guided multi-catheter interstitial brachytherapy for patients with bulky (≥4 cm) and high-risk, stage IIB–IVB advanced cervical cancer. Eighteen patients who underwent concurrent chemoradiotherapy with multi-catheter interstitial brachytherapy between September 2014 and August 2020 were enrolled. The prescribed dose of external beam radiotherapy was 45–50.4 Gy, and the brachytherapy high-dose-rate aim was 25–30 Gy per 5 fractions. The endpoints were four-year local and pelvic control rates, four-year disease-free and overall survival rates, and the adverse events rate. The median follow-up period was 48.4 months (9.1–87.5 months). Fifteen patients received concurrent cisplatin therapy (40 mg/m2, q1week). Four (22.2%), seven (38.9%), and seven (38.9%) patients had stage II, III, and IV cervical cancer, respectively. Pelvic and para-aortic lymph node metastases were observed in 11 (61.1%) and 2 (11.1%) patients, respectively. The median pre-treatment volume was 87.5 cm3. The four-year local control, pelvic control, disease-free survival, and overall survival rates were 100%, 100%, 81.6%, and 87.8%, respectively. Three (16.7%) patients experienced grade 3 adverse events, and none experienced grade 4–5 adverse events. CT-MRI-guided multi-catheter interstitial brachytherapy could be a promising treatment strategy for locally advanced cervical cancer.

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