BackgroundmiRNAs are involved in osteosarcoma (OS) chemoresistance, and TWIST reportedly enhances cisplatin-induced OS cell apoptosis by inhibiting multiple signaling pathways. In this study, we profiled miRNAs differentially expressed in chemoresistant OS, with a focus to identify miRNAs that regulate TWIST expression and OS chemoresistance.MethodsOS patients who showed <90% tumor necrosis after neochemotherapy were defined as poor responders (chemoresistant), and those who showed ≥90% tumor necrosis were defined as good responders (control). miRNA microarray analysis was carried out with a discovery cohort (n = 12) of age-, sex- and tumor stage-matched chemoresistant and control OS patients.ResultsAmong the up-regulated miRNAs in chemoresistant OS samples, miR-33a was verified to down-regulate TWIST expression, which was supported by an inverse miRNA-33a/TWIST expression trend in the validation cohort (n = 70), target-sequence-specific inhibition of TWIST-3′ untranslated region-luciferase reporter activity by miR-33a, and alteration of TWIST expression by overexpression or inhibition of miR-33a in human OS cell lines. In Saos-2 cells treated with cisplatin, inhibition of miR-33a by antagomir-33a markedly increased cell apoptosis, which was enhanced by overexpression of TWIST. The apoptosis-inducing effect of TWIST overexpression was reversed by overexpression of miR-33a. In MG-63 cells, overexpression of miR-33a significantly decreased cisplatin-induced cell apoptosis, which was enhanced by knockdown of TWIST. Antagomir-33a significantly increased cisplatin-induced cell apoptosis, which was reversed by knockdown of TWIST.ConclusionsWe have demonstrated in this study that miR-33a is up-regulated in chemoresistant OS and that the miR-33a level is negatively correlated with the TWIST protein level in OS. Our in vitro data indicate that miR-33a promotes OS cell resistance to cisplatin by down-regulating TWIST; on the other hand, inhibition of miR-33a by antagomir-33a enhances cisplatin-induced apoptosis in OS cells by up-regulating TWIST expression. The findings suggest that inhibition of miR-33a/TWIST signaling could be a potential new strategy to enhance neoadjuvant chemotherapy for OS.

Background: Isolated unilateral absence of pulmonary artery (UAPA) in adulthood is a rare congenital anomaly. Although some case reports exist, the clinical symptomatology, lung parenchymal features, collateral circulation and therapeutic approaches in adult patients with isolated UAPA remain unknown. The objectives of this study are to investigate the clinical characteristics, elucidate the correlation between clinical symptomatology and radiology, and summarize treatment of adult patients with isolated UAPA. Methods: Cases of adult patients with isolated UAPA who had been diagnosed at our hospital and identified from PubMed, EMBASE and Web of Science from 1990 to 2016 were analyzed. Results: Hemoptysis was present in 41.5% of patients, exertional dyspnea in 41.5%, and recurrent respiratory infection in 35.4%. Lung parenchymal abnormalities were found on chest computed tomography (CT) scan, including bronchiectasis, which occurred in 30.2% of the patients, interstitial changes in 14.0%, and multiple bullae in 14.0% of the patients. Exertional dyspnea was more frequent in patients with pulmonary hypertension than in those without pulmonary hypertension (P<0.001). Recurrent respiratory infection were more frequent in patients with bronchiectasis than in those without bronchiectasis (P<0.001).Hypertrophic bronchial, phrenic, internal thoracic and intercostal arteries were found in 71.9%, 46.9%, 43.8%, and 43.8% of the patients, respectively. Pneumonectomy reduced hemoptysis in seven cases. Oral phosphodiesterase inhibitors or endothelin receptor antagonist improved exertional dyspnea in three cases with pulmonary hypertension. Conclusions: Clinicians should be aware of undiagnosed cases of isolated UAPA in adults with unexplained hemoptysis or exertional dyspnea. Early recognition and management of isolated UAPA in adult patients are crucial to avoid the devastating effect of massive hemoptysis or severe pulmonary hypertension (PHT) in the long term.

In multiple sclerosis (MS), remyelination of demyelinated lesions diminishes with disease progression for unknown reasons. Oligodendrocyte progenitor cells contribute to remyelination; however, antibodies specific for oligodendrocyte progenitor antigens could block remyelination by eliminating or impeding these cells. In myelinating cultures, cell lysis with antibody recognizing a progenitor cell–specific surface glycoprotein (AN2) suppressed the synthesis of myelin proteins. Cerebrospinal fluid from patients with relapsing‐remitting active MS contains antibodies against AN2, whereas cerebrospinal fluid from patients with nonactive disease does not. This is the first report describing antibodies in MS against a progenitor cell–specific antigen that may contribute to the development and progression of chronically demyelinated lesions. Ann Neurol 2000;48:362–371