GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis

Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.     

Pulmonary artery pulsatility index predicts prolonged inotrope/pulmonary vasodilator use after implantation of continuous flow left ventricular assist device

Objective: Predictors of right ventricle (RV) dysfunction after continuous‐flow left ventricular assist device (CF‐LVAD) implantation in children are not well described. We explored the association of preimplantation Pulmonary Artery Pulsatility index (PAPi) and other hemodynamic parameters as predictors of prolonged postoperative inotropes/pulmonary vasodilator use after CF‐LVAD implantation.
Design: Retrospective chart review.
Setting: Single tertiary care pediatric referral center.
Patients: Patients who underwent CF‐LVAD implantation from January 2012 to October 2017.
Interventions: Preimplantation invasive hemodynamic parameters were analyzed to evaluate the association with post‐CF‐LVAD need for prolonged (>72 hours) use of inotropes/pulmonary vasodilators.
Measurements and main results: Preimplantation cardiac catheterization data was available for 12 of 44 patients who underwent CF‐LVAD implant during the study period. Median (IQR) age and BSA of the cohort were 15.3 years (10.2, 18) and 1.74 m2 (0.98, 2.03). Group 1 (n = 6) included patients with need for prolonged inotropes/pulmonary vasodilator use after CF‐LVAD implantation and Group 2 (n = 6) included those without. Baseline demographic parameters, cardiopulmonary bypass time, and markers of RV afterload (pulmonary vascular resistance, PA compliance and elastance) were similar among the two groups. PAPi was significantly lower in group 1 compared to group 2 (0.96 vs 3.6, respectively; P = .004). Post‐LVAD stay in the intensive care unit was longer for patients in group 1 (46 vs 23 days, P = .52). Brain natriuretic peptide was significantly higher at 3 months after implantation in group 1; P = .01.
Conclusions: The need for inotropes/pulmonary vasodilators in the postoperative period can be predicted by the preimplantation intrinsic RV contractile reserve as assessed by PAPi rather than the markers of RV afterload. Further investigation and correlation with clinical outcomes is needed.     

Serum tumor markers and testicular germ cell tumors: a primer for radiologists

Abdominal Radiology - Serum tumor markers (STMs) play a critical role in the diagnosis, staging and follow-up of both seminomatous and nonseminomatous testicular germ cell neoplasms. Levels of...     

胆囊息肉诊治的新进展

【摘要】 随着B超等影像学技术的广泛普及,胆囊息肉样病变(PLG)检出率越来越高,已成为胆道外科的常见疾病。目前针对PLG的处理方式主要是手术治疗,而迄今又无有效的方法在手术前明确PLG的类型,因此使得临床上大部分无恶变倾向的PLG实施了不必要的预防性胆囊切除术。鉴于此,本文将对PLG与恶变关系等进行综述,系统地认识PLG及其恶变的危险因素,从而确定预防性胆囊切除的手术指征及临床意义。