MiR-34a-5p promotes the multi-drug resistance of osteosarcoma by targeting the CD117 gene.

An association has been reported between miR-34a-5p and several types of cancer. Specifically, in this study, using systematic observations of multi-drug sensitive (G-292 and MG63.2) and resistant (SJSA-1 and MNNG/HOS) osteosarcoma (OS) cell lines, we showed that miR-34a-5p promotes the multi-drug resistance of OS through the receptor tyrosine kinase CD117, a direct target of miR-34a-5p. Consistently, the siRNA-mediated repression of CD117 in G-292 and MG63.2 cells led to a similar phenotype that exhibited all of the miR-34a-5p mimic-triggered changes. In addition, the activity of the MEF2 signaling pathway was drastically altered by the forced changes in the miR-34a-5p or CD117 level in OS cells. Furthermore, si-CD117 suppressed the enhanced colony and sphere formation, which is in agreement with the characteristics of a cancer stem marker. Taken together, our data established CD117 as a direct target of miR-34-5p and demonstrated that this regulation interferes with several CD117-mediated effects on OS cells. In addition to providing new mechanistic insights, our results will provide an approach for diagnosing and chemotherapeutically treating OS

Use of Radiomics Combined With Machine Learning Method in the Recurrence Patterns After Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma: A Preliminary Study

Objective: To analyze the recurrence patterns and reasons in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT) and to investigate the feasibility of radiomics for analysis of radioresistance.Methods: We analyzed 306 NPC patients treated with IMRT from Jul-2009 to Aug-2016, 20 of whom developed with recurrence. For the NPCs with recurrence, CT, MR, or PET/CT images of recurrent disease were registered with the primary planning CT for dosimetry analysis. The recurrences were defined as in-field, marginal or out-of-field, according to dose-volume histogram (DVH) of the recurrence volume. To explore the predictive power of radiomics for NPCs with in-field recurrences (NPC-IFR), 16 NPCs with non-progression disease (NPC-NPD) were used for comparison. For these NPC-IFRs and NPC-NPDs, 1117 radiomic features were quantified from the tumor region using pre-treatment spectral attenuated inversion-recovery T2-weighted (SPAIR T2W) magnetic resonance imaging (MRI). Intraclass correlation coefficients (ICC) and Pearson correlation coefficient (PCC) was calculated to identify influential feature subset. Kruskal-Wallis test and receiver operating characteristic (ROC) analysis were employed to assess the capability of each feature on NPC-IFR prediction. Principal component analysis (PCA) was performed for feature reduction. Artificial neural network (ANN), k-nearest neighbor (KNN), and support vector machine (SVM) models were trained and validated by using stratified 10-fold cross validation.Results: The median follow up was 26.5 (range 8–65) months. 9/20 (45%) occurred in the primary tumor, 8/20 (40%) occurred in regional lymph nodes, and 3/20 (15%) patients developed a primary and regional failure. Dosimetric and target volume analysis of the recurrence indicated that there were 18 in-field, and 1 marginal as well as 1 out-of-field recurrence. With pre-therapeutic SPAIR T2W MRI images available, 11 NPC-IFRs (11 of 18 NPC-IFRs who had available pre-therapeutic MRI) and 16 NPC-NPDs were subsequently employed for radiomic analysis. Results showed that NPC-IFRs vs. NPC-NPDs could be differentiated by 8 features (AUCs: 0.727–0.835). The classification models showed potential in prediction of NPC-IFR with higher accuracies (ANN: 0.812, KNN: 0.775, SVM: 0.732).Conclusion: In-field and high-dose region relapse were the main recurrence patterns which may be due to the radioresistance. After integration in the clinical workflow, radiomic analysis can be served as imaging biomarkers to facilitate early salvage for NPC patients who are at risk of in-field recurrence

CT ventilation image-guided helical Tomotherapy at sparing functional lungs for locally advanced lung cancer: analysis of dose-function metrics and the impact on pulmonary toxicity

Abstract Purpose CT ventilation image (CTVI)-guided radiotherapy that selectively avoids irradiating highly-functional lung regions has potential to reduce pulmonary toxicity. Considering Helical TomoTherapy (HT) has higher modulation capabilities, we investigated the capability and characteristic of HT at sparing functional lungs for locally advanced lung cancer. Methods and materials Pretreatment 4DCT scans were carried out for 17 patients. Local lung volume expansion (or contraction) during inspiration is related to the volume change at a given lung voxel and is used as a surrogate for ventilation. The ventilation maps were generated from two sets of CT images (peak-exhale and peak-inhale) by deformable registration and a Jacobian-based algorithm. Each ventilation map was normalized to percentile images. Six plans were designed for each patient: one anatomical plan without ventilation map and five functional plans incorporating ventilation map which designed to spare varying degrees of high-functional lungs that were defined as the top 10%, 20%, 30%, 40%, and 50% of the percentile ventilation ranges, respectively. The dosimetric and evaluation factors were recorded regarding planning target volume (PTV) and other organs at risk (OARs), with particular attention to the dose delivered to total lung and functional lungs. An established dose-function-based normal tissue complication probability (NTCP) model was used to estimate risk of radiation pneumonitis (RP) for each scenario. Results Patients were divided into a benefit group (8 patients) and a non-benefit group (9 patients) based on whether the RP-risk of functional plan was lower than that of anatomical plan. The distance between high-ventilated region and PTV, as well as tumor volume had significant differences between the two groups (P  0.05) but at the cost of increased dose received by OARs. Conclusion Ventilation image-guided HT plans can reduce the dose received by highly-functional lung regions with a range up to top 50% ventilated area. The spatial distribution of ventilation and tumor size were critical factors to better select patients who could benefit from the functional plan

Use of Pulsed Low–Dose Rate Radiotherapy in Refractory Malignancies

BACKGROUND: Most tumor cell lines exhibited low-dose hyperradiosensitivity (LDHRS) to radiation doses lower than 0.3 Gy. Pulsed low–dose rate radiotherapy (PLDR) took advantage of LDHRS and maximized the tumor control process. In this study, we retrospectively analyzed patients receiving PLDR for refractory malignancies. PATIENTS AND METHODS: In total, 22 patients were included in our study: 9 females and 13 males. The median age was 61 years old. All the patients previously received multiline treatments and failed with an estimated survival less than 6 months. Thus, palliative PLDR was given. The PLDR was delivered using 10 fractions of 2 Gy/day, with an interval of 3 minutes, for 5 days per week. The dose rate was 6.67 cGy/min. The median follow-up was 1 year (range 8-30 months). Nine patients underwent PLDR for reirradiation due to locally recurrent diseases. The time interval from last irradiation was 11 to 168 months. Ten patients received PLDR due to poor performance status. Three patients were given PLDR for bulky tumor. The irradiated sites included primary disease (seven patients), locally recurrent disease (nine patients), and retroperitoneal adenopathy (six patients). RESULTS: Five patients developed grade 3 or 4 toxicities. No grade 5 toxicities occurred. All the toxicities recovered after treatments. In general, the 1-year local-regional control rate was approximately 40%, and almost all the patients developed progression at the second year after PLDR. The 6-month survival rate was 76%, and the 1-year survival rate was 69%. For the three patients given PLDR for bulky tumor, all of them achieved partial remission 1 month after the PLDR, and one patient achieved complete response at the fourth month. CONCLUSION: PLDR is an effective and safe option not only for reirradiation but also for patients with poor performance status or bulky tumors. A prospective clinical trial (NCT03061162) is ongoing to validate our results

Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit

Abstract Cerebrovascular dysfunction characterized by the neurovascular unit (NVU) impairment contributes to the pathogenesis of Alzheimer's disease (AD). In this study, a cerebrovascular‐targeting multifunctional lipoprotein‐biomimetic nanostructure (RAP‐RL) constituted with an antagonist peptide (RAP) of receptor for advanced glycation end‐products (RAGE), monosialotetrahexosyl ganglioside, and apolipoprotein E3 is developed to recover the functional NVU and normalize the cerebral vasculature. RAP‐RL accumulates along the cerebral microvasculature through the specific binding of RAP to RAGE, which is overexpressed on cerebral endothelial cells in AD. It effectively accelerates the clearance of perivascular Aβ, normalizes the morphology and functions of cerebrovasculature, and restores the structural integrity and functions of NVU. RAP‐RL markedly rescues the spatial learning and memory in APP/PS1 mice. Collectively, this study demonstrates the potential of the multifunctional nanostructure RAP‐RL as a disease‐modifying modality for AD treatment and provides the proof of concept that remodeling the functional NVU may represent a promising therapeutic approach toward effective intervention of AD