Icariin stimulates differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) through activation of cAMP/PKA/CREB

Icariin, a prenylated flavonol glycoside isolated from Epimedium, has been considered as a potential alternative therapy for osteoporosis. The present study aimed to clarify the detailed molecular mechanisms of action of icariin on osteoblast function, using bone marrow-derived mesenchymal stem cells (BM‑MSCs). BM-MSCs were first stimulated by icariin. Then, gene and protein expression of cAMP/ PKA/CREB signaling molecules were analyzed by RT-PCR and western blotting (WB), and alkaline phosphatase (ALP) was analyzed in cell lysates by ELISA. MTT assays indicated that icariin did not have significant effects on cell viability up to 1 μM. Icariin showed a dose-dependent effect on the alkaline phosphatase activity of BM-MSCs. WB analysis showed that icariin treatment of BM-MSCs significantly enhanced the protein expression of protein kinase A (PKA) and cAMP-responsive element binding protein (CREB), while RT-PCR results showed that icariin dose-dependently increased the mRNA levels of PKA and CREB. Icariin induced BM-MSC differentiation by BMP2, Smad1, and Runx2. RT‑PCR and WB results indicated that icariin significantly increased the expression of BMP2, Smad1, and Runx2 in BM‑MSCs. These results suggest that icariin is an agonist of the cAMP/PKA/CREB pathway in BM-MSC differentiation, raising the possibility that it could be used in the treatment of osteoporosis

Single-Shot Two-Pronged Detector with Rectified IoU Loss

In the CNN based object detectors, feature pyramids are widely exploited to alleviate the problem of scale variation across object instances. These object detectors, which strengthen features via a top-down pathway and lateral connections, are mainly to enrich the semantic information of low-level features, but ignore the enhancement of high-level features. This can lead to an imbalance between different levels of features, in particular a serious lack of detailed information in the high-level features, which makes it difficult to get accurate bounding boxes. In this paper, we introduce a novel two-pronged transductive idea to explore the relationship among different layers in both backward and forward directions, which can enrich the semantic information of low-level features and detailed information of high-level features at the same time. Under the guidance of the two-pronged idea, we propose a Two-Pronged Network (TPNet) to achieve bidirectional transfer between high-level features and low-level features, which is useful for accurately detecting object at different scales. Furthermore, due to the distribution imbalance between the hard and easy samples in single-stage detectors, the gradient of localization loss is always dominated by the hard examples that have poor localization accuracy. This will enable the model to be biased toward the hard samples. So in our TPNet, an adaptive IoU based localization loss, named Rectified IoU (RIoU) loss, is proposed to rectify the gradients of each kind of samples. The Rectified IoU loss increases the gradients of examples with high IoU while suppressing the gradients of examples with low IoU, which can improve the overall localization accuracy of model. Extensive experiments demonstrate the superiority of our TPNet and RIoU loss.Comment: Accepted by ACM MM 202

MiRNA-Directed Regulation of VEGF and Other Angiogenic Factors under Hypoxia

MicroRNAs (miRNAs) are a class of 20–24 nt non-coding RNAs that regulate gene expression primarily through post-transcriptional repression or mRNA degradation in a sequence-specific manner. The roles of miRNAs are just beginning to be understood, but the study of miRNA function has been limited by poor understanding of the general principles of gene regulation by miRNAs. Here we used CNE cells from a human nasopharyngeal carcinoma cell line as a cellular system to investigate miRNA-directed regulation of VEGF and other angiogenic factors under hypoxia, and to explore the principles of gene regulation by miRNAs. Through computational analysis, 96 miRNAs were predicted as putative regulators of VEGF. But when we analyzed the miRNA expression profile of CNE and four other VEGF-expressing cell lines, we found that only some of these miRNAs could be involved in VEGF regulation, and that VEGF may be regulated by different miRNAs that were differentially chosen from 96 putative regulatory miRNAs of VEGF in different cells. Some of these miRNAs also co-regulate other angiogenic factors (differential regulation and co-regulation principle). We also found that VEGF was regulated by multiple miRNAs using different combinations, including both coordinate and competitive interactions. The coordinate principle states that miRNAs with independent binding sites in a gene can produce coordinate action to increase the repressive effect of miRNAs on this gene. By contrast, the competitive principle states when multiple miRNAs compete with each other for a common binding site, or when a functional miRNA competes with a false positive miRNA for the same binding site, the repressive effects of miRNAs may be decreased. Through the competitive principle, false positive miRNAs, which cannot directly repress gene expression, can sometimes play a role in miRNA-mediated gene regulation. The competitive principle, differential regulation, multi-miRNA binding sites, and false positive miRNAs might be useful strategies in the avoidance of unwanted cross-action among genes targeted by miRNAs with multiple targets

Platinum-based chemotherapy plus cetuximab first-line for Asian patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Results of an open-label, single-arm, multicenter trial

Background The purpose of this study was to assess the efficacy, safety, and pharmacokinetics of cisplatin-based chemotherapy plus cetuximab as first-line treatment in Chinese and Korean patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods Patients (n = 68) received cetuximab weekly plus 3-week cycles of cisplatin/5-fluorouracil (5-FU) chemotherapy for up to 6 cycles. The primary endpoint was overall response rate. Results The overall response rate was 55.9%, including 2 complete responses (CRs). Median overall survival (OS) was 12.6 months and median progression-free survival (PFS) was 6.6 months. Grade 3/4 adverse events (AEs) were reported in 41 (60.3%) patients. The safety profile was in line with previous clinical experience. The pharmacokinetic profile was in line with that observed with cetuximab in white and Japanese patients. Conclusion The efficacy, safety, and pharmacokinetic findings from this study support the use of first-line platinum-based chemotherapy plus cetuximab in Chinese and Korean patients with recurrent and/or metastatic SCCHN (ClinicalTrials.gov NCT01177956). © 2014 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 37: 1081–1087, 201

First-line treatment with chemotherapy plus cetuximab in Chinese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Efficacy and safety results of the randomised, phase III CHANGE-2 trial.

Abstract Background The EXTREME regimen (chemotherapy [CT; cisplatin/carboplatin and 5-fluorouracil]) plus cetuximab is a standard-of-care first-line (1L) treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), as supported by international guidelines. The phase III CHANGE-2 trial assessed the efficacy and safety of a modified CT regimen (with a reduced dose of both components) and cetuximab versus CT for the 1L treatment of Chinese patients with R/M SCCHN. Methods Patients were randomised to receive up to six cycles of CT plus cetuximab followed by cetuximab maintenance until progressive disease or CT alone. The primary end-point was the progression-free survival (PFS) time assessed by the independent review committee (IRC). Results Overall, 243 patients were randomised (164 to CT plus cetuximab; 79 to CT). The hazard ratios for PFS by IRC and overall survival (OS) were 0.57 (95% CI: 0.40–0.80; median: 5.5 versus 4.2 months) and 0.69 (95% CI: 0.50–0.93; median: 11.1 versus 8.9 months), respectively, in favour of CT plus cetuximab. The objective response rates (ORR) by IRC were 50.0% and 26.6% with CT plus cetuximab and CT treatment, respectively. Treatment-emergent adverse events of maximum grade 3 or 4 occurred in 61.3% (CT plus cetuximab) and 48.7% (CT) of patients. Conclusions CHANGE-2 showed an improved median PFS, median OS and ORR with the addition of cetuximab to a modified platinum/5-fluorouracil regimen, with no new or unexpected safety findings, thereby confirming CT plus cetuximab as an effective and safe 1L treatment for Chinese patients with R/M SCCHN. Clinical trial registration number NCT02383966