[Corrigendum] (­)­Epigallocatechingallate induces apoptosis in B lymphoma cells via caspase­dependent pathway and Bcl­2 family protein modulation.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that, in Fig. 3 on p. 1510, the western blot images selected to portray the caspase 7 and PARP/cleaved PARP experiments were remarkably similar. After having referred to their original data, the authors realized that the PARP/cleaved PARP blots had been inadvertently duplicated in the figure. The revised version of Fig. 3, showing the correct data for the caspase­7 experiment, is shown below. The authors confirm that the errors made during the assembly of Fig. 3 did not adversely affect the major conclusions presented in this paper, and are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a corrigendum. They also apologize to the readership for any inconvenience caused. [International Journal of Oncology 46: 1507­1515, 2015; DOI: 10.3892/ijo.2015.2869].

Preclinical Therapeutic Efficacy of RAF/MEK/ERK and IGF1R/AKT/mTOR Inhibition in Neuroblastoma.

Activating mutations in the RAS/MAPK pathway are observed in relapsed neuroblastoma. Preclinical studies indicate that these tumors have an increased sensitivity to inhibitors of the RAS/MAPK pathway, such as MEK inhibitors. MEK inhibitors do not induce durable responses as single agents, indicating a need to identify synergistic combinations of targeted agents to provide therapeutic benefit. We previously showed preclinical therapeutic synergy between a MEK inhibitor, trametinib, and a monoclonal antibody specific for IGF1R, ganitumab in RAS-mutated rhabdomyosarcoma. Neuroblastoma cells, like rhabdomyosarcoma cells, are sensitive to the inhibition of the RAS/MAPK and IGF1R/AKT/mTOR pathways. We hypothesized that the combination of trametinib and ganitumab would be effective in RAS-mutated neuroblastoma. In this study, trametinib and ganitumab synergistically suppressed neuroblastoma cell proliferation and induced apoptosis in cell culture. We also observed a delay in tumor initiation and prolongation of survival in heterotopic and orthotopic xenograft models treated with trametinib and ganitumab. However, the growth of both primary and metastatic tumors was observed in animals receiving the combination of trametinib and ganitumab. Therefore, more preclinical work is necessary before testing this combination in patients with relapsed or refractory RAS-mutated neuroblastoma.

Chlorogenic Acid as a Potential Therapeutic Agent for Cholangiocarcinoma.

Chlorogenic acid (CGA) has demonstrated anti-tumor effects across various cancers, but its role in cholangiocarcinoma (CCA) remains unclear. Our study revealed CGA's potent anti-tumor effects on CCA, significantly suppressing cell proliferation, migration, colony formation, and invasion while inhibiting the epithelial-mesenchymal transition. CGA induced apoptosis, modulated cell cycle progression, and exhibited a stable binding affinity to AKR1B10 in CCA. AKR1B10 was highly expressed in RBE cells, and CGA treatment reduced AKR1B10 expression. Knocking out AKR1B10 inhibited the proliferation of RBE cells, whereas the overexpression of AKR1B10 promoted their proliferation. Additionally, CGA suppressed the proliferation of RBE cells with AKR1B10 overexpression. Mechanistically, AKR1B10 activated AKT, and CGA exerted its inhibitory effect by reducing AKR1B10 levels, thereby suppressing AKT activation. Furthermore, CGA facilitated the polarization of tumor-associated macrophages towards an anti-tumor phenotype and enhanced T-cell cytotoxicity. These findings underscore CGA's potential as a promising therapeutic agent for CCA treatment.

Recent advances in functional nucleic acid decorated nanomaterials for cancer imaging and therapy.

Nanomaterials possess unusual physicochemical properties including unique optical, magnetic, electronic properties, and large surface-to-volume ratio. However, nanomaterials face some challenges when they were applied in the field of biomedicine. For example, some nanomaterials suffer from the limitations such as poor selectivity and biocompatibility, low stability, and solubility. To address the above-mentioned obstacles, functional nucleic acid has been widely served as a powerful and versatile ligand for modifying nanomaterials because of their unique characteristics, such as ease of modification, excellent biocompatibility, high stability, predictable intermolecular interaction and recognition ability. The functionally integrating functional nucleic acid with nanomaterials has produced various kinds of nanocomposites and recent advances in applications of functional nucleic acid decorated nanomaterials for cancer imaging and therapy were summarized in this review. Further, we offer an insight into the future challenges and perspectives of functional nucleic acid decorated nanomaterials.

Silencing of KIF2C enhances the sensitivity of hepatocellular carcinoma cells to cisplatin through regulating the PI3K/AKT/MAPK signaling pathway.

In the treatment of unresectable advanced hepatocellular carcinoma (HCC), cisplatin is administered transhepatic arterially for local treatment, but the clinical application of cisplatin drugs is frequently hindered by the emergence of drug resistance. Kinesin family member 2C( KIF2C ) has been shown as oncogene in a variety of tumors. Nevertheless, its effect on cisplatin sensitivity has yet to be ascertained. Herein, we aim to investigate the impact of the KIF2C gene on cisplatin sensitivity within HCC and the plausible underlying molecular mechanism. We examined the expression level of the KIF2C gene in HCC cells by real-time quantitative reverse transcription PCR and Western blot analysis, and analyzed bioinformatically by The Gene Expression Omnibus database and The Cancer Genome Atlas database. The KIF2C gene was silenced using the small interfering RNA technology, and its effect on cisplatin drug sensitivity in HCC cells was evaluated by flow cytometry, cell proliferation, cell migration, and invasion assays. Our results indicated that KIF2C was highly expressed in HCC cells. KIF2C silencing inhibits HCC cell proliferation, migration and invasion, promotes apoptosis, and keeps the cell cycle in G2 phase. In addition, KIF2C silencing enhanced the sensitivity of HCC cells to cisplatin. KIF2C silencing down-regulates the expression levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and mitogen-activated protein kinase 3 (MAPK3) proteins. In conclusion, KIF2C silencing amplifies the sensitivity of HCC cells to cisplatin by regulating the PI3K/AKT/MAPK signaling pathway. Consequently, targeting KIF2C shows great application potential as a strategy for enhancing the effectiveness of HCC treatment.

Standard ophthalmology residency training in China: an evaluation of resident satisfaction on training program in Guangdong Province.

BACKGROUND: National standardized training for resident doctors (STRD) in mainland China has been formally established since 2014 as a kind of postgraduate education. The purpose of this survey was to assess the satisfaction of the training residents in Guangdong Province on the ophthalmology STRD program after a duration of 5 years. METHOD: A 48-item survey was sent to all postgraduate ophthalmology residents from bases in Guangdong Province to inquire about their attitude towards the program. The survey contained questions about demographic and work-related information, job satisfaction, psychological resilience, and job performance. All responses were verified, and invalid questionnaires were excluded. Statistical analyses were performed using SPSS software version 22.0 (SPSS, Inc., Chicago, IL). Multiple logistic regression analysis was used to evaluate the factors (demographic information, working environment, clinical exposure, supervision and hands-on training opportunities, and involvement in academic activities) impacting the overall satisfaction. P < 0.05 was considered statistically significant. RESULTS: A total of 471/635 (74.17%) valid questionnaires were returned from all the STRD bases of Guangdong Province, which included 38 hospitals. 60.3% of the respondents reported overall satisfaction with their training. The satisfaction with operative teaching (60.7%) was slightly lower than the other settings of teaching experience (above 65%). Meanwhile, the satisfaction on different secessions of operative experience was all below 70%, of which in the areas of cornea and orbit were 55.42% and 57.53%, respectively. Some potential factors were found to affect general satisfaction, including the training grade, marriage, working time, income level, the doctor-patient relationship, family members working as doctors, the time proportion spent on writing medical documents during clinical work, and the frequency of attending academic meetings. Improvement was observed in both performing and reporting clinical examinations in the last year of training in comparison to the first year. Finally, 82.8% of the residents acknowledged this training was helpful for future clinical work. The first five career preferences for residents were cataract (67.1%), refractive surgery (42.3%), vitreo-retina (36.5%), optometry (28.7%), and oculoplastic (27.2%). CONCLUSION: Ophthalmology residents in Guangdong Province expressed comparable satisfaction with the STRD program. To further improve satisfaction, factors such as resident subsidy, harmonious marriage, the patient-doctor relationship, and chances of attending academic conferences should be emphasized.

hESC-Derived Epicardial Cells Promote Repair of Infarcted Hearts in Mouse and Swine.

Myocardial infarction (MI) causes excessive damage to the myocardium, including the epicardium. However, whether pluripotent stem cell-derived epicardial cells (EPs) can be a therapeutic approach for infarcted hearts remains unclear. Here, the authors report that intramyocardial injection of human embryonic stem cell-derived EPs (hEPs) at the acute phase of MI ameliorates functional worsening and scar formation in mouse hearts, concomitantly with enhanced cardiomyocyte survival, angiogenesis, and lymphangiogenesis. Mechanistically, hEPs suppress MI-induced infiltration and cytokine-release of inflammatory cells and promote reparative macrophage polarization. These effects are blocked by a type I interferon (IFN-I) receptor agonist RO8191. Moreover, intelectin 1 (ITLN1), abundantly secreted by hEPs, interacts with IFN-ß and mimics the effects of hEP-conditioned medium in suppression of IFN-ß-stimulated responses in macrophages and promotion of reparative macrophage polarization, whereas ITLN1 downregulation in hEPs cancels beneficial effects of hEPs in anti-inflammation, IFN-I response inhibition, and cardiac repair. Further, similar beneficial effects of hEPs are observed in a clinically relevant porcine model of reperfused MI, with no increases in the risk of hepatic, renal, and cardiac toxicity. Collectively, this study reveals hEPs as an inflammatory modulator in promoting infarct healing via a paracrine mechanism and provides a new therapeutic approach for infarcted hearts.

Tumor Targeting with Apatinib-loaded Nanoparticles and Sonodynamic Combined Therapy

INTRODUCTION: This study implies the enhancement of apatinib killing effect in 4T1 tumor cells through constructing drug-loaded nanoparticles apatinib/Ce6@ZIF-8@Membranes (aCZM) to enhance tumor therapeutic targeting and reduce toxic side following sonodynamic therapy (SDT). METHODS: apatinib/Ce6@ZIF-8 (aCZ) were synthesized by in situ encapsulation, and aCZM were constructed by encapsulating the nanoparticles with extracted breast cancer 4T1 cell membranes. aCZM were characterized and tested for the stability by electron microscopy, and the membrane proteins on the nanoparticles' surface were assessed using SDS-PAGE gel electrophoresis. The cell viability of 4T1 cells following treatment with aCZM was tested using cell counting kit-8 (CCK-8). The uptake of nanoparticles was detected by laser confocal microscopy and flow cytometry, and the SDT-mediated production of reactive oxygen species (ROS) was verified by singlet oxygen sensor green (SOSG), electron spin resonance (ESR), and DCFH-DA fluorescent probes. The CCK-8 assay and flow cytometry using Calcein/PI were used to assess the antitumoral effect of aCZM nanoparticles under SDT. The biosafety of aCZM was further verified in vitro and in vivo using the hemolysis assay, routine blood test and H&E staining of vital organs in Balb/c mice. RESULTS: aCZM with an average particle size of about 210.26 nm were successfully synthesized. The results of the SDS-PAGE gel electrophoresis experiment showed that aCZM have a band similar to that of pure cell membrane proteins. The CCK-8 assay demonstrated the absence of effects on cell viability at a low concentration range, and the relative cell survival rate reached more than 95%. Laser confocal microscopy and flow cytometry analysis showed that aCZM treated group has the strongest fluorescence and the highest cellular uptake of nanoparticles. SOSG, ESR, and DCFH-DA fluorescent probes all indicated that the aCZM + SDT treated group has the highest ROS production. The CCK-8 assay also showed that when the ultrasound intensity was fixed at 0.5 W/cm2, the relative cell survival rates in the medium concentration group (10 µg/ml) (5.54 ± 1.26%) and the high concentration group (20 µg/ml) (2.14 ± 1.63%) were significantly lower than those in the low concentration group (5 µg/ml) (53.40 ± 4.25%). Moreover, there was a concentration and intensity dependence associated with the cell-killing effect. The mortality rate of the aCZM in the ultrasound group (44.95±3.03%) was significantly higher than that of the non-ultrasound (17.00±2.26%) group and aCZ + SDT group (24.85 ± 3.08%) (P<0.0001). The live and dead cells' staining (Calcein/PI) also supported this result. Finally, in vitro hemolysis test at 4 and 24 hours showed that the hemolysis rate of the highest concentration group was less than 1%. The blood routine, biochemistry, and H&E staining results of major organs in Balb/c mice undergoing nano-treatments showed no obvious functional abnormalities and tissue damage in 30 days. CONCLUSION: In this study, a multifunctional bionic drug delivery nanoparticles (aCZM) system with good biosafety and compatibility in response to acoustic dynamics was successfully constructed and characterized. This system enhanced apatinib killing effect on tumor cells and reduced toxic side effects under SDT.

Effect of naringenin on the anti-inflammatory, vascularization, and osteogenesis differentiation of human periodontal ligament stem cells via the stromal cell-derived factor 1/C-X-C motif chemokine receptor 4 signaling axis stimulated by lipopolysaccharide.

OBJECTIVES: This study aimed to investigate how naringenin (Nar) affected the anti-inflammatory, vascula-rization, and osteogenesis differentiation of human periodontal ligament stem cells (hPDLSCs) stimulated by lipopolysaccharide (LPS) and to preliminarily explore the underlying mechanism. METHODS: Cell-counting kit-8 (CCK8), cell scratch test, and Transwell assay were used to investigate the proliferation and migratory capabilities of hPDLSCs. Alkaline phosphatase (ALP) staining, alizarin red staining, lumen-formation assay, enzyme-linked immunosorbent assay, quantitative timed polymerase chain reaction, and Western blot were used to measure the expression of osteopontin (OPN), Runt-related transcription factor 2 (RUNX2), vascular endothlial growth factor (VEGF), basic fibroblast growth factor (bFGF), von Willebrand factor (vWF), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6. RESULTS: We observed that 10 µmol/L Nar could attenuate the inflammatory response of hPDLSCs stimulated by 10 µg/mL LPS and promoted their proliferation, migration, and vascularization differentiation. Furthermore, 0.1 µmol/L Nar could effectively restore the osteogenic differentiation of inflammatory hPDLSCs. The effects of Nar's anti-inflammatory and promotion of osteogenic differentiation significantly decreased and inflammatory vascularization differentiation increased after adding AMD3100 (a specific CXCR4 inhibitor). CONCLUSIONS: Nar demonstrated the ability to promote the anti-inflammatory, vascularization, and osteogenic effects of hPDLSCs stimulated by LPS, and the ability was associated with the stromal cell-derived factor/C-X-C motif chemokine receptor 4 signaling axis.

The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models.

PURPOSE: PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Our previous studies revealed preclinical efficacy of the MEK1/2 inhibitor, trametinib, and an IGF1R inhibitor, BMS-754807, but this combination was not pursued clinically due to intolerability in preclinical murine models. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor, which would be tolerated in murine models and effective in both cell line and patient-derived xenograft models of RAS-mutant FN RMS. EXPERIMENTAL DESIGN: Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a mAb with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of trametinib/ganitumab was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models. RESULTS: Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in four of six models of RAS-mutant RMS. The combination had little effect on body weight and did not produce thrombocytopenia, neutropenia, or hyperinsulinemia in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the phosphorylation of AKT induced by MEK inhibition alone. Therapeutic response to the combination was observed in models without a mutation in the PI3K/PTEN axis. CONCLUSIONS: We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models. Our data also show that the trametinib/ganitumab combination likely has a favorable tolerability profile. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated FN RMS.