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Tumor cell lysate (TCL)-based vaccines contain a large number of tumor-specific and related antigens, albeit at low levels, that require active transfer and presentation by antigen-presenting cells (APCs) in vivo, which stimulate a weak immune response. The artificial APC (aAPC) system presented herein is a cell-based therapeutic system that can significantly enhance the immune response compared to TCL-based vaccines. This study combines these two treatment strategies to assess their in vitro and in vivo effects. We successfully prepared TCL-poly(lactic-co-glycolic acid)-PEI (TPP) and demonstrated that it was phagocytosed by the APCs and enhanced the maturation of DCs in vitro. The use of TPP in combination with the aAPCs resulted in better antitumor effects compared to the individual therapies. The combination therapy induced a higher proportion of CD4+ T, CD8+ T, and TRP2180–188-specific CD8+ T cells in comparison with the individual therapies. Additionally, the combination therapy enhanced the in vitro proliferation activity; greater inhibited regulatory T cells; and promoted inflammatory cytokine secretion, while reduced the production of inhibitory cytokines. In conclusion, the combination therapy consisting of the TPP tumor nanovaccine and the aAPC system enabled a broader immune response and achieve better antitumor effects compared to treatment with the individual therapies.

Background: Ovarian cancer is one of the three major gynecological cancers, which is closely related to squalene monooxygenase (SQLE). We aim to clarify the role of SQLE in ovarian cancer. Methods: The expression of SQLE was detected by qRT-PCR, Western Bolt and immunohistochemistry. The association between SQLE and ferroptosis was demonstrated by TCGA, GTEx database, TMT protein sequencing, qRT-PCR, Western Bolt, immunofluorescence, ROS detection, and lipid peroxide detection. Animal experiments verified the relationship between SQLE and ferroptosis in ovarian cancer. Results: The expression of SQLE increased in ovarian cancer tissues and cell lines. The decreased expression of SQLE caused ferroptosis of ovarian cancer cells, and enhanced the sensitivity of ovarian cancer cells to ferroptosis inducers. Conclusion: Our study shows that SQLE is highly expressed in ovarian cancer tissues and cells, and the high expression of SQLE in ovarian cancer may promote the occurrence and development of ovarian cancer by protecting ovarian cancer cells from ferroptosis, thus enlightening new treatment methods for ovarian cancer.

Zelai He,1,&ast; Jia Liu,1,&ast; Yuwei Ma,1,&ast; Hao Jiang,1 Zhen Cui,1 Guowen Wang,1 Yufeng Wu,2 Jiuzhou Liu,3 Xixi Cai,4 Jing Qian,1 Jingwen Huang,1 Huijun Zhang,5 Hongwei Li1 1The First Affiliated Hospital of Bengbu Medical College & Tumor Hospital Affiliated to Bengbu Medical College, Bengbu, 233004, People’s Republic of China; 2Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, 450008, People’s Republic of China; 3The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, 471003, People’s Republic of China; 4Department of Radiation Oncology, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, 233004, People’s Republic of China; 5Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huijun Zhang; Hongwei Li Email zhanghuijunhp@163.com; 1249223318@qq.comIntroduction: Cranial radiotherapy (CRT) is the main treatment for non-small cell lung cancer (NSCLC) with brain metastasis (BM) and non-EGFR/ALK/ROS1-TKIs indication, and anlotinib can improve overall prognosis. However, the clinical effects of CRT combined with anlotinib for the treatment of NSCLC with BM remain unclear.Methods: We retrospectively analyzed the clinical effects of anlotinib + CRT versus CRT alone in NSCLC patients with BM and non-EGFR/ALK/ROS1-TKIs indication from September 2016 to June 2020. The progression-free survival (PFS) and overall survival (OS) of anlotinib + CRT versus CRT alone were analyzed. After evaluation of the clinical characteristics to generate a baseline, the independent prognostic factors for intracranial PFS (iPFS) and OS were subjected to univariate and multivariate analysis. Finally, subgroup analysis for iPFS and OS was performed to assess treatment effects using randomized stratification factors and stratified Cox proportional hazards models.Results: This study included data for 73 patients with BM at baseline. Of the 73 patients, 45 patients received CRT alone, and 28 patients received CRT + anlotinib. There was no significant difference in clinical features between the two groups (P > 0.05). Compared with the CRT group, the combined group had longer iPFS (median iPFS [miPFS]: 3.0 months vs 11.0 months, P = 0.048). However, there were no significant differences in OS, extracranial PFS, and systemic PFS. For clinical features, univariate and multivariate analysis showed that the plus anlotinib treatment was an independent advantage predictor of iPFS (hazard ratio [HR] 0.51; 95% confidence interval [CI] 0.27– 0.95; P = 0.04), and age ≥ 57 years (HR 1.04, 95% CI 1.01– 1.08, P = 0.014) and KPS score ≤ 80 (HR 1.04, 95% CI 1.01– 1.08, P = 0.014) were independent disadvantage predictors of OS (P < 0.05). In addition, although this difference was not statistically significant (p > 0.05), the patients with the anlotinib + local CRT (LCRT) treatment had the longest iPFS (miPFS: 27.0 months) and OS (median OS [mOS]: 36 months). The miPFS and mOS values for the LCRT group were 11 months and 18 months, respectively, with shorter values for whole-brain RT (WBRT) + anlotinib group, WBRT + LCRT + anlotinib group, WBRT, and WBRT + LCRT.Conclusion: Anlotinib can improve the intracranial lesion control and survival prognosis of NSCLC patients with CRT.Keywords: radiotherapy, lung cancer, brain metastases, progression-free survival, overall survival

Liposarcoma is a type of common tumor in soft tissue, but liposarcoma originating in the mediastinum is rare. Here, we report a case of the anterior mediastinal liposarcoma resected by a median sternal incision and complicated with reexpansion pulmonary edema after surgery. A 68-year-old female patient with chest tightness and shortness of breath for more than 2 years, recently presents with increased chest tightness and shortness of breath, as well as right upper extremity and lower back pain. Enhanced chest CT scan showed an uneven and low-density mass in the anterior mediastinum with clear border. Most of the mass showed fat density, the anterior part of the mass was solid, and the liquid density was seen in the pericardial cavity. Surgery was performed with a median sternal incision, and part of the pericardium and the innominate vein wall were removed during the removal of the entire liposarcoma. The size of the tumor was about 20 cm × 10 cm × 8 cm. The patient developed a reexpansion pulmonary edema after the giant mediastinal liposarcoma resection, but she was discharged successfully on the 10th postoperative day with the treatment by anti-glucocorticoids and diuretics. Postoperative pathology showed well-differentiated liposarcoma. Now within the half-year follow-up, the patient remained well and there is no sign of recurrence. Median sternotomy is considered to be a good surgical procedure for giant mediastinal liposarcomas. Attention should be given to prevent reexpansion pulmonary edema after surgery.

The aim of the study is to investigate the role of GPR120 on the biological behavior of esophageal cancer cells in the setting of radiation and explore the mechanism. GPR120 knockdown was fulfilled by siRNA-mediated effects in two esophageal cancer cell lines Eca109 and EC9706. Colony formation, survival fraction calculation, viable cell evaluation by cell counting kit-8 assay and cell apoptosis analysis by phycoerythrin annexin V and 7-amino-actinomycin (7-AAD) staining and the flow cytometry examination was evaluated in Eca109 and EC9706 under the treatment of different radiation dosage. The mechanisms were explored by the evaluation of the Akt pathway and apoptosis protein level. Significantly decreased GPR120 mRNA and protein after GPR120 siRNA treatment compared to control siRNA treatment. Significantly decreased colony formation was found in GPR120 siRNA-treated Eca109 and EC9706 cells compared to control siRNA-treated cells at the radiation dosage of 2, 4, 6 and 8 Gy. Moreover, decreased survival fraction number with increased sensitive enhancing ratio was also found in GPR120 siRNA-treated Eca109 and EC9706 cells compared to control siRNA-treated cells. Decreased cell viability and increased cell apoptosis in GPR120 siRNA-treated esophageal cancer cells. GPR120 siRNA decreased the Akt phosphorylation and anti-apoptotic Bcl-2 expression level, but increased pro-apoptotic Bim expression level in esophageal cancer cell lines. GPR120 regulated the biological behavior of the esophageal cancer cells via affecting Akt pathway and apoptosis molecules. Moreover, GPR120 siRNA combined radiation treatment could be a therapeutic choice for esophageal cancer.

Lung cancer is the most frequent cancer type and is the leading cause of tumour‐associated deaths worldwide. Nuclear cap‐binding protein 1 (NCBP1) is necessary for capped RNA processing and intracellular localization. It has been reported that silencing of NCBP1 resulted in cell growth reduction in HeLa cells. Nevertheless, its clinical significance and underlying molecular mechanisms in non–small‐cell lung cancer remain unclear. In this study, we found that NCBP1 was significantly overexpressed in lung cancer tissues and several lung cancer cell lines. Through knockdown and overexpression experiments, we showed that NCBP1 promoted lung cancer cell growth, wound healing ability, migration and epithelial‐mesenchymal transition. Mechanistically, we found that cullin 4B (CUL4B) was a downstream target gene of NCBP1 in NSCLC. NCBP1 up‐regulated CUL4B expression via interaction with nuclear cap‐binding protein 3 (NCBP3). CUL4B silencing significantly reversed NCBP1‐induced tumorigenesis in vitro. Based on these findings, we propose a model involving the NCBP1‐NCBP3‐CUL4B oncoprotein axis, providing novel insight into how CUL4B is activated and contributes to LUAD progression.

Background: Castration-resistant prostate cancer (CRPC) accounts for the majority of prostate cancer deaths, and patients with CRPC are prone to developing drug resistance. Therefore, there is a need to develop effective therapeutics to treat CRPC, especially drug-resistant CRPC. Although various nanoparticles have been developed for drug or gene delivery and control release, approaches to reproducibly formulate the optimal treatment with nanoparticles that could effectively target CRPC and bone metastasis remain suboptimal. Recently, codelivery of a chemotherapeutic agent and a small interfering RNA (siRNA) has become a promising strategy for the treatment of drug-resistant prostate cancer. Methods: In a previous study, we prepared a novel RGD-PEG-DSPE/CaP nanoparticle as an effective and biocompatible drug and gene delivery system. In this study, we further modify the nanoparticle to obtain the LCP-RGD nanoparticle, which contains a calcium phosphate (CaP) core, dioleoyl phosphatidic acid (DOPA) and RGD modified poly(ethylene glycol)-conjugated distearoyl phosphatidylethanolamine (RGD-PEG-DSPE). This drug delivery system was used for codelivery of GRP78 siRNA and docetaxel (DTXL) for the treatment of the PC-3 CRPC. Results: The nanoparticles contain the CaP core, which can effectively compress the negatively charged siRNA, while the DOPA and RGD-PEG-DSPE component can effectively carry DTXL. The arginine-glycine-aspartic acid (RGD) segment can target the prostate cancer site, as the cancer site is neovascularized. This novel nanoparticle has good stability, excellent biocompatibility, high drug and siRNA loading capacity, and an in vitro sustainable release profile. Conclusion: Codelivery of DTXL and GRP78 siRNA has enhanced in vitro and in vivo anti-prostate cancer effects which are much greater than using free DTXL and free GRP78 siRNA together. Our study also indicated that codelivery of DTXL and GRP78 siRNA have an in vitro and in vivo combinational anti-prostate cancer effect and also could effectively sensitize the cell-killing effect of DTXL; this method may be especially suitable for drug-resistant CRPC treatment.

The combination of radiotherapy and chemotherapy is a common and useful treatment mode for tumours. But traditional methods inevitably lead to a variety of side effects. A drug delivery system (DDS), which has good biocompatibility and strong anti-tumour ability, is expected to solve this problem. Studies have shown that Ce-based nanoparticles (NPs) have good radiosensitization effect through the photoelectric effect. Hence, cisplatin-loaded LiLuF4 :Ce3+scintillation NPs (NP + Cis) were first constructed in this study, which was synthesized by the crystal precipitation method and characterized by transmission electron microscopy (TEM). Subsequently, its toxicity was verified, and the radiosensitization effect and basic radiosensitization mechanism on tumour cells and tumour-bearing mice were researched. Results showed that NP + Cis triggered massive DNA damage and effectively inhibited cell viability in vitro under the exposure of X-ray irradiation (IR). Moreover, the experiments in vivo showed that the NP + Cis had higher biosafety, which could absorb enough irradiation and produce a synergistic inhibitory effect on tumours through the releasing of Cis. NP + Cis can improve the performance of DDS in chemoradiotherapy.

Objectives Video assisted thoracoscopic surgery (VATS) can currently be used to diagnose and treat pulmonary nodules. However, intraoperative location of pulmonary nodules in VATS is challenging due to their small diameter and deep location in the pulmonary parenchyma. The purpose of this study was to report the clinical safety and effectiveness of CT-guided hook-wire for preoperative localization of malignant pulmonary nodules smaller than 1 cm in diameter. Methods From February 2017 to January 2018, we collected the data of 80 patients with malignant pulmonary nodules less than 1 cm in diameter who underwent CT-guided hook-wire preoperative localization and VATS surgery. The effectiveness of preoperative localization was evaluated based on surgical duration, success rate of VATS surgery, and localization-related complications. Results The diameter of pulmonary nodules were 0.85 ± 0.17 mm with a distance to the pleural surface of 19.66 ± 14.10 mm. The length of the hook-wire in the lung parenchyma was 29.17 ± 13.14 mm and hook-wire dislodgement occurred in 2 patients. Complications included 27 cases of minor pneumothorax and 18 cases of mild parenchymal hemorrhage. A significant correlation was observed between the length of the hook-wire in the lung parenchyma and mild parenchymal hemorrhage (P = 0.044). The average time of hook-wire localization was 9.0 ± 2.6 min and the average operation time for VATS was 89.02 ± 23.35 min without conversion thoracotomy. Conclusions CT-guided hook-wire localization of the lesion during VATS resection is safe for malignant pulmonary nodules with diameter less than 1 cm.

Background: Cranial radiotherapy (CRT) is the main treatment for lung malignant tumor with brain metastasis (BM) and lacking EGFR/ALK-TKIs indication. For non-small cell lung cancer with BM, anlotinib can improve progression free survival (PFS). We retrospectively analyzed the clinical effects of anlotinib + CRT versus CRT alone.Methods: In patients with lung cancer (adenocarcinoma, squamous carcinoma, or small cell carcinoma) with BM and non-EGFR/ALK-TKIs indication, the overall survival (OS) and PFS of anlotinib + CRT treatment versus CRT treatment alone were separately calculated and compared. The Cox proportional hazards model was used to analyze the independent prognostic factors for intracranial PFS (iPFS) and OS. All confounding factors were adjusted, including age, gender, Karnofsky Performance Status (KPS) score, smoking history, physiological characteristics, T/N stage, histology, metastases, and pathological characteristics. Subgroup analysis for iPFS and OS was performed to assess the effects on BM of treatment pattern.Results: The study included 100 patients with BM at baseline and the follow-up data. Of the 100 patients, 67 patients received CRT treatment alone and 33 patients received CRT + anlotinib treatment. The overall response rates of the CRT + anlotinib group and the CRT alone group were 90.91% and 83.58%, respectively. There was significantly more iPFS in the CRT + anlotinib group compared to CRT alone (median iPFS [miPFS]: 9.0 vs 3.0 months; hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.01-2.52; p = 0.038). The OS, extracranial PFS (ePFS), and systematic PFS (sPFS) of CRT + anlotinib group were longer than those of the CRT alone group, but there was no significant statistical difference (median OS [mOS]: 9.0 vs 7.0 months, HR 1.17, 95% CI 0.74-1.85; median ePFS [mePFS]: 9.0 vs 7.0 months, HR 1.23, 95% CI 0.72-2.11; median sPFS [msPFS]: 7.0 vs 4.0 months, HR 1.37, 95% CI 0.82-2.30). The Cox proportional hazards model analysis revealed that age was an independent prognostic factor of iPFS (HR 1.65, 95% CI 1.05-2.59, p = 0.03). Age (HR 1.74, 95% CI 1.09-2.77, p = 0.02) and KPS score (HR 1.88, 95% CI 1.17-3.01, p = 0.01) were identified as independent prognostic factors of OS. Further subgroup analysis of iPFS showed that when the number of BM in the CRT + anlotinib group was less than or equal to three lesions (≤ 3), the miPFS (12.0 months) was significantly longer than that for CRT alone (> 3) (3.0 months), for CRT alone (≤ 3) (3.0 months), and for CRT + anlotinib (> 3) (7.0 months) (p = 0.014). The OS of the CRT + anlotinib group (≤ 3) (mOS 37.0 months) was much longer than that in CRT alone (> 3) (mOS 6.0 months), CRT alone (≤ 3) (mOS 7.5 months), and CRT + anlotinib (> 3) (mOS 8.5 months) groups, but this difference was not statistically significant (p = 0.051).Conclusion: Anlotinib can improve the survival of patients with lung cancer BM, with better efficacy of a combined treatment of anlotinib + CRT compared to that of CRT alone, especially for the iPFS of patients with BM ≤ 3.

BACKGROUND: Rate of second primary malignancies (SPM) is steadily increasing over the last decades. New therapies, early diagnostic markers, screening tests for a larger number of individuals contribute to the increase prevalence of SPM. In the current study, we try to described the demographic composition of SPM victims, distribution of primary sites, and the impact of related factors on prognosis. METHODS: We conducted a retrospective study identifying patients over the age of 18 who were diagnosed with SPM from the 16 most common cancer sites between 2000 and 2013 from Surveillance, Epidemiology, and End Results data. Cox proportional hazards regression was used to analyze the relationship between different factors associated to the prognosis of SPM. Standard incidence rate of multiple primary (MP-SIR) was also calculated. RESULTS: A total of 303,753 patients were diagnosis with SPM and 76,168 of whom (25.08%) were included in our analytic cohort. Patients with prostate cancer was vulnerable to SPM, accounting for 34.59%, and SPM was prone to occur in lung and bronchus, accounting for 24.90%. The heat map shows that esophagus cancer survivors have the highest risk of developing stomachache tumors (SIR =5.08). The result of Cox regression suggests that a history of liver was associated with the shortest survival time (HR =1.64, 95% CI, 1.54–1.75, P

Background: To evaluate short-term safety and efficacy of helical tomotherapy (HT) versus intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC).Methods: Retrospective analysis of locally advanced nasopharyngeal carcinoma treated with radiotherapy and concurrent platinum based neoadjuvant chemotherapy (cisplatin 80 mg/m2 every 3 weeks for 1 cycle) in our hospital from February 2017 to October 2019, including 70 patients in HT group and 70 in IMRT group. The target area of ​​the tumor was delineated by magnetic resonance (MRI) imaging. The prescription doses delivered to the gross tumor volume (pGTVnx) and positive lymph nodes (pGTVnd), the high risk planning target volume (PTV1), and the low risk planning target volume (PTV2), were 69.96 Gy, 66-70 Gy, 60 Gy and 50-54 Gy, in 33 fractions, respectively. Acute reactions were evaluated according to the RTOG/EORTC criteria, whereas the therapeutic efficacy was assessed according to RECTST version 1.1 criteria in a 3-months period.Results: The CI of PGTVnx, PGTVnd, PTV1 and PTV2, and HI of PGTVnx, PTV1 and PTV2 in HT group was significantly better than those in IMRT group. The OAR Dmax and Dmean in HT group were better than those in IMRT group with a significant difference (all p

The prognosis for patients with HER-2 negative breast cancer is currently poor, largely due to the lack of efficacious targeted therapeutics. Photodynamic nanomaterial technologies have rapidly developed in recent years, but their anti-tumor effects are often limited by poor targeting, low transformation efficiency, toxicity, and other factors. Thus, we prepared a new type of nanoparticles (Ce6/Dox@NPs-cRGD, CDNR) with cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)) that target the ανβ3 receptor. We loaded those nanoparticles (NPs) with a combination of the doxorubicin (Dox) and photosensitizer chlorin E6 (Ce6) to test synergy between chemotherapy and photodynamic therapy (PDT) for the treatment of ανβ3 receptor positive and HER-2 negative breast cancer. Through analysis of the Fourier transform infrared and UV-vis spectra of these NPs, we found that Ce6 and Dox were successfully loaded into the CDNR. According to dynamic light scattering (DLS) analyses, CDNR particles had a diameter of 112.6 nm (polydispersity index 0.11), which was also confirmed via TEM characterization. The zeta potential was about -21.5 mV. Stability studies showed that CDNR particle size was stable in ddH2O, PBS, and DMEM + 5 % FBS for 16 days. The drug loading content of Dox and Ce6 were 5.3 and 6.8 %, respectively. Release studies of CDNR showed that the slow release of Dox was accelerated with increasing GSH concentration, and there was no burst release effect. From studying the absorbance of 9,10-dimethylanthrancene (ABDA), we found that CDNR produces high levels of ROS after excitation with a 670 nm laser, and ROS production increased with increasing radiation time. CDNR was significantly taken up by MCF-7 cells at 6 h because of cRGD targeting. In a CCK8 test, the relative growth rate (RGR) of CDNR +670 nm laser for MCF-7 cells was less than 75 % at 20 μg/mL after 24 h treatment and 15 μg/mL after 48 h treatment. We found that CDNR's effects on RGR were concentration dependent. Live-cell staining with a DCFH-DA kit and flow cytometry assay further supported that a CDNR +670 nm laser provided the maximum chemotherapy-PDT toxicity and production of intracellular ROS, and that cell death was mainly caused by necrosis and apoptosis. In vivo experiments showed that using the cRGD-targeting strategy, CDNR had a stronger affinity and increased half-life relative to Ce6/Dox@NPs in mice with MCF-7 xenograft tumors. Further, the Cmax of CDNR in the transplanted tumor occurred 8 h post-injection (HPI) and there was still detectable signal at 24 HPI. In addition, MCF-7 bearing mice that were treated with CDNR +670 nm PDT at 8 HPI had a significantly decreased tumor volume (P < 0.05) and prolonged survival time compared to other groups. Thus, CDNR plus 670 nm PDT was associated with favorable anti-tumor activity with no appreciable impact on body weight or the major organs in mice, as determined by immunohistochemistry/immunofluorescence and hematoxylin-eosin staining. In conclusion, CDNR with 670 nm laser irradiation represents a promising new potential treatment paradigm for the management of breast cancers that are ανβ3-receptor positive and HER-2 negative.

Patients with triple negative breast cancer (TNBC) often suffer relapse, and clinical improvements offered by radiotherapy and chemotherapy are modest. Although targeted therapy and immunotherapy have been a topic of significant research in recent years, scientific developments have not yet translated to significant improvements for patients with TNBC. In view of these current clinical treatment shortcomings, we designed a silica nanosystem (SNS) with Nano-Ag as the core and a complex of MnO2 and doxorubicin (Dox) as the surrounding mesoporous silica shell. This system was coated with anti-PD-L1 to target the PD-L1 receptor, which is highly expressed on the surface of tumor cells. MnO2 itself has been shown to act as chemodynamic therapy (CDT), and Dox is cytotoxic. Thus, the full SNS system presents a multimodal, potentially synergistic strategy for the treatment of TNBC. Given potential interest in the clinical translation of SNS, the biological safety and antitumor activity of SNS were evaluated in a series of studies that included physicochemical characterization, particle stability, blood compatibility, and cytotoxicity. We found that the particle size and zeta potential of SNS were 94.6 nm and -22.1 mV, respectively. Ultraviolet spectrum analysis showed that Nano-Ag, Dox, and MnO2 were successfully loaded into SNS, and the drug loading ratio of Dox was about 10.2%. Stability studies found that the particle size of SNS did not change in different solutions. Hemolysis tests showed that SNS, at levels far exceeding the anticipated physiologic concentrations, did not induce red blood cell lysis. Further in vitro and in vivo experiments found that SNS did not activate platelets or cause coagulopathy and had no significant effects on the total number of blood cells or hepatorenal function. Cytotoxicity experiments suggested that SNS significantly inhibited the growth of tumor cells by damaging cell membranes, increasing intracellular ROS levels, inhibiting the release of TGF-β1 cytokines by macrophages, and inhibiting intracellular protein synthesis. In general, SNS appeared to have favorable biosafety and antitumor effects and may represent an attractive new therapeutic approach for the treatment of TNBC.

(Arginine-Glycine-Aspartic)-methoxy polyethylene glycol-(1,2-distearoyl-sn-glycero-3-phosphoethanolaMine-N) (abbreviation: RGD-PEG2000-DSPE or RGD-PD) was successfully synthesized and verified by 1H-NMR and MALDI-TOF MS. Polyethylene glycol-poly-L-lysine/RGD-PD/phospholipid/calcium phosphate nanoparticles (PEG-PLL/RGD-PD/PL/CaP NPs or MNPs) were prepared using a novel, simple method conducted at room temperature. Transmission electron microscopy (TEM) analysis showed that the MNPs were spheres of uniform size, with a diameter of ∼30 nm, and smooth surface. Thermogravimetric analysis (TGA) revealed that the PEG-PLL/RGD-PD/PL micelle was packed in the CaP shell. MNPs had little effect on hemolysis, coagulation, cardiac oxidative stress, inflammatory response and DNA damage, indicating negligible cytotoxicity in vitro and in vivo. Experiments in Zebrafish indicated that the MNPs neither affected the survival rate and heartbeat rate, nor induced malformation and apoptosis during embryogenesis. In conclusion, these results demonstrate that the newly-developed MNPs have good biocompatibility and a great potential as drug and gene carrier.

Nasopharyngeal cancer (NPC) is one of the most common head and neck cancers in the world. The failure of the treatment of NPC is mainly caused by the metastasis of the cancer cells. There is a great need to study the mechanism of metastasis for accurate diagnosis, prognosis and efficient therapeutic strategy. The KISS1 gene has already been reported as a metastasis suppressor in numerous cancers. In this study, by integrating the Transwell assay, western blotting and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis, we found that the expression of KISS1 and its receptor gene (hOT7T175, KISS1R) negatively related with the metastasis of NPC cells. Overexpression of the KISS1 and KISS1R genes reduced migration and invasion of the SUNE-1-5-8F cells that are a cell line of NPC. Additionally, overexpression of these genes significantly increased the phosphorylation of focal adhesion kinase (FAK) and decreased the expression of ezrin (EZR), indicated by western blotting. Further study showed the metastasis suppression role of KISS1 and KISS1R was mediated though phosphorylation of the ERK1/2 pathway for that blocking the phosphorylation of the pathway with inhibitor (PD98059) reversed the metastasis suppression and phosphorylation of FAK as well as up-regulation of EZR simultaneously. Together, all of these results suggested for the first time that KISS1 and KISS1R suppress the metastasis of NPC cells by phosphorylation of FAK and decreasing EZR through phosphorylation of the ERK1/2 pathway.

Background Central giant cell granuloma (CGCG) is a rare, non-neoplastic, benign lesion that exhibits expansive and osteolytic biological behavior. CGCG treatment and management is challenging for clinicians. Case presentation This report presents the treatment and management of recurrent, aggressive CGCG after surgical resection. After informed consent was obtained, the patient underwent radiotherapy. The lesion size was reduced significantly, with no evidence of recurrence or malignant transformation. Conclusions This treatment experience indicates that radiotherapy can be used as a rescue treatment for complicated CGCG involving vital neurovascular structures of the cranial base.

Objective To examine the distribution of brain metastases (BM) in relation to the hippocampus, so as to determine the risk of metastasis in the hippocampus, and thus provide experimental evidence for the hippocampal avoidance (HA) in patients with BM during radiotherapy. Methods (1) For the retrospective analysis of 116 patients diagnosed with malignancies, confirmed as BM, from December 2014 to December 2016 at the First Affiliated Hospital of Bengbu Medical College. We obtained the T1-weighted, postcontrast axial, sagittal, and coronal Magnetic Resonance imaging (MRI) images f the patients, in supine position, using the head restraints and head thermoplastic masks to adjust the positioning, with computed tomography (CT) positioning scan ranging from the head to the mandible (layer thickness: 3 mm). CT and MRI images were fused on a Philips Pinnacle v9.8 treatment planning system;(2) Every metastasis of the 565 metastases was contoured;(3) hippocampus were contoured, and hippocampus with 5 mm expansion envelopes were analyzed;(4) Using the SPSS 16.0 software, we analyzed the relation between the distribution and age, sex, Karnofsky performance status (KPS), primary site, aggregate volume of intracranial metastases and the whole brain. The data were analyzed using a binary logistic regression analysis method, with two-sided P 0.05). Conclusion This study showed a low risk for the perihippocampal metastases (PHM) and no significant correlation between PHM and age, sex, KPS, primary site, aggregate volume of intracranial metastases and the whole brain. Accordingly, it is may be acceptable to avoid the perihippocampal region during whole brain radiotherapy.

Background: Castration-resistant prostate cancer (CRPC) accounts for the majority of prostate cancer deaths, and patients with CRPC are prone to developing drug resistance. Therefore, there is a need to develop effective therapeutics to treat CRPC, especially drug-resistant CRPC. Although various nanoparticles have been developed for drug or gene delivery and control release, approaches to reproducibly formulate the optimal treatment with nanoparticles that could effectively target CRPC and bone metastasis remain suboptimal. Recently, codelivery of a chemotherapeutic agent and a small interfering RNA (siRNA) has become a promising strategy for the treatment of drug-resistant prostate cancer. Methods: In a previous study, we prepared a novel RGD-PEG-DSPE/CaP nanoparticle as an effective and biocompatible drug and gene delivery system. In this study, we further modify the nanoparticle to obtain the LCP-RGD nanoparticle, which contains a calcium phosphate (CaP) core, dioleoyl phosphatidic acid (DOPA) and RGD modified poly(ethylene glycol)-conjugated distearoyl phosphatidylethanolamine (RGD-PEG-DSPE). This drug delivery system was used for codelivery of GRP78 siRNA and docetaxel (DTXL) for the treatment of the PC-3 CRPC. Results: The nanoparticles contain the CaP core, which can effectively compress the negatively charged siRNA, while the DOPA and RGD-PEG-DSPE component can effectively carry DTXL. The arginine-glycine-aspartic acid (RGD) segment can target the prostate cancer site, as the cancer site is neovascularized. This novel nanoparticle has good stability, excellent biocompatibility, high drug and siRNA loading capacity, and an in vitro sustainable release profile. Conclusion: Codelivery of DTXL and GRP78 siRNA has enhanced in vitro and in vivo anti-prostate cancer effects which are much greater than using free DTXL and free GRP78 siRNA together. Our study also indicated that codelivery of DTXL and GRP78 siRNA have an in vitro and in vivo combinational anti-prostate cancer effect and also could effectively sensitize the cell-killing effect of DTXL; this method may be especially suitable for drug-resistant CRPC treatment.

// Yufeng Wu 1 , Ruirui Si 2 , Sen Yang 1 , Suhua Xia 3 , Zelai He 4 , Lili Wang 1 , Zhen He 1 , Qiming Wang 1 , Hong Tang 1 1 Department of Internal Medicine, Affiliated cancer hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, 450008, P. R. China 2 Department of Health Center, Henan Airport Group Co., Ltd., Henan, 450000, P. R. China 3 Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, P. R. China 4 Department of Oncology, The 2nd Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, PR China Correspondence to: Qiming Wang, email: qimingwang1006@163.com Hong Tang, email: 852261201@qq.com Keywords: depression, chemotherapy, small cell lung cancer, brain derived neurotrophic factor, ABCG2 Received: August 04, 2016 Accepted: November 07, 2016 Published: November 11, 2016 ABSTRACT Patients with lung cancer often experience a state of depression, and these conditions may severely affect their quality of life (QoL) and prescription compliance. The current study was conducted to delineate the complex links between depression and the prognosis of patients with small cell lung cancer (SCLC) and the underlying mechanism was also explored. 186 patients who received platinum-based chemotherapy for newly diagnosed stage III or stage IV SCLC were enrolled. The Self-Rating Depression Scale (SDS) questionnaire was completed the day before the start of chemotherapy to assess the depression status of the patients. Patients with stage IV SCLC or lower BMI have higher depression scores. In terms of the adverse effects of chemotherapy, depression severely decreases patient tolerance to chemotherapy and their QoL score (R 2 = 0.2385) and is also associated with severe vomiting ( P < 0.001), leukopenia (R 2 = 0.2332), and prolonged hospital stay (R 2 = 0.1961). More importantly, severe depression reduces the PFS (R 2 = 0.1943) and OS ( P < 0.01) of the patients. We found that patients with severe depression displayed a downregulated level of serum BDNF and that the level of serum BDNF was highly correlated with the OS of the patients (R 2 = 0.2292). Using the MTT cell viability assay in vitro , we observed that cotreatment with BDNF clearly enhanced the chemosensitivity of NCI-H69 tumor cells to Cisplatin and induced the downregulation of ABCG2. Based on this evidence, it appears that a relationship does exist between depression and prognosis in SCLC and that the mechanism by which depression affects prognosis is achieved via the downregulation of BDNF expression.

// Zelai He 1, 3, * , Xiangyu Zhang 4, * , Jingwen Huang 1, 3, * , Yufeng Wu 5 , Xuanzhang Huang 1 , Jie Chen 1 , Junyong Xia 6 , Hao Jiang 3 , Jing Ma 2 , Jian Wu 1 1 The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China 2 Ultrasonic Department, Shanghai Songjiang Center Hospital, Shanghai, China 3 The First Affiliated Hospital of Bengbu Medical College, Bengbu, China 4 Department of Pathology, Jining No.1 Peoples’ Hospital, Jining, China 5 Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China 6 Department of Nuclear Medicine, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, China * These authors contributed equally to this work Correspondence to: Junyong Xia, email: xiabingbing@126.com Hao Jiang, email: jianghao1223@163.com Jing Ma, email: majing0709@163.com Jian Wu, email: wzzjian@hotmail.com Keywords: K237, folate, PEG-PLGA, nanoparticles, biodistribution Received: July 29, 2016 Accepted: October 12, 2016 Published: October 24, 2016 ABSTRACT In a previous study, amphiphilic copolymer, polypeptide K237 (HTMYYHHYQHHL) and folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (K237/FA-PEG-PLGA) nanoparticles were developed and studied as a drug carrier. To further promote the clinical application of K237/FA-PEG-PLGA nanoparticles and provide guidance for future research, we need to examine their specific biodistribution in vivo . In this study, K237/FA-PEG-PLGA nanoparticles were effectively labeled by a direct method with Technetium-99m ( 99m Tc) using stannous chloride as a reducing agent. The optimal stability of the labeled nanoparticles was determined by evaluating their radiochemical purity in serum, physiological saline, diethylenetriaminepentaacetic acid (DTPA) and cysteine solutions. The affinity of ligands and receptors was elicited by cell binding and blocking experiments in KDR/folate receptor high expressing SKOV-3 ovarian cancer cells. The nanoparticles biodistribution was studied after intravenous administration in healthy mice xenografted with SKOV-3 cells. A higher percent injected dose per gram of tissue (% ID/g) was observed in liver, kidney, spleen, blood and tumor at 3 and 9 h post-injection. Scintigraphic images revealed that the radioactivity was mainly concentrated in tumor, liver, kidney and bladder; and in the heart, lung, and muscle was significantly lower at 3 h. The radioactivity distribution in the images is consistent with the in vivo biodistribution data. Our works demonstrated that K237/FA-PEG-PLGA nanoparticles have great potential as biodegradable drug carriers, especially for tumors expressing the folate and KDr receptor.

In a previous study, a novel biodegradable multiblock copolymer, monomethoxy(poly-ethylene glycol)-poly(d,l-lactide-co-glycolide)-poly(l-lysine) (PEAL), was developed as a new drug carrier material. It is imperative to study the biocompatibility and degradation behavior of PEAL to pave the way for clinical applications. Here, we systematically demonstrated that the PEAL copolymer has the appropriate hydrophilicity and biosafety. The degradation rate of the PEAL films was obtained by observing changes in mass, molecular weight (Mw), Mw distribution and degradation products. The degradation rate was observed to have a highly positive correlation with the pH of the medium and negative correlation with the ratio of lactic acid to glycolic acid (LA/GA). Cytotoxicity tests indicated that the degradation products of the copolymer were non-toxic to cells. In zebrafish embryos, the PEAL nanoparticles had no obvious impact on heart rate, production of reactive oxygen species, mortality, or cell apoptosis, and they were observed to have a long circulation time. Therefore, the PEAL copolymer has great potential for use as a drug carrier material.

// Zelai He 1,2 , Jingwen Huang 2 , Yuanyuan Xu 3 , Xiangyu Zhang 3 , Yanwei Teng 3 , Can Huang 3 , Yufeng Wu 4 , Xi Zhang 2 , Huijun Zhang 5 and Wenjie Sun 1 1 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China 2 The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China 3 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China 4 Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China 5 Department of Cardio-thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China Correspondence to: Xi Zhang, email: // Huijun Zhang, email: // Wenjie Sun, email: // Keywords : nanoparticles, PLGA, biocompatibility, chemotherapy, cytotoxicity Received : January 31, 2015 Accepted : October 11, 2015 Published : October 26, 2015 Abstract An amphiphilic copolymer, folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) was prepared and explored as a nanometer carrier for the co-delivery of cisplatin (cis-diaminodichloroplatinum, CDDP) and paclitaxel (PTX). CDDP and PTX were encapsulated inside the hydrophobic inner core and chelated to the middle shell, respectively. PEG provided the outer corona for prolonged circulation. An in vitro release profile of the CDDP + PTX-encapsulated nanoparticles revealed that the PTX chelation cross-link prevented an initial burst release of CDDP. After an incubation period of 24 hours, the CDDP+PTX-encapsulated nanoparticles exhibited a highly synergistic effect for the inhibition of A549 (FA receptor negative) and M109 (FA receptor positive) lung cancer cell line proliferation. Pharmacokinetic experiment and distribution research shows that nanoparticles have longer circulation time in the blood and can prolong the treatment times of chemotherapeutic drugs. For the in vivo treatment of A549 cells xeno-graft lung tumor, the CDDP+PTX-encapsulated nanoparticles displayed an obvious tumor inhibiting effect with an 89.96% tumor suppression rate (TSR). This TSR was significantly higher than that of free chemotherapy drug combination or nanoparticles with a single drug. For M109 cells xeno-graft tumor, the TSR was 95.03%. In vitro and in vivo experiments have all shown that the CDDP+PTX-encapsulated nanoparticles have better targeting and antitumor effects in M109 cells than CDDP+PTX-loaded PEG-PLGA nanoparticles ( p < 0.05). In addition, more importantly, the enhanced anti-tumor efficacy of the CDDP+PTX-encapsulated nanoparticles came with reduced side-effects. No obvious body weight loss or functional changes occurred within blood components, liver, or kidneys during the treatment of A549 and M109 tumor-bearing mice with the CDDP+PTX-encapsulated nanoparticles. Thus, the FA modified amphiphilic copolymer-based combination of CDDP and PTX may provide useful guidance for effective and safe cancer chemotherapy, especially in tumors with high FA receptor expression.

Studies have shown that monomethoxy(polyethylene glycol)–poly(d,l-lactic-co-glycolic acid)–poly(l-lysine) (mPEG-PLGA-PLL)-prepared nanoparticles (NPs) are promising drugs carriers, with good drug l...

Inoperable lung adenocarcinoma is currently treated with platinum-based chemotherapy. However, the effectiveness of these chemotherapeutic agents is not the same for all patients. Patients either show quick chemoresistance (QCR) or delayed chemoresistance (DCR), which are defined by 87 and 242 days of progression-free survival (PFS) after initial platinum-based treatment, respectively. We found that QCR patients displayed an elevated level of serum cholesterol and that their tumors showed upregulated ABCG2 expression. We propose that chemoresistance may be attributed to cholesterol-induced ABCG2 expression and hypothesize that blocking ABCG2 may increase the efficacy of platinum-based chemotherapeutic agents. Using the MTT cell viability assay, we observed that cotreatment with ABCG2 blocker Nicardipine and platinum-based drugs Cisplatin, Oxaliplatin or Carboplatin significantly decreased cell viability of tumor cells. Importantly, our results also showed that incubating cells with cholesterol prior to chemotherapy treatment or cotreatment increased cell viability of tumor cells relative to the controls.

Type AB thymoma associated with multiple metastases is rarely encountered. This paper describes the therapeutic effect of new radiotherapy, helical tomotherapy (TOMO), in a thymoma patient with multiple metastases. A male patient aged 52 was diagnosed as type AB thymoma with multiple metastases. Two-cycle chemotherapy was administered as the primary therapy. The efficacy evaluation indicated progressive disease (PD), so radiotherapy was added to the initial treatment. The re-evaluation of efficacy indicated PD under chemotherapy and partial response (PR) in the radiotherapy area, so the latter treatment was changed to TOMO. The TOMO treatment was effective. However, due to the severe bone marrow suppression, the radiotherapy was stopped, and the patient was discharged. We concluded that the development of type AB thymoma associated with multiple metastases was fast, and the patient was sensitive to radiotherapy but not chemotherapy. Thus, TOMO can be selected as the primary palliative therapeutic regimen for chemotherapy-resistant thymoma patients, but the patient tolerance of TOMO requires careful evaluation and further clinical study.

In this study, we used folic-acid-modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) to encapsulate cisplatin and paclitaxel (separately or together), and evaluated their antitumor effects against lung cancer; this study was conducted in order to investigate the antitumor effects of the co-delivery of cisplatin and paclitaxel by a targeted drug delivery system. Blood compatibility assays and complement activation tests revealed that FA-PEG-PLGA nanoparticles did not induce blood hemolysis, blood clotting, or complement activation. The results also indicated that FA-PEG-PLGA nanoparticles had no biotoxic effects, the drug delivery system allowed controlled release of the cargo molecules, and the co-delivery of cisplatin and paclitaxel efficiently induces cancer cell apoptosis and cell cycle retardation. In addition, co-delivery of cisplatin and paclitaxel showed the ability to suppress xenograft lung cancer growth and prolong the survival time of xenografted mice. These results implied that FA-PEG-PLGA nanoparticles can function as effective carriers of cisplatin and paclitaxel, and that co-delivery of cisplatin and paclitaxel by FA-PEG-PLGA nanoparticles results in more effective antitumor effects than the combination of free-drugs or single-drug-loaded nanoparticles.

Biomaterial poly(lactic-co-glycolic acid) (PLGA), a FDA-approved material for clinical application, showed broad prospects in the past, but gradually can no longer meet present clinical developments and requirements, which we synthesized monomethoxy(polyethylene glycol)-poly(D,L-lactic-co-glycolic acid)-poly(L-lysine) (mPEG-PLGA-PLL) (PEAL) and have had some relevant reports. But studies on biocompatibility and the impacts of LA and GA ratio (LA/GA=60/40, 70/30, and 80/20) in main material have not yet been reported. Hemolysis experiment indicates that the hemolysis rate of PEAL extraction medium is less than 5%. Whole blood clotting time (CT), plasma recalcification time, activated partial thromboplastin time, prothrombin time evaluations, and dynamic CT assay show that the anticoagulant time of PEAL copolymer for blood is longer than that under negative and positive control. Protein adsorption assay indicates that PEAL films adsorb less protein than PLGA films (p0.01); but comparing with expanded polytetrafluoroethylene, the aforementioned difference is not significant (p0.05). Complement activation test shows that PEAL surface does not induce complement activation. CCK8 measurement shows that the relative growth rates of Huh7, L02, and L929 cells co-incubated with PEAL nanoparticles (NPs) are more than 90%. PEAL NPs co-incubated with 5% foetal bovine serum or 2% bovine serum albumin, through dynamic light scattering assay, remain stable. Different concentrations of PEAL NPs co-incubated with zebrafish embryos at 6-72 h post fertilization show that comparing with negative control, 10, 100, or 500 μM of NPs for embryos development has no significant effects (p0.05), only 1000 or 2000 μM of NPs has some effects (p0.05). It is concluded that the PEAL copolymer, with excellent biocompatibility, proves to be a high-safety dose as drug carrier and implant candidate in vivo.