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Yu Lu,1 Jing-Jing Zhao,2 Ping He1 1Department of Ultrasonography, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China; 2Department of Pathology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of ChinaCorrespondence: Ping He, Department of Ultrasonography, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, No. 2699 Gaoke West Road, Pudong District, Shanghai, 201204, People’s Republic of China, Tel +86-2120261000, Email hepinghmp0@126.comBackground: Microphthalmia is a rare autosomal recessive condition commonly known as Waardenburg anophthalmia syndrome (WAS) or oculo-acromal formation syndrome (MIM#206920).Case Description: Here, we report the case of a woman whose fetal ultrasonography at 12 weeks of pregnancy revealed multiple fetal abnormalities. These included the absence of the left upper limb, an unclear display of the right orbit, a visible maxillary space, and a round, echoless appearance measuring 4 mm in diameter in the middle of the forehead. There was also a significant echo in the sac wall. The possibility of a frontal meningocele or a proboscis-like nose was considered. The fetus was delivered with absence of the left upper limb, absence of the right eye, a cleft lip on the right side, and a milky white sac with a diameter of 5 mm on the forehead after the pregnancy was terminated at the hospital. Pathological investigation revealed a mature cystic teratoma. The conclusion was microphthalmia with limb anomalies (MLA) after missing limbs, absence of eyes, and cleft lip were input into the Online Mendelian Inheritance in Man database. The case was diagnosed with fetal microphthalmia with limb anomalies and an interfrontal teratoma.Conclusion: In this case, the entire exon analysis was not conducted, and as a result, the final diagnosis remains unclear. Based exclusively on the phenotype of the induced fetus, MLA was diagnosed. It is proposed that cases satisfying the requirements for a pathological diagnosis should undergo a pathological examination to establish a definitive diagnosis.Keywords: cleft lip, limb anomalies, microphthalmia, teratoma

Yuan Liu,1,2,* Jing-Jing Zhao,1,2,* Zi-Qi Zhou,1,2 Qiu-Zhong Pan,1,2 Qian Zhu,1,2 Yan Tang,1,2 Jian-Chuan Xia,1,2 De-Sheng Weng1,21State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workIntroduction: IL-37 is a cytokine of IL-1 family that plays an important role in innate immunity and inflammation, and has been studied as a tumor suppressor in many cancers. However, it remains unclear whether IL-37 plays a regulatory role in tumor-infiltrating dendritic cells (DCs) in hepatocellular carcinoma (HCC).Materials and methods: We evaluated the relationship between IL-37 expression and tumor infiltration by DCs in 155 HCC samples through immunohistochemical analysis and Kaplan–Meier survival analysis. The effects of IL-37 on the anti-tumor activity of DCs were investigated by ELISA, flow cytometry, real-time quantitative PCR, cytotoxicity assays and tumorigenicity assays.Results: The expression level of IL-37 in HCC samples was positively correlated with the degree of CD1a+ DCs infiltration. The survival rates of patients with both a high expression of IL-37 and a high infiltration by CD1a+ DCs were significantly higher than those of patients with a low expression of IL-37 and a low infiltration by CD1a+ DCs. In vitro chemotaxis analysis indicated that HCC cells overexpressing IL-37 recruited more DCs by secreting higher levels of specific chemokines (eg, CCL3 and CCL20). In addition, IL-37 indirectly up-regulated the expression of major histocompatibility class II molecules, CD86 and CD40 on DCs by acting on tumor cells; IL-37 also indirectly enhanced the anti-tumor effect of T lymphocytes by stimulating DCs to secrete cytokines such as IL-2, IL-12, IL-12p70, interferon-α (IFN-α) and IFN-γ. Finally, overexpression IL-37 in HCC cells significantly delayed tumor growth and increased recruitment of CD11c+ DCs to tumor tissues was also revealed in vivo mouse model.Conclusion: DCs play an important role in IL-37 mediated anti-tumor immune responses in HCC, which may contribute to the development of novel cancer immunotherapeutic strategies.Keywords: IL-37, dendritic cells, antitumor immunity, hepatocellular carcinoma

Jing-Jing Zhao,1,2,* Zi-Qi Zhou,1,2,* Peng Wang,3,4,* Chang-Long Chen,1,2 Yuan Liu,1,2 Qiu-Zhong Pan,1,2 Qian Zhu,1,2 Yan Tang,1,2 De-Sheng Weng,1,2 Jian-Chuan Xia1,2 1Department of Experimental Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; 2Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, China; 3Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; 4Department of Medical Research, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China *These authors contributed equally to this work Introduction: Esophageal squamous cell carcinoma (ESCC) develops in a background of chronic inflammation; therefore, it is a promising candidate for treatment by immunotherapy. Although tumor immunity is critically involved in tumor growth and metastasis in ESCC, important gaps exist in our understanding of its immune microenvironment. This study aimed to investigate the expression and prognostic significance of immune checkpoint proteins in ESCC and the associated T-cell densities.Materials and methods: We investigated the infiltration of CD8+ T cells and the expressions of immune checkpoint proteins (PD-1, TIGIT, PD-L1, and PD-L2) in 154 primary ESCC patients by immunohistochemistry. The correlation of immune checkpoint proteins’ expression and clinical outcomes was determined by Kaplan–Meier test and multivariate Cox regression analysis.Results: PD-L1 and PD-L2 expression were detected in 45.5 and 59.7% of the ESCC samples, respectively. The high densities of PD-1+ and TIGIT+ tumor-infiltrating lymphocytes (TILs) were expressed in 47.4 and 49.4% of the ESCC patients, respectively. The number of PD-1+ TILs was significantly positively correlated with CD8+ TILs (P

Yi Que,1,* Yao Liang,2,* Jingjing Zhao,1 Ya Ding,1 Ruiqing Peng,1 Yuanxiang Guan,2 Xing Zhang1 1Department of Medical Melanoma and Sarcoma, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Gastric and Pancreatic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China *These authors contributed equally to this work Objective: Research efforts have investigated therapies targeting tyrosine kinase signaling pathways. We performed a pooled analysis to determine the frequency of severe adverse effects in patients with soft tissue sarcoma treated with pazopanib, sorafenib and sunitinib. Materials and methods: We performed a comprehensive search of PubMed, Web of Science, Ovid, the Cochrane Library and Embase databases from the drugs’ inception to May 2017 to identify clinical trials. All-grade and severe adverse events (AEs; grade≥3) were analyzed. Results: A total of 10 trials published between 2009 and 2016, including 843 patients, were eligible for analysis. We included 424 patients (three studies) who received pazopanib 800 mg daily, 353 patients (five studies) who received sorafenib 400 mg twice daily and 66 patients (two studies) who received sunitinib 37.5 mg daily. The incidence of AEs is different among the three VEGFR-tyrosine kinase inhibitors (TKIs). Pazopanib showed higher incidence of all-grade nausea, diarrhea and hypertension compared with sorafenib and sunitinib. However, patients in the sorafenib group experienced a significantly higher frequency of all-grade rash (26.1%), hand–foot syndrome (33.4%) and mucositis (38.5%). The difference was highly significant for sorafenib vs. pazopanib in the incidence of all-grade rash (odds ratio [OR] 1.649, 95% CI 1.086–2.505, P=0.023), hand–foot syndrome (OR 3.096, 95% CI 1.271–7.544, P=0.009) and mucositis (OR 4.562, 95% CI 2.132–9.609, P

Xiao-long Wu,1,* Zhi-yu Li,1,* Xin-yu Bi,1 Hong Zhao,1 Jian-jun Zhao,1 Jian-guo Zhou,1 Yue Han,2 Zhen Huang,1 Ye-fan Zhang,1 Jian-qiang Cai1 1Department of Hepatobiliary Surgery, 2Department of Interventional Therapies, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China *These authors contributed equally to this work Background: Systemic inflammation (SI) is associated with tumor progression and overall survival (OS) in patients with hepatocellular carcinoma (HCC). The presence of some single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region can influence the prognosis of patients with hepatitis B virus (HBV)-related HCC, although the mechanism remains unknown. This study aimed to analyze the correlations between HLA gene polymorphisms and SI. Patients and methods: This study included 330 patients with HCC. The clinical parameters were reviewed, and five SNPs, namely rs2647073, rs3997872, rs3077, rs7453920, and rs7768538, were genotyped using the MassARRAY system. Results: The rs3997872, rs7453920, and rs7768538 genotypes were found to be significantly associated with OS (P

Wenxin Yao,1 Peicheng Xu,1 Zhiqing Pang,2,3 Jingjing Zhao,2,3 Zhilan Chai,2,3 Xiaoxia Li,4 Huan Li,2,3 Menglin Jiang,2,3 Hongbo Cheng,2,3 Bo Zhang,2,3 Nengneng Cheng4 1Shanghai Xuhui District Dental Center, 2Key Laboratory of Smart Drug Delivery, Ministry of Education, 3Department of Pharmaceutics, School of Pharmacy, Fudan University, 4Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China Background: Rapid local drug clearance of antimicrobials is a major drawback for the treatment of chronic periodontitis. In the study reported here, minocycline-loaded poly(ethylene glycol)-poly(lactic acid) nanoparticles were prepared and administered locally for long drug retention and enhanced treatment of periodontitis in dogs.Methods: Biodegradable poly(ethylene glycol)-poly(lactic acid) was synthesized to prepare nanoparticles using an emulsion/solvent evaporation technique. The particle size and zeta potential of the minocycline-loaded nanoparticles (MIN-NPs) were determined by dynamic light scattering and the morphology of the nanoparticles was observed by transmission electron microscopy. The in vitro release of minocycline from MIN-NPs and in vivo pharmacokinetics of minocycline in gingival crevice fluid, after local administration of MIN-NPs in the periodontal pockets of beagle dogs with periodontitis, were investigated. The anti-periodontitis effects of MIN-NPs on periodontitis-bearing dogs were finally evaluated.Results: Transmission electron microscopy examination and dynamic light scattering results revealed that the MIN-NPs had a round shape, with a mean diameter around 100 nm. The in vitro release of minocycline from MIN-NPs showed a remarkably sustained releasing characteristic. After local administration of the MIN-NPs, minocycline concentration in gingival crevice fluid decreased slowly and retained an effective drug concentration for a longer time (12 days) than Periocline®. Anti-periodontitis effects demonstrated that MIN-NPs could significantly decrease symptoms of periodontitis compared with Periocline and minocycline solution. These findings suggest that MIN-NPs might have great potential in the treatment of periodontitis. Keywords: minocycline, nanoparticles, periodontitis, local delivery

Simvastatin and fenofibrate are both commonly used lipid-regulating agents with distinct mechanisms of action, and their coadministration may be an attractive treatment for some patients with dyslipidemia. A 2-period, randomized, open-label, crossover study was conducted in 12 subjects to determine if fenofibrate and simvastatin are subject to a clinically relevant pharmacokinetic interaction at steady state. In treatment A, subjects received an 80-mg simvastatin tablet in the morning for 7 days. In treatment B, subjects received a 160-mg micronized fenofibrate capsule in the morning for 7 days, followed by a 160-mg micronized fenofibrate capsule dosed together with an 80-mg simvastatin tablet on days 8 to 14. Because food increases the bioavailability of fenofibrate, each dose was administered with food to maximize the exposure of fenofibric acid. The steady-state pharmacokinetics (AUC(0-24h), C(max), and t(max)) of active and total HMG-CoA reductase inhibitors, simvastatin acid, and simvastatin were determined following simvastatin administration with and without fenofibrate. Also, fenofibric acid steady-state pharmacokinetics were evaluated with and without simvastatin. The geometric mean ratios (GMRs) for AUC(0-24h) (80 mg simvastatin [SV] + 160 mg fenofibrate)/(80 mg simvastatin alone) and 90% confidence intervals (CIs) were 0.88 (0.80, 0.95) and 0.92 (0.82, 1.03) for active and total HMG-CoA reductase inhibitors. The GMRs and 90% CIs for fenofibric acid (80 mg SV + 160 mg fenofibrate/160 mg fenofibrate alone) AUC(0-24h) and C(max) were 0.95 (0.88, 1.04) and 0.89 (0.77, 1.02), respectively. Because both the active inhibitor and fenofibric acid AUC GMR 90% confidence intervals fell within the prespecified bounds of (0.70, 1.43), no clinically significant pharmacokinetic drug interaction between fenofibrate and simvastatin was concluded in humans. The coadministration of simvastatin and fenofibrate in this study was well tolerated. [ABSTRACT FROM AUTHOR]