Curcumin Encapsulated into Biocompatible Co-Polymer PLGA Nanoparticle Enhanced Anti-Gastric Cancer and Anti-Helicobacter Pylori Effect

Background: The current disadvantages (high cost, toxicity, resistance) of chemotherapy for gastric cancer opted people for alternative therapy from natural source. Curcumin (natural product) possess multiple biological activities but low bio-availability limits their uses as therapeutic. The Nano-formulation of curcumin increased the bioavailability and productivity of anti-cancer and anti-bacterial properties. The present study was initiated to determine the anti-cancer and anti-bacterial effect of Nano curcumin against gastric cancer and H. pylori. Methods: Curcumin loaded PLGA nanoparticles (CUR-NPs) was prepared by single emulsion solvent evaporation method. The MIC were determined using agar dilution method to find the anti-H. Pylori activity of Nano curcumin. The cytotoxicity of Nano curcumin was evaluated by MTT assay and the apoptotic effect (cell cycle arrest and morphology change) was shown by PI staining and microscopy. Results: The MIC of nanocurcumin and curcumin for all four H. pylori strains were 8 µg/ml and 16 µg/ml respectively. The inhibition rate of gastric cancer cells after treatment with curcumin was increased from 6% to 67% for 24h, from 8% to 75% for 48h, from 10% to 83% for 72h. In case of nanocurcumin, the inhibition rate increased from 7% to 69% for 24h, 11% to 87% for 48h and 16% to 97% for 72h. The IC50 of curcumin and Nano-curcumin were 24.20 µM and 18.78 µM respectively for 72 h. The population of cells in sub-G0 population increased from 4.1% in the control group to 24.5% and 57.8% when treated with curcumin and nanocurcumin respectively. After 72h of treatment with nanocurcumin, the apoptotic cells population increased as compared to native curcumin treated cells. Conclusion: The Nano curcumin might be used as a potential therapeutics against gastric cancer and H. Pylori. There is need of further in vivo study in order to validate CUR-NPs activity.     

Functional outcomes and complications after treatment of distal radius fracture in patients sixty years and over: A systematic review and network meta-analysis

AimThis network meta-analysis aims to compare functional outcomes and complications between conservative treatment and surgery for distal radius fractures in patients aged 60 years and over.MethodsWe searched the PubMed, EMBASE, and Web of Science databases for randomized controlled trials (RCTs) assessing the effect of conservative treatment and surgery for distal radius fractures in patients aged 60 years and over. Primary outcomes included grip strength and overall complications. Secondary outcomes included Disabilities of the Arm, Shoulder, and Hand (DASH) scores, Patient-Rated Wrist Evaluation (PRWE) scores, wrist range of motion and forearm rotation, and radiographic assessment. All continuous outcomes were assessed using standardized mean differences (SMDs) with 95% confidence intervals (CIs), and binary outcomes were assessed using odds ratio (OR) with 95% CIs. The surface under the cumulative ranking curve (SUCRA) was used to determine a hierarchy of treatments. Cluster analysis was performed for grouping treatments based on the SUCRA values of primary outcomes.ResultsFourteen RCTs were included to compare conservative treatment, volar lockedplate (VLP), K-wires fixation, and external-fixation. VLP outperformed conservative treatment for 1-year and minimum 2-year grip strength (SMD; 0.28 [0.07 to 0.48] and 0.27 [0.02 to 0.53], respectively). VLP yielded the optimal grip strength at 1-year and minimum 2-year follow-up (SUCRA; 89.8% and 86.7%, respectively). In a subgroup analysis of patients aged 60 to 80 years old, VLP outperformed conservative treatment in DASH and PRWE scores (SMD, 0.33 [0.10, 0.56] and 0.23 [0.01, 0.45], respectively). In addition, VLP had the fewest complications (SUCRA = 84.3%). Cluster analysis suggested that VLP and K-wire fixation were more effective treatment groups.ConclusionEvidence to date demonstrates that VLP provides measurable benefits in grip strength and fewer complications to those 60 years of age and over, and that benefit is not reflected in current practice guidelines. There is a subgroup of patients where K-wire fixation outcomes are similar to those of VLP; defining this subgroup may yield substantial societal benefits.     

Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

A prognostic signature based on immune-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is the fourth commonest female malignancy worldwide. CESC progresses in immune-microenvironment mainly composed of infiltrating immune and stromal cells. Here, we performed an integrated analysis incorporating the expression profiles from the Cancer Genome Atlas (TCGA) database and scores of immune and stromal cells calculated by Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm. A two-gene signature (CD1C and CD6 genes) was established to predict the prognosis of CESC. Based on this signature, patients were divided into the high- and low-risk groups, and this signature showed good prognostic performance according to the results of Kaplan-Meier analysis and receiver operating characteristic (ROC) analysis in train set and two validation sets. A nomogram was built for evaluating the clinical applicability of this signature. In addition, based on Tumor Immune Estimation Resource (TIMER) database, 2 hub genes showed negative correlations with tumor purity and positive correlations with infiltrating levels of immune filtrating cells. What’s more, we propose new treatment strategies for the two prognostic subtypes. Low- risk patients were found presenting with a higher level of immune checkpoint molecules and showing higher immunogenicity in immunophenoscore (IPS) analysis, which indicated a better response for immunotherapy. Meanwhile, estimated by Genomics of Drug Sensitivity in Cancer (GDSC) database, the high-risk patients showed sensitive responses to five chemotherapy drugs. Finally, 10 candidate small-molecule drugs for CESC were defined. In summary, the CD1C-CD6 signature can accurately predict the prognosis of CESC.     

臀部筋膜脂肪瓣修复坐骨结节和大转子复发性窦道型压疮

目的总结臀部筋膜脂肪瓣修复坐骨结节、大转子复发性窦道型压疮的效果。方法2018 年 2 月—2019 年 6 月，收治 12 例 13 处长期截瘫伴坐骨结节、大转子复发性窦道型压疮患者。其中男 10 例 11 处，女 2 例 2 处；年龄 46～56 岁，平均 51 岁。截瘫 10～20 年，平均 13 年；所有患者均有压疮手术史，术后 3 个月～12 年复发。其中坐骨结节处压疮 11 例，坐骨结节合并大转子处压疮 1 例。创面清创、切除窦道假性滑液囊，采用单侧或双侧臀部筋膜脂肪瓣填塞窦道，术区一期缝合闭合切口。结果术后 13 处压疮切口均Ⅰ期愈合，局部无红肿、渗液，术后 14 d 拆线出院。术后局部平坦，外观理想。术后患者均获随访，随访时间 8～24 个月，平均 14 个月。随访期间压疮均无复发。结论臀部脂肪组织丰富，利用筋膜脂肪瓣修复坐骨结节、大转子复发性窦道型压疮设计、操作简便，临床效果良好。     

Inhibiting Pathways Predicted From a Steroid Hormone Gene Signature Yields Synergistic Antitumor Effects in NSCLC

IntroductionMounting evidence supports a role for estrogen signaling in NSCLC progression. We previously reported a seven-gene signature that predicts prognosis in estrogen receptor β positive (ERβ+) NSCLC. The signature defines a network comprised of ER and human EGFR-2/3 (HER2/HER3) signaling.MethodsWe tested the efficacy of combining the pan-HER inhibitor, dacomitinib, with the estrogen antagonist, fulvestrant, in ERβ+ NSCLC models with differing genotypes. We assessed the potency of this combination on xenograft growth and survival of host mice, and the ability to reverse the gene signature associated with poor outcome.ResultsSynergy was observed between dacomitinib and fulvestrant in three human ERβ+ NSCLC models: 201T (wild-type EGFR), A549 (KRAS mutant), and HCC827 (EGFR 19 deletion) with combination indices of 0.1-0.6. The combination, but not single agents, completely reversed the gene signature associated with poor prognosis in a mechanism that is largely mediated by activator protein 1 downregulation. In vivo, the combination also induced tumor regression and reversed the gene signature. In HCC827 xenografts treated with the combination, survival of mice was prolonged after therapy discontinuation, tumors that recurred were less aggressive, and two mechanisms of HER inhibitor resistance involving c-Met activation and PTEN loss were blocked.ConclusionsThe combination of an ER blocker and a pan-HER inhibitor provides synergistic efficacy in different models of ERβ+ NSCLC. Our data support the use of this combination clinically, considering its ability to induce potent antitumor effects and produce a gene signature that predicts better clinical outcomes.     

SDF-1α/CXCR4 信号通路在轴向应力刺激促进骨再生中的作用研究

目的通过轴向应力刺激促进骨再生，观察基质细胞衍生因子 1α/趋化因子 CXC 亚族受体 4（stromal cell-derived factor 1α/cysteine X cysteine receptor 4，SDF-1α/CXCR4）信号通路变化，探讨轴向应力刺激促进骨再生的机制。方法取 72 只雄性新西兰大白兔，于右后肢胫骨近端内侧制备直径 8 mm 圆形皮质骨缺损并脱蛋白松质骨支架修复模型，随机分为 3 组（n=24）。A 组腹腔注射 PBS，B 组术肢给予应力刺激治疗+腹腔注射 PBS，C 组术肢给予应力刺激治疗+腹腔注射 CXCR4 拮抗剂（AMD3100）。术后 2、4、8、12 周，摄 X 线片并采用 Lane-Sandhu X 线评分标准评价骨愈合情况，取标本行 HE 染色观察新生骨组织及支架降解，免疫组织化学染色观察 VEGF、CXCR4 表达水平；4、8 周取标本 Western blot 检测 SDF-1α 及 CXCR4 蛋白表达水平；12 周行 Micro-CT 检查，计算新生骨体积及新生骨密度。 结果X 线片检查示，除术后 2 周各组骨缺损区及支架无明显变化外，4、8 及 12 周时 B 组骨愈合评分均高于 A、C 组（P<0.05）。12 周时 Micro-CT 扫描可见 B 组骨缺损修复、髓腔再通，新生骨体积及骨密度均高于 A、C 组（P<0.05）。HE 染色显示，术后 4 周开始 B 组骨再生及支架降解均明显快于 A、C 组。免疫组织化学染色示，各组 VEGF 及 CXCR4 阳性表达均在 4 周达峰值；各时间点 B 组 VEGF 及 CXCR4 表达量均显著高于 A、C 组（P<0.05）。Western blot 检测显示，4、8 周时 B 组 SDF-1α 与 CXCR4 表达量均显著高于 A、C 组（P<0.05）。 结论轴向应力刺激促进骨再生可能与其促进骨缺损区组织高表达 SDF-1α，激活与其下游调控 BMSCs 募集的 CXCR4 信号有关。     

股骨转子间骨折的稳定性重建概念演化与研究进展

目的总结近年来股骨转子间骨折在稳定性重建方面的概念演化与研究进展。方法查阅国内外相关文献并结合自身经验，从股骨转子间骨折的解剖特点、稳定型骨折与不稳定型骨折分类、稳定性复位与不稳定性复位、术中加压初始稳定与术后滑动二次稳定、内固定术后稳定性评估、早期下地站立负重等方面进行总结分析。结果股骨转子间骨折发生于股骨颈干骺端转换区，具有天然的内翻不稳定倾向。骨折复位质量是影响后续内固定物安放的最重要前提因素。判断骨折复位质量有对线和对位两方面，对线采用 Garden 指数；在对位方面，随着皮质对位理念（正性、中性、负性）的提出，特别强调前内侧皮质的相互砥住支撑（解剖、正性），是获得骨折稳定性复位的关键，而不再强调后内侧小转子骨块的作用。术后影像学的稳定性评分为早期下地站立负重提供了量化指标。但术中的前内侧皮质支撑复位，在术后头颈骨块滑动获得二次稳定的过程中，仍有皮质对位丢失现象，需研究其危险因素和防范措施。结论股骨转子间骨折在取得良好对线的基础上，只要获得了前内侧皮质的相互砥住和支撑，并用内固定器械维持住，就获得了术后稳定性。术后稳定性评分优良者，可以安全地早期下地负重、站立行走活动。     

Single-dose combination nanovaccine induces both rapid and durable humoral immunity and toxin neutralizing antibody responses against Bacillus anthracis

Bacillus anthracis, the causative agent of anthrax, continues to be a prominent biological warfare and bioterrorism threat. Vaccination is likely to remain the most effective and user-friendly public health measure to counter this threat in the foreseeable future. The commercially available AVA BioThrax vaccine has a number of shortcomings where improvement would lead to a more practical and effective vaccine for use in the case of an exposure event. Identification of more effective adjuvants and novel delivery platforms is necessary to improve not only the effectiveness of the anthrax vaccine, but also enhance its shelf stability and ease-of-use. Polyanhydride particles have proven to be an effective platform at adjuvanting the vaccine-associated adaptive immune response as well as enhancing stability of encapsulated antigens. Another class of adjuvants, the STING pathway-targeting cyclic dinucleotides, have proven to be uniquely effective at inducing a beneficial inflammatory response that leads to the rapid induction of high titer antibodies post-vaccination capable of providing protection against bacterial pathogens. In this work, we evaluate the individual contributions of cyclic di-GMP (CDG), polyanhydride nanoparticles, and a combination thereof towards inducing neutralizing antibody (nAb) against the secreted protective antigen (PA) from B. anthracis. Our results show that the combination nanovaccine elicited rapid, high titer, and neutralizing IgG anti-PA antibody following single dose immunization that persisted for at least 108 DPI.     

中国非小细胞肺癌免疫检查点抑制剂治疗专家共识（2020年版）

非小细胞肺癌（non-small cell lung cancer, NSCLC）是肺癌最常见的病理类型。晚期NSCLC的系统性抗肿瘤治疗经历了化疗、靶向治疗及免疫治疗的变革，患者总体生存时间不断延长。免疫检查点抑制剂（immune checkpoint inhibitors, ICIs），尤其是程序性死亡分子-1（programmed cell death protein 1, PD-1）/程序性死亡分子配体-1（programmed death-ligand 1, PD-L1）抗体已成为表皮生长因子受体（epidermal growth factor receptor, EGFR）/间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）阴性晚期NSCLC一线及二线的标准治疗和局部晚期NSCLC同步放化疗后标准治疗，并在辅助/新辅助治疗中显示出可喜的结果，改变了NSCLC整体治疗格局。随着越来越多的ICIs在国内获批肺癌适应证，中国临床肿瘤学会（Chinese Society of Clinical Oncology, CSCO）NSCLC专家委员会牵头，组织该领域的专家，结合2019年版专家共识，参考最新国内外文献、临床研究数据及系统评价，在专家共同讨论的基础上，达成统一意见并制定、更新本共识，为国内同行更好地应用ICIs治疗NSCLC提供参考意见。