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At present, acute myeloid leukemia (AML) is mainly treated with combination medication, high-dose, and early intensification. The treatment has achieved good results, but the long-term treatment effect is still not satisfactory. Studies have shown that the different levels of cytokine expression in AML patients can help AML risk stratification, search for treatment directions and predict the prognosis. It has been confirmed that the expression of IL-1β, IL-6, TNF-α, and TGF-β1 are increased in AML patients, and they all indicate a poor prognosis. However, IL-8, IFN-γ, and CCL5 have great research value in chemotherapy resistance and improvement of treatment effect. This article reviews the research progress of cytokine biomarkers in the prognosis of AML patients.细胞因子在急性髓系白血病预后中的研究进展.目前急性髓系白血病（AML）的治疗以联合用药、大剂量、早期强化为主，且取得了较好的治疗效果，但是远期治疗效果仍令人不满意。研究表明，AML患者细胞因子的不同程度表达有助于AML危险分层、寻找治疗方向以及预测AML患者预后。目前已证实IL-1β、IL-6、TNF-α、TGF-β1在AML患者中高表达，且均提示不良预后，而IL-8、IFN-γ、CCL5在化疗耐药性及改善治疗效果方面具有较大的研究价值。本文就细胞因子类生物标志在AML患者预后中的研究进展作一综述.

Background Chronic inflammatory pain significantly reduces the quality of life and lacks effective interventions. In recent years, human umbilical cord mesenchymal stem cells (huc-MSCs)-derived exosomes have been used to relieve neuropathic pain and other inflammatory diseases as a promising cell-free therapeutic strategy. However, the therapeutic value of huc-MSCs-derived exosomes in complete Freund's adjuvant (CFA)-induced inflammatory pain remains to be confirmed. In this study, we investigated the therapeutic effect and related mechanisms of huc-MSCs-derived exosomes in a chronic inflammatory pain model. Methods C57BL/6J male mice were used to establish a CFA-induced inflammatory pain model, and huc-MSCs-derived exosomes were intrathecally injected for 4 consecutive days. BV2 microglia cells were stimulated with lipopolysaccharide (LPS) plus adenosine triphosphate (ATP) to investigate the effect of huc-MSCs-derived exosomes on pyroptosis and autophagy. Bioinformatic analysis and rescue experiments were used to demonstrate the role of miR-146a-5p/ TRAF6 in regulating pyroptosis and autophagy. Western blotting, RT-qPCR, small interfering RNA and Yo-Pro-1 dye staining were performed to investigate the related mechanisms. Results Huc-MSCs-derived exosomes alleviated mechanical allodynia and thermal hyperalgesia in CFA-induced inflammatory pain. Furthermore, huc-MSCs-derived exosomes attenuated neuroinflammation by increasing the expression of autophagy-related proteins (LC3-II and beclin1) and inhibiting the activation of NLRP3 inflammasomes in the spinal cord dorsal horn. In vitro, NLRP3 inflammasome components (NLRP3, caspase1-p20, ASC) and gasdermin D (GSDMD-F, GSDMD-N) were inhibited in BV2 cells pretreated with huc-MSCs-derived exosomes. Western blot and Yo-Pro-1 dye staining demonstrated that 3-MA, an autophagy inhibitor, weakened the protective effect of huc-MSCs-derived exosomes on BV2 cell pyroptosis. Importantly, huc-MSCs-derived exosomes transfected with miR-146a-5p mimic promoted autophagy and inhibited BV2 cell pyroptosis. TRAF6, as a target gene of miR-146a-5p, was knocked down via small-interfering RNA, which increased pyroptosis and inhibited autophagy. Conclusion Huc-MSCs-derived exosomes attenuated inflammatory pain via miR-146a-5p/TRAF6, which increased the level of autophagy and inhibited pyroptosis. Graphical Abstract

Macroautophagy/autophagy, an evolutionarily conserved process, plays an important role in the regulation of immune inflammation and nervous system homeostasis. However, the exact role and mechanism of autophagy in pain is still unclear. Here, we showed that impaired autophagy flux mainly occurred in astrocytes during the maintenance of neuropathic pain. No matter the stage of neuropathic pain induction or maintenance, activation of autophagy relieved the level of pain, whereas inhibition of autophagy aggravated pain. Moreover, the levels of neuroinflammation and reactive oxygen species (ROS) were increased or decreased following autophagy inhibition or activation. Further study showed that inhibition of autophagy slowed the induction, but increased the maintenance of neuroinflammatory responses, which could be achieved by promoting the binding of TRAF6 (TNF receptor-associated factor 6) to K63 ubiquitinated protein, and increasing the levels of p-MAPK8/JNK (mitogen-activated protein kinase 8) and nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB/NF-κB). Impaired autophagy also reduced the protective effect of astrocytes on neurons against ROS stress because of the decrease in the level of glutathione released by astrocytes, which could be improved by activating the NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2) pathway. We also demonstrated that simultaneous activation of autophagy and the NFE2L2 pathway further relieved pain, compared to activating autophagy alone. Our study provides an underlying mechanism by which autophagy participates in the regulation of neuropathic pain, and a combination of autophagy and NFE2L2 activation may be a new treatment approach for neuropathic pain. Abbreviation: 3-MA: 3-methyladenine; 8-OHdG: 8-hydroxydeoxy-guanosine; ACTB: actin, beta; AMPAR: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor; ATG: autophagy-related; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CCL7: chemokine (C-C motif) ligand 7; CGAS: cyclic GMP-AMP synthase; CQ: chloroquine; GABA: gamma-aminobutyrate; GCLC: glutamate-cysteine ligase, catalytic subunit; GFAP: glial fibrillary acidic protein; GSH: glutathione; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch-like ECH-associated protein 1; MAP1LC3/LC3-II: microtubule-associated protein 1 light chain 3 beta (phosphatidylethanolamine-conjugated form); MAPK: mitogen-activated protein kinase; MAPK1/ERK: mitogen-activated protein kinase 1; MMP2: matrix metallopeptidase 2; MAPK8/JNK: mitogen-activated protein kinase 8; MAPK14/p38: mitogen-activated protein kinase 14; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; ROS: reactive oxygen species; SLC12A5: solute carrier family 12, member 5; SNL: spinal nerve ligation; TLR4: toll-like receptor 4; TRAF6: TNF receptor-associated factor; TRP: transient receptor potential.

Globally, postpartum hemorrhage (PPH) is the leading cause of maternal death. Women with immune thrombocytopenia (ITP) are at increased risk of developing PPH. Early identification of PPH helps to prevent adverse outcomes but is underused because clinicians do not have a tool to predict PPH for women with ITP. We therefore conducted a nationwide multicenter retrospective study to develop and validate a prediction model of PPH in patients with ITP. We included 432 pregnant women (677 pregnancies) with primary ITP from 18 academic tertiary centers in China from Jan 2008 to Aug 2018. A total of 157 (23.2%) pregnancies experienced PPH. The derivation cohort included 450 pregnancies. For the validation cohort, we included 117 pregnancies in the temporal validation cohort and 110 pregnancies in the geographical validation cohort. We assessed 25 clinical parameters as candidate predictors and used multivariable logistic regression to develop our prediction model. The final model included seven variables and was named MONITOR (maternal complication, WHO bleeding score, antepartum platelet transfusion, placental abnormalities, platelet count, previous uterine surgery, and primiparity). We established an easy-to-use risk heatmap and risk score of PPH based on the seven risk factors. We externally validated this model using both a temporal validation cohort and a geographical validation cohort. The MONITOR model had an AUC of 0.868 (95% CI 0.828-0.909) in internal validation, 0.869 (95% CI 0.802-0.937) in the temporal validation, and 0.811 (95% CI 0.713-0.908) in the geographical validation. Calibration plots demonstrated good agreement between MONITOR-predicted probability and actual observation in both internal validation and external validation. Therefore, we developed and validated a very accurate prediction model for PPH. We hope that the model will contribute to more precise clinical care, decreased adverse outcomes, and better health care resource allocation. This article is protected by copyright. All rights reserved.

Omega-3 polyunsaturated fatty acid (ω-3 PUFA) have been reported to have beneficial cardiovascular effects, but its mechanism of protection against acute myocardial infarction (AMI) who are under guideline-based therapy is not fully understood. Here, we used a metabolomic approach to systematically analyze the eicosanoid metabolites induced by ω-3 PUFA supplementation and investigated the underlying mechanisms.Participants with AMI after successful percutaneous coronary intervention were randomized to 3 months of 2 g daily ω-3 PUFA and guideline-adjusted therapy (n = 30, ω-3 therapy) or guideline-adjusted therapy alone (n = 30, Usual therapy). Functional PUFA-derived eicosanoids in plasma were profiled by metabolomics. Clinical and laboratory tests were obtained before and 3 months after baseline and after the study therapy.By intent-to-treat analysis, the content of 11-HDoHE, 20-HDoHE and 16,17-EDP and that of epoxyeicosatetraenoic acids (EEQs), derived from docosahexaenoic acid and eicosapentaenoic acid, respectively, were significantly higher with ω-3 group than Usual therapy, whereas that of prostaglandin J2 (PGJ2) and leukotriene B4, derived from arachidonic acid, was significantly decreased. As compared with Usual therapy, ω-3 PUFA therapy significantly reduced levels of triglycerides (-6.3%, P 0.05), apolipoprotein B (-4.9%, P 0.05) and lipoprotein(a) (-37.0%, P 0.05) and increased nitric oxide level (62.2%, P 0.05). In addition, the levels of these variables were positively correlated with change in 16,17-EDP and EEQs content but negatively with change in PGJ2 content.ω-3 PUFA supplementation may improve lipid metabolism and endothelial function possibly by affecting eicosanoid metabolic status at a systemic level during convalescent healing after AMI.URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1900025859.

In this study, we isolated and characterized HSP70 cDNA from pufferfish (Takifugu rubripes). The 3053 bp full-length TrHSP70 sequence consisted of a 167 bp 5′-UTR (untranslated region), a 2535 bp open reading frame, and a 351 bp 3′-UTR. BLAST analysis revealed that the TrHSP70 shared high similarity with HSP70 sequences in other species. In our study, we set 3 experimental groups as H1 group (20 °C), H2 group (24 °C), and H3 group (28 °C) for checking the expression level of TrHSP70 in T. rubripes. Tissue-specific gene expression results showed that TrHSP70 had higher expression in the intestines than other tissues of the T. rubripes by RT-qPCR. In the experimental group, we found that the expression of TrHSP70 was upregulated in different tissues in the H3 group. The results show that TrHSP70 is a constitutively expressed gene, which plays an important role in maintaining normal physiological function and coping with stress.

Purpose: Prediction models for acute myeloid leukemia (AML) are useful, but have considerable inaccuracy and imprecision. No current model includes covariates related to immune cells in the AML microenvironment. Here, an immune risk score was explored to predict the survival of patients with AML. Experimental Design: We evaluated the predictive accuracy of several in silico algorithms for immune composition in AML based on a reference of multi-parameter flow cytometry. CIBERSORTx was chosen to enumerate immune cells from public datasets and develop an immune risk score for survival in a training cohort using least absolute shrinkage and selection operator Cox regression model. Results: Six flow cytometry–validated immune cell features were informative. The model had high predictive accuracy in the training and four external validation cohorts. Subjects in the training cohort with low scores had prolonged survival compared with subjects with high scores, with 5-year survival rates of 46% versus 19% (P < 0.001). Parallel survival rates in validation cohorts-1, -2, -3, and -4 were 46% versus 6% (P < 0.001), 44% versus 18% (P = 0.041), 44% versus 24% (P = 0.004), and 62% versus 32% (P < 0.001). Gene set enrichment analysis indicated significant enrichment of immune relation pathways in the low-score cohort. In multivariable analyses, high-risk score independently predicted shorter survival with HRs of 1.45 (P = 0.005), 2.12 (P = 0.004), 2.02 (P = 0.034), 1.66 (P = 0.019), and 1.59 (P = 0.001) in the training and validation cohorts, respectively. Conclusions: Our immune risk score complements current AML prediction models.

To establish an immune gene prognostic model of acute myeloid leukemia (AML) and explore its correlation with immune cells in bone marrow microenvironment.Gene expression profile and clinical data of TCGA-AML were downloaded from TCGA database. Immune genes were screened by LASSO analysis to construct prognosis prediction model, and prediction accuracy of the model was quantified by receiver operating characteristic curve and area under the curve. Survival analysis was performed by Log-rank test. Enriched pathways in the different immune risk subtypes were evaluated from train cohort. The relationship between immune prediction model and bone marrow immune microenvironment was verified by flow cytometry in the real world.Patients with low-risk score of immune gene model had better prognosis than those with high-risk score. Multivariate analysis showed that the immune gene risk model was an independent prognostic factor. The risk ratio for AML patients in the training concentration was HR=24.594 (95%CI: 6.180-97.878), and the AUC for 1-year, 3-year, and 5-year overall survival rate was 0.811, 0.815, and 0.837, respectively. In addition, enrichment analysis of differential gene sets indicated activation of immune-related pathways such as cytokines and chemokines as well as autoimmune disease-related pathways. At the same time, real world data showed that patients with high immune risk had lower numbers of CD8We constructed a stable prognostic model for AML, which can not only predict the prognosis of AML, but also reveal the dysregulation of immune microenvironment.急性髓系白血病免疫评分的建立及验证.建立急性髓系白血病（AML）免疫基因预后模型并探索其与骨髓免疫微环境之间的关系.从TCGA数据库下载TCGA-AML基因表达谱以及临床资料数据。通过LASSO分析筛选构建预测模型的免疫基因，模型预测精度通过受试者工作特征曲线和曲线下面积来量化，生存分析采用Log-rank检验。通过基因集富集分析评估不同免疫风险状态下的通路以及功能富集状态，并在真实世界中通过流式分析验证免疫预测模型与骨髓免疫微环境之间的相关性.免疫基因模型风险低的患者预后优于风险高的患者，多因素分析显示，该免疫基因风险模型为独立预后因素。训练集中AML患者的危险比为HR=24.594（95%CI：6.180-97.878），1、3和5年总生存率的AUC分别为0.811、0.815和0.837。此外，差异基因集富集分析提示，细胞因子以及趋化因子等免疫相关通路激活以及自身免疫疾病相关通路激活。同时，真实世界数据显示，免疫风险高的患者CD8本研究构建了一个稳定的AML预后评估模型，它不仅可以用来预测AML的预后，还能进一步揭示了免疫微环境的失调.

Glycerophospholipids (GPs) and sphingolipids (SPs) are important lipid components in the body and play biological functions. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are important nutrients, and their supplements are commonly used for preventing some diseases. However, the effect of n-3 PUFAs on the human glycerophospholipidome and sphingolipidome is unclear. We used targeted lipidomics to study the GP and SP profile of healthy individuals after supplementation with n-3 PUFAs for 3, 7, 14 and 21 days. Fuzzy c-means clustering was used to cluster the lipid species into six classes reflecting different changed-content patterns after n-3 PUFA supplementation. Among the species with significantly changed content, lysophospholipids were the most sensitive; their content started to increase on day 3. The content of phosphatidylserines increased at a later stage. The content of most of the phosphatidylcholines and alkylphosphatidylcholines decreased on day 21. A correlation network analysis of lipid species suggested that some enzymes involved in the metabolism of lysophospholipids and phosphatidylserines were regulated by n-3 PUFAs. Levels of creatine kinase-MB (CK-MB), urea, glucose, triglycerides and total bilirubin were altered by n-3 PUFA at 21 days. Correlation analysis revealed that the level of CK-MB was negatively correlated with those of species in lysophosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine and phosphatidylserine classes, which were increased by n-3 PUFA supplementation. With the analysis in this work, we demonstrated the regular pattern of n-3 PUFAs on GP and SP metabolism, which provides a pharmacological basis for n-3 PUFAs for clinical application.

Neuropathic pain is characterized by hyperalgesia and allodynia. Inflammatory response is conducive to tissue recovery upon nerve injury, but persistent and exaggerated inflammation is detrimental and participates in neuropathic pain. Synaptic transmission in the nociceptive pathway, and particularly the balance between facilitation and inhibition, could be affected by inflammation, which in turn is regulated by glial cells. Importantly, glycometabolism exerts a vital role in the inflammatory process. Glycometabolism reprogramming of inflammatory cells in neuropathic pain is characterized by impaired oxidative phosphorylation in mitochondria and enhanced glycolysis. These changes induce phenotypic transition of inflammatory cells to promote neural inflammation and oxidative stress in peripheral and central nervous system. Accumulation of lactate in synaptic microenvironment also contributes to synaptic remodeling and central sensitization. Previous studies mainly focused on the glycometabolism reprogramming in peripheral inflammatory cells such as macrophage or lymphocyte, little attention was paid to the regulation effects of glycometabolism reprogramming on the inflammatory responses in glial cells. This review summarizes the evidences for glycometabolism reprogramming in peripheral inflammatory cells, and presents a small quantity of present studies on glycometabolism in glial cells, expecting to promote the exploration in glycometabolism in glial cells of neuropathic pain.

Ethnopharmacological relevance Traditional Chinese medicines (TCMs) are fascinating sources for natural drug candidates. Uncaria rhynchophylla (Gouteng) is a famous TCM used for alleviating central nervous system (CNS) disorders, while its antidepressant constituents are still disputed. Aim of the study The present study was designed to assess the antidepressant property of U. rhynchophylla and characterize the active constituents targeting melatonin receptors which are closely related to CNS diseases. Materials and methods The total extract and each fraction of U. rhynchophylla were extensively assessed for their agonistic activity on melatonin receptors in vitro. The following bioassay-guided fractionation yielded the active constituents, whose activity was confirmed by dose-dependent bioassay and antagonistic experiment on HEK293 cells. Their antidepressant effects were evaluated on forced swimming test (FST), tail suspension test (TST) and open-field test (OFT) mice models in vivo. Their metabolic profiles in mice plasma were analyzed by LCMS-IT-TOF. Results The stems and hooks of U. rhynchophylla were revealed with agonistic activity on melatonin receptors (MT1 and MT2). Under the guidance of bioassay, two flavanols, catechin and epicatechin were obtained and showed obviously activity agitating MT1 (EC50 = 25.8 and 156.1 μM) and MT2 (EC50 = 47.3 and 208.8 μM) receptors. The agonistic activity of catechin on melatonin receptors can be antagonized by luzindole at the concentrations of 1.57–100 μM. Catechin could significantly reduce the immobility time in both FST and TST mice models at doses of 80 and 40 mg/kg, without obvious effect on locomotor activity in OFT mice model. Five phase II (M1-M5) and one phase I (M6) metabolites of catechin were detected in mice plasma after intragastric (i.g.) administration. Conclusion Catechin is a potent antidepressant candidate from U. rhynchophylla by targeting melatonin receptors. The main metabolic pathways of catechin in mice plasma are glucuronidation (M3) and methylated glucuronidation (M4 and M5). This study provides valuable information for understanding the antidepressant potency of Gouteng and its active constituents.

Electromyography (EMG) signals can be used for clinical diagnosis and biomedical applications. It is very important to reduce noise and to acquire accurate signals for the usage of the EMG signals in biomedical engineering. Since EMG signal noise has the time-varying and random characteristics, the present study proposes an adaptive Kalman filter (AKF) denoising method based on an autoregressive (AR) model. The AR model is built by applying the EMG signal, and the relevant parameters are integrated to find the state space model required to optimally estimate AKF, eliminate the noise in the EMG signal, and restore the damaged EMG signal. To be specific, AR autoregressive dynamic modeling and repair for distorted signals are affected by noise, and AKF adaptively can filter time-varying noise. The denoising method based on the self-learning mechanism of AKF exhibits certain capabilities to achieve signal tracking and adaptive filtering. It is capable of adaptively regulating the model parameters in the absence of any prior statistical knowledge regarding the signal and noise, which is aimed at achieving a stable denoising effect. By comparatively analyzing the denoising effects exerted by different methods, the EMG signal denoising method based on the AR-AKF model is demonstrated to exhibit obvious advantages.

To detect the levels of microparticles (MP) in plasma of patients with esseutial thrombo-cythermia(ET) and analyze the relationship between the JAK2V617F mutant and MP in ET patients.The numerical values of MPs were analysed by using flow cytometry. Venous blood of 56 ET patients and 28 healthy persons was collected in the morning and anticoagulated with sodium citrate (1∶9). The RMP, PMP, TFThe detection results showed that the MP levels in ET group were higher than those in normal control group: RMP (157.2±304.9/μl vs 21.3±18.4/μl), PMP (1378.9±2454/μl vs 113.8±97.1/μl), TFThe numerical values of MP detected are more in ET patients than those in healthy controls. The number of MP is higher in patients with thrombus than that without thrombus, so do in patients with splenomegaly and without splenomegaly. Patients with JAK2V617F mutation show higher number of TFET患者血浆MP水平测定及其与JAK2V617F突变关系的研究.检测原发性血小板增多症（ET）患者血浆中的微颗粒（MP）水平，并分析其与JAK2V617F突变的关系.抽取56例ET患者及28例正常人空腹静脉血，枸橼酸钠抗凝(1∶9)，以藻红蛋白标记的特异性荧光抗体CD235a-PE、CD61-PE、CD142-PE和CD62E-PE 分别标记红细胞微颗粒（RMP）、血小板微颗粒（PMP）、组织因子微颗粒（TFET组的RMP（157.2±304.9/μl vs 21.3±18.4/μl）、PMP（1378.9±2454/μl vs 113.8±97.1/μl）、TFET组、血栓组、脾肿大组4种MP水平均高于对照组；JAK2V617F突变组患者TF

Involvement of long non-coding RNAs (lncRNAs) in hepatocarcinogenesis has been largely documented. Mitochondrial dynamics is identified to impact survival and metastasis in tumors including hepatocellular carcinoma (HCC), but the underlying mechanism remains poorly understood. This study planned to explore the regulation of lncRNA LL22NC03-N14H11.1 on HCC progression and mitochondrial fission. Dysregulated lncRNAs in HCC are identified through circlncRNAnet and GEPIA bioinformatics tools. Biological function of LL22NC03-N14H11.1 in HCC was detected by CCK-8 assay, flow cytometry analysis, transwell invasion, and wound healing assays. Molecular interactions were determined by RNA immunoprecipitation, RNA pull-down, and co-immunoprecipitation assays. Results showed that LL22NC03-N14H11.1 was upregulated in HCC tissues and cells. Functionally, LL22NC03-N14H11.1 contributed to cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) in HCC. Moreover, LL22NC03-N14H11.1 facilitated mitochondrial fission in HCC cells. Mechanistically, LL22NC03-N14H11.1 recruited Myb proto-oncogene (c-Myb) to repress the transcription of leucine zipper-like transcription regulator 1 (LZTR1), so as to inhibit LZTR1-mediated ubiquitination of H-RAS (G12V), leading to the activation of mitogen-activated protein kinase (MAPK) signaling and induction of p-DRP1 (Serine 616). In conclusion, this study firstly revealed that lncRNA LL22NC03-N14H11.1 promoted HCC progression through activating H-RAS/MAPK pathway to induce mitochondrial fission, indicating LL22NC03-N14H11.1 as a novel potential biomarker for HCC treatment.

Purpose: Flumatinib has been shown to be a more potent inhibitor of BCR-ABL1 tyrosine kinase than imatinib. We evaluated the efficacy and safety of flumatinib versus imatinib, for first-line treatment of chronic phase Philadelphia chromosome–positive chronic myeloid leukemia (CML-CP). Patients and Methods: In this study, 394 patients were randomized 1:1 to flumatinib 600 mg once daily (n = 196) or imatinib 400 mg once daily (n = 198) groups. Results: The rate of major molecular response (MMR) at 6 months (primary endpoint) was significantly higher with flumatinib than with imatinib (33.7% vs. 18.3%; P = 0.0006), as was the rate of MMR at 12 months (52.6% vs. 39.6%; P = 0.0102). At 3 months, the rate of early molecular response (EMR) was significantly higher in patients receiving flumatinib than in those receiving imatinib (82.1% vs. 53.3%; P < 0.0001). Compared with patients receiving imatinib, more patients receiving flumatinib achieved molecular remission 4 (MR4) at 6, 9, and 12 months (8.7% vs. 3.6%, P = 0.0358; 16.8% vs. 5.1%, P = 0.0002; and 23.0% vs. 11.7%, P = 0.0034, respectively). No patients had progression to accelerated phase or blast crisis in the flumatinib arm versus 4 patients in the imatinib arm by 12 months. Adverse events of edema, pain in extremities, rash, neutropenia, anemia, and hypophosphatemia were more frequent in imatinib arm, whereas diarrhea and alanine transaminase elevation were more frequent in flumatinib arm. Conclusions: Patients receiving flumatinib achieved significantly higher rates of responses, and faster and deeper responses compared with those receiving imatinib, indicating that flumatinib can be an effective first-line treatment for CML-CP. This trial was registered at www.clinicaltrials.gov as NCT02204644. See related commentary by Müller, p. 3

An enantiomeric pair of rare cyperane-type sesquiterpenoids, (+)- and (-)-gracilistones C (

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL or BCR-ABL1-like ALL) is a kind of acute leukemia which has the similar gene expression profiles and manifests the biological behavior same to Ph-positive ALL, but lacks the BCR-ABL1 fusion gene. Ph-like ALL was involved in multiple abnormal changes of genomes, activating kinase and cytokine receptor signaling. This review focuses on the progress of classical genetic abnormalities of PH-like ALL in the JAK-STAT signaling, ABL kinase activation, TKI resistance in Ph-like ALL, SH2B3 gene inactivating mutation and IKZF1 gene abnormality. Besides, also summarizes the frontier progress of novel gene mutation (ATF7IP exon 9 fused with PDGFRB exon 11, PDGFRBPh-like急性淋巴细胞白血病致病基因的研究进展.费城染色体样急性淋巴细胞白血病（Philadelphia chromosome-like acute lymphoblastic leukemia，Ph-like ALL或BCR-ABL1-like ALL）是指基因表达谱与Ph阳性ALL相似，但缺乏BCR-ABL1融合的一类急性白血病。Ph-like ALL涉及多种基因组，激活激酶和细胞因子受体信号的改变。本文将针对近几年Ph-like ALL在JAK-STAT通路异常激活，ABL激酶通路基因异常，TKI在Ph-like ALL中的抗性，SH2B3基因的失活性突变，IKZF1基因异常的研究进展作一总结。并就新型致病基因（ATF7IP外显子9和PDGFRB外显子11之间的融合，PDGFRB外显子11-23与AGGF1基因外显子1-6融合造成的PDGFRB

Pancreatic stellate cells (PSCs) are typically activated in pancreatic ductal adenocarcinoma (PDAC) and release exosomes containing high levels of microRNA‑21 (miR‑21). However, the specific roles of exosomal miR‑21 in regulating the PDAC malignant phenotype remain unknown. The present study aimed to determine the effects of exosomal miR‑21 on the migratory ability of PDAC cells and explore the potential underlying molecular mechanism. Weighted gene correlation network and The Cancer Genome Atlas database analysis revealed that high miR‑21 levels were associated with a poor prognosis in patients with pancreatic adenocarcinoma, and that the Ras/ERK signaling pathway may be a potential target of miR‑21. In vitro, PDAC cells were demonstrated to internalize the PSC-derived exosome, resulting in high miR‑21 levels, which subsequently promoted cell migration, induced epithelial‑to‑mesenchymal transition (EMT) and increased matrix metalloproteinase‑2/9 activity. In addition, exosomal miR‑21 increased the levels of ERK1/2 and Akt phosphorylation in PDAC cells. Collectively, these results suggested that PSC‑derived exosomal miR‑21 may promote PDAC cell migration and EMT and enhance Ras/ERK signaling activity. Thus, miR‑21 may be a potential cause of poor prognosis in patients with pancreatic cancer and a new treatment target.

To investigate the correlation of single nucleotide polymorphisms (SNP) in arachidonate 5-lipoxygenase gene (ALOX5) rs2029253, rs2228064 and rs2228065 sites, 5-lipoxygenase activating protein gene (ALOX5AP) rs10507391, rs4769874 sites with the risk for genesis of adult myeloid leukemia.By the approval from the hospital ethics committee and the informed consent of participants. 150 patients with myeloid leukemia (ML) as ML group and 134 healthy people as the control group were selected. The genomic DNA was extracted from the samples. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) combined with directly sequencing, PCR-amplified products were applied to test the polymorphism of 5 sites in ALOX5 and ALOX5AP gene.A allele frequencies of ALOX5 gene rs2029253 site in the ML group and the control group were 43.0% and 34.3%, respectively. And the G allele frequencies in the ML group and the control group were 57.0% and 65.7%, respectively. The genotype distributions of AA, AG and GG in ALOX5 gene rs2029253 site in the ML group were 32.2%, 21.5% and 46.3% respectively. That in the control group were 15.7%, 37.3% and 47.0% respectively. The genotype AA and A allele frequency of ALOX5 gene rs2029253 site were linked with the increased risk of myeloid leukemia (OR=2.26, 95% CI: 1.43-4.56, P＜0.05; OR=1.44, 95% CI: 1.02-2.03, P＜0.05). And the genotype AG and allele G reduced the susceptibility to myeloid leukemia (OR=0.46, 95% CI: 0.27-0.78, P＜0.01; OR=0.69, 95% CI: 0.50-0.98, P＜0.05), however, the polymorphisms of ALOX5 gene rs2228064 and rs2228065 site not correlated with the risk of myeloid leukemia (P＞0.05). The A allele frequency of ALOX5AP gene rs10507391 site in the ML group and the control group were 30.7% and 36.2% respectirely. The genotype distribution rates of AA, AT and TT in ALOX5AP gene rs10507391 site in the ML group was 1.3%, 58.7% and 40.0% respectively, that in the control group were 9.7%, 53.0% and 37.3% respectively. The genotype AA of ALOX5AP gene rs10507391 site correlated with the decreased risk of myeloid leukemia (OR=0.13, 95% CI: 0.03-0.57, P＜0.05), but the polymorphism of ALOX5AP gene rs4769874 site not correlated with the risk of myeloid leukemia (P＞0.05).The genotype AA, AG and allele A, G of ALOX5 rs2029253, as well as ALOX5AP rs10507391 may be correlate with the susceptibility to myeloid leukemia.ALOX5、ALOX5AP基因多态性与髓系白血病易感性的关系.探讨花生四烯5-脂氧合酶基因（arachidonate 5-lipoxygenase gene，ALOX5） rs2029253, rs2228064和rs2228065位点以及5-脂氧合酶激活蛋白基因（5-lipoxygenase activating protein gene，ALOX5AP）rs10507391和rs4769874位点的单核苷酸多态性（single nucleotide polymorphisms，SNP）与髓系白血病发病风险的相关性.经医院伦理委员会批准、患者知情同意，选取150例髓系白血病患者为髓系白血病（ML）组，134例健康人群为对照组。提取基因组DNA，采用聚合酶链反应及限制性片段长度多态技术（PCR-RFLP）联合PCR 产物直接测序法检测ALOX5、ALOX5AP基因5个位点的基因型.ALOX5 基因rs2029253位点在ML组和对照组中的A等位基因频率分别为43.0%和34.3%，而等位基因G的频率分别为57.0%、65.7%；基因型AA、AG和GG在ML组中的分布频率分别为32.2%，21.5%和46.3%，而在对照组中的分布频率分别为15.7%, 37.3%和47.0%。基因型AA和等位基因A可能增加髓系白血病的发病风险（OR=2.26，95% CI：1.43-4.56，P＜0.05；OR=1.44，95% CI：1.02-2.03，P＜0.05）；基因型AG与等位基因G可能降低对髓系白血病的易感性（OR=0.46，95% CI：0.27-0.78，P＜0.01；OR=0.69，95% CI：0.50-0.98，P＜0.05）。而ALOX5基因rs2228064、rs2228065位点多态性在ML组与对照组间的分布差异无统计学意义（P＞0.05）。ALOX5AP基因rs10507391位点等位基因A在髓系白血病组和对照组中频率分布分别为30.7%和36.2%；基因型AA、AT和TT在ML组中分布频率分别为1.3%，58.7%和40.0%，在对照组中的分布频率分别为9.7%, 53.0%和37.3%；基因型AA可能降低髓系白血病的发病风险（OR=0.13，95% CI：0.03-0.57，P＜0.05）；而ALOX5AP rs4769874位点基因型与等位基因分布频率在ML组与对照组间的分布差异无统计学意义（P＞0.05）.ALOX5 rs2029253位点基因型AA、AG和等位基因A、G以及ALOX5AP rs4769874位点AA基因型与髓系白血病发病的遗传易感性相关.

Ethnopharmacological relevance Artemisia capillaris (Yin-Chen) is a famous traditional Chinese medicine (TCM) for treating acute and chronic hepatitis in China. Enynes are one type of characteristic constituents in this herb, while their anti-hepatitis B virus (anti-HBV) properties have not been systemically investigated. Aim of the study This study is to reveal the active part of A. capillaris, and systemically investigate the enynes and their anti-HBV activity. Materials and methods The total extract and each fraction of A. capillaris were assayed for the anti-HBV activity to reveal the active part. Bioassay-guided fractionation using various chromatographic techniques yielded the enynes, whose structures were elucidated by spectroscopic analyses and ECD calculations. The anti-HBV properties inhibiting HBsAg and HBeAg secretions and HBV DNA replication were evaluated on HepG 2.2.15 cell line in vitro. Results ACT-2 and ACT-3 was revealed to be the respective active and toxic part of A. capillaris. Twelve enynes (1–12) involving four new ones (1–4) and two unusual enyne analogs (13–14) were isolated from the active part (ACT-2). All the isolates were assayed for their anti-HBV activity, and the preliminary structure-activity relationships were summarized based on the structural features. In particular, compound 4 could significantly inhibit the secretions of HBsAg and HBeAg, and HBV DNA replication with IC50 values of 197.2 (SI > 5.1), 48.7 (SI > 20.5) and 9.8 (SI > 102) μM. Conclusions Enynes are responsible for the anti-HBV effects of A. capillaris. Hydroxyl and glycosyl groups are preferable for maintaining activity. This is the first time to systematically investigate the anti-HBV activity of enynes in A. capillaris, which provides valuable information for understanding the ethnopharmacological application of Yin-Chen.

Depression is associated with high mortality and morbidity rates worldwide. By our random screening, it was first revealed that 23 magnolol derivatives were synthesized followed by in vitro and in vivo evaluation of their antidepressive potential. Compound 7c was found to be the most promising compound, with EC50 values of 396.5 and 383.0 μM agitating on MT1 and MT2 receptors, respectively. Additionally, we carried out in vivo experiments to confirm the efficacy and safety of compound 7c; the compound was found to be orally bioavailable and highly effective, leading to a significant reduction of immobility time in a mouse model of depression (forced swimming test and tail suspension test); the acting mechanism was explored by determining its effect on the levels of monoamine neurotransmitters and their metabolites in different mice brain regions; the acute toxicity study showed that the 50% lethal dose (LD50) of 7c was higher than 2000 mg/kg, p. o. A total of 25 metabolites of 7c were identified, including 5 metabolites in phase I and 20 metabolites in phase II. Altogether, these results indicate that magnolol derivative 7c is a promising lead compound for the development of a new chemical class of antidepressant drugs.

Primary immune thrombocytopenia (ITP) is a bleeding disorder commonly encountered in clinical practice. The International Working Group (IWG) on ITP has published several landmark papers on terminology, definitions, outcome criteria, bleeding assessment, diagnosis, and management of ITP. The Chinese consensus reports for diagnosis and management of adult ITP have been updated to the 4th edition. Based on current consensus positions and new emerging clinical evidence, the thrombosis and hemostasis group of the Chinese Society of Hematology issued Chinese guidelines for management of adult ITP, which aim to provide evidence-based recommendations for clinical decision making.

Background Adaptor proteins bridge the gap between cell surface receptors and their downstream signaling elements. The clinicopathological and prognostic values of adaptor proteins remain poorly understood. The purpose of the present study was to explore the expression and prognostic value of three adaptor proteins: GRB2-associated binding protein 2 (GAB2), CRK-like protein (CRKL) and fibroblast growth factor receptor substrate 2 (FRS2) in pancreatic ductal adenocarcinoma (PDAC). Methods The expression of GAB2, CRKL, and FRS2 in 77 formalin fixed paraffin embedded (FFPE) samples from 77 PDAC patients, along with three paired fresh PDAC and matched normal tissues from 3 PDAC patients was analyzed by immunohistochemistry and western blot, respectively. The association between the expression of the three proteins and the clinicopathological factors of PDAC was assessed by χ 2 test. The correlation between the expression levels of the three proteins was analyzed by Spearman rank correlation analyses; Kaplan-Meier survival analyses were also performed. Results IHC was successful in 75, 76, and 77 cases for GAB2, CRKL, and FRS2, respectively. Of which, the positive rate of GAB2, CRKL, and FRS2 protein expression was 40.00% (30/75), 53.95% (41/76) and 35.06% (27/77), respectively. The positive rate of GAB2, CRKL and FRS2 co-expression was 16.88% (13/77). Though there was no association between GAB2 expression, CRKL expression, FRS2 expression, GAB2/CRKL/FRS2 co-expression and the clinicopathological parameters of PDAC, positive correlations were observed between the expressions of the three proteins. Further, univariate survival analysis showed that positive expression of GAB2, CRKL and FRS2 and co-expression of GAB2/CRKL/FRS2 of PDAC predicted poor clinical outcomes, and multivariate survival analysis suggested that positive expression of GAB2 and positive co-expression of GAB2/CRKL/FRS2 were independent prognostic factors for disease-free survival (DFS) and overall survival (OS), respectively. Conclusion In conclusion, GAB2, CRKL, and FRS2 may be potential prognosticators and therapeutic targets for PDAC patients.

The immune system plays a pivotal role in defending against infection and cancer immunosurveillance during the onset and procession of malignant disease. Cancer patients are frequently immunocompromised and subject to refractory infection and relapse of leukemia, due to the cytotoxic agents and immunosuppressive glucocorticoids in the chemotherapy regimens. Bu Shen Hui Yang Fang (BSHY), a traditional Chinese compound, was widely used in China to enhance the immune system of leukemia patients combined with chemotherapy and effectively lowered their risk of infection, with specific mechanism unknown yet. Thus, we investigated the effects of BSHY on the immune system using immunosuppressive mouse models. By analyzing the immune system of immunosuppressed BALB/C mice induced by hydrocortisone, we found an increase of CD4+ and CD8+ lymphocytes in the spleens of mice after BSHY treatment. Furthermore, we found the enhanced immune system in BSHY treated group was due to increased proliferation and decreased apoptosis of lymphocytes. Cytokine array analysis revealed that interleukin 4 (IL-4) was reduced in the plasma of immunosuppressed mice but returned to a normal level after BSHY treatment. Moreover, we found IL-4 was an adverse prognostic factor in acute myeloid leukemia patients and part of them could be elevated by BSHY. Mechanistically, we found BSHY enhances the proliferation of lymphocytes in a Stat6-dependent manner. In summary, our current study demonstrates that BSHY enhances the proliferation of lymphocytes in the immunosuppressed mice via upregulating IL-4 signaling.

Pre-eclampsia (PE) is considered a leading cause of mortality and morbidity in pregnant women worldwide. Eicosanoids derived from polyunsaturated fatty acids (PUFAs) might play an important role in the occurrence and development of PE. Omega-3 PUFAs are nutrients that are popular supplements for pregnant women and can reduce blood pressure. However, the levels of eicosanoids derived from omega-3 PUFAs in women with PE is not clear. The purpose of this study was to investigate the eicosanoid metabolic signature of PE. We performed a case-control study using data for pregnant women (n = 10) with PE and normotensive pregnant women (n = 10). We investigated the difference in eicosanoid profile between the groups by LC-MS/MS-based metabolomics. The plasma levels of arachidonic acid metabolites and some of the lipoxygenase metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) showed an increasing trend, and those of the cytochrome P450 metabolites of EPA and DHA were decreased in women with PE. Levels of leukotriene B4, 14,15-dihydroxy-eicosatetraenoate, 16-hydroxydocosahexaenoic acid and 8,9-epoxy eicosatetraenoic acid were significantly correlated with PE occurrence. These eicosanoids might take part in the progression of PE in pregnant women.

To investigate the efficacy of hematopoietic stem cells cryopreserved by ladder-style freezing from low temperature refrigerator to liquid nitrogen in treatment of hematological malignancies, and to analyze the survival condition of patients after hematopoietic stem cell transplantation.The coyoprotectant formed by 3% hydroxyethyl starch, 4% albumin and 5% dimethyl sulfoxide (DMSO) was need for cryopreservation of hematopoietic stem cells,which were first placed in -80One case failed in implantation due to intracranial hemorrhage and the other 97 cases all succeeded in hematopoietic reconstitution. The average time needed for neutrophil count ≥0.5×10ladder-style freezing from low temperature refrigerator to liquid nitrogen can reach the same clinical transplantation effect with traditional programmed cooling freezing method in autologous hematopoietic stem cells transplantation. moreover the incidence of complications after transpeantatim does not show increase.

To better define the effect of JAK2V617F mutant allele burden on clinical presentation of patients with essential thrombo cythamia (ET), especially thrombosis.Two ml of heparin anti-coagulated bone marrow was collected from 229 ET cases, who were diagnosed and treated in the First People's Hospital of Yunnan Province during 2013.10 to 2016.12. and then the mononuclear cells were separated by Red Blood Cell Lysis Buffer, genomic DNA was extracted from mononuclear cells by using a commercial DNA isolation kit and amplified by allele specific polymerase chain reaction (PCR). According to the size of molecular weight, the amplified products were separated by electrophoresis on a 2% agarose gel to screen the JAK2V617F mutation, then the JAK2V617F mutation burden was detected by real-time polymerase chain reaction (RT-PCR) in 120 patients with JAK2V617F mutation. Meanwhile, these samples were sequenced in order to verify the accuracy of the PCR screewing.ET patients with thrombotic events had significantly higher JAK2V617F allele burden than those without thrombosis (23.2% vs 14.2%) ( P0.05). Meanwhile, ET patients showed increased JAK2V617F allele burden in the group with higher leukocytosis (WBC10×10The clinical presentations of ET patients, such as WBC counts, hemoglobin level and splenomegaly, are influenced by the JAK2V617F mutation burden. ET patients with thrombotic events has significantly higher JAK2V617F allele burden than those in ET palients without thrombosis.JAK2V617F mutation burden has no relations with sex and age..

Despite the advancement of medical science, diseases are part-and-parcel of human life. Plants have provided humans with medicines since time immemorial, and are still one of the primary sources for drug discovery. Brassica rapa L., commonly known as turnip, is one of the world's oldest cultivated vegetables. Besides being an important vegetable and source of oil, turnip is also used as a traditional medicine for the treatment of headaches, chest complaints, rheumatisms, oedemas, gonorrhoea, syphilis, and rabies. Glucosinolates and isothiocyanates (mainly 2-phenylethyl, 4-pentenyl, and 3-butenyl derivatives) are the main constituents of turnip with diverse bioactivities, especially for the protective effect against cancers. Besides, flavonoids, phenolics, indoles and volatiles are also concomitant in this plant. Pharmacological investigation on turnip revealed the antitumor, antihypertensive, antidiabetic, antioxidant, antiinflammatory, hepatoprotective, and nephroprotective effects. The anticancer property was found to be the most promising biological activity of turnip with 2-phenylethyl isothiocyanate, phenylpropionitrile, brassicaphenanthrene A, 6-paradol, and trans-6-shogaol as the major active constituents. Flavonoids and phenolics with high free radical scavenging activity should be corresponding to the antioxidant effects. Arvelexin, an indole derivative in turnip, was reported with various effects involving antiinflamatory, antihypertensive and hypolipidemic potency. In spite of many studies concerning either the chemical constituents or the biological activities of turnip, only a few cases disclosed the active ingredients responsible for diverse bioactivities. This review summarizes the research progress on the chemistry and health-benefits of turnip over the past 20 years to provide a reference for the further investigation.

The chimeric antigen receptor (CAR) T cell therapy has gradually became a new trend in the treatment of refractory and relapsed hematologic malignancies by developing for 30 years. With the exciting development of genetic engineering, CAR-T technology has subjected to 4 generations of innovation. Structure of CAR-T started from a single signal molecule to 2 or more than 2 co-stimulatory molecules, and then coding the CAR gene or promoter. CAR-T can specifically recognize tumor antigens, and does not be restricted by major histocompatibility complex (MHC), thus making a breakthrough in clinical treatment. In this review, the history, structure and mechanism of action of CAR-T, as well as the current status and challenges of CAR-T immunotherapy in acute lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia and multiple myeloma are summarized.

Vitamin BTo assess the effects of oral vitamin BWe searched CENTRAL, MEDLINE, Embase, and LILACS, as well as the WHO ICTRP and ClinicalTrials.gov. The latest search date was 17 July 2017. We applied no language restrictions. We also contacted authors of relevant trials to enquire about other published or unpublished studies and ongoing trials.Randomised controlled trials (RCTs) comparing the effect of oral versus IM vitamin BWe used standard methodological procedures expected by Cochrane. Our primary outcomes were serum vitamin BThree RCTs met our inclusion criteria. The trials randomised 153 participants (74 participants to oral vitamin BLow quality evidence shows oral and IM vitamin B

Background Programmed death ligand 1 (PD-L1) has shown potential as a therapeutic target in numerous solid tumors. Its prognostic significance has also been established in pancreatic ductal adenocarcinoma (PDAC). The present study aimed to explore PD-L1 expression in PDAC cases in a large Chinese cohort using an in vitro diagnostic (IVD) assay to provide further insight into the potential value of programmed cell death protein 1 (PD-1) as a therapeutic target. Methods Three hundred seventy-three PDAC patients were retrospectively recruited in this study. Tissue microarray (TMA) blocks were made from available formalin-fixed and paraffin-embedded (FFPE) tumor and matched adjacent tissue specimens. We evaluated PD-L1 protein expression via immunohistochemistry (IHC) using a U.S. Food and Drug Administration (FDA)-approved IVD assay. The relationships between PD-L1 positivity and both clinicopathological characteristics and patient prognosis were analyzed. PD-1 expression and clinicopathological significance were also evaluated. Results PD-L1 and PD-1 positivity were observed in 3.2% and 7.5% of cases, respectively. PD-L1 showed a predominantly membranous pattern in tumor cells, while no positive PD-L1 staining was observed in normal regions. Statistical analyses revealed that PD-L1 expression was associated with lymph node metastasis. PD-L1 positivity was a prognostic indicator of progression-free survival (PFS) and overall survival (OS) in univariate analyses, but only PFS remained statistically significant in multivariate analysis. PD-1 expression was detected in lymphocytes and was not associated with any clinicopathological feature except a history of pancreatitis. Conclusions The PD-L1 positivity rate is low in PDAC when evaluated using a companion diagnostic assay. It remains an independent prognostic factor for poor PFS. Electronic supplementary material The online version of this article (10.1186/s13000-017-0678-4) contains supplementary material, which is available to authorized users.

Three new dihydroisocoumarin glucosides, termed periplanosides A-C (1-3), a known analog, pericanaside (4), and the other twenty known compounds were isolated from the insect Periplaneta americana. Their structures including absolute configurations were determined by comprehensive spectroscopic analyses and computational methods. Biological evaluation showed that compound 2 could stimulate collagen production by 31.2% in human dermal fibroblasts-adult (HDFa) at the concentration of 30 μM, indicating its significance in skin repair and ulcer.

// Hui Zhang 1,* , Huanwen Wu 1,* , Jian Guan 2 , Li Wang 1 , Xinyu Ren 1 , Xiaohua Shi 1 , Zhiyong Liang 1 and Tonghua Liu 1 1 Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, PR China 2 Department of Pathology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, PR China * These authors contributed equally to this work Correspondence: Tonghua Liu, email: // Zhiyong Liang, email: // Keywords : Pancreatic cancer, Pancreatic stellate cells, Chemoresistance, SDF-1α, IL-6 Received : November 23, 2014 Accepted : December 25, 2014 Published : December 30, 2014 Abstract Pancreatic cancer exhibits the poorest prognosis among all tumors and is characterized by high resistance to the currently available chemotherapeutic agents. Our previous studies have suggested that stromal components could promote the chemoresistance of pancreatic cancer cells (PCCs). Here, we explored the roles of pancreatic stellate cells (PSCs) and the SDF-1α/CXCR4 axis in pancreatic cancer chemoresitance. Our results showed that primary PSCs typically expressed SDF-1α, whereas its receptor CXCR4 was highly expressed in PCCs. PSC-conditioned medium (PSC-CM) inhibited Gemcitabine (GEM)-induced cytotoxicity and apoptosis in the human PCC line Panc-1, which was antagonized by an SDF-1α neutralizing Ab. Recombinant human SDF-1α (rhSDF-1α) increased IL-6 expression and secretion in Panc-1 cells in a time and dose-dependent manner, and this effect was suppressed by the CXCR4 antagonist AMD3100. rhSDF-1α protected Panc-1 cells from GEM-induced apoptosis, and the protective effect was significantly reduced by blocking IL-6 using a neutralizing antibody. Moreover, rhSDF-1α increased FAK, ERK1/2, AKT and P38 phosphorylation in Panc-1 cells, and either FAK or ERK1/2 inhibition suppressed SDF-1α-upregulated IL-6 expression. SDF-1α-induced AKT activation was almost completely blocked by FAK inhibition. In conclusion, we demonstrate for the first time that PSCs promote the chemoresistance of PCCs to GEM, and this effect is mediated by paracrine SDF-1α/CXCR4 signaling-induced activation of the intracellular FAK-AKT and ERK1/2 signaling pathways and a subsequent IL-6 autocrine loop in PCCs. Our findings indicate that blocking the PSC-PCC interaction by inhibiting SDF-1α/CXCR4 signaling may be a promising therapeutic strategy for overcoming chemoresistance in pancreatic cancer.

Background There is limited data on the genotype distribution of human papillomavirus (HPV) in the Taihu River Basin, home to 1.29 million people on the coast of eastern China. This study evaluated the prevalence and genotypes among different female age groups in this region. Methods Twenty-six HPV strains (low-risk HPV 6, 11, 40, 42, 44, 61, 73 and high-risk HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 55, 56, 58, 59, 66, 68, 82, and 83) were detected using Tellgenplex™ HPV technology in samples obtained from three clinical hospitals located in different regions of the Taihu Lake Basin. Results The results showed that 1855 samples (20.97% of all samples) were found to be HPV-positive. Of these, 1375 samples (15.55% of all samples) were found to have a single HPV infection. Age-specific prevalence showed two peaks, one that corresponded to the group of 21–30 year-old women and the other peak that corresponded to the group of women over 51 years old. The three most prevalent genotypes were HPV52 (19.95%, 370/1855), HPV16 (13.48%, 150/1855), and HPV58 (11.32%, 210/1855). Mixed strains HPV58 + HPV33 and HPV58 + HPV52 were most commonly found in females infected with multiple HPV types. Conclusions This investigation reveals that HPV infection in the Taihu River Basin varied significantly among different age groups. The most prevalent genotypes are included in the nonavalent vaccine, V503, however this vaccine is not licensed for use in mainland China. The most frequently occurring genotypes should be considered in the development of next-generation HPV vaccines for optimal protection of public health. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2328-6) contains supplementary material, which is available to authorized users.

Recent studies focusing on unveiling the biological agents of Aspongopus chinensis have led to the identification of four new norepinephrine derivatives (1-4), three new sesquiterpenoids (5-7), and one new lactam (8). In addition, twenty-three known compounds have been identified, most of which were isolated from this insect for the first time. Selected members of insect-derived substances were evaluated for their biological activities against renal protection in high-glucose-induced mesangial cells and COX-2 inhibition. (C) 2014 Elsevier Ltd. All rights reserved.

Cancer diagnosis depending on microarray technology has drawn more and more attention in the past few years. Accurate and fast diagnosis results make gene expression profiling produced from microarray widely used by a large range of researchers. Much research work highlights the importance of gene selection and gains good results. However, the minimum sets of genes derived from different methods are seldom overlapping and often inconsistent even for the same set of data, partially because of the complexity of cancer disease. In this paper, cancer classification was attempted in an alternative way of the whole gene expression profile for all samples instead of partial gene sets. Here, the three common sets of data were tested by NIPALS-KPLS method for acute leukemia, prostate cancer and lung cancer respectively. Compared to other conventional methods, the results showed wide improvement in classification accuracy. This paper indicates that sample profile of gene expression may be explored as a better indicator for cancer classification, which deserves further investigation.

Three new isopimarane diterpenoids, trogopteroids A-C (1-3), our new aromatic diterpenoids, trogopteroids D-G (4-7), and 12 known diterpenoids were isolated from the feces of Trogopterus xanthipes. Their structures were identified using spectroscopic methods. The relative configuration of 1 was confirmed by quantum calculations. Compound 1 represents the first example of a norisopimarane diterpenoid with an 8 alpha,15 alpha-olide ring. With the exception of compound 14, all diterpenoids were evaluated for cytotoxicity against seven human tumor cell lines.

Context: The molecular pathogenesis of sporadic insulinomas is unknown. There is a lack of biomarker to distinguish benign and malignant form of insulinoma. Objective: Our objective was to confirm the occurrence of microsatellite instability (MSI) in insulinomas, to identify alterations of mismatch repair (MMR) genes in the tumors, and to evaluate the possibility to distinguish benign and malignant insulinoma or to predict the clinical outcome of patients with these alterations. Design and Patients: We detected MSI and inactivation of MLH1 gene in 55 sporadic insulinomas by PCR, immunohistochemical staining, allelic typing, analysis of promoter methylation, and exon mutations. Their correlations with clinicopathological characteristics were analyzed with univariate and multivariate statistic analysis. Results: A high rate of MSI (MSI-H) was found in 33% of sporadic insulinomas. Reduced expression of mutL homolog 1 (MLH1) protein was observed in 36% of insulinomas and correlated with MSI-H (P = 0.008). Promoter methylation and loss of heterozygosity of MLH1 gene was found in 31 and 49% of insulinomas, respectively. Reduced expression of MLH1 and MSI-H were significantly associated with both tumor malignancy (P = 0.033 and P = 4.8 × 10−6, respectively) and incurable disease (P = 0.006 and P = 0.001, respectively). Conclusion: High frequency of MSI occurred in sporadic insulinomas. The silencing of MLH1 gene may partially contribute to the MSI-H in the tumors. Assessing MSI-H and expressions of MLH1 could be used to distinguish benign and malignant insulinomas and to predict the outcome of patients. Detecting of a high rate of microsatellite instability can be used to distinguish malignancy from benign, and predict clinical outcome of the sporadic insulinomas.

OBJECTIVES To avoid unnecessary lymphadenectomy for renal cell cancer (RCC) in patients with retroperitoneal enlarged lymph nodes (ELNs). METHODS Frozen section examination (FSE) of ELNs was used to evaluate the lymphatic status. In the present study, 114 patients with RCC underwent FSE of ELNs and concurrent regional lymphadenectomy. The results of FSE were compared with the final histopathologic results of lymphadenectomy. Some clinical tumor characteristics were also considered to improve the evaluation effect of the FSE. Multiple regression analysis was applied to define the independent risk factors for lymphatic metastasis. RESULTS The final histopathologic results indicated that 36 patients (31.6%) had nodal metastases. In these 36 patients, the FSE of ELNs revealed positive findings in 32 patients and negative findings in 4 patients. The sensitivity, specificity, concordance, and false-negative rate of FSE was 88.9%, 100%, 96.5%, and 11.1%, respectively. Multivariate analysis revealed that distant metastasis and high T stage (T3-T4) were independent risk factors for lymphatic metastasis. When FSE indicated negative results, no nodal metastases were found (64 patients) without these 2 risk factors. CONCLUSIONS ELNs in patients with RCC do not necessarily indicate metastatic disease, and more than one half of ELNs were benign. FSE of ELNs can be used to evaluate the lymphatic status. Using the findings from FSE and the clinical characteristics of the primary tumor, we can avoid unnecessary lymphadenectomy in patients with retroperitoneal ELNs.

It has been reported that the local introduction of a promoter-less DNA containing the complementary DNA (cDNA) sequence of a gene could induce gene-specific silencing in plants. The feasibility of this kind of silencing in human cancer cells is as yet unknown. The current study was designed to investigate the anti-tumor effects of a homologous promoterless K-ras cDNA system on pancreatic cancer. A full-length K-ras cDNA fragment was cloned into the promoterless plasmid puc19 to yield puc-K-ras. This construct was then transfected into pancreatic cancer cells. Our results demonstrated that the transfection of a promoterless K-ras cDNA resulted in a significant decrease in endogenous K-ras in a dose- and time-dependent manner and induced pancreatic cell apoptosis. Furthermore, stable puc-K-ras transfection decreased the endogenous protein level of K-ras and inhibited cell proliferation, clone formation and tumorigenicity in vivo. These findings indicate a promising application of this homologous promoterless cDNA silencing system in pancreatic cancer gene therapy.

Objective This study aimed to determine a contrast medium injection rate that ensures both accuracy for data and safety for operation by comparing hemodynamic parameters of brain CT perfusion imaging with varied injection rates. Methods Twenty-four healthy volunteers were divided into three groups based on contrast medium injection rates (4.5, 6.0, and 7.5 ml/s). For all subjects, CT perfusion scanning was started at 4 s after antecubital venous bolus of contrast media injection. A perfusion-analyzing software package was used to produce a time–density curve in the anterior cerebral artery and the superior sagittal sinus and calculate the regional cerebral blood flow (rCBF) in the gray matter and the white matter. The hemodynamic indices were compared among the three groups, and statistical analysis was carried out using the F test. Results The time for the arterial rise to reach the peak value for the 7.5-ml/s group was only 0.2 s ahead of the initiation time for the rise of the superior sagittal sinus. The differences of rCBF in the gray matter and the white matter among the three groups were statistically significant. rCBF in the gray matter and the white matter for the 7.5-ml/s group was 52.8 ml · min −1 100 g −1 · (±3.1) and 21.9 ml · min −1 · 100 g −1 (±2.4), respectively. Conclusions The use of the 7.5-ml/s injection rate can meet the prerequisite of the maximum slope model, and the resulting rCBF can be very close to that measured by positron emission tomography. Therefore, 7.5 ml/s was an ideal contrast medium injection rate.

Cinnamon is a traditional folk herb used in Asia and has been reported to have antidiabetic effects. Our previous study showed that cinnamaldehyde (CA), a major effective compound in cinnamon, exhibited hypoglycemic and hypolipidemic effects together in db/db mice. The aim of the present study was to elucidate the molecular mechanisms of the effects of CA on the transcriptional activities of three peroxisome proliferator-activated receptors, (PPAR) α, δ, and γ. We studied the effects of CA through a transient expression assay with TSA201 cells, derivatives of human embryonic kidney cell line (HEK293). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was also performed to evaluate mRNA expression levels. We show here that CA induced PPARδ, PPARγ and retinoid X receptor (RXR) activation. CA may activate PPARγ in a different manner than pioglitazone, as CA selectively stimulated PPARγ S342A mutant while pioglitazone did not. In addition, CA and L-165041 had a synergistic effect on PPARδ activation. To gather the biological evidence that CA increases PPARs transcription, we further measured the expressions of PPARδ and PPARγ target genes in 3T3-L1 adipocytes. The data showed CA induced the expression of PPARδ and PPARγ target genes, namely aP2 and CD36, in differentiated adipocytes. As a result, PPARδ, PPARγ and their heterodimeric partner RXR appear to play a part in the CA action in the target tissues, thereby enhancing insulin sensitivity and fatty acid β-oxidation and energy uncoupling in skeletal muscle and adipose tissue.

The rhizome of Cyperus rotundus (C. rotundus) is a well-known traditional Chinese medicine to cure hepatitis in many formulae, but the active components responsible for hepatitis have not been elucidated. According to our bioassay on HepG2.2.15 cell line in vitro, the ethanol extract of C. rotundus demonstrated potent anti-HBV activity. This current study was designed to isolate and identify the anti-HBV active constituents from the rhizomes of C. rotundus.Bioactivity and LC-MS guided fractionation on the extract of C. rotundus using various chromatographic techniques including open-column, Sephadex LH-20 and semi-preparative high performance liquid chromatography led to the isolation and identification of thirty-seven sesquiterpenoids. Structural elucidation of the isolates was carried out by extensive spectroscopic analyses (UV, IR, HRMS, 1D- and 2D -NMR). The anti-HBV activity and cytotoxicity were evaluated on the HBV-transfected HepG2.2.15 cell line in vitro. The cytotoxicity effects of the isolates were assessed by a MTT assay. The secretions of HBsAg and HBeAg in the culture medium were detected by ELISA method, and the load of HBV DNA was quantified by real-time fluorescent PCR technique.Five new patchoulane-type sesquiterpenoids, namely cyperene-3, 8-dione (1), 14-hydroxy cyperotundone (2), 14-acetoxy cyperotundone (3), 3β-hydroxycyperenoic acid (4) and sugetriol-3, 9-diacetate (5), along with 32 known sesquiterpenoids were isolated from the active fractions of C. rotundus. Compounds 2 and 3 were the first cyperotundone-type sesquiterpenoids with a hydroxyl group at C-14 position. Nine eudesmane-type sesquiterpenoids (15-21 and 23-24) significantly inhibited the HBV DNA replication with IC50 values of 42.7±5.9, 22.5±1.9, 13.2±1.2, 10.1±0.7, 14.1±1.1, 15.3±2.7, 13.8±0.9, 19.7±2.1 and 11.9±0.6 μM, respectively, of which, compounds 17, 21, 23 and 24 possessed high SI values of 250.4, 125.5,259.6 and 127.5, respectively. Two patchoulane-type sesquiterpenoids (4 and 7) effectively suppressed the secretion of HBsAg in a dose-dependent manner with IC50 values of 46.6±14.3 (SI=31.0) and 77.2±13.0 (SI=1.7) μM, respectively. Compounds 2, 8, 12, 15, 17 and 25 possessed moderate activities against HBeAg secretion with IC50 values of 162.5±18.9 (SI=13.3), 399.2±90.0 (SI=10.6), 274.7±70.8 (SI=5.2), 313.9±87.5 (SI=7.2), 334.0±70.4 (SI=9.9) and 285.3±20.9 (SI=15.5) μM, respectively.This is the first study to reveal the anti-HBV constituents of C. rotundus, demonstrating that the eudesmane-type sesquiterpenoids might contribute to the anti-HBV activity of the rhizomes of C. rotundus.

Background and Aim: Survivin has functions in both the regulation of cell division and the inhibition of apoptosis, and it is expressed in most human tumors but not in normal adult tissues. It is a potential target for cancer gene therapy. In the present study, we designed a DNAzyme targeting human survivin mRNA and tried to determine its effect on human pancreatic carcinoma cell line PANC-1. Methods: We designed and synthesized a ‘10–23’ antisurvivin mRNA DNAzyme, testified its cleavage activity by cell-free test, then delivered it into the PANC-1 cell line through liposome, and detected its effect on survivin mRNA expression by reverse transcription polymerase chain reaction, Western blot methods, evaluated its influence on the growth of PANC-1 cells by apoptosis detection, growth curve, and flow cytometry. Results: Our results showed that the DNAzyme digested mRNA substrates of survivin efficiently in a dosage- and time-dependent manner, markedly increased apoptosis and inhibited the growth of human pancreatic carcinoma cell line PANC-1, compared with the disabled DNAzyme and untreated controls. Conclusions: Our results showed that the designed DNAzyme against survivin mRNA is a good candidate for cancer gene therapy of human pancreatic carcinoma.

Background and Aim: To our knowledge there are few reports on the K-ras mutation pattern of pancreatic adenocarcinoma from Chinese mainland patients. We examined surgically resected formalin-fixed, paraffin-embedded primary pancreatic adenocarcinoma tissue blocks for the presence of activating point mutations at codon 12 and 13 of the K-ras gene. Methods: Mutations were detected through the use of microdissection, polymerase chain reaction (PCR) and direct sequencing. The results were confirmed by reverse sequencing. Results: The combination of microdissection, PCR and direct sequencing techniques resulted in a rapid and sensitive detection of K-ras mutations at codon 12 and 13. Twenty-five (83%) of the 30 pancreatic adenocarcinomas examined harbored K-ras mutation. Among the 25 pancreatic adenocarcinomas, 24 showed K-ras mutation at codon 12 (11 with GGT-GTT, seven with GGT-GAT, four with GGT-CGT, and two with GGT-TGT), and only one showed a GGC-TGC mutation at codon 13. In this study most of K-ras mutations at codon 12 were at the second base (72%, 18/25) with a transition/transversion ratio of 1 : 1.57 (7/11). Conclusions: The mutation profiles of K-ras at codon 12 in our pancreatic adenocarcinoma samples were significantly different from those of European and Japanese samples.

Hepatitis C Virus (HCV) causes chronic infection in 80-90% of those exposed and persists despite evidence of immune recognition. To understand the immunological basis of this phenomenon, we have synthesized a non structural (NS) protein that is critical to HCV infection and replication, NS3, and used it to study in vitro helper T-cell responses from infected individuals. Strong proliferative responses were generated by peripheral T-cells isolated from a subset of chronically infected patients, but not by normal, non-infected controls. Interestingly, though gamma-interferon (gammaIfn) and IL-10 were both secreted in response to stimulation by NS3 antigen, IL-2 was not. In contrast, IL-2 was secreted in response to influenza virus vaccine antigen. Lack of IL-2 induction was confirmed by a failure to amplify IL-2 mRNA upon NS3 antigen stimulation, whereas IL-4, IL-15, and gammaIfn mRNA were seen as early as 24 h. The predominance of IL-4 and IL-10 and the lack of IL-2 suggests that in vitro responses to at least some HCV antigens are biased towards a Th2 phenotype, which may be conducive to viral persistence.

Glomus tumors,also known as glomangiomas,are rare and originate in the neuromyoarterial glomus,a normal arteriovenous shunt which is abundantly supplied with nerve fibers and fulfills a temperature-regulating function.The classic location of glomus tumor is the subungual region,but the tumor can occur elsewhere in the skin,soft tissues,nerves,stomach,nasal cavity,and trachea.In the gastrointestinal(GI)tract the tumor occurs more often in the stomach than other parts,and typically occurs as a solitary submucosal nodule in the antrum.We reported a case of glomus tumor originating from the greater curvature of stomach which was studied with contrast-enhanced helical computed tomography (CT)and described the characteristic helical CT findings of the rare lesion.

Chinese medical syndrome efficacy, as a second efficacy indicator, has been widely used in clinical trials of treating dementia by Chinese herbal medicine. The syndrome assessment tool is a key point in assessing the efficacy of Chinese medical syndrome. The syndrome assessment tool for dementia used nowadays needs to be optimized in content, reliability, and validity. In this paper, the authors reviewed some problems correlated with the design of Chinese medical assessment questionnaire on the basis of Chinese medical theories by combining the common requirements for questionnaire development.

To explore the clinicopathological characteristics of primary thyroid-like follicular carcinoma of the kidney.A case of primary thyroid-like follicular carcinoma of the kidney was studied with histology and immunohistochemical staining, and its clinical and pathological findings were further analyzed with review of the literature.The patient was a 26-year-old asymptomatic woman who had a kidney mass during her annual physical examination. The tumor was well-circumscribed. Pathologically, the tumor showed follicular structures with colloid-like material in the lumina. Immunohistochemically, the tumor cells showed intense staining for CK7 and vimentin and negative for thyoid transcripation factor-1, thyroglobulin, thyoid peroxidase and RCC.The diagnosis of primary thyroid-like follicular carcinoma of the kidney is based on the characteristic follicular architecture with colloid-like material, and the metastasis from a thyroid follicular carcinoma must be excluded clinically and pathologically before making the final diagnosis.