PKHD1L1 blocks the malignant behavior of lung adenocarcinoma cells and restricts tumor growth by regulating CBX7

Objective:To explore the role of polycystic kidney and hepatic disease 1-like 1(PKHD1L1)in lung adenocarcinoma(LUAD).Methods:Bioinformatics tools were utilized to examine the clinical profile of PKHD1L1 and chromobox protein homolog 7(CBX7)in LUAD.The Cell Counting Kit-8,colony formation,terminal deoxynucleotidyl transferase dUTP nick end labeling,Transwell,and wound-healing assays were carried out to assess the proliferative,apoptotic,invasive,and migrative capacities of the cells.Furthermore,the interrelation between PKHD1L1 and CBX7 was validated using a co-immunoprecipitation assay.A LUAD mice model was constructed by subcutaneous injection of A549 cells.Finally,immunohistochemical staining was performed to evaluate CBX7 and Ki67 expression.Results:PKHD1L1 was downregulated in LUAD and predicted dismal outcomes in patients with LUAD.PKHD1L1 upregulation repressed the proliferative,invasive,and migrative capabilities of A549 cells and exacerbated the apoptotic rate.Additionally,PKHD1L1 may bind to CBX7 and positively modulate CBX7 expression.CBX7 deletion partly abrogated the effects of PKHD1L1 upregulation on the cellular biological activities in A549 cells.Furthermore,the PKHD1L1/CBX7 axis regulates the Hippo signaling pathway in A549 cells.PKHD1L1 restricted tumor growth in LUAD xenograft mice;this was partly abolished by CBX7 knockdown.Conclusion:PKHD1L1 can hinder LUAD progression by regulating CBX7-mediated Hippo signaling.

CCR7/p-ERK1/2/VEGF signaling promotes retinal neovascularization in a mouse model of oxygen-induced retinopathy

AIM： To investigate the role of CCR7/p-ERKI/2/VEGF signaling in the mouse model of oxygen-induced retinopathy （OIR）. METHODS： Neonatal C57BL/6J mice were evenly randomized into four groups： normoxia, OIR, OIR control （treated with scramble siRNA）, and OIR treated （treated with CCR7 siRNA）. Normoxia group was not specially handled. Postnatal day 7 （P7） mice in the OIR group were exposed to 75%±5% oxygen for 5d （P7-P12） and then maintained under normoxic conditions for 5d （P12-P17）. Mice in the OIR control and OIR treated groups were given injections of scramble or CCR7 siRNA plasmid on P12 before returning to normoxic conditions for 5d （P12-P17）. Retina samples were collected from all mice on P17, stained with adenosine diphosphatase （ADPase）, and retinal neovascularization （RNV） was assessed. Retinas were also stained with hematoxylin and eosin （H＆E） for RNV quantitation. The distribution and expression of CCR7, p-ERKI/2 and vas- cular endothelial growth factor （VEGF） were assessed via immunohistochemistry, Western blot, and quantitative real-time polymerase chain reaction （qRT-PCR）. RESULTS： High oxygen promoted retinal neovascularization （P〈0.05） and increased the number of endothelial nuclei in new vessels extending from the retina to the vitreous body; CCR7 promoted this process （P〈0.05）. CCR7 and VEGF mRNA were expressed at higher levels in the OIR and OIR control groups than in the normoxia and OIR treated groups. CCR7, p-ERK1/2, and VEGF protein were expressed in the retinas of mice in the OIR and OIR control groups. Intravitreal injection of CCR7 siRNA significantly reduced CCR7, p-ERKI/2, and VEGF expression in the OIR mouse model （all P〈0.05）. CCR7 significantly enhancedthe neovascularization and non-perfusion areas in the OIR group （P〈0,05）, CCR7 siRNA significantly reduced levels of p-ERK1/2 and VEGF as compared to OIR controls （P〈0.05）. CONCLUSION： These results suggest that CCR7/p-ERK I/2NEGF signaling plays an important role in OIR, CCR7 may be a potential target for the prevention and treatment of retinopathy of prematurity.

Enteric nervous system and inflammatory bowel diseases:Correlated impacts and therapeutic approaches through the P2X7 receptor

The enteric nervous system(ENS)consists of thousands of small ganglia arranged in the submucosal and myenteric plexuses,which can be negatively affected by Crohn’s disease and ulcerative colitis-inflammatory bowel diseases(IBDs).IBDs are complex and multifactorial disorders characterized by chronic and recurrent inflammation of the intestine,and the symptoms of IBDs may include abdominal pain,diarrhea,rectal bleeding,and weight loss.The P2X7 receptor has become a promising therapeutic target for IBDs,especially owing to its wide expression and,in the case of other purinergic receptors,in both human and model animal enteric cells.However,little is known about the actual involvement between the activation of the P2X7 receptor and the cascade of subsequent events and how all these activities associated with chemical signals interfere with the functionality of the affected or treated intestine.In this review,an integrated view is provided,correlating the structural organization of the ENS and the effects of IBDs,focusing on cellular constituents and how therapeutic approaches through the P2X7 receptor can assist in both protection from damage and tissue preservation.

Cholangiocarcinoma, gone without the Wnt?

Cholangiocarcinoma(CCA) is a relatively rare malignancy of the intra- or extra-hepatic bile ducts that is classified according to its anatomical localization as intrahepatic, perihilar or distal. Overall, CCA has a dismal prognosis due to typical presentation at an advanced irresectable stage, lack of effective non-surgical treatments, and a high rate of disease recurrence. CCA frequently arises on a background of chronic liver inflammation and cholestasis. Chronic inflammation is accompanied by enhanced cell turnover with generation of additional inflammatory stimuli, and a microenvironment rich in pro-inflammatory mediators and proliferative factors that enable accumulation of mutations, transformation and expansion of mutated cells. A recent study by Boulter et al implicates the Wnt signaling cascade in cholangiocarcinogenesis. Wnt ligands Wnt7 B and Wnt10 A were found to be highly overexpressed in human CCA tissue. Wnt7 B protein was present throughout the tumor stroma, and often co-localized with a subset of CD68+ macrophages. To address in a direct manner whether Wnt signaling is engaged in development of CCA, Boulter et al explored the Wnt signaling pathway in an experimental model that recapitulates the multi-stage progression of human CCA.Wnt ligands found to be elevated in human CCA were also upregulated during the course of CCA development following thioacetamide treatment. Wnt10 a increased during the(pre-cancerous) regenerative phase, while Wnt7 b induction paralleled tumor growth. Along with upregulation of target genes, the findings demonstrate that the canonical Wnt pathway is progressively activated during cholangio-carcinogenesis. Macrophage depletion,eliminating a major source of Wnt7 b, prevented activation of the canonical Wnt cascade, and resulted in reduced number and volume of tumors in this model. Moreover,specific inhibitors of the canonical Wnt pathway(ICG-001 and C-59) caused reduction of tumor area and number,in xenograft and thioacetamide models of CCA. The aggregated findings show that experimental, and presumably human CCA, is a Wnt-driven tumor. Modulation of Wnt signaling, alone or in combination with surgicalor chemotherapy approaches, holds promise in the management of this fatal malignancy.

NO.7信令系统中的TCAP应用

阐述了七号信令中TCAP产生的背景,讨论了TCAP的结构、消息格式,并具体分析了TCAP的应用,举例说明了TCAP的操作过程,最后对TCAP的应用前景作了展望。

在No.7信令系统中实现TCAP的探讨

本文对Ｎｏ７信令系统中ＴＣＡＰ产生的背景、结构和功能进行了扼要的阐述．在此基础上。

Study of the roles of caspase-3 and nuclear factor kappa B in myenteric neurons in a P2X7 receptor knockout mouse model of ulcerative colitis

BACKGROUND The literature indicates that the enteric nervous system is affected in inflammatory bowel diseases(IBDs)and that the P2X7 receptor triggers neuronal death.However,the mechanism by which enteric neurons are lost in IBDs is unknown.AIM To study the role of the caspase-3 and nuclear factor kappa B(NF-κB)pathways in myenteric neurons in a P2X7 receptor knockout(KO)mouse model of IBDs.METHODS Forty male wild-type(WT)C57BL/6 and P2X7 receptor KO mice were euthanized 24 h or 4 d after colitis induction by 2,4,6-trinitrobenzene sulfonic acid(colitis group).Mice in the sham groups were injected with vehicle.The mice were divided into eight groups(n=5):The WT sham 24 h and 4 d groups,the WT colitis 24 h and 4 d groups,the KO sham 24 h and 4 d groups,and the KO colitis 24 h and 4 d groups.The disease activity index(DAI)was analyzed,the distal colon was collected for immunohistochemistry analyses,and immunofluorescence was performed to identify neurons immunoreactive(ir)for calretinin,P2X7 receptor,cleaved caspase-3,total caspase-3,phospho-NF-κB,and total NF-κB.We analyzed the number of calretinin-ir and P2X7 receptor-ir neurons per ganglion,the neuronal profile area(μm^(2)),and corrected total cell fluorescence(CTCF).RESULTS Cells double labeled for calretinin and P2X7 receptor,cleaved caspase-3,total caspase-3,phospho-NF-κB,or total NF-κB were observed in the WT colitis 24 h and 4 d groups.The number of calretinin-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(2.10±0.13 vs 3.33±0.17,P<0.001;2.92±0.12 vs 3.70±0.11,P<0.05),but was not significantly different between the KO groups.The calretinin-ir neuronal profile area was increased in the WT colitis 24 h group compared to the WT sham 24 h group(312.60±7.85 vs 278.41±6.65,P<0.05),and the nuclear profile area was decreased in the WT colitis 4 d group compared to the WT sham 4 d group(104.63±2.49 vs 117.41±1.14,P<0.01).The number of P2X7 receptor-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(19.49±0.35 vs 22.21±0.18,P<0.001;20.35±0.14 vs 22.75±0.51,P<0.001),and no P2X7 receptor-ir neurons were observed in the KO groups.Myenteric neurons showed ultrastructural changes in the WT colitis 24 h and 4 d groups and in the KO colitis 24 h group.The cleaved caspase-3 CTCF was increased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups,respectively(485949±14140 vs 371371±16426,P<0.001;480381±11336 vs 378365±4053,P<0.001),but was not significantly different between the KO groups.The total caspase-3 CTCF,phospho-NF-κB CTCF,and total NF-κB CTCF were not significantly different among the groups.The DAI was recovered in the KO groups.Furthermore,we demonstrated that the absence of the P2X7 receptor attenuated inflammatory infiltration,tissue damage,collagen deposition,and the decrease in the number of goblet cells in the distal colon.CONCLUSION Ulcerative colitis affects myenteric neurons in WT mice but has a weaker effect in P2X7 receptor KO mice,and neuronal death may be associated with P2X7 receptor-mediated caspase-3 activation.The P2X7 receptor can be a therapeutic target for IBDs.

Postmortem ^(7)Li NMR analysis for assessing the reversibility of lithium metal electrodes in lithium metal batteries

Despite the proficiency of lithium(Li)-7 NMR spectroscopy in delineating the physical and chemical states of Li metal electrodes,challenges in specimen preparation and interpretation impede its progress.In this study,we conducted a comprehensive postmortem analysis utilizing ^(7)Li NMR,employing a stan-dard magic angle spinning probe to examine protective-layer coated Li metal electrodes and LiAg alloy electrodes against bare Li metal electrodes within Li metal batteries(LMBs).Our investigation explores the effects of sample burrs,alignment with the magnetic field,the existence of liquid electrolytes,and precycling on the ^(7)Li NMR signals.Through contrasting NMR spectra before and after cycling,we identi-fied alterations in Li^(0) and Li^(+) signals attributable to the degradation of the Li metal electrode.Our NMR analyses decisively demonstrate the efficacy of the protective layer in mitigating dendrite and solid elec-trolyte interphase formation.Moreover,we noted that Li*ions near the Li metal surface exhibit magnetic susceptibility anisotropy,revealing a novel approach to studying diamagnetic species on Li metal elec-trodes in LMBs.This study provides valuable insights and practical guidelines for characterizing distinct lithium states within LMBs.

B7 homolog 3 in pancreatic cancer

Despite advances in cancer treatment,pancreatic cancer(PC)remains a disease with high mortality rates and poor survival outcomes.The B7 homolog 3(B7-H3)checkpoint molecule is overexpressed among many malignant tumors,including PC,with low or absent expression in healthy tissues.By modulating various immunological and nonimmunological molecular mechanisms,B7-H3 may influence the progression of PC.However,the impact of B7-H3 on the survival of patients with PC remains a subject of debate.Still,most available scientific data recognize this molecule as a suppressive factor to antitumor immunity in PC.Furthermore,it has been demonstrated that B7-H3 stimulates the migration,invasion,and metastasis of PC cells,and enhances resistance to chemotherapy.In preclinical models of PC,B7-H3-targeting monoclonal antibodies have exerted profound antitumor effects by increasing natural killer cell-mediated antibodydependent cellular cytotoxicity and delivering radioisotopes and cytotoxic drugs to the tumor site.Finally,PC treatment with B7-H3-targeting antibody-drug conjugates and chimeric antigen receptor T cells is being tested in clinical studies.This review provides a comprehensive analysis of all PC-related studies in the context of B7-H3 and points to deficiencies in the current data that should be overcome by future research.

No.7信令在智能网(IN)中的应用

主要介绍了No .7信令在智能网 (IN)中的应用 ,并对该应用给出了详细的应用实例——— 30 0业务。

祛痰化瘀利湿方对人滑膜细胞Wnt/β-catenin信号通路β-catenin、Cyclin D1、MMP-7的调控作用

目的观察祛痰化瘀利湿方对人滑膜细胞Wnt/β-catenin信号通路的调控作用。方法将GSK-3β选择性小分子抑制剂作用于正常人滑膜细胞,以激活Wnt/β-catenin信号通路。提取并检测胞核蛋白β-catenin的表达,从而确定最佳激活时间点。将对数生长期的滑膜细胞分为正常组、SB-216763激活组、祛痰化瘀利湿方组,分别采取相应的干预措施。Western blot方法检测滑膜细胞胞核蛋白β-catenin及其下游基因Cyclin D1和MMP-7的表达,酶联免疫吸附试验(ELISA)检测滑膜细胞培养上清液中Cyclin D1和MMP-7的表达。结果成功激活正常人滑膜细胞Wnt/β-catenin信号通路,SB-216763干预后激活组胞核蛋白β-catenin及其下游基因Cyclin D1和MMP-7表达较正常组显著升高(P<0.05);经中药含药血清干预后,祛痰化瘀利湿方组胞核蛋白β-catenin及其下游基因Cyclin D1和MMP-7表达与激活组相比显著下调(P<0.01)。结论印证了GSK-3β作为选择性小分子抑制剂能够激活人滑膜细胞Wnt/β-catenin信号通路;通路激活后,其下游基因Cyclin D1和MMP-7的表达显著升高;祛痰化瘀利湿方能够明显下调β-catenin、Cyclin D1、MMP-7的表达;提示从单一信号通路方面可阐释祛痰化瘀利湿方治疗骨性关节炎的分子作用机制。

Involvement of A5/A7 noradrenergic neurons and B2 serotonergic neurons in nociceptive processing:a fiber photometry study

In the central nervous system,the A6 noradrenaline(NA)and the B3 serotonin(5-HT)cell groups are well-recognized players in the descending antinociceptive system,while other NA/5-HT cell groups are not well characterized.A5/A7 NA and B25-HT cells project to the spinal horn and form descending pathways.We recorded G-Ca MP6 green fluorescence signal intensities in the A5/A7 NA and the B25-HT cell groups of awake mice in response to acute tail pinch stimuli,acute heat stimuli,and in the context of a non-noxious control test,using fiber photometry with a calcium imaging system.We first introduced G-Ca MP6 in the A5/A7 NA or B25-HT neuronal soma,using transgenic mice carrying the tetracycline-controlled transactivator transgene under the control of either a dopamineβ-hydroxylase or a tryptophan hydroxylase-2 promoters and by the site-specific injection of adeno-associated virus(AAV-Tet O(3 G)-G-Ca MP6).After confirming the specific expression patterns of G-Ca MP6,we recorded G-Ca MP6 green fluorescence signals in these sites in awake mice in response to acute nociceptive stimuli.G-Ca MP6 fluorescence intensity in the A5,A7,and B2 cell groups was rapidly increased in response to acute nociceptive stimuli and soon after,it returned to baseline fluorescence intensity.This was not observed in the non-noxious control test.The results indicate that acute nociceptive stimuli rapidly increase the activities of A5/A7 NA or B25-HT neurons but the non-noxious stimuli do not.The present study suggests that A5/A7 NA or B25-HT neurons play important roles in nociceptive processing in the central nervous system.We suggest that A5/A7/B2 neurons may be new therapeutic targets.All performed procedures were approved by the Institutional Animal Use Committee of Kagoshima University(MD17105)on February 22,2018.

No.7信令TCAP消息格式及其在GSM中的应用

Ｎｏ７信令ＴＣＡＰ消息格式及其在ＧＳＭ中的应用□纪红孙礼Ｎｏ７信令各种信令单元的消息格式是协议规程的具体体现，是开发、维护与测试Ｎｏ７信令时最直观地与我们见面的信息载体．主要应用在智能网、移动通信网和网管系统中的ＴＣＡＰ消息，采用统一的嵌套式信...

Activation of α7 nicotinic acetylcholine receptor protects against oxidant stress damage through reducing vascular peroxidase-1 in a JNK signaling-dependent manner in endothelial cells

Aim Alpha7 nicotinic acetylcholine receptor （α7nAChR）, a subtype of nAChR regulating neurotrans- mission in central nervous system, is an essential regulator of cholinergic antiinflammatory pathway in periphery. The present study was to determine the effects of activation of α7nAChR on oxidant stress-induced injury in endo- thelial cells. Methods Cultured human umbilical vein endothelial cells were treated with H202 （400 μmol · L^-1） or H202plus PNU-282987 （ 10 μmol · L^-1 ）. Cell viability and membrane integrity were measured. AnnexinV ＋ PI assay, immunoblotting of bcl-2, bax and cleaved caspase-3, and immunofluorescence of apoptosis inducing factor （AIF） were performed to evaluate apoptosis. Protein expression of vascular peroxidase-1 （ VPO-1 ） and phosphor- JNK were measured by immunoblotting. Results Activation of α7nAChR by a selective agonist PNU-282987 pre-vented H202-indced decrease of cell viability and increase of lactate dehydrogenase release. Activation of α7nAChR markedly reduced cell apoptosis and intracellular oxidative stress level. Moreover, activation of α7nAChR reduced H2 02 -induced VPO-1 protein upregulation and JNK1/2 phosphorylation. The inhibitory effect of α7nAChR activa- tion on VPO-1 was blocked by JNK inhibitor SP600125. In addition, pretreatment of α7nAChR antagonist methyl- lycaconitine blocked the cytoprotective effect of PNU-282987. Conclusion These results provide the first evidence that activation of α7nAChR protects against oxidant stress-induced damage by suppressing VPO-1 in a JNK signa- ling pathway-dependent manner in endothelial cells.

β-catenin和MMP-7在异常腺窝病灶中的表达差异的初步探讨

目的检测β-catenin及MMP-7在Wistar鼠大肠癌模型异常腺窝病灶中的表达差异,探讨其与大肠肿瘤的相关性及其发生途径。方法 20只Wistar鼠给予二甲肼经典造模处理,于24周处死,取其大肠组织进行病理和免疫组化检查。结果发现两种不同病理类型的ACF:hACF和dACF,两者β-catenin的表达异常率分别为4.84%和100%,在MMP-7的阳性表达率分别为7.87%和81.82%,而肿瘤的β-catenin的表达异常率和MMP-7的阳性表达率均为100%。dACF与肿瘤在两个癌基因表达率的差异均没有统计学意义。结论单纯增生型ACF与肿瘤发生无明显相关,非典型性增生型ACF与肿瘤发生关系密切,并且其发生可能遵循Wnt途径。

正常人滑膜细胞Wnt/β-catenin信号通路激活后对MMP-2、MMP-7和MMP-9的调控作用

目的观察人滑膜细胞Wnt/β-catenin信号通路激活后对其下游基因MMP-2、MMP-7和MMP-9的影响。方法采用GSK-3β选择性抑制剂SB-216763作用于正常人滑膜细胞,提取胞核蛋白β-catenin,采用Western blotting检测胞核蛋白β-catenin的表达变化;采用酶联免疫吸附法(ELISA)检测人滑膜细胞上清液中MMP-2、MMP-7和MMP-9的表达变化。结果 Western blotting结果显示,GSK-3β选择性抑制剂SB-216763作用于人滑膜细胞后,β-catenin在胞核蛋白中的表达水平明显升高,并随着GSK-3β选择性抑制剂作用时间的延长,β-catenin的表达逐渐增强,呈时间依赖性,而在其干预的第48小时,胞核蛋白β-catenin的表达变化最明显,是正常组滑膜细胞的5.8696倍,具有统计学意义(P<0.05);酶联免疫吸附法(ELISA)结果显示,与正常组滑膜细胞比较,SB-216763干预的滑膜细胞上清液中MMP-2、MMP-7和MMP-9的表达分别是正常滑膜细胞的4.6188、3.2443和2.9979倍,具有统计学意义(P<0.05)。结论①SB-216763成功激活人滑膜细胞Wnt/β-catenin信号通路;②MMP-2、7、9在人滑膜细胞Wnt/β-catenin信号通路激活后其表达显著升高,证明激活Wnt/β-catenin信号通路对MMP-2、MMP-7和MMP-9的表达有一定的调控作用。③Wnt/β-catenin信号通路在骨性关节炎患者中是激活的,而其对MMP-2、MMP-7和MMP-9的调控可能是导致关节软骨降解,促进骨关节炎形成的作用机制之一。该实验结果有助于从单一通路阐释Wnt/β-catenin信号通路对膝骨关节炎的作用机制。

miR-7-5p和miR-152-3p联合调控Wnt/β-catenin通路对乳腺癌细胞上皮-间质转化及化疗耐药的影响

目的探讨miR-7-5p和miR-152-3p协同抑制乳腺癌细胞上皮-间质转化(epithelial-mesenchymal transition,EMT)进程及紫杉醇耐药的分子机制。方法采用生物信息学软件预测miR-7-5p和miR-152-3p的靶基因,双荧光素酶报告基因检测两者与TCF4的靶向关系;Western blot法检测各组细胞中Wnt/β-catenin信号通路关键调控因子β-catenin及TCF4蛋白的表达;在转染miR-7-5p mimics和miR-152-3p mimics基础上给予Wnt/β-catenin通路激活剂LiCl处理后,Western blot法检测MCF-7/TAX细胞中β-catenin、TCF4和EMT相关蛋白(E-cadherin、vimentin)的表达,Transwell小室实验检测MCF-7/TAX细胞侵袭和迁移能力;MTT实验检测激活Wnt/β-catenin信号通路对MCF-7/TAX细胞紫杉醇耐药性的影响。结果TCF43′UTR区域存在能够与miR-7-5p及miR-152-3p互补的结合位点;转染miR-7-5p mimics和miR-152-3p mimics后可使TCF4野生型(TCF4-WT)报告基因载体的荧光素酶活性较NC组明显降低(P<0.05)。Western blot结果显示,与NC组相比,转染miR-7-5p mimics和miR-152-3p mimics后各组紫杉醇耐药MCF-7/TAX细胞中β-catenin和TCF4蛋白的表达水平明显降低(P<0.05),且两者共同转染后MCF-7/TAX细胞中β-catenin和TCF4蛋白的表达水平较miR-7-5p组或miR-152-3p组进一步降低(P<0.05)。Western blot结果显示,LiCl处理后MCF-7/TAX细胞中β-catenin、TCF4和vimentin蛋白表达水平明显升高,而E-cadherin蛋白表达水平明显降低(P<0.05)。Transwell小室结果显示,LiCl处理后MCF-7/TAX细胞侵袭和迁移能力明显增强(P<0.05)。MTT结果显示,不同浓度紫杉醇作用下,miR-7-5p+LiCl组细胞增殖活力较miR-7-5p组明显升高;同时miR-152-3p+LiCl组和miR-7-5p/152-3p+LiCl组细胞的增殖活力较NC组均明显升高(P<0.05)。结论TCF4是miR-7-5p和miR-152-3p的共同靶标。miR-7-5p和miR-152-3p可共同抑制MCF-7/TAX细胞中Wnt/β-catenin信号通路的活化。

P2X7 receptor signaling during adult hippocampal neurogenesis

Neurogenesis is a persistent and essential feature of the adult mammalian hippocampus.Granular neurons generated from resident pools of stem or progenitor cells provide a mechanism for the formation and consolidation of new memories.Regulation of hippocampal neurogenesis is complex and multifaceted,and numerous signaling pathways converge to modulate cell proliferation,apoptosis,and clearance of cellular debris,as well as synaptic integration of newborn immature neurons.The expression of functional P2X7 receptors in the central nervous system has attracted much interest and the regulatory role of this purinergic receptor during adult neurogenesis has only recently begun to be explored.P2X7 receptors are exceptionally versatile:in their canonical role they act as adenosine triphosphate-gated calcium channels and facilitate calcium-signaling cascades exerting control over the cell via calcium-encoded sensory proteins and transcription factor activation.P2X7 also mediates transmembrane pore formation to regulate cytokine release and facilitate extracellular communication,and when persistently stimulated by high extracellular adenosine triphosphate levels large P2X7 pores form,which induce apoptotic cell death through cytosolic ion dysregulation.Lastly,as a scavenger receptor P2X7 directly facilitates phagocytosis of the cellular debris that arises during neurogenesis,as well as during some disease states.Understanding how P2X7 receptors regulate the physiology of stem and progenitor cells in the adult hippocampus is an important step towards developing useful therapeutic models for regenerative medicine.This review considers the relevant aspects of adult hippocampal neurogenesis and explores how P2X7 receptor activity may influence the molecular physiology of the hippocampus,and neural stem and progenitor cells.

Clinical assessment and identification of immuno-oncology markers concerning the 19-gene based risk classifier in stage Ⅳ colorectal cancer

BACKGROUND Genomic profiling of tumors has contributed to the understanding of colorectal cancer(CRC), facilitating diagnosis, prognosis and selection of treatments,including targeted regimens. A report suggested that a 19-gene-based risk classifier(TCA19) was a prognostic tool for patients with stage III CRC. The survival outcomes in patients with stage IV CRC are still poor and appropriate selection of targeted therapies and immunotherapies is challenging.AIM To assess clinical implication of TCA19 in patients with stage IV CRC, and to identify TCA19 with involvement in immune-oncology.METHODS A retrospective review of the medical records of 60 patients with stage IV CRC was conducted, assessing clinicopathological variables and progression-free survival(PFS). TCA19 gene expression was determined by quantitative polymerase chain reaction(qPCR) in matched normal and tumor tissues taken from the study cohort. Expression of potential immune-oncology regulatory proteins and targets was examined by immunohistochemistry(IHC), western blot, immunofluorescence staining in tissues from a validation cohort of 10 patients, and in CRC cell lines co-cultured with monocyte in vitro.RESULTS In the patients with TCA19 score higher than the median, the PFS rates of eight patients who received the targeted regimens were significantly higher than the PFS rates of four patients who received 5-fluorouracil-based regimen(P = 0.041).In multivariate analysis, expression of signaling lymphocytic activation molecule family, member 7(SLAMF7) and triggering receptor expressed on myeloid cells 1(TREM1) was associated with PFS in the 60-patient cohort. After checking another 10 validate set, the expression of the IHC, the level of real-time qPCR,and the level of western blot were lower for SLAMF7 and higher for TREM7 in primary and metastatic tumors than in normal tissues. In CRC cells expressing SLAMF7 that were co-cultured with a monocytic cell line, levels of CD 68 and CD73 were significantly lower at day 5 of co-culture than at day 0.CONCLUSION The TCA19 score might be prognostic for target-regimen-specific PFS in stage IV CRC. Down-regulation of SLAMF7 and up-regulation of TREM1 occur in primary and metastatic tumor tissues.

β-catenin和MMP-7在食管鳞癌中的表达及意义

目的研究β-catenin和MMP-7在食管鳞癌中的表达,探讨其表达与食管癌生物学行为的关系。方法采用免疫组化SABC法检测β-cat和MMP-7在食管鳞癌中的表达。结果β-catenin在食管癌组织异常表达率为64.5%,其异常表达与分化程度、临床分期、淋巴结转移、静脉侵犯有关。MMP-7在食管癌中阳性表达率为43.4%,其表达与淋巴结转移、临床分期、静脉侵犯、浸润深度有关。β-cat的异常表达与MMP-7的表达有一定的相关性(P<0.01,r=0.32)。结论β-cat和MMP-7的表达在食管鳞癌进展中可能有重要作用。联合检测其在食管鳞癌中的表达,有利于食管癌治疗和预后的判断。