肺癌患者放疗前后外周血DC细胞和血清sIL-2R、HMGB-1变化及其与预后的关系研究

目的 探讨肺癌患者放疗前后外周血DC细胞和血清sIL-2R、HMGB-1水平变化及临床意义。方法 收集肺癌患者124例,采用适形调强放疗(intensity modulated radiation therapy, IMRT)技术治疗,于放疗前、放疗后抽取空腹状态下静脉血4 ml,采用免疫磁珠法检测外周血DC细胞(DC1、DC2)水平,采用双抗体夹心酶联免疫法检测血清sIL-2R、HMGB-1水平。统计不同性别、年龄、是否吸烟、病理类型、是否手术、KPS评分、临床分期的肺癌患者外周血DC细胞和血清sIL-2R、HMGB-1水平,并分析患者预后与血清sIL-2R、HMGB-1水平的关系,单因素和多因素COX回归分析影响肺癌患者预后因素。结果 肺癌患者放疗前后外周血DC细胞水平比较,P>0.05。肺癌患者治疗后血清sIL-2R、HMGB-1水平与治疗前比较,P<0.05。治疗前,血清sIL-2R水平在不同性别、年龄、是否吸烟、病理类型方面比较,P>0.05,在是否手术、不同KPS评分、临床分期、淋巴结转移方面比较,P<0.05;血清HMGB-1水平在不同病理类型方面比较,P>0.05,在不同性别、年龄、是否吸烟、是否手术、不同KPS评分、临床分期、淋巴结转移方面比较,P<0.05;治疗后,血清sIL-2R水平在不同性别、年龄、是否吸烟、病理类型方面比较,P>0.05,在是否手术、不同KPS评分、临床分期、淋巴结转移方面比较,P<0.05;血清HMGB-1水平在不同性别、年龄、是否吸烟、病理类型、是否手术、KPS评分、临床分期、淋巴结转移方面比较,P<0.05。死亡组患者血清sIL-2R、HMGB-1水平均高于生存组(P<0.05)。死亡组DC2低于生存组(P<0.05)。经单因素、多因素COX回归分析显示,临床分期(Ⅲ~Ⅳ期)、淋巴结转移、sIL-2R、HMGB-1水平异常上升、DC2比例下降均是导致肺癌患者预后差的独立危险因素。结论 肺癌患者放疗前后外周血DC细胞无明显变化,但血清sIL-2R、HMGB-1水平治疗后较治疗前均明显降低,其sIL-2R、HMGB-1水平异常上升及DC2比例下降均为患者预后独立危险因素,可预测预后。

Nrf2、LTBP2、PECAM1与NSCLC患者EGFR靶向治疗反应性关系及意义

目的:探讨血清核因子E2相关因子2(Nrf2)、转化生长因子结合蛋白2(LTBP2)、血小板内皮细胞黏附分子1(PECAM1)与非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)靶向治疗反应性关系及意义。方法:选取我院2021年1月—2023年1月收治的95例NSCLC患者为研究对象,根据EGFR靶向治疗3个月后的治疗反应性分为有效组(54例)、无效组(41例)。比较2组治疗前及治疗1个月、2个月后血清Nrf2、LTBP2、PECAM1水平,分析治疗1个月、2个月后血清Nrf2、LTBP2、PECAM1水平与NSCLC患者EGFR靶向治疗反应性相关性,偏回归分析治疗无效的影响因素,受试者工作特征曲线(ROC)分析治疗1个月、2个月后血清Nrf2、LTBP2、PECAM1水平联合检测对NSCLC患者EGFR靶向治疗效果的预测价值。结果:治疗1个月、2个月后无效组血清Nrf2、LTBP2、PECAM1水平均高于有效组(P<0.05);相关性分析发现,治疗1个月、2个月后血清Nrf2、LTBP2、PECAM1水平与治疗反应性均呈负相关(P<0.05);Logistic回归分析发现,治疗1个月、2个月后血清Nrf2、LTBP2、PECAM1水平为NSCLC患者EGFR靶向治疗效果的影响因素(P<0.05);ROC曲线分析发现,治疗1个月、2个月后血清Nrf2、LTBP2、PECAM1水平联合预测治疗无效的曲线下面积(AUC)分别为0.761、0.816,最佳预测敏感度、特异度分别为(85.37%、66.67%)、(92.68%、70.37%),高于单一指标预测(P<0.05)。结论:血清Nrf2、LTBP2、PECAM1水平与NSCLC患者EGFR靶向治疗反应性密切相关,并在预测治疗效果方面具有较高效能。

Tra2βEnhances Cell Proliferation by Inducing the Expression of Transcription Factor SP1 in Cervical Cancer

Objective In this study,the role and potential mechanism of transformer 2β(Tra2β)in cervical cancer were explored.Methods The transcriptional data of Tra2βin patients with cervical cancer from Gene Expression Profiling Interactive Analysis(GEPIA)and cBioPortal databases were investigated.The functions of Tra2βwere evaluated by using Western blot,MTT,colony formation,Transwell assays,and nude mouse tumor formation experiments.Target genes regulated by Tra2βwere studied by RNA-seq.Subsequently,representative genes were selected for RT-qPCR,confocal immunofluorescence,Western blot,and rescue experiments to verify their regulatory relationship.Results The dysregulation of Tra2βin cervical cancer samples was observed.Tra2βoverexpression in Siha and Hela cells enhanced cell viability and proliferation,whereas Tra2βknockdown showed the opposite effect.Alteration of Tra2βexpression did not affect cell migration and invasion.Furthermore,tumor xenograft models verified that Tra2βpromoted cervical cancer growth.Mechanically,Tra2βpositively regulated the mRNA and protein level of SP1,which was critical for the proliferative capability of Tra2β.Conclusion This study demonstrated the important role of the Tra2β/SP1 axis in the progression of cervical cancer in vitro and in vivo,which provides a comprehensive understanding of the pathogenesis of cervical cancer.

Metabolic and cardiovascular benefits with combination therapy of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes

Both GLP-1 receptor agonists(GLP-1RA)and SGLT-2 inhibitors(SGLT-2I)are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure(SBP)modestly.Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c,body weight,and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects.Since several agents from each class of these drugs have shown an improvement in cardiovascular(CV)and renal outcomes in their respective cardiovascular outcome trials(CVOT),combination therapy is theoretically expected to have additional CV and renal benefits.In this comprehensive opinion review,we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone,although body weight lowering was nearly additive and the SBP lowering was more than additive.Our additional meta-analysis of CV outcomes with GLP1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone,against placebo.Interestingly,a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials.Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.

Effect of photodynamic therapy with(17R,18R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt on pancreatic cancer cells in vitro and in vivo

AIM To investigate the antitumor effects and underlying mechanisms of(17 R,18 R)-2-(1-hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt(YLG-1)-induced photodynamic therapy(PDT) on pancreatic cancer in vitro and in vivo.METHODS YLG-1 is a novel photosensitizer extracted from spirulina. Its phototoxicity, cellular uptake and localization, as well as its effect on reactive oxygen species(ROS) production, apoptosis, and expression of apoptosis-associated proteins were detected in vitro. An in vivo imaging system(IVIS), the Lumina K imaging system, and mouse models of subcutaneous Panc-1-bearing tumors were exploited to evaluate the drug delivery pathway and pancreatic cancer growth in vivo.RESULTS YLG-1 was localized to the mitochondria, and the appropriate incubation time was 6 h. Under 650 nm light irradiation, YLG-1-PDT exerted a potent cytotoxic effect on pancreatic cancer cells in vitro, which could be abolished by the ROS scavenger N-acetyl-L-cysteine(NAC). The death mode caused by YLG-1-PDT was apoptosis, accompanied by upregulated Bax and cleaved Caspase-3 and decreased Bcl-2 expression. The results from the IVIS images suggested that the optimal administration route was intratumoral(IT) injection and that the best time to conduct YLG-1-PDT was 2 h post-IT injection. Consistent with the results in vitro, YLG-1-PDT showed great growth inhibition effects on pancreatic cancer cells in a mouse model.CONCLUSION YLG-1 is a potential photosensitizer for pancreatic cancer PDT via IT injection, the mechanisms of which are associated with inducing ROS and promoting apoptosis.

乳腺癌组织中COL11A1表达与ER、PR、HER-2和Ki-67的相关性分析

目的探讨乳腺癌组织中Ⅺ型胶原α1(COL11A1)表达与雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体-2(HER-2)和Ki-67的关系。方法采用免疫组化EnVision两步法检测18例乳腺纤维腺瘤组织和120例乳腺癌组织(36例原位癌组织、84例浸润性癌组织)中COL11A1的表达,同时对乳腺癌组织进行ER、PR、HER-2和Ki-67免疫组化检测,对HER-2(2+)进行荧光原位杂交检测;分析COL11A1表达与乳腺癌临床病理特征和多种免疫标记(ER、PR、HER-2和Ki-67)的关系。结果免疫组化结果显示COL11A1主要表达于乳腺癌细胞中。在纤维腺瘤组织中COL11A1表达呈弱阳性。COL11A1在原位癌中表达高于浸润性乳腺癌(P<0.05)。COL11A1表达与乳腺癌患者的年龄、部位、肿块大小和淋巴结转移无关(P>0.05),而中、高分化组织的COL11A1表达水平高于低分化组织,差异有统计学意义(P<0.05)。进一步分析COL11A1与乳腺癌其他免疫标记间的相关性发现,在Ki-67高表达组织中COL11A1低表达的比例更高,差异有统计学意义(P<0.05),而其他3种标记与COL11A1的表达无关(P>0.05)。结论COL11A1在浸润性乳腺癌中表达较原位癌低,在低分化乳腺癌中表达水平较中高分化更低,且与Ki-67表达有关,提示COL11Al表达在乳腺癌发生发展过程中是动态变化的,为乳腺癌的诊断治疗提供潜在标记物。

Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats withα-synucleinopathy

Parkinsonism by unilateral,intranigralβ-sitosterolβ-D-glucoside administration in rats is distinguished in that theα-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time,thus replicating several clinical features of Parkinson’s disease,a typicalα-synucleinopathy.As Nurr1 repressesα-synuclein,we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateralβ-sitosterolβ-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection.This study found that rNurr1-V5 expression but not that of the green fluorescent protein(the negative control)reducedβ-sitosterolβ-D-glucoside-induced neuropathology.Accordingly,a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum.In addition,tyrosine hydroxylase-positive cells displayed less senescence markerβ-galactosidase and more neuron-cytoskeleton markerβIII-tubulin and brain-derived neurotrophic factor.A significant decrease in activated microglia(positive to ionized calcium-binding adaptor molecule 1)and neurotoxic astrocytes(positive to glial fibrillary acidic protein and complement component 3)and increased neurotrophic astrocytes(positive to glial fibrillary acidic protein and S100 calcium-binding protein A10)also occurred in the substantia nigra.These effects followed the bilateral reduction inα-synuclein aggregates in the nigrostriatal system,improving sensorimotor behavior.Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration(senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells),neuroinflammation(activated microglia,neurotoxic astrocytes),α-synuclein aggregation,and sensorimotor deficits.Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect,supporting its potential clinical use in the treatment of Parkinson’s disease.

早期序贯治疗联合ASCT对中高危多发性骨髓瘤的临床疗效及对PD-1/PD-L1、T细胞和B细胞功能的影响

目的:分析早期序贯治疗联合自体造血干细胞移植(ASCT)对中高危多发性骨髓瘤的临床疗效及对PD-1/PD-L1、T细胞和B细胞功能的影响。方法:选择2019年1月—2022年5月南阳市中心医院收治的90例中高危多发性骨髓瘤患者作为研究对象,依照随机信封法分为观察组和对照组。对照组患者采用常规化疗方案进行治疗,观察组在对照组的基础上采用早期序贯治疗联合ASCT方案干预和治疗。干预治疗半年后对患者临床疗效进行评估,治疗前及治疗后半年时检测外周血中CD3^(+)T细胞、CD4^(+)T细胞、CD8^(+)T细胞、PD-1及PD-L1蛋白表达水平,检测受试者血清中T细胞相关细胞因子IFN-γ、TNF-α及B细胞相关抗体IgA、IgM和IgG水平情况。结果:观察组治疗临床疗效显著优于对照组,差异有统计学意义(χ^(2)=13.586,P<0.05);治疗后,两组患者血中CD3^(+)T细胞、CD4^(+)T细胞水平均显著升高,CD8^(+)T细胞水平显著降低,差异有统计学意义(t=7.299、2.521、12.629,P<0.05);治疗后,两组患者血清中PD-1及PD-L1蛋白均显著降低,差异有统计学意义(t=16.315、11.161,P<0.05);治疗后,两组患者血清中IFN-γ、TNF-α蛋白均显著升高,差异有统计学意义(t=30.046、32.084,P<0.05);治疗后,两组患者血清中IgA蛋白显著降低,IgM和IgG蛋白均显著升高,差异有统计学意义(t=47.013、50.959、27.694,P<0.05)。结论:联合早期序贯治疗联合ASCT对中高危多发性骨髓瘤患者干预可有效提高临床疗效,控PD-1及PD-L1水平,改善T细胞和B细胞功能。

胰岛素强化治疗2型糖尿病患者的疗效及对血清ICAM-1、hs-CRP表达的影响

目的探讨胰岛素强化治疗对2型糖尿病患者的疗效及对血清ICAM-1、hs-CRP表达的影响。方法选取2020年9月—2023年5月在平顶山市第二人民医院湛河分院就诊的2型糖尿病患者90例,按随机数字表法分为对照组和观察组各45例。对照组口服二甲双胍治疗,观察组给予胰岛素泵强化治疗。比较两组患者治疗前后血糖、糖化血红蛋白(HbA1c)水平、血糖达标时间、血清ICAM-1、hs-CRP水平。结果观察组患者治疗后空腹血糖(FBG)、餐后2 h血糖(2hPG)、HbA1c水平均低于对照组,差异有统计学意义(P<0.05);观察组患者血糖达标时间明显缩短,与对照组比较差异有统计学意义(P<0.05);观察组患者治疗后血清ICAM-1、hs-CRP水平均低于对照组,差异有统计学意义(P<0.05)。结论胰岛素强化治疗能有效改善2型糖尿病患者的血糖控制,缩短血糖达标时间,降低血清ICAM-1、hs-CRP水平,有利于减少2型糖尿病患者的心血管并发症风险。

Estrogen up-regulates MMP2/9 expression in endometrial epithelial cell via VEGF-ERK1/2 pathway

Objective:To study the effect of estrogen on anovulatory dysfunctional uterine bleeding(ADUB).Methods:Primary endometrial epithelial cells of Hainan Lizu female was cultured and hydrolylic activity of gelalinase was determined by gelatin zymography analysis.Cellular mRNA and protein synthesis was blocked respectively to determine whether the increased expression of MMP-2/9 was induced by estrogen.The expression of VEGF was blocked by siRNA.After treatment with various factors.MMP-9,VEGF,total Erk and phosphorylated Erk expression in primary uterine epithelial cells was detected by Western blotting analysis.Cell MMP-2/9mRNA levels was measured by real-time RT-PCR.Results:The activity and expression of MMP2/9 was inereased in the endometrium of patients with ADUB.Estrogen could up-regulate the expression of VEGF and activate Erk 1/2-Elk1 signal path.After interference by siRNA,ERK1/2 pathway was blocked in cells,and the expression of MMP-2/9 was down-regulated.ERK1/2 specific blocker U0126 blocked ERK phosphorylation,and it could down-regulate the expression of MMP-2/9.Conclusions:The results showed that the estrogen can increase the expression of VEGF,and thus activate ERK1/2 pathway to induce MMP-2/9 expression.

17β-Estradiol Regulates Cultured Immature Boar Sertoli Cell Proliferation via the cAMP-ERK1/2 Pathway and the Estrogen Receptor β

Estrogen plays an important role in regulating Sertoli cell number in the testis. The objective of the study was to identify whether 17β-estradiol affected the proliferation of cultured, immature boar Sertoli cells via the estrogen receptor β （ERβ） and the cAMP-extracellular signal-regulated kinase （ERK1/2） pathway. Low levels （10-10-10-8 mol L-1） of 17β-estradiol increased cell number, but high levels （10-7-10-6 mol L-1） decreased it （P〈0.05）. Sertoli cell number began to recover for an additional 24 h in the medium without 17β-estradiol （10-6 mol L-l） （P〉0.05）. The effects of 17β-estradiol （10-9 mol L-1） peaked at the first 24 h （P〈0.05）. 17β-estradiol activated ERK1/2 from 5 min to 24 h, but the activiy of ERK1/2 began to decrease after 4 h. Both PD98059 and U0126, two ERK inhibitors, blocked cell division （P〈0.05）. 17β-estradiol （10-10-10-6 mol L-1） dose-dependently increased cAMP production （P 〈 0.05）, and both 17β-estradiol （10-9 mol L-1） and forskolin, which increases cAMP levels, induced cell proliferation and activated ERK1/2 （P〈 0.05）. Rp-cAMP, an antagonist of cAMP, blocked this 17β-estradiol activity （P〈 0.05）. Two estrogen receptor antagonists, ICI 182780 and ERβ antagonist （ERβAnt）, reduced Sertoli cell number, cAMP production and ERK1/2 activation （P〈 0.05）, but ERaAnt did not （P〉 0.05）. Therefore, 17β- estradiol mainly promotes pig Sertoli cell proliferation via ERβ to induce cAMP production and ERK activation to promote cell proliferation.

1,3-Bis(2-chloroethyl)-1-nitrosourea enhances the inhibitory effect of Resveratrol on 5-fluorouracil sensitive/resistant colon cancer cells

AIM:To study the mechanism of 5-fluorouracil(5-FU)resistance in colon cancer cells and to develop strategies for overcoming such resistance by combination treatment.METHODS:We established and characterized a 5-FU resistance(5-FU-R)cell line derived from continuous exposure(25μmol/L)to 5-FU for 20 wk in 5-FU sensitive HCT-116 cells.The proliferation and expression of different representative apoptosis and anti-apoptosis markers in 5-FU sensitive and 5-FU resistance cells were measured by the MTT assay and by Western blotting,respectively,after treatment with Resveratrol(Res)and/or 1,3-Bis(2-chloroethyl)-1-nitrosourea(BCNU).Apoptosis and cell cycle arrest was measured by 4',6'-diamidino-2-phenylindole hydrochloride staining and fluorescence-activated cell sorting analysis,respectively.The extent of DNA damage was measured by the Comet assay.We measured the visible changes in the DNA damage/repair cascade by Western blotting.RESULTS:The widely used chemotherapeutic agents BCNU and Res decreased the growth of 5-FU sensitive HCT-116 cells in a dose dependent manner.Combined application of BCNU and Res caused more apoptosis in5-FU sensitive cells in comparison to individual treatment.In addition,the combined application of BCNU and Res caused a significant decrease of major DNA base excision repair components in 5-FU sensitive cells.We established a 5-FU resistance cell line(5-FU-R)from 5-FU-sensitive HCT-116(mismatch repair deficient)cells that was not resistant to other chemotherapeutic agents(e.g.,BCNU,Res)except 5-FU.The 5-FU resistance of 5-FU-R cells was assessed by exposure to increasing concentrations of 5-FU followed by the MTT assay.There was no significant cell death noted in5-FU-R cells in comparison to 5-FU sensitive cells after5-FU treatment.This resistant cell line overexpressed anti-apoptotic[e.g.,AKT,nuclear factorκB,FLICE-like inhibitory protein),DNA repair(e.g.,DNA polymerase beta(POL-β),DNA polymerase eta(POLH),protein Flap endonuclease 1(FEN1),DNA damage-binding protein 2(DDB2)]and 5-FU-resistance proteins(thymidylate synthase)but under expressed pro-apoptotic proteins(e.g.,DAB2,CK1)in comparison to the parental cells.Increased genotoxicity and apoptosis were observed in resistant cells after combined application of BCNU and Res in comparison to untreated or parental cells.BCNU increased the sensitivity to Res of 5-FU resistant cells compared with parental cells.Fifty percent cell death were noted in parental cells when 18μmol/L of Res was associated with fixed concentration(20μmol/L)of BCNU,but a much lower concentration of Res(8μmol/L)was needed to achieve the same effect in 5-FU resistant cells.Interestingly,increased levels of adenomatous polyposis coli and decreased levels POL-β,POLH,FEN1 and DDB2 were noted after the same combined treatment in resistant cells.CONCLUSION:BCNU combined with Res exerts a synergistic effect that may prove useful for the treatment of colon cancer and to overcome drug resistance.

Estrogen affects neuropathic pain through upregulating N-methyl-D-aspartate acid receptor 1 expression in the dorsal root ganglion of rats

Estrogen affects the generation and transmission of neuropathic pain,but the specific regulatory mechanism is still unclear.Activation of the N-methyl-D-aspartate acid receptor 1（NMDAR1） plays an important role in the production and maintenance of hyperalgesia and allodynia.The present study was conducted to determine whether a relationship exists between estrogen and NMDAR1 in peripheral nerve pain.A chronic sciatic nerve constriction injury model of chronic neuropathic pain was established in rats.These rats were then subcutaneously injected with 17β-estradiol,the NMDAR1 antagonist D（-）-2-amino-5-phosphonopentanoic acid（AP-5）,or both once daily for 15 days.Compared with injured drug na？ve rats,rats with chronic sciatic nerve injury that were administered estradiol showed a lower paw withdrawal mechanical threshold and a shorter paw withdrawal thermal latency,indicating increased sensitivity to mechanical and thermal pain.Estrogen administration was also associated with increased expression of NMDAR1 immunoreactivity（as assessed by immunohistochemistry） and protein（as determined by western blot assay） in spinal dorsal root ganglia.This 17β-estradiol-induced increase in NMDAR1 expression was blocked by co-administration with AP-5,whereas AP-5 alone did not affect NMDAR1 expression.These results suggest that 17β-estradiol administration significantly reduced mechanical and thermal pain thresholds in rats with chronic constriction of the sciatic nerve,and that the mechanism for this increased sensitivity may be related to the upregulation of NMDAR1 expression in dorsal root ganglia.

CYP2C19 polymorphism has no influence on rabeprazole-based hybrid therapy for Helicobacter pylori eradication

AIM To evaluate the impact of cytochrome P450 2C19(CYP2C19) and interleukin-1β(IL-1β) polymorphisms on the efficacy of Helicobacter pylori(H. pylori) eradication by using rabeprazole-based hybrid therapy.METHODS A total of 88 H. pylori-infected patients were recruited to receive 14-d of hybrid therapy from March 2013 to May 2014. Three patients were excluded from analysis because of incomplete compliance. Either a follow-up endoscopy or 13 C-urea test was performed to determine the results of H. pylori eradication therapy. The genotypes of CYP2C19 and IL-1β were analyzed to investigate the impact on treatment effect. RESULTS The total eradication rate of H. pylori was 92.94%(79/85). According to the CYP2C19 genotypes, the rates of H. pylori eradication were 89.19% in extensive metabolizers(EM) and 95.83% in non-EM. The H.pylori eradication rates regarding the IL-1β genotypes were 92.59% in the normal acid secretion group and 93.10% in the low acid secretion group. After multivariable logistic regression analysis, both the genotypes of CYP2C19 and IL-1β had no significant influences on the eradication rates of H. pylori.CONCLUSION The CYP2C19 and IL-1β polymorphisms are not significantly independent factors of H.pylori eradication using rabeprazole-based hybrid therapy.

Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly(ADP-ribose)polymerase inhibitors(PARPi).Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations,which restore the open-reading frame of the affected allele.This platinum/PARPi crossresistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies.There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance;however,their actual clinical relevance remains to be established.In addition,studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells.These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure,but become outcompeted by BRCA1-deficient cells during therapy holidays.Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches,which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.

Induction of anti-hepatoma immunity by recombinant retrovirus expressing B7-1 /B7-2 costimulatory molecules

Objective: To construct recombinant R7-l/B7-2 retrovirus vectors and observe the effects of B7-l/R7-2 gene expression on in ho and in for immune response against against murine hepatoma. Methods: The recombinant retrovirus vectors expressing B7-1/B7-2 were constructed by gene cloning technology to produce retrovirus-infected PE501 and PA317 cell lines and murine hepatoma Hepal-6. The expression of R7-l/B7-2 was detected by fluorescence activated cell soning analysis (FACS). B7-l/B7-2 positive Hepal-6 Cell lines were used in inducing anti-hepatoma immunity in ho and in the. Results: In contrast to the excessive growth of parental Hemal-6 tumor, the growth of B7-l/B7-2-positive Hepal-6 inoculated into syngenic mice regressed. B7-1/R7-2-positive or cytokine-treated Hepal-6 alone could only induce mild cytototicity; in contrast, B7-1/B7-2-positive Hemal-6 treated with cytokine-stimulated spleen cells and activated the cytotoxicity effectively. Immunity in mice with R7-1/B7-2-positive tumor cells or cytokine-beated Hepal-6 only provided partial protection against parental Hepa1-6 tumor, whereas pretreatment of the transfected tumor cells with IFN-r and TNF-a induced complete immunity protection in vivo. Mice receiving inoculation of cytokine-treated B7-l/R7-2-positive Hemal-6 cells presented regression of the establoshed pental tUmor and survived for more than l00 d, while those untreated mice died within 40 d. Conclu sions: B7-l/R7-2 expression is necessary but not sufficient in inducing anti-hepatoma immune response, whereas it is efficient when combined with the beatment of IFN-γ and TNF-a.

Chemical forms of cobalt and nickel extracted by M1,M3 and CaCl_(2)-DTPA

Mehlich 1(M1), mehlich 3(M3) and CaCl 2 DTPA have been used to predict the available micronutrient in soil. However, the forms of micronutrient extractable by these extractants are not known. In the present study, ten soils, collected from five provinces and the capital of China, representing a wide range of chemical and physical properties, were analyzed by sequential extraction to isolate five forms of cobalt and nickel, they are exchangeable, carbonate bound, Fe Mn oxide bound, organically bound and residual forms. The chemical forms extracted by M1, M3 and CaCl 2 DTPA were also investigated. The results show strong correlation between the carbonate bound or organically bound forms of Co or Ni and the amounts of extractable by any of the above three extractants. The main forms extracted by these extractants are carbonate and organically bound forms. The ranking of these three extractants for extraction of Co and Ni are M1>M3=CaCl 2 DTPA and M1=M3>CaCl 2 DTPA, respectively.

17β-Estradiol Regulates SKP2 Expression in Cultured Immature Boar Sertoli Cells Mainly via Estrogen Receptor β,cAMP-PKA and ERK1/2

Estrogen plays an important role in regulating testicular Sertoli cell number. Furthermore, S-phase kinase-associated protein 2 （SKP2） plays a central role in mammalian cell cycle progression. The objective of this study was to determine whether 17β-estradiol can regulate the expression of SKP2, and the Sertoli cell cycle, via estrogen receptor β （ERβ）, the cyclic adenosine monophosphate （cAMP）-protein kinase A （PKA） and extracellular signal-regulated kinase （ERK1/2） pathway. When cultured immature boar Sertoli cells were treated with 17β-estradiol, a time-dependent increase in SKP2 mRNA and protein level was observed by real-time PCR and Western blot, and 17β-estradiol activity peaked at 30 min. Treatment with ICI182780 and ERβ antagonist reduced 17β-estradiol-induced expression of SKP2 and proliferating cell nuclear antigen （PCNA）, while increasing the protein concentration of p27kip1. However, the effect of ERa antagonist on these parameters was lower than that of ICI 182780 and ERβ. Forskolin had a similar effect as 17β-estradiol on the expression of SKP2, PCNA and p27kip1, Rp-cAMP, H-89 and U0126 treatment reduced 17β-estradiol-induced changes, while H-89 also inhibited ERK1/2 activation. Therefore, 17β-estradiol mainly regulates SKP2 mRNA and protein expression via ERβ-cAMP-PKA and ERK1/2 activation. SKP2 and PCNA expression were positively correlated, while increased SKP2 expression likely resulted in p27kip1 degradation.

Efficacy and Safety of Basal-Supported Prandial GLP-1 Receptor Agonist Therapy

Aim: To assess the safety and efficacy of basal-supported prandial GLP-1 receptor agonist therapy (BPT)* in type 2 diabetes mellitus (T2DM). Methods: Patients with T2DM, who had previously received insulin injection therapy and who had had their treatment switched to BPT (liraglutide), were retrospectively recruited. The efficacy of BPT was assessed by determining changes in HbA1c, body weight and total daily insulin dose from baseline to 4 months after BPT initiation. Safety was assessed by comparing the frequency of hypoglycemic episodes at baseline and after 4 months. The Wilcoxon test was used to analyze changes in parameters throughout the study period. Results: Twenty-nine patients, previously treated with basal-supported oral therapy (BOT), basal-bolus insulin, or pre-mixed insulin, were recruited. When analyzed together, there was no change in HbA1c throughout the study period, but body weight decreased (baseline 68.8 ± 13.2 kg vs. month 4 67.3 ± 13.1 kg;p < 0.001). Total daily insulin dose decreased after 4 months (baseline 24.4 ± 15.5 U/day vs. month 4 14.7 ± 9.2 U/day;p < 0.001), and there was no change in the frequency of hypoglycemic episodes. Analysis was conducted within sub-groups based on previous treatment modality. In the BOT group, HbA1c decreased from baseline after 2 months and body weight did not change throughout the study period. In both the basal-bolus insulin group and the pre-mixed insulin group, HbA1c remained steady throughout and there was a decrease in body weight. No change in the frequency of hypoglycemia was observed in any of the sub-groups. Conclusion: BPT in T2DM was associated with weight loss without changes in glycemic control over 4 months, suggesting that it may be an effective and safe therapy.

Neurotensin Receptor 1 (NTSR1) Overexpression in Breast Carcinomas Is Common and Independent of ER/PR/Her2 Expression

Neurotensin (NT) is a 13-amino acid peptide with trophic effects on some neoplasms. Its bioactivities are mainly mediated by neurotensin receptor 1 (NTSR1). Both NT and NTSR1 were found to be upregulated in breast cancer. NT/NTSR1 thus becomes a potential therapeutic target. We studied whether any correlation exists between the expression of NTSR1 in breast carcinomas and the expression of ER, PR, and Her2. A total 85 cases of invasive ductal (62) and lobular (23) breast carcinomas were studied. Based on their ER/PR profiles, the ductal carcinomas (DCs) were subcategorized into ER+/PR+ (21), ER+/PR﹣ (20), and ER﹣/PR﹣ (21). All of the lobular carcinomas (LCs) were ER+/PR+. 21.57% of all DCs and 5.56% of LCs were Her2 positive. 77.78% of ER﹣/PR﹣ DCs were also Her2 negative (triple negative). The expression of NTSR1 was detected by immunohistochemistry and was semiquantitated (as negative, 1+, 2+, 3+). Both 2+ and 3+ were collectively defined as overexpression. The expression of NTSR1 was weak and focal in non-neoplastic mammary epithelial cells. It is increased in 74.19% of DCs (80.95% in ER+/PR+, 75% in ER+/PR﹣, and 66.67% in ER﹣/PR﹣ group), and in 95.65% of LCs. The overexpression of NTSR1 is similar between ER+ DCs and ER﹣ DCs (75% vs 66.67%, p > 0.05) as well as between PR+ DCs and PR﹣ DCs (80.95% in ER+/PR+ DCs vs 75% in ER+/PR﹣ DCs, p > 0.05). And it was seen in 77.78% of Her2+ DCs, 78.38% of Her2﹣ DCs, 94.12% of Her2﹣ LCs, and 78.57% of triple negative DCs. Overall, NTSR1 is commonly overexpressed in both ductal and lobular breast carcinomas and is independent of the ER/PR/Her2 profiles of the tumors. The present data supports the potential benefit of developing NTSR1 blockers in the adjuvant therapy of breast carcinomas, particularly for those “triple negative” tumors.