Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes:A new horizon

Type 1 diabetes(T1D)is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels.However,this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells.Recent research has explored the potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)as a novel intervention to modify the disease course and delay the onset of T1D.GLP-1RAs are medications initially developed for treating type 2 diabetes.They exert their effects by enhancing glucose-dependent insulin secretion,suppressing glucagon secretion,and slowing gastric emptying.Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D.This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D,possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells.This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification,which should open new avenues for preventing and treating T1D,improving the quality of life and long-term outcomes for individuals at risk of T1D.

Efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in treatment of advanced gastric cancer or gastroesophageal junction cancer: A meta-analysis

BACKGROUND Faced with limited and inadequate treatment options for patients with advanced gastric cancer or gastroesophageal junction cancer(GC/GEJC), researchers have turned toward, with the support of promising clinical trials, anti-PD-1/anti-PD-L1 antibody therapy. But there are also different clinical trial results. To better assess its efficacy and safety, we integrated data from 13 eligible studies for a systematic review and meta-analysis.AIM To comprehensively evaluate the efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in the treatment of advanced GC/GEJC patients.METHODS PubMed, Web of Science, Cochrane Library,and EMBASE databases were searched to identify eligible articles with outcomes including objective response rate(ORR), disease control rate(DCR), overall survival(OS), progression-free survival(PFS), and adverse events(AEs) of anti-PD-1/anti-PD-L1 antibody therapy.RESULTS Our study encompassed a total of 13 trials totaling 1618 patients. The outcomes showed a pooled ORR and DCR of 15%(95% confidence interval [CI]: 14%-18%) and 40%(95%CI: 33%-46%), respectively. The pooled 6-mo OS and PFS were 54%(95%CI: 45%-64%) and 26%(95%CI: 20%-32%), respectively, and the 12-mo OS and PFS were 42%(95%CI: 21%-62%) and 11%(95%CI: 8%-13%), respectively. In addition, the incidence of any-grade AEs and grade ≥ 3 AEs was 64%(95%CI: 54%-73%) and 18%(95%CI: 16%-20%), respectively. Most importantly, PD-L1 positive patients exhibited a higher ORR rate than PD-L1 negative patients(odds ratio = 2.54, 95%CI: 1.56-4.15).CONCLUSION Anti-PD-1/anti-PD-L1 antibody therapy has shown promising anti-tumor efficacy with manageable AEs in advanced GC/GEJC patients, with PD-L1 overexpressing patients exhibiting a higher ORR. What is more, the clinical efficacy of anti-PD-1/PD-L1 combined with traditional chemotherapy drugs is even better, although the occurrence of AEs still causes considerate concerns.

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.

Long noncoding RNA steroid receptor RNA activator 1 inhibits proliferation and glycolysis of esophageal squamous cell carcinoma

BACKGROUND The clinical effects and detailed roles of long non-coding RNA(LncRNA)steroid receptor RNA activator 1(SRA1)in esophageal squamous cell carcinoma(ESCC)remain ambiguous.In the present study,the complementary sites between lncRNA SRA1,miRNA-363-5p,and phospholysine phosphohistidine inorganic pyrophosphate phosphatase(LHPP)predicted via bioinformatics analysis stimulated us to hypothesize that miRNA-363-5p/LHPP axis might be required for SRA1-mediated ESCC progression.AIM To investigate the molecular events of SRA1 in the malignant behavior in ESCC.METHODS Thirty-eight ESCC tissues and paired adjacent normal tissues were acquired.SRA1 expression was detected in ESCC tissues and cell lines using quantitative reverse transcription-polymerase chain reaction.Cell counting Kit-8 assay,transwell invasion assay,glycolysis assay,and xenograft tumor model were performed to address the malignant biological behaviors of ESCC cells after the introduction of SRA1.The t-test and theχ2 test were used for comparison between groups.Survival curve analysis was performed using the Kaplan-Meier method.RESULTS SRA1 downregulation was identified in ESCC.ESCC patients exhibiting a low SRA1 expression faced shorter overall survival than those with a high SRA1 expression.The introduction of SRA1 inhibited cell proliferation,glucose uptake,and lactate production in ESCC.In vivo,the growth of ESCC was hindered by SRA1 overexpression.Then,SRA1 overexpresses the LHPP by inhibiting miRNA-363-5p.Lastly,the introduction of small interfering RNA si-LHPP or miRNA-363-5p mimic could abrogate the inhibition roles triggered by SRA1.CONCLUSION SRA1 inhibits the oncogenicity of ESCC via miRNA-363-5p/LHPP axis.The SRA1/miRNA-363-5p/LHPP pathway may be a therapeutic target for ESCC.

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.

受体相互作用蛋白激酶1调节癌症进展和免疫反应的研究现状

受体相互作用蛋白激酶1(receptor-interacting protein kinase 1,RIPK1)是一种多结构域丝氨酸/苏氨酸蛋白激酶。它通过磷酸化特定的蛋白质,引起下游的信号转导和生物效应。近年来,随着对RIPK1的深入研究,学者发现其在自身免疫性疾病、神经退行性疾病,以及多种实体瘤和血液肿瘤中具有重要意义。一方面,RIPK1通过激活特定通路如核因子-κB(nuclear factor-κB,NF-κB)和丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)等促进细胞存活及炎症反应。另一方面,RIPK1通过与胱天蛋白酶-8(cysteinyl aspartate specific proteinase-8,caspase-8)作用促进凋亡,或与RIPK3和混合谱系激酶结构域样假激酶(mixed lineage kinase domain-like protein,MLKL)作用促进坏死性凋亡的发生。RIPK1作为上游信号在不同肿瘤患者中表达水平不同。其支架功能和激酶活性可以调节癌症进展,也可以启动机体适应性免疫,抑制肿瘤进展;此外,还能产生免疫抑制性肿瘤微环境而促进肿瘤的发展。其双重作用在调节癌症的发生、发展及机体免疫反应方面都有所展现,可以作为新的治疗靶点控制癌症进展。该文从RIPK1的结构入手,深入探讨其功能,特别是其在调节癌症进展和免疫反应方面的功能,为癌症靶向药物的开发提供新的思路。

Effects of AT1 receptor antagonist,Iosartan,on rat hepatic fibrosis induced by CCl_4

AIM To investigate effect of losartan,an AT1receptor antagonist,on hepatic fibrosis induced byCCl;and to determine whether or not AT1receptors are expressed on hepatic stellate cells,METHODS AND RESULTS Fifty male Sprague-Dawley rats,weighing（180±20）g,wererandomized into five groups（control group,modelgroup,and three losartan treated groups）,inwhich all rats were given the subcutaneousinjection of 40% CCl4（every 3 days for 6 weeks）except for rats of control group.Rats of losartan-treated groups were treated with losartan（20 mg/kg,10 mg/kg,5 mg/kg,daily gavage）,After 6weeks liver tissue and serum samples of all ratswere examined.Serum hyaluronic acid（HA）,procollagen typeⅢ（PCⅢ）were detected byradioimmunoassays,van Giesion collagen stainingwas used to evaluate the extracellular matrix of ratswith liver fibrosis.The expression of AT1receptors,transforming growth factor-beta（TGF-β）,and alpha-smooth muscle actin（a-SMA）inliver tissue were determined byimmunohistochemical techniques.Compared withmodel group,serum ALT and AST of losartan-treated groups were significantly reduced（t=4.20,P【0.01 and t=4.57,P【0.01）.Serum HAand PCⅢalso had significant differences（t=3.53,P【0.01 and t=2.20,P【0.05）.Thedegree of fibrosis was improved by losartan and correlated with the expressions of AT1 receptors,TGF-β,and α-SMA in liver tissue.CONCLUSION AT1 receptor antagonist,losartan,could limit the progression of the hepatic fibrosisinduced by CCl4.The mechanism may be related tothe decrease in the expression of AT1 receptorsand TGF-β,ameliorating the injury of hepatocytes;activation of local renin-angiotensin system mightrelate to hepatic fibrosis;and during progressionof fibrosis,activated hepatic stellate cells mightexpress AT1 receptors.

T cells expressing a LMP1-specific chimeric antigen receptor mediate antitumor effects against LMP1-positive nasopharyngeal carcinoma cells in vitro and in vivo

T cells modified with chimeric antigen receptor are an attractive strategy to treat Epstein-Barr virus（EBV） associated malignancies.The EBV latent membrane protein 1（LMP1） is a 66-KD integral membrane protein encoded by EBV that consists of transmembrane-spanning loops.Previously,we have identified a functional signal chain variable fragment（scFv） that specifically recognizes LMP1 through phage library screening.Here,we constructed a LMP1 specific chimeric antigen receptor containing anti-LMP1 scFv,the CD28 signalling domain,and the CD3ζchain（HELA/CAR）.We tested its functional ability to target LMP1 positive nasopharyngeal carcinoma cells.HELA/CAR cells were efficiently generated using lentivirus vector encoding the LMP1-specific chimeric antigen receptor to infect activated human CD3＋ T cells.The HELA/CAR T cells displayed LMP1 specific cytolytic action and produced IFN-γ and IL-2 in response to nasopharyngeal carcinoma cells overexpressing LMP1.To demonstrate in vivo anti-tumor activity,we tested the HELA/CAR T cells in a xenograft model using an LMP1 overexpressing tumor.Intratumoral injection of anti-LMP1 HELA/CAR-T cells significantly reduced tumor growth in vivo.These results show that targeting LMP1 using HELA/CAR cells could represent an alternative therapeutic approach for patients with EBV-positive cancers.

Medical therapy for clinical benign prostatic hyperplasia:α1 Antagonists,5α reductase inhibitors and their combination

Medical therapy for clinical benign prostatic hyperplasia(BPH)has advanced significantly in the last 2 decades.Many new a1 antagonists and 5a reductase inhibitors(5ARi)are now commercially available.The practicing urologist must decide on the most appropriate medication for his patients,taking into consideration various factors like efficacy,dosing regime,adverse effects,cost,patient’s socioeconomic background,expectations,drug availability and his own clinical experience.The use of combination therapy added further to the complexity in clinical judgment when prescribing.We highlight some of the key points in prescribing a1 antagonists,5ARi and their combination,based on our viewpoints and experience as urologists in an Asian clinical setting.

The human application of gene therapy to re-program T-cell specificity using chimeric antigen receptors

The adoptive transfer of T cells is a promising approach to treat cancers. Primary human T cells can be modified using viral and non-viral vectors to promote the specific targeting of cancer cells via the introduction of exogenous T-cell receptors(TCRs) or chimeric antigen receptors(CARs). This gene transfer displays the potential to increase the specificity and potency of the anticancer response while decreasing the systemic adverse effects that arise from conventional treatments that target both cancerous and healthy cells. This review highlights the generation of clinical-grade T cells expressing CARs for immunotherapy, the use of these cells to target B-cell malignancies and, particularly, the first clinical trials deploying the Sleeping Beauty gene transfer system, which engineers T cells to target CD19+ leukemia and non-Hodgkin's lymphoma.

双罐串联连续血液净化对慢性肾衰竭尿毒症患者血清可溶性转铁蛋白受体和人巨噬细胞趋化蛋白-1水平及生存质量的影响

目的:探讨双罐串联连续血液净化(CRRT)对慢性肾衰竭尿毒症患者血清可溶性转铁蛋白受体(sTfR)和人巨噬细胞趋化蛋白-1(MCP-1)水平及生存质量的影响。方法:选择2022年4月至2023年4月新疆医科大学第一附属医院行血液透析治疗的96例慢性肾衰竭尿毒症患者,随机分为单罐组(CRRT连续血液净化单个灌流器)和双罐串联组(CRRT连续血液净化2个灌流器串联),每组48例。分别于治疗前,治疗后2个月、半年及1年时检测两组患者血清sTfR和MCP-1水平,判断其治疗后皮肤瘙痒缓解程度;分别于治疗前及治疗后72h记录两组白细胞水平、急性生理与慢性健康量表(APACHEⅡ)评分情况。采用中文版欧洲五维量表(CEQ-5D-3L)、视觉模拟量表(VAS)评分,评估两组患者治疗前后生命质量。结果:两组治疗前血清sTfR水平比较差异无统计学意义(P>0.05)。治疗后2个月、半年及1年各时间点,双罐串联组血清sTfR水平均低于单罐组,差异有统计学意义(t=5.089、18.410、41.306,P<0.05);两组治疗前血清MCP-1水平比较,差异无统计学意义(P>0.05)。治疗后2个月、半年及1年各时间点,双罐串联组血清MCP-1水平均低于单罐组,差异有统计学意义(t=8.554、8.019、10.744,P<0.05);两组治疗后原有皮肤瘙痒程度均有所改善,但单罐组缓解程度明显低于双罐串联组,差异有统计学意义(x^(2)=8.540,P<0.05);两组治疗前白细胞、APACHEⅡ评分比较,差异无统计学意义(P>0.05),治疗后72h白细胞、APACHEⅡ评分均降低,且双罐串联组改善程度均优于单罐组,差异有统计学意义(t=5.549、14.781,P<0.05);两组治疗前血清CEQ-5D-3L评分比较,差异无统计学意义(P>0.05)。治疗后2个月、半年及1年各时间点,双罐串联组健康描述系统标准总分均低于单罐组,VAS评分高于单罐组,差异有统计学意义(t健康描述系统标准总分=4.744、5.103、9.418,tVAS评分=3.375、2.866、3.126,P<0.05)。结论:双罐串联连续血液净化可有效降低慢性肾衰竭尿毒症患者血清sTfR,MCP-1水平,缓解皮肤瘙痒程度,提高生存质量,同时还能有效降低白细胞水平,改善APACHEⅡ评分和血常规。

Targeting the inflammasome and adenosine type-3 receptors improves outcome of antibiotic therapy in murine anthrax

AIM:To establish whether activation of adenosine type-3 receptors(A3Rs)and inhibition of interleukin- 1β-induced inflammation is beneficial in combination with antibiotic therapy to increase survival of mice challenged with anthrax spores. METHODS:DBA/2 mice were challenged with Bacillus anthracis spores of the toxigenic Sterne strain 43F2. Survival of animals was monitored for 15 d.Ciprofloxacin treatment(50 mg/kg,once daily,intraperitoneally) was initiated at day+1 simultaneously with the ad- ministration of inhibitors,and continued for 10 d.Two doses(2.5 mg/kg and 12.5 mg/kg)of acetyl-tyrosylvalyl-alanyl-aspartyl-chloromethylketone(YVAD)and three doses(0.05,0.15 and 0.3 mg/kg)of 1-[2-Chloro- 6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1- deoxy-N-methyl-β-D-ribofuranuronamide(Cl-IB-MECA) were tested.Animals received YVAD on days 1-4,and Cl-IB-MECA on days 1-10 once daily,subcutaneously. Human lung epithelial cells in culture were challenged with spores or edema toxin and the effects of IB-MECAon phosphorylation of AKT and generation of cAMP were tested. RESULTS:We showed that the outcome of antibiotic treatment in a murine anthrax model could be substantially improved by co-administration of the caspase-1/4 inhibitor YVAD and the A3R agonist Cl-IB-MECA.Combination treatment with these substances and ciprofloxacin resulted in up to 90%synergistic protection.All untreated mice died,and antibiotic alone protected only 30% of animals.We conclude that both substances target the aberrant host signaling that underpins anthrax mortality. CONCLUSION:Our findings suggest new possibilities for combination therapy of anthrax with antibiotics,A3R agonists and caspase-1 inhibitors.

Chidamide and sintilimab combination in diffuse large B-cell lymphoma progressing after chimeric antigen receptor T therapy

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is curable with first-line chemoimmunotherapy but patients with relapsed/refractory(R/R)DLBCL still face a poor prognosis.For patients with R/R DLBCL,the complete response rate to traditional next-line therapy is only 7%and the median overall survival is 6.3 mo.Recently,CD19-targeting chimeric antigen receptor T cells(CAR-T)have shown promise in clinical trials.However,approximately 50%of patients treated with CAR-T cells ultimately progress and few salvage therapies are effective.CASE SUMMARY Here,we report on 7 patients with R/R DLBCL whose disease progressed after CAR-T infusion.They received a PD-1 inhibitor(sintilimab)and a histone deacetylase inhibitor(chidamide).Five of the 7 patients tolerated the treatment without any serious adverse events.Two patients discontinued the treatment due to lung infection and rash.At the 20-mo follow-up,the median overall survival of these 7 patients was 6 mo.Of note,there were 2 complete response rates(CRs)and 2 partial response rates(PRs)during this novel therapy,with an overall response rate(ORR)of 57.1%,and one patient had a durable CR that lasted at least 20 mo.CONCLUSION In conclusion,chidamide combined with sintilimab may be a choice for DLBCL patients progressing after CD19-targeting CAR-T therapy.

Inhibition of Osteoarthritis in Rats by Electroporation with Interleukin-1 Receptor Antagonist

Gene therapy constitutes a promising strategy for the treatment of osteoarthritis (OA). We assessed the use of electroporation (EP) of non-viral gene vectors, and compared its efficacy with that of adeno-associated virus (AAV) vectors. EP- and AAV-mediated delivery of human interleukin-1 receptor antagonist (hIL-1Ra) was localized performed in the joints of rats following induction of OA. mRNA levels for hIL-1Ra, IL-1β, TNF-α, MMP-13 and ADAMTS-4 in the cartilage and synovial tissues were analyzed. Structural analyses of the subchondral bone at the medial femoral condyle were performed by Micro-CT after treatment. Knee joint specimens were staining with hematoxylin and eosin and Saffron O. Induction of hIL-1Ra by both EP and AAV inhibited inflammatory-induced sub-chondral bone reconstruction, and effectively suppressed IL-1β activity, as evidenced by decreased expression of MMP-13 and ADAMTS-4. Histological analyses revealed significant protection of cartilage, proteoglycan by EP and AAV. hIL-1Ra expression was similar in both the EP and AAV groups. Notably, this gene is not easier degraded transduced by EP compared with AAV. Taken together, these results show that EP offers transfection efficiency comparable to that of AAV, with the potential for longer gene expression, making EP a promising candidate for efficient non-viral delivery of OA gene therapy.

MWA联合抗PD-1抗体治疗原发性肝癌患者疗效研究

目的探讨微波消融(MWA)联合抗细胞程序性死亡受体-1(PD-1)抗体治疗原发性肝癌(PLC)患者的疗效。方法2019年6月~2020年12月我院收治的PLC患者102例,被分为对照组51例和观察组51例,分别接受MWA治疗或在MWA治疗的基础上应用信迪利单抗治疗6个月。采用SF-36量表评估生活质量,使用流式细胞仪检测外周血淋巴细胞亚群。随访1年。结果观察组客观有效率(ORR)为51.0%,显著高于对照组的29.4%(P<0.05);治疗后,观察组身体机能、生理职能、躯体疼痛、总体健康、精力、社会功能、角色限制和精神健康评分显著高于对照组(P<0.05);观察组外周血CD4^(+)细胞百分比和CD4^(+)/CD8^(+)比值显著高于对照组(P<0.05),而CD4^(+)CD25^(+)FOXP3^(+)Treg细胞和CD8^(+)细胞百分比显著低于对照组(P<0.05);经Kaplan-Meier分析,观察组中位无进展生存率为9.7(95%CI:7.971~11.429)个月,对照组为7.8(95%CI:5.931~9.729)个月,观察组1 a生存率为58.8%,显著高于对照组的37.3%(P<0.05)。结论在MWA治疗的基础上联合抗PD-1抗体治疗PLC患者能提高疗效,可能与纠正了免疫功能紊乱有关。

SP/NK-1R系统在乳腺癌中的研究进展

近年来,尽管乳腺癌的治疗已取得诸多进展,但其发病率仍呈上升趋势,寻找新的药物靶点和生物标志物已成为研究热点。越来越多的临床研究开始关注肿瘤细胞与肿瘤微环境的相互作用,认为肿瘤微环境对恶性肿瘤的进展起着至关重要的作用。物质P(Substance P,SP)能够参与癌变过程,在维持肿瘤微环境中发挥着关键作用。NK-1受体(Neurokinin 1 receptor,NK-1R)在肿瘤细胞的细胞质中表达,与诸多肿瘤特征显著相关。SP通过其受体NK-1R诱导肿瘤细胞增殖、血管生成和迁移,并发挥抗凋亡作用。在未来的治疗方案中,能否应用NK-1R拮抗剂为乳腺癌的诊断与治疗提供更精准的靶点成为热点话题。本文就SP/NK-1R系统在乳腺癌中的研究状况进行综述。

调气法针刺联合加巴喷丁治疗带状疱疹后遗神经痛的疗效观察及对血清β-EP和NK-1水平的影响

目的 观察调气法针刺联合加巴喷丁治疗带状疱疹后遗神经痛(postherpetic neuralgia, PHN)的临床疗效及对患者血清β-内啡肽(beta endorphin, β-EP)、神经激肽1-受体(neurokinin-1 receptor, NK-1)和P物质(substance P, SP)水平的影响。方法 将102例PHN患者随机分为对照组及治疗组,每组51例。对照组给予单纯加巴喷丁治疗,治疗组给予调气法针刺联合加巴喷丁治疗。观察两组治疗前后视觉模拟疼痛量表(visual analog scale, VAS)、睡眠状况自评量表(self-rating scale of sleep, SRSS)、汉密顿焦虑量表(Hamilton anxiety scale, HAMA)、世界卫生组织生存质量量表(World Health Organization quality of life assessment,WHOQOL)及血清β-EP、NK-1和SP水平,并比较两组临床疗效。结果 治疗后,两组VAS、SRSS及HAMA评分均低于治疗前(P<0.05),且治疗组VAS、SRSS及HAMA评分低于对照组(P<0.05)。治疗后,两组WHOQOL各维度评分均高于治疗前(P<0.05),且治疗组均高于对照组(P<0.05)。治疗后,两组血清β-EP水平升高(P<0.05),血清NK-1和SP水平降低(P<0.05),且治疗组优于对照组(P<0.05)。治疗组的总有效率为94.1%,高于对照组的82.4%(P<0.05)。结论 调气法针刺联合加巴喷丁治疗PHN疗效较好,可有效减轻患者不适症状,提高生活质量,有效降低血清NK-1、SP水平,升高血清β-EP水平。

The role of intestinal flora on tumorigenesis,progression,and the efficacy of PD-1/PD-L1 antibodies in colorectal cancer

Intestinal flora affects the maturation of the host immune system,serves as a biomarker and efficacy predictor in the immunotherapy of several cancers,and has an important role in the development of colorectal cancer(CRC).Anti-PD-1/PD-L1 antibodies have shown satisfactory results in MSI-H/d MMR CRC but performed poorly in patients with MSS/p MMR CRC.In recent years an increasing number of studies have shown that intestinal flora has an important impact on anti-PD-1/PD-L1 antibody efficacy in CRC patients.Preclinical and clinical evidence have suggested that anti-PD-1/PD-L1 antibody efficacy can be improved by altering the composition of the intestinal flora in CRC.Herein,we summarize the studies related to the influence of intestinal flora on anti-PD-1/PD-L1 antibody efficacy in CRC and discuss the potential underlying mechanism(s).We have focused on the impact of the intestinal flora on the efficacy and safety of anti-PD-1/PD-L1 antibodies in CRC and how to better utilize the intestinal flora as an adjuvant to improve the efficacy of anti-PD-1/PD-L1 antibodies.In addition,we have provided a basis for the potential of the intestinal flora as a new treatment modality and indicator for determining patient prognosis.

分泌型PD-1抗体可提高c-Met CAR-T细胞对胰腺癌细胞的杀伤作用

目的设计并制备能够分泌PD-1抗体和靶向c-Met的CAR-T细胞,以消除肿瘤对CAR-T细胞的免疫抑制作用,从而提高CAR-T细胞对胰腺癌的治疗效果。方法采用Kaplan-Meier Plotter、GEPIA和Timer2.0生物信息学数据库,分析c-Met在胰腺癌中的表达、生存期及免疫浸润。免疫组化检测胰腺癌临床样本c-Met和PD-L1表达,流式细胞术验证胰腺癌细胞Aspc-1 c-Met和PD-L1表达通过基因编辑将PD-1分泌型抗体和HIS标签连接至2代c-Met CAR分子后,构建PD-1/c-Met CAR质粒并包被慢病毒,慢病毒感染至活化T细胞内,通过流式细胞技术检测CAR-T阳性率和细胞亚群;Western blotting检测分泌型PD-1抗体在细胞上清液中的存在;体外功能试验中,通过LDH释放实验检测CAR-T对靶细胞的杀伤效率,CCK-8检测靶细胞存在下PD-1抗体对CAR-T增殖的促进作用。ELISA检测PD-1/c-Met CAR-T和c-Met CAR-T活化后细胞因子的分泌量。结果生信分析结果显示,胰腺癌组织c-Met表达高于正常组织(P<0.01);c-Met表达水平与胰腺癌患者生存期呈负相关(P<0.01)。c-Met的表达可能与多种免疫细胞浸润成正相关。免疫组化结果显示,胰腺癌c-Met和PD-L1表达均高于癌旁组织(P<0.01);流式细胞术结果显示,Aspc-1细胞c-Met和PD-L1表达量为90.7%和57.7%,琼脂糖凝胶电泳显示成功制备四代PD-1/c-Met CAR分子;流式细胞术和Western blotting显示,成功构建PD-1/c-Met CAR-T且PD-1抗体可顺利分泌。体外功能验证中LDH结果显示,PD-1/c-Met CART对肿瘤细胞杀伤效率在效靶比为20:1时高于c-Met CAR-T(P<0.01);CCK-8实验结果显示,靶细胞刺激72 h后增殖效率高于c-Met CAR-T(P<0.01);ELISA结果显示,PD-1/c-Met CAR-T分泌的细胞因子IL-2和TNF-α高于c-Met CAR-T(P<0.01)。结论PD-1抗体分泌型c-Met CAR-T可成功构建,并在体外胰腺癌细胞上显示出优于c-Met CAR-T肿瘤杀伤效率和增殖效率。

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。