PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer

BACKGROUND Patients with human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer have poor outcomes.Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer.Inetetamab is a novel anti-HER2 drug,and its efficacy and safety in gastric cancer have not yet been reported.AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin(SOX)regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer.METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroeso-phageal junction adenocarcinoma were randomly divided into two groups:One group received inetetamab combined with the SOX regimen,and the other group received trastuzumab combined with the SOX regimen.After 4-6 cycles,patients with stable disease received maintenance therapy.The primary endpoints were progression-free survival(PFS)and overall survival(OS),and the secondary endpoints were the objective response rate,disease control rate,and adverse events(AEs).RESULTS Thirty-seven patients completed the trial,with 18 patients in the inetetamab group and 19 patients in the trastuzumab group.In the inetetamab group,the median PFS was 8.5 months,whereas it was 7.3 months in the trastuzumab group(P=0.046);this difference was significant.The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months(P=0.33),and the objective response rate was 50%vs 42%(P=0.63),respectively;these differences were not significant.Common AEs included leukopenia,thrombocytopenia,nausea,and vomiting.The incidence rates of grade≥3 AEs were 56%in the inetetamab group and 47%in the trastuzumab group(P=0.63),with no significant difference.CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer,inetetamab and trastuzumab showed comparable efficacy.The inetetamab group showed superior PFS,and both groups had good safety.

BIRC3 induces the phosphoinositide 3-kinase-Akt pathway activation to promote trastuzumab resistance in human epidermal growth factor receptor 2-positive gastric cancer

BACKGROUND Trastuzumab-targeted therapy is currently the standard of care for advanced human epidermal growth factor receptor 2(HER2)-positive gastric cancer.However,the emergence of resistance to trastuzumab poses significant challenges.AIM To identify the key genes associated with trastuzumab resistance.These results provide a basis for the development of interventions to address drug resistance and improve patient outcomes.METHODS High-throughput sequencing and bioinformatics were used to identify the differentially expressed pivotal gene BIRC3 and delineate its potential function and pathway regulation.Tumor samples were collected from patients with HER2-positive gastric cancer to evaluate the correlation between BIRC3 expression and trastuzumab resistance.We established gastric cancer cell lines with both highly expressed and suppressed levels of BIRC3,followed by comprehensive in vitro and in vivo experiments to confirm the involvement of BIRC3 in trastuzumab resistance and to elucidate its underlying mechanisms.RESULTS In patients with HER2-positive gastric cancer,there is a significant correlation between elevated BIRC3 expression in tumor tissues and higher T stage,tumor node metastasis stage,as well as poor overall survival and progressionfree survival.BIRC3 is highly expressed in trastuzumab-resistant gastric cancer cell lines,where it inhibits tumor cell apoptosis and enhances trastuzumab resistance by promoting the phosphorylation and activation of the phosphoinositide 3-kinase-Akt(PI3K-AKT)pathway in HER2-positive gastric cancer cells,both in vivo and in vitro.CONCLUSION This study revealed a robust association between high BIRC3 expression and an unfavorable prognosis in patients with HER2-positive gastric cancer.Thus,the high expression of BIRC3 stimulated PI3K-AKT phosphorylation and activation,stimulating the proliferation of HER2-positive tumor cells and suppressing apoptosis,ultimately leading to trastuzumab resistance.

Inetetamab combined with tegafur as second-line treatment for human epidermal growth factor receptor-2-positive gastric cancer: A case report

BACKGROUND Human epidermal growth factor receptor-2(HER-2)plays a vital role in tumor cell proliferation and metastasis.However,the prognosis of HER2-positive gastric cancer is poor.Inetetamab,a novel anti-HER2 targeting drug independently developed in China,exhibits more potent antibody-dependent cell-mediated cytotoxicity than trastuzumab,which is administered as the first-line treatment for HER2-positive gastric cancer in combination with chemotherapy.In this case,the efficacy and safety of inetetamab combined with tegafur was investigated as a second-line treatment for HER2-positive gastric cancer.CASE SUMMARY A 52-year-old male patient with HER2-positive gastric cancer presented with abdominal distension,poor appetite,and fatigue two years after receiving six cycles of oxaliplatin combined with tegafur as first-line treatment after surgery,followed by tegafur monotherapy for six months.The patient was diagnosed with postoperative recurrence of gastric adenocarcinoma.He received 17 cycles of a combination of inetetamab,an innovative domestically developed anti-HER2 monoclonal antibody,and tegafur chemotherapy as the second-line treatment(inetetamab 200 mg on day 1,every 3 wk combined with tegafur twice daily on days 1–14,every 3 wk).Evaluation of the efficacy of the second-line treatment revealed that the patient achieved a stable condition and progression-free survival of 17 months.He tolerated the treatment well without exhibiting any grade 3-4 adverse events.CONCLUSION Inetetamab combined with chemotherapy for the treatment of metastatic HER2-positive gastric cancer demonstrates significant survival benefits and acceptable safety.

Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors

BACKGROUND Gastrointestinal stromal tumors(GISTs)are typical gastrointestinal tract neoplasms.Imatinib is the first-line therapy for GIST patients.Drug resistance limits the long-term effectiveness of imatinib.The regulatory effect of insulin-like growth factor 2(IGF2)has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis.AIM To further investigate the mechanism of IGF2 specific to GISTs.METHODS IGF2 was screened and analyzed using Gene Expression Omnibus(GEO:GSE225819)data.After IGF2 knockdown or overexpression by transfection,the phenotypes(proliferation,migration,invasion,apoptosis)of GIST cells were characterized by cell counting kit 8,Transwell,and flow cytometry assays.We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition(EMT)-associated proteins.We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST.RESULTS Data from the GEO indicated that IGF2 expression is high in GISTs,associated with liver metastasis,and closely related to drug resistance.GIST cells with high expression of IGF2 had increased proliferation and migration,invasiveness and EMT.Knockdown of IGF2 significantly inhibited those activities.In addition,OEIGF2 promoted GIST metastasis in vivo in nude mice.IGF2 activated IGF1R signaling in GIST cells,and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis.GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance.Moreover,2-deoxy-D-glucose(a glycolysis inhibitor)treatment reversed IGF2 overexpressionmediated imatinib resistance in GISTs.CONCLUSION IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.

Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Human epidermal growth factor receptor 2 expression level and combined positive score can evaluate efficacy of advanced gastric cancer

BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for high microsatellite instability.AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1(PD-1)inhibitor and chemotherapy.METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2(HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital,Chinese Academy of Medical Sciences between November 2020 and October 2022.All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.RESULTS As of July 1,2023,the objective response rate was 61.9%,and the disease control rate was 96.8%.The median progression-free survival(mPFS)for all patients was 6.3 months.The median overall survival was not achieved.Survival analysis showed that patients with a combined positive score(CPS)≥1 exhibited an extended trend in progression-free survival(PFS)when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment.PFS exhibited a trend for prolongation as the expression level of HER2 increased.Based on PFS,we divided patients into two groups:A treatment group with excellent efficacy and a treatment group with poor efficacy.The mPFS of the excellent efficacy group was 8 months,with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery.The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery.Using good/poor efficacy as the endpoint of our study,univariate analysis revealed that both CPS score(P=0.004)and HER2 expression level(P=0.015)were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC(AGC).Finally,multivariate analysis confirmed that CPS score was a significant influencing factor.CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.

Depletion of gut microbiota facilitates fibroblast growth factor 21-mediated protection against acute pancreatitis in diabetic mice

BACKGROUND Fibroblast growth factor 21(FGF21),primarily secreted by the pancreas,liver,and adipose tissues,plays a pivotal role in regulating glucose and lipid metabolism.Acute pancreatitis(AP)is a common inflammatory disease with specific clinical manifestations.Many patients with diabetes present with concurrent inflammatory symptoms.Diabetes exacerbates intestinal permeability and intestinal inflammation,thus leading to the progression to AP.Our previous study indicated that FGF21 significantly attenuated susceptibility to AP in mice.AIM To investigate the potential protective role of FGF21 against AP in diabetic mice.METHODS In the present study,a mouse model of AP was established in diabetic(db)/db diabetic mice through ceruletide injections.Thereafter,the protective effects of recombinant FGF21 protein against AP were evaluated,with an emphasis on examining serum amylase(AMS)levels and pancreatic and intestinal inflammatory cytokines[interleukin(IL)-6,tumor necrosis factor-alpha(TNF-),and intestinal IL-1β].Additionally,the impact of this treatment on the histopathologic changes of the pancreas and small intestinal was examined to elucidate the role of FGF21 in diabetic mice with AP.An antibiotic(Abx)cocktail was administered in combination with FGF21 therapy to investigate whether the effect of FGF21 on AP in diabetic mice with AP was mediated through the modulation of the gut microbiota. Subsequently, thePhylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), a bioinformaticssoftware package, was used to predict different pathways between the groups and to explore the potentialmechanisms by which the gut microbiota influenced the protective effect of FGF21.RESULTSThe results indicated that FGF21 notably diminished the levels of serum AMS (944.5 ± 15.9 vs 1732 ± 83.9, P < 0.01)and inflammatory factors including IL-6 (0.2400 ± 0.55 vs 1.233 ± 0.053, P < 0.01), TNF- (0.7067 ± 0.22 vs 1.433 ±0.051, P < 0.01), and IL-1β (1.377 ± 0.069 vs 0.3328 ± 0.02542, P < 0.01) in diabetic mice with AP. Moreover, notablesigns of recovery were observed in the pancreatic structure of the mice. The histologic evidence of inflammation inthe small intestine, including edema and villous damage, was significantly alleviated. FGF21 also significantlyaltered the composition of the gut microbiota, reestablishing the Bacteroidetes/Firmicutes ratio. Upon treatment withan Abx cocktail to deplete the gut microbiota, the FGF21 + Abx group showed lower levels of serum AMS (0.9328 ±0.075 vs 0.2249 ± 0.023, P < 0.01) and inflammatory factors (1.083 ± 0.12 vs 0.2799 ± 0.032, p < 0.01) than the FGF21group. Furthermore, the FGF21 + Abx group exhibited diminished injury to the pancreatic and small intestinaltissues, accompanied by a significant decrease in blood glucose levels (17.50 ± 1.1 vs 9.817 ± 0.69 mmol/L, P <0.001). These findings underscored the superior protective effects of the combination therapy involving an Abxcocktail with FGF21 over the FGF21 treatment alone in diabetic mice with AP. The gut microbiota compositionacross different groups was further characterized, and a differential expression analysis of gene functions wasundertaken using the PICRUSt2 prediction method. These findings suggested that FGF21 could potentially confertherapeutic effects on diabetic mice with AP by modulating the sulfate reduction I pathway and the superpathwayof n-acetylceramide degradation in the gut microbiota.CONCLUSION This study reveals the potential of FGF21 in improving pancreatic and intestinal damage recovery, reducing bloodglucose levels, and reshaping gut microbiota composition in diabetic mice with AP. Notably, the protective effectsof FGF21 are augmented when combined with the Abx cocktail.

血清miR-497-5p、FGF-2在阿尔茨海默病患者中的表达及相关性分析

目的探讨miR-497-5p、人成纤维细胞生长因子-2(fibroblast growth factor-2,FGF-2)在阿尔茨海默病(Alzheimer′s disease,AD)患者中的表达水平、诊断价值及两者的相关性。方法收集50例首诊AD患者和37例正常受试者(对照组)的临床资料,其中将AD患者分为轻度AD组18例、中度AD组18例和重度AD组14例,采用实时荧光定量聚合酶链反应(real-time quantitative polymerase chain reaction,RT-qPCR)检测miR-497-5p的表达水平,酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)检测FGF-2水平,采用简易精神状态量表(mini-mental state examination,MMSE)评估AD患者的认知功能,分析miR-497-5p与MMSE、FGF-2水平的相关性。采用受试者工作特征(receiver operator characteristic,ROC)曲线评价miR-497-5p,FGF-2水平对AD的诊断效能。结果与对照组和轻度AD组比较,中度、重度AD组患者miR-497-5p表达水平明显升高(P<0.01),FGF-2水平明显下降(P<0.01);AD组miR-497-5p与MMSE评分、FGF-2水平呈负相关(r分别为-0.724、-0.748,P<0.01);ROC曲线分析结果显示,miR-497-5p、FGF-2及两者联合指标诊断中度、重度AD及鉴别轻度和中度,轻度和重度AD时,均有较高的曲线下面积、敏感度和特异性,两者联合指标诊断及鉴别效能最优。结论中重度AD患者血清miR-497-5p上调,FGF-2水平下调,两者联合检测对中重度AD有一定的诊断价值,并提供一定的参考。

Roles of fibroblast growth factors in the treatment of diabetes

Diabetes affects about 422 million people worldwide,causing 1.5 million deaths each year.However,the incidence of diabetes is increasing,including several types of diabetes.Type 1 diabetes(5%-10%of diabetic cases)and type 2 diabetes(90%-95%of diabetic cases)are the main types of diabetes in the clinic.Accumulating evidence shows that the fibroblast growth factor(FGF)family plays important roles in many metabolic disorders,including type 1 and type 2 diabetes.FGF consists of 23 family members(FGF-1-23)in humans.Here,we review current findings of FGFs in the treatment of diabetes and management of diabetic complications.Some FGFs(e.g.,FGF-15,FGF-19,and FGF-21)have been broadly investigated in preclinical studies for the diagnosis and treatment of diabetes,and their therapeutic roles in diabetes are currently under investigation in clinical trials.Overall,the roles of FGFs in diabetes and diabetic complications are involved in numerous processes.First,FGF intervention can prevent high-fat diet-induced obesity and insulin resistance and reduce the levels of fasting blood glucose and triglycerides by regulating lipolysis in adipose tissues and hepatic glucose production.Second,modulation of FGF expression can inhibit renal and cardiac fibrosis by regulating the expression of extracellular matrix components,promote diabetic wound healing process and bone repair,and inhibit cancer cell proliferation and migration.Finally,FGFs can regulate the activation of glucoseexcited neurons and the expression of thermogenic genes.

硫酸氨基葡萄糖联合美洛昔康对膝骨关节炎患者血清FGF-2、TGF-β、IGF-1水平及膝关节运动功能的影响

目的 探究硫酸氨基葡萄糖联合美洛昔康对膝骨关节炎患者血清成纤维细胞生长因子-2(fibroblast growth factor-2, FGF-2)、转化生长因子-β(transforming growth factor-β, TGF-β)、胰岛素样生长因子-1(insulin-like growth factor-1, IGF-1)水平及膝关节运动功能的影响。方法 选择2021年6月-2023年6月就诊的膝骨关节炎114例,以随机数字表法分为联合组和美洛昔康组各57例。美洛昔康组予美洛昔康片治疗,联合组在美洛昔康组基础上加用硫酸氨基葡萄糖胶囊治疗,均治疗6周后观察疗效,比较2组治疗前、治疗6周后膝关节运动功能、炎性因子、生长因子水平及治疗期间安全性。结果 治疗6周后,联合组总有效率为91.23%(52/57)高于美洛昔康组的73.68%(42/57)(P<0.05)。治疗6周后,2组5次坐立试验、2.4 m起立行走试验所需时间短于治疗前,且联合组短于美洛昔康组(P<0.05,P<0.01);西安大略和麦克马斯特大学骨关节炎指数评分及血清前列腺素E2、白细胞介素-17、基质金属蛋白酶-3水平低于治疗前,且联合组低于美洛昔康组(P<0.05,P<0.01)。治疗6周后,2组血清FGF-2、TGF-β、IGF-1水平均高于治疗前,且联合组高于美洛昔康组(P<0.05,P<0.01)。2组治疗期间总不良反应发生率比较差异无统计学意义(P>0.05)。结论 硫酸氨基葡萄糖联合美洛昔康可有效升高膝骨关节炎患者血清FGF-2、TGF-β、IGF-1水平,延缓软骨退行性病变,控制机体炎症反应,进而有效改善患者膝关节运动功能,疗效显著,安全性良好。

血清CERP、SF、α-Klotho、FGF-23水平在2型糖尿病患者白蛋白尿进展中的预测价值

目的分析血清铜蓝蛋白(ceruloplasmin,CERP)、血清铁蛋白(serum ferritin,SF)、α-Klotho、成纤维细胞生长因子-23(fibroblast growth factor,FGF-23)在2型糖尿病患者白蛋白尿进展中的预测价值。方法选择2020年6月至2022年5月沭阳医院内分泌科因控制血糖重复收住院的120例2型糖尿病患者进行回顾性队列研究,将首次住院和第二次住院的资料分别作为基线资料和随访资料。根据基线中患者白蛋白尿情况将其分为3组:无白蛋白尿组、微量白蛋白尿组、大量白蛋白尿组,比较3组患者中CERP、SF、α-Klotho、FGF-23水平的差异;根据随访资料评价白蛋白尿进展的情况,比较白蛋白尿进展的患者与未进展的患者的基线临床资料及其CERP、SF、α-Klotho、FGF-23水平的差异,采用logistic回归分析白蛋白尿进展的影响因素,采用ROC曲线分析白蛋白尿进展的预测指标。结果随着2型糖尿病患者尿白蛋白水平升高,血清CERP、SF、FGF-23水平升高,而α-Klotho水平降低(P<0.05);白蛋白尿进展的2型糖尿病患者的糖尿病病程长于未进展的2型糖尿病患者,其二甲双胍及SGLT2抑制剂(SGLT2i)使用比例、α-Klotho水平均低于未进展的2型糖尿病患者,其高血压比例、FBG、UA、CERP、SF、FGF-23水平均高于未进展的2型糖尿病患者,差异有统计学意义(P<0.05);logistic回归分析显示CERP、SF、FGF-23水平升高是白蛋白尿进展的危险因素,而使用二甲双胍及SGLT2i以及α-Klotho水平的升高均是白蛋白尿进展的保护因素;ROC曲线分析显示首次住院时血清CERP、SF、α-Klotho、FGF-23的水平对白蛋白尿进展具有预测价值,logistic回归方程的联合指标预测尿白蛋白的灵敏度和特异性均优于单一指标。结论血清CERP、SF、FGF-23水平的升高及α-Klotho水平的降低与2型糖尿病患者中白蛋白尿进展有关,检测4项血清指标对白蛋白尿进展具有预测价值。

恩格列净联合rhBNP治疗射血分数降低型心力衰竭的疗效及对患者心功能和血清FGF-21、sVEGFR-2水平的影响

目的探究恩格列净联合重组人脑利钠肽(rhBNP)治疗射血分数降低型心力衰竭(HFrEF)的疗效及对患者心功能和血清成纤维细胞生长因子-21(FGF-21)、可溶性血管内皮生长因子受体-2(sVEGFR-2)水平的影响。方法前瞻性选取2022年1月至2023年3月山东第一医科大学附属人民医院心内科收治的100例HFrEF患者为研究对象。按照随机数字表法将其分为对照组和观察组,每组各50例。对照组予以常规强心、利尿治疗及静脉泵入rhBNP,观察组在对照组基础上加用恩格列净。比较两组治疗前、治疗3个月后糖化血红蛋白(HbA1c)、总胆固醇、低密度脂蛋白胆固醇(LDL-C)、6 min步行距离测试(6MWD)、N末端脑钠肽前体(NT-proBNP)、左室射血分数(LVEF)及血清FGF-21、sVEGFR-2水平,并记录两组主要心血管不良事件(MACE)发生情况。结果观察组临床总有效率为94.00%,高于对照组(80.00%),差异有统计学意义(P<0.05)。治疗3个月后,观察组HbA1c水平为(5.34±1.51)%,低于对照组[(6.03±1.65)%],差异有统计学意义(P<0.05);两组患者的总胆固醇、LDL-C水平比较,差异均无统计学意义(P>0.05)。治疗3个月后,观察组LVEF、6MWD水平分别为(38.52±7.24)%、(493.66±47.79)m,均高于对照组[(34.02±8.06)%、(455.92±50.25)m],NT-proBNP水平为(4386.75±875.89)pg/mL,低于对照组[(4326.04±843.66)pg/mL],差异均有统计学意义(P<0.05)。治疗3个月后,观察组血清FGF-21水平为(54.93±12.51)pg/mL,低于对照组[(61.50±15.66)pg/mL],sVEGFR-2水平为(8.96±1.95)ng/mL,高于对照组[(8.14±1.67)ng/mL],差异均有统计学意义(P<0.05)。观察组与对照组MACE总发生率分别为6.00%、16.00%,差异无统计学意义(P>0.05)。结论在rhBNP治疗HFrEF的基础上加用恩格列净可明显提高临床疗效,改善患者心功能,降低HbA1c、FGF-21水平,并提高sVEGFR-2水平可能是其增效的作用机制。

Tyrosine kinase inhibitors and human epidermal growth factor receptor-2 positive breast cancer

The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitors(TKIs)has been of particular interest in the treatment of human malignancies.This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.

Growth differentiation factor 11 promotes macrophage polarization towards M2 to attenuate myocardial infarction via inhibiting Notch1 signaling pathway

Background:Myocardial infarctions(MI)is a major threat to human health especially in people exposed to cold environment.The polarization of macrophages towards different functional phenotypes(M1 macrophages and M2 macrophages)is closely related to MI repairment.The growth differentiation factor 11(GDF11)has been reported to play a momentous role in inflammatory associated diseases.In this study,we examined the regulatory role of GDF11 in macrophage polarization and elucidated the underlying mechanisms in MI.Methods:In vivo,the mice model of MI was induced by permanent ligation of the left anterior descending coronary artery(LAD),and mice were randomly divided into the sham group,MI group,and MI+GDF11 group.The protective effect of GDF11 on myocardial infarction and its effect on macrophage polarization were verified by echocardiography,triphenyl tetrazolium chloride staining and immunofluorescence staining of heart tissue.In vitro,based on the RAW264.7 cell line,the effect of GDF11 in promoting macrophage polarization toward the M2 type by inhibiting the Notch1 Signaling pathway was validated by qRT-PCR,Western blot,and flow cytometry.Results:We found that GDF11 was significantly downregulated in the cardiac tissue of MI mice.And GDF11 supplementation can improve the cardiac function.Moreover,GDF11 could reduce the proportion of M1 macrophages and increase the accumulation of M2 macrophages in the heart tissue of MI mice.Furthermore,the cardioprotective effect of GDF11 on MI mice was weakened after macrophage clearance.At the cellular level,application of GDF11 could inhibit the expression of M1 macrophage(classically activated macrophage)markers iNOS,interleukin(IL)-1β,and IL-6 in a dose-dependent manner.In contrast,GDF11 significantly increased the level of M2 macrophage markers including IL-10,CD206,arginase 1(Arg1),and vascular endothelial growth factor(VEGF).Interestingly,GDF11 could promote M1 macrophages polarizing to M2 macrophages.At the molecular level,GDF11 significantly down-regulated the Notch1 signaling pathway,the activation of which has been demonstrated to promote M1 polarization in macrophages.Conclusions:GDF11 promoted macrophage polarization towards M2 to attenuate myocardial infarction via inhibiting Notch1 signaling pathway.

基于心功能及IGFBP7、sST2、CGRP、ET分析沙库巴曲缬沙坦在治疗冠心病合并慢性心力衰竭中的应用效果

目的 分析冠心病(CHD)合并慢性心力衰竭(CHF)患者应用沙库巴曲缬沙坦治疗的效果。方法 选择2020年1月至2023年1月邯郸市第四医院收治的86例CHD合并CHF患者,以随机数字表法将其分为对照组和试验组各43例。两组CHD治疗均应用硝酸酯类、他汀类及抗血小板药物,对照组CHF治疗应用坎地沙坦酯片、醛固酮受体拮抗剂及β受体阻滞剂,试验组治疗则将对照组中的坎地沙坦酯片替换为沙库巴曲缬沙坦钠片。比较两组疗效、不良反应、心功能指标[左室短轴缩短率(LVFS)、左室射血分数(LVEF)、6min步行距离(6 MWD)]、心室重构指标[Ⅲ型胶原前肽(PⅢP)、层粘蛋白(LN)、基质金属蛋白酶-9(MMP-9)]、心肌损伤和血管内皮功能相关指标[胰岛素样生长因子结合蛋白7(IGFBP7)、可溶性生长刺激表达基因2(sST2)、降钙素基因相关肽(CGRP)、内皮素(ET)]。结果与对照组比,试验组治疗3个月后的总有效率更高,差异有统计学意义(P<0.05)。两组治疗3个月后的LVFS、LVEF、6 MWD、IGFBP7、CGRP与治疗前比升高,且试验组与对照组比更高,差异有统计学意义(P<0.05);PⅢP、LN、MMP-9、sST2、ET降低,试验组与对照组比更低,差异有统计学意义(P<0.05)。两组不良反应总发生率对比差异无统计学意义(P>0.05)。结论 沙库巴曲缬沙坦可有效调节CHD合并CHF患者IGFBP7、sST2、CGRP、ET,改善血管内皮功能、心肌损伤、心室重构及心功能,进而可提高疗效,且具有良好的安全性。

血清FGF2和FGFR1对子痫前期患者不良妊娠结局的预测价值

目的 探讨血清成纤维细胞生长因子2(FGF2)和成纤维细胞生长因子受体1(FGFR1)与子痫前期(PE)患者妊娠结局的关系。方法 选取2021年1月—2022年12月河南省妇幼保健院PE患者82例(PE组)和健康孕妇82名(健康对照组)。收集所有研究对象的临床资料,并检测血清FGF2和FGFR1水平。根据PE患者的妊娠结局分为结局良好组(44例)和结局不良组(38例)。采用Pearson相关分析评估PE患者血清FGF2与FGFR1的相关性。采用Logistic回归分析评估PE患者发生不良妊娠结局的影响因素。采用受试者工作特征(ROC)曲线评价血清FGF2和FGFR1判断PE患者发生不良妊娠结局的效能。结果 PE组血清FGF2和FGFR1水平均低于健康对照组(P<0.05)。结局不良组血清FGF2和FGFR1水平均低于结局良好组(P<0.05),早发型PE和重度PE所占比例高于结局良好组(P<0.05),其他临床资料2个组之间差异均无统计学意义(P>0.05)。PE患者血清FGF2与FGFR1呈正相关(r=0.524,P<0.05)。早发型PE、重度PE是PE患者发生不良妊娠结局的危险因素[比值比(OR)值分别为3.682、4.029,95%可信区间(CI)分别为1.054~12.858、1.086~14.951,P<0.05],FGF2、FGFR1升高为保护因素(OR值分别为0.491、0.586,95%CI分别为0.293~0.822、0.382~0.898,P<0.05)。血清FGF2、FGFR1单项检测和联合检测判断PE患者发生不良妊娠结局的曲线下面积(AUC)分别为0.81、0.82、0.92。结论 PE患者血清FGF2和FGFR1水平显著降低,2项指标联合检测对PE患者发生不良妊娠结局有较高的预测效能。

入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ水平与CHB肝纤维化严重程度的相关性及对疾病预后的预测价值

目的探讨入院时血清转化生长因子-β1(TGF-β1)、Smad同源蛋白2(Smad2)、Smad同源蛋白3(Smad3)及透明质酸(HA)、Ⅲ型前胶原(PCⅢ)、层黏连蛋白(LN)、Ⅳ型胶原(CⅣ)水平与慢性乙型肝炎(CHB)肝纤维化严重程度的相关性及联合检测对疾病预后的预测价值。方法选取河南省中医院2021年3月至2022年3月收治的78例CHB肝纤维化患者作为研究组,选择同期78名健康体检者作为对照组。比较研究组和对照组及不同肝纤维化分期、不同炎症活动分级CHB肝纤维化患者入院时血清TGF-β1、Smad2、Smad3、HA、PCⅢ、LN、CⅣ水平;分析入院时血清TGF-β1、Smad2、Smad3、HA、PCⅢ、LN、CⅣ水平与肝纤维化分期、炎症活动分级的相关性。CHB肝纤维化患者治疗3个月后,根据患者预后分为预后良好和预后不良亚组,比较预后良好和预后不良患者入院时血清TGF-β1、Smad2、Smad3、HA、PCⅢ、LN、CⅣ水平;分析入院时血清TGF-β1、Smad2、Smad3、HA、PCⅢ、LN、CⅣ水平联合检测对CHB肝纤维化患者预后不良的预测价值。结果研究组入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ高于对照组(P<0.05);不同肝纤维化分期、炎症活动分级CHB肝纤维化患者入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ比较:S1<S2<S3<S4、G1<G2<G3<G4,差异有统计学意义(P<0.05);入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ水平与肝纤维化分期、炎症活动分级均呈正相关(P<0.05)。预后良好患者入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ水平均低于预后不良患者(P<0.05);入院时血清TGF-β1、Smad2、Smad3、HA、LN、PCⅢ、CⅣ水平联合预测肝纤维化患者预后不良的曲线下面积(AUC)优于各指标单一检测(P<0.05)。结论CHB肝纤维化患者入院时血清TGF-β1、Smad2、Smad3、HA、PCⅢ、LN、CⅣ水平均呈现高表达,且与肝纤维化分期、炎症活动分级密切相关,其联合检测对CHB肝纤维化患者预后有较高的预测价值,可用于评估CHB肝纤维化患者病情严重程度和预后,为制定针对性治疗措施提供参考。

PCNA、Bcl-2及EGFR在喉癌组织中的表达及与临床病理特征、生存的关系

目的探讨增殖细胞核抗原(PCNA)、B淋巴细胞瘤-2(Bcl-2)及表皮生长因子受体(EGFR)在喉癌组织中的表达及与临床病理特征、生存的关系。方法选取2017年3月—2020年1月在苏州大学附属第一医院因喉癌行手术治疗的92例患者的喉癌组织及对应癌旁组织标本。检测癌组织与癌旁组织PCNA mRNA、Bcl-2mRNA、EGFR mRNA相对表达量,多元线性回归分析其癌组织表达与临床病理特征的关系。随访3年,采用Kaplain-Maier曲线分析不同PCNA、Bcl-2、EGFR表达水平患者生存情况差异。结果癌组织PCNA mRNA、Bcl-2 mRNA、EGFR mRNA相对表达量高于癌旁组织(P<0.05)。不同年龄、肿瘤部位患者PCNA mRNA、Bcl-2 mRNA、EGFR mRNA相对表达量比较,差异无统计学意义(P>0.05);低分化,临床分期Ⅲ、Ⅳ期及淋巴结转移患者PCNA mRNA、Bcl-2 mRNA、EGFR mRNA相对表达量分别高于中、高分化,临床分期Ⅰ、Ⅱ期,无淋巴结转移患者(P<0.05)。多元线性回归分析结果显示,肿瘤分化程度、临床分期、淋巴结转移是喉癌组织PCNA mRNA、Bcl-2 mRNA、EGFR mRNA表达的影响因素。Kaplain-Maier曲线分析结果显示,PCNA mRNA高表达患者3年无进展生存率、总生存率分别为59.57%和70.21%,低于低表达患者的80.00%和88.89%(P<0.05);Bcl-2 mRNA高表达患者3年无进展生存率、总生存率分别为60.78%和70.59%,低于低表达患者的80.49%和90.24%(P<0.05);EGFR mRNA高表达患者3年无进展生存率、总生存率分别为59.09%和70.45%,低于低表达患者的79.17%、87.50%(P<0.05)。结论喉癌组织PCNA、Bcl-2、EGFR呈高表达,且其高表达状态与肿瘤分期高、分化程度低、淋巴结转移有关,PCNA、Bcl-2、EGFR表达水平可在一定程度上反映患者预后。

FGF2和BMP-2对Ⅲ、Ⅳ型慢性骨髓炎患者病灶清除联合封闭负压引流治疗预后的预测价值

目的探讨成纤维细胞生长因子2(FGF2)和骨形态发生蛋白-2(BMP-2)对Ⅲ、Ⅳ型慢性骨髓炎患者病灶清除联合封闭负压引流治疗预后的预测价值。方法前瞻性选取2020年1月—2021年12月在新疆医科大学第一附属医院住院治疗的105例Ⅲ、Ⅳ型慢性骨髓炎患者作为研究对象,均接受病灶清除联合封闭负压引流治疗,按不同治疗预后分为疗效好组75例(71.4%)和疗效差组30例(28.6%)。比较两组患者的临床资料、血清炎症因子、FGF2及BMP-2表达水平;采用多因素Logistic回归分析影响患者预后的独立危险因素,分析FGF2及BMP-2与预后的关系;构建相关列线图模型,绘制受试者工作特征(ROC)曲线和决策曲线,分析FGF2、BMP-2及联合预测模型的预测效能和净收益率。结果疗效差组Ⅳ型Cierny-Mader分型及窦道形成患者占比高于疗效好组(P<0.05)。疗效差组患者术前红细胞沉降率(ESR)、C反应蛋白(CRP)及肿瘤坏死因子-α(TNF-α)水平均高于疗效好组(P<0.05),疗效差组患者术前FGF2及BMP-2水平均低于疗效好组(P<0.05)。多因素Logistic回归分析结果显示,Cierny-Mader分型[O^R=5.036(95%CI:1.369,9.894)]、窦道形成[O^R=2.987(95%CI:1.156,7.247)]、FGF2[O^R=0.446(95%CI:0.129,0.735)]和BMP-2[O^R=0.485(95%CI:0.212,0.738)]为影响Ⅲ、Ⅳ型慢性骨髓炎患者预后的危险因素(P<0.05)。基于FGF2、BMP-2构建预测预后的列线图模型,校准曲线显示,Ⅲ、Ⅳ型慢性骨髓炎患者治疗疗效的预测值与实际观测值十分接近;ROC曲线分析结果显示,Cierny-Mader分型、窦道形成、FGF2及BMP-2预测预后的曲线下面积分别为0.783(95%CI:0.754,0.875)、0.752(95%CI:0.761,0.893)、0.823(95%CI:0.789,0.885)及0.811(95%CI:0.797,0.875),FGF2及BMP-2的最佳截断值分别为18.9 ng/L和113.5 ng/L,4者联合预测的曲线下面积为0.952(95%CI:0.896,0.991);决策曲线分析结果显示,Cierny-Mader分型、窦道形成、FGF2及BMP-2预测预后均具有良好的净收益率,并且联合预测的总体净收益率高于单一指标。结论基于Cierny-Mader分型、窦道形成、FGF2及BMP-24个指标构建的列线图模型能准确预测Ⅲ、Ⅳ型慢性骨髓炎患者病灶清除联合封闭负压引流治疗预后。