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.

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.

Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology

AIM:To assess human epidermal growth factor receptor-2 (HER2)-status in gastric cancer and matched lymph node metastases by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH).METHODS:120 cases of primary gastric carcinomas and 45 matched lymph node metastases from patients with full clinicopathological features were mounted onto multiple-punch and single-punch tissue microarrays,respectively,and examined for HER2 overexpression and gene amplification by IHC and CISH.RESULTS:Twenty-four tumors (20%) expressed HER2 immunohistochemically.An IHC score of ≥ 2+ was observed in 20 tumors (16.6%).HER2 amplification was detected by CISH in 19 tumors (15.8%) and in their matched lymph node metastases.A high concordancerate was found between HER2 positivity (as detected by IHC) and HER2 gene amplification (as detected by CISH),since 19 of the 20 IHC positive cases were amplified (95%).All amplified cases had 2+ or 3+ IHC results.Amplification was associated with intestinal phenotype (P < 0.05).No association with grading,staging or survival was found.CONCLUSION:In gastric cancer,HER2 amplification is the main mechanism for HER2 protein overexpression and is preserved in lymph node metastases.

High levels of serum platelet-derived growth factor-AA and human epidermal growth factor receptor-2 are predictors of colorectal cancer liver metastasis

AIM To develop predictive markers in blood for colorectal cancer liver metastasis.METHODS Twenty colorectal cancer patients were selected and divided into two groups. Group A consisted of 10 patients whose pathological TNM stage was ⅢC(T3-4N2M0), while another 10 patients with synchronous liver metastasis(TNM stage Ⅳ) were recruited for group B. During the surgical procedure, a 10-ml drainage vein(DV) blood sample was obtained from the DV of the tumor-bearing segment prior to the ligation of the DV. At the same time, a 10-ml peripheral vein(PV) blood sample was collected via peripheral venipuncture. The serum levels of 24 molecules that are potentially involved in the mechanism of liver metastasis in both DV blood and PV blood were analyzed by using high-throughput enzyme-linked immunosorbent assay technology.RESULTS Univariate analysis revealed that platelet-derivedgrowth factor AA(PDGFAA) in DV blood(d PDGFAA)(P = 0.001), PDGFAA in PV blood(p PDGFAA)(P = 0.007), and human epidermal growth factor receptor-2 in PV blood(p HER2)(P = 0.001), p MMP7(P = 0.028), pR ANTES(P = 0.013), and pE GF(P = 0.007) were significantly correlated with synchronous liver metastasis. Multivariate analysis identified d PDGFAA(HR = 1.001, P = 0.033) and p HER2(HR = 1.003, P = 0.019) as independent predictive factors for synchronous liver metastasis. Besides, high peripheral HER2 level may also be a risk factor for metachronous liver metastasis, although the difference did not reach statistical significance(P = 0.06). Significant correlations were found between paired DV and PV blood levels for PDGFAA(r = 0.794, P < 0.001), but not for HER2(r = 0.189, P = 0.424).CONCLUSION PDGFAA in tumor drainage and HER2 in PV blood may be useful predictive factors for synchronous liver metastasis of colorectal cancer.

Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer’s disease

Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease.Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease,there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways.This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial.In this review,the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed.Furthermore,their molecular mechanisms in neurodegeneration will be explained.Also,we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation.Finally,we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration.We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression.

黄芪多糖在Her-2阳性乳腺癌患者化疗中增效减毒的作用及其对血清Her-2-ECD、TAP和疗效的影响

目的:探讨黄芪多糖在人表皮生长因子受体-2(human epidermal growth factor receptor-2,Her-2)阳性乳腺癌患者化疗中增效减毒的作用及其对血清人表皮生长因子受体-2胞外段(human epidermal growth factor receptor-2-extracellular domain,Her-2-ECD)、肿瘤异常糖链糖蛋白(tumor abnormal protein,TAP)和疗效的影响。方法:选择2020年1月—2023年6月新余北湖医院收治的90例Her-2阳性乳腺癌患者作为研究对象,将患者随机分为对照组和观察组,各45例。两组均给予TCbHP(多西他赛+卡铂+曲妥珠单抗+帕妥珠单抗)方案治疗;观察组在此基础上给予注射用黄芪多糖治疗。比较两组治疗前后的中医症候积分、血清Her-2-ECD、TAP水平、免疫功能(CD4^(+)、CD8^(+))、白细胞(white blood cell,WBC)水平、乳腺癌患者的生活质量量表(functional assessment of cancer therapy-breast,FACT-B)评分、疗效及不良反应发生率。结果:治疗前,两组各项中医症候积分、Her-2-ECD、TAP、CD4^(+)、CD8^(+)、WBC、FACT-B评分比较,差异均无统计学意义(P>0.05)。治疗后,观察组各项中医症候评分、Her-2-ECD、TAP、CD8^(+)、FACT-B各项评分及不良反应发生率均低于对照组,CD4^(+)、WBC、总有效率均高于对照组,差异均有统计学意义(P<0.05)。结论:黄芪多糖能够改善Her-2阳性乳腺癌化疗患者的化疗效果,减轻化疗带来的毒性反应,提高患者的生活质量。

人脐静脉内皮细胞的分离培养和鉴定及酪氨酸激酶受体-2在其中的表达

目的分离和培养人脐静脉内皮细胞(HUVECs),对其进行鉴定,并探讨酪氨酸激酶受体-2(Tie-2)基因在HUVECs中的表达情况。方法用胰蛋白酶消化、分离HUVECs并对其进行培养,根据细胞生长特点、形态特征和Ⅷ因子免疫荧光组化技术对细胞进行鉴定。分别采用逆转录-聚合酶链反应(RT-PCR)和SABC免疫细胞化学染色对HUVECs中Tie-2mRNA和蛋白表达情况进行检测。结果原代培养的HUVECs约于24h完全贴壁,4～5d后融合成单层铺路石样结构。Ⅷ因子免疫荧光组化法证实细胞是HUVECs。RT-PCR检测到HUVECs中Tie-2mRNA条带明显,SABC免疫细胞组化法检测到Tie-2蛋白在HUVECs胞浆、核膜中呈强阳性表达,阳性率为85%以上。结论胰蛋白酶灌流消化法可获得高纯度的HUVECs,Tie-2在HUVECs中呈强阳性表达。

血清HER2 ECD+VEGF+HE4对乳腺癌术后复发转移的诊断价值

目的比较血清人类表皮生长因子受体2胞外片段(HER2 ECD)、人附睾蛋白4(HE4)、血管内皮细胞生长因子(VEGF)和HER2 ECD+VEGF+HE4在乳腺癌术后复发转移中的诊断价值,以期选择最佳的检测方法,提高检测乳腺癌术后复发转移的灵敏度。方法选取接受手术治疗的86例乳腺癌患者作为研究对象,其中,术后复发转移患者34例(复发组),术后未复发转移患者52例(未复发组);另选取同期体检的40例健康女性作为对照组。检测3组受试者的血清HER2 ECD、VEGF、HE4水平。以病理学诊断结果作为金标准,分析不同检测方法对乳腺癌术后复发转移的的诊断效能。结果复发组患者的血清HER2 ECD、VEGF、HE4水平均高于未复发组和对照组,差异均有统计学意义(P﹤0.05);未复发组患者的血清VEGF、HE4水平均高于对照组,差异均有统计学意义(P﹤0.05)。血清HER2 ECD+VEGF+HE4联合检测乳腺癌术后复发转移的灵敏度为88.24%(30/34),特异度为86.54%(45/52),漏诊率为11.76%(4/34),误诊率为13.46%(7/52)。结论血清HER2 ECD+VEGF+HE4联合检测较三者单独检测能够提高对乳腺癌术后复发转移诊断的灵敏度,具有较高的临床诊断价值。

RNA干扰酪氨酸激酶受体2对人脐静脉内皮细胞增殖的影响

目的研究抑制酪氨酸激酶受体2(Tie2)对内皮细胞凋亡和增殖活性的影响。方法采用RNA干扰技术,将含有Tie2基因的特异性短发夹状RNA(shRNA)片段的质粒转染入人脐静脉内皮细胞(HUVECs),采用实时定量逆转录聚合酶链反应和免疫印迹法检测细胞中Tie2 mRNA和蛋白表达的改变;噻唑蓝比色分析(MTT)法检测细胞的生长情况;显微镜下观察细胞凋亡情况。以转染了pGenesil-hk质粒组为阴性对照,未转染质粒组为空白对照。结果质粒转染入HUVECs后,实验组细胞中Tie2 mRNA和蛋白表达水平较阴性对照组和空白对照组下调,尤以转染后48 h Tie2的mRNA和蛋白表达水平下调更为明显(P<0.05)。MTT检测结果显示:实验组细胞的增殖活性受到明显抑制(P<0.05)。转染48 h后,实验组的细胞凋亡率明显高于两个对照组(P<0.05)。结论 RNA干扰技术沉默Tie2基因可致Tie2基因表达下调后诱导HUVECs凋亡,并抑制HUVECs的增殖。

Therapeutic options for HER-2 positive breast cancer: Perspectives and future directions

During the last 15 years we have witnessed an unprecedented expansion in the drugs developed to target human epidermal growth factor receptor-2(HER-2) positive breast cancer. Trastuzumab, pertuzumab, adotrastuzumab emtansine and lapatinib are currently food and drug administration(FDA)-approved for the treatment of breast cancer patients with HER-2 overexpressed. However, given the amount of information gathered from years of uninterrupted clinical research, it is essential to have periodic updates that succinctly recapitulate what we have learnt over these last years and help us to apply that information in our daily practice. This review will pursue that objective. We will summarize the most relevant and updated informationrelated to the state of the art management of HER-2 positive breast cancer in all the clinical scenarios including the adjuvant, neoadjuvant and metastatic settings. But we will also critically appraise that literature in order to highlight some key clinical concepts that should not be overlooked. Lastly, this review will also point out some of the most promising strategies that are currently being tested and may soon become available.

A Meta-Analysis of Lymphatic Vessel Invasion Correlated with Pathologic Factors in Invasive Breast Cancer

Objectives: The invasive breast cancer is divided into four clinical subtypes: Luminal A-like, Luminal B-like, HER-2 positive, and triple-negative according to the expression status of estrogen receptor (ER), progesterone receptor(PR), human epidermal growth factor receptor-2 (HER-2) and Ki-67. The prognosis and treatment strategy vary with subtypes. The current studies have reported the relation between lymphatic vessel invasion (LVI) and the expression status of ER, PR, HER-2, Ki-67 in invasive breast cancer, but the results were debatable. So the meta-analysis was conducted to confirm the relation between LVI and the four factors. Methods: Literature was searched by entering the terms: breast AND (neoplasm OR cancer OR carcinoma) AND (lymphovascular OR “lymph vessel” OR “lymphatic vessel” invasion OR carcinoma embolus) AND (ER OR estrogen receptor OR PR OR progesterone receptor OR HER-2 OR human epidermal growth factor receptor-2 OR Ki-67 OR clinicopathological) in Pubmed. The merged odds ratio (OR) and 95% confidence interval (CI) were estimated using fixed-effect model. Review Manager 5.2 was used to analysis the relation between LVI and the expression status of ER, PR, HER-2, Ki-67 in invasive breast cancer respectively. The fail-safe number was used to estimate publication bias. Results: The analysis included 5 studies, LVI positive rate was significant lower in ER positive, PR positive, HER-2 negative, low Ki-67 expression group statistically. The OR and 95% CI were 0.6(0.44 - 0.81), 0.64(0.43 - 0.95), 1.52(1.03 - 2.24), 5.29(1.53 - 18.35) respectively.Conclusions:?LVI was significantly correlated with the expression status of ER, PR, HER-2 and Ki-67 in invasive breast cancer. Furthermore, LVI was consistent with poor prognostic expression status of the four factors.

Correlation of expression of ER,PR and c-erbB-2 with ultrasonographic features in invasive ductal cancer of breast

Objective To analyze the relationship of the expression level of estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor-2(HER-2,c-erbB-2)of breast invasive ductal carcinoma(IDC)with ultrasonographic characteristics.Methods Totally 104 patients with IDCs confirmed pathologically were involved in this study.ER,PR and c-erbB-2 expression in the IDC specimens was determined by immunohistochemical staining technique.The correlation between the ultrasonographic features and the positive expression of ER,PR or c-erbB-2 was analyzed.Results The positive expression rate of ER and PR in the group with tumor spiculation sign and posterior acoustic attenuation was higher than that in the group without.The positive expression rate of ER differed significantly(P<0.05)while that of PR did not(P>0.05).The over-expression rate of c-erbB-2 in the group of microcalcification,sufficient blood flow and axillary lymph node metastasis was higher than that in the group of non-microcalcification,deficient blood flow or without axillary lymph node metastasis(P<0.05).The expression of ER,PR and c-erbB-2 was not related to the size of tumor(P>0.05).Conclusion The expression of ER and c-erbB-2 is closely related to the ultrasonographic characteristics of IDC,which may,to some extent,reflect the expression level of ER and c-erbB-2.

Effect of Herceptin combined with paclitaxel neoadjuvant chemotherapy on the proliferation viability of HER-2 positive breast cancer cell

Objective: To study the effect of Herceptin combined with paclitaxel neoadjuvant chemotherapy on the proliferation viability of HER-2 positive breast cancer cell. Methods:The patients who were diagnosed with breast cancer and received neoadjuvant chemotherapy in Ziyang First People's Hospital between February 2015 and October 2017 were selected and randomly divided into the experimental group who received Herceptin combined with docetaxel chemotherapy and the control group who received epirubicin combined with docetaxel chemotherapy. After chemotherapy ended, serum levels of tumor markers were measured;after surgical resection, the breast cancer lesions were collected to measure the mRNA expression of proliferation genes and tumor suppressor genes. Results: The differences in tumor marker levels as well as proliferation gene and tumor suppressor gene expression were statistically significant between the two groups;CA15-3, IGF-1, TSGF and TPS levels in serum as well as CyclinD1, PCNA, Bcl-2, Survivin and VEGF mRNA expression in breast cancer lesions of experimental group were lower than those of control group whereas PTEN, Bax, ARID1A, FasL and Caspase-3 mRNA expression in breast cancer lesions were higher than those of control group. Conclusion: Herceptin combined with paclitaxel neoadjuvant chemotherapy can more effectively inhibit the proliferation activity of HER-2 positive breast cancer cells than epirubicin combined with paclitaxel chemotherapy.

Effect of trastuzumab combined with paclitaxel neoadjuvant chemotherapy on the cell proliferation and invasion in HER-2-positive breast cancer lesions

Objective: To study the effect of trastuzumab combined with paclitaxel neoadjuvant chemotherapy on the cell proliferation and invasion in human epidermal growth factor receptor-2 (HER-2)-positive breast cancer lesions. Methods: Patients who were diagnosed with HER-2-positive breast cancer in the Central Hospital of Enshi Autonomous Prefecture Hubei Province between April 2015 and January 2017 were selected and randomly divided into two groups, the combined group received trastuzumab combined with paclitaxel chemotherapy, and the control group accepted paclitaxel chemotherapy. The surgically removed breast cancer lesions were collected to determine the expression of cell proliferation genes, cell invasion genes and angiogenesis molecules. Results: USP39, EphA2, NUAK1, Gab2, Raptor, ICAM-1, HIF-1α, VEGF, ANGPLT-2 and ANGPLT-4 mRNA expression in tumor lesion of combined group were significantly lower than those of control group while CCN5, ALEX1, ATG2B, ATG4D, E-cadherin and EBP50 mRNA expression were significantly higher than those of control group. Conclusion: Trastuzumab combined with paclitaxel neoadjuvant chemotherapy can inhibit the cell proliferation and invasion and decrease the angiogenesis in HER-2-positive breast cancer lesions.

Bronchiolar adenoma with unusual presentation:Two case reports

BACKGROUND The clinicopathological features,immunohistochemical characteristics,and genetic mutation profile of two unusual cases of distal bronchiolar adenoma are retrospectively analyzed and the relevant literature is reviewed.CASE SUMMARY Case 1 was a 63-year-old female patient who had a mixed ground-glass nodule,with mild cells in morphology,visible cilia,and bilayer structures in focal areas.Immunohistochemical staining for P63 and cytokeratin(CK)5/6 revealed the lack of a continuous bilayer structure in most areas,and no mutations were found in epidermal growth factor receptor,anaplastic lymphoma kinase,ROS1,Kirsten rat sarcoma,PIK3CA,BRAF,human epidermal growth factor receptor-2(HER2),RET,and neuroblastoma RAS genes.Case 2 was a 58-year-old female patient who presented with a solid nodule,in which most cells were observed to be medium sized,the nuclear chromatin was pale and homogeneous,local cells had atypia,and cilia were found locally.Immunohistochemical staining for P63 and CK5/6 showed no expression of these proteins in mild cell morphology whereas the heteromorphic cells showed a bilayer structure.The same nine genes as above were analyzed,and HER2 gene mutation was identified.CONCLUSION Some unresolved questions remain to be answered to determine whether the lesion is a benign adenoma or a part of the process of malignant transformation from benign adenoma of the bronchial epithelium.Furthermore,whether lesions with atypical bilayer structures are similar to atypical hyperplastic lesions of the breast remains to be elucidated.Moreover,clarity on whether these lesions can be called atypical bronchiolar adenoma and whether they are invasive precursor lesions is needed.Future studies should examine the diagnostic significance of HER2 gene mutation as a prognostic indicator.

表皮生长因子受体、人类表皮生长因子受体2、人类表皮生长因子受体3表达与非小细胞肺癌预后的关系

目的：探讨非小细胞肺癌（NSCLC）患者癌组织中表皮生长因子受体（EGFR）、人类表皮生长因子受体（HER）2、HER3蛋白的表达及其与临床病理因素的关系。方法采用MaxVision免疫组织化学两步法检测156例NSCLC患者癌组织中EGFR、HER2、HER3的表达，研究其与患者临床、病理特征间的关系，并回顾性分析蛋白表达与患者生存的关系。结果 EGFR、HER2、HER3蛋白在NSCLC中均存在过表达，过表达率分别为45.9%（73／156）、30.8%（49／156）和21.4%（37／156）。EGFR过表达多见于鳞状细胞癌、低分化、有淋巴结转移的患者，HER2过表达及三者共同过表达多见于晚期NSCLC患者，三者共同过表达多见于有淋巴结转移的患者。 EGFR、HER2、HER3过表达及三者共同过表达的患者生存率均低于低表达组。结论 EGFR、HER2、HER3过表达及三者共同过表达提示NSCLC患者预后不良。三项联合检测可能比单独检测能更好地预测NSCLC患者预后，指导临床治疗。

DEPTOR通过与ErbB2相互作用促进人牙周膜干细胞增殖和成骨分化

目的探讨含DEP结构域mTOR结合蛋白(DEPTOR)与人表皮生长因子受体2(ErbB2)的相互作用对人牙周膜干细胞(hPDLSCs)增殖和成骨分化能力的影响。方法收集联勤保障部队第九〇〇医院口腔科就诊的3例青少年患者正常人牙周膜组织,采用组织块培养方法分离hPDLSCs,并利用流式细胞术进行细胞鉴定。通过慢病毒将FLAG-DEP、FLAG-PDZ、FLAG-DEPTOR转染至P3代hPDLSCs,通过免疫共沉淀实验检测DEPTOR与ErbB2之间的结合关系。使用脂质体转染法将si-DEPTOR、si-ErbB2、si-NC转染至hPDLSCs,采用CCK8检测各组细胞的增殖能力;对细胞进行成骨诱导培养,采用茜素红染色观察细胞第21天成骨矿化形成情况,并用分光光度计法对矿化结节进行定量分析;利用RT-qPCR检测各组细胞Runt相关转录因子2(Runx2)、骨钙素(OCN)、1型胶原蛋白(COL1)、碱性磷酸酶(ALP)mRNA表达水平;采用Western blot检测各组细胞DEPTOR、Erb-b2受体酪氨酸激酶2(ErbB2)、磷酸化磷脂酰肌醇3激酶(p-PI3K)蛋白表达水平。多组间比较采用单因素方差分析,组间两两比较采用LSD-t检验。结果培养的P3代PDLSCs CD90和CD105表达呈阳性,CD34表达呈阴性。在过表达FLAG-DEPTOR和FLAG-DEP的免疫沉淀产物中可检测到ErbB2b蛋白。与si-NC比较,转染si-DEPTOR后DEPTOR蛋白表达水平(1.00±0.18比0.23±0.11)降低,差异有统计学意义(P<0.05);与si-NC比较,转染si-ErbB2和si-DEPTOR后ErbB2蛋白表达水平(1.00±0.07比0.50±0.10、0.23±0.05)均降低,差异有统计学意义(P<0.05)。与si-NC比较,转染si-DEPTOR、si-ERB2的细胞在第7天增殖能力(246.45±8.66比208.33±2.89、216.67±5.77)减弱,矿化结节形成OD值(1.23±0.09比0.78±0.06、0.64±0.09)减少,Runx2、OCN、COL1、ALP mRNA表达水平、p-PI3K蛋白表达水平(1.00±0.16比0.36±0.05、0.16±0.06;1.00±0.27比0.38±0.08、0.21±0.12;1.00±0.15比0.51±0.07、0.51±0.09;1.00±0.17比0.70±0.03、0.64±0.08;1.00±0.15比0.44±0.05、0.23±0.05)降低。结论在hPDLSCs中,DEPTOR的PDZ端与ErbB2结合。沉默DEPTOR能够降低其与ErbB2的相互作用,抑制PI3K信号通路,抑制细胞增殖和成骨分化。