Response to COVID-19 vaccine is reduced in patients with inflammatory bowel disease, but improved with additional dose

Background

Coronavirus disease 2019 (COVID-19) vaccination is recommended for patients with inflammatory bowel disease (IBD); however, suppressed immune responses have been reported for fully vaccinated patients under immunosuppressive therapy, mainly from Western countries. We prospectively analyzed antibody titers of IBD patients in Asia induced by two-dose and additional dose of messengerRNA COVID-19 vaccine.

Methods

After measuring high-affinity antibody titers, factors associated with antibody titers were identified by multiple regression analyses using the following covariates: sex, age (≥60 or <60 years), disease type (Crohn's disease or ulcerative colitis), vaccine type (BNT162b2 or mRNA-1273), time from second/third vaccination, molecular-targeted agent (anti-tumor necrosis factor [TNF] agents, ustekinumab, vedolizumab, tofacitinib, or no molecular-targeted agents), thiopurine, steroid, and 5-aminosalicylic acid.

Results

Among 409 patients analyzed, mean titer was 1316.7 U/mL (SD, 1799.3); 403 (98.5%) were judged to be seropositive (≥0.8 U/mL), and 389 (95.1%) had neutralizing antibodies (≥15 U/mL). After the third vaccination, mean titer raised up to 21 123.8 U/mL (SD, 23 474.5); all 179 were seropositive, and 178 (99.4%) had neutralizing antibodies. In 248 patients with genetic data, there was no difference in mean titer after two/third doses between carriers and non-carriers of HLA-A24 associated with severe disease during COVID-19 infection. A multiple regression analyses using covariates revealed that older age, vaccine type (BNT162b2), time from second/third dose, anti-TNF agent, tofacitinib, and thiopurine were independently associated with lower antibody titers.

Conclusions

Our findings further support the recommendation for COVID-19 vaccination in patients under immunosuppressive therapy, especially additional third dose for patients receiving anti-TNF agents and/or thiopurine or tofacitinib.     

异种基质金属蛋白酶-2肿瘤细胞疫苗的制备与功能研究

目的 构建异种基质金属蛋白酶-2(matrix metalloproteinase-2，MMP-2)肿瘤细胞疫苗，初步探讨疫苗的功能。方法 将鸡MMP-2转染到CT26细胞内制成肿瘤细胞疫苗，用MTT[四甲基偶氮唑盐，3-(4，5-dimetylthiazol-2-y1)-2，5-diphenyltetrazolium bromide3比色法检测转染后的细胞活性，在小鼠体内做疫苗的致瘤性实验和保护性实验。结果 用RT-PCR挑选出MMP-2表达量最高的细胞株作为研究对象。通过MTT比色法发现转染虽然增加了肿瘤细胞内MMP-2的表达，但是并没有改变肿瘤细胞的生长趋势。经过致瘤性实验和保护性实验，还初步发现疫苗可以起到抑制肿瘤生长和延长动物生存时间的作用。结论 异种基质金属蛋白酶-2肿瘤细胞疫苗构建成功，并且具有抗肿瘤的作用。     

Antitumor activity of aumolertinib,a third-generation EGFR tyrosine kinase inhibitor,in non-small-cell lung cancer harboring uncommon EGFR mutations

Uncommon epidermal growth factor receptor (EGFR) mutations account for 10%–20% of all EGFR mutations in non-small-cell lung cancer (NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors (TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC. Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models (V769-D770insASV and L861Q mutations) and a patient-derived xenografts model (H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.     

Enhancement of anti-tumor activity of hybrid peptide in conjugation with carboxymethyl dextran via disulfide linkers

To improve the anti-tumor activity of EGFR2R-lytic hybrid peptide, we prepared peptide-modified dextran conjugates with the disulfide bonds between thiolated carboxymethyl dextran (CMD-Cys) and cysteine-conjugated peptide (EGFR2R-lytic-Cys). In vitro release studies showed that the peptide was released from the CMD-s-s-peptide conjugate in a concentration-dependent manner in the presence of glutathione (GSH, 2 μM–2 mM). The CMD-s-s-peptide conjugate exhibited a similar cytotoxic activity with free peptide alone against human pancreatic cancer BxPC-3 cells in vitro. Furthermore, it was shown that the CMD-s-s-peptide conjugates were highly accumulated in tumor tissue in a mouse xenograft model using BxPC-3 cells, and the anti-tumor activity of the conjugate was more effective than that of the free peptide. In addition, the plasma concentrations of peptide were moderately increased and the elimination half-life of the peptide was prolonged after intravenous injection of CMD-s-s-peptide conjugates. These results demonstrated that the conjugate based on thiolated CMD polymer would be potentially useful carriers for the sustained release of the hybrid peptide in vivo.     

黄芪注射液对H22肝瘤小鼠的抑瘤作用及免疫功能的影响

目的:研究黄芪注射液对小鼠H22移植瘤的生长抑制作用及免疫功能的影响。方法:采用移植性H22肝癌小鼠模型,随机分为模型对照组,5-Fu处理组,黄芪注射液高、中、低剂量组。分别连续腹腔注射5-Fu(25 mg.kg-1),黄芪注射液(12 g.kg-1、8g.kg-1和4g.kg-1)10 d后,处死小鼠,计算抑瘤率、外周血白细胞数、脾指数、胸腺指数I、L-2、TNF-α等指标,分析黄芪注射液对小鼠H22移植瘤的生长抑制作用及免疫功能的影响。结果:与模型组相比,黄芪注射液低、中、高剂量组能显著减少移植瘤瘤重,其抑瘤率分别为18.23%,31.49%,43.09%,其中黄芪注射液高剂量组与CTX组抑瘤率比较,抑瘤率有显著性差异(P<0.05)。黄芪注射液各组可不同程度地升高荷瘤小鼠的白细胞数和胸腺指数、脾指数,且能提高荷瘤小鼠血清中IL-2和TNF-α的水平(P<0.05)。结论:黄芪注射液对小鼠H22移植瘤具有明显的抑瘤作用,其作用可能与增强机体的免疫功能有关。     

黄芪多糖免疫调节和抗肿瘤作用机制研究新进展

黄芪多糖（APS）作为黄芪的主要活性成分，因其在抗肿瘤过程中发挥了重要作用，日益受到关注。肿瘤相关中性粒细胞（TANs）在肿瘤的发生发展中的促瘤和抑瘤作用，已成为肿瘤学研究领域的热点。通过查询并总结APS对TANs抗肿瘤作用的促进及促肿瘤作用的抑制两方面的作用机制，对其相关研究进行综述，就抑制血管生产、蛋白质的水解、相关细胞因子的表达、调控细胞周期与细胞凋亡过程等方面进行分析，总结了相关中草药促进TANs发挥抗肿瘤作用的研究进展，为进一步明晰其相关的作用机制及发展现状提供理论支持。     

抗肿瘤药物的基因导向性个体化治疗

遗传药理学与药物基因组学的发展对于开展肿瘤的个体化治疗具有非常重要的意义。药物基因组学的发展使得多种影响肿瘤药物的遗传变异得以阐明，并进一步影响肿瘤治疗过程中的新药研发与个体化治疗。本文针对目前明确的能够影响抗肿瘤药物疗效的常见遗传变异进行综述，以促进抗肿瘤药物个体化治疗模式的推广。     

抗肿瘤药物的时辰药理学研究进展

恶性肿瘤是当前人类疾病中较难治愈且死亡率较高的疾病之一。目前临床应用的化疗药物在杀死肿瘤细胞的同时,也可对正常人体细胞造成损伤。针对抗肿瘤药物的时辰药理学研究成为目前研究的热点,以时辰疗法治疗肿瘤可提高患者的耐受剂量并降低毒副作用,本文就抗肿瘤药物的时辰药理学研究作一综述。     

丹参酮IIA的抗肿瘤药理作用及其纳米给药系统研究进展＊

近年来，肿瘤发病率不断攀升，化疗是目前临床治疗肿瘤的主要策略，但因多数化疗药物毒副作用大且容易造成化学耐药性，导致化疗效果并不理想。而传统中药凭借其多途径、多靶点、多通路的特点在抗肿瘤方面具有治疗温和不剧烈、毒副作用小等独特的优势。丹参酮IIA（Tanshinone IIA，TSA）作为丹参中提取的主要菲醌类衍生物，具有明显的抗肿瘤作用，具备被开发为毒性小、疗效好的新型抗肿瘤药物的条件。但因其难溶于水、半衰期短、生物利用度低等缺点极大程度上限制了其临床应用。利用纳米技术，可以改善丹参酮IIA的不足；构建中药纳米递药系统可以提高肿瘤组织靶向性来改善半衰期短、稳定性差等实际临床应用中的问题。本文主要综述丹参酮IIA的抗肿瘤机理及其纳米递药系统的研究进展，以期为丹参酮IIA的深入研究和临床应用提供参考。