Breast Cancer Vaccine Containing a Novel Toll-like Receptor 7 Agonist and an Aluminum Adjuvant Exerts Antitumor Effects

Mucin 1 (MUC1) has received increasing attention due to its high expression in breast cancer, in which MUC1 acts as a cancer antigen. Our group has been committed to the development of small-molecule TLR7 (Toll-like receptor 7) agonists, which have been widely investigated in the field of tumor immunotherapy. In the present study, we constructed a novel tumor vaccine (SZU251 + MUC1 + Al) containing MUC1 and two types of adjuvants: a TLR7 agonist (SZU251) and an aluminum adjuvant (Al). Immunostimulatory responses were first verified in vitro, where the vaccine promoted the release of cytokines and the expression of costimulatory molecules in mouse BMDCs (bone marrow dendritic cells) and spleen lymphocytes. Then, we demonstrated that SZU251 + MUC1 + Al was effective and safe against a tumor expressing the MUC1 antigen in both prophylactic and therapeutic schedules in vivo. The immune responses in vivo were attributed to the increase in specific humoral and cellular immunity, including antibody titers, CD4⁺, CD8⁺ and activated CD8⁺ T cells. Therefore, our vaccine candidate may have beneficial effects in the prevention and treatment of breast cancer patients.     

Disease Recurrence during Adjuvant Immune Checkpoint Inhibitor Treatment in Metastatic Melanoma: Clinical,Laboratory, and Radiological Characteristics in Patients from a Single Tertiary Referral Center

Despite the dramatic improvements in recurrence-free survival in patients with metastatic melanoma treated with immune checkpoint inhibitors (ICI), a number of patients develop metastases during adjuvant therapy. It is not currently possible to predict which patients are most likely to develop disease recurrence due to a lack of reliable biomarkers. Thus, we retrospectively analyzed the case records of all patients who commenced adjuvant ICI therapy between January 2018 and December 2021 in a single university skin cancer center (n = 46) (i) to determine the rates of disease recurrence, (ii) to examine the utility of established markers, and (iii) to examine whether re-challenge with immunotherapy resulted in clinical response. Twelve out of forty-six (26%) patients developed a relapse on adjuvant immunotherapy in our cohort, and the median time to relapse was 139 days. Adjuvant immunotherapy was continued in three patients. Of the twelve patients who developed recurrence during adjuvant immunotherapy, seven had further disease recurrence within the observation period, with a median time of 112 days after the first progress. There was no significant difference comparing early recurrence (<180 days after initiation) on adjuvant immunotherapy to late recurrence (>180 days after initiation) on adjuvant immunotherapy. Classical tumor markers, including serum lactate dehydrogenase (LDH) and S-100, were unreliable for the detection of disease recurrence. Baseline lymphocyte and eosinophil counts and those during immunotherapy were not associated with disease recurrence. Interestingly, patients with NRAS mutations were disproportionately represented (60%) in the patients who developed disease recurrence, suggesting that these patients should be closely monitored during adjuvant therapy.     

Landscape of Genomic Alterations and PD-L1 Expression in Early-Stage Non-Small-Cell Lung Cancer (NSCLC)—A Single Center,Retrospective Observational Study

Precision oncology and immunotherapy have revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). Emerging studies show that targeted therapies are also beneficial for patients with driver alterations such as epidermal growth factor receptor (EGFR) mutations in early-stage NSCLC (stages I–IIIA). Furthermore, patients with elevated programmed death-ligand 1 (PD-L1) expression appear to respond favorably to adjuvant immunotherapy. To determine the frequency of genomic alterations and PD-L1 status in early-stage NSCLC, we retrospectively analyzed data from 2066 unselected, single-center patients with NSCLC diagnosed using next-generation sequencing and immunohistochemistry. Nine-hundred and sixty-two patients (46.9%) presented with early-stage NSCLC. Of these, 37.0% had genomic alterations for which targeted therapies have already been approved for advanced NSCLC. The frequencies of driver mutations in the early stages were equivalent to those in advanced stages, i.e., the rates of EGFR mutations in adenocarcinomas were 12.7% (72/567) and 12.0% (78/650) in early and advanced NSCLC, respectively (p = 0778). In addition, 46.3% of early-stage NSCLC cases were PD-L1-positive, with a tumor proportion score (TPS) of ≥1%. With comparable frequencies of driver mutations in early and advanced NSCLC and PD-L1 overexpression in nearly half of patients with early-stage NSCLC, a broad spectrum of biomarkers for adjuvant and neoadjuvant therapies is available, and several are currently being investigated in clinical trials.     

Mucosal Adjuvants Delivered by a Mucoadhesive Patch for Sublingual Administration of Subunit Vaccines

Among mucosal administration routes for vaccines, the sublingual route has been proven capable of inducing a potent systemic and mucosal immune response. However, the absence of a simple and compliant delivery system and the lack of robust mucosal adjuvants impede the development of sublingual vaccines. Here, we describe a mucoadhesive patch made of a layer-by-layer assembly of polysaccharides, chitosan, and hyaluronic acid. The mucoadhesive patch was covered by adjuvanted nanoparticles carrying viral proteins. We showed that the nanoparticles effectively cross the outer layers of the sublingual mucosa to reach the epithelium. Furthermore, the encapsulated adjuvants, 3M-052 and mifamurtide, targeting toll-like receptor (TLR) 7/8 and nucleotide-binding oligomerization domain-2 (NOD2), respectively, remain fully active after encapsulation into nanoparticles and exhibit a cytokine/chemokine signature similar to the mucosal gold-standard adjuvant, the cholera toxin. However, the particulate adjuvants induced more moderate levels of proinflammatory interleukin (IL)-6 and keratinocyte chemoattractant (KC), suggesting a controlled activation of the innate immune response.     

农药助剂用有机硅表面活性剂

综述了农药助剂用有机硅表面活性剂的化学结构及其特性和功效，在农业中的应用等。分析了它们的使用限制因素、研究方向及应用前景。     

Bacterium‐Mimicking Vector with Enhanced Adjuvanticity for Cancer Immunotherapy and Minimized Toxicity

Bacteria are utilized as adjuvants for anticancer immunotherapy. However, immunotherapy with bacteria or their extracts is limited due to their toxicity. On the basis of the innate molecular interactions of foreign molecules from the bacterial components with the host pattern recognition receptors (PRRs), a synthetic adjuvant vector morphologically mimicking the bacterium is engineered, which comprises an optimal combination of components derived from bacterial cell wall, flagellum, and nucleoid. The bacterium‐mimicking vectors (BMVs) cooperatively trigger multiple signaling pathways of PRRs and display superior antitumor therapeutic and prophylactic effects to either that of the reported synthetic or bacterium‐derived adjuvant. Significantly, BMVs improve the efficacy of photothermal ablation therapy to eradicate 50% of large established tumor in mice that completely reject tumor rechallenge. The synthetic BMVs with the detoxified and controllable composition exhibit minimized toxicity. Such a bacterium‐mimicking engineering strategy provides a rational approach to select pathogen‐associated molecular patterns, which drives the desired antitumor immune response. The engineered BMVs offer a promising alternative to the bacterial adjuvant for cancer immunotherapy.     

Viromimetic STING Agonist‐Loaded Hollow Polymeric Nanoparticles for Safe and Effective Vaccination against Middle East Respiratory Syndrome Coronavirus

The continued threat of emerging, highly lethal infectious pathogens such as Middle East respiratory syndrome coronavirus (MERS‐CoV) calls for the development of novel vaccine technology that offers safe and effective prophylactic measures. Here, a novel nanoparticle vaccine is developed to deliver subunit viral antigens and STING agonists in a virus‐like fashion. STING agonists are first encapsulated into capsid‐like hollow polymeric nanoparticles, which show multiple favorable attributes, including a pH‐responsive release profile, prominent local immune activation, and reduced systemic reactogenicity. Upon subsequent antigen conjugation, the nanoparticles carry morphological semblance to native virions and facilitate codelivery of antigens and STING agonists to draining lymph nodes and immune cells for immune potentiation. Nanoparticle vaccine effectiveness is supported by the elicitation of potent neutralization antibody and antigen‐specific T cell responses in mice immunized with a MERS‐CoV nanoparticle vaccine candidate. Using a MERS‐CoV‐permissive transgenic mouse model, it is shown that mice immunized with this nanoparticle‐based MERS‐CoV vaccine are protected against a lethal challenge of MERS‐CoV without triggering undesirable eosinophilic immunopathology. Together, the biocompatible hollow nanoparticle described herein provides an excellent strategy for delivering both subunit vaccine candidates and novel adjuvants, enabling accelerated development of effective and safe vaccines against emerging viral pathogens.     

农药安全性评价对我国助剂的发展影响

介绍了我国农药安全性评价和农药助剂的发展概况,分析了助剂自身结构的安全性问题,并提出了我国农药助剂的发展策略。     

高性价比的水乳剂研究和增效剂的加入

2009年2月13日,工业和信息化部工[2009]第29号公告中第四条规定:自2009年8月1日起,不再颁发农药乳油产品批准证."这使新乳油产品的开发受到了很大影响,而水乳剂产品将是替代乳油产品最安全、经济、有效的选择.水乳剂使用的溶剂减少了,其安全性提高了,生产成本降低了,而且对环境友好,近年倍受人们的关注.典型的水乳剂配方是由原药、有机溶剂、表面活性剂、黏度调节体系、防腐剂、消泡剂、防冻剂和水组成.毒死蜱水乳剂配方是由水相(34.25%水、4%丙三醇、0.1%消泡剂、1%防腐剂和0.15%增稠剂)和油相(40%毒死蜱原药、16%Solvesso 200ND芳烃溶剂、2.25%Atlox 4912低HLB值高分子表面活性剂和2.25%Atlox G-5002L高HLB值高分子表面活性剂)组成.制剂样品放在5℃和54℃冷储和热储两周试验表明较长时间的均化可达到较小的粒径,粒径大小不随着时间推移而显著增长--表现出优良的稳定性.水乳液的稀释稳定性是用来评价水乳剂的一个非常重要的指标,与乳油的相同,即制剂被用标准硬水稀释20倍后的稳定性.试验表明剪切时间分别为1 min和10 min,储存25 h后乳液沉淀量分别为1%和0.5%.增效剂Atplus 245推荐用于提高制剂溶液喷洒的保持力和展布性能.增效剂Atplus 245添加在毒死蜱水乳剂中后,对粒径的影响很小,对热储稳定性没有形成致命的影响.试验结果表明高分子表面活性剂是用于开发稳定且高品质的水乳剂产品的非常好的助剂.