If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer

Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is “undruggable”, (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically “cold” tumors into “hot” ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich’s century-old “magic bullet” vision with Rudolf Virchow’s cancer inflammation theory.     

Improved Controlled Release and Brain Penetration of the Small Molecule S14 Using PLGA Nanoparticles

Phosphodiesterase 7 (PDE7) is an enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP), an important cellular messenger. PDE7’s role in neurotransmission, expression profile in the brain and the druggability of other phosphodiesterases have motivated the search for potent inhibitors to treat neurodegenerative and inflammatory diseases. Different heterocyclic compounds have been described over the years; among them, phenyl-2-thioxo-(1H)-quinazolin-4-one, called S14, has shown very promising results in different in vitro and in vivo studies. Recently, polymeric nanoparticles have been used as new formulations to target specific organs and produce controlled release of certain drugs. In this work, we describe poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles loaded with S14. Their preparation, optimization, characterization and in vivo drug release profile are here presented as an effort to improve pharmacokinetic properties of this interesting PDE7 inhibitor.     

咪唑啉缓蚀剂工艺条件优化及效果

在减缓金属腐蚀的研究中,为了缓解在酸性溶液、碱性溶液以及大气、土壤等介质中金属腐蚀较为严重的问题,对咪唑啉类缓蚀剂进行了工艺条件优化.采用静态失重法研究了碳钢在加入了缓蚀剂的盐酸溶液中的缓蚀性能.在最佳合成条件下苯甲酸与二乙烯三胺最佳摩尔比为1∶1.3,催化剂质量分数为1.2%,环化时间为1 h,咪唑啉中间体与氯化苄的最佳摩尔比为1∶1.1,季铵化反应时间为1 h,季铵化反应温度为70 ℃,缓蚀剂的最佳质量分数为1%,最终缓蚀率可以达到99.37%.     

Molybdate and tungstate as corrosion inhibitors for cold rolling steel in hydrochloric acid solution

The inhibition effects of molybdate and tungstate on the corrosion of cold rolling steel (CRS) in hydrochloric acid solution (0.1-0.5 M) were investigated by weight loss and electrochemistry methods. The results reveal that both molybdate and tungstate are very good inhibitors with little concentration. The adsorption of inhibitors on the CRS surface basically obeys the Langmuir adsorption isotherm equation. The effect of temperature on the corrosion behavior of CRS was also studied at 25 °C and 35 °C, the thermodynamic parameters such as adsorption heat (ΔH⁰) and adsorption free energy (ΔG⁰) were calculated. In the same conditions, a comparative study of corrosion inhibition of molybdate and tungstate indicated that molybdate was the better inhibitor in 0.1 M HCl. However, the value of percentage inhibition efficiency (IE) was dependent on the concentration of inhibitors in 0.2-0.5 M HCl. It seemed that molybdate did not have the strong inhibitive effect compared to tungstate with relatively small concentration of inhibitors, but molybdate was a better inhibitor over a wide concentration range of inhibitors. A kinetic study of cold rolling steel in uninhibited and inhibited acid was also discussed. Various parameters such as rate constant k and the kinetic parameter B were calculated for the reactions of corrosion. Polarization curves showed that both molybdate and tungstate are mixed-type inhibitors in acidic media.     

Deciphering the Binding Interactions between Acinetobacter baumannii ACP and β-ketoacyl ACP Synthase III to Improve Antibiotic Targeting Using NMR Spectroscopy

Fatty acid synthesis is essential for bacterial viability. Thus, fatty acid synthases (FASs) represent effective targets for antibiotics. Nevertheless, multidrug-resistant bacteria, including the human opportunistic bacteria, Acinetobacter baumannii, are emerging threats. Meanwhile, the FAS pathway of A. baumannii is relatively unexplored. Considering that acyl carrier protein (ACP) has an important role in the delivery of fatty acyl intermediates to other FAS enzymes, we elucidated the solution structure of A. baumannii ACP (AbACP) and, using NMR spectroscopy, investigated its interactions with β-ketoacyl ACP synthase III (AbKAS III), which initiates fatty acid elongation. The results show that AbACP comprises four helices, while Ca²⁺ reduces the electrostatic repulsion between acid residues, and the unconserved F47 plays a key role in thermal stability. Moreover, AbACP exhibits flexibility near the hydrophobic cavity entrance from D59 to T65, as well as in the α₁α₂ loop region. Further, F29 and A69 participate in slow exchanges, which may be related to shuttling of the growing acyl chain. Additionally, electrostatic interactions occur between the α₂ and α₃-helix of ACP and AbKAS III, while the hydrophobic interactions through the ACP α₂-helix are seemingly important. Our study provides insights for development of potent antibiotics capable of inhibiting A. baumannii FAS protein–protein interactions.     

Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.     

The Potential Role of Small-Molecule PERK Inhibitor LDN-0060609 in Primary Open-Angle Glaucoma Treatment

Primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma. Emerging evidence suggests that Endoplasmic Reticulum (ER) stress and the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated Unfolded Protein Response (UPR) signaling pathway play a key role in POAG pathogenesis. Thus, the main aim of the study was to evaluate the effectiveness of the PERK inhibitor LDN-0060609 in cellular model of glaucoma using primary human trabecular meshwork (HTM) cells. To evaluate the level of the ER stress marker proteins, Western blotting and TaqMan gene expression assay were used. The cytotoxicity was measured by XTT, LDH assays and Giemsa staining, whereas genotoxicity via comet assay. Changes in cell morphology were assessed by phase-contrast microscopy. Analysis of apoptosis was performed by caspase-3 assay and flow cytometry (FC), whereas cell cycle progression by FC. The results obtained have demonstrated that LDN-0060609 triggered a significant decrease of ER stress marker proteins within HTM cells with induced ER stress conditions. Moreover, LDN-0060609 effectively increased viability, reduced DNA damage, increased proliferation, restored normal morphology, reduced apoptosis and restored normal cell cycle distribution of HTM cells with induced ER stress conditions. Thereby, PERK inhibitors, such as LDN-0060609, may provide an innovative, ground-breaking treatment strategy against POAG.     

水质稳定剂HPDP缓蚀阻垢性能评定

用静态阻垢，旋转挂片失得法实验研究了ＨＰＤＰ对ＣａＣＯ３，Ｃａ３（ＰＯ４）２等的阻垢性能以及对Ｑ２３５碳钢的缓蚀性能等。试验证明，ＨＰＤＰ是一种优良的阻垢缓蚀剂，适用于高温，高碱，高ＰＨ，高浓缩倍数的循环冷却水处理，具有广阔的应用前景。     

海洋工程用钢的大气腐蚀与耐候钢的发展

综述了海洋工程用钢的大气腐蚀行为与耐候钢发展方面的研究,特别是近十余年来国内外的相关成果。首先介绍了钢大气腐蚀的电化学模型,并从耐候钢特殊的锈层结构与合金元素作用两方面论述了耐候钢的锈层保护机制;然后分析了环境因素,包括相对湿度与污染物、光照、锈层损伤等,对耐候钢大气腐蚀行为的影响;最后总结了耐候钢的发展历程以及晶粒尺寸与显微组织等非合金因素在耐候钢发展中的作用,可为新型耐候钢的设计与应用提供指导。     

常减压蒸馏装置高温部位的腐蚀与防护

阐述了常减压蒸馏装置高温部位的腐蚀机理，介绍了高温防腐蚀的三种方法：正确选材、高温缓蚀剂技术及喷涂渗铝技术，建议在类似的石化装置推广使用。