A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy

Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug resistance.The emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.

Mechanisms of tigecycline resistance in Gram-negative bacteria:A narrative review

Tigecycline serves as a critical“final-resort”antibiotic for treating bacterial infections caused by multidrug-resistant bacteria for which treatment options are severely limited.The increasing prevalence of tigecycline resistance,particularly among Gram-negative bacteria,is a major concern.Various mechanisms have been iden-tified as contributors to tigecycline resistance,including upregulation of nonspecific Resistance Nodulation Divi-sion(RND)efflux pumps due to mutations in transcriptional regulators,enzymatic modification of tigecycline by monooxygenase enzymes,and mutations affecting tigecycline binding sites.This review aims to consolidate our understanding of tigecycline resistance mechanisms in Gram-negative bacteria and offer insights and perspectives for further drug development.

Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma

Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment.Therefore,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against GBM.SYHA1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo.SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive tumors.Notably,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM xenografts.Moreover,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody.As a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial.The data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380).

In cell measurement of fluorescence lifetime imaging microscopy revealed C-terminal conformation changes of Ferroportin upon addition of Mn^2＋

Fluorescence microscopy, as a sensitive method to detect microenvironment of molecules, is widely used in protein conformation and dynamic studies in live cells. Fluorescence lifetime imaging microscopy（FLIM）, which is independent of fluorophore concentrations, scattering and bleaching, is a suitable tool to analyze membrane proteins in a single cell. Ferroportin（FPN）, a multi-ion exporter in vertebrates, was modulated by metal ions with unknown mechanism. Herein, we fused green fluorescence protein on Cterminal of FPN（FPN-eGFP） and applied fluorescence lifetime to monitor conformation changes of FPN in a live cell. The fluorescence lifetime distribution showed a shift to shorter lifetime upon Mn^（2＋） treatment,suggesting a preference conformation of FPN in Mn^（2＋） exposure. It is also observed that the lifetime（rather than intensity） measurement was not strongly influenced by laser power. The observed fluorescence lifetime changes of FPN-eGFP upon Mn^（2＋） treatments indicated that extracellular metal ions can modulate FPN through conformation exchanges between several different states.