PDZ-binding kinase aggravates pancreatic neuroendocrine neoplasm progression by activating the AKT/mTOR pathway.

The therapeutic effects of existing drug regimens against pancreatic neuroendocrine neoplasms (pNENs) remain limited, and identifying ideal therapeutic targets is warranted. PDZ binding kinase (PBK) may play an oncogenic role in most solid tumors. However, its function in pNEN remains unclear. In this study, pNEN samples and International Cancer Genome Consortium data were used to determine the clinical significance of PBK. Cell counting and CCK8 assays were used to assess cell proliferation. Flow cytometry was used to assess drug-induced apoptosis and cell cycle arrest. An in vivo PBK-targeting experiment was performed in mice bearing pNENs. Western blotting, quantitative PCR, and immunohistochemistry were performed to assess the molecular mechanisms. PBK was significantly upregulated in pNEN tissues compared with paracancerous tissues. Additionally, PBK was a poor prognostic factor for pNEN patients. PBK was found to promote the proliferation of pNEN cells by activating the AKT/mTOR pathway. Furthermore, PBK inhibition combined with everolimus treatment had enhanced antitumour effects on pNEN via inhibiting AKT/mTOR pathway and inducing G0/G1 phase cell cycle arrest. This study highlights that PBK plays an oncogenic role in and is a promising therapeutic target for pNEN.

Self-Disassembling and Oxygen-Generating Porphyrin-Lipoprotein Nanoparticle for Targeted Glioblastoma Resection and Enhanced Photodynamic Therapy.

The dismal prognosis for glioblastoma multiform (GBM) patients is primarily attributed to the highly invasive tumor residual that remained after surgical intervention. The development of precise intraoperative imaging and postoperative residual removal techniques will facilitate the gross total elimination of GBM. Here, a self-disassembling porphyrin lipoprotein-coated calcium peroxide nanoparticles (PLCNP) is developed to target GBM via macropinocytosis, allowing for fluorescence-guided surgery of GBM and improving photodynamic treatment (PDT) of GBM residual by alleviating hypoxia. By reducing self-quenching and enhancing lysosome escape efficiency, the incorporation of calcium peroxide (CaO2) cores in PLCNP amplifies the fluorescence intensity of porphyrin-lipid. Furthermore, the CaO2 core has diminished tumor hypoxia and improves the PDT efficacy of PLCNP, enabling low-dose PDT and reversing tumor progression induced by hypoxia aggravation following PDT. Taken together, this self-disassembling and oxygen-generating porphyrin-lipoprotein nanoparticle may serve as a promising all-in-one nanotheranostic platform for guiding precise GBM excision and empowering post-operative PDT, providing a clinically applicable strategy to combat GBM in a safe and effective manner.

Targeted drug delivery system inspired by macropinocytosis.

Macropinocytosis is a widely-observed and evolutionarily-conserved endocytic process found in the eukaryotic cells. In comparison to other endocytic routes, macropinocytosis allows for the internalization of greater quantities of fluid-phase drugs, making it an attractive avenue for drug delivery. Recent evidence showed that various drug delivery systems can be internalized through macropinocytosis. Utilizing macropinocytosis may therefore provide a new avenue for targeted intracellular delivery. In this review, we provide an overview into the origins and distinctive properties of macropinocytosis, summarize the roles of macropinocytosis under healthy and pathological settings. Furthermore, we highlight the biomimetic and synthetic drug delivery systems that employ macropinocytosis as the primary internalization mechanism. To facilitate the clinical applications of these drug delivery systems, additional research can be conducted to enhance the cell-type selectivity of macropinocytosis, the control of drug release at the target, and the prevention of potential toxicity. The rapidly emerging field of macropinocytosis-based targeted drug delivery and therapies holds great potential to drastically increase the efficiency and specificity of drug delivery.

Immune-active tumor-adjacent tissues are associated with favorable prognosis in stage I lung squamous cell carcinoma.

The immunogenomic features of tumor-adjacent lungs (TALs) in stage I lung squamous cell carcinoma (LUSC) are not clear. Multiomics analyses of tumor tissues and paired TALs from 59 stage I LUSC patients were performed. Compared to tumors, TALs exhibited a better-preserved immune contexture indicated by upregulation of immune pathways, increased immune infiltration, and higher expression of immune effector molecules. Notably, TALs had no mutations in PTEN and KEAP1, a lower incidence of human leukocyte antigen (HLA) loss and higher expression of HLA class I genes, major histocompatibility complex (MHC) I chaperones, and interferon (IFN)-γ-associated genes. Digital spatial profiling validated the generally higher immune infiltration in TALs and revealed a higher level of immune heterogeneity in LUSC tumors. Importantly, patients with higher immune infiltration in TALs had significantly longer survival, while high immune heterogeneity was associated with inferior patient survival. Our work can be considered in the selection of patients for adjuvant therapy, especially immunotherapy.

PDZ Binding Kinase/T-LAK Cell-Derived Protein Kinase Plays an Oncogenic Role and Promotes Immune Escape in Human Tumors.

BACKGROUND: PDZ binding kinase (PBK)/T-LAK cell-derived protein kinase (TOPK) is an important mitotic kinase that promotes tumor progression in some cancers. However, the pan-cancer analysis of PBK/TOPK and its role in tumor immunity are limited. METHODS: The oncogenic and immune roles of PBK in various cancers were explored using multiple databases, including Oncomine, Human Protein Atlas, ULCAN, Tumor Immune Estimation Resource 2.0, STRING, and Gene Expression Profiling Interactive Analysis 2, and data collected from The Cancer Genome Atlas and Genotype-Tissue Expression Project. Several bioinformatics tools and methods were used for quantitative analyses and panoramic descriptions, such as the DESeq2 and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. RESULTS: PBK was expressed at higher levels in most solid tumors than in normal tissues in multiple databases. PBK was associated with an advanced tumor stage and grade and a poor prognosis in most cases. PBK was associated with tumor immune cell infiltration in most cases and was especially positively correlated with TAMs, Tregs, MDSCs, and T cell exhaustion in KIRC, LGG, and LIHC. PBK was closely related to TMB, MSI, and immune checkpoint genes in various cancers, and patients with higher expression of PBK in KIRC, LGG, and LIHC had higher TIDE scores and lower immune responses in the predicted results. PBK was closely related to cell cycle regulation and immune-related processes in LIHC and LGG according to GO and KEGG enrichment analyses. CONCLUSIONS: PBK may play an oncogenic role in most solid tumors and promotes immune escape, especially in KIRC, LGG, and LIHC. This study suggests the potential value of PBK inhibitors combined with immunotherapy.

Biomimetic drug-delivery systems for the management of brain diseases.

Acting as a double-edged sword, the blood-brain barrier (BBB) is essential for maintaining brain homeostasis by restricting the entry of small molecules and most macromolecules from blood. However, it also largely limits the brain delivery of most drugs. Even if a drug can penetrate the BBB, its accumulation in the intracerebral pathological regions is relatively low. Thus, an optimal drug-delivery system (DDS) for the management of brain diseases needs to display BBB permeability, lesion-targeting capability, and acceptable safety. Biomimetic DDSs, developed by directly utilizing or mimicking the biological structures and processes, provide promising approaches for overcoming the barriers to brain drug delivery. The present review summarizes the biological properties and biomedical applications of the biomimetic DDSs including the cell membrane-based DDS, lipoprotein-based DDS, exosome-based DDS, virus-based DDS, protein template-based DDS and peptide template-based DDS for the management of brain diseases.