Rotor-based image-guided therapy of glioblastoma.

Glioblastoma (GBM), deep in the brain, is more challenging to diagnose and treat than other tumors. Such challenges have blocked the development of high-impact therapeutic approaches that combine reliable diagnosis with targeted therapy. Herein, effective cyanine dyes (IRLy) with the near-infrared two region (NIR-II) adsorption and aggregation-induced emission (AIE) have been developed via an "extended conjugation & molecular rotor" strategy for multimodal imaging and phototherapy of deep orthotopic GBM. IRLy was synthesized successfully through a rational molecular rotor modification with stronger penetration, higher signal-to-noise ratio, and a high photothermal conversion efficiency (PCE) up to ∼60%, which can achieve efficient NIR-II photo-response. The multifunctional nanoparticles (Tf-IRLy NPs) were further fabricated to cross the blood-brain barrier (BBB) introducing transferrin (Tf) as a targeting ligand. Tf-IRLy NPs showed high biosafety and good tumor enrichment for GBM in vitro and in vivo, and thus enabled accurate, efficient, and less invasive NIR-II multimodal imaging and photothermal therapy. This versatile Tf-IRLy nanosystem can provide a reference for the efficient, precise and low-invasive multi-synergistic brain targeted photo-theranostics. In addition, the "extended conjugation & molecular rotor" strategy can be used to guide the design of other photothermal agents.

Chitosan/NH2-MIL-125 (Ti) scaffold loaded with doxorubicin for postoperative bone tumor clearance and osteogenesis: An in vitro study.

Surgical resection remains the primary treatment modality for bone tumors. However, it is prone to local bone defects and tumor recurrence. Therefore, there is an urgent need for multifunctional biomaterials that combine tumor treatment and bone repair after bone tumor surgery. Herein, a chitosan composite scaffold (CS/DOX@Ti-MOF) was designed for both tumor therapy and bone repair. Among them, the amino-functionalized Ti-based metal-organic framework (NH2-MIL-125 (Ti), Ti-MOF) has a high specific surface area of 1116 m2/g and excellent biocompatibility, and promotes osteogenic differentiation. The doxorubicin (DOX) loading capacity of Ti-MOF was 322 ± 21 mg/g, and DOX@Ti-MOF has perfect antitumor activity. Furthermore, the incorporation of DOX@Ti-MOF improved the physical and mechanical properties of the composite scaffolds, making the scaffold surface rough and favorable for cells to attach. CS/DOX@Ti-MOF retains the unique properties of each component. It responds to the release of DOX in the tumor microenvironment to remove residual tumor cells, followed by providing a site for cell attachment, proliferation, and differentiation. This promotes bone repair and achieves the sequential treatment of postoperative bone tumors. Overall, CS/DOX@Ti-MOF may be a promising substitute for postoperative bone tumor clearance and bone defect repair. It also provides a possible strategy for postoperative bone tumor treatment.

In Vivo Base Editing of Scn5a Rescues Type 3 Long QT Syndrome in Mice.

BACKGROUND: Pathogenic variants in SCN5A can result in long QT syndrome type 3, a life-threatening genetic disease. Adenine base editors can convert targeted A T base pairs to G C base pairs, offering a promising tool to correct pathogenic variants. METHODS: We generated a long QT syndrome type 3 mouse model by introducing the T1307M pathogenic variant into the Scn5a gene. The adenine base editor was split into 2 smaller parts and delivered into the heart by adeno-associated virus serotype 9 (AAV9-ABEmax) to correct the T1307M pathogenic variant. RESULTS: Both homozygous and heterozygous T1307M mice showed significant QT prolongation. Carbachol administration induced Torsades de Pointes or ventricular tachycardia for homozygous T1307M mice (20%) but not for heterozygous or wild-type mice. A single intraperitoneal injection of AAV9-ABEmax at postnatal day 14 resulted in up to 99.20% Scn5a transcripts corrected in T1307M mice. Scn5a mRNA correction rate >60% eliminated QT prolongation; Scn5a mRNA correction rate <60% alleviated QT prolongation. Partial Scn5a correction resulted in cardiomyocytes heterogeneity, which did not induce severe arrhythmias. We did not detect off-target DNA or RNA editing events in ABEmax-treated mouse hearts. CONCLUSIONS: These findings show that in vivo AAV9-ABEmax editing can correct the variant Scn5a allele, effectively ameliorating arrhythmia phenotypes. Our results offer a proof of concept for the treatment of hereditary arrhythmias.

In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-line-associated mitigator of isoproterenol-induced cardiac injury.

Z-lines are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis. Yet a comprehensive proteomic atlas of Z-line-associated components remain incomplete. Here, we established an adeno-associated virus (AAV)-delivered, cardiomyocyte-specific, proximity-labeling approach to characterize the Z-line proteome in vivo. We found palmdelphin (PALMD) as a novel Z-line-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes. Germline and cardiomyocyte-specific palmd knockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment. By contrast, cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury. PALMD ablation perturbed transverse tubules (T-tubules) and their association with sarcoplasmic reticulum, which formed the Z-line-associated junctional membrane complex (JMC) essential for calcium handling and cardiac function. These phenotypes were associated with disrupted localization of T-tubule markers caveolin-3 (CAV3) and junctophilin-2 (JPH2) and the reduction of nexilin (NEXN) protein, a crucial Z-line-associated protein that is essential for both Z-line and JMC structures and functions. PALMD was found to interact with NEXN and enhance its protein stability while the Nexn mRNA level was not affected. Together, this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis. Highlights: In vivo proximity proteomics uncover novel Z-line components that are undetected in in vitro proximity proteomics in cardiomyocytes.PALMD is a novel Z-line-associated protein that is dispensable for baseline cardiomyocyte function in vivo.PALMD mitigates cardiac dysfunction and myocardial injury after repeated isoproterenol insults.PALMD stabilizes NEXN, an essential Z-line-associated regulator of the junctional membrane complex and cardiac systolic function.

Amino-Functionalized Zirconium-Based Metal-Organic Frameworks as Bifunctional Nanomaterials to Treat Bone Tumors and Promote Osteogenesis.

Bone tumor patients often encounter challenges associated with cancer cell residues and bone defects postoperation. To address this, there is an urgent need to develop a material that can enable tumor treatment and promote bone repair. Metal-organic frameworks (MOFs) have attracted the interest of many researchers due to their special porous structure, which has great potential in regenerative medicine and drug delivery. However, few studies explore MOFs with dual antitumor and bone regeneration properties. In this study, we investigated amino-functionalized zirconium-based MOF nanoparticles (UiO-66-NH2 NPs) as bifunctional nanomaterials for bone tumor treatment and osteogenesis promotion. UiO-66-NH2 NPs loading with doxorubicin (DOX) (DOX@UiO-66-NH2 NPs) showed good antitumor efficacy both in vitro and in vivo. Additionally, DOX@UiO-66-NH2 NPs significantly reduced lung injury compared to free DOX in vivo. Interestingly, the internalized UiO-66-NH2 NPs notably promoted the osteogenic differentiation of preosteoblasts. RNA-sequencing data revealed that PI3K-Akt signaling pathways or MAPK signaling pathways might be involved in this enhanced osteogenesis. Overall, UiO-66-NH2 NPs exhibit dual functionality in tumor treatment and bone repair, making them highly promising as a bifunctional material with broad application prospects.

Aggressive angiomyxoma of the epididymis: A case report.

BACKGROUND: Aggressive angiomyolipoma is an extremely rare benign mesenchymal tumor that was originally described as a locally recurrent mucinous spindle cell tumour. Aggressive angiomyolipoma originates from myofibroblasts, vascular smooth muscle cells, or fibroblasts, and displays various phenotypes of myofibroblasts and abnormal muscle arteries. Aggressive angiomyolipoma was first identified in 1983 and fewer than 50 male patients have been reported to date. It is an extremely rare mesenchymal tumour and often confused with other diseases. Patients with epididymal aggressive angiomyolipoma lack typical symptoms, most of which occur incidentally, although some patients may experience mild pain, discomfort, and swelling. Pain may be exacerbated by pressure from the mass. CASE SUMMARY: A 66-year-old male was admitted to the hospital on January 14, 2022 with chief complaint of swelling in the left scrotum for one year. There was no apparent cause for the swelling. The patient did not consult with any doctor or receive any treatment for the swelling. The enlarged scrotum increased in size gradually until it reached approximately the size of a goose egg, and was accompanied by discomfort and swelling of the left cavity of the scrotum. The patient had no history of any testicular trauma, infection, or urinary tract infection. The patient urinated freely, 1-2 times at night, without urgency, dysuria (painful urination), or haematuria. There was no significant family history of malignancy. The patient underwent excision of the enlarged tumour and the left epididymis under general anaesthesia on January 18, 2022. Twelve months of follow-up revealed no recurrence. The patient was satisfied with the treatment. CONCLUSION: Aggressive angiomyolipoma is extremely rare clinically and often confused with other diseases. The pathogenesis of aggressive angiomyolipoma is unclear and the clinical presentation is mostly a painless enlarged mass. The diagnosis of aggressive angiomyolipoma requires a combination of medical history, preoperative imaging such as computed tomography and magnetic resonance imaging, cytological examination and preoperative and postoperative pathological biopsy. The preferred treatment is surgery, with the possibility of a new alternative treatment option after hormonal therapy. Aggressive angiomyolipoma should be considered in the differential diagnosis of parametrial tumors of the male genital area that present as clinically significant masses. The high recurrence rate of aggressive angiomyolipoma may be related to incomplete tumor resection, and patients with aggressive angiomyolipoma are advised to undergo annual postoperative follow-up and imaging for recurrence.

Spatiotemporal cell junction assembly in human iPSC-CM models of arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes life-threatening arrhythmias and myocardial dysfunction. Pathogenic variants in Plakophilin-2 (PKP2), a desmosome component within specialized cardiac cell junctions, cause the majority of ACM cases. However, the molecular mechanisms by which PKP2 variants induce disease phenotypes remain unclear. Here we built bioengineered platforms using genetically modified human induced pluripotent stem cell-derived cardiomyocytes to model the early spatiotemporal process of cardiomyocyte junction assembly in vitro. Heterozygosity for truncating variant PKP2R413X reduced Wnt/ß-catenin signaling, impaired myofibrillogenesis, delayed mechanical coupling, and reduced calcium wave velocity in engineered tissues. These abnormalities were ameliorated by SB216763, which activated Wnt/ß-catenin signaling, improved cytoskeletal organization, restored cell junction integrity in cell pairs, and improved calcium wave velocity in engineered tissues. Together, these findings highlight the therapeutic potential of modulating Wnt/ß-catenin signaling in a human model of ACM.

Multifunctional CuFe2O4@HA as a GSH-depleting nanoplatform for targeted photothermal/enhanced-chemodynamic synergistic therapy.

Chemodynamic therapy (CDT), which converts overexpressed hydrogen peroxide (H2O2) in tumor cells to hydroxyl radicals (•OH) by Fenton reactions, is considered a prospective strategy in anticancer therapy. However, the high level of glutathione (GSH) and poor Fenton catalytic efficiency contribute to the suboptimal efficiency of CDT. Herein, we present a multifunctional nanoplatform (CuFe2O4@HA) that can induce GSH depletion and combine with photothermal therapy (PTT) to enhance antitumor efficacy. CuFe2O4@HA nanoparticles could release Cu2+ and Fe3+ after entering tumor cells by targeting hyaluronic acid (HA). Subsequently, Cu2+ and Fe3+ were reduced to Cu+ and Fe2+ by GSH, where Cu+/Fe2+ significantly catalyzed H2O2 to produce a higher level of •OH, and the depletion of GSH disrupted the antioxidant capacity of the tumor. Therefore, depleting GSH substantially enhances the level of •OH in tumor cells. In addition, CuFe2O4@HA nanoparticles have considerable absorption in the near-infrared (NIR) region, which can stimulate excellent PTT effects. More importantly, the heat generated by PTT can further enhance the Fenton catalysis efficiency. In vitro and in vivo experiments have demonstrated the excellent tumor-killing effect of CuFe2O4@HA nanoparticles. This strategy overcomes the problem of insufficient CDT efficacy caused by GSH overexpression and poor catalytic efficiency. Moreover, this versatile nanoplatform provides a reference for self-enhanced CDT and PTT/CDT synergistic targeted therapy.

Inhibiting Osteolytic Breast Cancer Bone Metastasis by Bone-Targeted Nanoagent via Remodeling the Bone Tumor Microenvironment Combined with NIR-II Photothermal Therapy.

Bone is one of the prone metastatic sites of patients with advanced breast cancer. The "vicious cycle" between osteoclasts and breast cancer cells plays an essential role in osteolytic bone metastasis from breast cancer. In order to inhibit bone metastasis from breast cancer, NIR-II photoresponsive bone-targeting nanosystems (CuP@PPy-ZOL NPs) are designed and synthesized. CuP@PPy-ZOL NPs can trigger the photothermal-enhanced Fenton response and photodynamic effect to enhance the photothermal treatment (PTT) effect and thus achieve synergistic anti-tumor effect. Meanwhile, they exhibit a photothermal enhanced ability to inhibit osteoclast differentiation and promote osteoblast differentiation, which reshaped the bone microenvironment. CuP@PPy-ZOL NPs effectively inhibited the proliferation of tumor cells and bone resorption in the in vitro 3D bone metastases model of breast cancer. In a mouse model of breast cancer bone metastasis, CuP@PPy-ZOL NPs combined with PTT with NIR-II significantly inhibited the tumor growth of breast cancer bone metastases and osteolysis while promoting bone repair to achieve the reversal of osteolytic breast cancer bone metastases. Furthermore, the potential biological mechanisms of synergistic treatment are identified by conditioned culture experiments and mRNA transcriptome analysis. The design of this nanosystem provides a promising strategy for treating osteolytic bone metastases.

Aggregation-Induced emission photosensitizer with lysosomal response for photodynamic therapy against cancer.

Photosensitizers play a key role in bioimaging and photodynamic therapy (PDT) of cancer. However, conventional photosensitizers usually do not achieve the desired efficacy in PDT due to their poor photostability, targeting ability, and responsiveness. Herein, we designed a series of photosensitizers with aggregation-induced emission (AIE) effect using benzothiazole- triphenylamine (BZT-triphenylamine) as the parent nucleus. The synthesized compound SIN ((E)-2-(4-(diphenylamino)styryl)-3-(4-iodobutyl)benzo[d]thiazol-3-ium) exhibits good biocompatibility, photostability, and bright emission in the near-infrared range (600-800 nm). The fluorescence emission intensity is responsive to viscosity, with significant fluorescence enhancement (48 times) and high fluorescence quantum yield (4.45 %) at high viscosity. Moreover, SIN has particular lysosome targeting properties with a Pearson correlation coefficient (PCC) of 0.97 and has good 1O2 generation ability under white light irradiation, especially in a weak acidic environment. Thus, SIN can realize good bioimaging ability and photodynamic therapeutic efficacy under the highly viscous and weakly acidic environment of lysosomes in the tumor cells. This study indicates that SIN has potential as a multifunctional organic photosensitizer for bioimaging and PDT of tumor.

All-in-one CoFe2O4@Tf nanoagent with GSH depletion and tumor-targeted ability for mutually enhanced chemodynamic/photothermal synergistic therapy.

In the complex and severe tumor microenvironment, the antitumor efficiency of nanomedicines is significantly limited by their low-efficacy monotherapy, non-tumor targeting, and systemic toxicity. Herein, to achieve tumor-targeted and enhanced chemodynamic/photothermal therapy (CDT/PTT), we fabricated an "all-in-one" biocompatible transferrin-loaded cobalt ferrate nanoparticle (CoFe2O4@Tf (CFOT)) with multiple functions by a simple solvothermal method and the following transferrin (Tf) functionalization. Upon exposure to 808 nm laser irradiation, CFOT, as a novel photothermal agent, exhibited outstanding phototherapeutic activity because of its excellent photothermal conversion efficiency (η = 46.5%) for high-performance PTT. Moreover, CFOT with multiple redox pairs could efficiently convert endogenous H2O2 to hazardous hydroxyl radicals (˙OH) via Fenton reactions while scavenging overexpressed GSH in the tumor microenvironment to realize self-reinforcing CDT. Importantly, CFOT undergoes a promoted Fenton-type reaction upon increasing the temperature under a photothermal effect and could augment PTT by high-level ˙OH, exhibiting a considerably enhanced synergistic therapeutic effect. In vitro and in vivo experimental results demonstrated that CFOT has good potential as an "all-in-one" nanoagent to combine photothermal, chemodynamic, and tumor targeting for efficient tumor elimination.

Generation of a NIS-EGFP-Fluc triple-reporter human embryonic stem cell line by PiggyBac transposon system.

One major challenge in stem cell therapy is to longitudinally track cell fate after cells transplantation. Molecular Imaging approaches enabling noninvasive long-term monitoring the transplanted cells are imperative for assessment of the safety and efficiency. Here, we used PiggyBac technology to insert triple reporter genes: NIS, EGFP and Firefly luciferase into a human embryonic stem cell line (hESCs, H9) and obtained a reporter hESCs line (NIS-EGFP-Fluc H9). The triple-reporters allows the transplanted NIS-EGFP-Fluc H9 cells and their derivates to be fluorescence, bioluminescence and even PET/SPECT imaged. This triple-reporter hESCs line provides a valuable imaging platform for cell-based therapeutics clinical translation.

Bifunctional scaffolds for tumor therapy and bone regeneration: Synergistic effect and interplay between therapeutic agents and scaffold materials.

Bone tumor patients often face the problems with cancer cell residues and bone defects after the operation. Therefore, researchers have developed many bifunctional scaffolds with both tumor treatment and bone repair functions. Therapeutic agents are usually combined with bioactive scaffolds to achieve the "bifunctional". However, the synergistic effect of bifunctional scaffolds on tumor therapy and bone repair, as well as the interplay between therapeutic agents and scaffold materials in bifunctional scaffolds, have not been emphasized and discussed. This review proposes a promising design scheme for bifunctional scaffolds: the synergistic effect and interplay between the therapeutic agents and scaffold materials. This review summarizes the latest research progress in bifunctional scaffolds for therapeutic applications and regeneration. In particular, it summarizes the role of tumor therapeutic agents in bone regeneration and the role of scaffold materials in tumor treatment. Finally, a perspective on the future development of bifunctional scaffolds for tumor therapy and bone regeneration is discussed.

A Facile and Universal Method for Preparing Polyethylene Glycol-Metal Hybrid Nanoparticles and Their Application in Tumor Theranostics.

Metal ions are of widespread interest owing to their brilliant biomedical functions. However, a simple and universal nanoplatform designed for assembling a range of functional metal ions has not been explored. In this study, a concept of polyethylene glycol (PEG)-mediated transport of metal ions is proposed. 31 types of PEG-metal hybrid nanoparticles (P-MNPs) are successfully synthesized through anionic ring-opening polymerization (ROP), "thiol-ene" click reaction, and subsequent incorporation with multiple metal ions. Compared with other methods, the facile method proposed in this study can provide a feasible approach to design MNPs (mostly <200 nm) containing different metal ions and thus to explore their potential for cancer theranostics. As a proof-of-concept demonstration, four types P-MNPs, i.e., PEG-metal hybrid copper nanoparticles (PEG-Cu NPs), ruthenium nanoparticles (PEG-Ru NPs), and manganese nanoparticles (PEG-Mn NPs) or gadolinium nanoparticles (PEG-Gd NPs), are proven to be tailored for chemodynamic therapy, photothermal therapy, and magnetic resonance imaging of tumors, respectively. Overall, this study provides several metal ions-based nanomaterials with versatile functions for broad applications in cancer theranostics. Furthermore, it offers a promising tool that can be utilized for processing other metal-based nanoparticles and exploring their potential in the biomedical field.

DUSP10 upregulation is a poor prognosticator and promotes cell proliferation and migration in glioma.

Dual-specificity phosphatase 10 (DUSP10) correlates with inflammation, cytokine secretion, cell proliferation, survival, and apoptosis. However, its role in glioma is unclear. Herein, we sought to examine the expression and the underlying carcinogenic mechanisms of DUSP10 action in glioma. DUSP10 expression in glioma was significantly higher than that in normal brain tissues. High DUSP10 expression indicated adverse clinical outcomes in glioma patients. Increased DUSP10 expression correlated significantly with clinical features in glioma. Univariate Cox analysis showed that high DUSP10 expression was a potential independent marker of poor prognosis in glioma. Furthermore, DUSP10 expression in glioma correlated negatively with its DNA methylation levels. DNA methylation level of DUSP10 also correlated negatively with poor prognosis in glioma. More importantly, DUSP10 expression correlated positively with the infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells in glioma. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis confirmed that DUSP10 participated in signaling pathways involved in focal adhesion, TNF cascade, Th17 cell differentiation, and NF-kappa B cascade. Finally, we uncovered that DUSP10 was dramatically upregulated in glioblastoma (GBM) cells and that the knockdown of DUSP10 inhibited glioma cell proliferation and migration. Our findings suggested that DUSP10 may serve as a potential prognostic biomarker in glioma.

Synergistic Effect of Surface Chemistry and Surface Topography Gradient on Osteogenic/Adipogenic Differentiation of hMSCs.

Much attention has been paid to understanding the individual effects of surface chemistry or topography on cell behavior. However, the synergistic influence of both surface chemistry and surface topography on differentiation of human mesenchymal stem cells (hMSCs) should also be addressed. Here, gold nanoparticles were immobilized in an increasing number density manner to achieve a surface topography gradient; a thin film rich in amine (-NH2) or methyl (-CH3) chemical groups was plasma-polymerized to adjust the surface chemistry of the outermost layer (ppAA and ppOD, respectively). hMSCs were cultured on these model substrates with defined surface chemistry and surface topography gradient. The morphology and focal adhesion (FA) formation of hMSCs were first examined. hMSC differentiation was then co-induced in osteogenic and adipogenic medium, as well as in the presence of extracellular-signal-regulated kinase1/2 (ERK1/2) and RhoA/Rho-associated protein kinase (ROCK) inhibitors. The results show that the introduction of nanotopography could enhance FA formation and osteogenesis but inhibited adipogenesis on both ppAA and ppOD surfaces, indicating that the surface chemistry could regulate hMSC differentiation, in a surface topography-dependent manner. RhoA/ROCK and ERK1/2 signaling pathways may participate in this process. This study demonstrated that surface chemistry and surface topography can jointly affect cell morphology, FA formation, and thus osteogenic/adipogenic differentiation of hMSCs. These findings highlight the importance of the synergistic effect of different material properties on regulation of cell response, which has important implications in designing functional biomaterials.

A mitochondria-targeted thiazoleorange-based photothermal agent for enhanced photothermal therapy for tumors.

Organic small molecules with near-infrared (NIR) absorption hold great promise as the phototheranostic agents for clinical translation by virtue of their inherent merits such as well-defined chemical structure, high purity and good reproducibility. Probes that happen to be based on cyanine dyes exhibit strong NIR-absorbing and efficient photothermal conversion, representing a new class of photothermal agents (PAs) for photothermal therapy (PTT), and taking into account the heat susceptibility of Mitochondria (Mito), we designed and prepared a mitochondria-targeted organic small molecule (Mito-BWQ) based on thiazole orange maternal unit that can effectively kill tumor cells through the hyperpyrexia generated in the lesions under exogenous laser irradiation. The Confocal laser scanning microscope was employed to determine the preferential targeting of Mito-BWQ to the mitochondria of MCF-7 cells and U87 cells. When subjected to 600 nm laser radiation, Mito-BWQ produced an increase in temperature in test systems and this increase was dependent on both the laser power and probe concentration. In vitro tests, cytotoxicity was observed when cells were incubated with Mito-BWQ and exposed to laser irradiation. The PTT in vivo also showed that Mito-BWQ performed remarkably in tumor inhibition. This study thus provides a vital starting point for the creation of thiazole orange-based PTT formulations and promotes further advances in the field of PAs-based anticancer research and therapy.

Depletion of CIP2A inhibits the proliferation, migration, invasion and epithelial-mesenchymal transition of glioma cells.

CIP2A is an oncoprotein that is overexpressed in multiple solid tumours and some malignant haematologic disorders. However, its function in glioma is poorly understood. In this study, our results demonstrated that the expression of CIP2A was higher in glioma tissues than in normal tissues. Using tissue microarrays for immunohistochemistry, we found that the intensity of CIP2A expression was higher in high-grade gliomas (grade III-IV) than in low-grade gliomas (grade I-II). In addition, we found that depletion of CIP2A inhibited glioma cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro. Taken together, our findings revealed that CIP2A was involved in glioma progression, indicating that CIP2A could be used as a potential therapeutic target in the future.

PDLIM2 repression by ROS in alveolar macrophages promotes lung tumorigenesis.

One of the most fundamental and challenging questions in the field of cancer is how immunity is transformed from tumor immunosurveillance to tumor-promoting inflammation. Here, we identified the tumor suppressor PDZ-LIM domain-containing protein 2 (PDLIM2) as a checkpoint of alveolar macrophages (AMs) important for lung tumor suppression. During lung tumorigenesis, PDLIM2 expression in AMs is downregulated by ROS-activated transcription repressor BTB and CNC homology 1 (BACH1). PDLIM2 downregulation leads to constitutive activation of the transcription factor STAT3, driving AM protumorigenic polarization/activation and differentiation from monocytes attracted from the circulation to suppress cytotoxic T lymphocytes and promote lung cancer. PDLIM2 downregulation also decreases AM phagocytosis. These findings establish ROS/BACH1/PDLIM2/STAT3 as a signaling pathway driving AMs for lung tumor promotion.