Genetic association between smoking and DLCO in idiopathic pulmonary fibrosis patients.

BACKGROUND: Observational studies have shown that smoking is related to the diffusing capacity of the lungs for carbon monoxide (DLCO) in individuals with idiopathic pulmonary fibrosis (IPF). Nevertheless, further investigation is needed to determine the causal effect between these two variables. Therefore, we conducted a study to investigate the causal relationship between smoking and DLCO in IPF patients using two-sample Mendelian randomization (MR) analysis. METHODS: Large-scale genome-wide association study (GWAS) datasets from individuals of European descent were analysed. These datasets included published lifetime smoking index (LSI) data for 462,690 participants and DLCO data for 975 IPF patients. The inverse-variance weighting (IVW) method was the main method used in our analysis. Sensitivity analyses were performed by MR‒Egger regression, Cochran's Q test, the leave-one-out test and the MR-PRESSO global test. RESULTS: A genetically predicted increase in LSI was associated with a decrease in DLCO in IPF patients [ORIVW = 0.54; 95% CI 0.32-0.93; P = 0.02]. CONCLUSIONS: Our study suggested that smoking is associated with a decrease in DLCO. Patients diagnosed with IPF should adopt an active and healthy lifestyle, especially by quitting smoking, which may be effective at slowing the progression of IPF.

Radiomics nomogram for prediction of glypican-3 positive hepatocellular carcinoma based on hepatobiliary phase imaging.

Introduction: The hepatobiliary-specific phase can help in early detection of changes in lesion tissue density, internal structure, and microcirculatory perfusion at the microscopic level and has important clinical value in hepatocellular carcinoma (HCC). Therefore, this study aimed to construct a preoperative nomogram for predicting the positive expression of glypican-3 (GPC3) based on gadoxetic acid-enhanced (Gd-EOB-DTPA) MRI hepatobiliary phase (HBP) radiomics, imaging and clinical feature. Methods: We retrospectively included 137 patients with HCC who underwent Gd-EOB-DTPA-enhanced MRI and subsequent liver resection or puncture biopsy at our hospital from January 2017 to December 2021 as training cohort. Subsequently collected from January 2022 to June 2023 as a validation cohort of 49 patients, Radiomic features were extracted from the entire tumor region during the HBP using 3D Slicer software and screened using a t-test and least absolute shrinkage selection operator algorithm (LASSO). Then, these features were used to construct a radiomics score (Radscore) for each patient, which was combined with clinical factors and imaging features of the HBP to construct a logistic regression model and subsequent nomogram model. The clinicoradiologic, radiomics and nomogram models performance was assessed by the area under the curve (AUC), calibration, and decision curve analysis (DCA). In the validation cohort,the nomogram performance was assessed by the area under the curve (AUC). Results: In the training cohort, a total of 1688 radiomics features were extracted from each patient. Next, radiomics with ICCs<0.75 were excluded, 1587 features were judged as stable using intra- and inter-class correlation coefficients (ICCs), 26 features were subsequently screened using the t-test, and 11 radiomics features were finally screened using LASSO. The nomogram combining Radscore, age, serum alpha-fetoprotein (AFP) >400ng/mL, and non-smooth tumor margin (AUC=0.888, sensitivity 77.7%, specificity 91.2%) was superior to the radiomics (AUC=0.822, sensitivity 81.6%, specificity 70.6%) and clinicoradiologic (AUC=0.746, sensitivity 76.7%, specificity 64.7%) models, with good consistency in calibration curves. DCA also showed that the nomogram had the highest net clinical benefit for predicting GPC3 expression.In the validation cohort, the ROC curve results showed predicted GPC3-positive expression nomogram model AUC, sensitivity, and specificity of 0.800, 58.5%, and 100.0%, respectively. Conclusion: HBP radiomics features are closely associated with GPC3-positive expression, and combined clinicoradiologic factors and radiomics features nomogram may provide an effective way to non-invasively and individually screen patients with GPC3-positive HCC.

Enhanced Nuclear Accumulation of Doxorubicin Delivered by pH-Triggered Polydopamine-Shelled Mesoporous Silica for Chemo-Photothermal Therapy.

Adequate delivery of therapeutic agents to their intended molecular targets is crucial in tumor therapy. Versatile drug carriers need to overcome the challenges coming from the systemic circulation, membrane barriers, and endo-lysosomal degradation. Herein, hyaluronic acid-conjugated polydopamine (HA-PDA)-shelled mesoporous silica nanoparticles encapsulated with doxorubicin (MSNs-DOX) were successfully fabricated for targeted tumor therapy. Compared with reported studies focusing on the pH-sensitive release in tumors, we especially revealed the significant role of lysosomal release in DOX nuclear accumulation. After active targeting and CD44-mediated endocytosis in tumor cells, the PDA layer of the nanoparticles would be peeled off to trigger drug release owing to MSNs gatekeeper in acidic lysosomes. Subsequently, DOX molecules passively diffused into nuclei. The intracellular DOX transportation was evidenced by DOX accumulation in nuclei, lysosomal location of nanoparticles, and lysosome acidification inhibition test. After discharging of the cargoes from nanoparticles, PDA shells from residual nanoparticles were able to produce localized hyperthermia under NIR irradiation entrapped in lysosomes, inducing synergistic chemo-photothermal effect. Under NIR treatment, HA-PDA@MSNs-DOX presented a prominent tumor inhibition rate without obvious side effects. This study indicated the potent nuclear delivery and synergetic chemo-photothermal therapy achieved by HA-PDA-shelled MSNs.

Tumor Tropic Delivery of Hyaluronic Acid-Poly (D,L-lactide-co-glycolide) Polymeric Micelles Using Mesenchymal Stem Cells for Glioma Therapy.

Tumor penetration and the accumulation of nanomedicines are crucial challenges in solid tumor therapy. By taking advantage of the MSC tumor-tropic property, we developed a mesenchymal stem cell (MSC)-based drug delivery system in which paclitaxel (PTX)-encapsulating hyaluronic acid-poly (D,L-lactide-co-glycolide) polymeric micelles (PTX/HA-PLGA micelles) were loaded for glioma therapy. The results indicated that CD44 overexpressed on the surface of both MSCs and tumor cells not only improved PTX/HA-PLGA micelle loading in MSCs, but also promoted the drug transfer between MSCs and adjacent cancer cells. It was hypothesized that CD44-mediated transcytosis played a crucial role and allowed deep glioma penetration depending on sequential intra-intercellular delivery via endocytosis-exocytosis. MSC-micelles were able to infiltrate from normal brain parenchyma towards contralateral tumors and led to the eradication of glioma. The survival of orthotopic glioma-bearing rats was significantly extended. In conclusion, the MSC-based delivery of HA-PLGA micelles is a potential strategy for tumor-targeting drug delivery.

Online Quaternized Derivatization Mapping and Glycerides Profiling of Cancer Tissues by Laser Ablation Carbon Fiber Ionization Mass Spectrometry.

Mass spectrometry imaging has become a hot research field owing to its ability to reflect the distribution of multiple metabolites in tissue. However, not all kinds of metabolites have great ionization efficiency in mass spectrometry imaging. The mass signals of low polar metabolites like monoglycerides and diglycerides may be seriously suppressed. Many strategies have been proposed to fix the problem, such as on-tissue derivatization and online derivatization. Also, some challenges were encountered when implementing these approaches. Herein, a platform coupled online quaternized derivatization and laser ablation carbon fiber ionization mass spectrometry imaging has been developed. The mass signals of monoglycerides and diglycerides were drastically increased in the platform, and high-quality mass images of these metabolites could be acquired readily. In the platform, metabolites were first desorbed by a laser and then reacted online with a derivatization reagent transmitted by carbon fiber ionization, which also undertook the postionization of derivatization products. Pyridine acted as the main derivatization reagent to target metabolites with hydroxyl groups. Remarkably, the derivatization reaction proceeded rapidly without any catalyst owing to the high energy provided by the laser. The mass images of eight monoglycerides and 21 diglycerides were achieved after applying the platform into human ovarian cancer tissues. Notably, a higher mass intensity of these glycerides was captured in cancerous tissues than in para-cancerous tissues, which might infer aberrations in glyceride metabolisms of cancerous tissues.

Long noncoding RNA LHFPL3-AS2 suppresses metastasis of non-small cell lung cancer by interacting with SFPQ to regulate TXNIP expression.

Lung cancer is the most common cancer and the leading cause of cancer deaths worldwide. In addition to coding genes, the contribution of long noncoding RNA (lncRNA) to non-small cell lung cancer (NSCLC) remains unclear. Here, we explored lncRNA expression profiles by Affymetrix Gene Chip Human Transcriptome Array 2.0 in 37 paired samples of tumorous NSCLC tissues and adjacent nontumorous tissues. We showed that LHFPL3-AS2 is a novel lncRNA, significantly decreased in NSCLC tissues. LHFPL3-AS2 was further validated in an additional 93 paired samples of NSCLC. Low levels of LHFPL3-AS2 expression were highly correlated with poor overall survival, TNM stage, and metastasis of NSCLC patients. Enhanced expression of LHFPL3-AS2 inhibited NSCLC invasion and metastasis in vitro and in vivo. Moreover, downregulation of LHFPL3-AS2 reduced its specific interaction with SFPQ, resulting in more SFPQ binding to the promoter of TXNIP and causing the transcriptional repression of TXNIP, thus finally promoting the migration and invasion of NSCLC cells. Furthermore, LHFPL3-AS2 was shown to be regulated by EGR1 under hypoxia.

Screening and identification of novel candidate biomarkers of focal cortical dysplasia type II via bioinformatics analysis.

PURPOSE: Focal cortical dysplasia (FCD) is the most common developmental malformation that causes refractory epilepsy. FCD II is a common neuropathological finding in tissues resected therapeutically from patients with drug-resistant epilepsy. However, its molecular genetic etiology remains unclear. This study aimed to identify potential molecular markers of FCD II using bioinformatics analysis. METHODS: We downloaded two datasets for FCD II from the Gene Expression Omnibus data repository. Differentially expressed genes (DEGs) between FCD II and normal brain tissues were identified, and functional enrichment analysis was performed. A protein-protein interaction network was constructed, and hub genes were identified from the DEGs. The hub gene expression was validated using WB in vitro. IHC staining was performed to verify the feasibility of the target molecular markers identified in the bioinformatics analysis. RESULTS: One hundred sixty-seven common DEGs were identified between the datasets. The GO and KEGG analyses showed that variations were prominently enriched in some functions associated with gene expression. Five hub genes (i.e., FANCI, FANCA, BRCA2, RAD18, and KEAP1) were identified. Western blotting confirmed that all hub gene expressions were higher in the FCD II tissue than in the normal brain tissue. IHC staining showed that the FANCI expression significantly increased in the FCD II tissue. CONCLUSION: There are DEGs between FCD II and normal brain tissues, which may be considered biomarkers for FCD II, along with FANCI. The DEGs and hub genes identified in the bioinformatics analysis could serve as candidate targets for diagnosing and treating FCD II.

LncRNA NORAD Mediates the Proliferation and Apoptosis of Diffuse Large-B-Cell Lymphoma via Regulation of miR-345-3p/TRAF6 Axis.

BACKGROUND: Diffuse large-B-cell lymphoma (DLBCL), as the most common subtype of B Cell Non-Hodgkin lymphoma (B-NHL), is one of the lymphoid malignancies with poor prognosis worldwide. Non-coding RNA activated by the DNA damage (NORAD), a novel identified lncRNA involved in the DNA repairment process, is reportedly to participate in carcinogenesis, and it is predicted to sponge miR-345-3p. However, LncRNA NORAD has never been investigated in DLBCL. AIM OF THE STUDY: To investigate the role of LncRNA NORAD and miR-345-3p in DLBCL cells and explore the underlying mechanisms. METHODS: LncRNA NORAD and miR-345-3p levels were determined in the blood samples from patients with B-NHL. Human DLBCL cell lines DB and SU-DHL-4 were transfected with LncRNA NORAD small interfering RNA, miRNA-345-3p mimics, or miRNA-345-3p inhibitor using Lipofectamine RNAiMAX Reagent. Cell cycle, proliferation, and apoptosis were assessed in the transfected cells. RESULTS: Silencing of lncRNA NORAD and overexpression of miR-345-3p both inhibited cell proliferation, induced cell cycle arrest, and triggered apoptosis in DLBCL cells. Inhibition of miR-345-3p counteracted the suppression effects of LncRNA NORAD silencing on DLBCL progression. In addition, LncRNA NORAD shared the regulatory binding sites of miR-345-3p with TNF receptor associated factor 6 (TRAF6). Knockdown of LncRNA NORAD decreased the levels of TRAF6, simultaneously, resulted in deactivation of PI3K/Akt pathway in DLBCL cells. CONCLUSION: LncRNA NORAD regulated DLBCL cell growth and apoptosis via miR-345-3p/TRAF6/PI3K/Akt axis.

MiR-382-5p suppresses M1 macrophage polarization and inflammatory response in response to bronchopulmonary dysplasia through targeting CDK8: Involving inhibition of STAT1 pathway.

Bronchopulmonary dysplasia (BPD) is an inflammation-related respiratory disorder in infants. MiR-382-5p has displayed low expression in developing lungs with BPD, while the effect of miR-382-5p on BPD remains elusive. Here, a hyperoxia (85% oxygen)-induced BPD model in neonatal mice was established. On postnatal days 10 and 15, hyperoxia reduced miR-382-5p expression in lungs of mice. Besides, CDK8, CD68 and CD86 levels were elevated on day 15 after birth, implying the involvement of CDK8 in M1 macrophage polarization. In addition, in vitro injury in RAW264.7 macrophages was induced by IFN-γ and LPS stimulation. Lentivirus-encoding miR-382-5p decreased CDK8 expression, alleviated the production of inflammatory cytokines TNF-α, IL-1ß and IL-6, and restricted the levels of CD40 and CD86 in response to IFN-γ and LPS. Moreover, miR-382-5p inhibited the phosphorylation of STAT1. Luciferase reporter assay verified that miR-382-5p might target the 3'UTR of CDK8. Rescue assays revealed that CDK8 reversed the mitigating roles of miR-382-5p in inflammatory response and M1 macrophage polarization, as reflected by increased IL-6 and CD40 levels. Taken together, these findings indicate that miR-382-5p may suppress M1 macrophage activation and inflammatory response via inhibiting CDK8, thereby regulating the development of BPD, which is possibly mediated by STAT1 signaling.

EGFR activation limits the response of liver cancer to lenvatinib.

Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options1. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit2. Here, using a kinome-centred CRISPR-Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancer cell lines that express EGFR and in vivo in xenografted liver cancer cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition of fibroblast growth factor receptor (FGFR)  by lenvatinib treatment leads to feedback activation of the EGFR-PAK2-ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinib treatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR.

Acidic extracellular pH induces autophagy to promote anoikis resistance of hepatocellular carcinoma cells via downregulation of miR-3663-3p.

Metastasis is the major reason for poor prognosis and high fatality in hepatocellular carcinoma (HCC). Due to the "Warburg effect", an acidic tumor microenvironment (TME) exists in solid tumors and plays a critical role in cancer metastasis. Thus, clarifying the mechanism underlying the acidic TME in tumor metastasis could facilitate the development of new therapeutic strategies for HCC. Anoikis resistance is one of the most important events in the early stage of cancer metastasis. Here, we report that acidic extracellular pH (pHe) promotes autophagy of HCC cells via the AMPK/mTOR pathway. We found that autophagy induced by acidity enhances anoikis resistance of HCC cells, which could be reversed by autophagy inhibitors. Furthermore, miR-3663-3p was downregulated by acidity, and overexpression of miR-3663-3p abolished acidic pHe-induced autophagy and anoikis resistance. In summary, acidic pHe enhances anoikis resistance of HCC cells by inducing autophagy, which is regulated by miR-3663-3p. Our findings provide new insight into how the acidic TME is involved in HCC progression.

circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity.

Circular RNAs (circRNA) are a class of covalently closed single-stranded RNAs that have been implicated in cancer progression. Here we identify circNDUFB2 to be downregulated in non-small cell lung cancer (NSCLC) tissues, and to negatively correlate with NSCLC malignant features. Elevated circNDUFB2 inhibits growth and metastasis of NSCLC cells. Mechanistically, circNDUFB2 functions as a scaffold to enhance the interaction between TRIM25 and IGF2BPs, a positive regulator of tumor progression and metastasis. This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N6-methyladenosine (m6A) modification of circNDUFB2. Moreover, circNDUFB2 is also recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the tumor microenvironment (TME). Our data thus provide evidences that circNDUFB2 participates in the degradation of IGF2BPs and activation of anti-tumor immunity during NSCLC progression via the modulation of both protein ubiquitination and degradation, as well as cellular immune responses.

PPARγ Coactivator-1α Suppresses Metastasis of Hepatocellular Carcinoma by Inhibiting Warburg Effect by PPARγ-Dependent WNT/ß-Catenin/Pyruvate Dehydrogenase Kinase Isozyme 1 Axis.

BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α (PGC1α) is a key regulator of mitochondrial biogenesis and respiration. PGC1α is involved in the carcinogenesis, progression, and metabolic state of cancer. However, its role in the progression of hepatocellular carcinoma (HCC) remains unclear. APPROACH AND RESULTS: In this study, we observed that PGC1α was down-regulated in human HCC. A clinical study showed that low levels of PGC1α expression were correlated with poor survival, vascular invasion, and larger tumor size. PGC1α inhibited the migration and invasion of HCC cells with both in vitro experiments and in vivo mouse models. Mechanistically, PGC1α suppressed the Warburg effect through down-regulation of pyruvate dehydrogenase kinase isozyme 1 (PDK1) mediated by the WNT/ß-catenin pathway, and inhibition of the WNT/ß-catenin pathway was induced by activation of PPARγ. CONCLUSIONS: Low levels of PGC1α expression indicate a poor prognosis for HCC patients. PGC1α suppresses HCC metastasis by inhibiting aerobic glycolysis through regulating the WNT/ß-catenin/PDK1 axis, which depends on PPARγ. PGC1α is a potential factor for predicting prognosis and a therapeutic target for HCC patients.

Prognosis and personalized treatment prediction in TP53-mutant hepatocellular carcinoma: an in silico strategy towards precision oncology.

TP53 mutation is one of the most common genetic changes in hepatocellular carcinoma (HCC). It is of great clinical significance to tailor specialized prognostication approach and to explore more therapeutic options for TP53-mutant HCCs. In this study, a total of 1135 HCC patients were retrospectively analyzed. We developed a random forest-based prediction model to estimate TP53 mutational status, tackling the problem of limited sample size in TP53-mutant HCCs. A multi-step process was performed to develop robust poor prognosis-associated signature (PPS). Compared with previous established population-based signatures, PPS manifested superior ability to predict survival in TP53-mutant patients. After in silico screening of 2249 drug targets and 1770 compounds, we found that three targets (CANT1, CBFB and PKM) and two agents (irinotecan and YM-155) might have potential therapeutic implications in high-PPS patients. The results of drug targets prediction and compounds prediction complemented each other, presenting a comprehensive view of potential treatment strategy. Overall, our study has not only provided new insights into personalized prognostication approaches, but also thrown light on integrating tailored risk stratification with precision therapy.

Exploring subclass-specific therapeutic agents for hepatocellular carcinoma by informatics-guided drug screen.

Almost all currently approved systemic therapies for hepatocellular carcinoma (HCC) failed to achieve satisfactory therapeutic effect. Exploring tailored treatment strategies for different individuals provides an approach with the potential to maximize clinical benefit. Previously, multiple studies have reported that hepatoma cell lines belonging to different molecular subtypes respond differently to the same treatment. However, these studies only focused on a small number of typical chemotherapy or targeted drugs across limited cell lines due to time and cost constraints. To compensate for the deficiency of previous experimental researches as well as link molecular classification with therapeutic response, we conducted a comprehensive in silico screening, comprising nearly 2000 compounds, to identify compounds with subclass-specific efficacy. Here, we first identified two transcriptome-based HCC subclasses (AS1 and AS2) and then made comparison of drug response between two subclasses. As a result, we not only found that some agents previously considered to have low efficacy in HCC treatment might have promising therapeutic effects for certain subclass, but also identified novel therapeutic compounds that were not routinely used as anti-tumor drugs in clinic. Discovery of agents with subclass-specific efficacy has potential in changing the status quo of population-based therapies in HCC and providing new insights into precision oncology.

Correction: A Trojan horse biomimetic delivery strategy using mesenchymal stem cells for PDT/PTT therapy against lung melanoma metastasis.

Correction for 'A Trojan horse biomimetic delivery strategy using mesenchymal stem cells for PDT/PTT therapy against lung melanoma metastasis' by Xumei Ouyang et al., Biomater. Sci., 2020, DOI: 10.1039/c9bm01401b.

A Trojan horse biomimetic delivery strategy using mesenchymal stem cells for PDT/PTT therapy against lung melanoma metastasis.

Mesenchymal stem cell (MSC)-based biomimetic delivery has been actively explored for drug accumulation and penetration into tumors by taking advantage of the tumor-tropic and penetration properties of MSCs. In this work, we further demonstrated the feasibility of MSC-mediated nano drug delivery, which was characterized by the "Trojan horse"-like transport via an endocytosis-exocytosis-endocytosis process between MSCs and cancer cells. Chlorin e6 (Ce6)-conjugated polydopamine nanoparticles (PDA-Ce6) were developed and loaded into the MSCs. Phototherapeutic agents are safe to the MSCs, and their very low dark toxicity causes no impairment of the inherent properties of MSCs, including tumor-homing ability. The MSCs loaded with PDA-Ce6 (MSC-PDA-Ce6) were able to target and penetrate into tumors and exocytose 60% of the payloads in 72 h. The released PDA-Ce6 NPs could penetrate deep and be re-endocytosed by the cancer cells. MSC-PDA-Ce6 tended to accumulate in the lungs and delivered PDA-Ce6 into the tumors after intravenous injection in the mouse model with lung melanoma metastasis. Phototoxicity can be selectively triggered in the tumors by sequentially treating with near-infrared irradiation to induce photodynamic therapy (PDT) and photothermal therapy (PTT). The MSC-based biomimetic delivery of PDA-Ce6 nanoparticles is a potential method for dual phototherapy against lung melanoma metastasis.

Self-Assembled and Self-Monitored Sorafenib/Indocyanine Green Nanodrug with Synergistic Antitumor Activity Mediated by Hyperthermia and Reactive Oxygen Species-Induced Apoptosis.

Liver cancer is a leading cause of cancer morbidity and mortality worldwide, especially in China. Sorafenib (SRF) is currently the most commonly used systemic agent against advanced hepatocellular carcinoma (HCC), which is the most common type of liver cancer. However, HCC patients have only limited benefit and suffer a serious side effect from SRF. Therefore, new approaches are urgently needed to improve the therapeutic effectiveness of SRF and reduce its side effect. In our current study, we developed a self-imaging and self-delivered nanodrug with SRF and indocyanine (ICG) to improve the therapeutic effect of sorafenib against HCC. With the π-π stacking effect between SRF and ICG, a one-step nanoprecipitation method was designed to obtain the SRF/ICG nanoparticles (SINP) via self-assembly. Pluronic F127 was used to shield the SINP to further improve the stability in an aqueous environment. The stability, photothermal effect, cell uptake, ROS production, cytotoxicity, tumor imaging, and tumor-targeting and tumor-killing efficacy of the SINP were evaluated in vitro and in vivo by using an HCC cell line Huh7 and its xenograft tumor model. We found that our designed SINP showed monodisperse stability and efficient photothermal effect both in vitro and in vivo. SINP could rapidly enter Huh7 cells and achieve potent cytotoxicity under near-infrared (NIR) laser irradiation partly by producing a great amount of reactive oxygen species (ROS). SINP had significantly improved stability and blood half-life, and could specifically target tumor via the enhanced permeability and retention (EPR) effect in vivo. In addition, SINP showed improved cytotoxicity in both subcutaneous and orthotopic HCC implantation models in vivo. Overall, this rationally designed sorafenib delivery system with a very high loading capacity (33%) has considerably improved antitumor efficiency in vitro and could completely eliminate subcutaneous tumors without any regrowth in vivo. In conclusion, our self-imaging and self-delivered nanodrug could improve the efficacy of SRF and might be a potential therapy for HCC patients.

circTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1.

Circular RNAs (circRNAs) are identified as vital regulators in a variety of cancers. However, the role of circRNA in lung squamous cell carcinoma (LUSC) remains largely unknown. Herein, we explore the expression profiles of circRNA and mRNA in 5 paired samples of LUSC. By analyzing the co-expression network of differentially expressed circRNAs and dysregulated mRNAs, we identify that a cell cycle-related circRNA, circTP63, is upregulated in LUSC tissues and its upregulation is correlated with larger tumor size and higher TNM stage in LUSC patients. Elevated circTP63 promotes cell proliferation both in vitro and in vivo. Mechanistically, circTP63 shares miRNA response elements with FOXM1. circTP63 competitively binds to miR-873-3p and prevents miR-873-3p to decrease the level of FOXM1, which upregulates CENPA and CENPB, and finally facilitates cell cycle progression.

Porphyrinic Probe for Fluorescence "Turn-On" Monitoring of Cu+ in Aqueous Buffer and Mitochondria.

A zinc(II) porphyrin derivative (ZPSN) was designed and synthesized, and this probe exhibited rapid, selective and reversible binding to Cu+ for fluorescence monitoring in pure aqueous buffer. The detection mechanism is based on Cu+-activated disruption of axial coordination between the pyridyl ligand and the zinc center, which changes the molecular geometry and inhibits intramolecular electron transfer (ET), leading to fluorescence enhancement of the probe. The proposed sensing mechanism was supported by UV-vis spectroscopy/fluorescence spectral titration, NMR spectroscopy, mass spectrometry, and time-resolved fluorescence decay studies. The dissociation constant was calculated to be 6.53 × 10-11 M. CLSM analysis strongly suggested that ZPSN could penetrate live cells and successfully visualize Cu+ in mitochondria. This strategy may establish a design and offer a potential building block for construction of other metal sensors based on a similar mechanism.