CRISPR/Cas9 screen reveals that targeting TRIM34 enhances ferroptosis sensitivity and augments immunotherapy efficacy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a prevalent malignancy characterized by complex heterogeneity and drug resistance. Resistance to ferroptosis is closely related to the progression of HCC. While HCC tumors vary in their sensitivity to ferroptosis, the precise factors underlying this heterogeneity remain unclear. In this study, we sought to elucidate the mechanisms that contribute to ferroptosis resistance in HCC. Whole-genome CRISPR/Cas9 screen using a subtoxic concentration (IC20) of ferroptosis inducer erastin in the HCC cell line Huh7 revealed TRIM34 as a critical driver of ferroptosis resistance in HCC. Further investigation revealed that TRIM34 suppresses ferroptosis in HCC cells, promoting their proliferation, migration, and invasion both in vitro and in vivo. Furthermore, TRIM34 expression is elevated in HCC tumor tissues, correlating with a poor prognosis. Mechanistically, TRIM34 directly interacts with Up-frameshift 1 (UPF1), a core component of the nonsense-mediated mRNA decay (NMD) pathway, to promote its ubiquitination and degradation. This interaction suppresses GPX4 transcript degradation, thus promoting the protein levels of this critical ferroptosis suppressor in HCC. In light of the close crosstalk between ferroptosis and the adaptive immune response in cancer, HCC cells with targeting knockdown of TRIM34 exhibited an improved response to anti-PD-1 treatment. Taken together, the TRIM34/UPF1/GPX4 axis mediates ferroptosis resistance in HCC, thereby promoting malignant phenotypes. Targeting TRIM34 may thus represent a promising new strategy for HCC treatment.

Hypomethylation-enhanced CRTC2 expression drives malignant phenotypes and primary resistance to immunotherapy in hepatocellular carcinoma.

The cyclic AMP-responsive element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a crucial regulator of hepatic lipid metabolism and gluconeogenesis and correlates with tumorigenesis. However, the mechanism through which CRTC2 regulates hepatocellular carcinoma (HCC) progression is largely unknown. Here, we found that increased CRTC2 expression predicted advanced tumor grade and stage, as well as worse prognosis in patients with HCC. DNA promoter hypomethylation led to higher CRTC2 expression in HCC. Functionally, CRTC2 contributed to HCC malignant phenotypes through the activated Wnt/ß-catenin pathway, which could be abrogated by the small-molecular inhibitor XAV-939. Moreover, Crtc2 facilitated tumor growth while concurrently downregulating the PD-L1/PD-1 axis, resulting in primary resistance to immunotherapy. In immunocompetent mice models of HCC, targeting Crtc2 in combination with anti-PD-1 therapy prominently suppressed tumor growth by synergistically enhancing responsiveness to immunotherapy. Collectively, targeting CRTC2 might be a promising therapeutic strategy to sensitize immunotherapy in HCC.

Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers worldwide. The tumor microenvironment (TME) contributes to the poor response of patients with HCC to current therapies, while tumor vascular endothelial cells (ECs) are fundamental TME components that significantly contribute to tumor progression. However, the specific functions and mechanisms of tumor vascular ECs in HCC remain unclear. METHODS: We screened and validated diacylglycerol kinase gamma (DGKG) hyper-expression specifically in HCC tumor vascular ECs. Single-cell RNA-sequencing, cytometry by time-of-flight, and in vitro and in vivo studies were performed to investigate the functions of endothelial DGKG. Multiplexed immunohistochemistry staining and flow cytometry were used to evaluate changes in the TME. RESULTS: Functionally, endothelial DGKG promotes tumor angiogenesis and immunosuppressive regulatory T-cell differentiation in HCC. Of significance, we found that HIF-1α activates DGKG transcription by directly binding to its promoter region under hypoxia. Upregulated DGKG promotes HCC progression by recruiting ubiquitin specific peptidase 16 to facilitate ZEB2 deubiquitination, which increases TGF-ß1 secretion, thus inducing tumor angiogenesis and regulatory T-cell differentiation. Importantly, targeting endothelial DGKG potentiated the efficiency of dual blockade of PD-1 and VEGFR-2. CONCLUSION: Hypoxia-induced EC-specific DGKG hyper-expression promotes tumor angiogenesis and immune evasion via the ZEB2/TGF-ß1 axis, suggesting EC-specific DGKG as a potential therapeutic target for HCC. IMPACT AND IMPLICATIONS: Here, we reported that hypoxia-induced endothelial cell-specific DGKG hyper-expression promotes angiogenesis and immune evasion in HCC by recruiting USP16 for K48-linked deubiquitination and inducing the subsequent stabilization of ZEB2, leading to increased TGF-ß1 secretion. Most importantly, endothelial DGKG inhibition greatly improved the efficacy of the dual combination of anti-VEGFR2 and anti-PD-1 treatment in a mouse HCC model, significantly inhibiting the malignant progression of HCC and improving survival. This preclinical study supports the targeting of endothelial DGKG as a potential strategy for precision HCC treatment.

Hepatocyte Deubiquitinating Enzyme OTUD5 Deficiency is a Key Aggravator for Metabolic Dysfunction-Associated Steatohepatitis by Disturbing Mitochondrial Homeostasis.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a common chronic liver disease worldwide. No effective pharmacologic therapies for MASH have been developed; to develop such promising drugs, the underlying mechanisms regulating MASH need to be elucidated. Here, we aimed to determine the role of ovarian tumor domain-containing protein 5 (OTUD5) in MASH progression and identify a specific mechanism. METHODS: The expression levels of OTUD subfamily under palmitic acid/oleic acid (PAOA) stimulation were screened. OTUD5 expression was assessed in human liver tissues without steatosis, those with simple steatosis, and those with MASH. MASH models were developed in hepatocyte-specific Otud5-knockout mice that were fed high-fat high-cholesterol and high-fat high-cholesterol plus high-fructose/sucrose diet for 16 weeks. RESULTS: The expression of OTUD5 was down-regulated in fatty liver and was negatively related to the progression of MASH. Lipid accumulation and inflammation were exacerbated by Otud5 knockdown but attenuated by Otud5 overexpression under PAOA treatment. Hepatocyte-specific Otud5 deletion markedly exacerbated steatosis, inflammation, and fibrosis in the livers of 2 MASH mouse models. We identified voltage-dependent anion channel 2 (VDAC2) as an OTUD5-interacting partner; OTUD5 cleaved the K48-linked polyubiquitin chains from VDAC2, and it inhibited subsequent proteasomal degradation. The anabolic effects of OTUD5 knockdown on PAOA-induced lipid accumulation were effectively reversed by VDAC2 overexpression in primary hepatocytes. Metabolomic results revealed that VDAC2 is required for OTUD5-mediated protection against hepatic steatosis by maintaining mitochondrial function. CONCLUSIONS: OTUD5 may ameliorate MASH progression via VDAC2-maintained mitochondrial homeostasis. Targeting OTUD5 may be a viable MASH-treatment strategy.

Thymidine kinase 1 drives hepatocellular carcinoma in enzyme-dependent and -independent manners.

Metabolic reprogramming plays a crucial role in the development of hepatocellular carcinoma (HCC). However, the key drivers of metabolic reprogramming underlying HCC progression remain unclear. Using a large-scale transcriptomic database and survival correlation screening, we identify thymidine kinase 1 (TK1) as a key driver. The progression of HCC is robustly mitigated by TK1 knockdown and significantly aggravated by its overexpression. Furthermore, TK1 promotes the oncogenic phenotypes of HCC not only through its enzymatic activity and production of deoxythymidine monophosphate (dTMP) but also by promoting glycolysis via binding with protein arginine methyltransferase 1 (PRMT1). Mechanistically, TK1 directly binds PRMT1 and stabilizes it by interrupting its interactions with tripartite-motif-containing 48 (TRIM48), which inhibits its ubiquitination-mediated degradation. Subsequently, we validate the therapeutic capacity of hepatic TK1 knockdown in a chemically induced HCC mouse model. Therefore, targeting both the enzyme-dependent and -independent activity of TK1 may be therapeutically promising for HCC treatment.

Impact of high-sensitivity troponin elevation and dynamic changes on 90-day mortality in patients with acute ischemic stroke after mechanical thrombectomy: results from an observational cohort.

BACKGROUND: A study was undertaken to evaluate the impact of high-sensitivity cardiac troponin I (hs-cTnI) elevation and hs-cTnI dynamic changes on 90-day mortality in patients with acute ischemic stroke (AIS) treated with mechanical thrombectomy (MT). METHODS: Patients with AIS receiving MT were included in the study. Sixty hours after AIS onset, hs-cTnI levels were measured before and after MT to determine elevated and dynamic changes. Patients were stratified into either normal or hs-cTnI elevation groups according to the pre-MT hs-cTnI cut-off value of 0.03 ng/L. hs-cTnI dynamic changes were defined as an increase or decrease of more than 20% pre-MT and post-MT, and at least one hs-cTnI level >0.03 ng/L. Multivariate Cox regression models were used to investigate the association between hs-cTnI elevation, hs-cTnI dynamic changes, and 90-day mortality in patients with AIS after MT. RESULTS: A total of 423 patients with AIS after MT were included in our final analysis, of whom only 72 (17%) showed hs-cTnI elevation. Post-MT hs-cTnI retesting was performed in 354 patients, and 90 (25.4%) patients presented with hs-cTnI dynamic changes. 119 patients died within 90 days. After adjusting for potential confounding factors, the Cox regression model showed that patients with hs-cTnI dynamic changes, rather than hs-cTnI elevation, were associated with 90-day mortality (p<0.05). Compared with the hs-cTnI non-dynamic changes, these results showed that a statistical association was present between rising hs-cTnI dynamic changes and 90-day mortality (p>0.05). CONCLUSIONS: hs-cTnI dynamic changes, dominated by the rising pattern rather than hs-cTnI elevation, were independent factors associated with 90-day mortality in patients with AIS after MT, especially in elderly subjects.

Etomidate elicits anti-tumor capacity by disrupting the JAK2/STAT3 signaling pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading malignancy of the digestive system, especially in China. Although radiotherapy, chemotherapy, and transarterial chemoembolization have achieved tremendous success, surgical resection remains the primary treatment for HCC patients. Recent studies have shown that intravenous anesthetic drugs may affect the malignant behaviors of tumor cells, ultimately leading to differences in the postoperative prognosis of patients. Etomidate is one of the most widely used intravenous anesthetic drugs for the induction and maintenance of anesthesia in tumor patients undergoing surgery. However, the effects and underlying mechanisms of etomidate on HCC cells have not yet been characterized. Our study indicated that etomidate significantly impedes the malignant progression of HCC cells. Mechanistically, etomidate inhibits phosphorylation and, ultimately, the activity of Janus kinase 2 (JAK2) by competing with ATP for binding to the ATP-binding pocket of JAK2. Thus, it suppresses the JAK2/STAT3 signaling pathway in HCC cells to exert its anti-tumor efficacy. Herein, we provide preclinical evidence that etomidate is the optimal choice for surgical treatment of HCC patients.

PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells.

Programmed death receptor-1 (PD-1) blockade have achieved some efficacy but only in a fraction of patients with hepatocellular carcinoma (HCC). Programmed cell death 1 ligand 1 (PD-L1) binds to its receptor PD1 on T cells to dampen antigen-tumor immune responses. However, the mechanisms underlying PD-L1 regulation are not fully elucidated. Herein, we identify that tumoral Prdm1 overexpression inhibits cell growth in immune-deficient mouse models. Further, tumoral Prdm1 overexpression upregulates PD-L1 levels, dampening anti-tumor immunity in vivo, and neutralizes the anti-tumor efficacy of Prdm1 overexpression in immune-competent mouse models. Mechanistically, PRDM1 enhances USP22 transcription, thus reducing SPI1 protein degradation through deubiquitination, which enhances PD-L1 transcription. Functionally, PD-1 mAb treatment reinforces the efficacy of Prdm1-overexpressing HCC immune-competent mouse models. Collectively, we demonstrate that the PRDM1-USP22-SPI1 axis regulates PD-L1 levels, resulting in infiltrated CD8+ T cell exhaustion. Furthermore, PRDM1 overexpression combined with PD-(L)1 mAb treatment provides a therapeutic strategy for HCC treatment.

Pan-cancer analysis identifies CDCA3 as a novel prognostic marker associated with immune infiltration in lung adenocarcinoma through bioinformatics analysis.

Background: Lung adenocarcinoma (LUAD) is the most common subtype of lung malignancy. However, the expression of cell division cycle-associated protein-3 (CDCA3) and its significance in LUAD remain unclear. In this study, we investigated the functional role of CDCA3 in LUAD through bioinformatics analysis and expected to provide a new direction for clinical treatment. Methods: The expression of CDCA3 was analyzed by online database. The association between the expression of CDCA3 and clinical parameters with LUAD was explored in TCGA. Survival and independent prognostic analysis were performed by TCGA database and the GSE30219 and GSE31210 datasets. Furthermore, Enrichment analyses were conducted to analyze the functions of CDCA3. Afterward, the relationship between CDCA3 and immune infiltration was investigated. Additionally, a competing endogenous RNA (ceRNA) regulatory network related to CDCA3 was constructed. Finally, CDCA3 expression was validated in clinical tissues by immunohistochemistry (IHC), real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and western blotting (WB). Results: CDCA3 expression was upregulated in 20 tumors and was significantly higher in LUAD compared with normal tissues in3 datasets. In addition, CDCA3 was significantly correlated with age, gender, stage, N, and smoking status. Kaplan-Meier survival curves showed that LUAD samples with higher CDCA3 expression were associated with poorer overall survival (OS) and disease-free survival (DFS). Univariate Cox regression analysis showed that the p value of CDCA3 expression was less than 0.05 (P<0.05) and it appeared in the results of multivariate Cox regression analysis (HR ≥1), indicating that CDCA3 can be used as an independent prognostic factor for LUAD. Intriguingly, Gene Set Enrichment Analysis (GSEA) suggested that CDCA3 was correlated with DNA-related terms and metabolic-related pathways in LUAD. CDCA3 expression was correlated with four immune scores and 14 immune cells in different groups. Next, a ceRNA network was constructed with CDCA3, and the experimental results of IHC, qRT-PCR, and WB were consistent with the bioinformatic analysis. Conclusions: CDCA3 could serve as a prognostic biomarker for LUAD.

Identification and Validation of Long Non-Coding RNA LCIIAR as a Biomarker in LUAD.

Lung cancer is the leading cause of cancer-related death worldwide. Therapies for lung cancer have relatively poor outcomes and need to be improved. Lung cancer immune cell infiltration associated RNA (LCIIAR) is a long noncoding RNA (lncRNA), which is overexpressed in human cancers. However, the clinical significance and functional role of LCIIAR in Lung Adenocarcinoma remain unclear. Here, we identified a novel long non-coding RNA (ENSG00000256802), termed LCIIAR (lung cancer immune cell infiltration associated lncRNA), up-regulated in lung cancer tissue and cell lines. We show that increase LCIIAR expression correlated with poor clinical stage and adverse clinical outcomes and that could also serve as an independent unfavorable prognostic factor in patients with Lung Adenocarcinima. GSEA analysis demonstrated that LCIIAR is mainly involved in the regulation of the immune response. We uncovered that elevate LCIIAR expression positively correlated with immune infiltration and immune modulator in Lung Adenocarcinoma. More importantly, we confirmed that silencing of LCIIAR expression significantly inhibits the proliferation, and migration abilities of these tumour cells. We also demonstrated that the LCIIAR/hsa-miR184/SLC16A3/CDCP1 network regulates SLC16A3/CDCP1 overexpression in and is associated with poor prognosis in this tumour. Therefore our findings revealed the critical role of LCIIAR in Lung Adenocarcinoma progression, which may also serve as a prognostic biomarker and novel therapeutic target.

Assessment of Therapeutic Benefit and Option Strategy on Intravesical Instillation for Preventing Bladder Cancer Recurrence after Radical Nephroureterectomy in Patients with Upper Urinary Tract Urothelial Carcinoma.

Objective: Upper urinary tract urothelial carcinoma (UUT-UC) is a very aggressive disease, characterized by 22%-50% of patients suffering from subsequent bladder recurrence after radical nephroureterectomy (RNU). Although the therapy of intravesical instillation is reported to be effective in preventing bladder recurrence, no study had been reported in Northeast China. The findings relating to the clinical effectiveness of intravesical instillation after RNU are somewhat controversial, and the best efficacy and least adverse effects of instillation drugs have not been widely accepted. Here, we aimed at evaluating the efficacy of intravesical instillation for the prevention intravesical recurrence systematically. Methods: In this retrospective cohort study, from October 2006 to September 2017, 158 UUT-UC patients underwent RNU were divided into 4 groups: epirubicin (EPB) instillation group, hydroxycamptothecin (HCPT) instillation group, bacillus Calmette-Guerin (BCG) instillation group, and noninstillation group. Cox univariate and multivariate analyses were employed to identify the risk factors for intravesical recurrence-free survival (IVRFS). The nomogram model was also applied to predict patient outcomes. Subsequently, to evaluate the clinical significance of intravesical instillation comprehensively, several databases including PubMed, Ovid, and Embase were searched and data from published studies with our results were combined by direct meta-analysis. Moreover, a network meta-analysis comparing instillation therapies was conducted to evaluate the clinical efficacy of different instillation drugs. Results: In our retrospective cohort study, the Kaplan-Meier survival curve demonstrated noninstillation groups were associated with worsened IVRFS. Meanwhile, multivariate analysis indicated that intravesical instillation was independent protective factors for IVRFS (hazard ratio [HR] = 0.731). Moreover, calibration plots, receiver operating characteristic (ROC) curves, area under the curve (AUC) values, and the C-index showed the priority of nomogram's predictive accuracy. Next, direct meta-analysis including 19 studies showed that intravesical instillation could prevent the recurrence of bladder cancer with a pooled risk ratio (RR) estimate of 0.53. Subgroup analysis by study type, year of intravesical recurrence, first instillation time, and instillation times also confirmed the robustness of the results. Moreover, intraoperative instillation was associated with a decrease in the risk of bladder recurrence compared with postoperative instillation. Then, a network meta-analysis including 7 studies indicated that pirarubicin (THP) (surface under the cumulative ranking curve [SUCRA] = 89.2%) is the most effective therapy to reduce the risk of bladder recurrence, followed by BCG (SUCRA = 83.5%), mitomycin C (MMC) (SUCRA = 53.6%), EPB (SUCRA = 52.6%), and HCPT (SUCRA = 5.1%) after the analysis of the value ranking. Conclusions: A maintenance schedule of intravesical instillation prevents the recurrence of bladder cancer after RNU in UUT-UC patients effectively. Large, prospective trials are needed to further confirm its value. Compared with other chemotherapy regimens, THP may be a promising drug with favorable efficacy to prevent bladder recurrence. As included studies had moderate risk of bias, the results of network meta-analysis should be applied with caution.

Advances in the Development of Biomarkers for Poststroke Epilepsy.

Stroke is the main cause of acquired epilepsy in elderly people. Poststroke epilepsy (PSE) not only affects functional recovery after stroke but also brings considerable social consequences. While some factors such as cortical involvement, hemorrhagic transformation, and stroke severity are associated with increased seizure risk, so far that remains controversial. In recent years, there are an increasing number of studies on potential biomarkers of PSE as tools for diagnosing and predicting epileptic seizures. Biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glutamate, and S100 calcium-binding protein B (S100B) in blood are associated with the occurrence of PSE. This review is aimed at summarizing the progress on potential biomarkers of PSE.

HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation.

N6-methyladenosine (m6A), and its reader protein YTHDF1, play a pivotal role in human tumorigenesis by affecting nearly every stage of RNA metabolism. Autophagy activation is one of the ways by which cancer cells survive hypoxia. However, the possible involvement of m6A modification of mRNA in hypoxia-induced autophagy was unexplored in human hepatocellular carcinoma (HCC). In this study, specific variations in YTHDF1 expression were detected in YTHDF1-overexpressing, -knockout, and -knockdown HCC cells, HCC organoids, and HCC patient-derived xenograft (PDX) murine models. YTHDF1 expression and hypoxia-induced autophagy were significantly correlated in vitro; significant overexpression of YTHDF1 in HCC tissues was associated with poor prognosis. Multivariate cox regression analysis identified YTHDF1 expression as an independent prognostic factor in patients with HCC. Multiple HCC models confirmed that YTHDF1 deficiency inhibited HCC autophagy, growth, and metastasis. Luciferase reporter assays and chromatin immunoprecipitation demonstrated that HIF-1α regulated YTHDF1 transcription by directly binding to its promoter region under hypoxia. The results of methylated RNA immunoprecipitation sequencing, proteomics, and polysome profiling indicated that YTHDF1 contributed to the translation of autophagy-related genes ATG2A and ATG14 by binding to m6A-modified ATG2A and ATG14 mRNA, thus facilitating autophagy and autophagy-related malignancy of HCC. Taken together, HIF-1α-induced YTHDF1 expression was associated with hypoxia-induced autophagy and autophagy-related HCC progression via promoting translation of autophagy-related genes ATG2A and ATG14 in a m6A-dependent manner. Our findings suggest that YTHDF1 is a potential prognostic biomarker and therapeutic target for patients with HCC.

Multifunctional Mesoporous Polydopamine With Hydrophobic Paclitaxel For Photoacoustic Imaging-Guided Chemo-Photothermal Synergistic Therapy.

BACKGROUND: Chemo-photothermal therapy has attracted intensive attention because of its low side effects and better therapeutic efficiency. Although many photothermal agents have been loaded with chemotherapeutic drugs for chemo-photothermal therapy, their applications are limited by complex synthetic protocols and long-term safety. Therefore, there is significant clinical value in the development of a simple system of biocompatible and biodegradable photothermal nanomaterials with high payloads of chemotherapeutic drugs for chemo-photothermal synergistic therapy. MATERIALS AND METHODS: In this study, PEG-modified polydopamine nanoparticles with mesoporous structure (MPDA-PEG) were successfully obtained by an emulsion-induced interface assembly strategy. Subsequently, paclitaxel (PTX) dissolved in acetone was loaded into the mesoporous channels of MPDA-PEG nanoparticles by solution absorption method. A PTX-loaded MPDA-PEG (MPDA-PEG-PTX) nanoplatform for combination of photothermal therapy (PTT) and chemotherapy was developed. RESULTS: The synthesized MPDA-PEG nanoparticles had a great photothermal effect under near-infrared (NIR) laser irradiation and exhibited an enhanced photothermal effect with the increase of particle size. Meanwhile, MPDA-PEG nanoparticles also had a high payload of PTX, and the PTX release could be greatly accelerated by elevated temperature from photothermal effect. In MTT cytotoxicity assay, A549 cells incubated with MPDA-PEG-PTX under NIR laser irradiation (PTT + chemotherapy group) exhibited better therapeutic effect than single chemotherapy (MPDA-PEG-PTX group) and PTT (MPDA-PEG + Laser group). The synergistic therapeutic effect of MPDA-PEG-PTX with NIR laser irradiation in vivo was further investigated under the guidance of photoacoustic imaging (PAI), tumors of nude mice treated with MPDA-PEG-PTX with NIR laser irradiation were completely eliminated with minimal side effect. CONCLUSION: The MPDA-PEG-PTX nanoplatform is a simple and effective platform which can completely inhibit tumor growth with minimal side effects under NIR irradiation, and it exhibits better therapeutic effect than single chemotherapy and PTT.

Metal-Organic Framework Nanoparticles with Near-Infrared Dye for Multimodal Imaging and Guided Phototherapy.

From the conception of atom economy to develop multifunctional nanomaterials, it is important to construct nanomaterials by maximizing functional units while minimizing unnecessary components. Noteworthy, metal-organic framework (MOF) nanoparticles are excellent examples to meet this idea. Current approaches for multifunctional MOFs are mainly based on encapsulation of functional molecules or multistep modification; however, high risk for leakage and burst release and time-consuming and complicated organic synthesis limit their applications. Here, we report a one-pot approach to build the defect structure of a metal organic framework with near-infrared dye (cypate), which is based on the interaction between Fe3+ and carboxyl group of cypate molecules, to construct a multifunctional MOF. Moreover, this system can achieve multimodal imaging guided phototherapy. Subsequently, the precise cancer phototherapy is investigated in vivo, and the tumors are entirely eliminated without obvious side effects, demonstrating the high efficacy and safety of this multifunctional platform. Hence, it is expected that not only this system is simple, safe, and highly effective but also our method of creating defect structures of MOFs will open a new way to develop multifunctional nanoplatforms for bioapplications.

Swelling Poly(ionic liquid) Supported by Three-Dimensional Wire Mesh for Oil/Water Separation.

A kind of oil/water separation membrane, combining poly(ionic liquid) (PIL) and three-dimensional (3D) wire mesh, was designed and prepared via one-step photopolymerization of an ionic liquid monomer 1,8-triethylene glycoldiyl-3,3'-divinylimidazolium dibromide ([DVIm-(EG)3]Br2) with acrylic acid in the mesh. The composite membrane (PIL@Mesh) had the advantages of anti-oil-adhesion property and high mechanical strength simultaneously. The morphology of PIL@Mesh characterized by scanning electron microscopy (SEM) and Cryo-SEM demonstrated that PIL swelled in water to construct microscale 3D networks. The 3D networks of swelling PIL were capable of forming a hydration layer and endowed PIL@Mesh with superhydrophilicity, which made the membrane to transport water but to intercept oil. PIL@Mesh showed excellent separation efficiency (above 99.9%) for various oil/water mixtures, large water flux (47 L·m-2·s-1), and high intrusion pressure (1.2 kPa). Meanwhile, it performed well in recyclability and corrosion-resistant under harsh conditions, such as acid, alkaline, and salty environments.

Genetic variants in cytokine signaling pathways and clinical outcomes in early-stage lung cancer patients.

OBJECTIVES: The purpose of this study was to explore the role of single nucleotide polymorphisms (SNPs) in cytokine signaling genes and to compare them with clinical outcomes in surgical patients with non-small cell lung cancer (NSCLC). METHODS: SNPs of the cytokine signaling pathway were analyzed using peripheral blood of 722 patients who underwent resection of stage I to III NSCLC between 1995 and 2009. Cox proportional hazard analyses were performed to identify SNPs associated with overall survival (OS) and risk of recurrence. Internal validation using bootstrap analysis selected SNPs for unfavorable genotype and survival tree analysis. RESULTS: Seventeen and 9 SNPs were independently associated with OS and recurrence, respectively. Patients with ≥9 unfavorable genotypes experienced worse OS (median, 41 months) than patients with 7 to 8 (89 months) and ≤6 (153 months) after median follow-up of 71 months (P = 2.86 × 10-23). Patients with ≤3 unfavorable genotypes had greater time to recurrence (median not reached) than those with 4 to 6 (114 months) and ≥7 (44 months; P = 1.3 × 10-5). Survival tree analysis classified patients into 3 risk groups. Patients in the intermediate- (median OS, 82 months) and high-risk groups (43 months) had worse survival than the low-risk group (176 months; P = 5.51 × 10-20). Median time to recurrence was worse in the intermediate- (114 months) and high-risk groups (58 months) than the low-risk group (median not reached; P = 2.52 × 10-9). CONCLUSIONS: Genetic variants in cytokine signaling pathways were associated with clinical outcomes in NSCLC patients treated with surgery individually and cumulatively. Further studies are necessary to elucidate our findings and translate them into the clinical setting.

Serum MicroRNA-150 Predicts Prognosis for Early-Stage Non-Small Cell Lung Cancer and Promotes Tumor Cell Proliferation by Targeting Tumor Suppressor Gene SRCIN1.

This integrative multistage study was aimed to identify circulating microRNAs (miRNAs) as prognostic biomarkers and investigate the treatment target for early-stage non-small cell lung cancer (NSCLC) patients. In stage I-II NSCLC patients, we screened and validated the miRNA ratio signatures predictive of prognosis in serum. In tumor, we found that the expression of miR-150 in identified miRNA signatures was also associated with survival. Increased miR-150 expression promoted NSCLC cell proliferation and migration and vice versa. Specific mRNA cleavage sites targeted by endogenous miR-150 in 3' untranslated region (UTR) of SRCIN1 was identified by utilizing our recently developed novel Stem-Loop-Array reverse-transcription polymerase chain reaction (SLA-RT-PCR) assay. The blocking action of miR-150 resulted in repressed NSCLC cell growth in vitro and knockdown of miR-150 caused substantial tumor volume reduction in vivo. Our findings suggest that miR-150 binding on specific recognition sites in 3' UTR of tumor suppressor gene SRCIN1 present a potential therapeutic target for NSCLC.

Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer.

BRCA1 associated protein-1 (BAP1) is a novel tumor suppressor that has recently been shown to be somatically mutated in several cancers. The BAP1 gene also carries rare germline mutations in families with a high incidence of several types of cancers, such as mesothelioma, uveal melanoma, lung adenocarcinoma, melanocytic neoplasms, and renal cell carcinoma. To test the hypothesis that common, germline genetic variants in BAP1 may also contribute to the risk of developing different types of cancer, we genotyped germline single nucleotide polymorphisms (SNPs) for BAP1 in a large population of patients with cancer, including 2,340 with colorectal cancer, 1,436 with bladder cancer, 3,313 with lung cancer, 1,325 with renal cell carcinoma, and 1,162 with esophageal cancer. We identified significant association of rs11708581 (P = 0.0034) and rs390802 (P = 0.015) with risk of renal cell carcinoma and rs12163565 (P = 0.038) with risk of lung cancer. Expression quantitative trait loci analysis in renal cell carcinoma using publicly available data from TCGA showed that the proxy SNPs for rs11708581 and rs390802 were negatively associated with the expression level of BAP1. Our study indicate that common germline genetic variants of BAP1 play a role in mediating the risk of developing renal cell carcinoma and lung cancer.

Lower mitochondrial DNA copy number in peripheral blood leukocytes increases the risk of endometrial cancer.

Mitochondria are the primary source of energy generation in human cells. Low mitochondrial DNA (mtDNA) copy number in peripheral blood leukocytes (PBLs) has been associated with obesity and increased risks of several cancers. Since obesity is a significant risk factor for endometrial cancer, we hypothesize that low mtDNA copy number in PBLs is associated with an increased susceptibility to endometrial cancer. Using a Caucasian case-control study, we measured mtDNA copy number in PBLs from 139 endometrial cancer patients and 139 age-matched controls and determined the association of mtDNA copy number with the risk of endometrial cancer using multivariate logistic regression analysis. The normalized mtDNA copy number was significantly lower in endometrial cancer cases (median, 0.84; range, 0.24-2.00) than in controls (median, 1.06; range, 0.64-1.96) (P < 0.001). Dichotomized into high and low groups based on the median mtDNA copy number value in the controls, individuals with low mtDNA copy number had a significantly increased risk of endometrial cancer (adjusted OR, 5.59; 95%CI, 3.05-10.25; P < 0.001) compared to those with high mtDNA copy number. There was a significant dose-response association in tertile analysis. In addition, there was a significant joint effect between lower mtDNA copy number and never smoking, hypertension, diabetes, and obesity in elevating the risk of endometrial cancer. Low mtDNA copy number in PBLs is significantly associated with an increased risk of endometrial cancer in Caucasians. © 2015 Wiley Periodicals, Inc.