DUBR suppresses migration and invasion of human lung adenocarcinoma cells via ZBTB11-mediated inhibition of oxidative phosphorylation.

Long noncoding RNAs (lncRNAs) are involved in a variety of cancers, but the role of LncRNA DUBR in lung adenocarcinoma (LUAD), the most prevalent form of lung cancer, remains unclear. In this study we investigated the expression of DUBR in LUAD to ascertain its association with the clinical pathology and prognosis of LUAD. Analysis of mRNA expression in The Cancer Genome Atlas (TCGA) LUAD database and in-house LUAD cohort (n = 94) showed that DUBR was significantly downregulated in LUAD, and was associated with poor prognosis. In LUAD cell lines (H1975, A549), overexpression of DUBR significantly suppressed the migration and invasion of the LUAD cells. We demonstrated that c-Myc could bind to the promoter of DUBR, and transcriptionally suppressed its expression. Knockdown of c-Myc almost completely blocked the invasion and migration of LUAD cells, whereas knockdown of DUBR partially rescued c-Myc-knockdown suppressed cell migration and invasion. Furthermore, DUBR overexpression significantly increased the expression of a downstream protein of DUBR, zinc finger, and BTB domain containing 11 (ZBTB11), in H1975 and A549 cells; knockdown of ZBTB11 partially rescued the DUBR-overexpression suppressed cell migration and invasion; knockdown of c-Myc significantly upregulated the expression of ZBTB11 in LUAD cells. Finally, we revealed that DUBR/ZBTB11 axis suppressed oxidative phosphorylation in LUAD cells. In short, we demonstrate that c-Myc/DUBR/ZBTB11 axis suppresses migration and invasion of LUAD by attenuating cell oxidative phosphorylation, which provides new insights into the regulatory mechanism of DUBR.

Prognostic and Predictive Value of Blood Tumor Mutational Burden in Patients With Lung Cancer Treated With Docetaxel.

BACKGROUND: Biomarkers for chemotherapy efficacy in non-small cell lung cancer (NSCLC) are lacking. This retrospective study assesses the association between blood-based tumor mutational burden (bTMB) and clinical benefit of chemotherapy. METHODS: Clinical and targeted next-generation sequencing data from the OAK trial (training set; n=318) and POPLAR trial (validation set; n=106) in the docetaxel arm were analyzed. The cutoff value of bTMB for outcome prediction was determined based on a time-dependent receiver operating characteristic curve in the training set, and propensity score matching (PSM) was conducted. The primary outcome was overall survival (OS). Durable clinical benefit (DCB) was defined as OS lasting >12 months. Interaction between treatment and bTMB was assessed in the combined set. RESULTS: A lower bTMB was observed in patients with DCB compared with no durable benefit, and in those with a partial response and stable disease compared with progressive disease. The optimized cutoff value of bTMB for predicting OS was 7 single-nucleotide variants per megabase. In the training set, a low bTMB was significantly associated with longer OS and progression-free survival (PFS). The prognostic value of bTMB was confirmed in the validation set and PSM set. The interaction between bTMB and treatment was significant for PFS (interaction P=.043) in the combined set. Mutations in KEAP1 were associated with high bTMB and a lack of benefit from chemotherapy. CONCLUSIONS: Low bTMB is associated with a survival advantage in patients with NSCLC treated with docetaxel, suggesting the prognostic and predictive potential of bTMB for determining chemotherapy efficacy.

A novel enzyme-based functional correlation algorithm for multi-omics reveals the potential mechanisms of traditional Chinese medicines: Taking Jian-Pi-Yi-Shen formula as an example.

The integrated analysis of host metabolome and intestinal microbiome is an opportunity to explore the complex therapeutic mechanisms of traditional Chinese medicines. Currently, researchers mainly employ various statistical correlation analytical methods to investigate metabolome-microbiome correlations. However, these conventional correlation techniques often focus on statistical correlations and their biological meanings are always ignored, especially the functional relevance between them. Here, we developed a novel enzyme-based functional correlation (EBFC) algorithm to further improve the interpretability and the identified scope of microbe-metabolite correlations based on the conventional Spearman's analysis. The proposed EBFC algorithm is successfully utilized to reveal the therapeutic mechanisms of Jian-Pi-Yi-Shen (JPYS) formula on the treatment of adenine-induced chronic kidney disease (CKD) rats. JPYS, a TCM formula for treating CKD, has beneficial clinical effects. We tentatively revealed the potential mechanism of JPYS for treating CKD rats from the perspective of the serum metabolome, gut microbiome, and their interactions. Specifically, 11 metabolites and 19 bacterial genera in the CKD rats were significantly regulated to approaching normal status after JPYS treatment, suggesting that JPYS could ameliorate the pathological symptoms of CKD rats by reshaping the disturbed metabolome and gut microbiota. Further correlation analysis between the significantly perturbed metabolites, microbiota, and the related enzymes provided more strong evidence for the study of host metabolism-microbiota interactions and the therapeutic mechanism of JPYS on CKD rats. In conclusion, these findings will help us to deeply understand the pathogenesis of CKD and provide new insights into the therapeutic mechanism of JPYS.

miR-150 is downregulated in osteosarcoma and suppresses cell proliferation, migration and invasion by targeting ROCK1.

[This retracts the article DOI: 10.3892/ol.2017.5709.].

Humulus lupulus L. Extract Prevents Ovariectomy-Induced Osteoporosis in Mice and Regulates Activities of Osteoblasts and Osteoclasts.

OBJECTIVE: To systematically evaluate the protective effects of Humulus lupulus L. extract (HLE) on osteoporosis mice. METHODS: In vivo experiment, a total of 35 12-week-old female ICR mice were equally divided into 5 groups: the sham control group (sham); the ovariectomy with vehicle group (OVX); the OVX with estradiol valerate [EV, 0.2 mg/(kg•d)] the OVX with low- or high-dose HLE groups [HLE, 1 g/(kg•d) and 3 g/(kg•d)], 7 in each group. Treatment began 1 week after the ovariectomized surgery and lasted for 12 weeks. Bone mass and trabecular bone mircoarchitecture were evaluated by micro computed tomography, and bone turnover markers in serum were evaluated using enzyme-linked immunosorbent assay (ELISA) kits. In vitro experiment, osteoblasts and osteoclasts were treated with HLE at doses of 0, 4, 20 and 100 µg/mL. Biomarkers for bone formation in osteoblasts and bone resorption in osteoclasts were analyzed. RESULTS: Compared with the OVX group, HLE exerted bone protective effects by the increase of estradiol (P<0.05), the improvement of cancellous bone structure, bone mineral density (P<0.01) and the reduction of serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), bone gla-protein, c-terminal telopeptides of type I collagen (CTX-I) and deoxypyridinoline levels (P<0.01 for all). In vitro experiment, compared with the control group, HLE at 20 µg/mL promoted the cell proliferation (P<0.01), and increased the expression of bone morphogenetic protein-2 and osteopontin levels in osteoblasts (both P<0.05). HLE at 100 µg/mL increased the osteoblastic ALP activities, and HLE at all dose enhanced the extracellular matrix mineralization (both P<0.01). Furthermore, compared with the control group, HLE at 20 µg/mL and 100 µg/mL inhibited osteoclastic TRAP activity (P<0.01), and reduced the expression of matrix metalloproteinase-9 and cathepsin K (both P<0.05). CONCLUSION: HLE may protect against bone loss, and have potentials in the treatment of osteoporosis.

Exploring the diagnostic value of photoacoustic imaging for breast cancer: the identification of regional photoacoustic signal differences of breast tumors.

We examined 14 benign and 26 malignant breast nodules by a handheld dual-modal PA/US imaging system and analyzed the data using the quantitative and semi-quantitative method. The PA signal spatial density and PA scores of different regions of the benign and malignant nodules were compared, and the diagnostic performances of two diagnostic methods based on PA parameters were evaluated. For both quantitative and semi-quantitative results, significant differences in the distributions of PA signals in different regions of benign and malignant breast lesions were identified. The PA parameters showed good performance in diagnosing breast cancer, indicating the potential of PAI in clinical utilization.

Atezolizumab prolongs overall survival over docetaxel in advanced non-small-cell lung cancer patients harboring STK11 or KEAP1 mutation.

Somatic mutations of STK11 or KEAP1 are associated with poor clinical outcomes for advanced non-small-cell lung cancer (aNSCLC) patients receiving immune checkpoint inhibitors (ICIs), chemotherapy, or targeted therapy. Which treatment regimens work better for STK11 or KEAP1 mutated (SKmut) aNSCLC patients is unknown. In this study, the efficacy of atezolizumab versus docetaxel in SKmut aNSCLC was compared. A total of 157 SKmut aNSCLC patients were identified from POPLAR and OAK trials, who were tested by blood-based FoundationOne next-generation sequencing assay. Detailed clinical data and genetic alterations were collected. Two independent cohorts were used for biomarker validation (n = 30 and 20, respectively). Median overall survival was 7.3 months (95% confidence interval [CI], 4.8 to 9.9) in the atezolizumab group versus 5.8 months (95% CI, 4.4 to 7.2) in the docetaxel group (adjusted hazard ratio [HR] for death, 0.70; 95% CI, 0.49 to 0.99; P = .042). Among atezolizumab-treated patients, objective response rate, disease control rate, and durable clinical benefit were higher when blood tumor mutation burden (bTMB) and PD-L1 being higher (biomarker 1, n = 61) or with FAT3 mutation-positive tumors (biomarker 2, n = 83) than otherwise. The interactions for survival between these two biomarkers and treatments were significant, which were further validated in two independent cohorts. In SKmut patients with aNSCLC, atezolizumab was associated with significantly longer overall survival in comparison to docetaxel. Having FAT3 mutation or high TMB and PD-L1 expression potentially predict favorable response in SKmut patients receiving atezolizumab.

Advanced Non-Small Cell Lung Cancer Patients With Low Tumor Mutation Burden Might Derive Benefit From Immunotherapy.

The aim of this study is to investigate the association between tumor mutation burden (TMB) and survival in non-small cell lung cancer (NSCLC) patients with anti-programmed cell death protein 1 and anti-programmed death-ligand 1 blockade. Two retrospective cohorts and The Cancer Genome Atlas NSCLC data set were included in this study. The restricted cubic spline analysis was used to explore the association between TMB and survival. The cutoff values for TMB were determined by X-tile software. Primary outcomes were overall survival (OS). The associations between TMB and intratumor heterogeneity, number of segments, fraction of genome alterations, aneuploidy score, and T-cell populations were also investigated. In the restricted cubic spline plots, TMB showed an inverted U-shaped curve with OS. The median OS in the low TMB group was significantly longer than those in the medium TMB group. In The Cancer Genome Atlas NSCLC data set, low TMB was also associated with longer OS in comparison with medium TMB. Furthermore, NSCLC patients with low TMB had significantly lower intratumor heterogeneity, number of segments, fraction of genome alterations, aneuploidy score, T-helper type 2 (Th2) cells, and CD8 T cells, but higher levels of Th1 and Th17 cells. Low TMB might be a prognostic factor for NSCLC patients receiving anti-programmed cell death protein 1/programmed death-ligand 1 immunotherapy.

A non-linear association between blood tumor mutation burden and prognosis in NSCLC patients receiving atezolizumab.

A significant association between high blood-based tumor mutational burden (bTMB) and improved progression-free survival (PFS) was observed in advanced non-small cell lung cancer (NSCLC) receiving atezolizumab. However, this result was unrepeatable in a recent prospective study. We hypothesized that there might be a non-linear association between bTMB and survival. This study used the clinical and genetic data from POPLAR (n = 105, training set) and OAK (n = 324, validation set) trials. The non-linear association between bTMB and survival was assessed using restricted cubic spline (RCS). The cutoff values for bTMB were calculated via X-tile software. Non-linear relationships were observed between bTMB and PFS and overall survival (OS) in RCS plots (both Pnon-linearity < 0.001). The optimal cutoff values of bTMB for predicting PFS and OS were 7 and 14 mutations/Mb, respectively. The median PFS and OS of patients with low and high bTMB were significantly longer than those of patients with medium bTMB in the training, validation, and combined sets. Low and high bTMB were also associated with longer PFS and OS in high-programmed death-ligand 1 (PD-L1) expression population. In conclusion, there was a positive non-linear association between bTMB and survival in NSCLC patients receiving atezolizumab. Patients with low bTMB could also derive benefit from immunotherapy.

COX-2 inhibition by celecoxib in epithelial ovarian cancer attenuates E-cadherin suppression through reduced Snail nuclear translocation.

Elevated cyclooxygenase-2 (COX-2) closely associates with tumor progression and distant metastasis in various human cancers. However, the role of COX-2 in epithelial ovarian cancer (EOC), and its mechanistic details, remain poorly understood. In the present study, we tested hypothesis that COX-2 induces loss of expression of E-cadherin, with resulting promotion of cancer cells' invasiveness in ovarian cancer. First, we observed an inverse relationship between COX-2 and E-cadherin expression as COX-2 was enhanced but E-cadherin was decreased in surgically-resected specimens of EOC. Depletion of COX-2, by celecoxib treatment, resulted in attenuated nuclear translocation of Snail, and, in turn, significantly increased E-cadherin in EOC cell line SKOV3, which was established to be due to the reduced binding of Snail onto E-cadherin promoter. Such COX-2 inhibition resulted in reduced invasion of EOC cells, similar to what was achieved through Snail silencing in SKOV as well as ES-2 EOC cells. These results suggest that COX-2-Snail signaling plays a critical role in regulation of E-cadherin and might provide insights into mechanisms for paracrine inflammation-mediated aggressiveness in EOC.

[Clinical efficiency and activity range of stiff knee by total knee arthroplasty].

OBJECTIVE: To observe clinical effect and influencing factor of total knee arthroplasty (TKA) for the treatment of stiff knee. METHODS: From January 2010 to October 2014, 20 patients(25 knees) with stiff knee were treated with TKA. Among them, including 2 males(3 knees) and 18 females(22 knees), aged from 55 to 78 years old with an average of(64.5± 4.9) years old, the courses of disease ranged from 5 to 21 years with an average 8.3 years. Preoperative and postoperative HSS (hospital for special surgery knee score) score, activity range and complications were observed and compared. RESULTS: All patients were followed up from 12 to 69 months with an average of 35.3 months. Ten patients occurred complications after operation. HSS score was improved from 32.36±12.31 preoperatively to 80.70±18.52 postoperatively, and had statistical difference between two groups;7 knees obtained excellent results, 15 knees good and 3 knees moderate. Activity range was improved from(39.4±5.3)°preoperatively to (92.5±11.2)° at the latest follow up. CONCLUSIONS: Total knee arthroplasty for stiffness knees is feasible and could obtain satisfied activity range and function.

miR-150 is downregulated in osteosarcoma and suppresses cell proliferation, migration and invasion by targeting ROCK1.

Osteosarcoma (OS) is the most common form of bone malignancy in children and adolescents. A class of molecules known as microRNAs (miRNAs) have been routinely associated in the development and progression of OS. The present study was centered on the less well-known miRNA, miRNA (miR)-150, and its role in OS was investigated. The levels of miR-150 were examined in 40 tissue specimens from patients with OS and adjacent normal tissues using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. In addition the expression levels of miR-150 were examined in three OS cell lines and a normal osteoblast cell line. Cell proliferation, migration and invasion assays were performed to establish the correlation between miR-150 and metastasis. The potential targets of miR-150 were theoretically predicted and one high-scoring target, Rho-associated kinase 1 (ROCK1), was established to be a direct target using RT-qPCR and western blot analyses and Pearson's correlation analysis. The results indicated that miR-150 was downregulated in tissues from patients with OS and cell lines. Secondly, it was shown that the overexpression of miR-150 was inversely correlated with OS cell proliferation, migration and invasion. It was also shown that miR-150 negatively regulated the gene expression of ROCK1 in the OS cell lines. Finally, the interaction between miR-150 and ROCK1 was established and it was shown that miR-150 directly targeted ROCK1. In conclusion, miR-150 was found to be a tumor suppressor, and the suppression of miR-150 resulted in elevation in the levels of ROCK1. This interaction between miR-150 and ROCK1 may be key in the progression of OS. Furthermore, miR-150 or ROCK1 may be potential therapeutic targets for the treatment of OS.

Near-infrared dye-loaded magnetic nanoparticles as photoacoustic contrast agent for enhanced tumor imaging.

Objective: Photoacoustic (PA) tomography (PAT) has attracted extensive interest because of its optical absorption contrast and ultrasonic detection. This study aims to develop a biocompatible and biodegradable PA contrast agent particularly promising for clinical applications in human body. Methods: In this study, we presented a PA contrast agent: 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[methoxy (polyethylene glycol)] (DSPE-PEG)-coated superparamagnetic iron oxide (SPIO) nanoparticles (NPs) loaded with indocyanine green (ICG). We used ICG and SPIO NPs because both drugs are approved by the U.S. Food and Drug Administration. Given the strong absorption of near-infrared laser pulses, SPIO@DSPE-PEG/ICG NPs with a uniform diameter of ~28 nm could significantly enhance PA signals. Results: We demonstrated the contrast enhancement of these NPs in phantom and animal experiments, in which the in vivo circulation time of SPIO@DSPE-PEG/ICG NPs was considerably longer than that of free ICG. These novel NPs also displayed a high efficiency of tumor targeting. Conclusions: SPIO@DSPE-PEG/ICG NPs are promising PAT contrast agents for clinical applications.

Aggregation-induced near-infrared absorption of squaraine dye in an albumin nanocomplex for photoacoustic tomography in vivo.

Photoacoustic tomography (PAT) is a newly emerging noninvasive imaging modality that could be further enhanced using near-infrared (NIR)-absorbing materials as contrast agents. To date, the most extensively studied photoacoustic imaging agents are inorganic nanomaterials because organic materials with NIR-absorption capabilities are limited. In this study, a NIR-absorbing nanocomplex composed of a squaraine dye (SQ) and albumin was prepared based on the aggregation-induced NIR absorption of SQ. Through aggregation, the absorption spectrum of SQ was widened from the visible-light region to the NIR region, which facilitated photoacoustic signal generation in the tissue-transparent NIR optical window (700-900 nm). Blood analysis and histology measurements revealed that the nanocomplex can be used for PAT applications in vivo without obvious toxicity to living mice.

Imaging guided photothermal therapy using iron oxide loaded poly(lactic acid) microcapsules coated with graphene oxide.

A novel multifunctional theranostic agent has been successfully fabricated by loading iron oxide nanoparticles into poly(lactic acid) (PLA) microcapsules followed by surface functionalization with graphene oxide. Both in vitro and in vivo experiments proved that the resulting microcapsules could serve as contrast agents to simultaneously enhance ultrasound, magnetic resonance and photoacoustic imaging. The composite microcapsules show good biocompatibility and rapid response to magnetic fields. Due to the strong absorption of the near-infrared light, the composite microcapsules could efficiently kill cancer cells upon NIR laser irradiation. In addition, it was found that such a photothermal effect could be obviously enhanced by applying an external magnetic field. In a nutshell, this multifunctional microcapsule can be developed as a promising platform that integrates multimodality imaging and therapy capabilities for effective cancer theranostics.

Electrically driven magnetic relaxation in multiferroic LuFe2O4.

We report the electrical control of magnetization in multiferroic LuFe2O4 by applying short current pulses. The magnitude of the induced magnetization change depends on the pulse width and current density. The voltage variation during the applied current pulses evidences an electric-field-induced breakdown of charge order and excludes the role of Joule heating. This current driven magnetization change can be interpreted with a three-temperature model in which the delocalized electrons accelerate spin relaxation through a strong spin-charge coupling inherent to multiferroicity. The electrically assisted magnetic relaxation provides a new approach for electrical control of magnetization.