Potentially functional variants of INPP5D and EXOSC3 in immunity B cell-related genes are associated with non-small cell lung cancer survival.

B cells are adaptive immune cells in the tumor microenvironment and play an important role in tumor development and metastasis. However, the roles of genetic variants of the immunity B cell-related genes in the survival of patients with non-small cell lung cancer (NSCLC) remain unknown. In the present study, we first evaluated associations between 10,776 single nucleotide polymorphisms (SNPs) in 220 immunity B cell-related genes and survival of NSCLC in a discovery dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that 369 SNPs were significantly associated with overall survival (OS) of NSCLC in multivariable Cox proportional hazards regression analysis (P ≤ 0.05, Bayesian false discovery probability ≤ 0.80), of which 18 SNPs were validated in another independent genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. We then performed linkage disequilibrium (LD) analysis, followed by stepwise analysis with a multivariable Cox regression model. Finally, two independent SNPs, inositol polyphosphate-5-phosphatase D (INPP5D) rs13385922 C>T and exosome component 3 (EXOSC3) rs3208406 A>G, remained significantly associated withNSCLC OS with a combined hazards ratio (HR) of 1.14 (95% confidence interval = 1.06-1.23, P = 2.41×10-4) and 1.20 (95% confidence interval = 1.14-1.28, P = 3.41×10-9), respectively. Furthermore, NSCLC patients with the combination of unfavorable genotypes for these two SNPs were associated with a poor OS (P trend = 0.0002) and disease-specific survival (DSS, P trend < 0.0001) in the PLCO dataset. Expression quantitative trait loci (eQTL) analysis suggested that the INPP5D rs6782875 T allele was significantly correlated with elevated INPP5D mRNA expression levels in normal lung tissues and whole blood samples, while the EXOSC3 rs3208406 G allele was significantly correlated with increased EXOSC3 mRNA expression levels in normal lung tissues. Our data indicated that genetic variants in these immunity B cell-related genes may predict NSCLC survival possibly by influencing the gene expression.

Potentially functional variants of ERRFI1 in hypoxia-related genes predict survival of non-small cell lung cancer patients.

BACKGROUND: Hypoxia is often involved in tumor microenvironment, and the hypoxia-induced signaling pathways play a key role in aggressive cancer phenotypes, including angiogenesis, immune evasion, and therapy resistance. However, it is unknown what role genetic variants in the hypoxia-related genes play in survival of patients with non-small cell lung cancer (NSCLC). METHODS: We evaluated the associations between 16,092 single-nucleotide polymorphisms (SNPs) in 182 hypoxia-related genes and survival outcomes of NSCLC patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were used as the discovery dataset, and the Harvard Lung Cancer Susceptibility (HLCS) Study served as the replication dataset. We also performed additional linkage disequilibrium analysis and a stepwise multivariable Cox proportional hazards regression analysis in the PLCO dataset. RESULTS: An independent SNP, ERRFI1 rs28624 A > C, was identified with an adjusted hazards ratio (HR) of 1.31 (95% CI = 1.14-1.51, p = 0.0001) for overall survival (OS). In further analyses, unfavorable genotypes AC and CC, compared with the AA genotype, were associated a worse OS (HR = 1.20, 95% CI = 1.03-1.39, p = 0.014) and disease-specific survival (HR = 1.21, 95% CI = 1.04-1.42, p = 0.016). Further expression quantitative trait loci analysis indicated that ERRFI1 rs28624C genotypes were significantly associated with higher ERRFI1 mRNA expression levels in the whole blood. Additional analysis showed that high ERRFI1 mRNA expression levels were associated with a worse OS in patients with lung adenocarcinoma. CONCLUSION: Our findings suggest that genetic variants in the hypoxia-related gene ERRFI1 may modulate NSCLC survival, potentially through their effect on the gene expression.

Escherichia coli exopolysaccharides disrupt Pseudomonas aeruginosa biofilm and increase its antibiotic susceptibility.

Pseudomonas aeruginosa (P. aeruginosa) is a major pathogen that causes infectious diseases. It has high tendency to form biofilms, resulting in the failure of traditional antibiotic therapies. Inspired by the phenomenon that co-culture of Escherichia coli (E. coli) and P. aeruginosa leads to a biofilm reduction, we reveal that E. coli exopolysaccharides (EPS) can disrupt P. aeruginosa biofilm and increase its antibiotic susceptibility. The results show that E. coli EPS effectively inhibit biofilm formation and disrupt mature biofilms in P. aeruginosa, Staphylococcus aureus, and E. coli itself. The maximal inhibition and disruption rates against P. aeruginosa biofilm are 40 % and 47 %, respectively. Based on the biofilm-disrupting ability of E. coli EPS, we develop an E. coli EPS/antibiotic combining strategy for the treatment of P. aeruginosa biofilms. The combination with E. coli EPS increases the antibacterial efficiency of tobramycin against P. aeruginosa biofilms in vitro and in vivo. This study provides a promising strategy for treating biofilm infections. STATEMENT OF SIGNIFICANCE: Biofilm formation is a leading cause of chronic infections. It blocks antibiotics, increases antibiotic-tolerance, and aids in immune evasion, thus representing a great challenge in clinic. This study proposes a promising approach to combat pathogenic Pseudomonas aeruginosa (P. aeruginosa) biofilms by combining Escherichia coli exopolysaccharides with antibiotics. This strategy shows high efficiency in different P. aeruginosa stains, including two laboratory strains, PAO1 and ATCC 10145, as well as a clinically acquired carbapenem-resistant strain. In addition, in vivo experiments have shown that this approach is effective against implanted P. aeruginosa biofilms and can prevent systemic inflammation in mice. This strategy offers new possibilities to address the clinical failure of conventional antibiotic therapies for microbial biofilms.

Histatin 5-Inspired Short-Chain Peptides Selectively Combating Pathogenic Fungi with Multifaceted Mechanisms.

Short-chain antifungal peptides (AFPs) inspired by histatin 5 have been designed to address the problem of antifungal drug resistance. These AFPs demonstrate remarkable antifungal activity, with a minimal inhibitory concentration as low as 2 µg mL-1. Notably, these AFPs display a strong preference for targeting fungi rather than bacteria and mammalian cells. This is achieved by binding the histidine-rich domains of the AFPs to the Ssa1/2 proteins in the fungal cell wall, as well as the reduced membrane-disrupting activity due to their low amphiphilicity. These peptides disrupt the nucleus and mitochondria once inside the cells, leading to reactive oxygen species production and cell damage. In a mouse model of vulvovaginal candidiasis, the AFPs demonstrate not only antifungal activity, but also promote the growth of beneficial Lactobacillus spp. This research provides valuable insights for the development of fungus-specific AFPs and offers a promising strategy for the treatment of fungal infectious diseases.

Combined application of gluteus maximus muscle flaps and random pattern skin flaps in repairing sacrococcygeal sinus tracts: a prospective study and technical note.

BACKGROUND: Sacrococcygeal sinus ulcers are caused by pressure sores, trauma, or surgery. Several surgical techniques have been developed for its treatment; however, studies are ongoing to develop the ideal method. The present study aims to introduce an innovative application of gluteus maximus muscle flaps (GMMFs) packing combined with local random pattern skin flaps (RPSFs) in repairing sacrococcygeal sinus tracts (SSTs). METHODS: This was a prospective analysis study conducted on the patients (n = 26) with SSTs underwent an innovative repairing surgery in Qilu Hospital of Shandong University, China between December 2015 and December 2020. The repairing surgery was GMMFs combined with RPSFs. The demographic information and the clinical parameters including operative time, postoperative healing time, and recurrence rate were used to evaluate the efficacy of the operation. RESULTS: Except one case of partial necrosis at the edge of the flap due to severe fibrosis, which was cured after dressing change, all the other cases showed effective healing after the operation. CONCLUSION: The combined application of GMMFs and RPSFs for the treatment of sacrococcygeal sinus tracts gains the advantages of short operative time, quick postoperative recovery, and low postoperative recurrence rate.

Surface decoration with leucine tetrapeptide: An antibacterial strategy against Gram-negative bacteria.

Surface-associated microbe contamination by Gram-negative bacteria poses a serious problem in medical care. Cationic peptides or polymers are the main materials used for antibacterial surface coating, but the positive charge may lead to blood coagulation. Therefore, exploiting surface coating which is free of positive charge and is effective for Gram-negative bacteria inactivation is in urgent need. In this study, inspired by the affinity between lipopolysaccharides of Gram-negative bacteria and Toll-like receptors of immune cells, we develop a leucine-based tetrapeptide coating strategy for combating Gram-negative bacteria. The obtained surface has excellent bactericidal activity against Gram-negative bacteria like Pseudomonas aeruginosa and Escherichia coli. A 1 mm2 coated glass surface could kill > 9.9 × 104 CFU bacteria in 1 h and has nearly no damage to mammal cells. Moreover, this surface coating strategy could be applied on various surfaces like glass slices, glass capillary cavity and thermoplastic polyurethane slices. And the coated surface could largely mitigate the microbe contamination in an in vivo subcutaneous implantation. This work paves a new way for antibacterial surface-coating which is behaving no positive charge and is of great importance for biomedical devices.

Overcoming the Stromal Barrier of the Cornea with a Peptide Conjugate Nano-Assembly to Combat Fungal Keratitis.

Fungal hyphae deeply invade the cornea in fungal keratitis. The corneal stroma hinders the infiltration of antifungal drugs and reduces their bioavailability. Here, this work reports a peptide conjugate nano-assembly that permeates the stroma and kills the pathogen without irritating the ocular cornea. The hydrophilic surface of the nano-assembly ensures deep permeation into the stroma. When encountering a fungal hyphal cell, the nano-assembly disassembles and exposes the α-helical peptide to destroy the fungal membrane, thus inactivating the pathogen. In a rabbit model of fungal keratitis, the nano-assembly exhibits a better therapeutic effect than commercially available natamycin ophthalmic suspension. Peptide conjugates with a nano-assembled structure and assembly-disassembly behavior could serve as the foundation of a new therapy for fungal keratitis.

One-Dimensional Rod-like Tobacco Mosaic Virus Promotes Macrophage Polarization for a Tumor-Suppressive Microenvironment.

The phenotype of tumor-associated macrophages plays an important role in their function of regulating the tumor immune microenvironment. The M1-phenotype macrophages display tumor-killing and immune activating functions. Here we show that the tobacco mosaic virus (TMV), a rod-like plant virus, can polarize macrophages to an M1 phenotype and shape a tumor-suppressive microenvironment. RAW 264.7 cells and bone marrow derived-macrophages (BMDMs) can recognize TMV via Toll-like receptor-4, and then the MAPK and NF-κB signaling pathways are activated, leading to the production of pro-inflammatory factors. Furthermore, the in vivo assessments on a subcutaneous co-injection tumor model show that the TMV-polarized BMDMs shape a tumor-suppressive microenvironment, resulting in remarkable delay of 4T1 tumor growth. Another in vivo assessment on an established tumor model indicates the high tumor-metastasis-inhibiting capacity of TMV-polarized BMDMs. This work suggests a role for this plant virus in macrophage-mediated therapeutic approaches and provides a strategy for tumor immunotherapy.

Pan-cancer analysis of prognostic and immunological role of DTYMK in human tumors.

Background: Deoxythymidylate kinase (DTYMK) has been reported to correlate with the progression of hepatocellular carcinoma. However, the role of DTYMK in human cancers is not studied. In this study, we studied the prognostic value, functional states, and correlations with immune infiltration of DTYMK in human cancers. Methods: The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), UALCAN, Clinical Proteomic Tumor Analysis Consortium (CPTAC), the search tool for the retrieval of interacting genes (STRING), GeneMANIA, cBioPortal, Cancer Single-cell State Atlas (CancerSEA), and Tumor IMmune Estimation Resource (TIMER) databases were utilized to analyze DTYMK in cancers. Results: In general, DTYMK is abnormally expressed between most human cancer and normal tissues from a pan-cancer perspective. DTYMK can be used as a diagnostic biomarker to differentiate tumor tissues from normal tissues in most tumors. Upregulation of DTYMK predicted poor survival status in most cancer types in TCGA. Moreover, DTYMK expression was correlated with the T stage in ACC, BRCA, KIRC, LIHC, and LUAD, with the N stage in BLCA, HNSC, KICH, KIRC, LUAD, LUSC, and THCA, with the M stage in ACC, KIRC, KIRP, and LUAD, with TNM stage in ACC, KIRC, LIHC, LUAD, and LUSC. In addition, based on single-cell sequencing data, we concluded that the expression of DTYMK was correlated with the functional status of the cell cycle, DNA damage, DNA repair, invasion, EMT, and proliferation. Finally, DTYMK expression was correlated with six infiltrating immune cells, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells by investigating TIMER. Conclusion: Our findings suggested that abnormally expressed DTYMK was correlated with poor survival, malignant functional status, and immune infiltrates. DTYMK might be served as a potential biomarker for diagnosis and poor prognosis in various cancer types. DTYMK might act as a potential target for immune therapy.

Prognostic Implication and Immunological Role of PSMD2 in Lung Adenocarcinoma.

Background: Although previous studies reported that 26S proteasome non-ATPase regulatory subunit 2 (PSMD2) is involved in many human cancers. However, its clinical significance and function in lung adenocarcinoma remain unclear. Here, we examined the prognostic and immunological role of PSMD2 in lung adenocarcinoma. Methods: The Cancer Genome Atlas (TCGA) was conducted to analyze PSMD2 expression and verified using UALCAN. PrognoScan and Kaplan-Meier curves were utilized to assess the effect of PSMD2 on survival. cBioPortal database was conducted to identify the mutation characteristics of PSMD2. Functional enrichment was performed to determine PSMD2-related function. Cancer Single-cell State Atlas (CancerSEA) was used to explore the cancer functional status of PSMD2 at single-cell resolution. PSMD2-related immune infiltration analysis was conducted. Tumor-Immune system interaction database (TISIDB) was performed to verify the correlation between PSMD2 expression and tumor-infiltrating lymphocytes (TILs). Results: Both mRNA and protein expression of PSMD2 were significantly elevated in lung adenocarcinoma. High expression of PSMD2 was significantly correlated with high T stage (p = 0.014), lymph node metastases (p < 0.001), and TNM stage p = 0.005). Kaplan-Meier curves indicated that high expression of PSMD2 was correlated with poor overall survival (38.2 vs. 59.7 months, p < 0.001) and disease-specific survival (59.9 months vs. not available, p = 0.004). Multivariate analysis suggested that PSMD2 was an independent biomarker for poor overall survival (HR 1.471, 95%CI, 1.024-2.114, p = 0.037). PSMD2 had a high mutation frequency of 14% in lung adenocarcinoma. The genetic mutation of PSMD2 was also correlated with poor overall survival, disease-specific survival, and progression-free survival in lung adenocarcinoma. Functional enrichment suggested PSMD2 expression was involved in the cell cycle, RNA transport, and cellular senescence. CancerSEA analysis indicated PSMD2 expression was positively correlated with cell cycle, DNA damage, and DNA repair. Immune infiltration analysis suggested that PSMD2 expression was correlated with immune cell infiltration levels and abundance of TILs. Conclusion: The upregulation of PSMD2 is significantly correlated with poor prognosis and immune infiltration levels in lung adenocarcinoma. Our findings suggest that PSMD2 is a potential biomarker for poor prognosis and immune therapeutic target in lung adenocarcinoma.

Bidirectional Mapping Coupled GAN for Generalized Zero-Shot Learning.

Bidirectional mapping-based generalized zero-shot learning (GZSL) methods rely on the quality of synthesized features to recognize seen and unseen data. Therefore, learning a joint distribution of seen-unseen classes and preserving the distinction between seen-unseen classes is crucial for GZSL methods. However, existing methods only learn the underlying distribution of seen data, although unseen class semantics are available in the GZSL problem setting. Most methods neglect retaining seen-unseen classes distinction and use the learned distribution to recognize seen and unseen data. Consequently, they do not perform well. In this work, we utilize the available unseen class semantics alongside seen class semantics and learn joint distribution through a strong visual-semantic coupling. We propose a bidirectional mapping coupled generative adversarial network (BMCoGAN) by extending the concept of the coupled generative adversarial network into a bidirectional mapping model. We further integrate a Wasserstein generative adversarial optimization to supervise the joint distribution learning. We design a loss optimization for retaining distinctive information of seen-unseen classes in the synthesized features and reducing bias towards seen classes, which pushes synthesized seen features towards real seen features and pulls synthesized unseen features away from real seen features. We evaluate BMCoGAN on benchmark datasets and demonstrate its superior performance against contemporary methods.

Prognostic Implications and Immune Infiltration Analysis of ALDOA in Lung Adenocarcinoma.

Background: aldolase A (ALDOA) has been reported to be involved in kinds of cancers. However, the role of ALDOA in lung adenocarcinoma has not been fully elucidated. In this study, we explored the prognostic value and correlation with immune infiltration of ALDOA in lung adenocarcinoma. Methods: The expression of ALDOA was analyzed with the Oncomine database, the Cancer Genome Atlas (TCGA), and the Human Protein Atlas (HPA). Mann-Whitney U test was performed to examine the relationship between clinicopathological characteristics and ALDOA expression. The receiver operating characteristic (ROC) curve and Kaplan-Meier method were conducted to describe the diagnostic and prognostic importance of ALDOA. The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape were used to construct PPI networks and identify hub genes. Functional annotations and immune infiltration were conducted. Results: The mRNA and protein expression of ALDOA were higher in lung adenocarcinoma than those in normal tissues. The overexpression of ALDOA was significantly correlated with the high T stage, N stage, M stage, and TNM stage. Kaplan-Meier showed that high expression of ALDOA was correlated with short overall survival (38.9 vs 72.5 months, p < 0.001). Multivariate analysis revealed that ALDOA (HR 1.435, 95%CI, 1.013-2.032, p = 0.042) was an independent poor prognostic factor for overall survival. Functional enrichment analysis showed that positively co-expressed genes of ALDOA were involved in the biological progress of mitochondrial translation, mitochondrial translational elongation, and negative regulation of cell cycle progression. KEGG pathway analysis showed enrichment function in carbon metabolism, the HIF-1 signaling pathway, and glycolysis/gluconeogenesis. The "SCNA" module analysis indicated that the copy number alterations of ALDOA were correlated with three immune cell infiltration levels, including B cells, CD8+ T cells, and CD4+ T cells. The "Gene" module analysis indicated that ALDOA gene expression was negatively correlated with infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, and macrophages. Conclusion: Our study suggested that upregulated ALDOA was significantly correlated with tumor progression, poor survival, and immune infiltrations in lung adenocarcinoma. These results suggest that ALDOA is a potential prognostic biomarker and therapeutic target in lung adenocarcinoma.

Patients' awareness about their own breast cancer characteristics.

BACKGROUND: Patients' knowledge about the characteristics of their own cancer could be an important factor for understanding treatment regimens and adhering to therapies. However, to date nothing is known about the awareness among Chinese breast cancer patients about the characteristics of their own tumors. AIM: To investigate how much knowledge that Chinese breast cancer patients have about their tumor characteristics and the impact of health and education literacy on the acquisition of such information. METHODS: The survey was administered to patients who were diagnosed with breast cancer from 2017 to 2019 in three hospitals in China, and who came in for regular follow-up on an outpatient basis. We collected responses from 226 respondents who were asked about their cancer characteristics (stage, grade, and estrogen receptor status and human epidermal growth factor receptor 2 status of the cancer), and evaluated the correctness by comparing with their medical records. Logistic regression was used to assess the probability of knowing and of correctly answering questions. We also analyzed the association between our findings and the level of the patient's education and their health literacy. RESULTS: Overall, 20.80% to 57.96% of the patients reported knowing about the characteristics of breast cancer; of these, 10.18% to 46.46% reported these characteristics correctly. Education, age, and health literacy were all significantly associated with awareness rate, and with the level to which this information was accurate. CONCLUSION: Breast cancer patients in China know little about their disease, and better education aimed at improving their knowledge about cancer characteristics is urgently needed. The low level of awareness could represent a deficiency of communication between surgeons and patients, which may be one of the reasons why medical disputes occur in China.

Upregulation of LIMK1 Is Correlated With Poor Prognosis and Immune Infiltrates in Lung Adenocarcinoma.

BACKGROUND: Protein-coding gene LIM Domain Kinase 1 (LIMK1) is upregulated in various tumors and reported to promote tumor invasion and metastasis. However, the prognostic values of LIMK1 and correlation with immune infiltrates in lung adenocarcinoma are still not understood. Therefore, we evaluated the prognostic role of LIMK1 and its correlation with immune infiltrates in lung adenocarcinoma. METHODS: Transcriptional expression profiles of LIMK1 between lung adenocarcinoma tissues and normal tissues were downloaded from the Cancer Genome Atlas (TCGA). The LIMK1 protein expression was assessed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas. Receiver operating characteristic (ROC) curve was used to differentiate lung adenocarcinoma from adjacent normal tissues. Kaplan-Meier method was conducted to assess the effect of LIMK1 on survival. Protein-protein interaction (PPI) networks were constructed by the STRING. Functional enrichment analyses were performed using the "ClusterProfiler" package. The relationship between LIMK1 mRNA expression and immune infiltrates was determined by tumor immune estimation resource (TIMER) and tumor-immune system interaction database (TISIDB). RESULTS: The expression of LIMK1 in lung adenocarcinoma tissues was significantly upregulated than those in adjacent normal tissues. Increased LIMK1 mRNA expression was associated with lymph node metastases and high TNM stage. The ROC curve analysis showed that with a cutoff level of 4.908, the accuracy, sensitivity, and specificity for LIMK1 differentiate lung adenocarcinoma from adjacent controls were 69.5, 93.2, and 71.9%, respectively. Kaplan-Meier survival analysis showed lung adenocarcinoma patients with high- LIMK1 had a worse prognosis than those with low- LIMK1 (43.1 vs. 55.1 months, P = 0.028). Correlation analysis indicated LIMK1 mRNA expression was correlated with tumor purity and immune infiltrates. CONCLUSION: Upregulated LIMK1 is significantly correlated with poor survival and immune infiltrates in lung adenocarcinoma. Our study suggests that LIMK1 can be used as a biomarker of poor prognosis and potential immune therapy target in lung adenocarcinoma.

Overexpression of hsa_circ_0001715 is a Potential Diagnostic and Prognostic Biomarker in Lung Adenocarcinoma.

BACKGROUND: Circular RNAs (circRNAs) play important roles in tumorigenesis, including lung cancer. However, the expression profile and clinical value of circRNAs in lung adenocarcinoma remain unclear. The purpose of this study was to establish the circRNAs expression profile of lung adenocarcinoma and determine its potential diagnostic and prognostic value. MATERIALS AND METHODS: The global expression profile of circRNAs in lung adenocarcinoma tissue was determined from five paired lung adenocarcinoma tissues and adjacent normal tissues. The expression levels of selected candidate circRNA were validated by qRT-PCR. Sequence analysis was used to confirm the specificity of amplified circRNA. The candidate circRNA level was further detected in plasma samples from lung adenocarcinoma patients and healthy controls. The relationships between their levels and clinicopathological factors were explored. Receiver operating characteristic (ROC) curve was constructed to differentiate lung adenocarcinoma from healthy controls. Kaplan-Meier was performed to show survival curves and survival characteristics. The significance of different prognostic factors for overall survival (OS) was analyzed using Cox proportional hazards model. RESULTS: CircRNA microarray showed 394 circRNAs were differentially expressed, including 215 up-regulated and 179 down-regulated circRNAs. Hsa_circ_0001715 was the most up-regulated circRNA in lung adenocarcinoma tissues. Plasma hsa_circ_0001715 levels were significantly higher in lung adenocarcinoma patients versus healthy controls (P < 0.001). We further found that high plasma hsa_circ_0001715 was significantly correlated with TNM stage (P = 0.039) and distant metastasis (P = 0.030). Furthermore, ROC curve analysis showed that hsa_circ_0001715 had high diagnostic value, and the area under the curve (AUC) was 0.871. Lung adenocarcinoma patients with plasma hsa_circ_0001715 levels over 0.417 had significantly shorter OS than those with lower levels (P = 0.004). Univariate and multivariate survival analysis showed that plasma hsa_circ_0001715 level was an independent prognostic factor for the OS. CONCLUSION: Our study revealed an aberrant circRNA expression profile in lung adenocarcinoma, and hsa_circ_0001715 is up-regulated and could act as a novel diagnostic and prognostic biomarker for lung adenocarcinoma.

Improving lung cancer treatment: Hyaluronic acid­modified and glutathione­responsive amphiphilic TPGS­doxorubicin prodrug­entrapped nanoparticles.

Lung cancer nanotherapeutics aim to overcome the limitations of conventional therapeutic methods. In the present study, a self­assembled amphiphilic prodrug­based nanocarrier delivery system was developed that exhibited high therapeutic efficiency. D­alpha­tocopheryl polyethylene glycol 1000 succinate (TPGS) conjugated to doxorubicin (DOX) through disulfide (S­S) bonds to constitute TPGS­S­S­DOX was synthesized; furthermore, hyaluronic acid (HA) was conjugated to TPGS to obtain HA­TPGS. TPGS­S­S­DOX prodrug­based and HA­TPGS ligand­modified nanoparticles (HA­TPGS DOX­NPs) were prepared for the treatment of lung cancer. In vitro and in vivo evaluation of the system was performed on lung cancer cell lines and lung tumor­bearing mice. HA­TPGS DOX­NPs had a uniformly spherical shape with a white core and grey shell, with a size of 172.3 nm and a polydispersity index of 0.16. All of the NPs exhibited a drug encapsulation efficiency of >90%. The blank NPs exhibited low toxicity to all the tested cell lines, resulting in viabilities of >85%. HA­TPGS DOX­NPs had a more prominent in vitro antitumor effect than the other NPs tested, with cell viabilities of 80.2, 73.4, 57.8, 39.1, 28.3 and 10.9% observed after 72 h of incubation with 0.01, 0.05, 0.1, 0.5, 1 and 5 µM, respectively. The in vivo results demonstrated that HA­TPGS DOX­NPs had the highest antitumor efficacy, with 10.5% tumor inhibition efficiency after 28 days of injection. Overall, HA­TPGS DOX­NPs had significant antitumor effects and minimal systemic toxicity, and their application may be a promising strategy for the treatment of lung cancer.

Acetylation of TIP60 at K104 is essential for metabolic stress-induced apoptosis in cells of hepatocellular cancer.

Tumor cells often encounter hypoglycemic microenvironment due to rapid cell expansion. It remains elusive how tumors reprogram the genome to survive the metabolic stress. The tumor suppressor TIP60 functions as the catalytic subunit of the human NuA4 histone acetyltransferase (HAT) multi-subunit complex and is involved in many different cellular processes including DNA damage response, cell growth and apoptosis. Attenuation of TIP60 expression has been detected in various tumor types. The function of TIP60 in tumor development has not been fully understood. Here we found that suppressing TIP60 inhibited p53 K120 acetylation and thus rescued apoptosis induced by glucose deprivation in hepatocellular cancer cells. Excitingly, Lys-104 (K104), a previously identified lysine acetylation site of TIP60 with unknown function, was observed to be indispensable for inducing p53-mediated apoptosis under low glucose condition. Mutation of Lys-104 to Arg (K104R) impeded the binding of TIP60 to human NuA4 complex, suppressed the acetyltransferase activity of TIP60, and inhibited the expression of pro-apoptotic genes including NOXA and PUMA upon glucose starvation. These findings demonstrate the critical regulation of TIP60/p53 pathway in apoptosis upon metabolic stress and provide a novel insight into the down-regulation of TIP60 in tumor cells.

Diagnostic and prognostic values of endothelial-cell-specific molecule-1 with malignant pleural effusions in patients with non-small cell lung cancer.

Over-expressed endothelial-cell-specific molecule-1 (ESM-1) in tumor vascular endothelium contributes to tumor angiogenesis, metastasis, and poor prognosis. However, the content of ESM-1 in pleural effusion is unclear. A retrospective study was carried out to investigate the diagnostic and prognostic values of ESM-1 with malignant pleural effusions in patients with non-small cell lung cancer (NSCLC). ESM-1 levels in malignant pleural effusion (MPE) from 70 patients with NSCLC and 50 cases of benign pleural effusion (BPE) were measured using enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) curve was calculated to assess the diagnostic value of ESM-1. Survival curves were performed by Kaplan-Meier method and survival characteristics were compared by log-rank test. Univariable and multivariate Cox proportional hazards model were carried out to analysis the significance of different prognostic factors for overall survival (OS). ESM-1 levels were significantly higher in MPE than those in BPE (p < 0.001). By ROC curve analysis, with a cutoff level of 19.58 ng/ml, the accuracy, sensitivity, and specificity for ESM-1 diagnosis MPE were 82.5%, 81.4%, and 84.0%, respectively. Moreover, NSCLC patients with pleural fluid ESM-1 levels below 19.58 ng/ml had significant longer OS than those patients with higher levels (22.09 months vs. 11.49 months, p = 0.003). Multivariate survival analysis showed that high MPE ESM-1 level was an independent prognostic factor (HR, 1.007; p = 0.039) for the OS of NSCLC patients. This study showed that ESM-1 level in pleural effusion could be a potential diagnostic and prognostic marker in NSCLC patients with MPE.

CELF1 is a central node in post-transcriptional regulatory programmes underlying EMT.

The importance of translational regulation in tumour biology is increasingly appreciated. Here, we leverage polyribosomal profiling to prospectively define translational regulatory programs underlying epithelial-to-mesenchymal transition (EMT) in breast epithelial cells. We identify a group of ten translationally regulated drivers of EMT sharing a common GU-rich cis-element within the 3'-untranslated region (3'-UTR) of their mRNA. These cis-elements, necessary for the regulatory activity imparted by these 3'-UTRs, are directly bound by the CELF1 protein, which itself is regulated post-translationally during the EMT program. CELF1 is necessary and sufficient for both mesenchymal transition and metastatic colonization, and CELF1 protein, but not mRNA, is significantly overexpressed in human breast cancer tissues. Our data present an 11-component genetic pathway, invisible to transcriptional profiling approaches, in which the CELF1 protein functions as a central node controlling translational activation of genes driving EMT and ultimately tumour progression.

A Robust Gradient Based Method for Building Extraction from LiDAR and Photogrammetric Imagery.

Existing automatic building extraction methods are not effective in extracting buildings which are small in size and have transparent roofs. The application of large area threshold prohibits detection of small buildings and the use of ground points in generating the building mask prevents detection of transparent buildings. In addition, the existing methods use numerous parameters to extract buildings in complex environments, e.g., hilly area and high vegetation. However, the empirical tuning of large number of parameters reduces the robustness of building extraction methods. This paper proposes a novel Gradient-based Building Extraction (GBE) method to address these limitations. The proposed method transforms the Light Detection And Ranging (LiDAR) height information into intensity image without interpolation of point heights and then analyses the gradient information in the image. Generally, building roof planes have a constant height change along the slope of a roof plane whereas trees have a random height change. With such an analysis, buildings of a greater range of sizes with a transparent or opaque roof can be extracted. In addition, a local colour matching approach is introduced as a post-processing stage to eliminate trees. This stage of our proposed method does not require any manual setting and all parameters are set automatically from the data. The other post processing stages including variance, point density and shadow elimination are also applied to verify the extracted buildings, where comparatively fewer empirically set parameters are used. The performance of the proposed GBE method is evaluated on two benchmark data sets by using the object and pixel based metrics (completeness, correctness and quality). Our experimental results show the effectiveness of the proposed method in eliminating trees, extracting buildings of all sizes, and extracting buildings with and without transparent roof. When compared with current state-of-the-art building extraction methods, the proposed method outperforms the existing methods in various evaluation metrics.