PDGFRA exhibits potential as an indicator of angiogenesis within the tumor microenvironment and is up-regulated in BLCA.

Bladder cancer (BLCA) is a common type of urogenital malignancy worldwide. The recurrence and metastasis of bladder cancer are closely related to angiogenesis, but the underlying mechanisms are unclear. In this study, we developed a method to predict survival outcomes among BLCA patients, which could be used to guide immunotherapy and chemotherapy. We obtained patient data from The Cancer Genome Atlas (TCGA) and identified angiogenesis-related genes from the GeneCards database. First, we used differential expression analysis and univariate Cox analysis to identify angiogenesis-related genes and used correlation analysis to generate molecular subtypes based on M2 macrophages. Next, we constructed a prognostic signature consisting of four genes (ECM1, EFEMP1, SLIT2, and PDGFRΑ), which was found to be an independent prognostic factor. Higher risk scores were associated with worse overall survival and higher expression of immune checkpoints. We also evaluated immune cell infiltration using the CIBERSORT and ssGSEA algorithms. Additionally, we performed stratification analyses, constructed a nomogram, and predicted chemotherapeutic responses based on the risk signature. Finally, we validated our findings by using qRT-PCR as well as IHC data to detect the expression levels of the four genes at mRNA and protein levels in BLCA patients and obtained results that were consistent with our predictions. Our study demonstrates the utility of a four-gene prognostic signature for prognostication in bladder cancer patients and designing personalized treatments, which could provide new avenues for personalized management of these patients.

The role of HIF-1α in BCG-stimulated macrophages polarization and their tumoricidal effects in vitro.

BCG is widely used for cancer treatment, where macrophages play an important role. However, the mechanism of BCG affecting macrophages remains poorly understood. In this study, we used BCG to stimulate myeloid-derived macrophages lacking HIF-1α, the levels of TNF-α, IL-1ß, CD86 of macrophages and their effects on the growth of tumor cells MCA207 and B16-F10 were detected. We found that the absence of HIF-1α prevents BCG-stimulated macrophages from polarizing towards the M (BCG) and attenuating its killing effect on tumor cells. In addition, we demonstrated that the tumors of mice lacking HIF-1α in macrophages were significantly increased by the experiment of mice transplantation. Our study provides relevant evidence for exploring the mechanism of the BCG vaccine in the prevention and treatment of related diseases.

TRIM59: A membrane protein expressed on Bacillus Calmette-Guérin-activated macrophages that induces apoptosis of fibrosarcoma cells by direct contact.

Bacillus Calmette-Guérin (BCG)-activated macrophages (BAMs) have anti-tumor effects, especially on fibrosarcoma cells. However, the mechanism governing this process has not been elucidated to date. TRIM59 is an up-regulated membrane protein expressed on the surface of BAMs. In this study, we found that up-regulated TRIM59 macrophages exhibited excellent growth inhibition on MCA207 fibrosarcoma and induced tumor apoptosis. Moreover, TRIM59 enhanced macrophage infiltration and increased the M1 phenotype macrophages inside the tumor. Furthermore, the cytotoxic T cells and B cells in the spleen and lymphnode have not been affected by TRIM59. These results showed that macrophages expressing TRIM59 exhibited the main cytotoxic effect on tumors. In vitro, we co-cultured TRIM59 up-regulated macrophages fixed with 1% paraformaldehyde or cell culture supernatant and tumor cells. We found that the killing activities of macrophages decreased after treatment with anti-TRIM59 antibody, and the supernatant of TRIM59 up-regulated macrophages had no tumoricidal effect on fibrosarcoma cells, which demonstrated that TRIM59 may be involved in tumoricidal effects via cell-cell contact. In addition, the PI3K-Akt pathway of MCA207 co-cultured with macrophages highly expressing TRIM59 was significantly inhibited, whereas the activation of the PI3K-Akt pathway in MCA207 was not affected after co-culture with TRIM59-CKO macrophages. These results define a vital role of TRIM59 as an anti-tumor effector molecule of BAMs and suggest a new therapeutic target for the treatment of fibrosarcoma.

NMAAP1 regulated macrophage polarizion into M1 type through glycolysis stimulated with BCG.

Bacillus Calmette Guerin (BCG) perfusion is widely used as cancer adjuvant therapy, in which macrophages play an important role. Novel macrophage activated associated protein 1 (NMAAP1), upregulated after BCG's activation, was proved to promote macrophage polarization to the M1 type. We found that BCG could stimulate mice BMDM to the M1 type and kill tumor cells. After the deletion of NMAAP1, the tumor volume of mice became larger, and the number of M1 type macrophages in the tumor decreased significantly. When macrophages were induced into the M1 type, aerobic glycolysis, the Warburg effect manifested in the increased uptake of glucose and the conversion of pyruvate to lactic acid. NMAAP1 could bind with IP3R and regulate macrophage polarization to the M1 type. However, the specific mechanism of how NMAAP1 regulates macrophage polarization towards the M1 type and plays an antitumor role must be clarified. NMAAP1 could promote the release of lactic acid and pyruvate, enhance the glycolysis of macrophages, and affect the expression of HIF-1α. After inhibition of glycolysis by 2-DG and lactic acid generation by FX11, the effects of NMAAP1 promoting macrophage polarization to the antitumor M1 type were weakened. Furthermore, NMAAP1 upregulated the expression of HIF-1α, which is associated with glycolysis. Moreover, the Ca2+/NF-κB pathway regulated HIF-1α expression by NMAAP1 in the macrophages. NMAAP1 promotes the polarization of macrophages towards the M1 type by affecting the Warburg effect stimulated by BCG.

A review of neonatal peripherally inserted central venous catheters in extremely or very low birthweight infants based on a 3-year clinical practice: Complication incidences and risk factors.

Background: The application of peripherally inserted central venous catheters (PICCs) in neonates has proven effective in avoiding repetitive insertions and excessive use of transfusion consumables. However, the frequent occurrence of PICC-associated complications deserves special attention, especially in extremely or very low birthweight (E/VLBW) infants, which in turn affects the quality of neonatal PICC practice. Therefore, we conducted a retrospective study of a 3-year clinical practice of neonatal PICCs in E/VLBW infants to understand the incidences of various catheter-related complications and their risk factors to help form an empirical summary and evidence-based guidance for the improvement of practice. Methods: A retrospective study was conducted based on a 3-year practice of neonatal PICCs in E/VLBW infants. Neonatal health records were collected, including demographic characteristics, PICC placement data, and treatment information. Results: A total of 519 E/VLBW infants were included in this study. There were 77 cases of complications involving 72 infants with an overall incidence of 12.13%. The order of incidences of different complications from high to low was phlebitis (7.71%), malposition (3.66%), leakage (1.35%), pleural effusion (1.15%), central line-associated bloodstream infection (0.58%, 0.25/1,000d), and accidental removal (0.38%). Multivariate analysis revealed that the inserted vessel was an independent risk factor for PICC-associated complications (mainly phlebitis; p = 0.002). Neonatal PICCs inserted in the axillary vein were only one-tenth (p = 0.026) as likely to cause phlebitis as in the basilic vein, whereas when applied in the saphenous vein, neonatal PICCs were five times as likely to cause phlebitis (p = 0.000). Conclusion: E/VLBW infants might be more inclined to develop PICC-associated phlebitis. Catheters inserted in the axillary or basilic vein are preferred if possible.

Effects of TRIM59 on RAW264.7 macrophage gene expression and function.

Macrophages have a variety of functions, such as secreting cytokines, phagocytosis, et al. Tripartite motif containing 59 (TRIM59) protein is highly expressed in tumor cells. It can regulate proliferation of tumor cells and promote tumor progression. Recent studies shown that the expression of TRIM59 was different in macrophages when stimulated by different stimuli, however, the effects of TRIM59 on macrophage gene expression profiles and functions are still unknown. In our study, we constructed RAW264.7 macrophages with high and low expression of TRIM59, and used next generation sequencing to explore the effects of TRIM59 on macrophage gene expression profiles. Results showed that TRIM59 affected an abundant number of genes, and may affect phagocytosis and cell cycles. We also examined the expression of surface molecules, secretion of cytokines, phagocytosis, proliferation, and apoptosis of macrophages, and confirmed that TRIM59 increased the expression of FcγRs CD16/32, CD64 and the secretion of TNF-α and IL-10, promoted phagocytosis and proliferation of RAW264.7 cells, inhibited the expression of complement receptor CD11b and antigen presentation related receptors (MHCII, CD80), but TRIM59 had no significant effect on apoptosis. Our study explored the effect of TRIM59 on the gene expression and function of macrophages comprehensively.

Knowledge of and willingness to promote advanced care planning among oncology nurses in southwest China.

BACKGROUND: Nurses feature prominently in promoting advance care planning (ACP), but only a limited amount of relevant research has been conducted from the nurses' viewpoint, and little is known about the nurses' knowledge of and their willingness to promote ACP in China. AIMS: The aims of this study were to investigate oncology nurses' knowledge of and their willingness to promote ACP, and to explore associated factors. METHODS: A multi-centre study was conducted to investigate 350 nurses in the oncology departments of four university hospitals in southwestern China. Cluster sampling was used in data collection, which involved three categories of questionnaires concerning demographic characteristics, knowledge about ACP and willingness to promote ACP. Chi-squared tests and multiple linear regression were employed in data analysis. RESULTS: Some 293 valid questionnaires were collected, among which, 60.1% of respondents never received palliative care education, 89.1% never received training about ACP and 72.7% had not even heard of ACP. Nurses with higher position titles (χ2=18.41, p<0.001) and longer working experience (χ2=12.25, p=0.001) were more likely to have received palliative care education; nurses with higher educational background levels (χ2=12.91, p<0.001), higher position titles (χ2=9.77, p=0.003) and longer working experience (χ2=7.92, p=0.006) were more likely to have learned about ACP; nurses with higher position titles had more access to relevant training (χ2=5.10, p=0.03). Furthermore, whether the nurse had 'heard about ACP' (B=3.113, p=0.018) and 'received training about ACP' (B=3.894, p=0.04) were both associated with their willingness to promote ACP. CONCLUSIONS: The findings of this study indicated that oncology nurses were highly inclined to promote ACP, but limited by their lack of knowledge and understanding of it. Therefore, a systematic and adequate training programme about ACP for nurses is an urgent requirement to effectively enhance the implementation of ACP in China.

Investigation and Analysis of Undergraduate Nursing Students' Attitudes Toward Advanced Care Planning and Their Willingness to Implement.

OBJECTIVE: The purpose of this study is to understand the attitude of undergraduate nursing students toward advanced care planning (ACP) and their willingness to implement ACP and to analyze its influencing factors, so as to provide evidence-based basis for life and death education and ACP-related training in colleges and universities. METHODS: A total of 312 nursing undergraduates from a university in Chengdu (China) were surveyed by using general information questionnaire, attitude scale of ACP, and willingness questionnaire to implement ACP. RESULTS: The scores of undergraduate nursing students' attitude toward ACP were 24.97 ± 2.75, and the scores of total willingness to ACP were 79.26 ± 9.70. Univariate analysis and multivariate linear regression analysis showed that religious belief, grade, family relationship, and family discussion of death were the factors influencing the willingness of nursing students to carry out ACP. CONCLUSIONS: The attitude of undergraduate nursing students toward ACP tended to be positive, but their cognition of ACP was misunderstood, and their willingness to implement ACP needed to be improved. To improve the awareness and implementating willingness of undergraduate nursing students to ACP, it was recommended that colleges and universities carried out systematic standardized life and death education courses and ACP-related training.

A novel serum miRNA-pair classifier for diagnosis of sarcoma.

Soft tissue sarcomas (STS) is a set of rare malignant tumor originated from mesoderm. For the prognosis of sarcoma, early diagnosis is important, however, currently no mature and non-invasive method for diagnosis exists. MicroRNAs (miRNAs) are a class of noncoding RNAs and their expression varies greatly, especially during tumor activity. The purpose of this study was to construct a predictive model for the diagnosis of sarcomas based on the relative expression level of miRNA in serum. miRNA array expression data of 677 samples including 402 malignant sarcoma samples and 275 healthy samples was used to construct the prediction model. Based on 6 gene pairs, random generalized linear model (RGLM) was constructed, with an accuracy of 100% in the internal test dataset and of 74.3% in the merged external dataset in prediction whether a serum sample was obtained from a sarcoma patient, with a specificity of 100% in the internal test dataset and 90.5% in the external dataset. In conclusion, our serum miRNA-pair classifier has the potential to be used for the screening of sarcoma with high accuracy and specificity.

TRIM59 Protects Mice From Sepsis by Regulating Inflammation and Phagocytosis in Macrophages.

Sepsis is associated with bacterial invasion and inflammation and has a high mortality rate. Previous studies have demonstrated that tripartite motif 59 (TRIM59) was involved in NF-κB signaling and could promote phagocytosis of macrophages, but the role of TRIM59 in sepsis is still unknown. In our study, we found that TRIM59 was downregulated in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs). In the cecal ligation and puncture (CLP) sepsis mice model, the mortality of Trim59flox/floxLyz-Cre (Trim59-cKO) mice was higher, the immune cell infiltration and damage of liver and lung were more severe, and bacteria burden was increased. We also found that TRIM59 altered the production of pro-inflammation cytokines, as well as macrophage phagocytosis ability. Further analysis indicated that NF-κB signal pathway and Fcγ receptors might be involved in these regulations. Our study demonstrated for the first time that TRIM59 protects mice from sepsis by regulating inflammation and phagocytosis in macrophages.

What Kind Of A Mobile Health App Do Patients Truly Want? A Pilot Study Among Ambulatory Surgery Patients.

BACKGROUND: An increasing number of surgeries are performed as ambulatory surgeries, and mobile health applications (m-health apps) have therefore been designed to help provide patients with more convenient health-care services and improve the working efficiency of health-care professionals (HCPs). To find an effective approach to design such m-health apps, a study to evaluate ambulatory surgery patients' preferences is necessary. METHODS: A structured questionnaire was distributed to 360 patients undergoing ambulatory surgery to understand their demographic characteristics, preferences regarding the features and functions of m-health apps and willingness to engage with m-health apps. RESULTS: In total, 84.16% of ambulatory surgery patients stated that they would be willing to engage with an m-health app during the perioperative period. In addition, their top 10 necessary features and functions of m-health apps were related mainly to ambulatory surgery and communication with HCPs. Furthermore, younger age (χ 2=10.42, p<0.01), employment (χ 2=9.04, p<0.01), higher education (χ 2=13.67, p<0.01), longer daily use of phones (χ 2=11.84, p<0.01) and more frequent usage of m-health apps (χ 2=23.23, p<0.01) were associated with patients' willingness to engage with m-health apps, but only more frequent usage of m-health apps (OR=2.97, 95% CI=1.54-5.71, p<0.01) was found to be a predictor. CONCLUSION: This study presents an initial evaluation of ambulatory surgery patients' preferences regarding m-health apps. Gaining these insights will be useful to help us design an evidence-based, highly functional m-health app that best meets the needs of patients undergoing ambulatory surgery.

Cross-Species Gene Expression Analysis Reveals Gene Modules Implicated in Human Osteosarcoma.

Background: Osteosarcoma (OS) is one of the malignant bone tumors occurring in both human and canine, and in both of them, it is characterized by a high rate of metastasis and poor prognosis. Cross-species analysis reveals previously neglected molecular or signaling pathways involved in the progression of diseases, and dogs are genetically comparable to humans and live in similar environments. Therefore, the aim of this study was to find out OS hub genes through a cross-species analysis. Materials and Methods: All the human and canine OS gene expression data obtained by the Affymetrix platform were collected. After quality assessment and normalization, co-expression network was performed using weighted gene co-expression network analysis (WGCNA). Species-specific modules and consensus modules were identified. Protein-protein interaction (PPI) networks analysis was performed based on consensus gene modules. Then, consensus modules were functionally annotated and correlated with clinical traits. Hub nodes were identified by a subnetwork analysis of PPI network and WGCNA module membership. Modules of interest and hub nodes were validated in an external data set. Results: Three modules for the human network, seven modules for the canine network, and four consensus modules were identified. The consensus module 3 (C3) showed a significant correlation with the metastatic status in the training data set and a significant correlation with metastasis-free survival in the external data set. Cluster of differentiation 86 (CD86) was identified as the hub gene of C3, showing a significant correlation with metastasis-free survival. Conclusion: Genes in C3 play an important role in OS metastasis, whereas CD86 might be a potential molecular biomarker for OS metastasis.

NMAAP1 Maintains M1 Phenotype in Macrophages Through Binding to IP3R and Activating Calcium-related Signaling Pathways.

BACKGROUND: NMAAP1 plays a role in regulating macrophage differentiation to the M1 type and exerting antitumoral functions. It is not clear what role and mechanism NMAAP1 does play in the reversal of macrophages from M1 to M2. METHODS: We detected the typing of macrophages with high or low expression of NMAAP1 by QPCR and ELISA, and detected the colocalization of NMAAP1 and endogenous IP3R by laser confocal microscopy, and detected the protein expression in cells by Western-blotting. RESULTS: Our study found that knockdown NMAAP1 in RAW264.7 cells induced macrophage polarization to the M2 type and up-regulation of NMAAP1 in RAW264.7 cells maintain M1 Phenotype even in the presence of IL-4, a stronger inducer of the M2 type. Additionally, Coimmunoprecipitation revealed a protein-protein interaction between NMAAP1 and IP3R and then activates key molecules in the PKC-dependent Raf/MEK/ERK and Ca2+/CaM/CaMKII signaling pathways. Activation of PKC (Thr638/641), ERK1/2 (Thr202/Tyr204) and CaMKII (Thr286) is involved in the regulation of cell differentiation. CONCLUSION: NMAAP1 interacts with IP3R, which in turn activates the PKC-dependent Raf/MEK/ERK and Ca2+/CaM/CaMKII signaling pathways. These results provide a new explanation of the mechanism underlying M1 differentiation.

TRIM59 loss in M2 macrophages promotes melanoma migration and invasion by upregulating MMP-9 and Madcam1.

The culture supernatant from macrophages overexpressing TRIM59 has a cytotoxic effect on melanoma, but the mechanism remains unclear. To investigate whether deletion of TRIM59 in macrophages affects the metastatic potential of melanoma cells, we polarized control and TRIM59-deficient bone marrow-derived macrophages to the M2 phenotype and collected the respective conditioned media (CM). Exposure to CM from TRIM59-/--M2 cultures significantly promoted migration and invasion by B16-F0 and B16-F10 cells. Cytokine profiling indicated a ~15-fold increase in TNF-α production in CM from TRIM59-/--M2 cultures, and neutralizing TNF-α activity abrogated the referred stimulatory effects on cell motility. Transcriptome analysis revealed significant upregulation of MMP-9 and Madcam1 in melanoma cells exposed to TRIM59-/--M2 CM. Inhibitory experiments determined that these changes were also TNF-α-dependent and mediated by activation of ERK signaling. Independent knockdown of MMP9 and Madcam1 in B16-F10 cells impeded epithelial-mesenchymal transition and inhibited subcutaneous tumor growth and formation of metastatic lung nodules in vivo. These data suggest TRIM59 expression attenuates the tumor-promoting effect of tumor-associated macrophages, most of which resemble the M2 phenotype. Moreover, they highlight the relevance of TRIM59 in macrophages as a potential regulator of tumor metastasis and suggest TRIM59 could serve as a novel target for cancer immunotherapy.