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Background: The aim of this study was to assess the microbial variations and biomarkers in the vaginal and oral environments of patients with human papillomavirus (HPV) and cervical cancer (CC) and to develop novel prediction models. Materials and methods: This study included 164 samples collected from both the vaginal tract and oral subgingival plaque of 82 women. The participants were divided into four distinct groups based on their vaginal and oral samples: the control group (Z/KZ, n = 22), abortion group (AB/KAB, n = 17), HPV-infected group (HP/KHP, n = 21), and cervical cancer group (CC/KCC, n = 22). Microbiota analysis was conducted using full-length 16S rDNA gene sequencing with the PacBio platform. Results: The vaginal bacterial community in the Z and AB groups exhibited a relatively simple structure predominantly dominated by Lactobacillus. However, CC group shows high abundances of anaerobic bacteria and alpha diversity. Biomarkers such as Bacteroides, Mycoplasma, Bacillus, Dialister, Porphyromonas, Anaerococcus, and Prevotella were identified as indicators of CC. Correlations were established between elevated blood C-reactive protein (CRP) levels and local/systemic inflammation, pregnancy, childbirth, and abortion, which contribute to unevenness in the vaginal microenvironment. The altered microbial diversity in the CC group was confirmed by amino acid metabolism. Oral microbial diversity exhibited an inverse pattern to that of the vaginal microbiome, indicating a unique relationship. The microbial diversity of the KCC group was significantly lower than that of the KZ group, indicating a link between oral health and cancer development. Several microbes, including Fusobacterium, Campylobacter, Capnocytophaga, Veillonella, Streptococcus, Lachnoanaerobaculum, Propionibacterium, Prevotella, Lactobacillus, and Neisseria, were identified as CC biomarkers. Moreover, periodontal pathogens were associated with blood CRP levels and oral hygiene conditions. Elevated oral microbial amino acid metabolism in the CC group was closely linked to the presence of pathogens. Positive correlations indicated a synergistic relationship between vaginal and oral bacteria. Conclusion: HPV infection and CC impact both the vaginal and oral microenvironments, affecting systemic metabolism and the synergy between bacteria. This suggests that the use of oral flora markers is a potential screening tool for the diagnosis of CC. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell cancer (ccRCC) is accompanied by T-cell infiltration. In this study, we sought to determine the difference in T-cell infiltration and the T-cell receptor (TCR) immune repertoire between ccRCC and peritumour tissue.Methods: T-cell infiltration was examined using immunohistochemistry (IHC) and haematoxylin and eosin (HE) staining. The chi-squared test and Pearson correlation analysis were applied to evaluate the relationship between clinical traits and CD3, CD4, and CD8 expression. Immune repertoire sequencing (IR-Seq) was used to describe the profile of the TCR repertoire.Results: The adjacent tissue showed increased expression of CD3, CD4 and CD8 compared with ccRCC tissue (PCD3 = 0.033; PCD4 = 0.014; PCD8 = 0.004). Indicated CD3+ T-cell density in ccRCC tissue was positively correlated with that in peritumour tissue (P = 0.010, r = 0.514), which implied the T cells in peritumour tissue directly infect the number of cells infiltrating in ccRCC tissue. Moreover, there was a positive correlation between Vimentin expression and indicated positive T-cell marker in ccRCC tissue (PCD3 = 0.035; PCD4 = 0.020; PCD8 = 0.027). Advanced stage revealed less CD4+ T-cell infiltration in ccRCC tissue (PCD4 = 0.023). The results from IR-Seq revealed an obvious increase in VJ and VDJ segment usage, as well as higher complementarity-determining region 3 (CDR3) amino acid (aa) clonotypes in ccRCC. The matched antigen recognized by the TCR of ccRCC may be potential targets.Conclusions: The current study collectively demonstrates diminished T-cell infiltration and increased CDR3 aa diversity in ccRCC, which may be associated with immunotherapeutic targets for ccRCC patients. [ABSTRACT FROM AUTHOR]

Background: According to the Global Cancer Statistics in 2020, the incidence and mortality of colorectal cancer (CRC) rank third and second among all tumors. The disturbance of ubiquitination plays an important role in the initiation and development of CRC, but the ubiquitinome of CRC cells and the survival-relevant ubiquitination are poorly understood.Methods: The ubiquitinome of CRC patients (n = 6) was characterized using our own data sets of proteomic and ubiquitin-proteomic examinations. Then, the probable survival-relevant ubiquitination was searched based on the analyses of data sets from public databases.Results: For the ubiquitinomic examination, we identified 1690 quantifiable sites and 870 quantifiable proteins. We found that the highly-ubiquitinated proteins (n ≥ 10) were specifically involved in the biological processes such as G-protein coupling, glycoprotein coupling, and antigen presentation. Also, we depicted five motif sequences frequently recognized by ubiquitin. Subsequently, we revealed that the ubiquitination content of 1172 proteins were up-regulated and 1700 proteins were down-regulated in CRC cells versus normal adjacent cells. We demonstrated that the differentially ubiquitinated proteins were relevant to the pathways including metabolism, immune regulation, and telomere maintenance. Then, integrated with the proteomic datasets from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) (n = 98), we revealed that the increased ubiquitination of FOCAD at Lys583 and Lys587 was potentially associated with patient survival. Finally, we depicted the mutation map of FOCAD and elucidated its potential functions on RNA localization and translation in CRC.Conclusions: The findings of this study described the ubiquitinome of CRC cells and identified abnormal ubiquitination(s) potentially affecting the patient survival, thereby offering new probable opportunities for clinical treatment. [ABSTRACT FROM AUTHOR]

Background: Acute Myeloid Leukemia (AML) is a hematological cancer characterized by heterogeneous hematopoietic cells. Through the use of multidimensional sequencing technologies, we previously identified a distinct myeloblast population, CD34+CD117dim, the proportion of which was strongly associated with the clinical outcome in t (8;21) AML. In this study, we explored the potential value of the CD34+CD117dim population signature (117DPS) in AML stratification.Methods: Based on the CD34+CD117dim gene signature, the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to construct the 117DPS model using the gene expression data from Gene Expression Omnibus (GEO) database (GSE37642-GPL96 was used as training cohort; GSE37642-GPL570, GSE12417-GPL96, GSE12417-GPL570 and GSE106291 were used as validation cohorts). In addition, the RNA-seq data from The Cancer Genome Atlas (TCGA)-LAML and Beat AML projects of de-novo AML patients were also analyzed as validation cohorts. The differences of clinical features and tumor-infiltrating lymphocytes were further explored between the high-risk score group and low-risk score group.Results: The high-risk group of the 117DPS model exhibited worse overall survival than the low-risk group in both training and validation cohorts. Immune signaling pathways were significantly activated in the high-risk group. Patients with high-risk score had a distinct pattern of infiltrating immune cells, which were closely related to clinical outcome.Conclusion: The 117DPS model established in our study may serve as a potentially valuable tool for predicting clinical outcome of patients with AML. [ABSTRACT FROM AUTHOR]

Background: Metastasis is critical for endometrial cancer (EC) progression and prognosis. Accumulating evidence suggests that circular RNAs (circRNAs) can operate as independent functional entities. However, the functional regulatory mechanisms of circRNAs in EC remain unclear.Methods: The levels of circESRP1, miR-874-3p, and CPEB4 mRNA in EC tissues and cells were determined by qRT-PCR. Sanger sequencing, PCR with divergent primers, an actinomycin D assay, and RNase R treatment were applied to verify the circular properties. Fluorescence in situ hybridization (FISH) and nuclear-cytoplasmic fractionation were used to determine the localization of circESRP1. CCK-8, EdU incorporation, colony formation, Transwell, and wound healing assays were applied to assess the effects of circESRP1 on cell proliferation, migration, and invasion. The mutual regulatory mechanism of ceRNAs was investigated using dual-luciferase reporter, RNA pulldown, RNA immunoprecipitation (RIP), and Western blot assays. The biological effects were further validated in vivo in nude mouse xenograft models.Results: circESRP1 was highly expressed in EC tissues and cells and was mainly localized in the cytoplasm. Silencing circESRP1 inhibited the proliferation, migration, and invasion of EC cells in vitro and in vivo; however, overexpression of circESRP1 had the opposite effects. Mechanistically, circESRP1 sponged miR-874-3p to upregulate CPEB4 expression and ultimately contribute to EC cell proliferation and metastasis. Furthermore, circESRP1 regulated tumour growth in xenograft models.Conclusions: CircESRP1 can interact with miR-874-3p to regulate EMT in endometrial cancer via the miR-874-3p/CPEB4 axis. CircESRP1 may serve as a promising therapeutic target for endometrial cancer. [ABSTRACT FROM AUTHOR]

Background: The identification of novel functional biomarkers is essential for recognizing high-risk patients, predicting recurrence, and searching for appropriate treatment. However, no prognostic biomarker has been applied for colorectal cancer (CRC) in the clinic.Methods: Integrated with transcriptomic data from public databases, multi-omics examinations were conducted to search prognostic biomarkers for CRC. Moreover, the potential biological functions and regulatory mechanism of these predictive genes were also explored.Results: In this study, we revealed that three mitochondrial genes were associated with the poor prognosis of CRC. Integrated analyses of transcriptome and proteome of CRC patients disclosed numerous down-regulated mitochondrial genes at both mRNA and protein levels, suggesting a vital role of mitochondria in carcinogenesis. Combined with the bioinformatics studies of transcriptomic datasets of 538 CRC patients, three mitochondrial prognostic genes were eventually selected out, including HIGD1A, SUCLG2, and SLC25A24. The expression of HIGD1A exhibited a significant reduction in two subtypes of adenoma and six subtypes of CRC, while the down-regulation of SUCLG2 and SLC25A24 showed more advantages in rectal mucinous adenocarcinoma. Moreover, we unveiled that these three genes had common expressions and might collaboratively participate in the synthesis of ribosomes. Our original multi-omics datasets, including DNA methylation, structural variants, chromatin accessibility, and phosphoproteome, further depicted the altered modifications on their potential transcriptional factors.Conclusions: In summary, HIGD1A, SUCLG2, and SLC25A24 might serve as predictive biomarkers for CRC. The biological activities they involved in and their upstream regulators we uncovered would provide a functional context for the further-in-depth mechanism study. [ABSTRACT FROM AUTHOR]

Background: Biological ageing is tightly linked to cardiovascular disease (CVD). We aimed to investigate the relationship between Life's Essential 8 (LE8), a currently updated measure of cardiovascular health (CVH), and biological ageing. Methods: This cross-sectional study selected adults ≥ 20 years of age from the 2005–2010 National Health and Nutrition Examination Survey. LE8 scores (range 0–100) were obtained from measurements based on American Heart Association definitions, divided into health behavior and health factor scores. Biological ageing was assessed by different methods including phenotypic age, phenotypic age acceleration (PhenoAgeAccel), biological age and biological age acceleration (BioAgeAccel). Correlations were analyzed by weighted linear regression and restricted cubic spline models. Results: Of the 11,729 participants included, the mean age was 47.41 ± 0.36 years and 5983 (51.01%) were female. The mean phenotypic and biological ages were 42.96 ± 0.41 and 46.75 ± 0.39 years, respectively, and the mean LE8 score was 67.71 ± 0.35. After adjusting for potential confounders, higher LE8 scores were associated with lower phenotypic age, biological age, PhenoAgeAccel, and BioAgeAccel, with nonlinear dose–response relationships. Negative associations were also found between health behavior and health factor scores and biological ageing, and were stronger for health factors. In health factor-specific analyses, the β negativity was greater for blood glucose and blood pressure. The inverse correlations of LE8 scores with phenotypic age and biological age in the stratified analyses remained solid across strata. Conclusions: LE8 and its subscale scores were strongly negatively related to biological ageing. Encouraging optimal CVH levels may be advantageous in preventing and slowing down ageing. [ABSTRACT FROM AUTHOR]

The pathogenesis of osteoporosis involves multiple factors, among which alterations in the bone microenvironment play a crucial role in disrupting normal bone metabolic balance. Transient receptor potential vanilloid 5 (TRPV5), a member of the TRPV family, is an essential determinant of the bone microenvironment, acting at multiple levels to influence its properties. TRPV5 exerts a pivotal influence on bone through the regulation of calcium reabsorption and transportation while also responding to steroid hormones and agonists. Although the metabolic consequences of osteoporosis, such as loss of bone calcium, reduced mineralization capacity, and active osteoclasts, have received significant attention, this review focuses on the changes in the osteoporotic microenvironment and the specific effects of TRPV5 at various levels. [ABSTRACT FROM AUTHOR]

The pathogenesis of osteoporosis involves multiple factors, among which alterations in the bone microenvironment play a crucial role in disrupting normal bone metabolic balance. Transient receptor potential vanilloid 5 (TRPV5), a member of the TRPV family, is an essential determinant of the bone microenvironment, acting at multiple levels to influence its properties. TRPV5 exerts a pivotal influence on bone through the regulation of calcium reabsorption and transportation while also responding to steroid hormones and agonists. Although the metabolic consequences of osteoporosis, such as loss of bone calcium, reduced mineralization capacity, and active osteoclasts, have received significant attention, this review focuses on the changes in the osteoporotic microenvironment and the specific effects of TRPV5 at various levels. [ABSTRACT FROM AUTHOR]

Background: Various clinical similarities are present in ischemic (ICM) and idiopathic dilated cardiomyopathy (IDCM), leading to ambiguity on some occasions. Previous studies have reported that intestinal microbiota appeared dysbiosis in ICM, whether implicating in the IDCM remains unclear. The aim of this study was to assess the alterations in intestinal microbiota and fecal metabolites in ICM and IDCM. Methods: ICM (n = 20), IDCM (n = 22), and healthy controls (HC, n = 20) were enrolled in this study. Stool samples were collected for 16S rRNA gene sequencing and gas chromatography-mass spectrometry (GC–MS) analysis. Results: Both ICM and IDCM exhibited reduced alpha diversity and altered microbial community structure compared to HC. At the genus level, nine taxa including Blautia, [Ruminococcus]_torques_group, Christensenellaceae_R-7_group, UCG-002, Corynebacterium, Oceanobacillus, Gracilibacillus, Klebsiella and Citrobacter was specific to ICM, whereas one taxa Alistipes uniquely altered in IDCM. Likewise, these changes were accompanied by significant metabolic differences. Further differential analysis displayed that 18 and 14 specific metabolites uniquely changed in ICM and IDCM, respectively. The heatmap was generated to display the association between genera and metabolites. Receiver operating characteristic curve (ROC) analysis confirmed the predictive value of the distinct microbial-metabolite features in disease status. The results showed that microbial (area under curve, AUC = 0.95) and metabolic signatures (AUC = 0.84) were effective in discriminating ICM from HC. Based on the specific microbial and metabolic features, the patients with IDCM could be separated from HC with an AUC of 0.80 and 0.87, respectively. Furthermore, the gut microbial genus (AUC = 0.88) and metabolite model (AUC = 0.89) were comparable in predicting IDCM from ICM. Especially, the combination of fecal microbial-metabolic features improved the ability to differentiate IDCM from ICM with an AUC of 0.96. Conclusion: Our findings highlighted the alterations of gut microbiota and metabolites in different types of cardiomyopathies, providing insights into the pathophysiological mechanisms of myocardial diseases. Moreover, multi-omics analysis of fecal samples holds promise as a non-invasive tool for distinguishing disease status. [ABSTRACT FROM AUTHOR]

Background: Novel biomarkers are required in gastric cancer (GC) treated by immunotherapy. Epstein-Barr virus (EBV) infection induces an immune-active tumor microenvironment, while its association with immunotherapy response is still controversial. Genes underlying EBV infection may determine the response heterogeneity of EBV + GC. Thus, we screened hub genes associated with EBV infection to predict the response to immunotherapy in GC. Methods: Prognostic hub genes associated with EBV infection were screened using multi-omic data of GC. EBV + GC cells were established and confirmed by EBV-encoded small RNA in situ hybridization (EBER-ISH). Immunohistochemistry (IHC) staining of the hub genes was conducted in GC samples with EBER-ISH assay. Infiltrating immune cells were stained using immunofluorescence. Results: CHAF1A was identified as a hub gene in EBV + GC, and its expression was an independent predictor of overall survival (OS). EBV infection up-regulated CHAF1A expression which also predicted EBV infection well. CHAF1A expression also predicted microsatellite instability (MSI) and a high tumor mutation burden (TMB). The combined score (CS) of CHAF1A expression with MSI or TMB further improved prognostic stratification. CHAF1A IHC score positively correlated with the infiltration of NK cells and macrophages M1. CHAF1A expression alone could predict the immunotherapy response, but its CS with EBV infection, MSI, TMB, or PD-L1 expression showed better effects and improved response stratification based on current biomarkers. Conclusions: CHAF1A could be a novel biomarker for immunotherapy of GC, with the potential to improve the efficacy of existing biomarkers. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) plays critical roles in cytoskeletal support, biomechanical transduction and biochemical signal transformation. Tumor-associated macrophage (TAM) function is regulated by matrix stiffness in solid tumors and is often associated with poor prognosis. ECM stiffness-induced mechanical cues can activate cell membrane mechanoreceptors and corresponding mechanotransducers in the cytoplasm, modulating the phenotype of TAMs. Currently, tuning TAM polarization through matrix stiffness-induced mechanical stimulation has received increasing attention, whereas its effect on TAM fate has rarely been summarized. A better understanding of the relationship between matrix stiffness and macrophage function will contribute to the development of new strategies for cancer therapy. In this review, we first introduced the overall relationship between macrophage polarization and matrix stiffness, analyzed the changes in mechanoreceptors and mechanotransducers mediated by matrix stiffness on macrophage function and tumor progression, and finally summarized the effects of targeting ECM stiffness on tumor prognosis to provide insight into this new field. [ABSTRACT FROM AUTHOR]

Background: Tissue-resident memory T (TRM) cells can reside in the tumor microenvironment and are considered the primary response cells to immunotherapy. Heterogeneity in functional status and spatial distribution may contribute to the controversial role of TRM cells but we know little about it. Methods: Through multiplex immunofluorescence (mIF) (CD8, CD103, PD-1, Tim-3, GZMB, CK), the quantity and spatial location of TRM cell subsets were recognized in the tissue from 274 patients with NSCLC after radical surgery. By integrating multiple machine learning methods, we constructed a TRM-based spatial immune signature (TRM-SIS) to predict the prognosis. Furthermore, we conducted a CD103-related gene set enrichment analysis (GSEA) and verified its finding by another mIF panel (CD8, CD103, CK, CD31, Hif-1α). Results: The density of TRM cells was significantly correlated with the expression of PD-1, Tim-3 and GZMB. Four types of TRM cell subsets was defined, including TRM1 (PD-1−Tim-3−TRM), TRM2 (PD-1+Tim-3−TRM), TRM3 (PD-1−Tim-3+TRM) and TRM4 (PD-1+Tim-3+TRM). The cytotoxicity of TRM2 was the strongest while that of TRM4 was the weakest. Compare with TRM1 and TRM2, TRM3 and TRM4 had better infiltration and stronger interaction with cancer cells. The TRM-SIS was an independent prognostic factor for disease-free survival [HR = 2.43, 95%CI (1.63–3.60), P < 0.001] and showed a better performance than the TNM staging system for recurrence prediction. Furthermore, by CD103-related GSEA and mIF validation, we found a negative association between tumor angiogenesis and infiltration of TRM cells. Conclusions: These findings reveal a significant heterogeneity in the functional status and spatial distribution of TRM cells, and support it as a biomarker for the prognosis of NSCLC patients. Regulating TRM cells by targeting tumor angiogenesis may be a potential strategy to improve current immunotherapy. [ABSTRACT FROM AUTHOR]

Tissue-engineered skin (TES), as an analogue of native skin, is promising for wound repair and regeneration. However, a major drawback of TES products is a lack of skin appendages and nerves to enhance skin healing, structural integrity and skin vitality. Skin appendages and nerves are important constituents for fully functional skin. To date, many studies have yielded remarkable results in the field of skin appendages reconstruction and nerve regeneration. However, patients often complain about a loss of skin sensation and even cutaneous chronic pain. Restoration of pain, temperature, and touch perceptions should now be a major challenge to solve in order to improve patients' quality of life. Current strategies to create skin appendages and sensory nerve regeneration are mainly based on different types of seeding cells, scaffold materials, bioactive factors and involved signaling pathways. This article provides a comprehensive overview of different strategies for, and advances in, skin appendages and sensory nerve regeneration, which is an important issue in the field of tissue engineering and regenerative medicine. [ABSTRACT FROM AUTHOR]

Background: Anti-PD-(L)1 immunotherapy has been recommended for non-small cell lung cancer (NSCLC) patients with lymph node metastases (LNM). However, the exact functional feature and spatial architecture of tumor-infiltrating CD8 + T cells remain unclear in these patients. Methods: Tissue microarrays (TMAs) from 279 IA-IIIB NSCLC samples were stained by multiplex immunofluorescence (mIF) for 11 markers (CD8, CD103, PD-1, Tim3, GZMB, CD4, Foxp3, CD31, αSMA, Hif-1α, pan-CK). We evaluated the density of CD8 + T-cell functional subsets, the mean nearest neighbor distance (mNND) between CD8 + T cells and neighboring cells, and the cancer-cell proximity score (CCPS) in invasive margin (IM) as well as tumor center (TC) to investigate their relationships with LNM and prognosis. Results: The densities of CD8 + T-cell functional subsets, including predysfunctional CD8 + T cells (Tpredys) and dysfunctional CD8 + T cells (Tdys), in IM predominated over those in TC (P < 0.001). Multivariate analysis identified that the densities of CD8 + Tpredys cells in TC and CD8 + Tdys cells in IM were significantly associated with LNM [OR = 0.51, 95%CI (0.29–0.88), P = 0.015; OR = 5.80, 95%CI (3.19–10.54), P < 0.001; respectively] and recurrence-free survival (RFS) [HR = 0.55, 95%CI (0.34–0.89), P = 0.014; HR = 2.49, 95%CI (1.60–4.13), P = 0.012; respectively], independent of clinicopathological factors. Additionally, shorter mNND between CD8 + T cells and their neighboring immunoregulatory cells indicated a stronger interplay network in the microenvironment of NSCLC patients with LNM and was associated with worse prognosis. Furthermore, analysis of CCPS suggested that cancer microvessels (CMVs) and cancer-associated fibroblasts (CAFs) selectively hindered CD8 + T cells from contacting with cancer cells, and were associated with the dysfunction of CD8 + T cells. Conclusion: Tumor-infiltrating CD8 + T cells were in a more dysfunctional status and in a more immunosuppressive microenvironment in patients with LNM compared with those without LNM. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by a progressive loss of memory that cannot be efficiently managed by currently available AD therapeutics. So far, most treatments for AD that have the potential to improve memory target neural circuits to protect their integrity. However, the vulnerable neural circuits and their dynamic remodeling during AD progression remain largely undefined. Methods: Circuit-based approaches, including anterograde and retrograde tracing, slice electrophysiology, and fiber photometry, were used to investigate the dynamic structural and functional remodeling of a GABAergic circuit projected from the medial septum (MS) to the dentate gyrus (DG) in 3xTg-AD mice during AD progression. Results: We identified a long-distance GABAergic circuit that couples highly connected MS and DG GABAergic neurons during spatial memory encoding. Furthermore, we found hyperactivity of DG interneurons during early AD, which persisted into late AD stages. Interestingly, MS GABAergic projections developed a series of adaptive strategies to combat DG interneuron hyperactivity. During early-stage AD, MS-DG GABAergic projections exhibit increased inhibitory synaptic strength onto DG interneurons to inhibit their activities. During late-stage AD, MS-DG GABAergic projections form higher anatomical connectivity with DG interneurons and exhibit aberrant outgrowth to increase the inhibition onto DG interneurons. Conclusion: We report the structural and functional remodeling of the MS-DG GABAergic circuit during disease progression in 3xTg-AD mice. Dynamic MS-DG GABAergic circuit remodeling represents a compensatory mechanism to combat DG interneuron hyperactivity induced by reduced GABA transmission. [ABSTRACT FROM AUTHOR]

In the repair of maxillofacial bone defects, autogenous craniofacial bone can often provide superior clinical results over long bone grafts. Most current studies have focused on the osteogenic differences between alveolar bone marrow (ABM) and long bone marrow (LBM), however, studies about the angiogenic differences between the two are currently lacking. We downloaded single-cell RNA sequencing (scRNA-seq) of mouse ABM and LBM respectively from the public database, and the data were processed by using Seurat package. CellphoneDB2 results showed that macrophages had the strongest interaction with mesenchymal stem cells (MSCs) and endothelial cells (ECs). ELISA results confirmed that ABM macrophages secreted a higher level of vascular endothelial growth factor A (Vegfa) compared to LBM macrophages, which further promoted angiogenesis of ECs and MSCs. Using SCENIC package, six key transcription factors (TFs) were identified to regulate the difference between ABM and LBM macrophages, and activating transcription factor 4 (Atf4) was confirmed to be more expressed in ABM macrophages by polymerase chain reaction (PCR) and western blot (WB), with predicted target genes including Vegfa. Besides, the result of scRNA-seq implied ABM macrophages more in M1 status than LBM macrophages, which was confirmed by the following experiments. From the results of another assay for transposase accessible chromatin sequencing (ATAC-seq) and RNA-seq about M1 macrophages, Atf4 was also confirmed to regulate the M1 polarization. So, we suspected that Atf4 regulated the different expression of Vegfa between ABM and LBM macrophages by activating M1 polarization. After knocking down Atf4, the expression of M1 polarization markers and Vegfa were downregulated and vasculogenic differences were eliminated, which were subsequently reversed by the addition of LPS/IFN-γ. Our study might provide a new idea to improve the success rate of autologous bone grafting and treatment of oral diseases. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized. Methods: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model. Results: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model. Conclusions: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Secretory phospholipase A2 group IIA (sPLA2-IIA) is an independent risk factor for cardiovascular disease, but its role on high-density lipoprotein cholesterol (HDL-C) level has not been clarified. The aim of the present study was to explore the association between circulating sPLA2-IIA and HDL-C, and to evaluate if sPLA2-IIA enhances cholesterol efflux capacity through regulation of peroxisome proliferator-activated receptor γ (PPAR-γ), liver X receptor α (LXR-α), and ATP-binding cassette A1 (ABCA1).Methods: 131 patients with coronary artery disease were enrolled. The plasma level of sPLA2-IIA was tested with enzyme-linked immunosorbent assay kit, and serum lipids were assessed by biochemical analyzer. Human monocyte-macrophage cell line THP-1 was co-incubated with sPLA2-IIA in the presence/absence of selective PPAR-γ antagonist GW9662 in vitro. Real-time PCR and Western-blot were employed to measure the mRNA and protein expressions of PPAR-γ, LXR-α, and ABCA1, respectively. The cholesterol efflux was evaluated by using an assay kit.Results: In subjects, circulating level of sPLA2-IIA was positively related with that of HDL-C (r = 0.196, p = 0.024). The plasma level of sPLA2-IIA was significantly higher in the high HDL-C (≥ 1.04 mmol/L) group (7477.828 pg/mL) than that in low HDL-C (< 1.04 mmol/L) group (5836.92 pg/mL, p = 0.004). For each increase of 1 pg/μl in sPLA2-IIA level, the adjusted odds ratio for HDL-C ≥ 1.04 mmol/L was 1.143. Co-incubation of THP-1 cells with sPLA2-IIA resulted in increased expressions of PPAR-γ, LXR-α, and ABCA1, as well as enhanced cholesterol efflux capacity, that were all reversed by administration of GW9662.Conclusions: Circulating sPLA2-IIA was positively associated with HDL-C. PPAR-γ/LXR-α/ABCA1 might be responsible for sPLA2-IIA-regulated cholesterol efflux in macrophages. [ABSTRACT FROM AUTHOR]

Background: To ensure the safety of plasma derivatives, screening for human parvovirus B19V genomic DNA in donated plasma using a pooling strategy is performed in some countries. We investigated the prevalence of B19V DNA and anti-B19V antibodies in Chinese plasma pools, plasma derivatives and plasma donations to evaluate the risk posed by B19V.Methods: Using a Q-PCR assay developed in-house, we tested for B19V genomic DNA in 142 plasma pools collected between January 2009 and June 2011 from two Chinese blood products manufacturers. Plasma derivatives collected between 1993-1995 (10 batches of albumin, 155 batches of intravenous immunoglobulin, IVIG) and 2009-2011 (50 batches of albumin, 54 batches of IVIG, 35 batches of factor VIII, 7 batches of fibrinogen, and 17 batches of prothrombin complex concentrate, PCC) were also tested for B19V contamination. In addition, B19V genome prevalence in minipools(including 90 individual donations) of 49680 individual plasma samples collected between August 2011 and March 2012 by a single Chinese manufacturer was investigated. IgM/IgG was also investigated in plasma pools/derivatives and in minipools with B19V-DNA titers above 1x10(4) and 1x10(6) geq/mL using B19 ELISA IgM/IgG assay(Virion-Serion, Würzburg, Germany), respectively.Results: B19V-DNA was detected in 54.2% of plasma pools from two Chinese blood product manufacturers; among recently produced blood products, B19V was detected in 21/54 IVIG samples, 19/35 factor VIII samples, 6/7 fibrinogen samples, and 12/17 PCC samples, but not in albumin samples. The levels of B19V-DNA in these samples varied from 10(2)-10(7) geq/mL. In samples with >10(4) geq/mL genome DNA, B19V-specific IgG was also found in all corresponding plasma pools and IVIG, whereas none was detected in the majority of other plasma derivatives. Screening of plasma donations indicated that most minipools were contaminated with B19V-DNA (10(2)-10(8) geq/mL) and one donation had 1.09 × 10(10) geq/mL B19V genomic DNA along with a non-classical IgG/IgM profile.Conclusions: Despite the implementation of some inactivation/removal methods designed to prevent viral contamination, B19V DNA was detectable in Chinese plasma pools and plasma derivatives. Thus, the introduction of B19V screening and discard donation with high viramic concentration for Chinese plasma donors would be desirable. [ABSTRACT FROM AUTHOR]

Background: The prevalence of metabolic syndrome (Mets) is closely related to an increased incidence of cardiovascular events. Angiopoietin-like protein 4 (ANGPTL4) is contributory to the regulation of lipid metabolism, herein, may provide a target for gene-aimed therapy of Mets. This observational case control study was designed to elucidate the relationship between ANGPTL4 gene single nucleotide polymorphism (SNP) rs1044250 and the onset of Mets, and to explore the interaction between SNP rs1044250 and weight management on Mets.Methods: We have recruited 1018 Mets cases and 1029 controls in this study. The SNP rs1044250 was genotyped with blood samples, base-line information and Mets-related indicators were collected. A 5-year follow-up survey was carried out to track the lifestyle interventions and changes in Mets-related indicators.Results: ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference (OR 1.618, 95% CI [1.119-2.340]; p = 0.011), elevated blood pressure (OR 1.323, 95% CI [1.002-1.747]; p = 0.048), and Mets (OR 1.875, 95% CI [1.363-2.580]; p < 0.001). The follow-up survey shows that rs1044250 CC genotype patients with weight gain have an increased number of Mets components (M [Q1, Q3]: CC 1 (0, 1), CT + TT 0 [- 1, 1]; p = 0.021); The interaction between SNP rs1044250 and weight management is a risk factor for increased systolic blood pressure (β = 0.075, p < 0.001) and increased diastolic blood pressure (β = 0.097, p < 0.001), the synergistic effect of weight management and SNP rs1044250 is negative (S < 1).Conclusion: ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference and elevated blood pressure, therefore, for Mets. However, patients with wild type SNP 1044250 are more likely to have Mets when the body weight is increased, mainly due to elevated blood pressure. [ABSTRACT FROM AUTHOR]

Background: COVID-19 has caused a global pandemic and the death toll is increasing. However, there is no definitive information regarding the type of clinical specimens that is the best for SARS-CoV-2 detection, the antibody levels in patients with different duration of disease, and the relationship between antibody level and viral load.Methods: Nasopharyngeal swabs, anal swabs, saliva, blood, and urine specimens were collected from patients with a course of disease ranging from 7 to 69 days. Viral load in different specimen types was measured using droplet digital PCR (ddPCR). Meanwhile, anti-nucleocapsid protein (anti-N) IgM and IgG antibodies and anti-spike protein receptor-binding domain (anti-S-RBD) IgG antibody in all serum samples were tested using ELISA.Results: The positive detection rate in nasopharyngeal swab was the highest (54.05%), followed by anal swab (24.32%), and the positive detection rate in saliva, blood, and urine was 16.22%, 10.81%, and 5.41%, respectively. However, some patients with negative nasopharyngeal swabs had other specimens tested positive. There was no significant correlation between antibody level and days after symptoms onset or viral load.Conclusions: Other specimens could be positive in patients with negative nasopharyngeal swabs, suggesting that for patients in the recovery period, specimens other than nasopharyngeal swabs should also be tested to avoid false negative results, and anal swabs are recommended. The antibody level had no correlation with days after symptoms onset or the viral load of nasopharyngeal swabs, suggesting that the antibody level may also be affected by other factors. [ABSTRACT FROM AUTHOR]

Background: Patients with critical illness due to infection with the 2019 coronavirus disease (COVID-19) show rapid disease progression to acute respiratory failure. The study aimed to screen the most useful predictive factor for critical illness caused by COVID-19.Methods: The study prospectively involved 61 patients with COVID-19 infection as a derivation cohort, and 54 patients as a validation cohort. The predictive factor for critical illness was selected using LASSO regression analysis. A nomogram based on non-specific laboratory indicators was built to predict the probability of critical illness.Results: The neutrophil-to-lymphocyte ratio (NLR) was identified as an independent risk factor for critical illness in patients with COVID-19 infection. The NLR had an area under receiver operating characteristic of 0.849 (95% confidence interval [CI], 0.707 to 0.991) in the derivation cohort and 0.867 (95% CI 0.747 to 0.944) in the validation cohort, the calibration curves fitted well, and the decision and clinical impact curves showed that the NLR had high standardized net benefit. In addition, the incidence of critical illness was 9.1% (1/11) for patients aged ≥ 50 and having an NLR < 3.13, and 50% (7/14) patients with age ≥ 50 and NLR ≥ 3.13 were predicted to develop critical illness. Based on the risk stratification of NLR according to age, this study has developed a COVID-19 pneumonia management process.Conclusions: We found that NLR is a predictive factor for early-stage prediction of patients infected with COVID-19 who are likely to develop critical illness. Patients aged ≥ 50 and having an NLR ≥ 3.13 are predicted to develop critical illness, and they should thus have rapid access to an intensive care unit if necessary. [ABSTRACT FROM AUTHOR]

Background: As the most common form of lymphoma, diffuse large B-cell lymphoma (DLBCL) is a clinical highly heterogeneous disease with variability in therapeutic outcomes and biological features. It is a challenge to identify of clinically meaningful tools for outcome prediction. In this study, we developed a prognosis model fused clinical characteristics with drug resistance pharmacogenomic signature to identify DLBCL prognostic subgroups for CHOP-based treatment.Methods: The expression microarray data and clinical characteristics of 791 DLBCL patients from two Gene Expression Omnibus (GEO) databases were used to establish and validate this model. By using univariate Cox regression, eight clinical or genetic signatures were analyzed. The elastic net-regulated Cox regression analysis was used to select the best prognosis related factors into the predictive model. To estimate the prognostic capability of the model, Kaplan-Meier curve and the area under receiver operating characteristic (ROC) curve (AUC) were performed.Results: A predictive model comprising 4 clinical factors and 2 pharmacogenomic gene signatures was established after 1000 times cross validation in the training dataset. The AUC of the comprehensive risk model was 0.78, whereas AUC value was lower for the clinical only model (0.68) or the gene only model (0.67). Compared with low-risk patients, the overall survival (OS) of DLBCL patients with high-risk scores was significantly decreased (HR = 4.55, 95% CI 3.14-6.59, log-rank p value = 1.06 × 10-15). The signature also enables to predict prognosis within different molecular subtypes of DLBCL. The reliability of the integrated model was confirmed by independent validation dataset (HR = 3.47, 95% CI 2.42-4.97, log rank p value = 1.53 × 10-11).Conclusions: This integrated model has a better predictive capability to ascertain the prognosis of DLBCL patients prior to CHOP-like treatment, which may improve the clinical management of DLBCL patients and provide theoretical basis for individualized treatment. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs have the potential as diagnostic biomarkers and therapeutic targets in autoimmune diseases. However, very limited studies have evaluated the expression of microRNA profile in thyroid gland related to Hashimoto's thyroiditis (HT).Methods: MicroRNA microarray expression profiling was performed and validated by quantitative RT-PCR. The expression pattern of miR-142-5p was detected using locked nucleic acid-in situ hybridization. The target gene was predicted and validated using miRNA targets prediction database, gene expression analysis, quantitative RT-PCR, western blot, and luciferase assay. The potential mechanisms of miR-142-5p were studied using immunohistochemistry, immunofluorescence, and quantitative assay of thyrocyte permeability.Results: Thirty-nine microRNAs were differentially expressed in HT (Fold change ≥2, P < 0.05) and miR-142-5p, miR-142-3p, and miR-146a were only high expression in HT thyroid gland (P < 0.001). miR-142-5p, which was expressed at high levels in injured follicular epithelial cells, was also detected in HT patient serum and positively correlated with thyroglobulin antibody (r ≥ 0.6, P < 0.05). Furthermore, luciferase assay demonstrated CLDN1 was the direct target gene of miR-142-5p (P < 0.05), and Immunohistochemical staining showed a reverse expression patterns with miR-142-5p and CLDN1. Overexpression of miR-142-5p in thyrocytes resulted in reducing of the expression of claudin-1 both in mRNA and protein level (P = 0.032 and P = 0.009 respectively) and increasing the permeability of thyrocytes monolayer (P < 0.01).Conclusions: Our findings indicate a previously unrecognized mechanism that miR-142-5p, targeting CLDN1, plays an important role in HT pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Trimetazidine, as an anti-ischemic and antioxidant agent, has been demonstrated to have many cardioprotective effects. However, whether early administration of trimetazidine has an effect on diabetic cardiomyopathy and the mechanisms underlying the effect have not yet been elucidated.Methods: We established a type 2 DCM rat model by high-fat diet and low-dose streptozotocin. Rats were separated into different groups: control, diabetes, and diabetes + trimetazidine (n = 6, each). Cardiac autophagy, cardiac functions, and cardiomyocyte apoptosis were monitored.Results: Rats with type 2 DCM showed severe insulin resistance, left ventricular dysfunction, increased cardiomyocyte apoptosis, and reduced cardiac autophagy. Collagen volume fraction (CVF) and perivascular collagen area/luminal area (PVCA/LA) ratio were significantly higher in the diabetic group than the control group. We found that trimetazidine treatment ameliorated metabolic disturbance and insulin resistance, reduced cardiomyocyte apoptosis, and restored cardiac autophagy. CVF and PVCA/LA ratio were also lower in the diabetes + trimetazidine group than the diabetic group (CVF, 4.75 ± 0.52 % vs. 11.04 ± 1.67 %, p < 0.05; PVCA/LA, 8.37 ± 0.51 vs. 17.97 ± 2.66, p < 0.05). Furthermore, trimetazidine inhibited phosphorylation of ERK and P38 MAPK to reduce myocardial fibrosis. Inhibited phosphorylation of AMPK was restored and the interaction between Bcl-2 and Beclin1 was enhanced in diabetes + trimetazidine group, resulting in the initiation of autophagy and alleviation of apoptosis.Conclusions: Early administration of trimetazidine could ameliorate diabetic cardiomyopathy by inhibiting myocardial fibrosis and cardiomyocyte apoptosis and enhancing autophagy. Therefore, trimetazidine may be a good choice in the prevention of diabetic cardiomyopathy if applied at the early stage of diabetes. [ABSTRACT FROM AUTHOR]

Background: Impaired Toll-like receptor 2 (TLR2) function has been associated with the pathogenesis of atopic dermatitis (AD). However, there are only few studies reporting on the TLR2-induced immunological responses of circulating leucocytes of AD patients. We thus investigated the expression and secretion of Th1, Th2 and Th17/22 cytokines triggered by TLR2 ligands in human peripheral blood mononuclear cells (PBMCs) from AD patients. Expression of TLR2, 1, 6 and high-affinity receptor for IgE (FcεRI) were further investigated to evaluate the outcome of immune response in AD.Methods: Expression of TLR2, 1, 6 and FcεRI in PBMCs from AD patients and healthy individuals were measured by qPCR. Subsequent to stimulation with TLR2 ligands PGN and Pam3CSK4, expression and secretion of Th1, Th2 and Th17/22 cytokines were investigated by qPCR and ELISA.Results: The levels of TLR2, 1, 6 mRNA were not altered in both groups of subjects while that of FcεRI was increased in AD patients. Subsequent to the activation by TLR2 ligands, PBMCs from AD patients significantly released less IFN-γ, IL-17F and IL-22 than those from healthy controls while no detectable level of release was observed with the other cytokines. In contrast, significantly higher levels of mRNA expression for TNF-α, IL5, IL-17A and IL-22 were observed in TLR2 activated PBMCs of AD patients than those of healthy control.Conclusions: PBMCs from AD patients are defective in the secretion of Th1 and Th17/22 cytokines in response to TLR2 ligands. The inconsistent increased expression of the mRNA for the corresponding Th1 cytokines and the Th2 cytokines IL-5 suggested that there may be alterations of downstream signaling events in the cytokine release mechanisms of PBMCs that are associated with the development of AD. [ABSTRACT FROM AUTHOR]

Background At present, no effective clinical treatment is available for the late effects of radiation myelopathy. The aim of the present study was to assess the therapeutic effects of human umbilical cord-derived mesenchymal stromal cells (UC-MSCs) in a rat model of radiation myelopathy. Methods An irradiated cervical spinal cord rat model was generated. UC-MSCs were injected through the tail vein at 90, 97, 104 and 111 days post-irradiation. Behavioral tests were performed using the forelimb paralysis scoring system, and histological damage was examined using Nissl staining. The microcirculation in the spinal cord was assessed using von Willebrand factor (vWF) immunohistochemical analysis and laser-Doppler flowmetry. The microenvironment in the spinal cord was determined by measuring the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the serum and the anti-inflammatory cytokines brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the spinal cord. Results Multiple injections of UC-MSCs through the tail veil decreased the forelimb paralysis, decreased spinal cord histological damage, increased the number of neurons in the anterior horn of the spinal cord, increased the endothelial cell density and the microvessel density in the white matter and gray matter of the spinal cord, increased the relative magnitude of spinal cord blood flow, down-regulated pro-inflammatory cytokine expression in the serum, and increased anti-inflammatory cytokine expression in the spinal cord. Conclusion Multiple injections of UC-MSCs via the tail vein in a rat model of radiation myelopathy significantly improved the microcirculation and microenvironment through therapeutic paracrine effects. [ABSTRACT FROM AUTHOR]

Background: Leukemia stem cell (LSC)-enriched genes have been shown to be highly prognostic in acute myeloid leukemia (AML). However, the prognostic value of tumor suppressor genes (TSGs) that are repressed early in LSC remains largely unknown.Methods: We compared the public available expression/methylation profiling data of LSCs with that of hematopoietic stem cells (HSCs), in order to identify potential tumor suppressor genes in LSC. The prognostic relevance of PCDH17 was analyzed on a cohort of 173 AML patients from The Cancer Genome Atlas (TCGA), and further validated in three independent cohorts (n = 339).Results: We identified protocadherin17 (PCDH17) and demonstrated that it was significantly down-regulated and hypermethylated in LSCs compared with HSCs. Our analyses of primary AML patient samples also confirmed these deregulations. Clinically, low PCDH17 expression was associated with female sex (P = 0.01), higher WBC (P < 0.0001), higher percentages of blasts in bone marrow (BM) and peripheral blood (PB) (P = 0.04 and < 0.001, respectively), presence of FLT3-internal tandem duplications (P = 0.002), mutated NPM1 (P = 0.02), and wild-type TP53 (P = 0.005). Moreover, low PCDH17 expression predicted worse overall survival (OS) in four independent cohorts as well as in the molecularly defined subgroups of AML patients. In multivariable analyses, low PCDH17 expression retained independent prognostic value for OS. Biologically, PCDH17 expression-associated gene signatures were characterized by deregulations of EMT- and Wnt pathway-related genes.Conclusions: PCDH17 gene was silenced by DNA methylation in AML. Low PCDH17 expression is associated with distinct clinical and biological features and improves risk stratification in patients with AML. [ABSTRACT FROM AUTHOR]

Background: Deregulated inflammation and immune deficit both intricately associate with cancer initiation and progression, which have been increasingly exploited as prognostic biomarkers and therapeutic targets. Recently, systemic immune-inflammation index (SII) based on peripheral neutrophil, lymphocyte and platelet counts serves as a novel and powerful cancer biomarker with prognostic significance in multiple types of malignancies. Here, we sought to evaluate the prognostic value of preoperative SII in patients with primary oral squamous cell carcinoma (OSCC) after curative resection.Methods: Two independent cohorts with a total number of 309 patients with OSCC from two tertiary referral hospitals were included and defined as training (Nanjing, 138) and validation (Wuxi, 171) cohort, respectively. Preoperative SII in both cohorts was calculated and its optimal cutoff value was initially determined by X-tile software in the training cohort and then verified in the validation cohort.Results: Our data indicated that high SII (≥ 484.5) was significantly associated with larger tumor size (P < 0.05, Chi square test), reduced overall and disease-free survival (Kaplan-Meir, P < 0.05, Log-rank test). Univariate and multivariate analyses further revealed that SII was an independent prognostic predictor for patient survival. Moreover, the area under receiver operating characteristic curve of SII for survival was significantly greater or comparable to other well-established prognostic parameters, indicative of its satisfactory prediction accuracy and specificity.Conclusions: Our findings reveal that high preoperative SII associates with poor outcome and serves as a non-invasive, low-cost and powerful prognostic predictor for patients with OSCC. This inflammation/immune-related biomarker holds translational potentials to supplement currently prognostic regime to better stratification of patients and treatment planning. [ABSTRACT FROM AUTHOR]

Background: Increasing studies showed that miR-200 family (miR-200s) clusters are aberrantly expressed in multiple human cancers, and miR-200s clusters function as tumor suppressor genes by affecting cell proliferation, self-renewal, differentiation, division and apoptosis. Herein, we aimed to investigate the expression and clinical implication of miR-200s clusters in acute myeloid leukemia (AML).Methods: RT-qPCR was performed to detect expression of miR-200s clusters in 19 healthy donors, 98 newly diagnosed AML patients, and 35 AML patients achieved complete remission (CR).Results: Expression of miR-200a/200b/429 cluster but not miR-200c/141 cluster was decreased in newly diagnosed AML patients as compared to healthy donors and AML patients achieved CR. Although no significant differences were observed between miR-200s clusters and most of the features, low expression of miR-200s clusters seems to be associated with higher white blood cells especially for miR-200a/200b. Of the five members of miR-200s clusters, low expression of miR-200b/429/200c was found to be associated with lower CR rate. Logistic regression analysis further revealed that low expression of miR-429 acted as an independent risk factor for CR in AML. Based on Kaplan-Meier analysis, low expression of miR-200b/429/200c was associated with shorter OS, whereas miR-200a/141 had a trend. Moreover, multivariate analysis of Cox regression models confirmed the independently prognostic value of miR-200b expression for OS in AML.Conclusions: Expression of miR-200a/200b/429 cluster was frequently down-regulated in AML, and low expression of miR-429 as an independent risk factor for CR, whereas low expression of miR-200b as an independent prognostic biomarker for OS. [ABSTRACT FROM AUTHOR]

Background: At present, no effective clinical treatment is available for the late effects of radiation myelopathy. The aim of the present study was to assess the therapeutic effects of human umbilical cord-derived mesenchymal stromal cells (UC-MSCs) in a rat model of radiation myelopathy.Methods: An irradiated cervical spinal cord rat model was generated. UC-MSCs were injected through the tail vein at 90, 97, 104 and 111 days post-irradiation. Behavioral tests were performed using the forelimb paralysis scoring system, and histological damage was examined using Nissl staining. The microcirculation in the spinal cord was assessed using von Willebrand factor (vWF) immunohistochemical analysis and laser-Doppler flowmetry. The microenvironment in the spinal cord was determined by measuring the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the serum and the anti-inflammatory cytokines brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the spinal cord.Results: Multiple injections of UC-MSCs through the tail veil decreased the forelimb paralysis, decreased spinal cord histological damage, increased the number of neurons in the anterior horn of the spinal cord, increased the endothelial cell density and the microvessel density in the white matter and gray matter of the spinal cord, increased the relative magnitude of spinal cord blood flow, down-regulated pro-inflammatory cytokine expression in the serum, and increased anti-inflammatory cytokine expression in the spinal cord.Conclusion: Multiple injections of UC-MSCs via the tail vein in a rat model of radiation myelopathy significantly improved the microcirculation and microenvironment through therapeutic paracrine effects. [ABSTRACT FROM AUTHOR]

Background: The bone morphogenetic family proteins (BMP) are phytogenetically conserved proteins, which are essential for embryonic development. The key regulatory subunit, the bone morphogenetic protein 4 (BMP4), is overexpressed and associated with tumor metastasis in a variety of cancers. However, the prognostic and molecular features of gliomas with BMP4 expression is still unclear.Methods: We obtained whole genome mRNA expression microarray data of 220 glioma samples of all grades from Chinese Glioma Genome Atlas (CGGA) database (http://www.cgga.org.cn) as discovery set. Of the 123 high-grade gliomas in this set, 33 Grade III tumors and 88 GBMs were analyzed by Kaplan-Meier method. Immunohistochemistry was used for validating the expression of BMP4 in another 77 glioma samples. Three additional datasets were obtained as validation sets. Gene ontology (GO) analysis and gene set variation analysis (GSVA) were used for functional annotation of BMP4.Results: In the discovery set, BMP4 overexpression was significantly associated with low grade as well as the lower mortality of high-grade gliomas in survival analysis (log-rank, p<0.05 in GBM patients and p<0.01 in anaplastic gliomas, respectively). BMP4 also showed a Proneural subtype, G1 subtype and Isocitrate Dehydrogenase 1 (IDH1) mutation preference and cell development association. The results of validation 4 datasets showed similar findings. The overexpression of BMP4 was also detected in low grade gliomas compared to the high grade ones by immunohistochemistry (p<0.05, chi-square test).Conclusion: BMP4 expression was independently associated with grade and good prognosis in grade III and grade IV gliomas, suggesting BMP4 as a novel biomarker with potential important therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: This study was designed to determine whether advanced non-small-cell lung cancer (NSCLC) patients with high copy number of epidermal growth factor receptor (EGFR) can benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs).Methods: EGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) and EGFR mutations was tested using Luminex xTAG technology in 502 TKI-treated NSCLC patients. The association between both biomarkers and clinical benefit from EGFR-TKI were analyzed.Results: EGFR FISH+and EGFR mutations were significantly associated with higher response rates (37.2% and 43.7%, respectively), superior progression-free survival (PFS) (FISH+, 11.2 months; hazard ratio [HR], 0.51; 95% CI, 0.42 to 0.62; p<0.001; mutation+, 11.7 months; HR, 0.37; 95% CI, 0.31 to 0.45; p<0.001) and overall survival (OS) (FISH+, 30.2 months; HR, 0.51; 95% CI, 0.40 to 0.65; p<0.001; mutation+, 30.2 months; HR, 0.45; 95% CI, 0.36 to 0.58; p<0.001). In patients with wild-type EGFR, EGFR FISH+correlated with longer PFS than EGFR FISH- status (4.4 months vs. 2.0 months; HR, 0.56; 95% CI, 0.41 to 0.75; p<0.001), so did amplification (5.0 months vs. 2.0 months; HR, 0.43; 95% CI, 0.24 to 0.76; p=0.003). However, FISH+had no association with improved PFS in EGFR-mutated patients (HR, 0.77; 95% CI, 0.57 to 1.03; p=0.076).Conclusions: A combined analysis of EGFR FISH and mutation is an effective predictor of EGFR-TKI therapy. Specifically, a high EGFR copy number may predict benefit from TKIs treatment for NSCLC patients with wild-type EGFR. [ABSTRACT FROM AUTHOR]