Purpose
A subset of skull base meningiomas (SBM) may show early progression/recurrence (P/R) as a result of incomplete resection. The purpose of this study is the implementation of MR radiomics to ...predict P/R in SBM.
Methods
From October 2006 to December 2017, 60 patients diagnosed with pathologically confirmed SBM (WHO grade I, 56; grade II, 3; grade III, 1) were included in this study. Preoperative MRI including T2WI, diffusion-weighted imaging (DWI), and contrast-enhanced T1WI were analyzed. On each imaging modality, 13 histogram parameters and 20 textural gray level co-occurrence matrix (GLCM) features were extracted. Random forest algorithms were utilized to evaluate the importance of these parameters, and the most significant three parameters were selected to build a decision tree for prediction of P/R in SBM. Furthermore, ADC values obtained from manually placed ROI in tumor were also used to predict P/R in SBM for comparison.
Results
Gross-total resection (Simpson Grades I–III) was performed in 33 (33/60, 55%) patients, and 27 patients received subtotal resection. Twenty-one patients had P/R (21/60, 35%) after a postoperative follow-up period of at least 12 months. The three most significant parameters included in the final radiomics model were T1 max probability, T1 cluster shade, and ADC correlation. In the radiomics model, the accuracy for prediction of P/R was 90%; by comparison, the accuracy was 83% using ADC values measured from manually placed tumor ROI.
Conclusions
The results show that the radiomics approach in preoperative MRI offer objective and valuable clinical information for treatment planning in SBM.
Against a rapidly aging population, projections are done to size up the demand for long-term care (LTC) services for long-range policy planning. These projections are typically focused on functional ...factors such as disability. Recent studies indicate the importance of social factors, for example, socially isolated seniors living alone are more likely to be institutionalized, resulting in higher demand for LTC services. This is one the first known studies to complete a 40-year projection of LTC demand based on disability and social isolation. The primary micro dataset was the Retirement and Health Survey, Singapore's first nationally representative longitudinal study of noninstitutionalized older adults aged 45 to 85 with over 15,000 respondents. Disability prevalence across the mild to severe spectrum is projected to increase five-fold over the next 40 years, and the number of socially isolated elders living alone is projected to grow four-fold. Regression models of living arrangements revealed interesting ethnic differences: Malay elders are 2.6 times less likely to live alone than their Chinese counterparts, controlling for marital status, age, and housing type. These projections provide a glimpse of the growing demand for LTC services for a rapidly aging Singapore and underscore the need to shore up community-based resources to enable seniors to age-in-place.
The epidermal growth factor (EGF) receptor (EGFR) overexpressed in many cancers, including lung and head and neck cancers, and is involved in cancer cell progression and survival. PD‐L1, increases in ...tumor cells to evade and inhibit CD8+ T cells, is a clinical immunotherapeutic target. This study investigated the molecular mechanism of EGF on regulating PD‐L1 in EGFR‐positive cancers and determined potential agents to reduce PD‐L1 expression. RNA sequencing (RNAseq) and bioinformatics analysis were performed to determine potential driver genes that regulate PD‐L1 in tumor cells‐derived tumorspheres which mimicking cancer stem cells. Then, the specific inhibitors targeting EGFR were applied to reduce the expression of PD‐L1 in vitro and in vivo. We validated that EGF could induce PD‐L1 expression in the selected EGFR‐positive cancers. RNAseq results revealed that STAT1 increased as a driver gene in KOSC‐3‐derived tumorspheres; these data were analyzed using PANTHER followed by NetworkAnalyst. The blockade of EGFR by afatinib resulted in decreased STAT1 and IRF‐1 levels, both are transcriptional factors of PD‐L1, and disabled the IFNr‐STAT1‐mediated PD‐L1 axis in vitro and in vivo. Moreover, STAT1 knockdown significantly reduced EGF‐mediated PD‐L1 expression, and ruxolitinib, a JAK1/JAK2 inhibitor, significantly inhibited STAT1 phosphorylation to reduce the IFNr‐mediated PD‐L1 axis. These results indicate that EGF exacerbates PD‐L1 by increasing the protein levels of STAT1 to enforce the IFNr‐JAK1/2‐mediated signaling axis in selected EGFR‐positive cancers. The inhibition of EGFR by afatinib significantly reduced PD‐L1 and may be a potential strategy for enhancing immunotherapeutic efficacy.
Dengue (DENV) and Zika (ZIKV) viruses are clinically important members of the Flaviviridae family with an 11 kb positive strand RNA genome that folds to enable virus function. Here, we perform ...structure and interaction mapping on four DENV and ZIKV strains inside virions and in infected cells. Comparative analysis of SHAPE reactivities across serotypes nominates potentially functional regions that are highly structured, conserved, and contain low synonymous mutation rates. Interaction mapping by SPLASH identifies many pair-wise interactions, 40% of which form alternative structures, suggesting extensive structural heterogeneity. Analysis of shared interactions between serotypes reveals a conserved macro-organization whereby interactions can be preserved at physical locations beyond sequence identities. We further observe that longer-range interactions are preferentially disrupted inside cells, and show the importance of new interactions in virus fitness. These findings deepen our understanding of Flavivirus genome organization and serve as a resource for designing therapeutics in targeting RNA viruses.
A subset of non-functioning pituitary macroadenomas (NFPAs) may exhibit early progression/recurrence (P/R) after surgical resection. The purpose of this study was to apply radiomics in predicting P/R ...in NFPAs.
Only patients who had undergone preoperative MRI and postoperative MRI follow-ups for more than 1 year were included in this study. From September 2010 to December 2017, 50 eligible patients diagnosed with pathologically confirmed NFPAs were identified. Preoperative coronal T2WI and contrast-enhanced (CE) T1WI imaging were analyzed by computer algorithms. For each imaging sequence, 32 first-order features and 75 texture features were extracted. Support vector machine (SVM) classifier was utilized to evaluate the importance of extracted parameters, and the most significant three parameters were used to build the prediction model. The SVM score was calculated based on the three selected features.
Twenty-eight patients exhibited P/R (28/50, 56%) after surgery. The median follow-up time was 38 months, and the median time to P/R was 20 months. Visual disturbance, hypopituitarism, extrasellar extension, compression of the third ventricle, large tumor height and volume, failed optic chiasmatic decompression, and high SVM score were more frequently encountered in the P/R group (
< 0.05). In multivariate Cox hazards analysis, symptoms of sex hormones, hypopituitarism, and SVM score were high risk factors for P/R (
< 0.05) with hazard ratios of 10.71, 2.68, and 6.88. The three selected radiomics features were T1 surface-to-volume radio, T1 GLCM-informational measure of correlation, and T2 NGTDM-coarseness. The radiomics predictive model shows 25 true positive, 16 true negative, 6 false positive, and 3 false negative cases, with an accuracy of 82% and AUC of 0.78 in differentiating P/R from non-P/R NFPAs. For SVM score, optimal cut-off value of 0.537 and AUC of 0.87 were obtained for differentiation of P/R. Higher SVM scores were associated with shorter progression-free survival (
< 0.001).
Our preliminary results showed that objective and quantitative MR radiomic features can be extracted from NFPAs. Pending more studies and evidence to support the findings, radiomics analysis of preoperative MRI may have the potential to offer valuable information in treatment planning for NFPAs.
Objectives:
A subset of meningiomas may show progression/recurrence (P/R) after surgical resection. This study applied pre-operative MR radiomics based on support vector machine (SVM) to predict P/R ...in meningiomas.
Methods:
From January 2007 to January 2018, 128 patients with pathologically confirmed WHO grade I meningiomas were included. Only patients who had undergone pre-operative MRIs and post-operative follow-up MRIs for more than 1 year were studied. Pre-operative T2WI and contrast-enhanced T1WI were analyzed. On each set of images, 32 first-order features and 75 textural features were extracted. The SVM classifier was utilized to evaluate the significance of extracted features, and the most significant four features were selected to calculate SVM score for each patient.
Results:
Gross total resection (Simpson grades I–III) was performed in 93 (93/128, 72.7%) patients, and 19 (19/128, 14.8%) patients had P/R after surgery. Subtotal tumor resection, bone invasion, low apparent diffusion coefficient (ADC) value, and high SVM score were more frequently encountered in the P/R group (
p
< 0.05). In multivariate Cox hazards analysis, bone invasion, ADC value, and SVM score were high-risk factors for P/R (
p
< 0.05) with hazard ratios of 7.31, 4.67, and 8.13, respectively. Using the SVM score, an AUC of 0.80 with optimal cutoff value of 0.224 was obtained for predicting P/R. Patients with higher SVM scores were associated with shorter progression-free survival (
p
= 0.003).
Conclusions:
Our preliminary results showed that pre-operative MR radiomic features may have the potential to offer valuable information in treatment planning for meningiomas.
Identifying host factors is key to understanding RNA virus pathogenicity. Besides proteins, RNAs can interact with virus genomes to impact replication.
Here, we use proximity ligation sequencing to ...identify virus-host RNA interactions for four strains of Zika virus (ZIKV) and one strain of dengue virus (DENV-1) in human cells. We find hundreds of coding and non-coding RNAs that bind to DENV and ZIKV viruses. Host RNAs tend to bind to single-stranded regions along the virus genomes according to hybridization energetics. Compared to SARS-CoV-2 interactors, ZIKV-interacting host RNAs tend to be downregulated upon virus infection. Knockdown of several short non-coding RNAs, including miR19a-3p, and 7SK RNA results in a decrease in viral replication, suggesting that they act as virus-permissive factors. In addition, the 3'UTR of DYNLT1 mRNA acts as a virus-restrictive factor by binding to the conserved dumbbell region on DENV and ZIKV 3'UTR to decrease virus replication. We also identify a conserved set of host RNAs that interacts with DENV, ZIKV, and SARS-CoV-2, suggesting that these RNAs are broadly important for RNA virus infection.
This study demonstrates that host RNAs can impact virus replication in permissive and restrictive ways, expanding our understanding of host factors and RNA-based gene regulation during viral pathogenesis.
Cancer stem cells are capable of undergoing cell division after surviving cancer therapies, leading to tumor progression and recurrence. Inhibitory agents against cancer stem cells may be ...therapeutically used for efficiently eradicating tumors. Therefore, the aim of this study was to identify the relevant driver genes that maintain cancer stemness in epidermal growth factor receptor (EGFR)-positive colorectal cancer (CRC) cells and to discover effective therapeutic agents against these genes.
In this study, EGFR-positive cancer stem-like cells (CSLCs) derived from HCT116 and HT29 cells were used as study models for in vitro inductions. To identify the differential genes that maintain CSLCs, RNAseq analysis was conducted followed by bioinformatics analysis. Moreover, a panel containing 172 therapeutic agents targeting the various pathways of stem cells was used to identify effective therapeutics against CSLCs.
RNAseq analysis revealed that 654 and 840 genes were significantly upregulated and downregulated, respectively, in the HCT116 CSLCs. Among these genes, notably, platelet-derived growth factor A (PDGFA) and signal transducer and activator of transcription 3 (STAT3) were relevant according to the cancer pathway analyzed using NetworkAnalyst. Furthermore, therapeutic screening revealed that the agents targeting STAT3 and Wnt signaling pathways were efficient in reducing the cell viabilities of both HCT116 and HT29 cells. Consequently, we discovered that STAT3 inhibition using homoharringtonine and STAT3 knockdown significantly reduced the formation and survival of HT29-derived tumorspheres. We also observed that STAT3 phosphorylation was regulated by epidermal growth factor (EGF) to induce PDGFA and Wnt signaling cascades.
We identified the potential genes involved in tumorsphere formation and survival in selective EGFR-positive CRCs. The results reveal that the EGF-STAT3 signaling pathway promotes and maintains CRC stemness. In addition, a crosstalk between STAT3 and Wnt activates the Wnt/β-catenin signaling pathway, which is also responsible for cancer stemness. Thus, STAT3 is a putative therapeutic target for CRC treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
•ILF3 was a downstream protein of EGFR and mutually regulated EGFR expression.•ILF3 regulated expressions of oncogenic receptor, including ErbB3, IGF1R, and FGFR4.•Targeting to ILF3 inhibited ...formation of A549-derived cancer stem-like tumorspheres.•Targeting to ILF3 by YM155 synergized the therapeutic efficacy of afatinib.•ILF3 was a potential therapeutic target against EGFR-positive lung cancers.
YM155, an inhibitor of interleukin enhancer-binding factor 3 (ILF3), significantly suppresses cancer stemness property, implying that ILF3 contributes to cell survival of cancer stem cells. However, the molecular function of ILF3 inhibiting cancer stemness remains unclear. This study aimed to uncover the potential function of ILF3 involving in cell survival of epidermal growth factor receptor (EGFR)-positive lung stem-like cancer, and to investigate the potential role to improve the efficacy of anti-EGFR therapeutics.
The association of EGFR and ILF3 in expression and regulations was first investigated in this study. Lung cancer A549 cells with deprivation of ILF3 were created by the gene-knockdown method and then RNAseq was applied to identify the putative genes regulated by ILF3. Meanwhile, HCC827- and A549-derived cancer stem-like cells were used to investigate the role of ILF3 in the formation of cancer stem-like tumorspheres.
We found that EGFR induced ILF3 expression, and YM155 reduced EGFR expression. The knockdown of ILF3 reduced not only EGFR expression in mRNA and protein levels, but also cell proliferation in vitro and in vivo, demonstrating that ILF3 may play an important role in contributing to cancer cell survival. Moreover, the knockdown and inhibition of ILF3 by shRNA and YM155, respectively, reduced the formation and survival of HCC827- and A549-derived tumorspheres through inhibiting ErbB3 (HER3) expression, and synergized the therapeutic efficacy of afatinib, a tyrosine kinase inhibitor, against EGFR-positive A549 lung cells.
This study demonstrated that ILF3 plays an oncogenic like role in maintaining the EGFR-mediated cellular pathway, and can be a therapeutic target to improve the therapeutic efficacy of afatinib. Our results suggested that YM155, an ILF3 inhibitor, has the potential for utilization in cancer therapy against EGFR-positive lung cancers.
The molecular pathogenesis of extranodal NK/T-cell lymphoma (NKTCL) remains obscured despite the next-generation sequencing (NGS) studies explored on ever larger cohorts in the last decade. We ...addressed the highly variable mutation frequencies reported among previous studies with comprehensive amplicon coverage and enhanced sequencing depth to achieve higher genomic resolution for novel genetic discovery and comparative mutational profiling of the oncogenesis of NKTCL. Targeted exome sequencing was conducted to interrogate 415 cancer-related genes in a cohort of 36 patients with NKTCL, and a total of 548 single nucleotide variants (SNVs) and 600 Copy number variances (CNVs) were identified. Recurrent amplification of the
MCL1
(67%) and
PIM1
(56%) genes was detected in a dominant majority of patients in our cohort. Functional mapping of genetic aberrations revealed that an enrichment of mutations in the JAK-STAT signaling pathway, including the cytokine receptor LIFR (copy number loss) upstream of JAK3, STAT3 (activating SNVs), and downstream effectors of MYC, PIM1 and MCL1 (copy number gains). RNA in situ hybridization showed the significant consistence of MCL1 RNA level and copy number of
MCL1
gene. We further correlated molecular and clinical parameters with overall survival (OS) of these patients. When correlations were analyzed by univariate followed by multivariate modelling, only copy number loss of
LIFR
gene and stage (III-IV) were independent prognostic factors of reduced OS. Our findings identified that novel loss of
LIFR
gene significantly correlated with the adverse clinical outcome of NKTCL patients and provided therapeutic opportunities for this disease through manipulating LIFR.
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