scholarly journals Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer

Gut ◽  
2021 ◽  
pp. gutjnl-2020-322835
Author(s):  
Elias Orouji ◽  
Ayush T Raman ◽  
Anand K Singh ◽  
Alexey Sorokin ◽  
Emre Arslan ◽  
...  
Keyword(s):  
Tumour Progression ◽  
Synergistic Effects ◽  
Chromatin State ◽  
Patient Specific ◽  
Normal Tissues ◽  
Comprehensive Knowledge ◽  
Active Enhancer ◽  
Significant Survival ◽  
Colon Cancer Cell Lines ◽  
Survival Differences

ObjectiveEnhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described.DesignWe performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin.ResultsWe demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFβi, mTORi and SRCi) for EpiC groups.ConclusionOur data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.

scholarly journals Chromatin State Dynamics Confers Specific Therapeutic Strategies in Enhancer Subtypes of Colorectal Cancer

2020 ◽  
Author(s):  
Elias Orouji ◽  
Ayush T. Raman ◽  
Anand K. Singh ◽  
Alexey Sorokin ◽  
Emre Arslan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Synergistic Effects ◽  
Expression Patterns ◽  
Chromatin State ◽  
Patient Specific ◽  
Normal Tissues ◽  
Active Enhancer ◽  
Colorectal Cancer Progression ◽  
And Function

ABSTRACTThe extent and function of chromatin state aberrations during colorectal cancer (CRC) progression is not completely understood. Here, by comprehensive epigenomic characterization of 56 tumors, adenomas, and their matched normal tissues, we define the dynamics of chromatin states during the progression of colorectal cancer. H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumor-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was crucial for excessive proliferation. Consistently, combination of MEK plus bromodomain (BET) inhibition was found to have synergistic effects in CRC patient-derived xenograft (PDX) models. Probing inter-tumor heterogeneity, we identified four distinct enhancer subtypes (EpiC), three of which correlate well with previously defined transcriptomic subtypes (CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, and TGFβi) for three EPIC groups. Our data suggest that the dynamics of active enhancer underlies colorectal cancer progression and the patient-specific active enhancer patterns govern their unique gene expression patterns which can be leveraged for precision combination therapy.

scholarly journals Causal network perturbations for instance-specific analysis of single cell and disease samples

2019 ◽  
Vol 36 (8) ◽  
pp. 2515-2521 ◽  
Author(s):  
Kristina L Buschur ◽  
Maria Chikina ◽  
Panayiotis V Benos
Keyword(s):  
Single Cell ◽  
Gene Networks ◽  
Underlying Mechanism ◽  
Alternative Methods ◽  
Supplementary Information ◽  
Patient Specific ◽  
Data Dependencies ◽  
Significant Survival ◽  
Specific Analysis ◽  
Survival Differences

Abstract Motivation Complex diseases involve perturbation in multiple pathways and a major challenge in clinical genomics is characterizing pathway perturbations in individual samples. This can lead to patient-specific identification of the underlying mechanism of disease thereby improving diagnosis and personalizing treatment. Existing methods rely on external databases to quantify pathway activity scores. This ignores the data dependencies and that pathways are incomplete or condition-specific. Results ssNPA is a new approach for subtyping samples based on deregulation of their gene networks. ssNPA learns a causal graph directly from control data. Sample-specific network neighborhood deregulation is quantified via the error incurred in predicting the expression of each gene from its Markov blanket. We evaluate the performance of ssNPA on liver development single-cell RNA-seq data, where the correct cell timing is recovered; and two TCGA datasets, where ssNPA patient clusters have significant survival differences. In all analyses ssNPA consistently outperforms alternative methods, highlighting the advantage of network-based approaches. Availability and implementation http://www.benoslab.pitt.edu/Software/ssnpa/. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Immunotherapy as a Precision Medicine Tool for the Treatment of Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 173
Author(s):  
Maria Adamaki ◽  
Vassilios Zoumpourlis
Keyword(s):  
Prostate Cancer ◽  
Precision Medicine ◽  
Checkpoint Inhibitors ◽  
Invasive Disease ◽  
Patient Specific ◽  
Treatment Alternative ◽  
Substantial Evidence ◽  
Significant Survival ◽  
Localized Disease ◽  
Specific Antigens

Prostate cancer (PCa) is the most frequently diagnosed type of cancer among Caucasian males over the age of 60 and is characterized by remarkable heterogeneity and clinical behavior, ranging from decades of indolence to highly lethal disease. Despite the significant progress in PCa systemic therapy, therapeutic response is usually transient, and invasive disease is associated with high mortality rates. Immunotherapy has emerged as an efficacious and non-toxic treatment alternative that perfectly fits the rationale of precision medicine, as it aims to treat patients on the basis of patient-specific, immune-targeted molecular traits, so as to achieve the maximum clinical benefit. Antibodies acting as immune checkpoint inhibitors and vaccines entailing tumor-specific antigens seem to be the most promising immunotherapeutic strategies in offering a significant survival advantage. Even though patients with localized disease and favorable prognostic characteristics seem to be the ones that markedly benefit from such interventions, there is substantial evidence to suggest that the survival benefit may also be extended to patients with more advanced disease. The identification of biomarkers that can be immunologically targeted in patients with disease progression is potentially amenable in this process and in achieving significant advances in the decision for precision treatment of PCa.

PINSPlus: a tool for tumor subtype discovery in integrated genomic data

2018 ◽  
Vol 35 (16) ◽  
pp. 2843-2846 ◽  
Author(s):  
Hung Nguyen ◽  
Sangam Shrestha ◽  
Sorin Draghici ◽  
Tin Nguyen
Keyword(s):  
Personal Computer ◽  
Genomic Data ◽  
Supplementary Information ◽  
Omics Data ◽  
Tumor Subtype ◽  
Supplementary Data ◽  
Significant Survival ◽  
Survival Differences

Abstract Summary Since cancer is a heterogeneous disease, tumor subtyping is crucial for improved treatment and prognosis. We have developed a subtype discovery tool, called PINSPlus, that is: (i) robust against noise and unstable quantitative assays, (ii) able to integrate multiple types of omics data in a single analysis and (iii) dramatically superior to established approaches in identifying known subtypes and novel subgroups with significant survival differences. Our validation on 12,158 samples from 44 datasets shows that PINSPlus vastly outperforms other approaches. The software is easy-to-use and can partition hundreds of patients in a few minutes on a personal computer. Availability and implementation The package is available at https://cran.r-project.org/package=PINSPlus. Data and R script used in this manuscript are available at https://bioinformatics.cse.unr.edu/software/PINSPlus/. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Combined secondary compounds naturally found in nectars enhance honeybee cognition and survival

2021 ◽  
Vol 224 (6) ◽  
Author(s):  
Ignacio L. Marchi ◽  
Florencia Palottini ◽  
Walter M. Farina
Keyword(s):  
Cognitive Ability ◽  
Sucrose Solution ◽  
Synergistic Effects ◽  
Secondary Compounds ◽  
Learning Performance ◽  
Memory Retention ◽  
Olfactory Conditioning ◽  
Significant Survival ◽  
Short And Long Term

ABSTRACT The alkaloid caffeine and the amino acid arginine are present as secondary compounds in nectars of some flower species visited by pollinators. Each of these compounds affects honeybee appetitive behaviours by improving foraging activity and learning. While caffeine potentiates responses of mushroom body neurons involved in honeybee learning processes, arginine acts as precursor of nitric oxide, enhancing the protein synthesis involved in memory formation. Despite existing evidence on how these compounds affect honeybee cognitive ability individually, their combined effect on this is still unknown. We evaluated acquisition and memory retention in a classical olfactory conditioning procedure, in which the reward (sucrose solution) contained traces of caffeine, arginine or a mixture of the two. The results indicate that the presence of the single compounds and their most concentrated mixture increases bees' learning performance. However, memory retention, measured in the short and long term, increases significantly only in those treatments offering combinations of the two compounds in the reward. Additionally, the most concentrated mixture triggers a significant survival rate in the conditioned bees. Thus, some nectar compounds, when combined, show synergistic effects on cognitive ability and survival in an insect.

scholarly journals Radionuclide Imaging of Apoptosis in Malignancies: Promise and Pitfalls of 99mTc-Hynic-rh-Annexin V Imaging

2008 ◽  
Vol 2 ◽  
pp. CMO.S349
Author(s):  
M.S. Kartachova ◽  
M. Verheij ◽  
B.L. Van Eck ◽  
C.A. Hoefnagel ◽  
R.A. Valdes Olmos
Keyword(s):  
Tumour Progression ◽  
Annexin V ◽  
Malignant Tumour ◽  
Biochemical Properties ◽  
Favourable Outcome ◽  
Tracer Uptake ◽  
Mri Imaging ◽  
Early Therapy ◽  
Normal Tissues

Radionuclide detection of apoptosis with of 99mTc-Hynic-rh-Annexin V scintigraphy is an effective tool for in vivo visualisation and monitoring of apoptosis in various malignant tumour. Early therapy-induced increase of the tumour tracer uptake correlates with favourable outcome, whereas stable or decreased uptake correlates with stable disease or tumour progression. Therefore sequential 99mTc-Hynic-rh-Annexin V scintigraphy could be used to predict therapy outcome on a patient-to-patient basis within 48 hours after the start of treatment. However, moderate tumour-to-background ratio and therapy-induced changes in normal tissues could confound image analysis. To assure accurate interpretation of Annexin V scans, the awareness of the biophysiological and biochemical properties contributing to the tracer distribution is essential. In with manuscript we discuss the patterns of Annexin V tumour uptake and illustrate the most frequent pitfalls associated with Annexin V imaging in correlation with CT and MRI imaging.

scholarly journals The Novel Notch-induced Long Noncoding RNA LUNAR1 Determines the Proliferation and Prognosis of Colorectal Cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zixi Zhang ◽  
Gai Li ◽  
He Qiu ◽  
Jingyi Yang ◽  
Xin Bu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Noncoding Rna ◽  
Target Genes ◽  
Tumour Progression ◽  
Regulation Of Gene Expression ◽  
Disease Free Survival ◽  
Notch Signalling ◽  
Normal Tissues ◽  
Sw620 Cells ◽  
The Impact

AbstractIn contrast to what is known about the complicated roles of Notch signalling in human malignancies, the direct target genes of Notch signalling are still unclear. Recently, long noncoding RNAs (lncRNAs) have been found to play various roles in the post-transcriptional regulation of gene expression. In the present study, we investigated the potential role of the Notch-induced lncRNA LUNAR1 in colorectal cancer (CRC). We recruited 196 cases of clinical CRC specimens and investigated LUNAR1 levels in these specimens. The associations of LUNAR1 with tumour aggressiveness and clinical outcomes were evaluated. Moreover, the impact of LUNAR1 on the malignant behaviour of tumour cells was tested in cell lines. Significantly increased expression of LUNAR1 in clinical CRC specimens was detected compared with that in matching normal tissues. LUNAR1 expression in CRC was found to be associated with the tumour aggressiveness, disease-free survival and overall survival of patients. The downregulation of LUNAR1 in SW620 cells inhibited cell proliferation, migration, invasion and tumour growth while inducing apoptosis. Moreover, the inhibition of LUNAR1 can significantly suppress IGF1 signalling in CRC. These results indicated that LUNAR1 was increased in CRC and might promote tumour progression. Thus, LUNAR1 may constitute a promising prognostic marker for the clinical management of CRC.

The emergence of solid stress as a potent biomechanical marker of tumour progression

2018 ◽  
Vol 2 (5) ◽  
pp. 739-749
Author(s):  
Alain Vella ◽  
Enanga M. Eko ◽  
Armando del Río Hernández
Keyword(s):  
Stromal Cells ◽  
Tumour Growth ◽  
Tumour Progression ◽  
Tissue Structure ◽  
Signalling Pathways ◽  
Matrix Stiffness ◽  
Cell Behaviour ◽  
Solid Stress ◽  
Comprehensive Knowledge ◽  
Macro Scale

Cancer is a disease of dysregulated mechanics which alters cell behaviour, compromises tissue structure, and promotes tumour growth and metastasis. In the context of tumour progression, the most widely studied of biomechanical markers is matrix stiffness as tumour tissue is typically stiffer than healthy tissue. However, solid stress has recently been identified as another marker of tumour growth, with findings strongly suggesting that its role in cancer is distinct from that of stiffness. Owing to the relative infancy of the field which draws from diverse disciplines, a comprehensive knowledge of the relationships between solid stress, tumorigenesis, and metastasis is likely to provide new and valuable insights. In this review, we discuss the micro- and macro-scale biomechanical interactions that give rise to solid stresses, and also examine the techniques developed to quantify solid stress within the tumour environment. Moreover, by reviewing the effects of solid stress on tissues, cancer and stromal cells, and signalling pathways, we also detail its mode of action at each level of the cancer cascade.

scholarly journals DriverDBv3: a multi-omics database for cancer driver gene research

2019 ◽  
Author(s):  
Shu-Hsuan Liu ◽  
Pei-Chun Shen ◽  
Chen-Yang Chen ◽  
An-Ni Hsu ◽  
Yi-Chun Cho ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Synergistic Effects ◽  
Driver Gene ◽  
Driver Genes ◽  
Specific Patient ◽  
Mutation Status ◽  
Cancer Driver ◽  
Cancer Driver Gene ◽  
Significant Survival ◽  
Gene Database

Abstract An integrative multi-omics database is needed urgently, because focusing only on analysis of one-dimensional data falls far short of providing an understanding of cancer. Previously, we presented DriverDB, a cancer driver gene database that applies published bioinformatics algorithms to identify driver genes/mutations. The updated DriverDBv3 database (http://ngs.ym.edu.tw/driverdb) is designed to interpret cancer omics’ sophisticated information with concise data visualization. To offer diverse insights into molecular dysregulation/dysfunction events, we incorporated computational tools to define CNV and methylation drivers. Further, four new features, CNV, Methylation, Survival, and miRNA, allow users to explore the relations from two perspectives in the ‘Cancer’ and ‘Gene’ sections. The ‘Survival’ panel offers not only significant survival genes, but gene pairs synergistic effects determine. A fresh function, ‘Survival Analysis’ in ‘Customized-analysis,’ allows users to investigate the co-occurring events in user-defined gene(s) by mutation status or by expression in a specific patient group. Moreover, we redesigned the web interface and provided interactive figures to interpret cancer omics’ sophisticated information, and also constructed a Summary panel in the ‘Cancer’ and ‘Gene’ sections to visualize the features on multi-omics levels concisely. DriverDBv3 seeks to improve the study of integrative cancer omics data by identifying driver genes and contributes to cancer biology.

scholarly journals Changes in Background Liver Function in Patients with Hepatocellular Carcinoma over 30 Years: Comparison of Child-Pugh Classification and Albumin Bilirubin Grade

Liver Cancer ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 518-528 ◽  
Author(s):  
Takashi Kumada ◽  
Hidenori Toyoda ◽  
Toshifumi Tada ◽  
Satoshi Yasuda ◽  
Junko Tanaka
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Function ◽  
Hepatic Function ◽  
Hepatic Reserve ◽  
Significant Survival ◽  
Detailed Evaluation ◽  
Group A ◽  
Group B ◽  
Survival Differences ◽  
Group D

Background: Background liver function in patients with hepatocellular carcinoma (HCC) has improved remarkably with advances in various treatments. Recently, the Child-Pugh classification (CPC) system has been recognized as limited in its ability to assess patients with good hepatic reserve. We compared the albumin-bilirubin (ALBI) grade, which is suitable for a more detailed evaluation of patients with good liver function, with CPC over a 30-year period. Methods: A total of 2,347 patients were analyzed. Patients were stratified by year of diagnosis into 6 groups: Group A (1990–1994, n = 376), Group B (1995–1999, n = 434), Group C (2000–2004, n = 438), Group D (2005–2009, n = 444), Group E (2010–2014, n = 392), and Group F (2015–2018, n = 263). We compared ALBI grade and CPC across the groups. Results: The prevalence of patients with CPC A at diagnosis increased throughout the study period, reaching nearly 80% in Groups E and F (p < 0.001). By contrast, the percentage of patients with ALBI grade 1 disease remained approximately 50% in Groups E and F (p < 0.001). Modified ALBI (mALBI) grade 2a corresponds to patients with CPC A who have poor hepatic function. There were significant survival differences between patients with mALBI grade 1 versus 2a, 1 versus 2b, and 2a versus 2b disease, respectively (p < 0.0001), in patients with CPC A. Conclusions: CPC is not suitable for assessing patients with recently diagnosed HCC and good remnant hepatic function. In such patients with HCC, the prognosis can be stratified by ALBI grade rather than CPC.

Sign in / Sign up

Export Citation Format

Share Document