scholarly journals An ANOCEF Genomic and Transcriptomic Microarray Study of the Response to Irinotecan and Bevacizumab in Recurrent Glioblastomas

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Julien Laffaire ◽  
Anna Luisa Di Stefano ◽  
Olivier Chinot ◽  
Ahmed Idbaih ◽  
Jaime Gallego Perez-Larraya ◽  
...  
Keyword(s):  
Response Rate ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Molecular Characteristics ◽  
Egfr Amplification ◽  
Lower Response ◽  
Lower Response Rate ◽  
Cdkn2a Deletion

Background. We performed a retrospective study to assess whether the initial molecular characteristics of glioblastomas (GBMs) were associated with the response to the bevacizumab/irinotecan chemotherapy regimen given at recurrence.Results. Comparison of the genomic and gene expression profiles of the responders (n=12) and nonresponders (n=13) demonstrated only slight differences and could not identify any robust biomarkers associated with the response. In contrast, a significant association was observed between GBMs molecular subtypes and response rates. GBMs assigned to molecular subtype IGS-18 and to classical subtype had a lower response rate than those assigned to other subtypes. In an independent series of 33 patients, neither EGFR amplification nor CDKN2A deletion (which are frequent in IGS-18 and classical GBMs) was significantly associated with the response rate, suggesting that these two alterations are unlikely to explain the lower response rate of these GBMs molecular subtypes.Conclusion. Despite its limited sample size, the present study suggests that comparing the initial molecular profiles of responders and nonresponders might not be an effective strategy to identify biomarkers of the response to bevacizumab given at recurrence. Yet it suggests that the response rate might differ among GBMs molecular subtypes.

scholarly journals Pan-cancer machine learning predictors of primary site of origin and molecular subtype

2018 ◽  
Author(s):  
William F. Flynn ◽  
Sandeep Namburi ◽  
Carolyn A. Paisie ◽  
Honey V. Reddi ◽  
Sheng Li ◽  
...  
Keyword(s):  
Machine Learning ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Metastatic Cancer ◽  
Gene Expression Profiles ◽  
Primary Site ◽  
Cancer Types ◽  
Tissue Of Origin ◽  
Pan Cancer

ABSTRACTBackgroundIt is estimated by the American Cancer Society that approximately 5% of all metastatic tumors have no defined primary site (tissue) of origin and are classified as cancers of unknown primary (CUPs). The current standard of care for CUP patients depends on immunohistochemistry (IHC) based approaches to identify the primary site. The addition of post-mortem evaluation to IHC based tests helps to reveal the identity of the primary site for only 25% of the CUPs, emphasizing the acute need for better methods of determination of the site of origin. CUP patients are therefore given generic chemotherapeutic agents resulting in poor prognosis. When the tissue of origin is known, patients can be given site specific therapy with significant improvement in clinical outcome. Similarly, identifying the primary site of origin of metastatic cancer is of great importance for designing treatment.Identification of the primary site of origin is an import first step but may not be sufficient information for optimal treatment of the patient. Recent studies, primarily from The Cancer Genome Atlas (TCGA) project, and others, have revealed molecular subtypes in several cancer types with distinct clinical outcome. The molecular subtype captures the fundamental mechanisms driving the cancer and provides information that is essential for the optimal treatment of a cancer. Thus, along with primary site of origin, molecular subtype of a tumor is emerging as a criterion for personalized medicine and patient entry into clinical trials.However, there is no comprehensive toolset available for precise identification of tissue of origin or molecular subtype for precision medicine and translational research.Methods and FindingsWe posited that metastatic tumors will harbor the gene expression profiles of the primary site of origin of the cancer. Therefore, we decided to learn the molecular characteristics of the primary tumors using the large number of cancer genome profiles available from the TCGA project. Our predictors were trained for 33 cancer types and for the 11 cancers where there are established molecular subtypes. We estimated the accuracy of several machine learning models using cross-validation methods. The extensive testing using independent test sets revealed that the predictors had a median sensitivity and specificity of 97.2% and 99.9% respectively without losing classification of any tumor. Subtype classifiers achieved median sensitivity of 87.7% and specificity of 94.5% via cross validation and presented median sensitivity of 79.6% and specificity of 94.6% in two external datasets of 1,999 total samples. Importantly, these external data shows that our classifiers can robustly predict the primary site of origin from external microarray data, metastatic cancer data, and patient-derived xenograft (PDX) data.ConclusionWe have demonstrated the utility of gene expression profiles to solve the important clinical challenge of identifying the primary site of origin and the molecular subtype of cancers based on machine learning algorithms. We show, for the first time to our knowledge, that our pan-cancer classifiers can predict multiple cancers’ primary site of origin from metastatic samples. The predictors will be made available as open source software, freely available for academic non-commercial use.

scholarly journals Identifying Methylation-Driven Immune-related Molecular Subtypes Predicts the Prognosis of Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Qian Yan ◽  
Baoqian Ye ◽  
Boqing Wang ◽  
Wenjiang Zheng ◽  
Xiongwen Wang
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
The Cancer Genome Atlas ◽  
Cpg Sites ◽  
Prognosis Model ◽  
Immune Related Genes

Abstract The purpose of this study is to analyze the DNA methylation and gene expression profiles of immune-related CpG sites to identify the molecular subtypes and CpG sites related to the prognosis of HCC. In this study, the DNA methylation and gene expression datasets were downloaded from The Cancer Genome Atlas database, together with immune-related genes downloaded from the immunology database and analysis portal database to explore the prognostic molecular subtypes of HCC. By performing consistent clustering analysis on 830 immune-related CpG sites, we identified seven subgroups with significant differences in overall survival. Finally, 16 classifiers of immune-related CpG sites were constructed and used in the testing set to verify the prognosis of DNA methylation subgroups, and the results were consistent with the training set. Using the TIMER database, we analyzed 16 immune-related CpG sites expression with the abundance of six types of immune infiltrating cells and found that most are positively correlated with the level of infiltration of multiple immune cells in HCC. This study screened potential immune-related prognostic methylation sites and established a new prognosis model of HCC based on DNA methylation molecular subtype, which may help in the early diagnosis of HCC and developing more effective personalized treatments.

scholarly journals Effectiveness of SMS messaging for diarrhoea measurement: a factorial cross-over randomised controlled trial

2020 ◽  
Author(s):  
Ryan Trevor Titus Rego ◽  
Samuel Watson ◽  
Philbert Ishengoma ◽  
Philemon Langat ◽  
Hezekiah Pireh Otieno ◽  
...  
Keyword(s):  
Randomised Controlled Trial ◽  
Text Messaging ◽  
Response Rate ◽  
Financial Incentive ◽  
Controlled Trial ◽  
Response Rates ◽  
Lower Response ◽  
Lower Response Rate ◽  
The Mean ◽  
Randomised Controlled

Abstract Background Text messaging systems are used to collect data on symptom prevalence. Using a text messaging system, we evaluated the effects of question load, question frequency, and financial incentive on response rates and reported infant diarrhoea rates in an infant diarrhoea survey. Methods We performed a factorial cross-over randomised controlled trial of an SMS surveying system for infant diarrhoea surveillance with treatments: financial incentive (yes/no), question load (1-question/3-question), and questioning frequency (daily/fortnightly). Participants progressed through all treatment combinations over eight two-week rounds. Data were analysed using multivariable logistic regressions to determine the impacts of the treatments on the response rates and reported diarrhoea rates. Attitudes were explored through qualitative interviews. Results For the 141 participants, the mean response rate was 47%. In terms of percentage point differences (ppd), daily questioning was associated with a lower response rate than fortnightly (-1·2[95%CI:-4·9,2·5]); high (3-question) question loads were associated with a lower response rate than low (1-question) question loads (-7·0[95%CI:-10·8,-3·1]); and financial incentivisation was associated with a higher response rate than no financial incentivisation (6·4[95%CI:2·6,10·2]). The mean two-week diarrhoea rate was 36·4%. Daily questioning was associated with a higher reported diarrhoea rate than fortnightly (29·9[95%CI:22·8,36·9]); with little evidence for impact by incentivisation or question load. Conclusions Close to half of all participants responded to the SMS survey. Daily questioning evoked a statistically higher rate of reported diarrhoea, while financial incentivisation and low (1-question) question loads evoked higher response rates than no incentive and high (3-question) question loads respectively. Trial Registration The protocol was registered on ISRCTN on the 20 th of March 2019 under number ISRCTN11410773 .

Patients with Inflammatory Bowel Disease Have a Lower Response Rate to HBV Vaccination Compared to Controls

2011 ◽  
Vol 57 (4) ◽  
pp. 1039-1044 ◽  
Author(s):  
Mustafa Erhan Altunöz ◽  
Ebubekir Şenateş ◽  
Atakan Yeşil ◽  
Turan Çalhan ◽  
Ayşe Oya Kurdaş Övünç
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Response Rate ◽  
Lower Response ◽  
Hbv Vaccination ◽  
Lower Response Rate ◽  
Inflammatory Bowel

scholarly journals Characterization of an Aging-Based Diagnostic Gene Signature and Molecular Subtypes With Diverse Immune Infiltrations in Atherosclerosis

2022 ◽  
Vol 8 ◽  
Author(s):  
Lei Zhao ◽  
Fengfeng Lv ◽  
Ye Zheng ◽  
Liqiu Yan ◽  
Xufen Cao
Keyword(s):  
Western Blotting ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Macrophage Polarization ◽  
Differential Expression Analysis ◽  
Gene Signature ◽  
Immune Checkpoints ◽  
Foam Cell Formation ◽  
Diagnostic Model

Objective: Advancing age is a major risk factor of atherosclerosis (AS). Nevertheless, the mechanism underlying this phenomenon remains indistinct. Herein, this study conducted a comprehensive analysis of the biological implications of aging-related genes in AS.Methods: Gene expression profiles of AS and non-AS samples were curated from the GEO project. Differential expression analysis was adopted for screening AS-specific aging-related genes. LASSO regression analysis was presented for constructing a diagnostic model, and the discriminatory capacity was evaluated with ROC curves. Through consensus clustering analysis, aging-based molecular subtypes were conducted. Immune levels were estimated based on the expression of HLAs, immune checkpoints, and immune cell infiltrations. Key genes were then identified via WGCNA. The effects of CEBPB knockdown on macrophage polarization were examined with western blotting and ELISA. Furthermore, macrophages were exposed to 100 mg/L ox-LDL for 48 h to induce macrophage foam cells. After silencing CEBPB, markers of cholesterol uptake, esterification and hydrolysis, and efflux were detected with western blotting.Results: This study identified 28 AS-specific aging-related genes. The aging-related gene signature was developed, which could accurately diagnose AS in both the GSE20129 (AUC = 0.898) and GSE43292 (AUC = 0.685) datasets. Based on the expression profiling of AS-specific aging-related genes, two molecular subtypes were clustered, and with diverse immune infiltration features. The molecular subtype–relevant genes were obtained with WGCNA, which were markedly associated with immune activation. Silencing CEBPB triggered anti-inflammatory M2-like polarization and suppressed foam cell formation.Conclusion: Our findings suggest the critical implications of aging-related genes in diagnosing AS and modulating immune infiltrations.

scholarly journals A novel immune subtype classification of ER-positive, PR-negative and HER2-negative breast cancer based on the genomic and transcriptomic landscape

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Peiling Xie ◽  
Rui An ◽  
Shibo Yu ◽  
Jianjun He ◽  
Huimin Zhang
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Clinical Outcomes ◽  
Immune Escape ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Molecular Characteristics ◽  
Consensus Clustering ◽  
Breast Cancers ◽  
Her2 Breast Cancer

Abstract Background The diversity and plasticity behind ER+/PR−/HER2− breast cancer have not been widely explored. It is essential to identify heterogeneous microenvironment phenotypes and investigate specific genomic events driving the formation of these phenotypes. Methods Based on the immune-related gene expression profiles of 411 ER+/PR−/HER2− breast cancers in the METABRIC cohort, we used consensus clustering to identify heterogeneous immune subtypes and assessed their reproducibility in an independent meta-cohort including 135 patients collected from GEO database. We further analyzed the differences of cellular and molecular characteristics, and potential immune escape mechanism among immune subtypes. In addition, we constructed a transcriptional trajectory to visualize the distribution of individual patient. Results Our analysis identified and validated five reproducible immune subtypes with distinct cellular and molecular characteristics, potential immune escape mechanisms, genomic drivers, as well as clinical outcomes. An immune-cold subtype, with the least amount of lymphocyte infiltration, had a poorer prognosis. By contrast, an immune-hot subtype, which demonstrated the highest infiltration of CD8+ T cells, DCs and NK cells, and elevated IFN-γ response, had a comparatively favorable prognosis. Other subtypes showed more diverse gene expression and immune infiltration patterns with distinct clinical outcomes. Finally, our analysis revealed a complex immune landscape consisting of both discrete cluster and continuous spectrum. Conclusion Overall, this study revealed five heterogeneous immune subtypes among ER+/PR–/HER2− breast cancer, also provided important implications for clinical translations.

scholarly journals Therapeutic Responses to Chemotherapy or Immunotherapy by Molecular Subtype in Bladder Cancer Patients: A Meta-Analysis and Systematic Review

2021 ◽  
Author(s):  
Shunde Wang ◽  
Xiaoyu Yuan ◽  
Chengguo Ge ◽  
Junyong Zhang ◽  
Zhongjie Shen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Therapeutic Response ◽  
Response Rate ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Meta Analysis ◽  
Response Rates ◽  
Cancer Treatments ◽  
Response To Chemotherapy ◽  
Neo Adjuvant Chemotherapy

Abstract Background Bladder cancer (BC) is a heterogeneous disease characterized by high recurrence and a poor prognosis. Molecular subtypes of BC portend personalized and precision medicine. However, whether there is a difference in therapeutic response to chemotherapy or immunotherapy between different molecular subtypes of BC has not been systematically evaluated.Methods A comprehensive literature search was performed up to October 2020. Consensus clusters 1 (CC1), CC2 and CC3 molecular subtypes were defined according to the heterogeneity and similarity of BC molecular subtypes from published studies to perform meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the therapeutic response, and a fixed- or random-effects model was used according to the existence of heterogeneity.Results Eight studies involving 1463 patients were included in this research. For immunotherapy, CC3 showed the highest respond rate (CC3 vs CC1: OR 0.52, CI [0.34–0.78], P = 0.002. CC3 vs CC2: OR 0.42, CI [0.28–0.62], P < 0.0001), which was mainly reflected in the highest response rate to atezolizumab (CC3 vs CC1: OR 0.47, CI [0.29–0.75], P = 0.002. CC3 vs CC2: OR 0.38, CI [0.24–0.59], P < 0.0001), and the response rates to nivolumab showed no advantage over CC1 and CC2. No difference in response to the two immunotherapies between CC1 and CC2. For chemotherapy, CC3 had the lowest response rate to the overall chemotherapy (CC3 vs CC1: OR 2.28, CI [1.39–3.74], P = 0.001. CC3 vs CC2: OR = 2.25, 95% CI 1.34–3.76, P = 0.002). Compared with CC2, CC3 responded poorly to both neo-adjuvant chemotherapy (NAC) (OR 1.93, CI [1.09–3.41], P = 0.02) and chemoradiation therapy (CRT) (OR 4.53, CI [1.26–16.27], P = 0.02). Compared with CC1, CC3 only showed a poorer response to CRT (OR 6.07, CI [1.87–19.71], P = 0.003), and no difference in NAC. No difference between CC1 and CC2 subtypes in the response rates to NAC and CRT.Conclusions Our study suggested that molecular classifications are important predictors of cancer treatment outcomes of BC patients and could identify subgroup patients who are most likely to benefit from specific cancer treatments.

scholarly journals Predisposing factors of long-term responsiveness in a cardio-metabolic cohort: Tehran Lipid and Glucose Study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Leila Cheraghi ◽  
Parisa Amiri ◽  
Golnaz Vahedi-Notash ◽  
Sara Jalali-Farahani ◽  
Davood Khalili ◽  
...  
Keyword(s):  
Large Scale ◽  
Response Rate ◽  
Age Groups ◽  
Lifestyle Factors ◽  
Men And Women ◽  
Lower Response ◽  
Factors Associated ◽  
Lower Response Rate

Abstract Background Non-participation in cohort studies, if associated with both the exposure and occurrence of the event, can introduce bias in the estimates of interest. This study aims to identify factors associated with follow-up participation in Tehran Lipid and Glucose Study, a large-scale community-based prospective study in West Asia. Methods A sample of 10,368 adults from TLGS was included in the analysis. All analyses were split according to sex and age groups (20–39, 40–59, and 60 years). The associations between socio-demographic, health, and lifestyle factors with response rate were identified using the Generalized Estimating Equations model. Results Over the median of 15.7 years of follow up the response rate was 64.5%. The highest response rate was observed in those aged 40–59 years for both sexes. Current smokers had lower odds of response in both sexes for all age groups, ranging from 0.51 to 0.74, p < 0.01. In young adults, being single (OR = 0.79, OR = 0.57, p ≤ 0.01, respectively for men and women) and unemployed (OR = 0.73, OR = 0.76, p ≤ 0.01, respectively for men and women) in both sexes, high physical activity in men (OR = 0.77, p < 0.01), high education (OR = 0.75, p = 0.02) and obesity (OR = 0.85, p = 0.05) in women were associated with lower response rate. For the middle-aged group, diabetes in men (OR = 0.77, p = 0.05) and hypertension (OR = 0.84, p = 0.05), and having a history of cancer (OR = 0.43, p = 0.03) in women were factors associated with lower response rates. Finally, interventions for both sexes (OR = 0.75, OR = 0.77, p ≤ 0.05, respectively for men and women) and being divorced/widow in women (OR = 0.77, p = 0.05) were the factors associated with the lower response rate in the elderly. Conclusions Long-term participation was influenced by socio-demographic, health, and lifestyle factors in different sex- and age-specific patterns in TLGS. Recruitment strategies targeting these factors may improve participant follow-up in longitudinal studies.

Epigenetically regulated gene expression profiles reveal four molecular subtypes with prognostic and therapeutic implications in colorectal cancer

2020 ◽  
Author(s):  
Xiaokang Wang ◽  
Jinfeng Liu ◽  
Danwen Wang ◽  
Maohui Feng ◽  
Xiongzhi Wu
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Metabolic Activity ◽  
Poor Prognosis ◽  
Molecular Subtypes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Epigenetic Mechanisms ◽  
Regulated Gene Expression ◽  
Marked Proliferation

Abstract Transcriptomic deregulation by epigenetic mechanisms plays a crucial role in the heterogeneous progression of colorectal cancer (CRC). Herein, we first demonstrated that the frequencies of the aberrancies of DNA methylation-correlated (METcor) and microRNA (miRNA)-correlated (MIRcor) genes were significantly co-regulated. Next, through integrative clustering of the expression profiles of METcor and MIRcor genes, four molecular subtypes were identified in CRC patients from The Cancer Genome Atlas and then validated in four independent datasets. More importantly, the four subtypes were well characterized and showed distinct clinical and molecular features: (i) S-I: high metabolic activity, sensitive to 5-fluorouracil-based chemotherapy and good prognosis; (ii) S-II: moderate metabolic activity, marked proliferation, frequent KRAS mutation and intermediate prognosis; (iii) S-III: moderate metabolic activity, marked proliferation, promoter DNA hypermethylation, high mutation burden, frequent BRAF and EGFR mutations, moderate levels of epithelial-mesenchymal transition (EMT) and transforming growth factor β (TGFβ) signals, immune-inflamed phenotype, sensitive to cetuximab and death protein-1 inhibitor treatment and relatively poor prognosis and (iv) S-IV: miRNA overexpression, stem/serrated/mesenchymal-like properties, hypoxia, high levels of EMT and TGFβ signals, immune-excluded phenotype and poor prognosis. Overall, this study established a molecular classification based on epigenetically regulated gene expression profiles, thereby providing a better understanding of the epigenetic mechanisms underlying CRC heterogeneity.

Renal Cell and Urothelial Carcinoma: Biomarkers for New Treatments

2020 ◽  
pp. e197-e206
Author(s):  
Andrew L. Schmidt ◽  
Arlene Siefker-Radtke ◽  
David McConkey ◽  
Bradley McGregor
Keyword(s):  
Renal Cell ◽  
Large Scale ◽  
Kinase Inhibitor ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Immune Checkpoint Blockade ◽  
Molecular Characteristics ◽  
Molecular Heterogeneity ◽  
Prognostic Information ◽  
Similar Work

Therapies for genitourinary malignancies have evolved considerably in the past 5 years. Combination treatment targeting biologically relevant immune and angiogenic pathways is improving patient survival in metastatic renal cell carcinoma (RCC), whereas immune checkpoint blockade (ICB), novel targeted therapy, and antibody drug conjugates have changed the landscape of urothelial cancer (UC) treatment. A daily challenge for clinicians is identifying patients who derive a preferential benefit from the available therapeutic options. The completion of large-scale genomics projects has yielded comprehensive descriptions of the molecular heterogeneity present in RCC and UC, although clinical applications of these data continue to evolve. Major molecular subtypes of RCC align well with histology subtype, and although some molecular characteristics appear to carry prognostic information, biomarkers predicting benefit from tyrosine kinase inhibitor (TKI) or immunotherapy are generally lacking. Unexpectedly, similar work has demonstrated that UC can be grouped into “molecular subtypes” that share properties with those found in breast cancer and other solid tumors. Furthermore, this molecular subtype classification is prognostic and potentially predictive of differential benefit from conventional and targeted therapies. This article provides an update on the current state of molecular biomarker development and potential clinical utility in RCC and UC.

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