Molecular Classification Of Patients Research Articles

Identification of Heparan Sulfate in Dilated Cardiomyopathy by Integrated Bioinformatics Analysis.

ObjectivesHeparan sulfate (HS) forms heparan sulfate proteoglycans (HSPGs), such as syndecans (SDCs) and glypicans (GPCs), to perform biological processes in the mammals. This study aimed to explore the role of HS in dilated cardiomyopathy (DCM).MethodsTwo high throughput RNA sequencing, two microarrays, and one single-cell RNA sequencing dataset of DCM hearts were downloaded from the Gene Expression Omnibus (GEO) database and integrated for bioinformatics analyses. Differential analysis, pathway enrichment, immunocytes infiltration, subtype identification, and single-cell RNA sequencing analysis were used in this study.ResultsThe expression level of most HSPGs was significantly upregulated in DCM and was closely associated with immune activation, cardiac fibrosis, and heart failure. Syndecan2 (SDC2) was highly associated with collagen I and collagen III in cardiac fibroblasts of DCM hearts. HS biosynthetic pathway was activated, while the only enzyme to hydrolyze HS was downregulated. Based on the expression of HSPGs, patients with DCM were classified into three molecular subtypes, i.e., C1, C2, and C3. Cardiac fibrosis and heart failure were more severe in the C1 subtype.ConclusionHeparan sulfate is closely associated with immune activation, cardiac fibrosis, and heart failure in DCM. A novel molecular classification of patients with DCM is established based on HSPGs.

Molecular classification of patients with NMIBC predicts the efficacy of intravesical chemotherapy with pirarubicin, pharmorubicin and gemcitabine-immunohistochemistry-based classification.

To investigate the relationships between non-muscle invasive bladder cancer molecular subtypes and predict the efficacy of intravesical chemotherapy with pirarubicin, pharmorubicin and gemcitabine. A total of 160 patients with T1 stage non-muscle invasive bladder cancer were enrolled in this study. Fifty-three patients underwent anthracycline (Pirarubicin and Pharmorubicin) therapy and 107 patients accepted gemcitabine therapy. Uroplakin II and CK20 were categorized as immunohistochemistry (IHC) markers for luminal subtype, whereas CK5/6 and CD44 were categorized as immunohistochemistry markers for basal subtype. The cluster results with immunohistochemical score indicated that non-muscle invasive bladder cancer can be subgrouped into three major classes. Class 2 showed the luminal-like characteristics, whereas class 3 showed the basal-like characteristics. Class 1 showed no high expression of luminal or basal-associated immunohistochemistry markers. The molecular subtype is an independent risk factor for recurrence-free survival (P=0.030) and progression-free survival (P=0.006) in patients with T1 stage non-muscle invasive bladder cancer. In class 1 and class 2 (luminal-like) subtypes, gemcitabine and anthracycline show no difference in recurrence-free survival and progression-free survival. Gemcitabine was associated with reduced recurrence compared with anthracycline (P=0.039) in class 3 (basal-like) subtypes and show no difference in decreasing progression. The molecular classification based on immunohistochemical results is an independent risk factor for the prognosis of non-muscle invasive bladder cancer with T1 stage. Different therapeutic methods should be selected according to different molecular subtypes.

Characterization of terminal-ileal and colonic Crohn\u2019s disease in treatment-na\xefve paediatric patients based on transcriptomic profile using logistic regression

BackgroundInflammatory bowel disease (IBD) is a chronic and idiopathic inflammatory disorder of the gastrointestinal tract and comprises ulcerative colitis (UC) and Crohn’s disease (CD). Crohn’s disease can affect any part of the gastrointestinal tract, but mainly the terminal ileum and colon. In the present study, we aimed to characterize terminal-ileal CD (ICD) and colonic CD (CCD) at the molecular level, which might enable a more optimized approach for the clinical care and scientific research of CD.MethodsWe analyzed differentially expressed genes in samples from 23 treatment-naïve paediatric patients with CD and 25 non-IBD controls, and compared the data with previously published RNA-Seq data using multi-statistical tests and confidence intervals. We implemented functional profiling and proposed statistical methods for feature selection using a logistic regression model to identify genes that are highly associated in ICD or CCD. We also validated our final candidate genes in independent paediatric and adult cohorts.ResultsWe identified 550 genes specifically expressed in patients with CD compared with those in healthy controls (p < 0.05). Among these DEGs, 240 from patients with CCD were mainly involved in mitochondrial dysfunction, whereas 310 from patients with ICD were enriched in the ileum functions such as digestion, absorption, and metabolism. To choose the most effective gene set, we selected the most powerful genes (p-value ≤ 0.05, accuracy ≥ 0.8, and AUC ≥ 0.8) using logistic regression. Consequently, 33 genes were identified as useful for discriminating CD location; the accuracy and AUC were 0.86 and 0.83, respectively. We then validated the 33 genes with data from another independent paediatric cohort (accuracy = 0.93, AUC = 0.92) and adult cohort (accuracy = 0.88, AUC = 0.72).ConclusionsIn summary, we identified DEGs that are specifically expressed in CCD and ICD compared with those in healthy controls and patients with UC. Based on the feature selection analysis, 33 genes were identified as useful for discriminating CCD and ICD with high accuracy and AUC, for not only paediatric patients but also independent cohorts. We propose that our approach and the final gene set are useful for the molecular classification of patients with CD, and it could be beneficial in treatments based on disease location.

Molecular Classification Based on Prognostic and Cell Cycle-Associated Genes in Patients With Colon Cancer.

The molecular classification of patients with colon cancer is inconclusive. The gene set enrichment analysis (GSEA) of dysregulated genes among normal and tumor tissues indicated that the cell cycle played a crucial role in colon cancer. We performed univariate Cox regression analysis to find out the prognostic-related genes, and these genes were then intersected with cell cycle-associated genes and were further recognized as prognostic and cell cycle-associated genes. Unsupervised non-negative matrix factorization (NMF) clustering was performed based on cell cycle-associated genes. Two subgroups were identified with different overall survival, clinical features, cell cycle enrichment profile, and mutation profile. Through nearest template prediction (NTP), the molecular classification could be effectively repeated in the original data set and validated in several independent data sets indicating that the classification is highly repeatable. Furthermore, we constructed two prognostic signatures in two subgroups, respectively. Our molecular classification based on cell cycle may provide novel insight into the treatment and the prognosis of colon cancer.

European Society of Intensive Care Medicine и Society of Critical Care Medicine: 6 key provisions for management of sepsis patients. Where do we go next?

The objective: to analyze the validity of recommendations of the special research committee of the European Society of Intensive Care Medicine ( ESICM ) and Society of Critical Care Medicine ( SCCM ) concerning the most important provisions for the management of patients with sepsis and septic shock identifying predictors of lon g-t erm need for medical care and lethality. Subjects and methods. The article analyses the publications based on which experts in sepsis management identified the key provisions of the above recommendations. Results . Attention is focused on six issues: empirical combined antibiotic therapy, individual infusion volume, express diagnosis of infection, assessment of organ and systemic dysfunction, identification of predictors of lon g-t erm need for medical care and lethality, and implementation attempts and prospects of precis e/p ersonalized medicine. It has been shown that the values of SOFA score, heart rate, syst. blood pressure, lactate and albumin levels should reflect the balance of the groups in these parameters. Molecular classification of patients with sepsis providing different endotypes allows better patients enrollment in clinical trials.

Molecular classification of patients with grade II/III glioma using quantitative MRI characteristics.

Molecular markers of WHO grade II/III glioma are known to have important prognostic and predictive implications and may be associated with unique imaging phenotypes. The purpose of this study is to determine whether three clinically relevant molecular markers identified in gliomas-IDH, 1p/19q, and MGMT status-show distinct quantitative MRI characteristics on FLAIR imaging. Sixty-one patients with grade II/III gliomas who had molecular data and MRI available prior to radiation were included. Quantitative MRI features were extracted that measured tissue heterogeneity (homogeneity and pixel correlation) and FLAIR border distinctiveness (edge contrast; EC). T-tests were conducted to determine whether patients with different genotypes differ across the features. Logistic regression with LASSO regularization was used to determine the optimal combination of MRI and clinical features for predicting molecular subtypes. Patients with IDH wildtype tumors showed greater signal heterogeneity (p = 0.001) and lower EC (p = 0.008) within the FLAIR region compared to IDH mutant tumors. Among patients with IDH mutant tumors, 1p/19q co-deleted tumors had greater signal heterogeneity (p = 0.002) and lower EC (p = 0.005) compared to 1p/19q intact tumors. MGMT methylated tumors showed lower EC (p = 0.03) compared to the unmethylated group. The combination of FLAIR border distinctness, heterogeneity, and pixel correlation optimally classified tumors by IDH status. Quantitative imaging characteristics of FLAIR heterogeneity and border pattern in grade II/III gliomas may provide unique information for determining molecular status at time of initial diagnostic imaging, which may then guide subsequent surgical and medical management.

Bridging translation for acute kidney injury with better preclinical modeling of human disease.

The current lack of effective therapeutics for patients with acute kidney injury (AKI) represents an important and unmet medical need. Given the importance of the clinical problem, it is time for us to take a few steps back and reexamine current practices. The focus of this review is to explore the extent to which failure of therapeutic translation from animal studies to human studies stems from deficiencies in the preclinical models of AKI. We will evaluate whether the preclinical models of AKI that are commonly used recapitulate the known pathophysiologies of AKI that are being modeled in humans, focusing on four common scenarios that are studied in clinical therapeutic intervention trials: cardiac surgery-induced AKI; contrast-induced AKI; cisplatin-induced AKI; and sepsis associated AKI. Based on our observations, we have identified a number of common limitations in current preclinical modeling of AKI that could be addressed. In the long term, we suggest that progress in developing better preclinical models of AKI will depend on developing a better understanding of human AKI. To this this end, we suggest that there is a need to develop greater in-depth molecular analyses of kidney biopsy tissues coupled with improved clinical and molecular classification of patients with AKI.

Impact of tissue type and content of neoplastic cells of samples on the quality of epidermal growth factor receptor mutation analysis among patients with lung adenocarcinoma.

Assessment of the epidermal growth factor receptor (EGFR) mutational status has become crucial in recent years in the molecular classification of patients with lung cancer. The impact of the type and quantity of malignant cells of the neoplastic specimen on the quality of mutation analysis remains to be elucidated, and only empirical and sporadic data are available. The aim of the present study was to investigate the impact of tissue type and content of neoplastic cells in the specimen on the quality of EGFR mutation analysis among patients with lung adenocarcinoma. A total of 515 patients with histologically-confirmed disease were included in the present study. Formalin-fixed paraffin embedded tissue samples were used for the mutation analysis and the content of the neoplastic cells was evaluated using light microscopy. Genomic DNA was isolated using a standard protocol. The coding sequences and splice junctions of exons 18, 19 and 21 in the EGFR gene were then screened for mutations by direct automated sequencing. The mean age of the patients examined was 64.9 years and 357 (69.3%) were male. A total of 429 tissue samples (83.3%) were obtained by biopsy and the remaining samples were obtained by surgery. A total of 456 samples (88.5%) were observed from primary lung adenocarcinomas, while 59 (11.5%) were from metastatic lesions. EGFR mutations occurred in 59 cases (11.5%); exon 18 mutations were detected in one case (1.7%), whereas exon 19 and 21 mutations were detected in 30 (51%) and 28 (47.3%) cases, respectively. EGFR mutations were more frequent in females and patients that had never smoked. The distribution of the mutations among primary and metastatic tissues exhibited no significant differences in the proportions of EGFR mutations detected. However, a statistically significant difference in the number of mutations detected was found between samples with at least 50% of neoplastic cells (450 cases-57 mutations; 12.7%) and those with <50% of neoplastic cells (65 cases-2 mutations; 3.1%).

Relationship between detection of circulating tumor cells and molecular subtypes in breast cancer patients

Objective To investigate the correlation between circulating tumor cells (CTCs) and the predefined molecular classification of patients with breast cancer.Methods We used real-time quanti-tative reverse transcription-polymerase chain reaction (RT-qPCR) to detect cytokeratin 19 (CK19),human mammaglobin (hMAM),and small breast epithelial mucin (SBEM) mRNA expression levels in 285 cases of breast cancer and 123 controls.Statistical analyses were additionally performed to examine the correlation between the mRNA expression levels of these markers with the clinicopathological features of breast cancer patients.Results The sensitivity of these three mRNA markers of the patients with breast cancer was 33.3％,17.9％,and 18.2％ respectively,which was significantly higher than the control group (P ＜ 0.05).The sensitivity of these three markers combined was 47％,which was significantly higher than that of single marker detection (P ＜ 0.05).However,no significant difference in CTC detection was noted among the predefined molecular classifications.Statistical analysis demonstrated that high expression levels of CTC were correlated with the age and menopause status (P ＜ 0.05).In addition,overexpression of these three mRNA markers was positively correlated with tumor size (P ＜ 0.05).Conclusion Combined detection of three markers (CK19,hMAM and SBEM) based on a RT-qPCR platform has higher sensitivity to detect CTC in peripheral blood of breast cancer patients.Although CTC have no clear correla-tion with breast cancer molecular subgroups,but close correlation with age,postmenopausal status and tumor size of patients with breast cancer. Key words: Breast cancer; Circulating tumor cells; Molecular classification

Abstract P3-05-01: Molecular subtyping improves stratification of patients into diagnostically more meaningful risk groups

Abstract Background: Microarray-based gene expression profiling demonstrated that breast cancer is a heterogeneous group of different diseases characterized by distinct molecular aberrations, rather than one disease. Improved understanding of the molecular phenotypes of the disease has already shown prognostic and predictive value and, when prospectively applied, could have dramatic implications in establishing a more personalized approach to the management of early-stage breast cancer. Combined use of MammaPrint and a molecular subtyping profile (BluePrint) identifies disease subgroups with marked differences in long-term outcome and response to neo-adjuvant therapy [Glück et al. ASCO 2012]. The aim of this study was to evaluate the implication of accurate molecular subtyping using MammaPrint and BluePrint in women with early-stage breast cancer treated at US Institutions following National Comprehensive Cancer Network (NCCN) standard guidelines. Methods: 208 frozen tumor samples from consecutive BC patients (TI-III, N0-Ib) were obtained from 2 US centers. Median age at diagnosis was 56 years (range 28–89 years). Between 1992 and 2010 patients were treated either with breast-conserving therapy or mastectomy with axillary lymph node dissection followed by systemic adjuvant therapy when indicated. Sixty-three percent of patients received adjuvant endocrine therapy (ET), 58% received adjuvant chemotherapy (CT) and 32% received both. Hormone Receptor (HR) and HER2 status were assessed by immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH), following standard guidelines. Median follow-up was 11.3 years. Survival was assessed for patient groups according to local pathological assessment and compared with molecular classification of patients (centrally assessed full genome expression at Agendia laboratory). Results: Standard HR and HER2 status assessment revealed that 57% of all tumors examined were luminal-like (ER/PR positive, HER2 negative), 20% HER2 positive and 24% triple negative. Molecular classification demonstrated discordance in the following clinical groups: 16 out of 41 patients previously identified as HER2 positive were reclassified as Luminal-type, with 97% 5-year distant metastases-free survival (DMFS) for Luminal A (MammaPrint Low Risk/Luminal-type) and 98% for Luminal B (MammaPrint High Risk/Luminal-type). Ten patients identified with clinical triple-negative tumors were reclassified with molecular subtyping as HER2 positive (n = 6) and Luminal-type (n = 4). Of the patients classified with BluePrint Basal-type tumors, 58 (28%) had a 5-year DMFS of 82% (81% received adjuvant CT). Of those with HER2-type tumors, 25 (12%) had a 5-year DMFS of 76% (88% received adjuvant CT without trastuzumab). Discordant cases are being centrally re-assessed for ER, PR and HER2. Conclusions: This retrospective study showed that Molecular Subtyping with BluePrint and MammaPrint leads to clinically significant prognostic and molecular stratification. The use of MammaPrint and BluePrint in the management of patients with primary breast cancer should be considered for a more accurate selection of adjuvant therapies in this era of personalized medicine. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-05-01.

Molecular Classification of Patients with Cutaneous Melanoma: A Reality

Melanoma is the most aggressive skin cancer and, despite great progresses recently assessed into the biology research and the diagnosis approaches, its incidence and mortality have extremely risen in all developed countries during the last half century