Project description:Background: Immunoadsorption with subsequent IgG substitution (IA/IgG) represents a novel therapeutic approach in treatment of dilated cardiomyopathy (DCM) which leads to improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical and molecular parameters for prediction of the response of patients with DCM to IA/IgG. Methods & Results: Forty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In 8 patients with normal LVEF (controls) EMB were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes and gene expression profiles of EMBs were analyzed. DCM patients displaying improvement of LVEF (≥ 20% relative and ≥ 5% absolute) six month after IA/IgG were considered responders. Compared to non-responders (n=16), responders (n=24) displayed shorter disease duration (p=0.006), smaller LV internal diameter in diastole (LVIDd) (p=0.019) and stronger NIA of antibodies. Antibodies obtained from controls were devoid of NIA. Myocardial gene expression patterns were different in responders and non-responders for genes of oxidative phosphorylation, mitochondrial dysfunction, hypertrophy, and ubiquitin proteasome pathway. Integration of scores of NIA and expression levels of four genes allowed robust discrimination of responders from non-responders at baseline (sensitivity of 100 % (95% CI, 85.8%-100%); specificity up to 100% (95 % CI, 79.4%-100%, cut-off value: -0.28), and was superior to scores derived from antibodies, gene expression or clinical parameters only. Conclusion: Combined assessment of NIA of antibodies and gene expression patterns of DCM patients at baseline predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention.
Project description:Dysregulated cardiac function after sepsis is common in intensive care unit (ICU) and known to predict poor long-term outcome and increase mortality. Effective therapeutic strategies are largely lacking. Moreover, the pathological feature and the molecular mechanism underlying cardiac dysfunction induced by sepsis remain unclear. Here, by performing echocardiograms on rodents after induction of polymicrobial sepsis with cecum ligation and puncture (CLP), we assessed the temporal dynamics of left ventricular ejection fraction (LVEF) and a serial of hemodynamics parameters on animals at different time point after CLP. Intriguingly, the mean LVEF is comparable in mice induced by CLP and sham, whereas survivors post CLP had stable LVEF and non-survivors had markedly fluctuated LVEF at early phase of CLP induction, suggesting LVEF away from normal range is highly associated with mortality. Consistent with clinical observations of depressed, preserved or hyperdynamic LVEF in septic patients from data compiled using our ICU cohort and from other studies, CLP-induced mice fall into three groups based on LVEF measured at 24 hours after surgery: high LVEF (HEF, LVEF>=90%), low LVEF (LEF, LVEF<65%), and normal LVEF (NEF, 65%=<LVEF<90%). We performed genome-wide transcriptomic and proteomic profiling on left ventricle samples collected from three CLP groups and sham mice. By implementing pathway analysis, gene set enrichment and coexpression network analysis, we identified jointly and distinctively changed genes, proteins and biologically-essential processes and pathways in three CLP groups with different LVEF. Notably, transmission electron microscopy examination shows remarkable mitochondrial and sarcomere defects in three CLP groups with different phenotypes associated with LVEF variances. Together, this study systematically characterizes the molecular, morphological, and functional alterations in CLP-induced cardiac injury, serving as a framework for future research into pathology and molecular mechanism of sepsis-induced cardiomyopathy.
Project description:Transcription profiling by array of human cytogenetically normal acute myeloid leukemia patient samples with FLT3 internal tandem duplications
Project description:Punch biopsies of patients enrolled in phase II clinical trial study was obtained at various time points. Skin biopsies from 16 responders and 8 non responders and partial responders, chosen after the completion of clinical trial, was evaluated before Itolizumab treatment (Day 1) and at Day 57. Responders had a PASI improvement >75% while non responders had a PASI improvement <60%. The gene expression values at Day 57 were normalised with values obtained at Day 1 of the respective patient sample. The genes with a minimum fold change of 1.8 spontaneously clustered into predominantly responders and non responders. Agilent Custom Human Gene Expression 8X15k (AMADID: 16332) designed by Genotypic Technology Private Limited .
Project description:Heart failure (HF) impacts 2-3% of adults in the West, with prevalence rising with age. This condition, leading to high mortality and morbidity, increasingly involves HF with preserved left ventricular (LV) ejection fraction (HFpEF) in the aging population, having a similar stable prognosis as HF with reduced LVEF (HFrEF). However, HFpEF lacks many evidence-based therapies, partly due to its distinct pathophysiology compared to HFrEF. Molecularly, heart failure shows distinct gene expression changes, indicative of varying diseases. Prior research, including our early report from the CABG-PREFERS study, shows gene expression differences in HFpEF and normal hearts, although studies are limited. Both HFpEF and HFrEF patients exhibit altered LV myocardial structure and function, often affecting the right ventricle (RV) secondarily. In the CABG-PREFERS sub-study, part of the PREFERS programme, we classified patients by LVEF, structural abnormalities, diastolic dysfunction, and NT-proBNP levels into HFpEF physiology, HFrEF physiology, and normal LV function groups. Our hypothesis suggests gene expression and transcriptomic variations between LV and RV, and between HFpEF, HFrEF, and normal LV function, providing insights into different HF phenotypes and guiding future therapies.
Project description:Transcription profiling by array of human lymphoblast cells from a patient with Freidriech's ataxia after treatment with pyrrole-imidazole polyamides
Project description:Transcription profiling by array of human cytogenetically normal acute myeloid leukemia patient samples with and without Wilms tumor 1 gene mutations
Project description:We compared gene panel sequencing and DNA methylation analysis with RNA sequencing results from 125 patients. We could demonstrate improvement of diagnostic accuracy and clinical patient benefit by the addition of RNA sequencing fom fresh frozen tumor tissue.
Project description:Transcription profiling of human psoriasis patient matched lesion and normal tissue vs. normal controls - type i interferon: potential therapeutic target for psoriasis?