We have a case of two siblings (twins) who were born with nodular blue rashes over their body. The first twin had a large periorbital subcutaneous mass which was diagnosed as infantile undifferentiated sarcoma. This baby was too systematically unwell for chemotherapy and died at 12 days of age. The second sibling received two cycles of emergency chemotherapy however died due to disease progression and secondary haemorrhage at 2 months of age. Post-mortem normal and tumour samples have been taken. In addition to placental tissue and parental germline DNA, the goal will be to investigate intra-uterine transfer of sarcoma and the phylogenetic relationship of tumours in both twins.
Small intestinal neuroendocrine tumors (SI-NETs) arise from hormone-producing cells in the gut, yet the molecular changes driving malignant transformation remain poorly understood. Bulk tissue-based analyses make it challenging to distinguish signals derived from normal cells from those of normal hormone-producing cells. In this study, we analyzed SI-NETs at single-cell resolution and directly compared tumor cells with their corresponding normal hormone-producing counterparts using single-cell RNA sequencing. Tissue samples were obtained from two patients undergoing tumor resection surgery. Cells from corresponding normal intestinal mucosa and SI-NET tumors were isolated using specific markers and analyzed for direct comparison.
This study aims to define the landscape of somatic mutations in sun exposed human skin by deep sequencing, analyse their frequency and use the data to infer the effect of mutations on proliferating cell behaviour. The frequency of each mutation will reflect the size of the clone of cells in the tissue sample. By analyzing small samples, clones with as few as 100 cells will be detectable. Allele frequency distributions for each mutation will be used to infer cell fate using published methods (Klein et al. 2010). This study will shed unprecedented light on the early clonal events that lead to the emergence of cancer.
Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in childhood diffuse midline gliomas (DMGs) of the pons, but are also increasingly recognized in adult DMGs. Their potential heterogeneity at different ages and midline locations are vastly understudied. Here, through dissecting the single-cell epigenomic architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We analyzed the open chromatin profiles of 8 tumors utilizing the single-cell/nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq)
The Kibbutzim Family Study (KFS) aimed to investigate the environmental and genetic determinants of cardiometabolic traits (phenotype is LDL-C)
Retinoblastoma is a rare childhood cancer of the retina. We studied retinoblastoma by Whole-Exome-Sequencing.
The dataset includes 13 bam files. Each bam file is a different colorectal cancer patient organoid.
Related StudiesWhole genome and whole exome data is available on a subset of participants with phs001411. ECG signal data is available with phs003562.ObjectivesThe purpose of this study was to determine if intensive glycemic control, multiple lipid management and intensive blood pressure control could prevent major cardiovascular events (myocardial infarction, stroke or cardiovascular death) in adults with type 2 diabetes mellitus. Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life and cost-effectiveness. BackgroundGlycemia Trial:Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates two to four times higher than non-diabetic populations of similar demographic characteristics. They also experience increased rates of nonfatal myocardial infarction and stroke. With the growing prevalence of obesity in the United States, CVD associated with type 2 diabetes is expected to become an even greater public health challenge in the coming decades than it is now. Expected increases in event rates will be associated with a concomitant rise in suffering and resource utilization.The ACCORD study investigated whether intensive therapy to target normal glycated hemoglobin (HbA1c) levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors when compared to standard therapy (HbA1c between 7.0% and 7.9%). A separate analysis investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in these patients. Lipid Therapy Trial: Patients with type 2 diabetes mellitus have an increased incidence of atherosclerotic cardiovascular disease attributable, in part, to associated risk factors such as dyslipidemia. This is characterized by elevated plasma triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol and small, dense low-density lipoprotein (LDL) particles. The ACCORD Lipid Therapy trial was designed to test the effect of a therapeutic strategy that uses a fibrate to raise HDL-C and lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C on cardiovascular outcomes in patients with type 2 diabetes that were at high risk for cardiovascular disease. Blood Pressure Trial: Diabetes mellitus increases the risk of cardiovascular disease at every level of systolic blood pressure. Because cardiovascular risk in patients with diabetes is graded and continuous across the entire range of levels of systolic blood pressure, even at prehypertensive levels, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended beginning drug treatment in patients with diabetes who have systolic blood pressures of 130 mm Hg or higher, with a treatment goal of reducing systolic blood pressure to below 130 mm Hg. There is, however, a paucity of evidence from randomized clinical trials to support these recommendations. The ACCORD Blood Pressure trial tested the effect of a target systolic blood pressure below 120 mm Hg on major cardiovascular events among high-risk persons with type 2 diabetes compared to a strategy that targeted a SBP of EYE Substudy: Diabetic retinopathy, an important microvascular complication of diabetes, is a leading cause of blindness in the United States. Randomized, controlled clinical trials in cohorts of patients with type 1 diabetes and those with type 2 diabetes have shown the beneficial effects of intensive glycemic control and intensive treatment of elevated blood pressure on the progression of diabetic retinopathy. Elevated serum cholesterol and triglyceride levels have been implicated, in observational studies and small trials, as additional risk factors for the development of diabetic retinopathy and visual loss. The ACCORD EYE Substudy evaluated the effects of the ACCORD medical strategies on the progression of diabetic retinopathy in a subgroup of trial patients. MIND Substudy: Studies suggest that older persons with type 2 diabetes have at least twice the likelihood of developing late-life cognitive impairment or dementia compared to those without. The mechanisms underlying these cognitive disorders are increasingly thought to reflect a mixed pathology pattern with contributions from vascular, neurodegenerative and neurovascular processes. Pathophysiological mechanisms that have been described include inflammation, oxidative stress, energy imbalance, protein misfolding, glucocorticoid-mediated effects and differences in genetic susceptibilities. The ACCORD MIND substudy took as a premise that early intervention with the ACCORD therapeutic strategies to improve glycemic control could mitigate the adverse effects of type 2 diabetes on the brain. Participants10,251 participants with type 2 diabetes and HbA1c concentrations of 7.5% or more participated in the trial. Of these patients, 5518 were assigned to the lipid therapy arm and 4733 to the blood pressure arm. EYE Substudy: A subgroup of 2856 participants was evaluated for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy. Participants who, at baseline, had a history of proliferative diabetic retinopathy that had been treated with laser photocoagulation or vitrectomy were excluded. MIND Substudy: A subgroup of 2977 participants was evaluated for cognitive function and brain volume. The ACCORD MIND substudy excluded participants aged Design Participants were randomly assigned to undergo either intensive glycemic control (targeting a glycated hemoglobin level EYE Substudy: EYE Substudy participants were evaluated at two standardized and comprehensive eye examinations for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. MIND Substudy: The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 patients. All patients with follow-up data were included in the primary analyses. Conclusions Glycemia Trial: As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. (Action to Control Cardiovascular Risk in Diabetes Study Group, et al.,2008, PMID:18539917). Microvascular Outcomes of the Glycemia Trial: Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Microvascular benefits of intensive therapy should be weighed against the risk of increased total and cardiovascular disease-related mortality, increased weight gain, and higher risk for severe hypoglycemia. (Ismail-Beigi et al., 2010, PMID: 20594588) Lipid Therapy Trial: The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes (ACCORD Study Group, et al., 2010, PMID: 20228404). Blood Pressure Trial: In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events (ACCORD Study Group, et al., 2010, PMID: 20228401). EYE Substudy: Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy (ACCORD Study Group, et al., 2010, PMID: 20587587). MIND Substudy: Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND patients (Launer et al., 2011, PMID: 21958949).
Somatic mutations in T cells can cause cancer but also have implications for immunological diseases and cell therapies. The mutation spectrum in non-malignant T cells is unclear. Here, we examined somatic mutations in CD4+ and CD8+ T cells from 90 patients with hematological and immunological disorders and used T cell receptor (TCR) and single-cell sequencing to link mutations with T cell expansions and phenotypes. CD8+ cells had higher mutation burden than CD4+ cells. Notably, the biggest variant allele frequency (VAF) of non-synonymous variants was higher than synonymous variants in CD8+ T cells, indicating non-random occurrence. The non-synonymous VAF in CD8+ T cells strongly correlated with the TCR frequency, but not age. We identified mutations in pathways essential for T cell function and often affected in lymphoid neoplasia. Single-cell sequencing revealed cytotoxic Temra phenotypes of mutated T cells. Our findings suggest that somatic mutations contribute to CD8+ T cell expansions without malignant transformation.
