Biomedical subjects
Publications and source records attributed to Christine Brown.
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Somatic variant detection is an integral part of cancer genomics analysis. While most methods have focused on short-read sequencing, long-read technologies offer potential advantages in repeat mapping and variant phasing. We present DeepSomatic, a deep-learning method for detecting somatic small nucleotide variations and insertions and deletions from both short-read and long-read data. The method has modes for whole-genome and whole-exome sequencing and can run on tumor-normal, tumor-only and formalin-fixed paraffin-embedded samples. To train DeepSomatic and help address the dearth of publicly available training and benchmarking data for somatic variant detection, we generated and make openly available the Cancer Standards Long-read Evaluation (CASTLE) dataset of six matched tumor-normal cell line pairs whole-genome sequenced with Illumina, PacBio HiFi and Oxford Nanopore Technologies, along with benchmark variant sets. Across samples, both cell line and patient-derived, and across short-read and long-read sequencing technologies, DeepSomatic consistently outperforms existing callers.
In order to evaluate the changes within the VWF gene that might contribute to the pathogenesis of type 1 von Willebrand disease (VWD), a large multicenter Canadian study was undertaken. We present data from the sequence analysis of the VWF gene in 123 type 1 VWD index cases and their families. We have identified putative mutations within the VWF gene in 63% (n = 78) of index cases, leaving 37% (n = 45) with no identified changes. These changes comprise 50 different putative mutations: 31 (62%) missense mutations, 8 (16%) changes involving the VWF transcriptional regulatory region, 5 (10%) small deletions/insertions, 5 (10%) splicing consensus sequence mutations, and 1 nonsense mutation. Twenty-one of the index cases had more than one putative VWF mutation identified. We were somewhat more likely to identify putative mutations in cases with lower VWF levels, and the contribution of other factors, such as ABO blood group, seems more important in milder cases. Taken as a whole, our data support a complex spectrum of molecular pathology resulting in type 1 VWD. In more severe cases, genetic changes are common within the VWF gene and are highly penetrant. In milder cases, the genetic determinants are more complex and involve factors outside of the VWF gene.
Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.
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The interleukin (IL) 13 receptor alpha2 (IL13Ralpha2) is a glioma-restricted cell-surface epitope not otherwise detected within the central nervous system. Here, we describe a novel approach for targeting glioblastoma multiforme (GBM) with IL13Ralpha2-specific cytolytic T cells (CTLs) by their genetic modification to express a membrane-tethered IL13 cytokine chimeric T-cell antigen receptor, or zetakine. Our prototype zetakine incorporates an IL13 E13Y mutein for selective binding to IL13Ralpha2. Human IL13-zetakine(+)CD8(+) CTL transfectants display IL13Ralpha2-specific antitumor effector function including tumor cell cytolysis, T(C)1 cytokine production, and zetakine-regulated autocrine proliferation. The E13Y amino acid substitution of the IL13 mutein of the zetakine endows CTL transfectants with the capacity to discriminate between IL13Ralpha2(+) GBM targets from targets expressing IL13Ralpha1. In vivo, the adoptive transfer of IL13-zetakine(+)CD8(+) CTL clones results in the regression of established human glioblastoma orthotopic xenografts. Pilot clinical trials have been initiated to evaluate the feasibility and safety of local-regional delivery of autologous IL13-zetakine redirected CTL clones in patients with recurrent GBM. Our IL13-zetakine is a prototype of a new class of chimeric immunoreceptors that signal through an engineered immune synapse composed of membrane-tethered cytokine muteins bound to cell-surface cytokine receptors on tumors.
Mechanisms of tissue-restricted patterns of von Willebrand factor (VWF) expression involve activators and repressors that limit expression to endothelial cells and megakaryocytes. The relative transcriptional activity of the proximal VWF promoter was assessed in VWF-producing and -nonproducing cells, and promoter activity was highest in endothelial cells followed by megakaryocytes. Only basal VWF promoter activity was seen in nonendothelial cells. Here we identify a negative response element located at nucleotides (nts) +96/+105 and demonstrate, using chromatin immunoprecipitation (ChIP) analysis, that in vivo this sequence interacts with the E4BP4 transcriptional repressor. Differences in size and relative abundance of nuclear E4BP4 were observed. In HepG2 cells, low levels of larger forms of E4BP4 are present that directly interact with the negative response element. In VWF-expressing cells, high levels of smaller forms predominate with no evidence of direct DNA binding. However, in endothelial cells, mutation of the VWF E4BP4 binding motif not only restores but also further elevates VWF promoter activity, suggesting that E4BP4 may be part of a coordinated binding complex. These observations implicate this binding motif in repressing both activated and basal levels of VWF transcription by different cell type-specific mechanisms, and support the hypothesis that E4BP4 sequesters negative regulators of transcription, thereby enhancing activated gene expression.
OBJECTIVE: To report a case of hyponatremia in a patient receiving systemic unfractionated heparin (UFH) therapy and parenteral nutrition. CASE SUMMARY: A 70-year-old African American woman was started on parenteral nutrition for postoperative ileus following an elective surgical procedure. Three days later, she was diagnosed with a pulmonary embolism and intravenous UFH therapy was initiated. During the 7-day course of UFH therapy, the patient's serum sodium concentration steadily declined and urine sodium concentration progressively increased. Physical examination revealed no signs or symptoms of hypo- or hypervolemia. The patient's serum potassium concentration increased modestly, although significant hyperkalemia was not observed. After discontinuation of UFH, serum concentrations of both sodium and potassium returned to baseline levels. DISCUSSION: Although heparin-induced hyperkalemia is well documented, cases associated with substantial hyponatremia have been reported less frequently. An objective causality assessment revealed that the adverse drug reaction was probable in this case. Hyponatremia and hyperkalemia result from the antagonism of aldosterone by UFH within the zona glomerulosa of the adrenal glands. CONCLUSIONS: The use of UFH may result in significant hyponatremia as well as hyperkalemia. Reversal of these electrolyte disturbances occurs after discontinuation of heparin.
OBJECTIVE: To evaluate the demographic characteristics, clinical course, and outcome in organ transplant recipients with metastatic skin cancer. DESIGN AND SETTING: An international, multicenter, Internet-coordinated collaborative group retrospectively analyzed data from 68 organ transplant recipients with 73 distinct metastatic skin cancers. MAIN OUTCOME MEASUREMENTS: The Kaplan-Meier method was used to estimate the cumulative incidence of relapse, overall survival, and disease-specific survival after metastatic skin cancer. Univariate Cox proportional hazards models were fit to evaluate factors for an association with survival. RESULTS: Metastasis from skin cancer in organ transplant recipients most commonly consisted of squamous cell carcinoma in regional nodal basins. It was predominantly treated with a combination of surgery and irradiation. By 1 year after metastasis, the cumulative incidence of relapse was 29%, and the 3-year disease-specific survival was 56%. Patients whose initial metastases were distant or systemic had a significantly poorer disease-specific survival than those whose initial metastases were in-transit or regional (risk ratio, 6.5; P<.001). CONCLUSIONS: Metastatic skin cancer in organ transplant recipients has a poor prognosis. Preventive, early, and aggressive therapeutic interventions are required to minimize this serious complication of transplant-associated immunosuppression.