Publications by authors named "Tim Beck"

39 Publications

Case report: multiple gastrointestinal stroma tumors in the background of neurofibromatosis type 1.

J Surg Case Rep 2020 Dec 24;2020(12):rjaa516. Epub 2020 Dec 24.

Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies of the gastrointestinal tract. GISTs can occur in the background of neurofibromatosis 1 (NF-1), where chemotherapeutic treatment is not optimal and surgical intervention is the only management option. In this case report, we present a case involving a 61-year-old gentleman with NF-1. The patient presented with acute blood loss anemia that was initially controlled with embolization of a hyper-vascular mass abutting the distal jejunum. The patient was taken to the operating room for excision of the mass. All macroscopic disease was excised and the pathology noted GISTs. Surgical decision making is not clearly delineated in the literature for GISTs in patients with NF-1, where targeted therapy is not a treatment option. Resection of all disease should be considered, since NF-1 associated GISTs generally do not have harbor mutations that can be targeted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jscr/rjaa516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758994PMC
December 2020

Thyroid Cancer Identified After Positron Emission Tomography (PET) Shows Aggressive Histopathology.

J Surg Res 2021 04 23;260:245-250. Epub 2020 Dec 23.

Department of Endocrine Surgery, Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Background: Incidental thyroid nodules with focal uptake on positron emission tomography (PET) have an increased risk for malignancy, with the majority being differentiated thyroid cancer (DTC). It is unclear whether these cancers have more aggressive histopathology compared with DTC diagnosed via other means.

Method: Electronic medical record of two medical centers was queried for the period of 2001-2016 to identify patients who underwent PET imaging for nonthyroid-related indications and who were found to have focal thyroid uptake. Patients who underwent thyroid nodule fine needle aspiration biopsy (FNAB) and subsequent thyroidectomy with a final diagnosis of DTC were further reviewed. A comparison group, matched for age, tumor type, and tumor size, was selected from consecutive patients who underwent surgery for DTC.

Results: Among 35,124 PET scans reviewed, 227 (0.6%) patients were found to have focal thyroid uptake and underwent FNAB: Fourty-seven (21%) were found to have cancer (36 papillary thyroid cancer (PTC), 9 metastases, and 2 lymphoma). Sixty-seven patients proceeded to surgery: Thirty-one with FNAB of PTC and the rest with indeterminate FNAB necessitating diagnostic thyroidectomy. Compared with the control group, the PET PTC patients involved more men (54% versus 26%, P = 0.003), had more advanced tumor stage (P = 0.03), and had increased BRAF mutation on final pathology (78% versus 42%, P = 0.05).

Conclusions: This study demonstrates that DTC detected on PET is most commonly of the papillary type. Despite the small sample size, the results suggest that these PTC may be more aggressive than PTC detected through other means and more frequently harbor BRAF mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jss.2020.11.012DOI Listing
April 2021

GWAS Central: a comprehensive resource for the discovery and comparison of genotype and phenotype data from genome-wide association studies.

Nucleic Acids Res 2020 01;48(D1):D933-D940

Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK.

The GWAS Central resource provides a toolkit for integrative access and visualization of a uniquely extensive collection of genome-wide association study data, while ensuring safe open access to prevent research participant identification. GWAS Central is the world's most comprehensive openly accessible repository of summary-level GWAS association information, providing over 70 million P-values for over 3800 studies investigating over 1400 unique phenotypes. The database content comprises direct submissions received from GWAS authors and consortia, in addition to actively gathered data sets from various public sources. GWAS data are discoverable from the perspective of genetic markers, genes, genome regions or phenotypes, via graphical visualizations and detailed downloadable data reports. Tested genetic markers and relevant genomic features can be visually interrogated across up to sixteen multiple association data sets in a single view using the integrated genome browser. The semantic standardization of phenotype descriptions with Medical Subject Headings and the Human Phenotype Ontology allows the precise identification of genetic variants associated with diseases, phenotypes and traits of interest. Harmonization of the phenotype descriptions used across several GWAS-related resources has extended the phenotype search capabilities to enable cross-database study discovery using a range of ontologies. GWAS Central is updated regularly and available at https://www.gwascentral.org.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkz895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145571PMC
January 2020

Tumor-Targeted Drug Conjugates as an Emerging Novel Therapeutic Approach in Small Cell Lung Cancer (SCLC).

Cancers (Basel) 2019 Sep 3;11(9). Epub 2019 Sep 3.

Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

There are few effective therapies for small cell lung cancer (SCLC), a highly aggressive disease representing 15% of total lung cancers. With median survival <2 years, SCLC is one of the most lethal cancers. At present, chemotherapies and radiation therapy are commonly used for SCLC management. Few protein-targeted therapies have shown efficacy in improving overall survival; immune checkpoint inhibitors (ICIs) are promising agents, but many SCLC tumors do not express ICI targets such as PD-L1. This article presents an alternative approach to the treatment of SCLC: the use of drug conjugates, where a targeting moiety concentrates otherwise toxic agents in the vicinity of tumors, maximizing the differential between tumor killing and the cytotoxicity of normal tissues. Several tumor-targeted drug conjugate delivery systems exist and are currently being actively tested in the setting of SCLC. These include antibody-drug conjugates (ADCs), radioimmunoconjugates (RICs), small molecule-drug conjugates (SMDCs), and polymer-drug conjugates (PDCs). We summarize the basis of action for these targeting compounds, discussing principles of construction and providing examples of effective versus ineffective compounds, as established by preclinical and clinical testing. Such agents may offer new therapeutic options for the clinical management of this challenging disease in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11091297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769513PMC
September 2019

Gene loci associated with insulin secretion in islets from non-diabetic mice.

J Clin Invest 2019 07 25;129(10):4419-4432. Epub 2019 Jul 25.

University of Wisconsin-Madison, Biochemistry Department, Madison, Wisconsin, USA.

Genetic susceptibility to type 2 diabetes is primarily due to β-cell dysfunction. However, a genetic study to directly interrogate β-cell function ex vivo has never been previously performed. We isolated 233,447 islets from 483 Diversity Outbred (DO) mice maintained on a Western-style diet, and measured insulin secretion in response to a variety of secretagogues. Insulin secretion from DO islets ranged >1,000-fold even though none of the mice were diabetic. The insulin secretory response to each secretagogue had a unique genetic architecture; some of the loci were specific for one condition, whereas others overlapped. Human loci that are syntenic to many of the insulin secretion QTL from mouse are associated with diabetes-related SNPs in human genome-wide association studies. We report on three genes, Ptpn18, Hunk and Zfp148, where the phenotype predictions from the genetic screen were fulfilled in our studies of transgenic mouse models. These three genes encode a non-receptor type protein tyrosine phosphatase, a serine/threonine protein kinase, and a Krϋppel-type zinc-finger transcription factor, respectively. Our results demonstrate that genetic variation in insulin secretion that can lead to type 2 diabetes is discoverable in non-diabetic individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI129143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763251PMC
July 2019

An improved method of delivering a sclerosing agent for the treatment of malignant pleural effusion.

BMC Cancer 2019 Jun 24;19(1):614. Epub 2019 Jun 24.

Department of Cardiothoracic Surgery, Drexel University College of Medicine, Hahnemann University Hospital, 230 North Broad Street, Philadelphia, PA, 19102, USA.

Background: Malignant pleural effusion (MPE) is a devastating sequela associated with cancer. Talc pleurodesis is a common treatment strategy for MPE but has been estimated to be unsuccessful in up to 20-50% of patients. Clinical failure of talc pleurodesis is thought to be due to poor dispersion. This monograph reports the development of a foam delivery system designed to more effectively coat the pleural cavity.

Methods: C57BL/6 mice were injected with Lewis lung carcinoma (LL/2) cells intrapleurally to induce MPE. The mice then received either normal saline (NS) control, foam control (F), talc slurry (TS, 2 mg/g) or talc foam (TF, 2 mg/g). Airspace volume was evaluated by CT, lungs/pleura were collected, and percent fibrosis was determined.

Results: The TF group had significantly better survival than the TS group (21 vs 13.5 days, p < 0.0001). The average effusion volume was less in the talc groups compared to the control group (140 vs 628 μL, p < 0.001). TF induced significant lung fibrosis (p < 0.01), similar to TS. On CT, TF significantly (p < 0.05) reduced loss of right lung volume (by 30-40%) compared to the control group. This was not seen with TS (p > 0.05).

Conclusions: This report describes using a novel talc foam delivery system for the treatment of MPE. In the LL/2 model, mice treated with the TF had better survival outcomes and less reduction of lung volume than mice treated with the standard of care TS. These data provide support for translational efforts to move talc foam from animal models into clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-5777-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589887PMC
June 2019

Circulating tumor cell and cell-free RNA capture and expression analysis identify platelet-associated genes in metastatic lung cancer.

BMC Cancer 2019 Jun 19;19(1):603. Epub 2019 Jun 19.

Protocol Support Laboratory, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Background: Circulating tumor cells (CTC) and plasma cell-free RNA (cfRNA) can serve as biomarkers for prognosis and treatment response in lung cancer. One barrier to the selected or routine use of CTCs and plasma cfRNA in precision oncology is the limited quantity of both, and CTCs are only seen in metastatic disease. As capture of CTCs and plasma cfRNA presents an opportunity to monitor and assess malignancies without invasive procedures, we compared two methods for CTC capture and identification, and profiled mRNA from CTCs and plasma cfRNA to identify potential tumor-associated biomarkers.

Methods: Peripheral blood was collected from ten patients with small cell lung cancer (SCLC), ten patients with non-small cell lung cancer (NSCLC) and four healthy volunteers. Two methods were used for CTC capture: the standard epithelial cell adhesion molecule (EpCam) CellSearch kit (unicapture) and EpCAM plus HER2, EGFR and MUC-1 specific combined ferrofluid capture (quadcapture). For the quadcapture, anti-cytokeratin 7 (CK7) was additionally used to assist in CTC identification. NanoString analysis was performed on plasma cfRNA and on mRNA from combined ferrofluid isolated CTCs. Expression data was analyzed using STRING and Reactome.

Results: Unicapture detected CTCs in 40% of NSCLC and 60% of SCLC; whereas, quadcapture/CK7 identified CTCs in 20% of NSCLC and 80% of SCLC. Bioinformatic analysis of NanoString data identified high expression of a platelet factor 4 (PF4)-related group of transcripts.

Conclusions: Quadcapture ferrofluid reagent did not significantly improve CTC capture efficacy. NanoString analysis based on CTC and plasma cfRNA data highlighted an intriguing PF-4-centric network in patients with metastatic lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-5795-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582501PMC
June 2019

Case report: reinitiating pembrolizumab treatment after small bowel perforation.

BMC Cancer 2019 Apr 24;19(1):379. Epub 2019 Apr 24.

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Background: Immune checkpoint inhibitors (ICIs) have emerged as paradigm shifting treatment options for a number of cancers. Six antibodies targeting the immune checkpoint proteins programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) or cytotoxic T-lymphocyte associated protein 4 (CTLA4) have been approved. In some cases, response rates have been impressive, but not uniformly so and not consistently; similarly, toxicity to this class of therapeutic is often unpredictable and can be life threatening. Predicting treatment response and toxicity are two main obstacles to truly individualize treatment with ICIs. One of the most severe and life-threatening adverse events is colitis induced colonic perforation, estimated to occur in 1.0 to 1.5% of patients treated with ICIs. An important question to address is, under what circumstances is it appropriate to reinitiate ICI treatment post-bowel perforation?

Case Presentation: The patient is a 62-year-old woman, who presented with stage IV lung cancer. Immunohistochemical staining indicated that 80% of the patient's tumor cells expressed PD-L1. The patient was started on a three-week cycle of pembrolizumab. Subsequent reducing in tumor burden was observed within ten weeks. Initially, pembrolizumab was tolerated fairly well, with the exception of immunotherapy related hypothyroidism. However, the patient experienced a second, more serious immune-related adverse event (irAE), in the form of enteritis, which led to small bowel perforation and necessitated exploratory laparotomy. The concerning part of the small bowel was resected, and a primary anastomosis was created. Based on the pathological and surgical findings, the patient was diagnosed with pembrolizumab-associated small bowel perforation. The patient recovered well from surgery and, considering the patient's remarkable response to treatment, a collective decision was made to reinitiate pembrolizumab on post-operative day twenty-eight. The patient is continuing her immunotherapy with ongoing partial response and is able to continue her full-time job.

Conclusions: This case report highlights the challenges of identifying patients likely to respond to ICIs and those that are likely to experience irAEs and it discusses the impressive work that has been done to start to address these challenges. Lastly, the topic of reinitiating pembrolizumab treatment even after colonic perforation is discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-5577-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482547PMC
April 2019

Regional perturbation of gene transcription is associated with intrachromosomal rearrangements and gene fusion transcripts in high grade ovarian cancer.

Sci Rep 2019 03 5;9(1):3590. Epub 2019 Mar 5.

Department of Medicine, University of Toronto, Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario, Canada.

Genomic rearrangements are a hallmark of cancer biology and progression, allowing cells to rapidly transform through alterations in regulatory structures, changes in expression patterns, reprogramming of signaling pathways, and creation of novel transcripts via gene fusion events. Though functional gene fusions encoding oncogenic proteins are the most dramatic outcomes of genomic rearrangements, we investigated the relationship between rearrangements evidenced by fusion transcripts and local expression changes in cancer using transcriptome data alone. 9,953 gene fusion predictions from 418 primary serious ovarian cancer tumors were analyzed, identifying depletions of gene fusion breakpoints within coding regions of fused genes as well as an N-terminal enrichment of breakpoints within fused genes. We identified 48 genes with significant fusion-associated upregulation and furthermore demonstrate that significant regional overexpression of intact genes in patient transcriptomes occurs within 1 megabase of 78 novel gene fusions that function as central markers of these regions. We reveal that cancer transcriptomes select for gene fusions that preserve protein and protein domain coding potential. The association of gene fusion transcripts with neighboring gene overexpression supports rearrangements as mechanism through which cancer cells remodel their transcriptomes and identifies a new way to utilize gene fusions as indicators of regional expression changes in diseased cells with only transcriptomic data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-39878-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401071PMC
March 2019

Molecular mechanisms of the preventable causes of cancer in the United States.

Genes Dev 2018 07 26;32(13-14):868-902. Epub 2018 Jun 26.

Koch Institute for Integrative Cancer Research, Biology Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Annually, there are 1.6 million new cases of cancer and nearly 600,000 cancer deaths in the United States alone. The public health burden associated with these numbers has motivated enormous research efforts into understanding the root causes of cancer. These efforts have led to the recognition that between 40% and 45% of cancers are associated with preventable risk factors and, importantly, have identified specific molecular mechanisms by which these exposures modify human physiology to induce or promote cancer. The increasingly refined knowledge of these mechanisms, which we summarize here, emphasizes the need for greater efforts toward primary cancer prevention through mitigation of modifiable risk factors. It also suggests exploitable avenues for improved secondary prevention (which includes the development of therapeutics designed for cancer interception and enhanced techniques for noninvasive screening and early detection) based on detailed knowledge of early neoplastic pathobiology. Such efforts would complement the current emphasis on the development of therapeutic approaches to treat established cancers and are likely to result in far greater gains in reducing morbidity and mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/gad.314849.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075032PMC
July 2018

Miliary Adenocarcinoma of the Lung Responds to Gefitinib and Afatinib.

J Thorac Oncol 2018 06;13(6):e95-e97

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania; Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2018.01.018DOI Listing
June 2018

Rare antibody-associated hemolytic transfusion reaction and transfusion-related acute lung injury: a case report.

BMC Surg 2017 Apr 26;17(1):48. Epub 2017 Apr 26.

Department of Surgery, WellSpan York Hospital, York, PA, 17403, USA.

Background: Hemolytic transfusion reactions and transfusion-related acute lung injury (TRALI) are life-threatening complications associated with the transfusion of blood products. Hemorrhage is one of the most common surgical complications and the risk of bleeding is particularly acute in patients with hematologic deficiencies. Management of surgical bleeding can be divided into two phases. The first phase centers on immediate control of acute bleeding and the second phase focuses on keeping the patient stable and on reducing the sequelae associated with blood transfusions and blood loss.

Case Presentation: We present the case of a 53-year-old woman with long-standing immune thrombocytopenia who underwent repair of a symptomatic ventral hernia. On post-operative day one the patient developed hemoperitoneum, requiring exploratory laparotomy and massive transfusion of blood products. The patient's recovery was complicated by consistently low hemoglobin, hematocrit and platelets, prompting frequent transfusion of additional blood products. Shortly after activation of the massive transfusion protocol, the patient developed TRALI. Compounding the situation, on post-operative day sixteen the patient's serum started to show hemolysis: lactate dehydrogenase (LDH) levels rose to 1,845 IU/L, with haptoglobin at less than 5.8 mg/dL and with a high reticulocyte count (4.38%). Previous testing had shown that the patient was positive for most major antigens implicated in antibody formation and was only producing anti-E and anti-K antibodies (considered for all transfusions). Initial pre- and post-transfusion direct antiglobulin tests (DAT) were indeed negative. However, repeat DATs in the days following the noted serum changes were consistent with new allo-antibody formation. These findings prompted immediate withholding of all blood products and a thorough blood bank work up. Despite strong evidence for new allo-antibody formation, no specific known antibody could be identified. The patient recover well when blood products were withheld.

Discussion: We present the case of a 53-year-old woman with long-standing immune thrombocytopenia who underwent repair of a symptomatic ventral hernia. On post-operative day one the patient developed hemoperitoneum, requiring exploratory laparotomy and massive transfusion of blood products. The patient's recovery was complicated by consistently low hemoglobin, hematocrit and platelets, prompting frequent transfusion of additional blood products. Shortly after activation of the massive transfusion protocol, the patient developed TRALI. Compounding the situation, on post-operative day sixteen the patient's serum started to show hemolysis: lactate dehydrogenase (LDH) levels rose to 1,845 IU/L, with haptoglobin at less than 5.8 mg/dL and with a high reticulocyte count (4.38%). Previous testing had shown that the patient was positive for most major antigens implicated in antibody formation and was only producing anti-E and anti-K antibodies (considered for all transfusions). Initial pre- and post-transfusion direct antiglobulin tests (DAT) were indeed negative. However, repeat DATs in the days following the noted serum changes were consistent with new allo-antibody formation. These findings prompted immediate withholding of all blood products and a thorough blood bank work up. Despite strong evidence for new allo-antibody formation, no specific known antibody could be identified. The patient recover well when blood products were withheld. Suspicion for hemolytic transfusion reactions should be high in patients with prior allo-antibody formation; these may present as acute hemolysis or as a delayed hemolytic transfusion reaction. Withholding blood products from these patients until compatible products have been identified is recommended. Moreover, TRALI is the leading cause of transfusion-related fatalities and should always be considered in transfusion settings.

Conclusions: Suspicion for hemolytic transfusion reactions should be high in patients with prior allo-antibody formation; these may present as acute hemolysis or as a delayed hemolytic transfusion reaction. Withholding blood products from these patients until compatible products have been identified is recommended. Moreover, TRALI is the leading cause of transfusion-related fatalities and should always be considered in transfusion settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12893-017-0241-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405478PMC
April 2017

A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis.

Acta Neuropathol Commun 2017 03 16;5(1):23. Epub 2017 Mar 16.

Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that lacks a predictive and broadly applicable biomarker. Continued focus on mutation-specific upstream mechanisms has yet to predict disease progression in the clinic. Utilising cellular pathology common to the majority of ALS patients, we implemented an objective transcriptome-driven approach to develop noninvasive prognostic biomarkers for disease progression. Genes expressed in laser captured motor neurons in direct correlation (Spearman rank correlation, p < 0.01) with counts of neuropathology were developed into co-expression network modules. Screening modules using three gene sets representing rate of disease progression and upstream genetic association with ALS led to the prioritisation of a single module enriched for immune response to motor neuron degeneration. Genes in the network module are important for microglial activation and predict disease progression in genetically heterogeneous ALS cohorts: Expression of three genes in peripheral lymphocytes - LILRA2, ITGB2 and CEBPD - differentiate patients with rapid and slowly progressive disease, suggesting promise as a blood-derived biomarker. TREM2 is a member of the network module and the level of soluble TREM2 protein in cerebrospinal fluid is shown to predict survival when measured in late stage disease (Spearman rank correlation, p = 0.01). Our data-driven systems approach has, for the first time, directly linked microglia to the development of motor neuron pathology. LILRA2, ITGB2 and CEBPD represent peripherally accessible candidate biomarkers and TREM2 provides a broadly applicable therapeutic target for ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-017-0424-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353945PMC
March 2017

Identification of evolutionarily conserved DNA damage response genes that alter sensitivity to cisplatin.

Oncotarget 2017 Mar;8(12):19156-19171

Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Ovarian, head and neck, and other cancers are commonly treated with cisplatin and other DNA damaging cytotoxic agents. Altered DNA damage response (DDR) contributes to resistance of these tumors to chemotherapies, some targeted therapies, and radiation. DDR involves multiple protein complexes and signaling pathways, some of which are evolutionarily ancient and involve protein orthologs conserved from yeast to humans. To identify new regulators of cisplatin-resistance in human tumors, we integrated high throughput and curated datasets describing yeast genes that regulate sensitivity to cisplatin and/or ionizing radiation. Next, we clustered highly validated genes based on chemogenomic profiling, and then mapped orthologs of these genes in expanded genomic networks for multiple metazoans, including humans. This approach identified an enriched candidate set of genes involved in the regulation of resistance to radiation and/or cisplatin in humans. Direct functional assessment of selected candidate genes using RNA interference confirmed their activity in influencing cisplatin resistance, degree of γH2AX focus formation and ATR phosphorylation, in ovarian and head and neck cancer cell lines, suggesting impaired DDR signaling as the driving mechanism. This work enlarges the set of genes that may contribute to chemotherapy resistance and provides a new contextual resource for interpreting next generation sequencing (NGS) genomic profiling of tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.13353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386675PMC
March 2017

Head and neck squamous cell carcinoma: Ambiguous human papillomavirus status, elevated p16, and deleted retinoblastoma 1.

Head Neck 2017 03 8;39(3):E34-E39. Epub 2016 Nov 8.

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Background: Head and neck squamous cell carcinoma (HNSCC) is potentially curable, but treatment planning remains a challenge. Oncogenic human papillomavirus (HPV)-positive disease is often associated with a good prognosis compared with HPV-negative disease. However, some HPV-positive HNSCC recurs, often with distant metastases and significant treatment resistance.

Methods And Results: We performed p16 immunohistochemistry (IHC), in situ hybridization (ISH) for high-risk HPV, and comprehensive genomic profiling on oropharyngeal HNSCC with basaloid features and particularly aggressive disease course, noting a rare genetic event: a deleting mutation (exons 5-17) of the tumor suppressor and dominant cell cycle regulator retinoblastoma 1 (RB1). Genomic and transcriptomic data available through FoundationOne and The Cancer Genome Atlas (TCGA) were reviewed for additional HNSCC cases with RB1 alterations.

Conclusion: RB1 alterations may have important prognostic implications, particularly in the context of high p16 expression, in both HPV-positive and HPV-negative HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 39: E34-E39, 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hed.24604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439525PMC
March 2017

EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer.

Mol Cancer Ther 2016 10 9;15(10):2486-2497. Epub 2016 Aug 9.

Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania. Molecular and Cell Biology & Genetics Program, Drexel University College of Medicine, Philadelphia, Pennsylvania.

Clinical decision making for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is predominantly guided by disease stage and anatomic location, with few validated biomarkers. The epidermal growth factor receptor (EGFR) is an important therapeutic target, but its value in guiding therapeutic decision making remains ambiguous. We integrated analysis of clinically annotated tissue microarrays with analysis of data available through the TCGA, to investigate the idea that expression signatures involving EGFR, proteins regulating EGFR function, and core cell-cycle modulators might serve as prognostic or drug response-predictive biomarkers. This work suggests that consideration of the expression of NSDHL and proteins that regulate EGFR recycling in combination with EGFR provides a useful prognostic biomarker set. In addition, inactivation of the tumor suppressor retinoblastoma 1 (RB1), reflected by CCND1/CDK6-inactivating phosphorylation of RB1 at T356, inversely correlated with expression of EGFR in patient HNSCC samples. Moreover, stratification of cases with high EGFR by expression levels of CCND1, CDK6, or the CCND1/CDK6-regulatory protein p16 (CDKN2A) identified groups with significant survival differences. To further explore the relationship between EGFR and RB1-associated cell-cycle activity, we evaluated simultaneous inhibition of RB1 phosphorylation with the CDK4/6 inhibitor palbociclib and of EGFR activity with lapatinib or afatinib. These drug combinations had synergistic inhibitory effects on the proliferation of HNSCC cells and strikingly limited ERK1/2 phosphorylation in contrast to either agent used alone. In summary, combinations of CDK and EGFR inhibitors may be particularly useful in EGFR and pRB1-expressing or CCND1/CDK6-overexpressing HPV-negative HNSCC. Mol Cancer Ther; 15(10); 2486-97. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1535-7163.MCT-16-0243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522587PMC
October 2016

Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer.

Cell Rep 2016 07 7;16(3):657-71. Epub 2016 Jul 7.

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19129, USA. Electronic address:

Anti-Müllerian hormone (AMH) and its type II receptor AMHR2, both previously thought to primarily function in gonadal tissue, were unexpectedly identified as potent regulators of transforming growth factor (TGF-β)/bone morphogenetic protein (BMP) signaling and epithelial-mesenchymal transition (EMT) in lung cancer. AMH is a TGF-β/BMP superfamily member, and AMHR2 heterodimerizes with type I receptors (ALK2, ALK3) also used by the type II receptor for BMP (BMPR2). AMH signaling regulates expression of BMPR2, ALK2, and ALK3, supports protein kinase B-nuclear factor κB (AKT-NF-κB) and SMAD survival signaling, and influences BMP-dependent signaling in non-small cell lung cancer (NSCLC). AMH and AMHR2 are selectively expressed in epithelial versus mesenchymal cells, and loss of AMH/AMHR2 induces EMT. Independent induction of EMT reduces expression of AMH and AMHR2. Importantly, EMT associated with depletion of AMH or AMHR2 results in chemoresistance but sensitizes cells to the heat shock protein 90 (HSP90) inhibitor ganetespib. Recognition of this AMH/AMHR2 axis helps to further elucidate TGF-β/BMP resistance-associated signaling and suggests new strategies for therapeutic targeting of EMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2016.06.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956518PMC
July 2016

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis.

Proc Natl Acad Sci U S A 2016 06 6;113(25):6955-60. Epub 2016 Jun 6.

Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Department of Medical Oncology, University of New Mexico Cancer Center, Albuquerque, NM 87131; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111

Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of Kras(LA1/+);P53(R172HΔG/+) (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial-mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelial-mesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1513616113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922167PMC
June 2016

Genomic insights into head and neck cancer.

Cancers Head Neck 2016 3;1. Epub 2016 Jun 3.

Program in Molecular Therapeutics, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is frequently impervious to curative treatment efforts. Similar to other cancers associated with prolonged exposure to carcinogens, HNSCCs often have a high burden of mutations, contributing to substantial inter- and intra-tumor heterogeneity. The heterogeneity of this malignancy is further increased by the rising rate of human papillomavirus (HPV)-associated (HPV+) HNSCC, which defines an etiological subtype significantly different from the more common tobacco and alcohol associated HPV-negative (HPV-) HNSCC. Since 2011, application of large scale genome sequencing projects by The Cancer Genome Atlas (TCGA) network and other groups have established extensive datasets to characterize HPV- and HPV+ HNSCC, providing a foundation for advanced molecular diagnoses, identification of potential biomarkers, and therapeutic insights. Some genomic lesions are now appreciated as widely dispersed. For example, HPV- HNSCC characteristically inactivates the cell cycle suppressors TP53 (p53) and CDKN2A (p16), and often amplifies CCND1 (cyclin D), which phosphorylates RB1 to promote cell cycle progression from G1 to S. By contrast, HPV+ HNSCC expresses viral oncogenes E6 and E7, which inhibit TP53 and RB1, and activates the cell cycle regulator E2F1. Frequent activating mutations in PIK3CA and inactivating mutations in NOTCH1 are seen in both subtypes of HNSCC, emphasizing the importance of these pathways. Studies of large patient cohorts have also begun to identify less common genetic alterations, predominantly found in HPV- tumors, which suggest new mechanisms relevant to disease pathogenesis. Targets of these alterations including AJUBA and FAT1, both involved in the regulation of NOTCH/CTNNB1 signaling. Genes involved in oxidative stress, particularly CUL3, KEAP1 and NFE2L2, strongly associated with smoking, have also been identified, and are less well understood mechanistically. Application of sophisticated data-mining approaches, integrating genomic information with profiles of tumor methylation and gene expression, have helped to further yield insights, and in some cases suggest additional approaches to stratify patients for clinical treatment. We here discuss some recent insights built on TCGA and other genomic foundations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638139PMC
http://dx.doi.org/10.1186/s41199-016-0003-zDOI Listing
June 2016

Phospho-T356RB1 predicts survival in HPV-negative squamous cell carcinoma of the head and neck.

Oncotarget 2015 Aug;6(22):18863-74

Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.

Locally advanced squamous cell carcinoma of the head and neck (SCCHN) that is not associated with human papillomavirus (HPV) has a poor prognosis in contrast to HPV-positive disease. To better understand the importance of RB1 activity in HPV-negative SCCHN, we investigated the prognostic value of inhibitory CDK4/6 phosphorylation of RB1 on threonine 356 (T356) in archival HPV-negative tumor specimens from patients who underwent surgical resection and adjuvant radiation. We benchmarked pT356RB1 to total RB1, Ki67, pT202/Y204ERK1/2, and TP53, as quantified by automatic quantitative analysis (AQUA), and correlated protein expression with tumor stage and grade. High expression of pT356RB1 but not total RB1 predicted reduced overall survival (OS; P = 0.0295), indicating the potential relevance of post-translational phosphorylation. Paired analysis of The Cancer Genome Atlas (TCGA) data for regulators of this RB1 phosphorylation identified loss or truncating mutation of negative regulator CDKN2A (p16) and elevated expression of the CDK4/6 activator CCND1 (cyclin D) as also predicting poor survival. Given that CDK4/6 inhibitors have been most effective in the context of functional RB1 and low expression or deletion of p16 in other tumor types, these data suggest such agents may merit evaluation in HPV-negative SCCHN, specifically in cases associated with high pT356RB1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662460PMC
http://dx.doi.org/10.18632/oncotarget.4321DOI Listing
August 2015

Anti-necrotic and cardioprotective effects of a cytosolic renin isoform under ischemia-related conditions.

J Mol Med (Berl) 2016 Jan 11;94(1):61-9. Epub 2015 Aug 11.

Department of Physiology, University Medicine of Greifswald, Greifswalder Str. 11C, D-17495, Karlsburg, Germany.

Unlabelled: In the heart, secretory renin promotes hypertrophy, apoptosis, necrosis, fibrosis, and cardiac failure through angiotensin generation from angiotensinogen. Thus, inhibitors of the renin-angiotensin system are among the most potent drugs in the treatment of cardiac failure. Renin transcripts have been identified encoding a renin isoform with unknown targets and unknown functions that are localized to the cytosol and mitochondria. We hypothesize that this isoform, in contrast to secretory renin, exerts cardioprotective effects in an angiotensin-independent manner. Cells overexpressing cytosolic renin were generated by transfection or obtained from CX(exon2-9)renin transgenic rats. Overexpression of cytosolic renin reduced the rate of necrosis in H9c2 cardiomyoblasts and in primary cardiomyocytes after glucose depletion. These effects were not mediated by angiotensin generation since an inhibitor of renin activity did not influence the in vitro effects. siRNA-mediated knockdown of endogenous cytosolic renin increased the rate of necrosis and aggravated the pro-necrotic effects of glucose depletion. Isolated perfused hearts obtained from transgenic rats overexpressing cytosolic renin exhibited a 50% reduction of infarct size after ischemia-reperfusion injury. Cytosolic renin is essential for survival, both under basal conditions and during glucose starvation. The protective effects are angiotensin-independent and contrary to the known actions of secretory renin.

Key Messages: A cytosolic isoform of renin with unknown functions is expressed in the heart. Cytosolic renin diminishes ischemia induced damage to the heart. The protective effects of cytosolic renin contradict the known function of secretory renin. The effects of cytosolic renin are not mediated via angiotensin generation. Renin-binding protein is a potential target for cytosolic renin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00109-015-1321-zDOI Listing
January 2016

Cafe Variome: general-purpose software for making genotype-phenotype data discoverable in restricted or open access contexts.

Hum Mutat 2015 Oct 25;36(10):957-64. Epub 2015 Aug 25.

Department of Genetics, University of Leicester, Leicester, UK.

Biomedical data sharing is desirable, but problematic. Data "discovery" approaches-which establish the existence rather than the substance of data-precisely connect data owners with data seekers, and thereby promote data sharing. Cafe Variome (http://www.cafevariome.org) was therefore designed to provide a general-purpose, Web-based, data discovery tool that can be quickly installed by any genotype-phenotype data owner, or network of data owners, to make safe or sensitive content appropriately discoverable. Data fields or content of any type can be accommodated, from simple ID and label fields through to extensive genotype and phenotype details based on ontologies. The system provides a "shop window" in front of data, with main interfaces being a simple search box and a powerful "query-builder" that enable very elaborate queries to be formulated. After a successful search, counts of records are reported grouped by "openAccess" (data may be directly accessed), "linkedAccess" (a source link is provided), and "restrictedAccess" (facilitated data requests and subsequent provision of approved records). An administrator interface provides a wide range of options for system configuration, enabling highly customized single-site or federated networks to be established. Current uses include rare disease data discovery, patient matchmaking, and a Beacon Web service.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22841DOI Listing
October 2015

The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease.

Am J Hum Genet 2015 Jul 25;97(1):111-24. Epub 2015 Jun 25.

Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany; Berlin Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Institute of Bioinformatics, Department of Mathematics and Computer Science, Freie Universität Berlin, Takustrasse 9, 14195 Berlin, Germany. Electronic address:

The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000 rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2015.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572507PMC
July 2015

The BioMart community portal: an innovative alternative to large, centralized data repositories.

Nucleic Acids Res 2015 Jul 20;43(W1):W589-98. Epub 2015 Apr 20.

Oncology Computational Biology, Pfizer, La Jolla, USA.

The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkv350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489294PMC
July 2015

Adaptors for disorders of the brain? The cancer signaling proteins NEDD9, CASS4, and PTK2B in Alzheimer's disease.

Oncoscience 2014 23;1(7):486-503. Epub 2014 Jul 23.

Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA ; Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA, USA.

No treatment strategies effectively limit the progression of Alzheimer's disease (AD), a common and debilitating neurodegenerative disorder. The absence of viable treatment options reflects the fact that the pathophysiology and genotypic causes of the disease are not well understood. The advent of genome-wide association studies (GWAS) has made it possible to broadly investigate genotypic alterations driving phenotypic occurrences. Recent studies have associated single nucleotide polymorphisms (SNPs) in two paralogous scaffolding proteins, NEDD9 and CASS4, and the kinase PTK2B, with susceptibility to late-onset AD (LOAD). Intriguingly, NEDD9, CASS4, and PTK2B have been much studied as interacting partners regulating oncogenesis and metastasis, and all three are known to be active in the brain during development and in cancer. However, to date, the majority of studies of these proteins have emphasized their roles in the directly cancer relevant processes of migration and survival signaling. We here discuss evidence for roles of NEDD9, CASS4 and PTK2B in additional processes, including hypoxia, vascular changes, inflammation, microtubule stabilization and calcium signaling, as potentially relevant to the pathogenesis of LOAD. Reciprocally, these functions can better inform our understanding of the action of NEDD9, CASS4 and PTK2B in cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278314PMC
http://dx.doi.org/10.18632/oncoscience.64DOI Listing
January 2015

Non-transpeptidase binding arylthioether β-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis.

Bioorg Med Chem 2015 Feb 12;23(3):632-47. Epub 2014 Dec 12.

Department of Chemistry, American University, Washington, DC 20016, USA. Electronic address:

The prevalence of drug resistance in both clinical and community settings as a consequence of alterations of biosynthetic pathways, enzymes or cell wall architecture is a persistent threat to human health. We have designed, synthesized, and tested a novel class of non-transpeptidase, β-lactamase resistant monocyclic β-lactams that carry an arylthio group at C4. These thioethers exhibit inhibitory and cidal activity against serine β-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n=8) β-lactamase producing Moraxella catarrhalis clinical isolates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2014.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415315PMC
February 2015

Bioinformatic approaches to augment study of epithelial-to-mesenchymal transition in lung cancer.

Physiol Genomics 2014 Oct 5;46(19):699-724. Epub 2014 Aug 5.

Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania; Temple University School of Medicine, Philadelphia, Pennsylvania; and Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, Pennsylvania; and

Bioinformatic approaches are intended to provide systems level insight into the complex biological processes that underlie serious diseases such as cancer. In this review we describe current bioinformatic resources, and illustrate how they have been used to study a clinically important example: epithelial-to-mesenchymal transition (EMT) in lung cancer. Lung cancer is the leading cause of cancer-related deaths and is often diagnosed at advanced stages, leading to limited therapeutic success. While EMT is essential during development and wound healing, pathological reactivation of this program by cancer cells contributes to metastasis and drug resistance, both major causes of death from lung cancer. Challenges of studying EMT include its transient nature, its molecular and phenotypic heterogeneity, and the complicated networks of rewired signaling cascades. Given the biology of lung cancer and the role of EMT, it is critical to better align the two in order to advance the impact of precision oncology. This task relies heavily on the application of bioinformatic resources. Besides summarizing recent work in this area, we use four EMT-associated genes, TGF-β (TGFB1), NEDD9/HEF1, β-catenin (CTNNB1) and E-cadherin (CDH1), as exemplars to demonstrate the current capacities and limitations of probing bioinformatic resources to inform hypothesis-driven studies with therapeutic goals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/physiolgenomics.00062.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187119PMC
October 2014

GWAS Central: a comprehensive resource for the comparison and interrogation of genome-wide association studies.

Eur J Hum Genet 2014 Jul 4;22(7):949-52. Epub 2013 Dec 4.

Department of Genetics, University of Leicester, Leicester, UK.

To facilitate broad and convenient integrative visualization of and access to GWAS data, we have created the GWAS Central resource (http://www.gwascentral.org). This database seeks to provide a comprehensive collection of summary-level genetic association data, structured both for maximal utility and for safe open access (i.e., non-directional signals to fully preclude research subject identification). The resource emphasizes on advanced tools that allow comparison and discovery of relevant data sets from the perspective of genes, genome regions, phenotypes or traits. Tested markers and relevant genomic features can be visually interrogated across up to 16 multiple association data sets in a single view, starting at a chromosome-wide view and increasing in resolution down to individual bases. In addition, users can privately upload and view their own data as temporary files. Search and display utility is further enhanced by exploiting phenotype ontology annotations to allow genetic variants associated with phenotypes and traits of interest to be precisely identified, across all studies. Data submissions are accepted from individual researchers, groups and consortia, whereas we also actively gather data sets from various public sources. As a result, the resource now provides over 67 million P-values for over 1600 studies, making it the world's largest openly accessible online collection of summary-level GWAS association information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2013.274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060122PMC
July 2014

Integrating in silico resources to map a signaling network.

Methods Mol Biol 2014 ;1101:197-245

Fox Chase Cancer Center, Philadelphia, PA, USA.

The abundance of publicly available life science databases offers a wealth of information that can support interpretation of experimentally derived data and greatly enhance hypothesis generation. Protein interaction and functional networks are not simply new renditions of existing data: they provide the opportunity to gain insights into the specific physical and functional role a protein plays as part of the biological system. In this chapter, we describe different in silico tools that can quickly and conveniently retrieve data from existing data repositories and we discuss how the available tools are best utilized for different purposes. While emphasizing protein-protein interaction databases (e.g., BioGrid and IntAct), we also introduce metasearch platforms such as STRING and GeneMANIA, pathway databases (e.g., BioCarta and Pathway Commons), text mining approaches (e.g., PubMed and Chilibot), and resources for drug-protein interactions, genetic information for model organisms and gene expression information based on microarray data mining. Furthermore, we provide a simple step-by-step protocol for building customized protein-protein interaction networks in Cytoscape, a powerful network assembly and visualization program, integrating data retrieved from these various databases. As we illustrate, generation of composite interaction networks enables investigators to extract significantly more information about a given biological system than utilization of a single database or sole reliance on primary literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-62703-721-1_11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831179PMC
June 2014
-->