ABSTRACT
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.
Subject(s)
Neoplasms/genetics , Neoplasms/prevention & control , Primary Prevention , Early Detection of Cancer , Humans , Neoplasms/physiopathology , Risk Factors , United StatesABSTRACT
The GWAS Central resource gathers and curates extensive summary-level genome-wide association study (GWAS) data and puts a range of user-friendly but powerful website tools for the comparison and visualisation of GWAS data at the fingertips of researchers. Through our continued efforts to harmonise and import data received from GWAS authors and consortia, and data sets actively collected from public sources, the database now contains over 72.5 million P-values for over 5000 studies testing over 7.4 million unique genetic markers investigating over 1700 unique phenotypes. Here, we describe an update to integrate this extensive data collection with mouse disease model data to support insights into the functional impact of human genetic variation. GWAS Central has expanded to include mouse gene-phenotype associations observed during mouse gene knockout screens. To allow similar cross-species phenotypes to be compared, terms from mammalian and human phenotype ontologies have been mapped. New interactive interfaces to find, correlate and view human and mouse genotype-phenotype associations are included in the website toolkit. Additionally, the integrated browser for interrogating multiple association data sets has been updated and a GA4GH Beacon API endpoint has been added for discovering variants tested in GWAS. The GWAS Central resource is accessible at https://www.gwascentral.org/.
Subject(s)
Databases, Genetic , Genome-Wide Association Study , Humans , Animals , Mice , Genotype , Phenotype , Data Collection , Polymorphism, Single Nucleotide , MammalsABSTRACT
Enzymes are indispensable in many biological processes, and with biomedical literature growing exponentially, effective literature review becomes increasingly challenging. Natural language processing methods offer solutions to streamline this process. This study aims to develop an annotated enzyme corpus for training and evaluating enzyme named entity recognition (NER) models. A novel pipeline, combining dictionary matching and rule-based keyword searching, automatically annotated enzyme entities in >4800 full-text publications. Four deep learning NER models were created with different vocabularies (BioBERT/SciBERT) and architectures (BiLSTM/transformer) and evaluated on 526 manually annotated full-text publications. The annotation pipeline achieved an F1-score of 0.86 (precision = 1.00, recall = 0.76), surpassed by fine-tuned transformers for F1-score (BioBERT: 0.89, SciBERT: 0.88) and recall (0.86) with BiLSTM models having higher precision (0.94) than transformers (0.92). The annotation pipeline runs in seconds on standard laptops with almost perfect precision, but was outperformed by fine-tuned transformers in terms of F1-score and recall, demonstrating generalizability beyond the training data. In comparison, SciBERT-based models exhibited higher precision, and BioBERT-based models exhibited higher recall, highlighting the importance of vocabulary and architecture. These models, representing the first enzyme NER algorithms, enable more effective enzyme text mining and information extraction. Codes for automated annotation and model generation are available from https://github.com/omicsNLP/enzymeNER and https://zenodo.org/doi/10.5281/zenodo.10581586.
Subject(s)
Algorithms , Deep Learning , Enzymes , Natural Language Processing , Molecular Sequence Annotation/methods , Humans , Data Mining/methodsABSTRACT
Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance. To refine the QTL and link them to disease risk in humans, we asked if the human homologs of genes located at each QTL were associated with lipid traits in human genome-wide association studies. Integration of mouse QTL with human genome-wide association studies yielded candidate gene drivers for 18 of the 21 QTL. This approach enabled us to nominate the gene encoding the neutral ceramidase, Asah2, as a novel candidate driver at a QTL on chromosome 19 for large HDL particles (HDL-2b). To experimentally validate Asah2, we surveyed lipoproteins in Asah2-/- mice. Compared to wild-type mice, female Asah2-/- mice showed an increase in several lipoproteins, including HDL. Our results provide insights into the genetic regulation of circulating lipoproteins, as well as mechanisms by which lipoprotein subfractions may affect cardiovascular disease risk in humans.
Subject(s)
Collaborative Cross Mice , Genome-Wide Association Study , Female , Humans , Mice , Animals , Lipoproteins/genetics , Quantitative Trait Loci/genetics , Phenotype , Lipoproteins, VLDLABSTRACT
BACKGROUND: The parathyroidectomy approach has shifted over the last few decades from routine bilateral to more commonly focused exploration. The purpose of this study is to assess the operative experience in parathyroidectomy for surgical trainees as well as overall parathyroidectomy trends. METHODS: Data from the Collaborative Endocrine Surgery Quality Improvement Program (CESQIP) were analyzed between 2014 and 2019. RESULTS: The overall distribution of focused versus bilateral parathyroidectomy remained stable (2014: 54 % focused and 46 % bilateral approach; 2019: 55 % focused and 45 % bilateral). Ninety three percent of procedures involved a trainee (fellow or resident) in 2014, this dropped to 74 % in 2019 (P < 0.005). Fellow involvement decreased significantly from 31 % to 17 % (P < 0.05) over the six-year period. CONCLUSIONS: Resident exposure to parathyroidectomies mirrored that of practicing endocrine surgeons. This works highlights the opportunities to capture more information regarding the surgical trainee experience in endocrine surgeries.
Subject(s)
Hyperparathyroidism, Primary , Surgeons , Humans , Parathyroidectomy/methods , Quality Improvement , Hyperparathyroidism, Primary/surgeryABSTRACT
Beacon is a basic data discovery protocol issued by the Global Alliance for Genomics and Health (GA4GH). The main goal addressed by version 1 of the Beacon protocol was to test the feasibility of broadly sharing human genomic data, through providing simple "yes" or "no" responses to queries about the presence of a given variant in datasets hosted by Beacon providers. The popularity of this concept has fostered the design of a version 2, that better serves real-world requirements and addresses the needs of clinical genomics research and healthcare, as assessed by several contributing projects and organizations. Particularly, rare disease genetics and cancer research will benefit from new case level and genomic variant level requests and the enabling of richer phenotype and clinical queries as well as support for fuzzy searches. Beacon is designed as a "lingua franca" to bridge data collections hosted in software solutions with different and rich interfaces. Beacon version 2 works alongside popular standards like Phenopackets, OMOP, or FHIR, allowing implementing consortia to return matches in beacon responses and provide a handover to their preferred data exchange format. The protocol is being explored by other research domains and is being tested in several international projects.
Subject(s)
Genomics , Information Dissemination , Humans , Information Dissemination/methods , Phenotype , Rare Diseases , SoftwareABSTRACT
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.
Subject(s)
Computational Biology/methods , Databases, Genetic , Genome-Wide Association Study , Genomics , Genotype , Phenotype , Software , Gene Ontology , Genome-Wide Association Study/methods , Genomics/methods , Software Design , User-Computer Interface , Web BrowserABSTRACT
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.
Subject(s)
Lymphoma/diagnostic imaging , Lymphoma/pathology , Positron-Emission Tomography , Thyroid Cancer, Papillary/diagnostic imaging , Thyroid Cancer, Papillary/pathology , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/pathology , Adult , Aged , Biopsy, Fine-Needle , Female , Humans , Incidental Findings , Lymphoma/surgery , Male , Matched-Pair Analysis , Middle Aged , Neoplasm Staging , Retrospective Studies , Thyroid Cancer, Papillary/surgery , Thyroid Neoplasms/surgery , ThyroidectomyABSTRACT
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.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Carcinoma, Non-Small-Cell Lung/therapy , Intestinal Perforation/surgery , Lung Neoplasms/therapy , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Female , Humans , Immunotherapy , Intestinal Perforation/chemically induced , Intestine, Small/pathology , Intestine, Small/surgery , Lung Neoplasms/metabolism , Middle AgedABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung/secondary , Cell-Free Nucleic Acids/blood , Lung Neoplasms/pathology , Neoplastic Cells, Circulating/metabolism , Small Cell Lung Carcinoma/secondary , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell-Free Nucleic Acids/genetics , Epithelial Cell Adhesion Molecule/blood , Humans , Lung Neoplasms/genetics , Platelet Factor 4/blood , Prognosis , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/pathologyABSTRACT
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.
Subject(s)
Drug Delivery Systems/methods , Pleural Effusion, Malignant/therapy , Pleurodesis/methods , Sclerosing Solutions/therapeutic use , Talc/therapeutic use , Animals , Carcinoma, Lewis Lung/complications , Disease Models, Animal , Female , Fibrosis/diagnosis , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Lung/pathology , Lung Volume Measurements , Male , Mice , Mice, Inbred C57BL , Pleura/pathology , Pleural Effusion, Malignant/etiology , Sclerosing Solutions/administration & dosage , Talc/administration & dosage , Transition Temperature , Treatment OutcomeABSTRACT
Non-small cell lung cancer (NSCLC) has a 5-y survival rate of â¼16%, 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-ß receptor 1 (TGFßR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFßRI 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 TGFßR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.
Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Claudins/antagonists & inhibitors , Lung Neoplasms/pathology , RNA-Binding Proteins/physiology , Signal Transduction , Transforming Growth Factor beta/metabolism , Animals , Cell Line, Tumor , Claudins/physiology , Humans , Mice , Neoplasm MetastasisABSTRACT
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.
Subject(s)
Gene Ontology/trends , Genetic Diseases, Inborn/classification , Genetic Diseases, Inborn/genetics , Phenotype , Terminology as Topic , Genetic Diseases, Inborn/pathology , Humans , MEDLINE , Models, BiologicalABSTRACT
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.
Subject(s)
Database Management Systems , Genomics , Humans , Internet , Neoplasms/genetics , ProteomicsABSTRACT
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.
Subject(s)
Acute Lung Injury/etiology , Hemolysis/immunology , Isoantibodies/immunology , Transfusion Reaction , Transfusion Reaction/complications , Acute Lung Injury/immunology , Female , Humans , Middle Aged , Transfusion Reaction/immunologyABSTRACT
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.
Subject(s)
Databases, Bibliographic , Information Dissemination/methods , Rare Diseases/genetics , Genetic Predisposition to Disease , Genotype , Humans , Phenotype , Software , User-Computer Interface , Web BrowserABSTRACT
MOTIVATION: Copy number variations (CNVs) are a major source of genomic variability and are especially significant in cancer. Until recently microarray technologies have been used to characterize CNVs in genomes. However, advances in next-generation sequencing technology offer significant opportunities to deduce copy number directly from genome sequencing data. Unfortunately cancer genomes differ from normal genomes in several aspects that make them far less amenable to copy number detection. For example, cancer genomes are often aneuploid and an admixture of diploid/non-tumor cell fractions. Also patient-derived xenograft models can be laden with mouse contamination that strongly affects accurate assignment of copy number. Hence, there is a need to develop analytical tools that can take into account cancer-specific parameters for detecting CNVs directly from genome sequencing data. RESULTS: We have developed WaveCNV, a software package to identify copy number alterations by detecting breakpoints of CNVs using translation-invariant discrete wavelet transforms and assign digitized copy numbers to each event using next-generation sequencing data. We also assign alleles specifying the chromosomal ratio following duplication/loss. We verified copy number calls using both microarray (correlation coefficient 0.97) and quantitative polymerase chain reaction (correlation coefficient 0.94) and found them to be highly concordant. We demonstrate its utility in pancreatic primary and xenograft sequencing data. AVAILABILITY AND IMPLEMENTATION: Source code and executables are available at https://github.com/WaveCNV. The segmentation algorithm is implemented in MATLAB, and copy number assignment is implemented Perl. CONTACT: lakshmi.muthuswamy@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
DNA Copy Number Variations , High-Throughput Nucleotide Sequencing/methods , Neoplasms/genetics , Algorithms , Alleles , Aneuploidy , Animals , Humans , Mice , Sequence Analysis, DNA , Software , Xenograft Model Antitumor AssaysABSTRACT
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, ß-lactamase resistant monocyclic ß-lactams that carry an arylthio group at C4. These thioethers exhibit inhibitory and cidal activity against serine ß-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n=8) ß-lactamase producing Moraxella catarrhalis clinical isolates.
Subject(s)
Anti-Bacterial Agents/pharmacology , Moraxella catarrhalis/drug effects , Mycobacterium tuberculosis/drug effects , beta-Lactams/pharmacology , Anti-Bacterial Agents/chemistry , Microbial Sensitivity Tests , Moraxella catarrhalis/enzymology , Mycobacterium tuberculosis/enzymology , beta-Lactams/chemistry , beta-Lactams/metabolismABSTRACT
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-ß (TGFB1), NEDD9/HEF1, ß-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.
Subject(s)
Computational Biology/methods , Computational Biology/trends , Epithelial-Mesenchymal Transition/physiology , Gene Expression Regulation, Neoplastic/physiology , Lung Neoplasms/physiopathology , Models, Biological , Signal Transduction/physiology , Adaptor Proteins, Signal Transducing/genetics , Cadherins/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , Phosphoproteins/genetics , Signal Transduction/genetics , Transforming Growth Factor beta1/genetics , beta Catenin/geneticsABSTRACT
BACKGROUND: Primary thyroid lymphoma (PTL) is rare and diagnosis is challenging. METHODS: We conducted a multicenter retrospective study of patients with PTL from 1990 to 2023 to determine method of diagnosis, treatment, and outcomes. RESULTS: The study cohort included 31 patients with PTL; all had thyroid enlargement; 21 (68 â%) had compressive symptoms, 11 (35 â%) had hypothyroidism and 3 had (10 â%) B symptoms. Diagnosis was established from incisional biopsy in 8 (26 â%), needle biopsy in 4 (13 â%), excisional lymph node biopsy in 1 (3 â%), and thyroidectomy specimens in 18 (58 â%). 15 (48 â%) patients had Hashimoto thyroiditis. Treatment included chemotherapy in 19 (61 â%); surgery alone in 7 (23 â%); and radiation alone or with surgery in 5 (16 â%) patients. One (3 â%) patient recurred, and 4 (13 â%) patients died after a median 4.2 years. CONCLUSION: Diagnosis of PTL was made in only 13 â% of patients preoperatively. There may be opportunity for needle biopsy to facilitate earlier diagnosis and treatment.