While next-generation sequencing (NGS) has become the primary technology for discovering gene fusions, we are still faced with the challenge of ensuring that causative mutations are not missed while ...minimizing false positives. Currently, there are many computational tools that predict structural variations (SV) and gene fusions using whole genome (WGS) and transcriptome sequencing (RNA-seq) data separately. However, as both WGS and RNA-seq have their limitations when used independently, we hypothesize that the orthogonal validation from integrating both data could generate a sensitive and specific approach for detecting high-confidence gene fusion predictions. Fortunately, decreasing NGS costs have resulted in a growing quantity of patients with both data available. Therefore, we developed a gene fusion discovery tool, INTEGRATE, that leverages both RNA-seq and WGS data to reconstruct gene fusion junctions and genomic breakpoints by split-read mapping. To evaluate INTEGRATE, we compared it with eight additional gene fusion discovery tools using the well-characterized breast cell line HCC1395 and peripheral blood lymphocytes derived from the same patient (HCC1395BL). The predictions subsequently underwent a targeted validation leading to the discovery of 131 novel fusions in addition to the seven previously reported fusions. Overall, INTEGRATE only missed six out of the 138 validated fusions and had the highest accuracy of the nine tools evaluated. Additionally, we applied INTEGRATE to 62 breast cancer patients from The Cancer Genome Atlas (TCGA) and found multiple recurrent gene fusions including a subset involving estrogen receptor. Taken together, INTEGRATE is a highly sensitive and accurate tool that is freely available for academic use.
Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides ...a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.
We have profiled promoter DNA methylation alterations in 272 glioblastoma tumors in the context of The Cancer Genome Atlas (TCGA). We found that a distinct subset of samples displays concerted ...hypermethylation at a large number of loci, indicating the existence of a glioma-CpG island methylator phenotype (G-CIMP). We validated G-CIMP in a set of non-TCGA glioblastomas and low-grade gliomas. G-CIMP tumors belong to the proneural subgroup, are more prevalent among lower-grade gliomas, display distinct copy-number alterations, and are tightly associated with
IDH1 somatic mutations. Patients with G-CIMP tumors are younger at the time of diagnosis and experience significantly improved outcome. These findings identify G-CIMP as a distinct subset of human gliomas on molecular and clinical grounds.
► Identification of a CpG island methylator phenotype (G-CIMP) in gliomas ► G-CIMP is tightly associated with
IDH1 mutation ► G-CIMP patients are younger at diagnosis and display improved survival ► G-CIMP is more prevalent among low- and intermediate-grade gliomas
Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), ...normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is “captured” as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.
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► Normal HSPCs contain random background mutations that increase with aging ► AML genomes contain hundreds of mutations, but very few are recurrent ► Comparison of M1 and M3 AML genomes identifies initiating versus cooperating mutations ► Most AML mutations are probably background events in HSPCs, “captured” by cloning
Comparison of the genomes of two groups of patients, each with a different form of AML, allows the resolution of potential driver and cooperating mutations in each disease and reveals that the genetic history of all AML cases is marked by random, benign mutations acquired by normal HSPCs as a function of age.
We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and ...557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.
•General anesthesia is primarily used in atrial fibrillation ablation procedures•Anesthetic type varies with patient, procedural, and hospital characteristics•Patients receiving monitored anesthesia ...care had 31% shorter median case duration
The authors evaluated the type of anesthesia administered in atrial fibrillation ablation, hypothesizing that monitored anesthesia care is used less frequently than general anesthesia.
A retrospective study.
National Anesthesia Clinical Outcomes Registry data, which are multi-institutional from across the United States.
Adult patients who underwent elective atrial fibrillation ablation between 2013 and 2018.
None.
National Anesthesia Clinical Outcomes Registry data were evaluated, and covariates were selected a priori within multivariate models to assess for predictors of anesthetic type. A total of 54,321 patients underwent atrial fibrillation ablation; 3,251 (6.0%) received monitored anesthesia care. Patients who received monitored anesthesia care were more likely to be >80 years old (12.4% v 4.9%; p < 0.0001), female (36.1% v 34.3%; p < 0.0001), have American Society of Anesthesiologists physical status >III (17.28% v 10.48%; p < 0.0001), and reside in urban areas (62.23% v 53.37%; p < 0.0001). They received care in the Northeast (17.6% v 10.1%; p < 0.0001) at low-volume centers (median 224 v 284 procedures; p < 0.0001). Multivariate analysis revealed that each five-year increase in age, being female, and having an American Society of Anesthesiologists physical status >III resulted in a 7% (p < 0.0001), 9% (p = 0.032), and 200% (p < 0.0001) increased odds of receiving monitored anesthesia care, respectively. Requiring additional ablation of atria or of a second arrhythmia and residing outside the Northeast resulted in a decreased odds of monitored anesthesia care (adjusted odds ratio 0.24 p=0.002 and < 0.5 p < 0.03, respectively). For each 50 cases performed annually at a center, the odds decreased by 5% (p = 0.005).
General anesthesia is the most common type of anesthesia administered for atrial fibrillation ablation. The type of anesthesia administered, however, varies with patient, procedural, and hospital characteristics.
The creative process is fun, complex, and sometimes frustrating, but it is critical to the future of our nation and progress in science, technology, engineering, mathematics (STEM), as well as other ...fields. Thus, we set out to see if implementing methods of active learning typical to the theater department could impact the creativity of senior capstone design students in the bioengineering (BE) department. Senior bioengineering capstone design students were allowed to self-select into groups. Prior to the beginning of coursework, all students completed a validated survey measuring engineering design self-efficacy. The control and experimental groups both received standard instruction, but in addition the experimental group received 1 h per week of creativity training developed by a theater professor. Following the semester, the students again completed the self-efficacy survey. The surveys were examined to identify differences in the initial and final self-efficacy in the experimental and control groups over the course of the semester. An analysis of variance was used to compare the experimental and control groups with p < 0.05 considered significant. Students in the experimental group reported more than a twofold (4.8 (C) versus 10.9 (E)) increase of confidence. Additionally, students in the experimental group were more motivated and less anxious when engaging in engineering design following the semester of creativity instruction. The results of this pilot study indicate that there is a significant potential to improve engineering students' creative self-efficacy through the implementation of a "curriculum of creativity" which is developed using theater methods.
Leadless cardiac pacemakers were developed to reduce complications associated with conventional transvenous pacemakers. While this technology is still relatively new, devices are increasingly being ...implanted. The perioperative management of patients with these devices has been underreported; we thus seek to add to the limited body of knowledge of perioperative management of patients with leadless cardiac pacemakers. An elderly female patient with a Micra VR transcatheter pacing system leadless cardiac pacemaker placed for tachycardia-bradycardia syndrome with intermittent complete heart block was scheduled for elective tricuspid valve replacement for severe tricuspid regurgitation. Pacemaker interrogation was performed several hours prior to the scheduled surgery based on the electrophysiologist’s availability; the device was kept in its programmed VVIR mode, and the base rate was increased from 60 to 80 beats per minute in anticipation of the upcoming surgery. Upon preoperative evaluation, the anesthesiologist asked that the electrophysiology team be placed on standby intraoperatively due to the concern that either oversensing in the setting of pacemaker dependence and/or undesirable tachycardia from rate-responsive pacing could occur. The surgeon used monopolar electrocautery for the duration of the cardiac surgery. Despite the patient having evidence of pacemaker dependence in the intensive care unit preoperatively, no electromagnetic interference leading to oversensing nor rate modulation was detected during intraoperative electrocardiographic and intraarterial invasive monitoring. Evidence-based guidelines regarding perioperative management specifically of leadless cardiac pacemakers do not exist. As these devices become more prevalent, further evaluation will be paramount to determine whether existing guidelines for perioperative management of conventional transvenous pacemakers apply.
Producing gene fusions through genomic structural rearrangements is a major mechanism for tumor evolution. Therefore, accurately detecting gene fusions and the originating rearrangements is of great ...importance for personalized cancer diagnosis and targeted therapy. We present a tool, BreakTrans, that systematically maps predicted gene fusions to structural rearrangements. Thus, BreakTrans not only validates both types of predictions, but also provides mechanistic interpretations. BreakTrans effectively validates known fusions and discovers novel events in a breast cancer cell line. Applying BreakTrans to 43 breast cancer samples in The Cancer Genome Atlas identifies 90 genomically validated gene fusions. BreakTrans is available at http://bioinformatics.mdanderson.org/main/BreakTrans.
We sought to determine who is involved in the care of a trauma patient.
We recorded hospital personnel involved in 24 adult Priority 1 trauma patient admissions for 12 h or until patient demise. ...Hospital personnel were delineated by professional background and role.
We cataloged 19 males and 5 females with a median age of 50-y-old (interquartile range IQR, 35.5-67.5). The average number of hospital personnel involved was 79.71 (standard deviation, 17.62; standard error 3.6). A median of 51.2% (IQR, 43.4%-59.8%) of personnel were first involved within hour 1. More personnel were involved in direct versus indirect care (median 54.5 IQR, 47.5-67.0 vs 25.0 IQR, 22.0-30.5;
< 0.0001). Median number of health-care professionals and auxiliary staff were 74.5 (IQR, 63.5-90.5) and 6.0 (IQR, 5.0-7.0), respectively. More personnel were first involved in hospital locations external to the emergency department (median, 53.0 IQR, 41.5-63.0 vs 27.5 IQR, 24.0-30.0;
< 0.0001). No differences existed in total personnel by Injury Severity Score (
= 0.1266), day (
= 0.7270), or time of admission (
= 0.2098).
A large number of hospital personnel with varying job responsibilities respond to severe trauma. These data may guide hospital staffing and disaster preparedness policies.