A genetic network that suppresses genome rearrangements in Saccharomyces cerevisiae and contains defects in cancers.

Gross chromosomal rearrangements (GCRs) play an important role in human diseases, including cancer. The identity of all Genome Instability Suppressing (GIS) genes is not currently known. Here multiple Saccharomyces cerevisiae GCR assays and query mutations were crossed into arrays of mutants to identify progeny with increased GCR rates. One hundred eighty two GIS genes were identified that suppressed GCR formation. Another 438 cooperatively acting GIS genes were identified that were not GIS genes, but suppressed the increased genome instability caused by individual query mutations. Analysis of TCGA data using the human genes predicted to act in GIS pathways revealed that a minimum of 93% of ovarian and 66% of colorectal cancer cases had defects affecting one or more predicted GIS gene. These defects included loss-of-function mutations, copy-number changes associated with reduced expression, and silencing. In contrast, acute myeloid leukaemia cases did not appear to have defects affecting the predicted GIS genes

Identification and Characterization of the Cdc73 Transcription Factor as a Suppressor of Genome Instability

Genome instability is an increasingly well-appreciated aspect of tumorigenesis, and genome rearrangements, such as translocations, copy number changes, and aneuploidy, are seen in many cancers. The Kolodner Laboratory has developed a variety of assays to study the formation of Gross Chromosomal Rearrangements (GCRs) in the model organism Saccharomyces cerevisiae, and our goal based on this work is to leverage the power of yeast genetics to gain insights in to the mechanisms by which increased genome instability contributes to cancer in humans. In Chapter 1, we describe collaborative efforts that used a large-scale screen to identify all the genes and pathways that interact to suppress genome instability in budding yeast. This led to the identification of 183 genes that directly suppress the accumulation of GCRs, 65 of which have not been previously identified. Bioinformatic analysis of cancer genome databases found that the human homologs of these genes are mutated in 90% and 70% of ovarian and colorectal cancers, respectively. Among the 65 novel suppressors was CDC73, a member of the Paf1 Complex that functions in transcription elongation and whose human homolog is a tumor suppressor. In Chapter 2, we investigate the mechanisms by which this gene suppresses genome instability. We demonstrate loss of CDC73 synergizes with mutations in telomere maintenance genes, and we show that increased GCRs rates are due to defects in telomerase and the accumulation of recombinogenic RNA: DNA hybrids. In Chapter 3, we expand this analysis to the rest of the Paf1 Complex members and demonstrate there is not a direct correlation between loss of complex function and an increase in GCR rate. We also defined an approximately 100 residue region of Cdc73 that is necessary and sufficient for its function and determined this region is necessary for nuclear localization and binding to Paf1. These findings on the structure and function of Cdc73 provide insights into how the human homolog functions as a tumor suppresso

Identification and Characterization of the Cdc73 Transcription Factor as a Suppressor of Genome Instability

Genome instability is an increasingly well-appreciated aspect of tumorigenesis, and genome rearrangements, such as translocations, copy number changes, and aneuploidy, are seen in many cancers. The Kolodner Laboratory has developed a variety of assays to study the formation of Gross Chromosomal Rearrangements (GCRs) in the model organism Saccharomyces cerevisiae, and our goal based on this work is to leverage the power of yeast genetics to gain insights in to the mechanisms by which increased genome instability contributes to cancer in humans. In Chapter 1, we describe collaborative efforts that used a large-scale screen to identify all the genes and pathways that interact to suppress genome instability in budding yeast. This led to the identification of 183 genes that directly suppress the accumulation of GCRs, 65 of which have not been previously identified. Bioinformatic analysis of cancer genome databases found that the human homologs of these genes are mutated in 90% and 70% of ovarian and colorectal cancers, respectively. Among the 65 novel suppressors was CDC73, a member of the Paf1 Complex that functions in transcription elongation and whose human homolog is a tumor suppressor. In Chapter 2, we investigate the mechanisms by which this gene suppresses genome instability. We demonstrate loss of CDC73 synergizes with mutations in telomere maintenance genes, and we show that increased GCRs rates are due to defects in telomerase and the accumulation of recombinogenic RNA: DNA hybrids. In Chapter 3, we expand this analysis to the rest of the Paf1 Complex members and demonstrate there is not a direct correlation between loss of complex function and an increase in GCR rate. We also defined an approximately 100 residue region of Cdc73 that is necessary and sufficient for its function and determined this region is necessary for nuclear localization and binding to Paf1. These findings on the structure and function of Cdc73 provide insights into how the human homolog functions as a tumor suppresso

Cardiac Tamponade After COVID-19 Vaccination.

BackgroundAcute pericarditis is a diffuse inflammation of the pericardial sac with many well-defined etiologies. Acute pericarditis as a vaccine-related adverse event is a rare entity, and the association between pericarditis and the immunogenic response to Coronavirus disease 2019 (COVID-19) vaccines is still being fully characterized.Case reportA previously healthy 18-year-old man presented with fever, pleuritic chest pain, and shortness of breath 3 weeks after receiving the first dose of a COVID-19 mRNA-based vaccine. The patient was found to have a large pericardial effusion with early tamponade physiology requiring pericardiocentesis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As COVID-19 vaccination becomes more prevalent globally, physicians should be aware of pericarditis as a rare but potentially serious adverse reaction. Although a direct causal link cannot be demonstrated, we present this case to increase awareness among emergency physicians of pericarditis as a rare, but potentially serious adverse event associated with COVID-19 vaccination

Real-time Point-of-care Ultrasound for the Diagnosis and Treatment of Testicular Torsion

Background: Testicular torsion is a surgical emergency that needs prompt diagnosis and treatment. Point-of-Care ultrasound (POCUS) can not only establish the diagnosis but also guide the Emergency Physician in evaluating the response to manual detorsion. Case Report: We describe the case of a 13-year-old male who presented with acute scrotal pain. We demonstrate how bedside ultrasound was used to make the diagnosis of testicular torsion, guide the technique for manual detorsion, and confirm adequate return of blood flow. Our case illustrates the ease with which POCUS can be used in real time to diagnose and treat organ-threatening pathology, but more importantly, it shows how real-time POCUS was used to detorse a testicle that was refractory to the standard detorsion technique. Conclusion: The acute scrotum is a time-sensitive presentation and if testicular torsion is present, the diagnosis should be made as soon as possible. Many Emergency Departments do not have 24-hour coverage of ultrasound technicians, which would delay the diagnosis and treatment. Moreover, when manual detorsion is attempted, it often does not work because the testicle may need more than the standard 180 degree medial to lateral rotation. POCUS provides real-time analysis of return of blood flow and can thus guide further rotation, or opposite direction rotation, as needed