Citations

Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p< 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was >20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was < 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.

The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor–1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.

Abstract Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set. Results We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls. Conclusions In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).

Abstract Histological and lineage immunofluorescence examination revealed that healthy conducting airways of humans and animals harbor sporadic poorly differentiated epithelial patches mostly in the dorsal noncartilage regions that remarkably manifest squamous differentiation. In vitro analysis demonstrated that this squamous phenotype is not due to intrinsic functional change in underlying airway basal cells. Rather, it is a reversible physiological response to persistent Wnt signaling stimulation during de novo differentiation. Squamous epithelial cells have elevated gene signatures of glucose uptake and cellular glycolysis. Inhibition of glycolysis or a decrease in glucose availability suppresses Wnt-induced squamous epithelial differentiation. Compared with pseudostratified airway epithelial cells, a cascade of mucosal protective functions is impaired in squamous epithelial cells, featuring increased epithelial permeability, spontaneous epithelial unjamming, and enhanced inflammatory responses. Our study raises the possibility that the squamous differentiation naturally occurring in healthy airways identified herein may represent “vulnerable spots” within the airway mucosa that are sensitive to damage and inflammation when confronted by infection or injury. Squamous metaplasia and hyperplasia are hallmarks of many airway diseases, thereby expanding these areas of vulnerability with potential pathological consequences. Thus, investigation of physiological and reversible squamous differentiation from healthy airway basal cells may provide critical knowledge to understand pathogenic squamous remodeling, which is often nonreversible, progressive, and hyperinflammatory.

AbstractRespiratory viruses are a common cause of morbidity and mortality around the world. Viruses like influenza, RSV, and most recently SARS‐CoV‐2 can rapidly spread through a population, causing acute infection and, in vulnerable populations, severe or chronic disease. Developing effective treatment and prevention strategies often becomes a race against ever‐evolving viruses that develop resistance, leaving therapy efficacy either short‐lived or relevant for specific viral strains. On June 29 to July 2, 2022, researchers met for the Keystone symposium “Respiratory Viruses: New Frontiers.” Researchers presented new insights into viral biology and virus–host interactions to understand the mechanisms of disease and identify novel treatment and prevention approaches that are effective, durable, and broad.

AbstractThis report reviews the image acquisition and reconstruction characteristics of C‐arm Cone Beam Computed Tomography (C‐arm CBCT) systems and provides guidance on quality control of C‐arm systems with this volumetric imaging capability. The concepts of 3D image reconstruction, geometric calibration, image quality, and dosimetry covered in this report are also pertinent to CBCT for Image‐Guided Radiation Therapy (IGRT). However, IGRT systems introduce a number of additional considerations, such as geometric alignment of the imaging at treatment isocenter, which are beyond the scope of the charge to the task group and the report.Section 1 provides an introduction to C‐arm CBCT systems and reviews a variety of clinical applications. Section 2 briefly presents nomenclature specific or unique to these systems. A short review of C‐arm fluoroscopy quality control (QC) in relation to 3D C‐arm imaging is given in Section 3. Section 4 discusses system calibration, including geometric calibration and uniformity calibration. A review of the unique approaches and challenges to 3D reconstruction of data sets acquired by C‐arm CBCT systems is give in Section 5. Sections 6 and 7 go in greater depth to address the performance assessment of C‐arm CBCT units. First, Section 6 describes testing approaches and phantoms that may be used to evaluate image quality (spatial resolution and image noise and artifacts) and identifies several factors that affect image quality. Section 7 describes both free‐in‐air and in‐phantom approaches to evaluating radiation dose indices.The methodologies described for assessing image quality and radiation dose may be used for annual constancy assessment and comparisons among different systems to help medical physicists determine when a system is not operating as expected. Baseline measurements taken either at installation or after a full preventative maintenance service call can also provide valuable data to help determine whether the performance of the system is acceptable. Collecting image quality and radiation dose data on existing phantoms used for CT image quality and radiation dose assessment, or on newly developed phantoms, will inform the development of performance criteria and standards. Phantom images are also useful for identifying and evaluating artifacts. In particular, comparing baseline data with those from current phantom images can reveal the need for system calibration before image artifacts are detected in clinical practice. Examples of artifacts are provided in Sections 4, 5, and 6.

Abstract Intronic G4C2 hexanucleotide repeat expansions (HRE) of C9orf72 are the most common cause of familial variants of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). G4C2 HREs in C9orf72 undergo non-canonical repeat-associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain. Previous work has demonstrated the profound effects of a poly(GR) model of C9orf72 FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease. Here, using an established mouse model of C9orf72 FTD/ALS we investigate the contributions of the nod-like receptor pyrin-containing 3 (NLRP3) inflammasome in the pathogenesis of FTD/ALS. We find that inflammasome-mediated neuroinflammation is increased with microglial activation, cleavage of caspase-1, production of IL-1β and upregulation of Cxcl10 in the brain of C9orf72 FTD/ALS mice. Excitingly, we find that genetic ablation of Nlrp3 significantly improved survival, protected behavioral deficits and prevented neurodegeneration suggesting a novel mechanism involving HRE-mediated induction of innate immunity. The findings provide experimental evidence of the integral role of HRE in inflammasome-mediated innate immunity in the C9orf72 variant of FTD/ALS pathogenesis and suggest the NLRP3 inflammasome as a therapeutic target.

PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Abstract Aging has been shown to be one of the major risk factors for host morbidity and mortality following infections with respiratory viruses including influenza virus and SARS-CoV-2. The unique immune properties of the aged hosts not only influence pathogen clearance and tissue damage responses, but also modulate the pathogenesis of the long-term sequalae post acute viral clearance. Currently, the dynamics and features of mucosal immune responses following acute respiratory viral infections in the aged hosts remain to be fully elucidated. Here, we characterized the lung cellular and molecular profiles following influenza virus infection in young (~3-month-old) or aged (~24-month-old) mice with a chronological manner from acute to chronic phase. Using DNA-oligo-conjugated CD45 antibody and i.v. labeling, we were able to distinguish the unique responses of circulating vs lung-resident immune cells to influenza virus infection during aging. These responses were further validated by spectral flow cytometry analysis of the lung innate and adaptive immune cells. Further data analysis and integration are warranted for this unique large data set detailing the single cell molecular profiles of mucosal responses to influenza virus infection comparing young and aged hosts.

Abstract Alcoholic hepatitis (AH) develops in a small percentage of heavy drinkers. The adaptive immune system of AH patients is hyper-activated, yet dysregulated and ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are found in liver, intestinal mucosa, and peripheral blood and contribute to protection against infectious diseases. To determine whether MAIT cells were dysregulated in heavy drinkers and the effect of alcohol abstinence on MAIT cell recovery, we compared peripheral MAIT cells between AH patients and heavy drinkers without liver disease (HDC) at baseline and 6- and 12-month followup. At baseline, AH patients had severely reduced frequency of MAIT cells than HDC and healthy donor controls (HC), whereas MAIT cell frequency was not significantly different between HDC and HC. In addition, MAIT cells in AH patients expressed higher levels of the activation markers (CD69, CD38, and HLA-DR) as well as the immune checkpoint inhibitor PD-1. Multiplex immunoassays showed that plasma levels of several cytokines related to MAIT cell activation were elevated in AH patients (IFN-s, IL-7, IL-15, IL-17, IL-18, and IL-23, and TNF-a). In AH patients, the frequency MAIT cells and CD38-expressing MAIT cells correlated with levels of several cytokines and AST. At followup, AH patients had increased MAIT cell frequency and decreased MAIT cell activation with cessation of alcohol. However, abstinent AH patients still had higher levels of CD38-expressing MAIT cells than HDC at 6-month followup. Conclusion Blood MAIT cells were severely reduced and were dysregulated in AH patients and alcohol abstinence partially reversed abnormalities in MAIT cell frequency and phenotype.