Publications by authors named "M M Bertagnolli"

211 Publications

Genome-wide association studies of survival in 1,520 cancer patients treated with bevacizumab-containing regimens.

Int J Cancer 2021 Sep 16. Epub 2021 Sep 16.

UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta-analysis of genome-wide association studies (GWAS) was conducted in 1,520 patients from phase III trials (CALGB 80303, 40503, 80405, and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and SNPs associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause-specific Cox model was used to test the SNP-OS association in both arms combined (prognostic), and the effect of SNPs-bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta-analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (p=1.02x10 , HR=1.57, 95% CI:1.33-1.86), as well as in TCGA (p=0.0219, HR=1.58, 95% CI:1.07-2.35). In the GWAS meta-analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (p=1.40x10 , HR=1.51, 95% CI:1.25-1.82) as well as in TCGA (p=1.39x10 , HR=3.09, 95% CI:1.73-5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the non-bevacizumab arm (p=1.43x10 ). The largest GWAS meta-analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33810DOI Listing
September 2021

Treatment of Older Adults with Cancer - Addressing Gaps in Evidence.

N Engl J Med 2021 Sep 11;385(12):1062-1065. Epub 2021 Sep 11.

From Brigham and Women's Hospital, Boston (M.M.B.), and the Food and Drug Administration, Silver Spring, MD (H.S.).

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http://dx.doi.org/10.1056/NEJMp2106089DOI Listing
September 2021

Association of Preterm Birth With Myocardial Fibrosis and Diastolic Dysfunction in Young Adulthood.

J Am Coll Cardiol 2021 Aug;78(7):683-692

Oxford Cardiovascular Clinical Research Facility, University of Oxford, Oxford, United Kingdom; Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Background: Preterm birth affects about 10% of live births worldwide and is associated with cardiac alterations. Animal models of preterm birth suggest that left ventricular functional impairment may be due to an up-regulation of myocardial fibrosis.

Objectives: The aim of this study was to determine whether diffuse left ventricular fibrosis is evident in young adults born preterm.

Methods: One hundred one normotensive young adults born preterm (n = 47, mean gestational age 32.8 ± 3.2 weeks) and term (n = 54) were included from YACHT (Young Adult Cardiovascular Health sTudy). Left ventricular structure and function were quantified by cardiovascular magnetic resonance and echocardiography. Intravenous administration of a gadolinium-based contrast agent during cardiovascular magnetic resonance was used to quantify focal myocardial fibrosis on the basis of late gadolinium enhancement and, in combination with T1 mapping, to quantify diffuse myocardial fibrosis on the basis of assessment of myocardial extracellular volume fraction.

Results: Adults born preterm had smaller left ventricular end-diastolic and stroke volumes, with greater left ventricular mass and wall thickness (P < 0.001). In addition, longitudinal peak systolic strain and diastolic strain rate by both cardiovascular magnetic resonance and echocardiography, and E/A ratio measured by echocardiography, were lower in preterm-born compared to term-born adults (P < 0.05). Extracellular volume fraction was greater in preterm-born compared with term-born adults (27.81% ± 1.69% vs 25.48% ± 1.41%; P < 0.001) and was a significant mediator in the relationship between gestational age and both longitudinal peak diastolic strain rate and E/A ratio.

Conclusions: Preterm-born young adults have greater extracellular volume fraction in the left ventricle that is inversely related with gestational age and may underlie their diastolic functional impairments.
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http://dx.doi.org/10.1016/j.jacc.2021.05.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363934PMC
August 2021

Rodent models of hypertension.

Br J Pharmacol 2021 Aug 7. Epub 2021 Aug 7.

Hypertension Research Laboratory, School of Biological Sciences, Faculty of Science, Monash University, Melbourne, Australia.

Elevated blood pressure (BP), or hypertension, is the main risk factor for cardiovascular disease. As a multifactorial and systemic disease that involves multiple organs and systems, hypertension remains a challenging disease to study. Models of hypertension are invaluable to support the discovery of the specific genetic, cellular and molecular mechanisms underlying essential hypertension, as well as to test new possible treatments to lower BP. Rodent models have proven to be an invaluable tool for advancing the field. In this review, we discuss the strengths and weaknesses of rodent models of hypertension through a systems approach. We highlight the ways how target organs and systems including the kidneys, vasculature, the sympathetic nervous system (SNS), immune system and the gut microbiota influence BP in each rodent model. We also discuss often overlooked hypertensive conditions such as pulmonary hypertension and hypertensive-pregnancy disorders, providing an important resource for researchers.
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http://dx.doi.org/10.1111/bph.15650DOI Listing
August 2021

Role of ACE2 in pregnancy and potential implications for COVID-19 susceptibility.

Clin Sci (Lond) 2021 08;135(15):1805-1824

Research Center of the Hospital Sacré-Coeur, CIUSSS Nord-de-l'Île-de-Montréal, Montréal, Canada.

In times of coronavirus disease 2019 (COVID-19), the impact of severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 infection on pregnancy is still unclear. The presence of angiotensin-converting enzyme (ACE) 2 (ACE2), the main receptor for SARS-CoV-2, in human placentas indicates that this organ can be vulnerable for viral infection during pregnancy. However, for this to happen, additional molecular processes are critical to allow viral entry in cells, its replication and disease manifestation, particularly in the placenta and/or feto-maternal circulation. Beyond the risk of vertical transmission, COVID-19 is also proposed to deplete ACE2 protein and its biological actions in the placenta. It is postulated that such effects may impair essential processes during placentation and maternal hemodynamic adaptations in COVID-19 pregnancy, features also observed in several disorders of pregnancy. This review gathers information indicating risks and protective features related to ACE2 changes in COVID-19 pregnancies. First, we describe the mechanisms of SARS-CoV-2 infection having ACE2 as a main entry door and current evidence of viral infection in the placenta. Further, we discuss the central role of ACE2 in physiological systems such as the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS), both active during placentation and hemodynamic adaptations of pregnancy. Significant knowledge gaps are also identified and should be urgently filled to better understand the fate of ACE2 in COVID-19 pregnancies and the potential associated risks. Emerging knowledge will be able to improve the early stratification of high-risk pregnancies with COVID-19 exposure as well as to guide better management and follow-up of these mothers and their children.
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http://dx.doi.org/10.1042/CS20210284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329853PMC
August 2021
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