Avrum Spira's research while affiliated with Beverly Hospital, Boston MA and other places

Publications (447)

Article
Lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths in lifetime smokers. Relative to recent advances in immunotherapy of advanced-stage LUAD, there are very limited strategies for early immune-based treatment or interception of the malignancy in its primitive stages. This is largely due to a poor understanding of the roles and...
Article
With an increasing number of positive lung cancer screening trials and the growing utilization of low dose CT screening, the detection of indeterminate pulmonary nodules is an important clinical problem. A biomarker that will be able to differentiate between benign andmalignant nodules would help to accelerate diagnosis and reduce unnecessary and i...
Article
Lung adenocarcinomas (LUADs) constitute the most frequently diagnosed lung cancer subtype and are typified by poor clinical outcome and inferior response to therapy. Strategies to treat LUAD at its earliest stages heavily rely on improved understanding of its pathogenesis. Accumulating evidence shows that progression of cancers, including LUADs, is...
Article
Background: Bronchial pre-malignant lesions (PMLs) are the putative precursors for bronchial squamous cell carcinoma. PMLs represent a spectrum of histologies, from low-grade lesions (hyperplasia, metaplasia) to high-grade lesions (dysplasia, carcinoma in situ). The majority of these lesions will regress or remain stable without clinical interventi...
Article
Lung adenocarcinomas (LUADs) represent the most common lung cancer subtype and frequently harbor somatic mutations in the KRAS oncogene (KM-LUADs). While enhanced screening has improved early diagnosis of KM-LUAD, patient prognosis remains moderate to poor. Decoding the earliest events driving KM-LUADs can inform of ideal targets for its intercepti...
Preprint
Understanding cellular processes underlying early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies ¹ . Here, we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal alveolar and airway lineages as well as cancer cell populati...
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The imminent release of tissue atlases combining multichannel microscopy with single-cell sequencing and other omics data from normal and diseased specimens creates an urgent need for data and metadata standards to guide data deposition, curation and release. We describe a Minimum Information about Highly Multiplexed Tissue Imaging (MITI) standard...
Article
Introduction Although three randomized control trials have proven mortality benefit of CT lung cancer screening (CTLS), <5% of eligible US smokers are screened. Some attribute this to fear of harm conveyed at shared decision visits, including the harm of overdiagnosis/overtreatment of indolent BAC-like adenocarcinoma. Methods Since the frequency o...
Article
Rationale Peripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD. Methods Ten explanted lung specimens donated by patients with very-severe C...
Preprint
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Background: SARS-CoV-2 infection and disease severity are influenced by viral entry (VE) gene expression patterns in airway epithelium. The similarities and differences of VE gene expression (ACE2, TMPRSS2, and CTSL) across nasal and bronchial compartments has not been fully characterized using matched samples from large cohorts. Results: Gene exp...
Article
Full-text available
Objective The immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical,...
Article
Rationale- Patients with indeterminate pulmonary nodules (IPNs) at risk of cancer undergo high rates of invasive, costly, and morbid procedures. Objectives: To train and externally validate a risk prediction model which combined clinical, blood, and imaging biomarkers to improve the noninvasive management of IPNs. Methods - In this prospectively co...
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Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung...
Article
8551 Background: The goal of lung nodule management is to make an early diagnosis in patients with lung cancer while avoiding unnecessary, costly and potentially harmful procedures in patients with benign lesions. Increased implementation of low dose CT screening will lead to increased numbers of both benign and malignant nodules that will require...
Article
Full-text available
Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from 5 early-stage LUADs and 14 multi-region normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomi...
Article
Background COPD is characterised by progressive lung function decline. Leveraging prior work demonstrating bronchial airway COPD-associated gene expression alterations, we sought to determine if there are alterations associated with differences in the rate of FEV 1 decline. Methods We examined gene expression among ever smokers with and without CO...
Article
Molecular events that drive the development of precancerous lesions in the bronchial epithelium, which are precursors of lung squamous cell carcinoma (LUSC), are poorly understood. We demonstrate that disruption of epithelial cellular polarity, via the conditional deletion of the apical determinant Crumbs3 (Crb3), initiates and sustains precancerou...
Preprint
Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infects host cells with help from the Viral Entry (VE) proteins ACE2, TMPRSS2, and CTSL. Proposed risk factors for viral infection, as well as the rate of disease progression, include age, sex, chronic obstructive pulmonary disease,...
Article
Full-text available
Background The transition from normal lung anatomy to minimal and established fibrosis is an important feature of the pathology of idiopathic pulmonary fibrosis (IPF). The purpose of this report is to examine the molecular and cellular mechanisms associated with this transition. Methods Pre-operative thoracic Multidetector Computed Tomography (MDC...
Article
Full-text available
The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Severely symptomatic COVID-19 is associated with lung inflammation, pneumonia, and respiratory failure, thereby raising concerns of elevated risk of COVID-19-associated mortality among lung cancer patients. Angiotensin-converting enzyme 2 (ACE2) is the major receptor...
Preprint
Objective: The immune response to invasive carcinoma has been the focus of published work, but little is known about the adaptive immune response to bronchial premalignant lesions (PMLs), precursors of lung squamous cell carcinoma. This study was designed to characterize the T cell receptor (TCR) repertoire in PMLs and its association with clinical...
Preprint
Determining the clinical significance of CT scan-detected subsolid pulmonary nodules requires an understanding of the molecular and cellular features that may foreshadow disease progression. We studied the alterations at the transcriptome level in both immune and non-immune cells, utilizing single-cell RNA sequencing, to compare the microenvironmen...
Article
p>Lung cancer is the leading worldwide cause of cancer mortality, as it is often detected at an advanced stage. Since 2011, low-dose CT scan-based screening has promised a 20% reduction in lung cancer mortality. However, effectiveness of screening has been limited by eligibility only for a high-risk population of heavy smokers and a large number of...
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Full-text available
Hyperinflation contributes to dyspnea intensity in COPD. Little is known about the molecular mechanisms underlying hyperinflation and how inhaled corticosteroids (ICS) affect this important aspect of COPD pathophysiology. To investigate the effect of ICS/long-acting β2-agonist (LABA) treatment on both lung function measures of hyperinflation, and t...
Article
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Background: Chronic tobacco smoke exposure results in a broad range of lung pathologies including emphysema, airway disease and parenchymal fibrosis as well as a multitude of extra-pulmonary comorbidities. Prior work using computed tomography imaging has identified several clinically relevant subgroups of smoking related lung disease, but these in...
Preprint
Full-text available
Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and fourteen multi-region normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and tran...
Conference Paper
Lung adenocarcinoma (LUAD) is the most frequently diagnosed histological subtype of lung cancer and accounts for most smoking-related cancer deaths, warranting strategies for early intervention. Earlier work revealed genome-wide aberrations in LUADs and the adjacent premalignant field, known as “field carcinogenesis”, that are pertinent to LUAD pat...
Conference Paper
Rationale: We have previously identified lung cancer-associated gene expression alterations in normal bronchial airway epithelial cells of ever smokers with and without lung cancer. It is unclear, however, whether or not gene expression in the bronchial airway also reflects non-small cell lung cancer (NSCLC) subtypes. In this study, we sought to id...
Conference Paper
Introduction: Bronchial premalignant lesions (PMLs), precursors to lung squamous cell carcinoma, represent a relevant system for studying early tumor development. Some PMLs will progress through increasing grades of dysplasia to become squamous cell carcinoma, while others will regress back to normal airway without intervention. Previous work has i...
Article
BACKGROUND The Percepta genomic classifier has been clinically validated as a complement to bronchoscopy for lung nodule evaluation. This study examines the impact on clinical management decisions of the Percepta result in patients with low/ intermediate risk lung nodules. METHODS We instituted a prospective “real world” registry across 35 U.S. ce...
Article
Rationale: Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator lipocalin-2 (Lcn2) was increased in normal airways from mice with knockout of the airway lineage gene Gprc5a (Gprc5a-/-), and that are prone to developing inflammation and LUAD. Yet, the r...
Article
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Background Sleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment. Methods In two discovery cohorts, Framingham Offspring Study...
Preprint
Full-text available
The novel coronavirus SARS-CoV-2 was identified as the causative agent of the ongoing pandemic COVID 19. COVID-19-associated deaths are mainly attributed to severe pneumonia and respiratory failure. Recent work demonstrated that SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) in the lung. To better understand ACE2 abundance and expressio...
Article
Full-text available
Crucial transitions in cancer—including tumor initiation, local expansion, metastasis, and therapeutic resistance—involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecede...
Article
Crucial transitions in cancer—including tumor initiation, local expansion, metastasis, and therapeutic resistance—involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecede...
Article
The human bronchial epithelium is composed of multiple distinct cell types that cooperate to defend against environmental insults. While studies have shown that smoking alters bronchial epithelial function and morphology, its precise effects on specific cell types and overall tissue composition are unclear. We used single-cell RNA sequencing to pro...
Article
A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. We conducted a randomized, double-blinded study in current heavy smokers comparing modulating effects of intermittent versus continuous low dose ASA on nasal epithelium gene expression and arachidonic acid (ARA) metabolism. Fifty-fou...
Preprint
Sleep Disordered Breathing (SDB) is associated with a wide range of physiological changes due, in part, to the influence of hypoxemia during sleep. We studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum...
Conference Paper
RATIONALE: The National Lung Screening and Nelson Trials demonstrated a 20% and 26% (for men) reduction, respectively in lung cancer mortality for patients screened using low-dose CT. However, lung cancer screening has the potential for over-diagnosis of indolent tumors. Therefore, we sought to identify molecular features that could distinguish ind...
Conference Paper
There is a critical need to identify strategies for lung cancer prevention, as it remains the leading cause of cancer-related death in the US. A critical barrier to developing new approaches to prevent lung cancer is the lack of understanding of key molecular and cellular changes that lead to cancer initiation and progression. Our group has initiat...
Conference Paper
RATIONALE: The National Lung Screening and Nelson Trials demonstrated a 20% and 26% (for men) reduction, respectively in lung cancer mortality for patients screened using low-dose CT. However, lung cancer screening has the potential for over-diagnosis of indolent tumors. Therefore, we sought to identify molecular features that could distinguish ind...
Conference Paper
Introduction The immune system is critical to surveying and eradicating abnormal cells, but tumor cells develop ways to escape immunosurveillance and induce an immunosuppressive state. We previously developed and validated gene expression (GE) signatures measured in the normal airway-epithelial brushings in patients undergoing bronchoscopy for susp...
Article
Background Although e-cigarette (ECIG) use has increased in the United States, their potential health effects remain uncertain. Understanding the effects of tobacco cigarette (TCIG) smoke on bronchial airway epithelial gene expression have previously provided insights into tobacco-related disease pathogenesis. Identifying the impact of ECIGs on air...
Article
Epithelial cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may escape immune surveillance and progress to invasive cancer, however the mutational landscape that may predict progression has not been determined. Knowledge of premalignant lesion compos...
Article
Full-text available
The physiologic response to tobacco smoke can be measured by gene-expression profiling of the airway epithelium. Temporal resolution of kinetics of gene-expression alterations upon smoking-cessation might delineate distinct biological processes that are activated during recovery from tobacco smoke exposure. Using whole genome gene-expression profil...
Article
Full-text available
Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling...