Dr. Guo is a radiologist and nuclear medicine physician with subspecialty training in thoracic imaging and PET-CT. Dr. Guo's clinical and research focus are on diseases of the lungs. Dr. Guo specializes in cancer imaging as part of his work in nuclear medicine and PET, and helps to care for patients in the Thoracic Cancer Program, Lung Cancer Screening, lung graft-versus-host disease Clinic, Infectious Diseases, Interstitial Lung Diseases Clinic, Sarcoidosis, Intensive Care, and in the Nuclear Medicine Clinic.
His research background is in molecular biology, genetics, and cancer pathogenesis, and combines the tools of molecular and anatomic imaging to improve patients' outcomes. His current research projects include: imaging markers of lung and heart diseases, aided by artificial intelligence, early cancer detection, low radiation dose CT, PET-CT of the lungs, quantitative CT, and in 3D printing of thoracic structures from clinical scans.
- Chest imaging
- Nuclear Medicine
- Oncologic imaging
- Intersitital lung diseases
- Infectious diseases
- Lung graft versus host disease
- 3-D printing
- quantitative CT
- Lung cancer screening
- Pulmonary Hypertension
Clinical Professor, Radiology
Member, Cardiovascular Institute
Honors & Awards
Clinician of the Year, Stanford Department of Radiology (2019)
Faculty Educator of the year (early career), Stanford Radiology Residency (2014)
Alpha Omega Alpha, (AOA)
Sigma Xi, MIT
ARCS Scholar, University of Washington
MSTP, University of Washington
Boards, Advisory Committees, Professional Organizations
Member, RSNA (2007 - Present)
Member, ACR (2007 - Present)
Member, SNMMI (2010 - Present)
Member, Society of Thoracic Imaging (2012 - Present)
Internship: Scripps Mercy Hospital San Diego (2007) CA
Fellowship: Stanford University Radiology Fellowships (2012) CA
Residency: Stanford University Radiology Residency (2011) CA
Medical Education: University of Washington School of Medicine (2006) WA
Board Certification: American Board of Nuclear Medicine, Nuclear Medicine (2012)
Fellowship in Chest Radiology, Stanford Hospital and Clinics, CA USA (2012)
Board Certification: American Board of Radiology, Diagnostic Radiology (2011)
PhD, University of Washington, Pathology and Molecular Biology (2004)
Bachelor of Science, Massachusetts Institute of Technology, Molecular Biology (1997)
Haiwei Guo, Husham Sharifi, Serena, Yeung. "United States Patent 17/398,904 Systems and Methods for Identification of Pulmonary Conditions", Stanford University, Feb 10, 2022
Current Research and Scholarly Interests
AI assisted radiology interpretation
PET imaging of lung diseases
CT imaging biomarkers heart and lung diseases
Quality assurance of ultralow dose CT scans
Post radiation treatment changes of lung tumors
Detection of Integrin avb6 in IPF, PSC, and COVID19 Using PET/CT
Detection of Integrin avb6 in Idiopathic Pulmonary Fibrosis, Primary Sclerosing Cholangitis, and Coronavirus Disease 2019 with [18F]FP-R01-MG-F2 with PET/CT
PET-CT in lung fibrosis (September 17, 2012)
Deep learning assisted quantitative chest CT, stanford university
300 pasteur drive, stanford ca
- Serena Yeung, Stanford University
3D printing of lung (January 2014)
- Jia Wang, Medical Physicist, Stanford University
Post bone marrow transplant lung diseases, stanford university
Quality Assurance in ultralow dose CT, Stanford (January 2014)
Post radiation change of lung and lung tumors, Stanford
Immediate and Follow-up Imaging Findings after Cone-Beam CT-guided Transbronchial Lung Cryobiopsy.
Radiology. Cardiothoracic imaging
2023; 5 (2): e220149
To evaluate findings after transbronchial lung cryobiopsy (TBLC) using intraprocedural cone-beam CT (CBCT) and follow-up chest CT examinations.A single-center, prospective cohort study was performed with 14 participants (mean age, 65 years ± 13 [SD]; eight male participants) undergoing CBCT-guided TBLC between August 2020 and February 2021 who underwent follow-up chest CT imaging. Intraprocedural CBCT and follow-up chest CT images were interpreted for changes compared with baseline CT images. Statistical analyses were performed using independent samples t test and analysis of variance.A total of 62 biopsies were performed, with 48 in the field of view of CBCT immediately after biopsy. All 48 biopsy sites had evidence of postprocedural hemorrhage, and 17 (35%) had pneumatoceles at the biopsy site. Follow-up CT images showed resolution of these findings. Solid nodules developed at 18 of the 62 (29%) biopsy sites.Postbiopsy hemorrhage and pneumatoceles on intraprocedural CBCT images (which were clinically occult and resolved spontaneously) and new solid nodules on follow-up chest CT images were commonly observed after TBLC. These findings may help alleviate unnecessary follow-up imaging and tissue sampling.Keywords: Biopsy/Needle Aspiration, CT, Lungs, Lung Biopsy, Interventional Bronchoscopy© RSNA, 2023.
View details for DOI 10.1148/ryct.220149
View details for PubMedID 37124647
View details for PubMedCentralID PMC10141444
Pulmonary Vein Sign on Computed Tomography Pulmonary Angiography in Proximal and Distal Chronic Thromboembolic Pulmonary Hypertension With Hemodynamic Correlation.
Journal of thoracic imaging
BACKGROUND: Pulmonary vein sign (PVS) indicates abnormal pulmonary venous flow on computed tomography pulmonary angiography (CTPA) is a frequent finding in proximal chronic thromboembolic pulmonary hypertension (CTEPH). PVS's occurrence in distal CTEPH and correlation to disease severity is unknown. Using right heart catheterization data, we evaluated the relationship between PVS and CTEPH disease distribution and severity.MATERIALS AND METHOD: A total of 93 consecutive CTEPH cases with both CTPA and right heart catheterization were identified in this retrospective multi-institutional study. After excluding 17 cases with suboptimal CTPA, there were 52 proximal and 24 distal CTEPH cases. Blood flow in the major pulmonary veins was graded qualitatively. Subgroup analysis of PVS was performed in 38 proximal CTEPH cases before and after pulmonary endarterectomy.RESULTS: PVS was more frequent in proximal (79%) than distal CTEPH (29%) (P<0.001). No significant difference was noted in invasive mean pulmonary artery pressure (46±11 and 41±12mmHg) or pulmonary vascular resistance (9.4±4.5 and 8.4±4.8 WU) between the 2 groups. In the subgroup analysis, PVS was present in 29/38 patients (76%) before surgery. Postoperatively, 33/38 cases (87%, P<0.001) had normal venous flow (mean pulmonary artery pressure 46±11 and 25; pulmonary vascular resistance 9.2±4.3 and 2.6 WU preop and postop, respectively).CONCLUSION: PVS is a common feature in proximal but infrequent findings in distal CTEPH. PVS does not correlate with hemodynamic severity. PVS resolution was seen in the majority of patients following successful endarterectomy.
View details for DOI 10.1097/RTI.0000000000000706
View details for PubMedID 36919975
Opportunistic Screening for Atrial Fibrillation on Routine Chest Computed Tomography.
Journal of thoracic imaging
PURPOSE: Quantitative biomarkers from chest computed tomography (CT) can facilitate the incidental detection of important diseases. Atrial fibrillation (AFib) substantially increases the risk for comorbid conditions including stroke. This study investigated the relationship between AFib status and left atrial enlargement (LAE) on CT.MATERIALS AND METHODS: A total of 500 consecutive patients who had undergone nongated chest CTs were included, and left atrium maximal axial cross-sectional area (LA-MACSA), left atrium anterior-posterior dimension (LA-AP), and vertebral body cross-sectional area (VB-Area) were measured. Height, weight, age, sex, and diagnosis of AFib were obtained from the medical record. Parametric statistical analyses and receiver operating characteristic curves were performed. Machine learning classifiers were run with clinical risk factors and LA measurements to predict patients with AFib.RESULTS: Eighty-five patients with a diagnosis of AFib were identified. Mean LA-MACSA and LA-AP were significantly larger in patients with AFib than in patients without AFib (28.63 vs. 20.53cm2, P<0.000001; 4.34 vs. 3.5cm, P<0.000001, respectively), both with area under the curves (AUCs) of 0.73. Multivariable logistic regression analysis including age, sex, and VB-Area with LA-MACSA improved the AUC for predicting AFib (AUC=0.77). An LA-MACSA threshold of 30cm2 demonstrated high specificity for AFib diagnosis at 92% and sensitivity of 48%, and LA-AP threshold at 4.5cm demonstrated 90% specificity and 42% sensitivity. A Bayesian machine learning model using age, sex, height, body surface area, and LA-MACSA predicted AFib with an AUC of 0.743.CONCLUSIONS: LA-MACSA or LA-AP can be rapidly measured from routine chest CT, and when >30 cm2 and >4.5cm, respectively, are specific indicators to predict patients at increased risk for AFib.
View details for DOI 10.1097/RTI.0000000000000702
View details for PubMedID 36917506
- alphavbeta6 Integrin Positron Emission Tomography of Lung Fibrosis in Idiopathic Pulmonary Fibrosis and Long-COVID. American journal of respiratory and critical care medicine 2023
64Cu-DOTATATE Uptake in a Pulmonary Hamartoma.
Clinical nuclear medicine
2023; 48 (1): 58-60
DOTATATE PET/CT is frequently used to evaluate indeterminant pulmonary nodules suspected to be pulmonary carcinoid. We report an unexpected case of pulmonary hamartoma demonstrating 64Cu-DOTATATE uptake in a 43-year-old woman with a slowly enlarging pulmonary nodule. Histopathological staining showed somatostatin receptor 2 expression on vascular endothelial cells and a proportion of cartilage and smooth muscle cells within the hamartoma.
View details for DOI 10.1097/RLU.0000000000004390
View details for PubMedID 36469060
Induction EGFR tyrosine kinase inhibitors prior to definitive chemoradiotherapy in unresectable stage III EGFR-mutated non-small cell lung cancer.
Cancer treatment and research communications
2022; 33: 100659
INTRODUCTION: Increasing evidence suggests that consolidation durvalumab confers limited benefits for patients with stage III EGFR-mutated NSCLC. Induction or maintenance EGFR tyrosine kinase inhibitors (TKIs) added to concurrent chemoradiotherapy (CRT) may optimize definitive treatment, but there are limited data supporting an induction TKI strategy.METHODS: We evaluated the efficacy and safety of induction EGFR TKIs administered before concurrent CRT in a retrospective series of patients with unresectable locally advanced EGFR-mutated NSCLC. Circulating tumor DNA (ctDNA) analysis was performed on a patient subset using CAPP-seq and correlated with outcomes.RESULTS: Of six patients, three received erlotinib and three osimertinib as induction therapy before CRT. Induction TKIs were administered for a median of 2.5 months. The objective response rate after induction TKI was 83%. One patient had a complete response to induction erlotinib and continued erlotinib for 4 years until local progression, which was treated with CRT. Two patients completed maintenance erlotinib after CRT, and another received consolidation durvalumab. After a median follow-up of 20.5 months, only one patient developed disease recurrence, with rising ctDNA coinciding with recurrence. ctDNA remained undetectable in patients without recurrence, or low-level in a patient receiving maintenance erlotinib. Adverse events were mild and expected, and none developed pneumonitis.CONCLUSION: Induction EGFR TKI before CRT may achieve high disease control rates with promising signs of durability in patients with locally advanced EGFR-mutated NSCLC. ctDNA analysis after CRT can correlate well with clinical outcomes. Prospective studies are needed to define the role of induction EGFR TKIs in this setting.
View details for DOI 10.1016/j.ctarc.2022.100659
View details for PubMedID 36427429
Applications of Three-Dimensional Printing in Surgical Oncology.
Surgical oncology clinics of North America
2022; 31 (4): 673-684
A variety of three-dimensional (3D) printing techniques and materials facilitate the creation of customized models that promise to improve surgical procedures and patient outcomes. Three-dimensional-printed models allow patients, trainees, and experienced surgeons to explore anatomy through direct visualization and tactile feedback. Although 3D-printed models serve a range of purposes including preoperative planning, education, skills refinement, patient-specific intraprocedural guides, and implants, much work remains to decrease the turnaround time and cost of printing models, collect long-term effectiveness data, and refine regulatory oversight of 3D printing in medicine.
View details for DOI 10.1016/j.soc.2022.06.005
View details for PubMedID 36243500
- Three-dimensional-printed model of surgically resectable angioinvasive pulmonary mucormycosis. JTCVS techniques 2022; 13: 244-246
- An Opportunity to Reduce Disparities in Lung Cancer Screening JAMA NETWORK OPEN 2021; 4 (10): e2129126
Radiopaque Recreations of Lung Pathologies From Clinical Computed Tomography Images Using Potassium Iodide Inkjet 3-dimensional Printing: Proof of Concept.
Journal of thoracic imaging
PURPOSE: The purpose of this study was to develop a 3-dimensional (3D) printing method to create computed tomography (CT) realistic phantoms of lung cancer nodules and lung parenchymal disease from clinical CT images.MATERIALS AND METHODS: Low-density paper was used as substrate material for inkjet printing with potassium iodide solution to reproduce phantoms that mimic the CT attenuation of lung parenchyma. The relationship between grayscale values and the corresponding CT numbers of prints was first established through the derivation of exponential fitted equation from scanning data. Next, chest CTs from patients with early-stage lung cancer and coronavirus disease 2019 (COVID-19) pneumonia were chosen for 3D printing. CT images of original lung nodule and the 3D-printed nodule phantom were compared based on pixel-to-pixel correlation and radiomic features.RESULTS: CT images of part-solid lung cancer and 3D-printed nodule phantom showed both high visual similarity and quantitative correlation. R2 values from linear regressions of pixel-to-pixel correlations between 5 sets of patient and 3D-printed image pairs were 0.92, 0.94, 0.86, 0.85, and 0.83, respectively. Comparison of radiomic measures between clinical CT and printed models demonstrated 6.1% median difference, with 25th and 75th percentile range at 2.4% and 15.2% absolute difference, respectively. The densities and parenchymal morphologies from COVID-19 pneumonia CT images were well reproduced in the 3D-printed phantom scans.CONCLUSION: The 3D printing method presented in this work facilitates creation of CT-realistic reproductions of lung cancer and parenchymal disease from individual patient scans with microbiological and pathology confirmation.
View details for DOI 10.1097/RTI.0000000000000607
View details for PubMedID 34334783
A calibration CT mini-lung-phantom created by 3-D printing and subtractive manufacturing.
Journal of applied clinical medical physics
We describe the creation and characterization of a calibration CT mini-lung-phantom incorporating simulated airways and ground-glass densities. Ten duplicate mini-lung-phantoms with Three-Dimensional (3-D) printed tubes simulating airways and gradated density polyurethane foam blocks were designed and built. Dimensional accuracy and CT numbers were measured using micro-CT and clinical CT scanners. Micro-CT images of airway tubes demonstrated an average dimensional variation of 0.038mm from nominal values. The five different densities of incorporated foam blocks, simulating ground-glass, showed mean CT numbers (±standard deviation) of -897.0±1.5, -844.1±1.5, -774.1±2.6, -695.3±1.6, and -351.0±3.7HU, respectively. Three-Dimensional printing and subtractive manufacturing enabled rapid, cost-effective production of ground-truth calibration mini-lung-phantoms with low inter-sample variation that can be scanned simultaneously with the patient undergoing lung quantitative CT.
View details for DOI 10.1002/acm2.13263
View details for PubMedID 33949078
Prevalence and significance of pulmonary disease on lung ultrasonography in outpatients with SARS-CoV-2 infection.
BMJ open respiratory research
2021; 8 (1)
The majority of patients with SARS-CoV-2 infection are diagnosed and managed as outpatients; however, little is known about the burden of pulmonary disease in this setting. Lung ultrasound (LUS) is a convenient tool for detection of COVID-19 pneumonia. Identifying SARS-CoV-2 infected outpatients with pulmonary disease may be important for early risk stratification.To investigate the prevalence, natural history and clinical significance of pulmonary disease in outpatients with SARS-CoV-2.SARS-CoV-2 PCR positive outpatients (CV(+)) were assessed with LUS to identify the presence of interstitial pneumonia. Studies were considered positive based on the presence of B-lines, pleural irregularity and consolidations. A subset of patients underwent longitudinal examinations. Correlations between LUS findings and patient symptoms, demographics, comorbidities and clinical outcomes over 8 weeks were evaluated.102 CV(+) patients underwent LUS with 42 (41%) demonstrating pulmonary involvement. Baseline LUS severity scores correlated with shortness of breath on multivariate analysis. Of the CV(+) patients followed longitudinally, a majority showed improvement or resolution in LUS findings after 1-2 weeks. Only one patient in the CV(+) cohort was briefly hospitalised, and no patient died or required mechanical ventilation.We found a high prevalence of LUS findings in outpatients with SARS-CoV-2 infection. Given the pervasiveness of pulmonary disease across a broad spectrum of LUS severity scores and lack of adverse outcomes, our findings suggest that LUS may not be a useful as a risk stratification tool in SARS-CoV-2 in the general outpatient population.
View details for DOI 10.1136/bmjresp-2021-000947
View details for PubMedID 34385149
View details for PubMedCentralID PMC8361701
- Tracheobronchial Tumors: Radiologic-Pathologic Correlation of Tumors and Mimics CURRENT PROBLEMS IN DIAGNOSTIC RADIOLOGY 2020; 49 (4): 275–84
Prognostic values of quantitative and morphological parameters of dbPET in patients with luminal-type breast cancer: A pilot study
SOC NUCLEAR MEDICINE INC. 2020
View details for Web of Science ID 000568290500482
- Radiology-pathology Correlation in Recovered COVID-19, Demonstrating Organizing Pneumonia. American journal of respiratory and critical care medicine 2020
Using Online Survey Software to Enhance Radiology Learning.
Online educational modules can augment radiology learning by creating opportunities to interact with images in more dynamic ways than with static presentation of images in lectures or journal articles. Building these modules on an online survey platform allows for quantitative assessment and learner feedback, without requiring programming knowledge or need for new website creation.Interactive online tutorials were built on a web-based survey platform (Qualtrics, Provo, Utah) accessible by computer or mobile device to teach radiology imaging findings of selected high-morbidity diagnoses. Topics included congenital-type internal hernias (module 1), acute appendicitis in the pregnant patient (module 2), and unintentionally retained surgical instruments (RSI; module 3). Modules consisted of pretest, educational module, and post-test components. For modules 1 and 2, graphics interchange formats were utilized to show CT and MRI image stacks for the diagnosis of congenital-type internal hernias and acute appendicitis in pregnant patients, respectively. For module 3, the "Heat Map" format was chosen to showcase intraoperative radiograph cases, which allowed participants to click on the potential RSI in the image. Pre- and post-test scores were evaluated. To determine statistical significance, an alpha level of 0.05 was utilized.Module 1 (Internal Hernia): Twenty-one radiology trainees completed the module. The mean pretest score was 3.66 (±1.13) points out of a total 6 possible points (61%), compared to 4.52 (±1.03) points on the post-test (75%). This was a statistically significant increase on the post-test of 0.87 points (95% CI [confidence interval] 0.36, 1.38), t(20) = 3.53, p= 0.002. Module 2 (MR Appendicitis): Seventeen radiology trainees completed the module. The mean pretest score was 3.18 (±1.42) points out of a total 6 possible points (53%), compared to 5.12 (±0.86) points on the post-test (85%). This was a statistically significant increase on the post-test of 1.94 points (95% CI 1.12, 2.76), t(16) = 5.00, p< 0.001. Module 3 (RSI): One hundred seven participants completed the module. The mean pretest score was 3.60 (±1.53) points out of a total 6 possible points (60%), compared to 4.54 (±1.36) points on the post-test (76%). This was a statistically significant increase on the post-test of 0.94 points (95% CI 0.67, 1.21), t(106) = 6.84, p< 0.001.An online survey platform can be used to build interactive education modules. Post-test scores significantly improved from pretest scores with these educational modules.
View details for DOI 10.1016/j.acra.2020.08.032
View details for PubMedID 32972839
Anatomical variability in the upper tracheobronchial tree: sex-based differences and implications for personalized inhalation therapies.
Journal of applied physiology (Bethesda, Md. : 1985)
The morphometry of the large conducting airways is presumed to have a strong effect on the regional deposition of inhaled aerosol particles. Nevertheless, sex-based differences have not been fully quantified and are still largely ignored in designing inhalation therapies. To this end, we retrospectively analyzed high-resolution computer-tomography scans for 185 individuals (90 women, 95 men) in the age range of 12-89 years to determine airway luminal areas, airway lengths and bifurcation angles. Only subjects free of chronic airway disease were considered. In men, luminal areas of the upper conducting airways were on the average ~ 30-50% larger when compared to those in women, with the largest differences found in the trachea (289.72±54.25mm2 vs. 193.50±42.37mm2 for men/women respectively). The ratio of the largest luminal area in men to the smallest luminal area in women (in any given segment) ranged between 4.5 and 8.6, the largest differences being found in the lobar bronchi. Sex-based differences were minor in the case of bifurcation angles (e.g. average main bifurcation angle: 93.04±9.58o vs. 91.03±9.81o for men/women respectively), but large inter-subject variability was found irrespective of sex (e.g. range of main bifurcation angle: 65.04-122.01o vs. 69.46-113.94o for men/women respectively). Bronchial segments were shorter by ~ 5-20% in women relative to men, the largest differences being located in the upper lobes. False discovery rate (FDR) analysis revealed statistically significant associations among morphometric measures of the right lung in women (but not in men) suggesting two phenotypes among women that we attribute to the smaller female thoracic volume.
View details for DOI 10.1152/japplphysiol.00144.2020
View details for PubMedID 33180641
Rituximab Versus Mycophenolate in the Treatment of Recalcitrant Connective Tissue Disease-Associated Interstitial Lung Disease.
ACR open rheumatology
Interstitial lung disease (ILD) is a major cause of morbidity and mortality in connective tissue diseases (CTDs). We aimed to assess the effect of rituximab ± mycophenolate mofetil (MMF) compared with MMF on pulmonary function and prednisone dosage in patients with CTD-related ILD (CTD-ILD).This retrospective study included 83 patients from Stanford and Centre Hospitalier de l'Universite de Montreal. Fifteen patients received rituximab ± MMF (rituximab group), and 68 patients received MMF only (control group).Median ILD duration at the start of treatment was longer in the rituximab group at 47 months (range: 4-170) versus 6.5 months (range: 0-164) in controls. Forced vital capacity (FVC) decreased by 3.0% (range: 11%-21%) after treatment in the rituximab group, whereas it increased by 2.0% (range: 14%-25%) in the control group (p = 0.025). Diffusing capacity of carbon monoxide (DLCO) decreased by 3.0% (range: 10%-12%) after treatment in the rituximab group, whereas it increased by 4.5% (range: 30%-36%) in the control group (p = 0.046). Mixed model analysis controlling for ILD duration, baseline DLCO, systemic sclerosis, pulmonary hypertension, and prednisone use showed no significant difference in FVC or DLCO between groups at 6 months or 1 year. The average daily prednisone dose score decreased after treatment in the rituximab group, whereas it remained unchanged in the control group (p = 0.017).Rituximab ± MMF did not significantly change pulmonary function compared with MMF alone, but it did result in a relative decrease in average daily prednisone dose in a population with recalcitrant CTD-ILD.
View details for DOI 10.1002/acr2.11210
View details for PubMedID 33274857
Evaluation of integrin alphavbeta6 cystine knot PET tracers to detect cancer and idiopathic pulmonary fibrosis.
2019; 10 (1): 4673
Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin alphavbeta6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer's safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin alphavbeta6.
View details for DOI 10.1038/s41467-019-11863-w
View details for PubMedID 31611594
Thoracic Radiologists' Versus Computer Scientists' Perspectives on the Future of Artificial Intelligence in Radiology.
Journal of thoracic imaging
BACKGROUND: There is intense interest and speculation in the application of artificial intelligence (AI) to radiology. The goals of this investigation were (1) to assess thoracic radiologists' perspectives on the role and expected impact of AI in radiology, and (2) to compare radiologists' perspectives with those of computer science (CS) experts working in the AI development.METHODS: An online survey was developed and distributed to chest radiologists and CS experts at leading academic centers and societies, comparing their expectations of AI's influence on radiologists' jobs, job satisfaction, salary, and role in society.RESULTS: A total of 95 radiologists and 45 computer scientists responded. Computer scientists reported having read more scientific journal articles on AI/machine learning in the past year than radiologists (mean [95% confidence interval]=17.1 [9.01-25.2] vs. 7.3 [4.7-9.9], P=0.0047). The impact of AI in radiology is expected to be high, with 57.8% and 73.3% of computer scientists and 31.6% and 61.1% of chest radiologists predicting radiologists' job will be dramatically different in 5 to 10 years, and 10 to 20 years, respectively. Although very few practitioners in both fields expect radiologists to become obsolete, with 0% expecting radiologist obsolescence in 5 years, in the long run, significantly more computer scientists (15.6%) predict radiologist obsolescence in 10 to 20 years, as compared with 3.2% of radiologists reporting the same (P=0.0128). Overall, both chest radiologists and computer scientists are optimistic about the future of AI in radiology, with large majorities expecting radiologists' job satisfaction to increase or stay the same (89.5% of radiologists vs. 86.7% of CS experts, P=0.7767), radiologists' salaries to increase or stay the same (83.2% of radiologists vs. 73.4% of CS experts, P=0.1827), and the role of radiologists in society to improve or stay the same (88.4% vs. 86.7%, P=0.7857).CONCLUSIONS: Thoracic radiologists and CS experts are generally positive on the impact of AI in radiology. However, a larger percentage, but still small minority, of computer scientists predict radiologist obsolescence in 10 to 20 years. As the future of AI in radiology unfolds, this study presents a historical timestamp of which group of experts' perceptions were closer to eventual reality.
View details for DOI 10.1097/RTI.0000000000000453
View details for PubMedID 31609778
Single-Lumen Endotracheal Tube and Bronchial Blocker for Airway Management During Tracheobronchoplasty for Tracheobronchomalacia: A Case Report.
We present a case of a 69-year-old man who underwent tracheobronchoplasty for tracheobronchomalacia using a single-lumen endotracheal tube and a Y-shaped bronchial blocker for airway management. Tracheobronchoplasty is performed by sewing mesh to plicate the posterior, membranous wall of the distal trachea and main bronchi through a right posterolateral thoracotomy. The goals of airway management include continuous left-lung ventilation and lung protection from aspiration. Ideally, only conventional airway management tools are used. This case demonstrates that a single-lumen endotracheal tube with a bronchial blocker can be a straightforward strategy for airway management during tracheobronchoplasty.
View details for DOI 10.1213/XAA.0000000000001076
View details for PubMedID 31385817
A Young Woman With a Rapidly GrowingThoracic Tumor.
2019; 155 (5): e145–e148
CASE PRESENTATION: A 38-year-old woman presented with 2months of dry cough, progressiveshortness of breath, central chest pain, nausea, vomiting, and dizziness. She was previously healthy and was not taking any medications. She denied fever, night sweats, or weight loss. She had a two pack-year smoking history and had quit smoking at 27 years of age. She denied drug use and had no recent travel history. Family history was pertinent for ovarian cancer, breast cancer, and colon cancer.
View details for DOI 10.1016/j.chest.2018.12.014
View details for PubMedID 31060712
- Serial Cardiac FDG-PET for the Diagnosis and Therapeutic Guidance of Patients With Cardiac Sarcoidosis JOURNAL OF CARDIAC FAILURE 2019; 25 (4): 307–11
Left Atrial Volume as a Biomarker of Atrial Fibrillation at Routine Chest CT: Deep Learning Approach
Radiology: Cardiothoracic Imaging
2019; 1 (5): 1-7
View details for DOI 10.1148/ryct.2019190057
The Intralobular Gradient as Seen in Re-Expansion Pulmonary Edema
Radiology: Cardiothoracic Imaging
2019; 1 (5): 1
View details for DOI 10.1148/ryct.2019190084
3D Printing and the Cystic Fibrosis Lung.
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
View details for PubMedID 30361143
- From Ocean Deep to Mountain High: Similar Computed Tomography Findings in Immersion and High-Altitude Pulmonary Edema. American journal of respiratory and critical care medicine 2018; 198 (8): 1088-1089
Synchronous primary lung adenocarcinomas harboring distinct MET Exon 14 splice site mutations.
Lung cancer (Amsterdam, Netherlands)
2018; 122: 187–91
When a patient is found to have multiple lung tumors, distinguishing whether they represent metastatic nodules or separate primary cancers is crucial for staging and therapy. We report the case of a 79-year-old patient with two surgically resected synchronous left upper lobe adenocarcinomas initially pathologically staged as T3 (IIB), indicating adjuvant chemotherapy should be recommended. However, the tumors appeared radiographically distinct, so next-generation sequencing was performed on each nodule. Each tumor harbored a different mesenchymal-to-epithelial transition (MET) exon 14 skipping mutation, an emerging targetable mutation, suggestive of distinct clonality. While the in frame protein deletion was the same in each tumor, the nucleotide base substitutions were different. Thus, the patient was down-staged to having two separate IA tumors, spared of adjuvant chemotherapy, and routine surveillance was recommended. This case highlights the utility of using molecular analysis in diagnosing and treating multifocal lung tumors, and the process of convergent molecular evolution toward a common oncogenic driver mutation. This is the first case of multiple synchronous lung tumors each harboring a distinct MET exon 14 splice site mutation.
View details for PubMedID 30032829
- SERIAL CARDIAC FDG-PET IN THE DIAGNOSIS AND THERAPEUTIC GUIDANCE OF PATIENTS WITH CARDIAC SARCOIDOSIS: A STANFORD EXPERIENCE ELSEVIER SCIENCE INC. 2018: 1690
Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer.
Clinical lung cancer
Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker.We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS).On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014).The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.
View details for PubMedID 29759331
Improving Quality of Dynamic Airway Computed Tomography Using an Expiratory Airflow Indicator Device.
Journal of thoracic imaging
Dynamic computed tomography (CT) of the airways is increasingly used to evaluate patients with suspected expiratory central airway collapse, but current protocols are susceptible to inadequate exhalation caused by variable patient compliance with breathing instructions during the expiratory phase. We developed and tested a low-cost single-use expiratory airflow indicator device that was designed to improve study quality by providing a visual indicator to both patient and operator when adequate expiratory flow was attained.A total of 56 patients undergoing dynamic airway CT were evaluated, 35 of whom were scanned before introduction of the indicator device (control group), with the rest comprising the intervention group. Lung volumes and tracheal cross-sectional areas on inspiratory/expiratory phases were computed using automated lung segmentation and quantitative software analysis. Inadequate exhalation was defined as absolute volume change of <500 mL during the expiratory phase.Fewer patients in the intervention group demonstrated inadequate exhalation. The average change in volume was higher in the intervention group (P=0.004), whereas the average minimum tracheal cross-sectional area was lower (P=0.01).The described expiratory airflow indicator device can be used to ensure adequate exhalation during the expiratory phase of dynamic airway CT. A higher frequency of adequate exhalation may improve reliability and sensitivity of dynamic airway CT for diagnosis of expiratory central airway collapse.
View details for PubMedID 29470258
Initial Experience With Simultaneous 18F-FDG PET/MRI in the Evaluation of Cardiac Sarcoidosis and Myocarditis.
Clinical nuclear medicine
2017; 42 (7): e328-e334
The purpose of this study was to compare combined PET/MRI with PET/CT and cardiac MRI in the evaluation of cardiac sarcoidosis and myocarditis.Ten patients (4 men and 6 women; 56.1 ± 9.6 years old) were prospectively enrolled for evaluation of suspected cardiac sarcoidosis or myocarditis. Written informed consent was obtained. Following administration of 9.9 ± 0.9 mCi F-FDG, patients underwent standard cardiac PET/CT followed by combined PET/MRI using a simultaneous 3-T scanner. Cardiac MRI sequences included ECG-triggered cine SSFP, T2-weighted, and late gadolinium-enhanced imaging. Myocardial involvement was assessed with separate analysis of combined PET/MRI, PET/CT, and cardiac MRI data using dedicated postprocessing software. Estimates of radiation dose were derived from the applied doses of F-FDG and CT protocol parameters.Imaging was acquired with a delay from F-FDG injection of 90.2 ± 27.4 minutes for PET/CT and 207.7 ± 40.3 minutes for PET/MRI. Total scan time for PET/MRI was significantly longer than for PET/CT (81.4 ± 14.8 vs 12.0 minutes, P < 0.001). Total effective radiation dose was significantly lower for PET/MRI compared with PET/CT (6.9 ± 0.6 vs 8.2 ± 1.1 mSv, P = 0.007). There was no significant difference in the number of positive cases identified between combined PET/MRI (n = 10 [100%]), PET/CT (n = 6 [60%]), and cardiac MRI (n = 8 [80%]), P = 0.091.Simultaneous cardiac PET/MRI is feasible in the evaluation of cardiac sarcoidosis and myocarditis achieving diagnostic image quality.
View details for DOI 10.1097/RLU.0000000000001669
View details for PubMedID 28418949
Identification of Pulmonary Hypertension Caused by Left Heart Disease (World Health Organization Group 2) Based on Cardiac Chamber Volumes Derived from Chest CT.
Evaluations of patients with pulmonary hypertension (PH) commonly include chest computed tomography (CT). We hypothesized that cardiac chamber volumes calculated from the same CT scans can yield additional information to distinguish left heart disease-related PH (WHO Group 2) from other PH subtypes.Patients with right heart catheterization (RHC)-confirmed PH and contrast-enhanced chest CT studies were enrolled in this retrospective multicenter study. Cardiac chamber volumes were calculated using automated segmentation software and compared between Group 2 and non-Group 2 PH patients.This study included 114 PH patients, of whom 27 (24%) were classified as Group 2 based on their pulmonary capillary wedge pressure. Group 2 PH patients exhibited significantly larger median left atrial (LA) volumes (118 vs. 63 mL, P < 0.001), larger median left ventricular (LV) volumes (90 vs. 76 mL, P = 0.02), and smaller median right ventricular (RV) volumes (173 vs. 210 mL, P = 0.005) than non-Group 2 patients. On multivariate analysis adjusted to age, gender, and mean pulmonary arterial pressure, Group 2 PH was significantly associated with larger median LA and LV volumes (P < 0.001 and P = 0.008, respectively), and decreased volume ratios of RA/LA, RV/LV and RV/LA (P = 0.001, P = 0.004, and P < 0.001, respectively). Enlarged LA volumes demonstrated high discriminatory ability for Group 2 PH (AUC=0.92; 95%CI, 0.870-0.968).Volumetric analysis of the cardiac chambers from non-gated chest CTs, particularly with findings of an enlarged LA, exhibited high discriminatory ability for identifying patients with PH due to left heart disease.
View details for DOI 10.1016/j.chest.2017.04.184
View details for PubMedID 28506612
Pulmonary function after lung tumor stereotactic ablative radiotherapy depends on regional ventilation within irradiated lung.
Radiotherapy and oncology
2017; 123 (2): 270-275
To determine if regional ventilation within irradiated lung volume predicts change in pulmonary function test (PFT) measurements after stereotactic ablative radiotherapy (SABR) of lung tumors.We retrospectively identified 27 patients treated from 2007 to 2014 at our institution who received: (1) SABR without prior thoracic radiation; (2) pre-treatment 4-dimensional computed tomography (4-D CT) imaging; (3) pre- and post-SABR PFTs <15months from treatment. We defined the ventilation ratio (VR20BED3) as the quotient of mean ventilation (mean Jacobian-based per-voxel volume change on deformably registered inhale/exhale 4-D CT phases) within the 20Gy biologically effective dose (α/β=3Gy) isodose volume and that of the total lung volume (TLV).Most patients had moderate to very severe COPD by GOLD criteria (n=19, 70.1%). Higher VR20BED3 significantly predicted worse change in Forced Expiratory Volume/s normalized by baseline value (ΔFEV1/FEV1pre, p=0.04); n=7 had VR20BED3>1 (high regional ventilation) and worse ΔFEV1/FEV1pre (median=-0.16, range=-0.230 to -0.20). Five had VR20BED3<1 (low regional ventilation) and improved ΔFEV1/FEV1pre (median=0.13, range=0.07 to 0.20). In a multivariable linear model, increasing VR20BED3 and time to post-SABR PFT predicted decreasing ΔFEV1/FEV1pre (R(2)=0.25, p=0.03).After SABR to high versus low functioning lung regions, we found worsened or improved global pulmonary function, respectively. If pre-SABR VR20BED3 is validated as a predictor of eventual post-SABR PFT in larger studies, it may be used for individualized treatment planning to preserve or even improve pulmonary function after SABR.
View details for DOI 10.1016/j.radonc.2017.03.021
View details for PubMedID 28460826
Left Atrium Maximal Axial Cross-Sectional Area is a Specific Computed Tomographic Imaging Biomarker of World Health Organization Group 2 Pulmonary Hypertension.
Journal of thoracic imaging
2017; 32 (2): 121-126
Left heart disease is associated with left atrial enlargement and is a common cause of pulmonary hypertension (PH). We investigated the relationship between left atrium maximal axial cross-sectional area (LA-MACSA), as measured on chest computed tomography (CT), and PH due to left heart disease (World Health Organization group 2) in patients with right heart catheterization-proven PH.A total of 165 patients with PH who had undergone right heart catheterization with pulmonary artery pressure and pulmonary capillary wedge pressure (PCWP) measurements and nongated chest CTs were included. LA-MACSA, LA anterior-posterior, and LA transverse measurements were independently obtained using the hand-drawn region-of-interest and distance measurement tools on standard PACS by 2 blinded cardiothoracic radiologists. Nonparametric statistical analyses and receiver operating characteristic curve were performed.Forty-three patients had group 2 PH (PCWP>15 mm Hg), and 122 had nongroup 2 PH (PCWP≤15 mm Hg). Median LA-MACSA was significantly different between the group 2 PH and nongroup 2 PH patients (2312 vs. 1762 mm, P<0.001). Interobserver concordance correlation for LA-MACSA was high at 0.91 (P<0.001). At a threshold of 2400 mm, LA-MACSA demonstrated 93% specificity for classifying group 2 PH (area under the curve, 0.73; P<0.001).LA-MACSA is a readily obtainable and reproducible measurement of left atrial enlargement on CT and can distinguish between group 2 and nongroup 2 PH with high specificity.
View details for DOI 10.1097/RTI.0000000000000252
View details for PubMedID 28009778
Predictive radiogenomics modeling of EGFR mutation status in lung cancer
Molecular analysis of the mutation status for EGFR and KRAS are now routine in the management of non-small cell lung cancer. Radiogenomics, the linking of medical images with the genomic properties of human tumors, provides exciting opportunities for non-invasive diagnostics and prognostics. We investigated whether EGFR and KRAS mutation status can be predicted using imaging data. To accomplish this, we studied 186 cases of NSCLC with preoperative thin-slice CT scans. A thoracic radiologist annotated 89 semantic image features of each patient's tumor. Next, we built a decision tree to predict the presence of EGFR and KRAS mutations. We found a statistically significant model for predicting EGFR but not for KRAS mutations. The test set area under the ROC curve for predicting EGFR mutation status was 0.89. The final decision tree used four variables: emphysema, airway abnormality, the percentage of ground glass component and the type of tumor margin. The presence of either of the first two features predicts a wild type status for EGFR while the presence of any ground glass component indicates EGFR mutations. These results show the potential of quantitative imaging to predict molecular properties in a non-invasive manner, as CT imaging is more readily available than biopsies.
View details for DOI 10.1038/srep41674
View details for PubMedID 28139704
Coccidioidomycosis: Surgical Issues and Implications.
Coccidioidomycosis, commonly called "valley fever," "San Joaquin fever," "desert fever," or "desert rheumatism," is a multi-system illness caused by infection with Coccidioides fungi (C. immitis or C. posadasii). This organism is endemic to the desert Southwest regions of the United States and Mexico and to parts of South America. The manifestations of infection occur along a spectrum from asymptomatic to mild self-limited fever to severe disseminated disease.Review of the English-language literature.There are five broad indications for surgical intervention in patients with coccidioidomycosis: Tissue diagnosis in patients at risk for co-existing pathology, perforation, bleeding, impingement on critical organs, and failure to resolve with medical management. As part of a multidisciplinary team, surgeons may be responsible for the care of infected patients, particularly those with severe disease.This review discusses the history, microbiology, epidemiology, pathology, diagnosis, and treatment of coccidioidomycosis, focusing on situations that may be encountered by surgeons.
View details for PubMedID 27740893
Clinical significance of extraskeletal computed tomography findings on 18F-NaF PET/CT performed for osseous metastatic disease evaluation.
Nuclear medicine communications
2016; 37 (9): 975-982
Extraskeletal findings detected on whole-body low-dose unenhanced computed tomography (CT) as a part of F-NaF PET/CT scans can be numerous and present challenges for further management. Here, we investigate the frequency and clinical significance of extraskeletal findings among 130 consecutive patients undergoing F-NaF PET/CT for osseous metastatic disease.F-NaF PET/CT performed on 130 patients (101 men and 29 women; mean age: 61.4 years) with biopsy-proven malignancies were reviewed independently. Incidental soft tissue findings detected on unenhanced low-dose CT portions of the scans were compiled and categorized by clinical significance.A total of 275 incidental extraskeletal CT findings were observed in 114 out of 130 patients (87.7%). Seven patients (5.4%) showed clinically significant findings. One patient developed new lung nodules that were resected and proven to be metastases. Two patients showed new hypodense hepatic lesions that were highly suspicious for liver metastases. One patient with prostate cancer was found to have previously unknown retroperitoneal lymphadenopathy. Three patients showed indeterminate renal and adrenal lesions that necessitated further correlative imaging.Although CT indicated a large number of incidental extraskeletal lesions in the majority of patients undergoing F-NaF PET/CT, clinically significant incidental findings requiring further evaluation were relatively infrequently observed in 5.4% of patients. Thus, the low-dose unenhanced CT in F-NaF PET/CT performed for oncologic evaluation may indicate unexpected soft tissue lesions that can impact patient management and therefore should be interpreted by physicians skilled in CT reading, with correlation to available imaging, and familiar with established guidelines for work-up of incidental findings.
View details for DOI 10.1097/MNM.0000000000000531
View details for PubMedID 27111100
A Wandering Pulmonary Nodule.
American journal of respiratory and critical care medicine
View details for PubMedID 27512939
Pre-treatment non-target lung FDG-PET uptake predicts symptomatic radiation pneumonitis following Stereotactic Ablative Radiotherapy (SABR).
Radiotherapy and oncology
2016; 119 (3): 454-460
To determine if pre-treatment non-target lung FDG-PET uptake predicts for symptomatic radiation pneumonitis (RP) following lung stereotactic ablative radiotherapy (SABR).We reviewed a 258 patient database from our institution to identify 28 patients who experienced symptomatic (grade ⩾ 2) RP after SABR, and compared them to 57 controls who did not develop symptomatic RP. We compared clinical, dosimetric and functional imaging characteristics between the 2 cohorts including pre-treatment non-target lung FDG-PET uptake.Median follow-up time was 26.9 months. Patients who experienced symptomatic RP had significantly higher non-target lung FDG-PET uptake as measured by mean SUV (p < 0.0001) than controls. ROC analysis for symptomatic RP revealed area under the curve (AUC) of 0.74, with sensitivity 82.1% and specificity 57.9% with cutoff mean non-target lung SUV > 0.56. Predictive value increased (AUC of 0.82) when mean non-target lung SUV was combined with mean lung dose (MLD). We developed a 0-2 point model using these 2 variables, 1 point each for SUV > 0.56 or MLD > 5.88 Gy equivalent dose in 2 Gy per fraction (EQD2), predictive for symptomatic RP in our cohort with hazard ratio 10.01 for score 2 versus 0 (p < 0.001).Patients with elevated pre-SABR non-target lung FDG-PET uptake are at increased risk of symptomatic RP after lung SABR. Our predictive model suggests patients with mean non-target lung SUV > 0.56 and MLD > 5.88 Gy EQD2 are at highest risk. Our predictive model should be validated in an external cohort before clinical implementation.
View details for DOI 10.1016/j.radonc.2016.05.007
View details for PubMedID 27267049
Methyl Methacrylate Mimicking a Retained Guide Wire.
Journal of vascular and interventional radiology : JVIR
2016; 27 (12): 1906
View details for PubMedID 27886956
- Demonstration of peripheral nerve root involvement by non-Hodgkin's lymphoma on F-18-FDG PET/CT EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2012; 39 (4): 729-730
Frameshift Mutagenesis and Microsatellite Instability Induced by Human Alkyladenine DNA Glycosylase
2010; 37 (6): 843-853
Human alkyladenine DNA glycosylase (hAAG) excises alkylated purines, hypoxanthine, and etheno bases from DNA to form abasic (AP) sites. Surprisingly, elevated expression of hAAG increases spontaneous frameshift mutagenesis. By random mutagenesis of eight active site residues, we isolated hAAG-Y127I/H136L double mutant that induces even higher rates of frameshift mutation than does the wild-type hAAG; the Y127I mutation accounts for the majority of the hAAG-Y127I/H136L-induced mutator phenotype. The hAAG-Y127I/H136L and hAAG-Y127I mutants increased the rate of spontaneous frameshifts by up to 120-fold in S. cerevisiae and also induced high rates of microsatellite instability (MSI) in human cells. hAAG and its mutants bind DNA containing one and two base-pair loops with significant affinity, thus shielding them from mismatch repair; the strength of such binding correlates with their ability to induce the mutator phenotype. This study provides important insights into the mechanism of hAAG-induced genomic instability.
View details for DOI 10.1016/j.molcel.2010.01.038
View details for Web of Science ID 000276135100011
View details for PubMedID 20347426
View details for PubMedCentralID PMC2894629
- Best Cases from the AFIP Fatal 2009 Influenza A (H1N1) Infection, Complicated by Acute Respiratory Distress Syndrome and Pulmonary Interstitial Emphysema RADIOGRAPHICS 2010; 30 (2): 327-333
Substrate binding pocket residues of human alkyladenine-DNA glycosylase critical for methylating agent survival
2008; 7 (10): 1731-1745
Human alkyladenine-DNA glycosylase (AAG) initiates base excision repair (BER) of alkylated and deaminated bases in DNA. Here, we assessed the mutability of the AAG substrate binding pocket, and the essentiality of individual binding pocket amino acids for survival of methylation damage. We used oligonucleotide-directed mutagenesis to randomize 19 amino acids, 8 of which interact with substrate bases, and created more than 4.5 million variants. We expressed the mutant AAGs in repair-deficient Escherichia coli and selected for protection against the cytotoxicity of either methylmethane sulfonate (MMS) or methyl-lexitropsin (Me-lex), an agent that produces 3-methyladenine as the predominant base lesion. Sequence analysis of 116 methylation-resistant mutants revealed no substitutions for highly conserved Tyr(127)and His(136). In contrast, one mutation, L180F, was greatly enriched in both the MMS- and Me-lex-resistant libraries. Expression of the L180F single mutant conferred 4.4-fold enhanced survival at the high dose of MMS used for selection. The homogeneous L180F mutant enzyme exhibited 2.2-fold reduced excision of 3-methyladenine and 7.3-fold reduced excision of 7-methylguanine from methylated calf thymus DNA. Decreased excision of methylated bases by the mutant glycosylase could promote survival at high MMS concentrations, where the capacity of downstream enzymes to process toxic BER intermediates may be saturated. The mutant also displayed 6.6- and 3.0-fold reduced excision of 1,N(6)-ethenoadenine and hypoxanthine from oligonucleotide substrates, respectively, and a 1.7-fold increase in binding to abasic site-containing DNA. Our work provides in vivo evidence for the substrate binding mechanism deduced from crystal structures, illuminates the function of Leu(180) in wild-type human AAG, and is consistent with a role for balanced expression of BER enzymes in damage survival.
View details for DOI 10.1016/j.dnarep.2008.06.019
View details for Web of Science ID 000260621500012
View details for PubMedID 18706524
Protein tolerance to random amino acid change
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2004; 101 (25): 9205-9210
Mutagenesis of protein-encoding sequences occurs ubiquitously; it enables evolution, accumulates during aging, and is associated with disease. Many biotechnological methods exploit random mutations to evolve novel proteins. To quantitate protein tolerance to random change, it is vital to understand the probability that a random amino acid replacement will lead to a protein's functional inactivation. We define this probability as the "x factor." Here, we develop a broadly applicable approach to calculate x factors and demonstrate this method using the human DNA repair enzyme 3-methyladenine DNA glycosylase (AAG). Three gene-wide mutagenesis libraries were created, each with 10(5) diversity and averaging 2.2, 4.6, and 6.2 random amino acid changes per mutant. After determining the percentage of functional mutants in each library using high-stringency selection (>19,000-fold), the x factor was found to be 34% +/- 6%. Remarkably, reanalysis of data from studies of diverse proteins reveals similar inactivation probabilities. To delineate the nature of tolerated amino acid substitutions, we sequenced 244 surviving AAG mutants. The 920 tolerated substitutions were characterized by substitutability index and mapped onto the AAG primary, secondary, and known tertiary structures. Evolutionarily conserved residues show low substitutability indices. In AAG, beta strands are on average less substitutable than alpha helices; and surface loops that are not involved in DNA binding are the most substitutable. Our results are relevant to such diverse topics as applied molecular evolution, the rate of introduction of deleterious alleles into genomes in evolutionary history, and organisms' tolerance of mutational burden.
View details for DOI 10.1073/pnas.0403255101
View details for Web of Science ID 000222278600009
View details for PubMedID 15197260
View details for PubMedCentralID PMC438954
Tumbling down a different pathway to genetic instability
JOURNAL OF CLINICAL INVESTIGATION
2003; 112 (12): 1793-1795
Ulcerative colitis (UC), a chronic inflammatory condition associated with a predisposition to colon cancer, is frequently characterized by DNA damage in the form of microsatellite instability (MSI). A new report links inflammation in UC with increases in the DNA repair enzymes 3-methyladenine DNA glycosylase and apurinic/apyrimidinic endonuclease, and, paradoxically, with increased MSI. These findings may represent a novel mechanism contributing to MSI in chronic inflammation.
View details for DOI 10.1172/JCI200320502
View details for Web of Science ID 000187348300006
View details for PubMedID 14679175
View details for PubMedCentralID PMC297004
Endogenous mutagenesis and cancer.
2002; 509 (1-2): 17-21
Mutations in DNA accrue relentlessly, largely via stochastic processes. Random changes accumulate, eventually disabling genetic components which result in the formation of the cancer phenotype. Given the infrequency of measured nucleotide changes and the requirement for several mutations to occur in the same cell, it has been postulated that the rate of mutation must become elevated early in the course of evolution of the cancer. Recently, large scale sequencing of tumor DNA has sought to directly measure random mutations. We discuss the implications of these findings and the factors that must be considered in order for fruitful determination of whether a mutator phenotype is a necessary precursor for cancer.
View details for PubMedID 12427528