Bio

Bio


Dr. Guo is a diagnostic radiologist with board certifications in Radiology and Nuclear Medicine. He is subspecialty fellowship trained in chest (thoracic) imaging and nuclear medicine, including PET-CT and SPECT-CT. As a dedicated chest radiologist, Dr. Guo's emphasis is on diseases of the lungs, including: interstitial lung diseases, lung cancer, COPD, and disease of the airways. Dr. Guo also specializes in cancer imaging as part of his work in nuclear medicine and PET. He helps to care for patients in the Thoracic Cancer Program, Interstitial Lung Diseases Clinic, 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. He current research projects include: imaging markers of lung and heart diseases, low radiation dose CT, PET-CT of the lungs, quantitative CT, and in 3D printing of lung tumors to optimize pre-treatment planning.

He is a native of the South Bay and enjoys working in the dynamic environment of the Silicon Valley. At home, he has fun keeping up with his two young boys, running, and hiking.

Clinical Focus


  • Diagnostic Radiology
  • Chest imaging
  • Nuclear Medicine
  • Diagnosis and follow up of diseases by CT and nuclear medicine, with emphasis on lung, cancers, early detection, and PET
  • 3-D printing
  • quantitative CT

Academic Appointments


  • Clinical Assistant Professor, Radiology

Honors & Awards


  • Alpha Omega Alpha, (AOA)
  • Sigma Xi, MIT
  • Junior Faculty of the year, Stanford Radiology Residency (2014)
  • 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)

Professional Education


  • Internship:Scripps Mercy Hospital Transitional Internship (2007) CA
  • Medical Education:University of Washington (2006) WA
  • Board Certification: Nuclear Medicine, American Board of Nuclear Medicine (2012)
  • Fellowship:Stanford University School of Medicine (2012) CA
  • Residency:Stanford University School of Medicine (2011) CA
  • Fellowship in Chest Radiology, Stanford Hospital and Clinics, CA USA (2012)
  • Board Certification, Nuclear Medicine, American Board of Nuclear Medicine (2012)
  • Board Certification: Diagnostic Radiology, American Board of Radiology (2011)
  • PhD, University of Washington, Pathology and Molecular Biology (2004)
  • Bachelor of Science, Massachusetts Institute of Technology, Molecular Biology (1997)

Research & Scholarship

Current Research and Scholarly Interests


3D printing of lung
Quality assurance of ultralow dose CT scans
Post radiation treatment changes of lung tumors
CT features as predictor of cardiovascular disease
FDG uptake in lung diseases

Projects


  • FDG PET-CT in lung diseases (September 17, 2012)

    Location

    Stanford CA

    Collaborators

  • 3D printing of lung (January 2014)

    Location

    Stanford

    Collaborators

    • Jia Wang, Medical Physicist, Stanford University
  • Quality Assurance in ultralow dose CT, Stanford (January 2014)

    Location

    Stanford

  • Post radiation change of lung and lung tumors, Stanford

    Location

    Stanford

    Collaborators

  • CT perfusion of post-SABR lung tumors, Stanford (August 2014)

    Location

    Stanford

    Collaborators

    • Aya Kamaya, Associate Professor, Stanford University
    • Billy Loo, Associate Professor, Stanford University

Publications

All Publications


  • Improving Quality of Dynamic Airway Computed Tomography Using an Expiratory Airflow Indicator Device. Journal of thoracic imaging Hahn, L. D., Sung, A. W., Shafiq, M., Guo, H. H. 2018

    Abstract

    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 DOI 10.1097/RTI.0000000000000325

    View details for PubMedID 29470258

  • Initial Experience With Simultaneous 18F-FDG PET/MRI in the Evaluation of Cardiac Sarcoidosis and Myocarditis. Clinical nuclear medicine Hanneman, K., Kadoch, M., Guo, H. H., Jamali, M., Quon, A., Iagaru, A., Herfkens, R. 2017; 42 (7): e328-e334

    Abstract

    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. Chest Aviram, G., Rozenbaum, Z., Ziv-Baran, T., Berliner, S., Topilsky, Y., Fleischmann, D., Sung, Y. K., Zamanian, R. T., Guo, H. H. 2017

    Abstract

    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 Binkley, M. S., King, M. T., Shrager, J. B., Bush, K., Chaudhuri, A. A., Popat, R., Gensheimer, M. F., Maxim, P. G., Henry Guo, H., Diehn, M., Nair, V. S., Loo, B. W. 2017; 123 (2): 270-275

    Abstract

    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 Jivraj, K., Bedayat, A., Sung, Y. K., Zamanian, R. T., Haddad, F., Leung, A. N., Rosenberg, J., Guo, H. H. 2017; 32 (2): 121-126

    Abstract

    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 SCIENTIFIC REPORTS Gevaert, O., Echegaray, S., Khuong, A., Hoang, C. D., Shrager, J. B., Jensen, K. C., Berry, G. J., Guo, H. H., Lau, C., Plevritis, S. K., Rubin, D. L., Napel, S., Leung, A. N. 2017; 7

    Abstract

    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 Web of Science ID 000393094200001

    View details for PubMedID 28139704

    View details for PubMedCentralID PMC5282551

  • Coccidioidomycosis: Surgical Issues and Implications. Surgical infections Forrester, J. D., Guo, H. H., Weiser, T. G. 2016: -?

    Abstract

    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 Guo, H. H., Moradi, F., Iagaru, A. 2016; 37 (9): 975-982

    Abstract

    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 Van Wert, R., Gayer, G., Guo, H. H., Nair, V. S. 2016: -?

    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 Chaudhuri, A. A., Binkley, M. S., Rigdon, J., Carter, J. N., Aggarwal, S., Dudley, S. A., Qian, Y., Kumar, K. A., Hara, W. Y., Gensheimer, M., Nair, V. S., Maxim, P. G., Shultz, D. B., Bush, K., Trakul, N., Le, Q., Diehn, M., Loo, B. W., Guo, H. H. 2016; 119 (3): 454-460

    Abstract

    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 Moradzadeh, N., Hwang, G., Nair, V., Guo, H. H. 2016; 27 (12): 1906

    View details for DOI 10.1016/j.jvir.2016.07.020

    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 Guo, H., Mosci, C., Iagaru, A. 2012; 39 (4): 729-730

    View details for DOI 10.1007/s00259-011-2000-0

    View details for Web of Science ID 000302287500024

    View details for PubMedID 22124779

  • Frameshift Mutagenesis and Microsatellite Instability Induced by Human Alkyladenine DNA Glycosylase MOLECULAR CELL Klapacz, J., Lingaraju, G. M., Guo, H. H., Shah, D., Moar-Shoshani, A., Loeb, L. A., Samson, L. D. 2010; 37 (6): 843-853

    Abstract

    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 Guo, H. H., Sweeney, R. T., Regula, D., Leung, A. N. 2010; 30 (2): 327-333

    View details for DOI 10.1148/rg.302095213

    View details for Web of Science ID 000275622400003

    View details for PubMedID 20068001

  • Substrate binding pocket residues of human alkyladenine-DNA glycosylase critical for methylating agent survival DNA REPAIR Chen, C., Guo, H. H., Shah, D., Blank, A., Samson, L. D., Loeb, L. A. 2008; 7 (10): 1731-1745

    Abstract

    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 GUO, H. H., Choe, J., Loeb, L. A. 2004; 101 (25): 9205-9210

    Abstract

    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

  • Tumbling down a different pathway to genetic instability JOURNAL OF CLINICAL INVESTIGATION GUO, H. H., Loeb, L. A. 2003; 112 (12): 1793-1795

    Abstract

    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