Timothy R Morgan

VA Long Beach Healthcare System, Long Beach, California, United States

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Publications (159)1585.91 Total impact

  • Cancer Prevention Research 10/2015; 8(10 Supplement):A21-A21. DOI:10.1158/1940-6215.PREV-14-A21 · 4.44 Impact Factor
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    ABSTRACT: Background: The combination of daclatasvir, a hepatitis C virus (HCV) NS5A inhibitor, and the NS5B inhibitor sofosbuvir has shown efficacy in patients with HCV monoinfection. Data are lacking on the efficacy and safety of this combination in patients coinfected with human immunodeficiency virus type 1 (HIV-1). Methods: This was an open-label study involving 151 patients who had not received HCV treatment and 52 previously treated patients, all of whom were coinfected with HIV-1. Previously untreated patients were randomly assigned in a 2:1 ratio to receive either 12 weeks or 8 weeks of daclatasvir at a standard dose of 60 mg daily (with dose adjustment for concomitant antiretroviral medications) plus 400 mg of sofosbuvir daily. Previously treated patients were assigned to undergo 12 weeks of therapy at the same doses. The primary end point was a sustained virologic response at week 12 after the end of therapy among previously untreated patients with HCV genotype 1 who were treated for 12 weeks. Results: Patients had HCV genotypes 1 through 4 (83% with genotype 1), and 14% had compensated cirrhosis; 98% were receiving antiretroviral therapy. Among patients with genotype 1, a sustained virologic response was reported in 96.4% (95% confidence interval [CI], 89.8 to 99.2) who were treated for 12 weeks and in 75.6% (95% CI, 59.7 to 87.6) who were treated for 8 weeks among previously untreated patients and in 97.7% (95% CI, 88.0 to 99.9) who were treated for 12 weeks among previously treated patients. Rates of sustained virologic response across all genotypes were 97.0% (95% CI, 91.6 to 99.4), 76.0% (95% CI, 61.8 to 86.9), and 98.1% (95% CI, 89.7 to 100), respectively. The most common adverse events were fatigue, nausea, and headache. There were no study-drug discontinuations because of adverse events. HIV-1 suppression was not compromised. Conclusions: Among previously untreated HIV-HCV coinfected patients receiving daclatasvir plus sofosbuvir for HCV infection, the rate of sustained virologic response across all genotypes was 97.0% after 12 weeks of treatment and 76.0% after 8 weeks. (Funded by Bristol-Myers Squibb; ALLY-2 ClinicalTrials.gov number, NCT02032888.).
    New England Journal of Medicine 07/2015; 373(8). DOI:10.1056/NEJMoa1503153 · 55.87 Impact Factor
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    ABSTRACT: Genetic polymorphisms within the interferon lambda (IFN-) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-ΔG/TT (rs368234815) polymorphism, which controls generation of the IFN-4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3' untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability. We compared IFNL4-ΔG/TT and rs4803217 for association with response to pegylated-IFN-α/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-ΔG/TT and rs4803217 genotypes by a bootstrap approach. Among European Americans, linkage disequilibrium between IFNL4-ΔG/TT and rs4803217 was strong (r(2)=0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-ΔG/TT than rs4803217 (p=0.003); the IFNL4-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p=0.03, comparison to IFNL4-ΔG:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-ΔG/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep C (p=0.03) and week 20 in HALT-C (p=0.03), as well as for spontaneous HCV clearance (p=0.048). IFNL4-ΔG/TT is the primary IFN- region polymorphism for impaired HCV clearance. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 07/2015; DOI:10.1016/j.jhep.2015.06.035 · 11.34 Impact Factor
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    ABSTRACT: In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC while administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum AFP level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 grams/day, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. 110 subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury, or markers of oxidative stress or antioxidant potential. Copyright © 2015, American Association for Cancer Research.
    Cancer Prevention Research 06/2015; 8(9). DOI:10.1158/1940-6207.CAPR-15-0029 · 4.44 Impact Factor
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    ABSTRACT: Background The risk of alcohol-related liver cirrhosis increases with increasing alcohol consumption, but many people with very high intake escape from liver disease. We postulate that susceptibility to alcoholic cirrhosis has a complex genetic component and propose that this can be dissected through a large and sufficiently powered genomewide association study (GWAS).Methods The GenomALC Consortium comprises researchers from Australia, France, Germany, Switzerland, United Kingdom, and United States, with a joint aim of exploring the genetic and genomic basis of alcoholic cirrhosis. For this National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism funded study, we are recruiting high-risk drinkers who are either cases (with alcoholic cirrhosis) or controls (drinking comparable amounts over similar time, but free of significant liver disease). Extensive phenotypic data are obtained using semistructured interviews and patient records, and blood samples are collected.ResultsWe have successfully recruited 859 participants including 538 matched case–control samples as of September 2014, using study-specific inclusion–exclusion criteria and data collection protocols. Of these, 580 are cases (442 men and 138 women) and 279 are controls (205 men and 74 women). Duration of excessive drinking was slightly greater in cases than controls and was significantly less in women than men. Cases had significantly lower lifetime alcohol intake than controls. Both cases and controls had a high prevalence of reported parental alcohol problems, but cases were significantly more likely to report that a father with alcohol problems had died from liver disease (odds ratio 2.53, 95% confidence interval 1.31 to 4.87, p = 0.0055).Conclusions Recruitment of participants for a GWAS of alcoholic cirrhosis has proved feasible across countries with multiple sites. Affected patients often consume less alcohol than unaffected ones, emphasizing the existence of individual vulnerability factors. Cases are more likely to report liver disease in a father with alcohol problems than controls, consistent with a potential genetic component to the risk of alcoholic cirrhosis.
    Alcoholism Clinical and Experimental Research 05/2015; 39(5). DOI:10.1111/acer.12693 · 3.21 Impact Factor
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    ABSTRACT: & Aims: Several models have been used to determine prognoses of patients with alcoholic hepatitis. These include static systems (the Maddrey discriminant function; the age, bilirubin, international normalized ratio, creatinine [ABIC] score; and model for end-stage liver disease [MELD] score) and dynamic models (the Lille model). We aimed to combine features of all these models to develop a better method to predict outcomes of patients with alcoholic hepatitis. We collected data from several databases of patients with severe alcoholic hepatitis treated with corticosteroids in France and the UK to create a model to predict patient survival (derivation cohort, n=538 patients). We compared the performances of 3 joint-effect models (Maddrey+Lille, MELD+Lille, ABIC+Lille) to determine which combination had the best prognostic value, based on known patient outcomes. The model was validated using data from trials of the effects of corticosteroids in patients in the US, France, Korea, and Belgium (n=604 patients). We created a joint-effect model to predict patient survival after 2 and 6 months; in the derivation and validation cohorts, it predicted outcome significantly better than either static or dynamic models alone (P<.01 for all comparisons). The joint model accurately predicted patient survival regardless of patient risk level. The MELD+Lille combination was better than the Maddrey+Lille or ABIC+Lille in predicting patient survival, with Akaike information criterion values of 1305, 1313, and 1312 respectively. For example, based on the MELD+Lille combination model, predicted 6-month mortality of complete responders with MELD scores of 15-45 (Lille score 0.16) was 8.5% to 49.7%, compared with 16.4%-75.2% for non-responders (Lille score 0.45). According to the joint-effect model, for 2 patients with the same baseline MELD score of 21, the patient with a Lille score of 0.45 had a 1.9-fold higher risk of death than the patient with a Lille score of 0.16 (23.7% vs 12.5%). By combining results from static and dynamic scoring systems for liver disease, we can better predict outcomes of patients with alcoholic hepatitis, compared with either model alone. This may help patient management and design of clinical trials. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Gastroenterology 04/2015; 149(2). DOI:10.1053/j.gastro.2015.04.044 · 16.72 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-1194. DOI:10.1016/S0016-5085(15)34078-6 · 16.72 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-1002. DOI:10.1016/S0016-5085(15)33420-X · 16.72 Impact Factor
  • Journal of Hepatology 04/2015; 62:S757-S758. DOI:10.1016/S0168-8278(15)31285-X · 11.34 Impact Factor
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    Douglas L Nguyen · Daniel Chao · Grace Ma · Timothy Morgan
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    ABSTRACT: Chronic liver disease increases the socioeconomic and emotional burden on the patient's caregiver. This is important because a patient's adherence to therapy and transplant eligibility is dependent on the caregiver's ability to handle these challenges. This was a prospective, cross-sectional study of 50 primary caregivers of patients with advanced liver disease. Caregivers completed the RAND 36-item (Short Form [SF-36]) Health Survey and the Zarit Burden Scale survey. Caregiver quality of life, based on the SF-36, was compared using t-tests with the scores of the National reference population as controls. In our cohort, the mean age of caregivers was 56.9±11.4 years, 40 (83.3%) were female, and 34 (70.8%) were spouses/significant others of the patient. Compared with the adjusted National norm data, caregivers scored substantially lower in categories of role limitations due to emotional problems (P<0.001), vitality (P=0.025), mental health (P=0.005), and social functioning (P=0.002). While the adjusted physical component score of the caregivers was comparable to the National mean, the mental component score (MCS) was lower than the National average (42.4±13.3 vs. 50.0±10, P<0.001). Though only 8 of 50 (16.0%) subjects reported a formal diagnosis of depression or anxiety, 23 (46.0%) had MCS <42, a strong predictor of clinical depression, based on previous studies. Primary caregivers of patients with advanced liver disease have significantly lower SF-36 mental health scores compared with the general population. Comparison of SF-36 scores to caregiver history suggests under recognition of mental health problems in this population.
    Annals of Gastroenterology 01/2015; 28(1):124-129.
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    ABSTRACT: Colorectal cancer (CRC) progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal Growth Factor Receptor (EGFR) inhibitors are efficacious in advanced tumors including CRC. There is significant evidence that EGFR also plays important roles in CRC initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to CRC, and normal rectal tissue. A total of N=45 patients were randomized to one of three erlotinib doses (25 mg, 50 mg, 100 mg) with randomization stratified by non-steroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with Erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphoERK, phosphoEGFR and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional pre-screening stratification or potentially longer duration of use.
    Cancer Prevention Research 01/2015; 8(3). DOI:10.1158/1940-6207.CAPR-14-0148 · 4.44 Impact Factor
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    Timothy R. Morgan
    Journal of Hepatology 12/2014; DOI:10.1016/j.jhep.2014.12.021 · 11.34 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):3247-3247. DOI:10.1158/1538-7445.AM2014-3247 · 9.33 Impact Factor
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    ABSTRACT: Binge drinking, a common pattern of alcohol ingestion, is known to potentiate liver injury caused by chronic alcohol abuse. This study was aimed to investigate the effects of acute binge alcohol on hypoxia-inducible factor-1α (HIF-1α)-mediated liver injury and roles of alcohol metabolizing enzymes in alcohol-induced hypoxia and hepatotoxicity. Mice and human specimens assigned as binge or non-binge group were analyzed for blood alcohol concentration (BAC), alcohol metabolizing enzymes, HIF-1α-related protein nitration and apoptosis. Binge alcohol promoted acute liver injury in mice with elevated levels of ethanol-inducible cytochrome P450-2E1 (CYP2E1) and hypoxia, both of which were co-localized in centrilobular areas. We observed positive correlations among elevated BAC, CYP2E1, and HIF-1α in mice and humans exposed to binge alcohol. The CYP2E1 protein levels (r=0.629, p=0.001) and activities (r=0.641, p=0.001) showed significantly positive correlation with BACs in human livers. HIF-1α levels were also positively correlated with BACs (r=0.745, p<0.001) or CYP2E1 activities (r=0.792, p<0.001) in humans. Binge alcohol promoted protein nitration and apoptosis with significant correlations observed between inducible nitric oxide synthase and BACs, CYP2E1, or HIF-1α in human specimens. Binge alcohol-induced HIF-1α activation and subsequent protein nitration or apoptosis seen in wild-type were significantly alleviated in the corresponding Cyp2e1-null mice while pretreatment with an HIF-1α inhibitor PX-478 prevented HIF-1α elevation with a trend of decreased levels of 3-nitrotyrosine and apoptosis, supporting the roles of CYP2E1and HIF-1α in binge alcohol-mediated protein nitration and hepatotoxicity. Thus binge alcohol promotes acute liver injury in mice and humans at least partly through a CYP2E1-HIF-1α-dependent apoptosis pathway.
    Free Radical Biology and Medicine 09/2014; 77. DOI:10.1016/j.freeradbiomed.2014.08.030 · 5.74 Impact Factor
  • Gregory J. Botwin · Timothy R. Morgan
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    ABSTRACT: Bacterial infections occur in 25-35 % of cirrhotics admitted to hospital. Health-care associated and hospital acquired (nosocomial) infections are the most common epidemiology, with community acquired infections less common (15-30 %). Spontaneous bacterial peritonitis and urinary infections are the most common sites, with spontaneous bacteremia, pneumonia, cellulitis and other sites being less common. The risk of infection is increased among subjects with more severe liver disease and an infection in the past 6 months. Bacteria are isolated from approximately half of patients with a clinical diagnosis of infection. Gram-negative enterobacteriaceae are the most common organisms among community acquired infections; Gram-positive cocci are the most common organisms isolated among subjects with nosocomial infections. Up to 30 % of hospital associated infections are with multidrug resistant bacteria. Consequently, empiric antibiotic therapy that is recommended for community acquired infections is often inadequate for nosocomial infections. Infections worsen liver function. In-hospital and 1-year mortality of cirrhotics with infections is significantly higher than among cirrhotics without infection. In-hospital complications of infections, such as severe sepsis and septic shock, and mortality, are increased among subjects with multidrug-resistant infections as compared with cirrhotics with susceptible bacteria. Short-term antibiotic prophylaxis of cirrhotics with upper gastrointestinal bleeding and long-term antibiotic prophylaxis of selected cirrhotics with spontaneous bacterial peritonitis reduces infections and improves survival. Albumin administration to cirrhotics with SBP and evidence of advanced liver disease improves survival. The benefit of albumin administration to cirrhotics with infections other than SBP is under investigation.
    Hepatology International 09/2014; 8(S2):467-474. DOI:10.1007/s12072-014-9522-z · 1.78 Impact Factor
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    ABSTRACT: Recent studies indicate that the inflammasome activation plays important roles in the pathogenesis of alcoholic hepatitis (AH). Nod-like receptor protein 3 (NLRP3) is a key component of the macromolecular complex that is so called the inflammasome that triggers caspase 1-dependent maturation of the precursors of IL-1β and IL-18 cytokines. It is also known that the adaptor proteins including apoptosis-associated speck-like protein containing CARD (ASC) and the mitochondrial antiviral signaling protein (MAVS) are necessary for NLRP3-dependent inflammasome function. Steatohepatitis frequently includes Mallory-Denk body (MDB) formation. In the case of alcoholic steatohepatitis, MDB formation occurs in 80% of biopsies (French 1981; French 1981). While previous studies have focused on in vitro cell lines and mouse models, we are the first group to investigate inflammasome activation in AH liver biopsy specimen and correlate it with MDB formation. Expression of NOD1, NLRP3, ASC, NAIP, MAVS, caspase 1, IL-1β, IL-18, and other inflammatory components including IL-6, IL-10, TNF-α, IFN-γ, STAT3, and p65 was measured in three to eight formalin-fixed paraffin-embedded AH specimens and control normal liver specimens by immunofluorescence staining and quantified by immunofluorescence intensity. The specimens were double stained with ubiquitin to demonstrate the relationship between inflammasome activation and MDB formation. MAVS, caspase1, IL-18, and TNF-α showed increases in expression in AH compared to the controls (p<0.05), and NAIP expression markedly increased in AH compared to the controls (p<0.01). There was a trend that levels of NLRP3, ASC, caspase1, IL-18, IL-10, and p65 expression correlated with the number of MDBs found in the same field of measurement (correlation coefficients were between 0.62 and 0.93, p<0.05). Our results demonstrate the activation of the inflammasome in AH and suggest that MDB could be an indicator of the extent of inflammasome activation.
    Experimental and Molecular Pathology 08/2014; 97(2). DOI:10.1016/j.yexmp.2014.08.006 · 2.71 Impact Factor
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    ABSTRACT: Activation of Toll-like receptor (TLR) signaling which stimulates inflammatory and proliferative pathways is the key element in the pathogenesis of Mallory-Denk bodies (MDBs) in mice fed DDC. However, little is known as to how TLR signaling is regulated in MDB formation during chronic liver disease development. The first systematic study of TLR signaling pathway transcript regulation in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies with MDB formation is presented here. When compared to the activation of Toll-like signaling in alcoholic hepatitis (AH) and Non alcoholic steatohepatitis (NASH) patients, striking similarities and obvious differences were observed. Similar TLRs (TLR3 and TLR4, etc.), TLR downstream adaptors (MyD88 and TRIF, etc.) and transcript factors (NFκB and IRF7, etc.) were all up regulated in the patients' livers. MyD88, TLR3 and TLR4 were significantly induced in the livers of AH and NASH compared to normal subjects, while TRIF and IRF7 mRNA were only slightly up regulated in AH patients. This is a different pathway from the induction of the TLR4-MyD88-independent pathway in the AH and NASH patients with MDBs present. Importantly, chemokine receptor 4 and 7 (CXCR4/7) mRNAs were found to be induced in the patients livers in FAT10 positive hepatocytes. The CXCR7 pathway was significantly up regulated in patients with AH and the CXCR4 was markedly up regulated in patients with NASH, indicating that CXCR4/7 is crucial in liver MDB formation. This data constitutes the first demonstration of the up regulation of the MyD88-dependent TLR4/ NFκB pathway in AH and NASH where MDBs formed, via the NFκB-CXCR4/7 pathway, and provides further insight into the mechanism of MDB formation in human liver diseases.
    Experimental and Molecular Pathology 07/2014; 97(2). DOI:10.1016/j.yexmp.2014.07.001 · 2.71 Impact Factor
  • Alan S Wang · Ruth M Pfeiffer · Timothy R Morgan · Thomas R O'Brien
    Hepatology 06/2014; 59(6). DOI:10.1002/hep.26771 · 11.06 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-950. DOI:10.1016/S0016-5085(14)63453-3 · 16.72 Impact Factor

Publication Stats

8k Citations
1,585.91 Total Impact Points


  • 2005–2015
    • VA Long Beach Healthcare System
      Long Beach, California, United States
  • 1995–2015
    • University of California, Irvine
      • Division of Gastroenterology
      Irvine, California, United States
  • 1992–2014
    • Long Beach Memorial Medical Center
      Long Beach, California, United States
  • 2010
    • California State University, Long Beach
      Long Beach, California, United States
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2009
    • National Institutes of Health
      • Branch of Liver Diseases Branch (LDB)
      Bethesda, MD, United States
  • 2008
    • VA Palo Alto Health Care System
      Palo Alto, California, United States
  • 2006
    • Long Beach City College
      Long Beach, California, United States
  • 2001–2005
    • Harbor-UCLA Medical Center
      • Department of Pediatrics
      Torrance, California, United States
  • 2004
    • University of Texas Southwestern Medical Center
      • Division of Digestive and Liver Diseases
      Dallas, Texas, United States
  • 1993
    • United States Department of Veterans Affairs
      Бедфорд, Massachusetts, United States
  • 1988
    • University of Southern California
      • Division of Gastrointestinal and Liver Diseases
      Los Angeles, California, United States
  • 1986
    • Rancho Los Amigos Rehabilitation Center
      Downey, California, United States