Lawrence Blatt | University of California, Los Angeles (original) (raw)

Papers by Lawrence Blatt

Clinical Immunology and Immunopathology, 1992

Previous in vitro and in vivo studies have shown a synergism between interferon (IFN) and B-fluor... more Previous in vitro and in vivo studies have shown a synergism between interferon (IFN) and B-fluorouracil (5.FU) against different tumor cell lines. In the present study we report that the combination of IFN-cz and 5-FU has a significant effect not only on the inhibition of tumor cell growth but also on the regulation of natural killer cellmediated cytotoxicity (NK-CMC). The addition of 5-FU to effector cell population neither a&&s NK cell activity nor activation of NK cells by IFN or by interleukin (IL)-2 However, p~t~atment of target cells with 5-FU increased their su~eptibility to NK activity and abolished the protective effect induced by IFN against NK-CMC. This dual effect of IFN-a and 5-FU was found to be applicable to target cells of different origins including a cervical carcinoma cell line (ME-1801, a hairy cell leukemia-like cell line (Eskol), a CML cell line (K-5621 and a primary culture of AIDS-related Kaposi's sarcoma cells. Similar results were found with IL-2 treatment of Eskol cells but not other cells. Combination of IL-2 with 5-FU resulted in enhancement of the sensitivity of the cells to NK activity and abolished the protection against NK-CMC. Based on these results we propose that the eombination of 1FN-a and 5-FU not only has a direct growth inhibit04 effect on tumor cells but also has a regulatory role on the immunological arm of the NK-CMC. Moreover, since the combination gave the same pattern of response in different tumor cells, both NK-sensitive and NK-resistant, this combination treatment may be a candidate for clinical trials in various types of tumors.

Journal of Gastroenterology and Hepatology, 2003

Hyaluronic acid (HA) is a glycosaminoglycan synthesized by hepatic stellate cells that has been s... more Hyaluronic acid (HA) is a glycosaminoglycan synthesized by hepatic stellate cells that has been shown to correlate with liver fibrosis in chronic hepatitis C (HCV) patients. However, its use in monitoring fibrosis over time has not been established. The aim of the present study was to assess the serial relationships between HA and liver fibrosis before and after treatment. Seventy-six previously untreated chronic HCV patients received interferon-based therapy over 48 weeks. Serum HA levels were measured and liver biopsies were obtained at baseline, and 24 weeks post-treatment. Histological fibrosis was assessed by using the Knodell and METAVIR scoring systems. Knodell fibrosis was evaluated in 76 patients; METAVIR fibrosis in 72 patients. Following treatment, patients were grouped into those with increased fibrosis (Knodell = 17; METAVIR = 16), no change (Knodell = 50; METAVIR = 45), or decreased fibrosis (Knodell = 9; METAVIR = 11), relative to baseline. Moderate correlations between HA and fibrosis scores were found before treatment (Knodell R = 0.45; METAVIR R = 0.40) and post-treatment (Knodell R = 0.45; METAVIR R = 0.61). However, changes in HA correlated poorly with changes in fibrosis scores over the study period (Knodell R = 0.11; METAVIR R = 0.06). There was poor qualitative agreement between the direction of HA change and the direction of change in fibrosis scores (Knodell kappa = 0.04; METAVIR kappa = 0.08). The sustained virological response group (n = 18) had a significantly decreased mean HA compared with non-responders (-27.9 vs 21.7 micro g/L; P = 0.009), but pretreatment HA did not predict a response. Serum HA showed a modest association with hepatic fibrosis, and remains a useful non-invasive marker. However, serum HA alone has limited value in predicting histological changes over a treatment period.

CHEST Journal, 2006

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is the most common and most aggressive form of idiop... more PURPOSE: Idiopathic pulmonary fibrosis (IPF) is the most common and most aggressive form of idiopathic interstitial pneumonia. Transforming growth factor beta (TGF-β) has been shown to be a particularly important mediator of fibroblast proliferation and extracellular matrix (ECM) production in IPF lungs. Interferon gamma-1b (IFN-γ 1b) inhibits TGF-β-induced collagen synthesis by up-regulating SMAD7 expression and inducing formation of an inhibitory RFX5 complex on the collagen promoter region. We recently discovered that pirfenidone exerts antifibrotic effects by inhibiting p38 MAPK, an essential intracellular mediator of TGF-βinduced collagen synthesis. Given their distinctive modes of action against TGF-β-induced collagen expression, we wanted to determine whether the concomitant administration of IFN-γ 1b and pirfenidone would result in complementary or antagonistic effects against TGF-β-induced gene induction in human lung fibroblasts (HFL-1). METHODS: HFL-1 cells were pre-treated with pirfenidone (185 mg/L) and IFN-γ 1b (300 pg/mL) for 1 hour, then TGF-β was added and cells were incubated for 24 hours in serumcontaining complete FK12 growth medium. Total RNA isolation, gene chip hybridization, Western blot and ELISA were performed according to manufacturer protocols.

Antiviral Chemistry and Chemotherapy, 2004

The recent West Nile virus (WNV) outbreak in the United States has increased the need to identify... more The recent West Nile virus (WNV) outbreak in the United States has increased the need to identify effective therapies. Studies were conducted in cell culture and in rodent animal models to determine the efficacy of interferon-alpha (IFN-α), interferon (IFN) inducers and ribavirin, alone or in combination with IFN, in treating WNV. Intraperitoneal injection of IFN-α B/D (qd for 7 days), polyIpolyC(12)U [Ampligen (every other day for 7 days)] and topically applied imiquimod (qd for 7 days), administered from 1 day before viral challenge, were effective in protecting, respectively, 100%, 100% and 70% of BALB/c mice from mortality induced by subcutaneous injection of WNV. When IFN-α B/D or Ampligen treatments were delayed to 4–6 h before viral challenge in mice, efficacy was greatly diminished. Infected Syrian golden hamsters treated with interferon alphacon-1 (Infergen) and Ampligen 4–6 h before viral challenge gained more weight and had a greater survival than saline-treated animals. ...

Antiviral chemistry & chemotherapy, 2006

Several arenaviruses endemic to South America (Junin, Machupo, and Guanarito) and Africa (Lassa) ... more Several arenaviruses endemic to South America (Junin, Machupo, and Guanarito) and Africa (Lassa) are known to cause frequently fatal haemorrhagic fever. With the exception of ribavirin, which has demonstrated efficacy in cases of Lassa fever, there is no other effective therapeutic for the treatment of arenaviral haemorrhagic fever. We have recently reported that consensus interferon-a (IFN alfacon-1) can protect hamsters from lethal Pichinde virus (PCV) infection, which serves as a model for acute arenaviral disease in humans. Here we demonstrate highly effective therapy through the combined use of ribavirin with IFN alfacon-1 for the treatment of PCV infection in hamsters. Ribavirin was given orally, twice per day for 7 days, and IFN alfacon-1 was administered intraperitoneally once per day for 10 days. Treatments were initiated 1-5 days post-virus challenge using various dose combinations, many of which were less than optimal when the drugs were given independently. Combining sub...

Virology, 2007

Mice are used as models for western equine encephalitis virus (WEEV) infection, but high mortalit... more Mice are used as models for western equine encephalitis virus (WEEV) infection, but high mortality is generally only seen with intracranial or intranasal challenge, while peripheral inoculation results in approximately 50% mortality, and is not dose dependant. Hamsters were therefore studied as a model for WEEV infection. Hamsters were highly sensitive to intraperitoneal (i.p.) infection with WEEV. Disease progression was rapid, and virus titers in serum, brain, liver, and kidney of infected hamsters peaked between 2 and 4 days post-virus inoculation (dpi). Foci of virus infection were detected in neurons of the cerebral cortex and midbrain. Pre-treatment i.p. with either interferon alfacon-1 (5 μg/kg/d), or with Ampligen® (3.2 mg/kg/d), resulted in complete survival, reduced brain titers, and improved weight gain. This model of WEEV infection in hamsters appears to serve as a suitable model for the evaluation of potential therapeutic agents for the treatment of WEE disease.

Biochemical and Biophysical Research Communications, 2008

The primary targets for SARS-CoV infection are the epithelial cells in the respiratory and intest... more The primary targets for SARS-CoV infection are the epithelial cells in the respiratory and intestinal tract. The angiotensin-converting enzyme 2 (ACE-2) has been identified as a functional receptor for SARS-CoV. ACE-2 has been shown to be expressed at the apical domain of polarized Calu-3 cells. In this report, interferon alfacon 1 was examined for inhibitory activities against SARS-CoV on human lung carcinoma epithelial Calu-3 cell line and the other three African green monkey kidney epithelial cell lines. Interferon alfacon 1 demonstrated significant antiviral activity in neutral red uptake assay and virus yield reduction assay. The data might provide an important insight into the mechanism of pathogenesis of SARS-CoV allowing further development of antiviral therapies for treating SARS infections.

Antiviral Research, 2007

Antiviral compounds were evaluated for efficacy against yellow fever virus (YFV) in a hamster mod... more Antiviral compounds were evaluated for efficacy against yellow fever virus (YFV) in a hamster model of YFV-induced liver disease. Challenge with a 10 2 50% cell culture infectious doses of YFV resulted in a 50-80% mortality rate in female hamsters. Virus was detected by quantitative real-time RT-PCR (QRT-PCR) in liver, kidney, spleen and serum with peak titers on 4-6 days post-viral challenge (dpi). Serum levels of alkaline phosphatase, alanine aminotransferase (ALT), bilirubin, blood urea nitrogen, potassium and creatinine were significantly elevated, while serum levels of albumin, amylase, glucose, calcium, globulin, phosphorus, sodium and total protein were significantly reduced. Packed cell volume and white blood cell count were significantly elevated during the course of the infection. Intraperitoneal treatment of hamsters with 0.5-5 g/kg/day interferon (IFN) alfacon-1, 100 mg/kg/day viramidine or 50 mg/kg/day ribavirin, initiated 4 h prior to YFV challenge, resulted in significant improvement in survival and serum ALT levels. Treatment with IFN alfacon-1 or ribavirin starting 2 dpi, also significantly improved survival and serum ALT levels in hamsters challenged with YFV. Pre-and post-virus exposure treatment with IFN alfacon-1 was efficacious in improving disease in YFV-infected hamsters.

Antiviral Research, 2008

Punta Toro virus (PTV) is a member of the Bunyaviridae family, genus Phlebovirus, related to the ... more Punta Toro virus (PTV) is a member of the Bunyaviridae family, genus Phlebovirus, related to the highly pathogenic Rift Valley fever virus (RVFV). It produces a disease in hamsters that models severe Rift Valley fever (RVF) in humans. The recent outbreak of RVF in Kenya stresses the need to identify prophylactic and therapeutic measures for preventing and treating severe forms of disease. To this end, interferon (IFN) alfacon-1 (consensus IFN-α) was evaluated in cell culture against RVFV and PTV, and in the hamster PTV infection model. Survival outcome following treatment initiated pre-and post-virus challenge and the suppression of viral burden and liver disease in infected hamsters was determined. Pre-treatment of cell cultures with IFN alfacon-1 induced marked antiviral activity against both viruses. Intraperitoneal treatment of hamsters initiated 4 h prior to infection with PTV was highly protective and greatly limited liver disease and systemic and liver viral burden. Complete protection from a highly lethal challenge dose was afforded by treatment initiated 36 h following viral inoculation. Although efficacy was much reduced, IFN alfacon-1 therapy was still beneficial when started as late as 3−5 days post-virus exposure. These studies suggest that IFN alfacon-1 may be an effective treatment for early intervention following infection with RVFV.

Antimicrobial Agents and Chemotherapy, 2005

Hemorrhagic fever of arenaviral origin is a frequently fatal infectious disease of considerable p... more Hemorrhagic fever of arenaviral origin is a frequently fatal infectious disease of considerable priority to the biodefense mission. Historically, the treatment of arenaviral infections with alpha interferons has not yielded favorable results. Here we present evidence that interferon alfacon-1, a nonnaturally occurring bioengineered alpha interferon approved for the treatment of chronic hepatitis C, is active against Pichinde and Tacaribe arenaviruses in cell culture. In the hamster model of Pichinde virus (PCV) infection, interferon alfacon-1 treatment significantly protected animals from death, prolonged the survival of those that eventually died, reduced virus titers, and limited liver damage characteristic of PCV-induced disease. Moreover, interferon alfacon-1 also demonstrated therapeutic activity, to a lesser degree, when the initiation of treatment was delayed up to 2 days post-virus challenge. Despite the observed advantages of interferon alfacon-1 therapy, efforts to stimula...

Liver International, 2007

Background: Chronic hepatitis B virus (HBV) infection is associated with hepatocellular carcinoma... more Background: Chronic hepatitis B virus (HBV) infection is associated with hepatocellular carcinoma (HCC), and specific viral factors have been identified that may increase the risk for HCC development. However, the differences in these viral factors in chronic carriers who seldom develop HCC compared with HCC patients have not been adequately evaluated. Methods: From 1989 to 2005, 101 hepatitis B surface antigen-positive patients presented to our clinic with HCC. Baseline basal core promoter (BCP) T1762/A1764 mutants, precore (PC) A1896 mutants, HBV genotypes and HBV DNA in HCC patients were compared with 67 chronic carriers who had been followed for a mean of 112.1 AE 77.7 standard deviation months. Results: At baseline, HCC patients had lower levels of serum albumin, but higher values of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin and a-foetoprotein than those of chronic carriers (P o 0.001 for all comparisons). The presence of genotype C, higher frequencies of PC A1896 mutants, BCP T1762/A1764 mutants and higher circulating levels of HBV DNA were more frequently detected in HCC patients than that in chronic carriers (P o 0.001 for all observations). Logistic regression analysis revealed that BCP T1762/A1764 mutants [odds ratio (OR) 11.14, 95% confidence interval (CI) 3.05-40.72; P o 0.001] and PC A1896 mutants (OR 3.75, 95% CI 1.14-12.34; P o 0.05) were significantly associated with HCC development. Conclusion: Our results indicate that the presence of BCP and PC mutations significantly increases the risk for HCC in chronic hepatitis B patients. These mutations were less often detected in chronic carriers who seldom develop HCC. Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

Biochemical and Biophysical Research Communications, 2021

There is an urgent need for antivirals targeting the SARS-CoV-2 virus to fight the current COVID-... more There is an urgent need for antivirals targeting the SARS-CoV-2 virus to fight the current COVID-19 pandemic. The SARS-CoV-2 main protease (3CLpro) represents a promising target for antiviral therapy. The lack of selectivity for some of the reported 3CLpro inhibitors, specifically versus cathepsin L, raises potential safety and efficacy concerns. ALG-097111 potently inhibited SARS-CoV-2 3CLpro (IC50 = 7 nM) without affecting the activity of human cathepsin L (IC50 > 10 µM). When ALG-097111 was dosed in hamsters challenged with SARS-CoV-2, a robust and significant 3.5 log10 (RNA copies/mg) reduction of the viral RNA copies and 3.7 log10 (TCID50/mg) reduction in the infectious virus titers in the lungs was observed. These results provide the first in vivo validation for the SARS-CoV-2 3CLpro as a promising therapeutic target for selective small molecule inhibitors.

Hepatology (Baltimore, Md.), Jan 2, 2018

This open-label, Phase IIa study assessed the safety, pharmacokinetics, and efficacy of direct-ac... more This open-label, Phase IIa study assessed the safety, pharmacokinetics, and efficacy of direct-acting antiviral agent (DAA) regimens in patients with chronic hepatitis C virus (HCV) infection. Multiple 6-12-week oral regimens of 400-800 mg once daily (QD) AL-335 + 50 mg QD/every other day odalasvir ± 75-150 mg QD simeprevir were evaluated in treatment-naïve, HCV genotype (GT)1/3-infected patients without cirrhosis. Safety/pharmacokinetic parameters, HCV-RNA, and sequencing data were assessed. Treatment regimens for later study cohorts were adjusted based on emerging data. In total, 112 patients were enrolled. Three serious treatment-emergent adverse events occurred, one of which (Wenckebach) was possibly related to high odalasvir exposure and resulted in premature discontinuation of study drugs. No other clinically significant safety findings were identified. GT1-infected patients receiving 3-DAA for 6-8 weeks achieved 100% sustained virologic response 12 and 24 weeks after end of t...

Open Forum Infectious Diseases, 2015