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Dive into the research topics where Kathryn E. Tanaka is active.

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Featured researches published by Kathryn E. Tanaka.


Hepatology | 2009

Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance.

Rajat Singh; Yongjun Wang; Youqing Xiang; Kathryn E. Tanaka; William A. Gaarde; Mark J. Czaja

Activation of c‐Jun N‐terminal kinase (JNK) has been implicated as a mechanism in the development of steatohepatitis. This finding, together with the reported role of JNK signaling in the development of obesity and insulin resistance, two components of the metabolic syndrome and predisposing factors for fatty liver disease, suggests that JNK may be a central mediator of the metabolic syndrome and an important therapeutic target in steatohepatitis. To define the isoform‐specific functions of JNK in steatohepatitis associated with obesity and insulin resistance, the effects of JNK1 or JNK2 ablation were determined in developing and established steatohepatitis induced by a high‐fat diet (HFD). HFD‐fed jnk1 null mice failed to develop excessive weight gain, insulin resistance, or steatohepatitis. In contrast, jnk2−/− mice fed a HFD were obese and insulin‐resistant, similar to wild‐type mice, and had increased liver injury. In mice with established steatohepatitis, an antisense oligonucleotide knockdown of jnk1 decreased the amount of steatohepatitis in concert with a normalization of insulin sensitivity. Knockdown of jnk2 improved insulin sensitivity but had no effect on hepatic steatosis and markedly increased liver injury. A jnk2 knockdown increased hepatic expression of the proapoptotic Bcl‐2 family members Bim and Bax and the increase in liver injury resulted in part from a Bim‐dependent activation of the mitochondrial death pathway. Conclusion: JNK1 and JNK2 both mediate insulin resistance in HFD‐fed mice, but the JNK isoforms have distinct effects on steatohepatitis, with JNK1 promoting steatosis and hepatitis and JNK2 inhibiting hepatocyte cell death by blocking the mitochondrial death pathway. (HEPATOLOGY > 2009;49:87‐96.)


Infection and Immunity | 2001

The Inducible Nitric Oxide Synthase Locus Confers Protection against Aerogenic Challenge of Both Clinical and Laboratory Strains of Mycobacterium tuberculosis in Mice

Charles A. Scanga; Vellore P. Mohan; Kathryn E. Tanaka; David Alland; JoAnne L. Flynn; John S.D. Chan

ABSTRACT Murine macrophages effect potent antimycobacterial function via the production of nitric oxide by the inducible isoform of the enzyme nitric oxide synthase (NOS2). The protective role of reactive nitrogen intermediates (RNI) against Mycobacterium tuberculosisinfection has been well established in various murine experimental tuberculosis models using laboratory strains of the tubercle bacillus to establish infection by the intravenous route. However, important questions remain about the in vivo importance of RNI in host defense against M. tuberculosis. There is some evidence that RNI play a lesser role following aerogenic, rather than intravenous,M. tuberculosis infection of mice. Furthermore, in vitro studies have demonstrated that different strains of M. tuberculosis, including clinical isolates, vary widely in their susceptibility to the antimycobacterial effects of RNI. Thus, we sought to test rigorously the protective role of RNI against infection with recent clinical isolates of M. tuberculosis following both aerogenic and intravenous challenges. Three recently isolated and unique M. tuberculosis strains were used to infect both wild-type (wt) C57BL/6 and NOS2 gene-disrupted mice. Regardless of the route of infection, NOS2−/− mice were much more susceptible than wt mice to any of the clinical isolates or to either the Erdman or H37Rv laboratory strain of M. tuberculosis. Mycobacteria replicated to much higher levels in the organs of NOS2−/− mice than in those of wt mice. Although the clinical isolates all exhibited enhanced virulence in NOS2−/− mice, they displayed distinct growth rates in vivo. The present study has provided results indicating that RNI are required for the control of murine tuberculous infection caused by both laboratory and clinical strains of M. tuberculosis. This protective role of RNI is essential for the control of infection established by either intravenous or aerogenic challenge.


Clinical Colorectal Cancer | 2012

PTEN GENE EXPRESSION AND MUTATIONS IN THE PIK3CA GENE AS PREDICTORS OF CLINICAL BENEFIT TO ANTI EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY THERAPY IN PATIENTS WITH KRAS WILD TYPE METASTATIC COLORECTAL CANCER

Arjun Sood; Danielle McClain; Radhashree Maitra; Atrayee Basu-Mallick; Raviraja Seetharam; Andreas Kaubisch; Lakshmi Rajdev; John M. Mariadason; Kathryn E. Tanaka; Sanjay Goel

PURPOSE To identify novel genetic markers predictive of clinical benefit from epidermal growth factor receptor-directed antibody therapy in patients with metastatic colorectal cancer. PATIENTS AND METHODS Seventy-six consecutive patients who received cetuximab or panitumumab, either alone or in combination with chemotherapy and with available tumor tissue were included. Tumor tissue was tested by pyrosequencing for mutations at known hot spots in the KRAS, BRAF, PIK3CA, PIK3R1, AKT1, and PTEN genes. PTEN promoter methylation status was analyzed by methylation-specific polymerase chain reaction, and expression was determined by immunohistochemistry (IHC). Forty-four patients had 4 weeks of therapy and were considered for clinical correlates. RESULTS Consistent with previous studies, KRAS gene mutations were associated with a shorter progression-free survival (PFS) and overall survival (OS). Among the patients with wild-type KRAS, preservation of PTEN expression and PIK3CA wild-type status was associated with improved OS (median OS, 80.4 vs. 32.5 weeks; hazard ratio, 0.33; P = .0008) and a trend toward improved PFS (median PFS, 24.8 vs. 15.2 weeks; hazard ratio, 0.51; P = .06), compared with PTEN-negative or PIK3CA-mutant tumors. PTEN methylation was more common in the metastatic samples than in the primary samples (P = .02). The simultaneous presence of methylation and mutation in the PTEN gene was associated with IHC negativity (P = .026). CONCLUSION In addition to KRAS mutation, loss of PTEN expression (by IHC) and PIK3CA mutation is likely to be predictive of a lack of benefit to anti-EGFR therapy in metastatic colorectal cancer. PTEN promoter methylation and mutation status was predictive of PTEN expression and may be used as an alternative means of predicting response to EGFR-targeted therapy.


Hepatology | 2013

Aging promotes the development of diet‐induced murine steatohepatitis but not steatosis

Luis Fontana; Enpeng Zhao; Muhammad Amir; Hanqing Dong; Kathryn E. Tanaka; Mark J. Czaja

The prevalence of the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in humans increases with age. It is unknown whether this association is secondary to the increased incidence of risk factors for NAFLD that occurs with aging, reflects the culmination of years of exposure to lifestyle factors such as a high‐fat diet (HFD), or results from physiological changes that characterize aging. To examine this question, the development of NAFLD in response to a fixed period of HFD feeding was examined in mice of different ages. Mice aged 2, 8, and 18 months were fed 16 weeks of a low‐fat diet or HFD. Increased body mass and insulin insensitivity occurred in response to HFD feeding irrespective of the age of the mice. The amount of HFD‐induced hepatic steatosis as determined biochemically and histologically was also equivalent among the three ages. Liver injury occurred exclusively in the two older ages as reflected by increased serum alanine aminotransferase levels, positive terminal deoxynucleotide transferase–mediated deoxyuridine triphosphate nick end‐labeling, and caspase activation. Older mice also had an elevated innate immune response with a more pronounced polarization of liver and adipose tissue macrophages into an M1 phenotype. Studies of cultured hepatocytes from young and old mice revealed that aged cells were selectively sensitized to the Fas death pathway. Conclusion: Aging does not promote the development of hepatic steatosis but leads to increased hepatocellular injury and inflammation that may be due in part to sensitization to the Fas death pathway and increased M1 macrophage polarization. (HEPATOLOGY 2013)


Cellular Microbiology | 2003

Gene expression in the tuberculous granuloma: analysis by laser capture microdissection and real‐time PCR

Guofeng Zhu; Huifang Xiao; Vellore P. Mohan; Kathryn E. Tanaka; Sanjay Tyagi; Fred Tsen; Padmini Salgame; John Chan

We have assessed the kinetics of host gene expression in granulomas of mice infected with virulent Mycobacterium tuberculosis, using an approach that incorporates the laser capture microdissection (LCM) and real‐time PCR technology in conjunction with a newly derived mathematical equation. The results have provided evidence indicating that conventional use of whole infected lungs to study granuloma‐specific gene expression can yield data that may not genuinely reflect intralesional events. Significantly, the expression of nine host genes known to regulate the inflammatory response to M. tuberculosis, as determined by real‐time PCR analysis of microdissected granuloma‐derived cDNAs, was downregulated (up to 27‐fold) at around the time when the rapid growth phase of the bacilli in the lungs of infected mice ends. This downregulation was masked when whole infected lungs were used for the studies. The data suggest that the host immune system can adjust and respond to, or can be modulated by specific physiological states of the tubercle bacillus in vivo. The LCM/real‐time PCR‐based system described in this study can be applied to safely and accurately evaluate gene expression in any lesions that can be microscopically visualized, including those contained in biohazardous tissues.


Journal of Surgical Oncology | 1997

Morphologic pattern of tenascin as a diagnostic biomarker in colon cancer

Basem F. Iskaros; Kathryn E. Tanaka; Xiaoping Hu; Anna S. Kadish; Jacob J. Steinberg

Immunohistochemical methods were used to study the pattern of expression of tenascin (TN) in invasive colon cancer and its relation to prognosis.


Journal of Hepatology | 2016

Macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin-1β

Ghulam Ilyas; Enpeng Zhao; Kun Liu; Yu Lin; Lydia Tesfa; Kathryn E. Tanaka; Mark J. Czaja

BACKGROUND & AIMS Overactivation of the innate immune response underlies many forms of liver injury including that caused by hepatotoxins. Recent studies have demonstrated that macrophage autophagy regulates innate immunity and resultant tissue inflammation. Although hepatocyte autophagy has been shown to modulate hepatic injury, little is known about the role of autophagy in hepatic macrophages during the inflammatory response to acute toxic liver injury. Our aim therefore was to determine whether macrophage autophagy functions to down regulate hepatic inflammation. METHODS Mice with a LysM-CRE-mediated macrophage knockout of the autophagy gene ATG5 were examined for their response to toxin-induced liver injury from D-galactosamine/lipopolysaccharide (GalN/LPS). RESULTS Knockout mice had increased liver injury from GalN/LPS as determined by significant increases in serum alanine aminotransferase, histological evidence of liver injury, positive terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling, caspase activation and mortality as compared to littermate controls. Levels of proinflammatory tumor necrosis factor and interleukin (IL)-6 hepatic mRNA and serum protein were unchanged, but serum IL-1β was significantly increased in knockout mice. The increase in serum IL-1β was secondary to elevated hepatic caspase 1 activation and inflammasome-mediated cleavage of pro-IL-1β to its active form. Cultured hepatic macrophages from GalN/LPS-treated knockout mice had similarly increased IL-1β production. Dysregulation of IL-1β was the mechanism of increased liver injury as an IL-1 receptor antagonist prevented injury in knockout mice in concert with decreased neutrophil activation. CONCLUSIONS Macrophage autophagy functions to limit acute toxin-induced liver injury and death by inhibiting the generation of inflammasome-dependent IL-1β.


Liver International | 2007

Fulminant liver failure secondary to haemorrhagic dengue in an international traveller

James Gasperino; Jose Yunen; Alice Guh; Kathryn E. Tanaka; Vladimir Kvetan; Howard Doyle

Dengue infections are caused by a single‐stranded RNA virus, which has four serotypes (DEN 1–4); mosquitoes of the genus Aedes serve as vectors of transmission. Risk factors for dengue infection are related to both the host and virus. Age, gender, immune status, and genetic background of the host all contribute to the severity of dengue infection. Recently, international travel to endemic areas has also been identified as a major risk factor for both primary and secondary dengue infection. Dengue remains a diagnostic challenge, given its protean nature, ranging from mild febrile illness to profound shock. The most severe manifestation of dengue infection is dengue shock syndrome, which has an estimated mortality rate close to 50%. Dengue shock syndrome typically presents with increased anion gap metabolic acidosis, disseminated intravascular coagulation, severe hypotension, and jaundice. Liver involvement appears to occur more frequently when infections involve DEN‐3 and DEN‐4 serotypes. While hepatocellular damage has been reported previously in dengue infection, acute liver failure is an extremely rare occurrence in adults. We report a patient with dengue shock syndrome who presented with acute liver failure and hepatic encephalopathy after recent travel to an endemic area.


American Journal of Physiology-gastrointestinal and Liver Physiology | 2016

Autophagy confers resistance to lipopolysaccharide-induced mouse hepatocyte injury

Gadi Lalazar; Ghulam Ilyas; Shoaib Ahmad Malik; Kun Liu; Enpeng Zhao; Mohammad Amir; Yu Lin; Kathryn E. Tanaka; Mark J. Czaja

During sepsis, bacterial products, particularly LPS, trigger injury in organs such as the liver. This common condition remains largely untreatable, in part due to a lack of understanding of how high concentrations of LPS cause cellular injury. In the liver, the lysosomal degradative pathway of autophagy performs essential hepatoprotective functions and is induced by LPS. We, therefore, examined whether hepatocyte autophagy protects against liver injury from septic levels of LPS. Mice with an inducible hepatocyte-specific knockout of the critical autophagy gene Atg7 were examined for their sensitivity to high-dose LPS. Increased liver injury occurred in knockout mice, as determined by significantly increased serum alanine aminotransferase levels, histological evidence of liver injury, terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling, and effector caspase-3 and -7 activation. Hepatic inflammation and proinflammatory cytokine induction were unaffected by the decrease in hepatocyte autophagy. Although knockout mice had normal NF-κB signaling, hepatic levels of Akt1 and Akt2 phosphorylation in response to LPS were decreased. Cultured hepatocytes from knockout mice displayed a generalized defect in Akt signaling in response to multiple stimuli, including LPS, TNF, and IL-1β. Akt activation mediates hepatocyte resistance to TNF cytotoxicity, and anti-TNF antibodies significantly decreased LPS-induced liver injury in knockout mice, indicating that the loss of autophagy sensitized to TNF-dependent liver damage. Hepatocyte autophagy, therefore, protects against LPS-induced liver injury. Conditions such as aging and steatosis that impair hepatic autophagy may predispose to poor outcomes from sepsis through this mechanism.


Hepatology | 2017

Pentamidine Blocks Hepatotoxic Injury in Mice

Enpeng Zhao; Ghulam Ilyas; Francesca Cingolani; Jae Ho Choi; François Ravenelle; Kathryn E. Tanaka; Mark J. Czaja

Toxin‐induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti‐inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the d‐galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase–mediated deoxyuridine triphosphate nick end‐labeling (TUNEL)‐positive cells and mortality compared with vehicle‐injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS‐treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c‐Jun N‐terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol‐induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL‐positive cells. Conclusion: VLX103 effectively decreases toxin‐induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. (Hepatology 2017;66:922–935).

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Mark J. Czaja

Albert Einstein College of Medicine

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Enpeng Zhao

Albert Einstein College of Medicine

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Ghulam Ilyas

Albert Einstein College of Medicine

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John S.D. Chan

Université de Montréal

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Alan A. Alfieri

Albert Einstein College of Medicine

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Chandan Guha

Albert Einstein College of Medicine

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