Serum interleukin (IL)-10 and IL-12 levels and IL28B gene polymorphisms: pretreatment prediction of treatment failure in chronic hepatitis C

Background: Both IL28B gene polymorphisms and serum levels of interleukin (IL)-10, IL-12p40 and IL-18 have been reported to affect the outcome of natural and pegylated interferon and ribavirin-treated HCV infection. Methods: To clarify their association and predictive value in treatment outcome of genotype 1 HCV-infected patients, we measured pretreatment serum IL-10, IL-12p40 and IL-18 levels using multiplex assays and determined IL28B gene polymorphisms (rs 8099917) in 52 cases with chronic hepatitis C. Results: High baseline levels of IL-10 (P<0.001) and low levels of IL-12p40 (P<0.001) were significantly associated with a non-virological response (NVR) in our cohort. The IL28B polymorphism was tested and TT, TG or GG genotypes were found in 60%, 38% and 2% of patients, respectively, with corresponding NVR rates of 10%, 60% and 100% (P<0.001). Serum cytokine levels were significantly correlated with IL28B gene polymorphisms. When serum IL-10 levels were stratified at 5.0 pg/ml, NVR rates were 50% versus 0% (P=0.004) for the IT genotype and 87% versus 0% (P=0.001) for the TG or GG genotypes. Similarly, low IL-12p40 levels were associated with an NVR in patients with TG or GG genotypes (P=0.006). In multivariate analysis, high IL-10, low IL-12p40 and IL28B TG or GG genotypes were independently associated with an NVR. Conclusions: Serum IL-10 and IL-12p40 levels in combination with IL28B genotype, especially G-allele carriage, are strong predictive markers of an NVR to HCV treatment with pegylated interferon and ribavirin.ArticleANTIVIRAL THERAPY. 16(7):1073-1080 (2011)journal articl

Serum chemokine levels are associated with the outcome of pegylated interferon and ribavirin therapy in patients with chronic hepatitis C

Aim: Serum chemokine levels and amino acid substitutions in the interferon-sensitivity determining region (ISDR) and core region have been associated with treatment outcome of pegylated interferon and ribavirin therapy in genotype 1 hepatitis C virus (HCV)-infected patients. The present study was conducted to clarify the association between serum chemokines and treatment outcome in patients with chronic HCV-1 infection in a Japanese cohort. Methods: A total of six serum chemokines were quantified before, during and after pegylated interferon and ribavirin treatment in 79 genotype 1 chronic HCV patients using a multiple bead array system. Viral ISDR and core region variants were determined by direct sequencing. Results: The baseline serum levels of eotaxin, IP-10 and RANTES were significantly higher in chronic HCV patients than in controls. High levels of eotaxin and macrophage inflammatory protein (MIP)-1 beta before therapy and more than two mutations in the ISDR were associated with a sustained virological response, and patients with more than two mutations in the ISDR also had significantly higher MIP-1 beta levels. Receiver-operator curve analysis showed a 77% sensitivity and 73% specificity for predicting an SVR using MIP-1 beta values. Conclusion: Serum MIP-1 beta levels may predict the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR.ArticleHEPATOLOGY RESEARCH. 41(6):587-593 (2011)journal articl

Antiresorptive agent-related osteonecrosis of the jaw: Position Paper 2017 of the Japanese Allied Committee on Osteonecrosis of the Jaw

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is an intractable, though rare, complication in cancer patients with bone metastases and patients with osteoporosis who are treated with antiresorptive agents, including bisphosphonates and denosumab. Despite the more than 10 years that have passed since the first cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) were reported, our understanding of the epidemiology and pathophysiology of ARONJ remains limited, and data supported by evidence-based medicine are still sparse. However, the diagnosis and staging of ARONJ, identification of risk factors, and development of preventive and therapeutic approaches have advanced significantly over the past decade. The Position Paper 2017 is an updated version of the Position Paper 2010 of the Japanese Allied Committee on Osteonecrosis of the Jaw, which now comprises six Japanese academic societies. The Position Paper 2017 describes a new diagnostic definition for ARONJ, as proposed by the American Association of Oral and Maxillofacial Surgeons (AAOMS), summarizes our current understanding of the pathophysiology of ARONJ based on a literature search, and suggests methods for physicians and dentists/oral surgeons to manage the disease. In addition, the appropriateness of discontinuing antiresorptive medications (drug holiday) before, during, and after invasive dental treatments is discussed extensively. More importantly, the manuscript also proposes, for the first time, the importance of interactive communication and cooperation between physicians and dentists/oral surgeons for the successful treatment of ARONJ. The Position Paper 2017 is intended to serve as a guide for improving the management of ARONJ patients in Japan

Repeat protein scaffolds: ordering photo- and electroactive molecules in solution and solid state

The precise control over the organization of photoactive components at the nanoscale is one of the main challenges for the generation of new and sophisticated macroscopically ordered materials with enhanced properties. In this work we present a novel bioinspired approach using protein-based building blocks for the arrangement of photo and electroactive porphyrin derivatives. We used a designed repeat protein scaffold with demonstrated unique features that allow for the control of their structure, functionality, and assembly. Our designed domains act as exact biomolecular templates to organize porphyrin molecules at the required distance. The hybrid conjugates retain the structure and assembly properties of the protein scaffold and display the spectroscopic features of orderly aggregated porphyrins along the protein structure. Finally,we achieved a solid ordered bio-organic hybrid thin film with anisotropic photoconductivity

Association of Serum Cytokine Levels With Treatment Response to Pegylated Interferon and Ribavirin Therapy in Genotype 1 Chronic Hepatitis C Patients

Methods. We quantified a total of 8 serum cytokines before, during, and after treatment in 79 genotype 1 chronic HCV patients. Viral ISDR and core region variants were determined by direct sequencing. Results. High levels of interleukin (IL)-12 and IL-18 and more than 2 mutations in the ISDR were associated with a sustained virological response (SVR). Conversely, high baseline IL-10 levels and glutamine at amino acid 70 of the HCV core protein (Gln70) were significantly associated with a nonresponse to treatment, and patients with Gln70 had significantly higher IL-10 levels. In multivariate analysis, low IL-10, high IL-12, and high IL-18 levels were independently associated with an SVR. These 3 cytokine levels were decreased from baseline levels 4 weeks into treatment and remained low in patients with an SVR. Conclusion. Serum IL-10, IL-12, and IL-18 levels are predictive of the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR and core region.ArticleJOURNAL OF INFECTIOUS DISEASES. 203(8):1087-1095 (2011)journal articl

Consequences of Two Different Amino-Acid Substitutions at the Same Codon in KRT14 Indicate Definitive Roles of Structural Distortion in Epidermolysis Bullosa Simplex Pathogenesis

Numerous inherited diseases develop due to missense mutations, leading to an amino-acid substitution. Whether an amino-acid change is pathogenic depends on the level of deleterious effects caused by the amino-acid alteration. We show an example of different structural and phenotypic consequences caused by two individual amino-acid changes at the same position. Epidermolysis bullosa simplex (EBS) is a genodermatosis resulting from KRT5 or KRT14 mutations. Mutation analysis of an EBS family revealed that affected individuals were heterozygous for a, to our knowledge, previously unreported mutation of c.1237G>C (p.Ala413Pro) in KRT14. Interestingly, 2 of 100 unrelated normal controls were heterozygous, and 1 of the 100 was homozygous for a different mutation in this position, c.1237G>A (p.Ala413Thr). In silico modeling of the protein demonstrated deleterious structural effects from proline substitution but not from threonine substitution. In vitro transfection studies revealed a significantly larger number of keratin-clumped cells in HaCaT cells transfected with mutant KRT14 complementary DNA (cDNA) harboring p.Ala413Pro than those transfected with wild-type KRT14 cDNA or mutant KRT14 cDNA harboring p.Ala413Thr. These results show that changes in two distinct amino acids at a locus are destined to elicit different phenotypes due to the degree of structural distortion resulting from the amino-acid alterations

Serum interleukin (IL)-10 and IL-12 levels and IL28B gene polymorphisms: pretreatment prediction of treatment failure in chronic hepatitis C

Background: Both IL28B gene polymorphisms and serum levels of interleukin (IL)-10, IL-12p40 and IL-18 have been reported to affect the outcome of natural and pegylated interferon and ribavirin-treated HCV infection. Methods: To clarify their association and predictive value in treatment outcome of genotype 1 HCV-infected patients, we measured pretreatment serum IL-10, IL-12p40 and IL-18 levels using multiplex assays and determined IL28B gene polymorphisms (rs 8099917) in 52 cases with chronic hepatitis C. Results: High baseline levels of IL-10 (P<0.001) and low levels of IL-12p40 (P<0.001) were significantly associated with a non-virological response (NVR) in our cohort. The IL28B polymorphism was tested and TT, TG or GG genotypes were found in 60%, 38% and 2% of patients, respectively, with corresponding NVR rates of 10%, 60% and 100% (P<0.001). Serum cytokine levels were significantly correlated with IL28B gene polymorphisms. When serum IL-10 levels were stratified at 5.0 pg/ml, NVR rates were 50% versus 0% (P=0.004) for the IT genotype and 87% versus 0% (P=0.001) for the TG or GG genotypes. Similarly, low IL-12p40 levels were associated with an NVR in patients with TG or GG genotypes (P=0.006). In multivariate analysis, high IL-10, low IL-12p40 and IL28B TG or GG genotypes were independently associated with an NVR. Conclusions: Serum IL-10 and IL-12p40 levels in combination with IL28B genotype, especially G-allele carriage, are strong predictive markers of an NVR to HCV treatment with pegylated interferon and ribavirin.ArticleANTIVIRAL THERAPY. 16(7):1073-1080 (2011)journal articl

Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study

Background: Glutathione plays crucial roles in the detoxification and antioxidant systems of cells and has been used to treat acute poisoning and chronic liver diseases by intravenous injection. This is a first study examining the therapeutic effects of oral administration of glutathione in patients with nonalcoholic fatty liver disease (NAFLD). Methods: The study was an open label, single arm, multicenter, pilot trial. Thirty-four NAFLD patients diagnosed using ultrasonography were prospectively evaluated. All patients first underwent intervention to improve their lifestyle habits (diet and exercise) for 3 months, followed by treatment with glutathione (300 mg/day) for 4 months. We evaluated their clinical parameters before and after glutathione treatment. We also quantified liver fat and fibrosis using vibration-controlled transient elastography. The primary outcome of the study was the change in alanine aminotransferase (ALT) levels. Results: Twenty-nine patients finished the protocol. ALT levels significantly decreased following treatment with glutathione for 4 months. In addition, triglycerides, non-esterified fatty acids, and ferritin levels also decreased with glutathione treatment. Following dichotomization of ALT responders based on a median 12.9% decrease from baseline, we found that ALT responders were younger in age and did not have severe diabetes compared with ALT non-responders. The controlled attenuation parameter also decreased in ALT responders. Conclusions: This pilot study demonstrates the potential therapeutic effects of oral administration of glutathione in practical dose for patients with NAFLD. Large-scale clinical trials are needed to verify its efficacy. Trial registration: UMIN000011118 (date of registration: July 4, 2013)

How is the IUGONET project using TDAS?

GEM Mini-Workshop, San Francisco; 2011-12-0