MicroRNAs in hepatic pathophysiology

MicroRNAs (miRNAs) are a group of small non‐coding RNAs that range in length from 20 to 25 nucleotides. MicroRNAs are specific for multiple cellular functions, including cell generation, differentiation, multiplication, carcinogenesis, and apoptosis. Many researchers have recently reported that the aberrant expression of miRNAs in hepatic tissue was related to the pathogenesis of liver disease, including viral hepatitis, hepatocellular carcinoma, and fatty liver disease. Multiple studies have proposed that an analysis of circulating miRNAs may be useful for diagnosing etiologies or staging the progression of liver disease, as well as for therapeutic purposes, for example, nucleic acid therapy. This review summarizes and discusses recent advances in the knowledge of miRNAs for chronic liver diseases, with special interest in viral hepatitis, liver fibrosis, and biomarkers.     

Therapeutic potential of new hydrogen sulfide-releasing hybrids

A new class of hydrogen sulfide (H₂S)-donating hybrids combined with pharmacologically active compounds is presented in this article. The pharmacological profiles of some hybrid lead compounds in the areas of inflammation, H₂S-donating diclofenac (ACS 15); cardiovascular, H₂S-donating aspirin (ACS 14); urology, H₂S-donating sildenafil (ACS 6); and neurodegenerative, H₂S-donating latanoprost (ACS 67) for glaucoma treatment and H₂S-donating levodopa (ACS 84) for Parkinson’s disease, are described. The new H₂S-releasing hybrids demonstrate remarkable improvement in activity and tolerability as compared with the related parent compounds, suggesting an active pharmacological role for H₂S. Finally the mechanism(s) of action of glutathione-dependent and independent, and of gas (H₂S) release (spontaneous or enzymatic) and its implications for clinical pharmacology perspectives will be also discussed.     

Mammaglobin peptide as a novel biomarker for breast cancer detection

Among the different types of tests used for cancer diagnosis, molecular tests have been increrasingly incorporated because of their ability to detect either expression or functional changes in the molecules associated with the disease. Mammaglobin is a protein found in mammary tissue and can be detected in serum. This protein has been proposed as a biomarker to diagnose breast cancer, given that patients exhibit an increased amount of the protein in serum and tumor tissue, in comparison to healthy individuals. The ELISA test was used in the present study to detect mammaglobin in blood samples from 51 breast cancer patients and 51 control individuals. Antibodies against mamaglobin were generated in rabbits by using the following synthetic peptides: A (amino acids 13 to 21), B (amino acids 31 to 39), C (amino acids 56 to 64) and a D peptide, corresponding to the protein isoform without three amino acids (59, 60 and 61 amino acids) from peptide C. All peptides were immunogenic and allowed generation of antibodies that were able to discriminate patients from controls. The best results were obtained for antiserum B, achieving the best sensitivity (86.3%) and specificity (96%).     

Vitamin B12 and its binding proteins in hepatocellular carcinoma and chronic liver diseases

Abstract

Background. The vitamin B₁₂ (B₁₂)-binding protein haptocorrin (HC) has proven to be a potentially useful biomarker in patients with fibrolamellar hepatocellular carcinoma (HCC). Little is known concerning the level of HC and other B₁₂-related proteins in patients with HCC as compared to patients with other chronic liver diseases (CLDs) and healthy controls. We hypothesized that HC could be a biomarker of HCC. Aims. To investigate levels of HC and B₁₂-related proteins in HCC compared to CLDs and healthy controls. Methods. We investigated two patient populations: A cross-sectional cohort of HCC patients (n = 130), CLD patients (n = 102) and healthy controls (n = 46) and a cohort of 38 HCC patients studied at baseline and 1, 4, and 12 weeks following ablative treatment. Patients were evaluated by standard biochemistry, Child–Pugh-score and Barcelona Clinic Liver Cancer (BCLC) classification. We analyzed total B₁₂ by routine methods and HC, transcobalamin (TC), B₁₂ saturated TC (holoTC), and the soluble cell surface receptor for holoTC (sCD320) by in-house enzyme-linked immunosorbent assay. Results. HC showed higher median (range) levels for both HCC (590 [290–5860]) and CLD patients (620 [310–4010]) compared to controls (460 [250–2020]) (p < 0.01). Total B₁₂, TC, holoTC, and sCD320 showed elevated levels in both HCC and CLD compared to controls. Only holoTC changed following treatment, without a concurrent change in TC. Conclusion. B₁₂ and B₁₂-related proteins (total B₁₂, HC, TC, holoTC, and sCD320) show elevations in both HCC and CLD patients compared to controls, suggesting a relation to CLD in general rather than to primary liver cancer. Thus, HC is not useful as a biomarker for HCC.     

Biomarker-based adaptive trials for patients with glioblastoma—lessons from I-SPY 2

The traditional clinical trials infrastructure may not be ideally suited to evaluate the numerous therapeutic hypotheses that result from the increasing number of available targeted agents combined with the various methodologies to molecularly subclassify patients with glioblastoma. Additionally, results from smaller screening studies are rarely translated to successful larger confirmatory studies, potentially related to a lack of efficient control arms or the use of unvalidated surrogate endpoints. Streamlining clinical trials and providing a flexible infrastructure for biomarker development is clearly needed for patients with glioblastoma. The experience developing and implementing the I-SPY studies in breast cancer may serve as a guide to developing such trials in neuro-oncology.     

Structural abnormalities revealed by magnetic resonance imaging in rats prenatally exposed to methylazoxymethanol acetate parallel cerebral pathology in schizophrenia

Schizophrenia is a highly familial, neurodevelopmental disorder that is associated with several neuropsychiatric, psychological, and neuropathological features. Although pharmacological animal models of dopaminergic and glutamatergic dysfunction have helped advance our understanding of the disease biology, there is a clear need for translational models that capture the neuropathological and functional manifestations associated with the intermediate phenotype and the clinical illness. Neuroimaging of preclinical neurodevelopmental approaches such as methylazoxymethanol acetate (MAM) exposure may afford a powerful translational tool to establish endpoints with greater congruency across animals and humans. Using in vivo volumetric magnetic resonance imaging (MRI), manganese‐enhanced MRI, and diffusion tensor imaging (DTI), we investigated morphological and cytoarchitectural changes of brain structures in MAM‐exposed rats, a neurodevelopmental model of schizophrenia. Compared to saline‐exposed controls, MAM‐exposed rats showed significant enlargement of lateral and third ventricles as well as reduced hippocampal volumes, which is consistent with findings observed in schizophrenia. In addition, DTI revealed that diffusion fractional anisotropy retrieved from corpus callosum and cingulum were significantly decreased in MAM‐exposed rats, suggesting that demyelination occurred in these white‐matter fiber tracts. Imaging findings were confirmed by conducting histological analysis using hematoxylin and eosin and Luxol fast blue stainings. In summary, structural abnormalities resulting from a MAM environmental challenge parallel cerebral pathology observed in schizophrenia. The MAM model incorporating noninvasive imaging techniques may therefore serve as an improved translational research tool for assessing new treatments for schizophrenia. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

乳腺癌中STC1的表达与乳腺癌肺转移相关

 目的  研究乳腺癌中分泌蛋白斯坦尼钙调节蛋白1(stanniocalcin 1,STC1)的表达与乳腺癌转移的关系。方法  用质谱及Western blot 分析STC1在具有不同转移能力细胞系中的蛋白表达情况。荧光定量RT-PCR(qRT-PCR)分析STC1 mRNA在乳腺癌细胞系及23例患者样本中的表达情况,并通过网上数据库分析1 609例乳腺癌患者STC1 mRNA的表达水平与患者发生远端转移之间的关系。结果  质谱及Western blot分析结果显示,具有高转移能力的乳腺癌细胞系高表达STC1。qRT-PCR分析结果显示,STC1在高转移乳腺癌细胞系中高表达,STC1在转移性乳腺癌患者中的表达高于非转移性患者。另外,通过对数据库中乳腺癌患者样本的分析发现,原位癌高表达STC1的乳腺癌患者更容易发生远端转移。结论  STC1的表达与乳腺癌的转移具有相关性,提示STC1具有临床预测乳腺癌肺转移的潜在价值。