Extent of Laminin-5 Assembly and Secretion Effect Junctional Epidermolysis Bullosa Phenotype

Junctional epidermolysis bullosa (JEB) is an autosomal recessive skin blistering disease with both lethal and nonlethal forms, with most patients shown to have defects in laminin-5. We analyzed the location of mutations, gene expression levels, and protein chain assembly of the laminin-5 heterotrimer in six JEB patients to determine how the type of genetic lesion influences the pathophysiology of JEB. Mutations within laminin-5 genes were diversely located, with the most severe forms of JEB correlating best with premature termination codons, rather than mapping to any particular protein domain. In all six JEB patients, the laminin-5 assembly intermediates we observed were as predicted by our previous work indicating that the α3β3γ2 heterotrimer assembles intracellularly via a β3γ2 heterodimer intermediate. Since assembly precedes secretion, mutations that disrupt protein–protein interactions needed for assembly are predicted to limit the secretion of laminin-5, and likely to interfere with function. However, our data indicate that typically the most severe mutations diminish mRNA stability, and serve as functional null alleles that block chain assembly by resulting in either a deficiency (in the nonlethal mitis variety) or a complete absence (in lethal Herlitz-JEB) of one of the chains needed for laminin-5 heterotrimer assembly.     

Thrombolysis and thromboaspiration for acute thromboembolic occlusion in the upper extremity

Purpose  

To report technical aspects of thrombolysis and thromboaspiration for acute thromboembolic occlusion in the upper extremity.     

Beta-catenin-activated hepatocellular adenoma showing hyperintensity on hepatobiliary-phase gadoxetic-enhanced magnetic resonance imaging and overexpression of OATP8

We report a male case of beta-catenin-activated hepatocellular adenoma (HCA) focusing on findings of gadoxetic-acid-enhanced magnetic resonance imaging (EOB-MRI) and discussing the molecular background and possible clinical significance. The patient was a 31-year-old man in whom computed tomography (CT) showed a large nodule of 14?cm in diameter in the right liver lobe. On dynamic contrast-enhanced CT, heterogeneous and slight to moderate enhancement was observed during the early phase, with washout in the late phase. Focal fat deposits and a scar-like portion in the lesion were also seen. Most of the lesion was slightly hyperintense compared with the background liver on the hepatobiliary phase of EOB-MRI. After operation, this patient was confirmed pathologically as having beta-catenin-activated HCA with a portion suggestive of malignant transformation. In addition, intense organic anion transporter polypeptide 8 expression was observed throughout the tumor by immunohistochemical staining.     

Efficacy of dibutyryl cyclic AMP in heart failure unresponsive to catecholamines

The efficacy of dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) was evaluated in eight patients with heart failure unresponsive to catecholamine therapy. Seven patients who were hemodynamically at Forrester's hemodynamic subset stage H-IV and had a left ventricular stroke work index (LVSWI) of less than 20 g-m/m2 despite administration of unloading drugs and catecholamines were studied both hemodynamically and clinically. Another patient with dilated cardiomyopathy, in whom invasive hemodynamic monitoring could not be carried out, was studied clinically. The DBcAMP was administered intravenously at a mean (+/- SD) of 0.05 +/- 0.036 mg/kg/min, and hemodynamic measurements were made 63 +/- 37 min after administration. The cardiac index (CI) increased from 1.92 +/- 0.22 to 2.49 +/- 0.59 L/min/m2, and LVSWI from 14 +/- 4.0 to 18 +/- 5.1 g-m/m2, both significantly (CI, P less than 0.01; LVSWI, P less than 0.025). The total systemic vascular resistance index (TSVRI) decreased significantly from 2,746 +/- 427.2 to 2,218 +/- 582.6 dan.sec.cm-5.m2 ( P less than 0.01). The increase in CI was accompanied by a proportional decrease in TSVRI in all patients. Left ventricular function, which was estimated by the relation between pulmonary arterial end-diastolic pressure and LVSWI, was improved in five of seven patients after administration of DBcAMP. Two patients in whom DBcAMP was given intermittently improved clinically and survived. The authors conclude that DBcAMP has powerful vasodilating and mild positive inotropic effects and hence can be useful for treating heart failure unresponsive to catecholamines.     

Interleukin-28B acts synergistically with cisplatin to suppress the growth of head and neck squamous cell carcinoma

Interleukin-28B (IL-28B), also referred to as interferon-λ3, belongs to the type III interferon family. Earlier studies showed that IL-28B suppresses proliferation of some tumor cells in vitro. IL-28B gene transfection ex vivo also resulted in growth retardation of tumor cells in mice, through either direct antiproliferative action or induction of antitumor immunity. However, it has not been reported whether in vivo therapeutic administration of recombinant IL-28B can inhibit the growth of a pre-established tumor. Here, we found that repetitive subcutaneous administration of recombinant mouse IL-28B significantly induced tumor-specific cytotoxic T lymphocytes and augmented natural killer cytolytic activity, leading to moderate suppression of the growth of a murine head and neck squamous cell carcinoma (HNSCC) cell line that was completely resistant to the direct antiproliferative effect of IL-28B. Moreover, co-administration of recombinant mouse IL-28B and cisplatin (CDDP) more significantly inhibited in vivo growth of the tumor that had been established in syngenic mice and induced tumor-specific cytotoxic T lymphocytes. The CDDP treatment induced the expression of major histocompatibility complex class I and Fas molecules on the surface of HNSCC cells both in vitro and in vivo; this may be the mechanism underlying the synergistic tumor suppression activity of IL-28B and CDDP. Unlike type I interferon, IL-28B did not suppress growth of bone marrow cells in culture. Therefore, IL-28B may be useful as a tool for a novel multidisciplinary therapy against cancer, significantly potentiating innate and adaptive antitumor immune responses, especially when co-administrated with CDDP, which is currently the first choice chemotherapeutic agent against various tumors including HNSCCs.     

Cystic duct remnant carcinoma with widespread invasion along the extrahepatic bile duct wall: dynamic CT findings

We report a case of remnant cystic duct carcinoma with widespread invasion along the common bile duct wall. Thin-slice dynamic computed tomography showed circumferential wall thickening of the extrahepatic bile duct (from the common hepatic duct to the intrapancreatic common bile duct) and the remnant cystic duct. Pathologically, the extrahepatic bile duct wall was thickened due to submucosal tumor infiltration by cystic duct papillary adenocarcinoma.     

Potent vaccine therapy with dendritic cells genetically modified by the gene-silencing-resistant retroviral vector GCDNsap.

Dendritic cells (DCs) genetically modified to express tumor-associated antigens (TAAs) would be promising tools in cancer immunotherapy. However, the use of retroviral vectors for such modifications is still a challenge because of low transduction efficiency and gene silencing in DCs. We have established an efficient method to prepare such DCs by in vitro differentiation of hematopoietic progenitor cells transduced with chicken ovalbumin (OVA) cDNA via the gene-silencing-resistant retroviral vector GCDNsap packaged in vesicular stomatitis virus G protein. When c-KIT(+)/lineage(-) cells were transduced with OVA followed by expansion and differentiation, more than 90% of mature DCs expressed the transgene. Mice inoculated with those cells completely rejected the OVA-expressing tumor E.G7-OVA, and the anti-tumor effects were stronger than those observed in mice inoculated with the same number of OVA peptide-pulsed DCs. The mice harbored more cytotoxic T lymphocytes (CTLs) against E.G7-OVA and produced antibody against OVA, suggesting the generation of multiple CTLs recognizing different OVA epitopes and OVA-specific CD4(+) T cells. Successive inoculations of the transduced DCs in a therapeutic setting eradicated preexisting E.G7-OVA and prevented the progression of retransplanted tumors. Thus, this vaccine therapy may represent a potent immunotherapeutic approach for various malignant tumors that express suitable TAAs.     

Receptor-type tyrosine kinase inhibitors for the treatment of many human diseases

Since the discovery of several oncogenes encoding growth factor and its specific receptor in the early 1980s, small molecule inhibitors as well as monoclonal antibodies for receptor-type tyrosine kinases have been successfully developed for cancer therapy. Such growth factor signaling is perturbed not only in cancer but also in many human diseases. This article reviews the perspective of tyrosine kinase inhibitors on the clinical use for cancer as well as non-malignant diseases, such as vascular disorders, fibrosis and viral infections involving platelet-derived growth factor(PDGF) signaling.