[Evaluation of cardiac dysfunction after herceptin treatment in patients with metastatic breast cancer by echocardiography].

Herceptin (Trastuzumab) is a humanized recombinant monoclonal antibody that binds the extracellular domain of the human epidermal growth factor receptor 2 (HER2) and is used in the treatment of patients with HER2 overexpressing metastatic breast cancer. Treatment with Herceptin is generally well tolerated. At times, however, it exerts cardiac toxicity especially when used in combination with anthracyclines. We evaluated cardiac function before and after Herceptin treatment in nine patients with metastatic breast cancer by echocardiography, measuring ejection fraction (EF) and deceleration time (DcT). EF was significantly reduced after treatment(P<0.05). Although the present study failed to show significant changes in DcT, definite diastolic disturbance of the left ventricle did occur in a couple of patients. We conclude that cardiac dysfunction may be a common side effect of Herceptin even in early stages of treatment and that echocardiography will be a useful means of monitoring cardiac function in these patients.

Structural characterization and promoter analysis of human potassium channel Kv8.1 (KCNV1) gene.

The voltage-gated K(+) channel (Kv) family comprises four subfamilies: Kv1, Kv2, Kv3 and Kv4. Kv6, Kv7, Kv8 and Kv9 subfamilies have also recently been reported. The gene for Kv8.1 (KCNV1) maps onto chromosome 8q23.3, a locus for benign adult familial myoclonic epilepsy. Despite sequence identity with other K(+) channel genes, KCNV1 does not display K(+) channel activity when expressed in Xenopus oocytes, instead inhibiting activity of Kv2 and Kv3 channels. The present study investigated the molecular structure of KCNV1. In silico analysis detected a new 5' noncoding exon, which extended the reported cDNA sequence to approximately 600 bp. A promoter motif was found only in the upstream region of the newly detected exon 1. To determine the transcriptional mechanism of KCNV1, we generated a series of deletion mutants and random mutants, and examined promoter activities using the luciferase system. Three Sp1 motifs were found to be active in the core promoter sequence, spanning from nt -1350 to -911 (A of the ATG initiation codon was counted as +1). At least two additional sequences were detected as essential elements for promoter activity. A possible alternative 3' end was also detected at 280 bp downstream from the reported 3' end. These results provide useful information in developing KCNV1 screening for epileptic disease.

C18orf1 located on chromosome 18p11.2 may confer susceptibility to schizophrenia.

The pericentromeric region of chromosome 18, especially 18p11.2, is described as a schizophrenia susceptibility locus. We had previously cloned two novel brain-derived transcripts from this region: the gene for a second human myo-inositol monophosphatase (IMPA2) and a gene of unknown function, C18orf1. Recently, we reported a distortion of transmission of the tandem repeat marker D18S852, embedded in the 3'-untranslated region of C18orf1, in schizophrenia, using a family-based association test. A subsequent case-control study also revealed a significant association between the haplotype constructed from D18S852 and the 6409T>C polymorphism located in C18orf1 and schizophrenia. In the present study, we screened the C18orf1 gene for mutations and identified a novel single nucleotide polymorphism (SNP), -96T>C in exon 2. This SNP showed significant genotypic (P = 0.048) and allelic association (P = 0.005) with schizophrenia in a case-control study. The distributions of haplotypes defined by D18S852 and -96T>C were different between control and schizophrenia groups (P = 0.021). These findings suggest that C18orf1 or a gene nearby may contribute to the overall genetic risk for schizophrenia.

Gaseous neuromodulator-related genes expressed in the brain of honeybee Apis mellifera.

Nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO) are thought to act as gaseous neuromodulators in the brain across species. For example, in the brain of honeybee Apis mellifera, NO plays important roles in olfactory learning and discrimination, but the existence of H2S- and CO-mediated signaling pathways remains unknown. In the present study, we identified the genes of nitric oxide synthase (NOS), soluble guanylyl cyclase (sGC), cystathionine beta-synthase (CBS), and heme oxygenase (HO) from the honeybee brain. The honeybee brain contains at least one gene for each of NOS, CBS, and HO. The deduced proteins for NOS, CBS, and HO are thought to contain domains to generate NO, H2S, and CO, respectively, and to contain putative Ca2+/calmodulin-binding domains. On the other hand, the honeybee brain contains three subunits of sGC: sGCalpha1, sGCbeta1, and sGCbeta3. Phylogenetic analysis of sGC revealed that Apis sGCalpha1 and sGCbeta1 are closely related to NO- and CO-sensitive sGC subunits, whereas Apis sGCbeta3 is closely related to insect O2-sensitive sGC subunits. In addition, we performed in situ hybridization for Apis NOS mRNA and NADPH-diaphorase histochemistry in the honeybee brain. The NOS gene was strongly expressed in the optic lobes and in the Kenyon cells of the mushroom bodies. NOS activity was detected in the optic lobes, the mushroom bodies, the central body complex, the lateral protocerebral lobes, and the antennal lobes. These findings suggest that NO is involved in various brain functions and that H2S and CO can be endogenously produced in the honeybee brain.

Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity.

The cellular protein retinoic acid-inducible gene I (RIG-I) senses intracellular viral infection and triggers a signal for innate antiviral responses including the production of type I IFN. RIG-I contains a domain that belongs to a DExD/H-box helicase family and exhibits an N-terminal caspase recruitment domain (CARD) homology. There are three genes encoding RIG-I-related proteins in human and mouse genomes. Melanoma differentiation associated gene 5 (MDA5), which consists of CARD and a helicase domain, functions as a positive regulator, similarly to RIG-I. Both proteins sense viral RNA with a helicase domain and transmit a signal downstream by CARD; thus, these proteins share overlapping functions. Another protein, LGP2, lacks the CARD homology and functions as a negative regulator by interfering with the recognition of viral RNA by RIG-I and MDA5. The nonstructural protein 3/4A protein of hepatitis C virus blocks the signaling by RIG-I and MDA5; however, the V protein of the Sendai virus selectively abrogates the MDA5 function. These results highlight ingenious mechanisms for initiating antiviral innate immune responses and the action of virus-encoded inhibitors.

The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses.

Intracellular double-stranded RNA (dsRNA) is a chief sign of replication for many viruses. Host mechanisms detect the dsRNA and initiate antiviral responses. In this report, we identify retinoic acid inducible gene I (RIG-I), which encodes a DExD/H box RNA helicase that contains a caspase recruitment domain, as an essential regulator for dsRNA-induced signaling, as assessed by functional screening and assays. A helicase domain with intact ATPase activity was responsible for the dsRNA-mediated signaling. The caspase recruitment domain transmitted 'downstream' signals, resulting in the activation of transcription factors NF-kappaB and IRF-3. Subsequent gene activation by these factors induced antiviral functions, including type I interferon production. Thus, RIG-I is key in the detection and subsequent eradication of the replicating viral genomes.