Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin

Since a variety of cell intrinsic and extrinsic molecular abnormalities cooperatively promote tumor formation in multiple myeloma (MM), therapeutic approaches that concomitantly target more than one molecule are increasingly attractive. We herein demonstrate the anti-myeloma effect of a cephalotaxus alkaloid, homoharringtonine (HHT), an inhibitor of protein synthesis, through the induction of apoptosis. HHT significantly reduced Mcl-1, a crucial protein involved in myeloma cell survival, in all three myeloma cell lines examined, whereas certain BH3-only proteins, such as Bim, Bik, and Puma, remained unchanged following HHT treatment, and their expression levels depended on the cell type. HHT also reduced the levels of c-FLIP(L/S), activated caspase-8, and induced active truncated-Bid. Thus, HHT-induced apoptosis appears to be mediated via both intrinsic and extrinsic apoptosis pathways, and the resultant imbalance between BH3-only proteins and Mcl-1 may be pivotal for apoptosis by HHT. In addition, HHT treatment resulted in reduced levels of beta-catenin and XIAP proteins, which also contribute to disease progression and resistance to chemotherapy in MM. In combination, HHT enhanced the effects of melphalan, bortezomib, and ABT-737. These results suggest that HHT could constitute an attractive option for MM treatment though its ability to simultaneously target multiple tumor-promoting molecules.     

Reciprocal synaptic relationships between orexin- and melanin-concentrating hormone-containing neurons in the rat lateral hypothalamus: a novel circuit implicated in feeding regulation

OBJECTIVE: Both orexin (ORX)- and melanin-concentrating hormone (MCH) are expressed in different neurons in the lateral hypothalamic area (LH), and are considered to have common effects on stimulating food intake. There are no reports to demonstrate neural interactions between them at the ultrastructural level. We observed these neurons in the LH to evaluate the relationships between them. DESIGN: We used two different types of double immunostaining to reveal the ultrastructure of both the ORX- and MCH-containing neurons. A preembedding double immunostaining technique was used to study the synaptic relationships between the two kinds of neuron. RESULTS: The main new findings are as follows: 1) Both ORX- and MCH-containing neurons received other synaptic input and made synaptic input to other neurons; 2) Reciprocal synaptic relationships were observed between the ORX- and MCH-containing neurons. CONCLUSION: The ORX- and MCH-containing neurons in the lateral hypothalamic area may influence food intake through synapse with each other.     

Marked elevation of CA19-9 in a patient with idiopathic pulmonary fibrosis: CA19-9 as a bad prognostic factor

Abstract A 53-year-old Japanese female, who had been suffering from idiopathic pulmonary fibrosis (IPF) for 3 years, was admitted with dyspnoea. The important laboratory finding on admission was a serum CA19-9 level of 649 U/mL. Despite steroid treatment for IPF, her respiratory condition gradually deteriorated with the increase of serum CA19-9 level up to 3020 U/mL and she died of respiratory failure. Immunohistochemistry showed the positive stain of CA19-9 in bronchoepithelial cells. We also reviewed the Index Medics and picked up the cases who had elevation of CA19-9 more than 1000 U/mL, and six patients were listed. Five of these six patients died within 6 months, therefore the marked elevation of CA19-9 seemed to be a bad prognostic factor in patients with pulmonary fibrosis.     

Role of fibrinolysis in tissue-factor-induced disseminated intravascular coagulation in rats - an effect of tranexamic acid

We clarified the role of fibrinolysis in tissue-factor (TF)-induced rat disseminated intravascular coagulation (DIC) using tranexamic acid (TA). TA suppressed the elevation in D-dimer levels normally observed following TF-induced DIC, and an increase in organ dysfunction was seen. Enhanced fibrinolysis plays an important role in preventing the development of organ failure in TF-induced DIC.     

Effect of radioactivity outside the field of view on image quality of dedicated breast positron emission tomography: preliminary phantom and clinical studies

Annals of Nuclear Medicine - Semi-quantitative positron emission tomography (PET) values, such as the maximum standardized uptake value (SUVmax), are widely used to identify malignant lesions and...     

Clinical impact of amyloid PET using 18F-florbetapir in patients with cognitive impairment and suspected Alzheimer’s disease: a multicenter study

Annals of Nuclear Medicine - Amyloid positron emission tomography (PET) can reliably detect senile plaques and fluorinated ligands are approved for clinical use. However, the clinical impact of...     

Voxel-based analysis of age and gender effects on striatal [123I] FP-CIT binding in healthy Japanese adults

Annals of Nuclear Medicine - Although previous studies have investigated age and gender effects on striatal subregional dopamine transporter (DaT) binding, these studies were mostly based on a...     

Expression of pulmonary VEGF family declines with age and is further down-regulated in lipopolysaccharide (LPS)-induced lung injury

Vascular endothelial growth factor (VEGF) is a survival factor in endothelial cells and a promoter of angiogenesis that reportedly plays a pivotal role protecting against injury. In aged humans and animals, lung injuries are generally more serious and cause higher mortality. We thus hypothesized that the expression of VEGF and its related molecules in the lung declines with age. In this study, we first examined the expression of VEGF family (VEGF-A, -B, -C and -D), VEGF-A isoforms (VEGF120, 164, 188), and VEGF-specific receptors (VEGFR-1: Flt-1; VEGFR-2: Flk-1 and VEGFR-3: Flt-4) by quantitative RT-PCR in lungs from young and old mice. Expression of all these except for VEGF-D was significantly lower in old mice than in young mice. We then subjected young and old mice to lipopolysaccaride (LPS)-induced lung injury. Old animals demonstrated poor survival and prolonged lung inflammation when compared with young counterparts. At 24 and 72 h after intratracheal LPS administration, expression of the examined factors was down-regulated in the lungs irrespective of age. In conclusion, pulmonary expression of the VEGF family and their receptors declines with age, and is further down-regulated in LPS-induced lung injury, although the mechanism of age- and/or injury-related down-regulation of VEGF remains unknown.     

Clinical significance of serum autoantibodies against Ras-like GTPases,RalA, in patients with esophageal squamous cell carcinoma

Background

The Ras-like GTPases, RalA and RalB are members of the Ras superfamily of small GTPases. Aberrant activation of Ral is a major cause of human tumorigenesis induced by oncogenic Ras. Serum anti-RalA antibodies are induced in esophageal carcinoma patients. However, detailed comparisons of their pathological characteristics are unavailable, and conventional serum markers have not been well evaluated.

Methods

Serum samples of 171 patients with esophageal squamous cell carcinoma and 73 healthy individuals were analyzed using specifically developed ELISA system for serum anti-RalA antibodies. A cut-off optical density value was fixed at 0.255 (the control mean + 2 SD). Clinicopathological characteristics and positive rates of conventional tumor markers were evaluated for seropositive patients.

Results

Overall positive rate for serum anti-RalA antibodies was 18 %, which gradually increased with the tumor stages. Although the positive rate for serum anti-RalA antibodies was comparable with that of carcinoembryonic antigen (24 %) and CYFRA21-1 (21 %), it was lower than the rate for serum p53 antibodies (31 %) and squamous cell carcinoma antigen (37 %). Although serum anti-RalA antibodies were not associated with other serum markers, it was inversely associated with serum p53 antibodies. No clear association was observed between serum anti-RalA antibodies and RalA immunoreactivity.

Conclusions

Presence of serum anti-RalA antibodies is associated with tumor stages, but not with conventional tumor markers. Serum anti-RalA antibodies may be candidate serum markers in combination with other serum markers for esophageal squamous cell carcinoma.

     

Acute hepatitis E of a man who consumed wild boar meat prior to the onset of illness in Nagasaki, Japan.

Zoonotic infection of hepatitis E virus (HEV) has been suggested. To date, pigs, deer, and wild boar have been implicated as reservoirs of HEV in Japan. However, it is not known to what extent zoonotic transmission of HEV play roles of causing HEV transmission. In the present report, we describe a case of acute hepatitis E in which a transmission of HEV by a zoonotic transmission is strongly suggested. The patient had eaten grilled wild boar meat 59 days prior to onset of acute hepatitis. Although the meat was not stored, one of the two people who ate boar meat with the patient at the same time showed high levels of HEV-IgM and -IgG and normal levels of liver enzymes, suggesting a subclinical infection of HEV. Accumulating evidence suggests that eating wild boars is associated with a high risk of acquiring hepatitis E infection.