Circumferential membranous GPC3 immunoreactivity in HCC indicates poorer prognosis particularly in patients with HCV infection.

A series of phthalazine and 1,2,3-benzotriazine derivatives which have heterocyclylpiperidino groups was synthesized and tested for cardiotonic activity in anesthetized dogs. Several 6,7-dimethoxyphthalazine derivatives showed relatively potent cardiotonic activity comparable to that of amrinone.

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Previously, we demonstrated that membrane expression of glypican-3 (GPC3) stimulates the recruitment of macrophages into human hepatocellular carcinoma (HCC) tissues. However, functional polarization of the macrophages and the chemoattractant factors related to the recruitment has yet to be determined. In this study, to clarify the polarization (M1 or M2) of the macrophages and provide a clue as to the factors involved in the recruitment, we used xenograft models of SK-HEP-1 and SK03 cell lines with undetectable and high-level membrane expression of GPC3, respectively and analyzed the expression profiles of the relevant genes in both xenografts mainly using microarray techniques. Clustering analyses with mouse genome arrays revealed that the SK-HEP-1 and SK03 xenografts showed different expression profiles for M2 macrophage-related genes but not for M1 macrophage-related genes. Many of the M2 macrophage-related genes were upregulated in the SK03 xenografts compared to the SK-HEP-1 xenografts. Additionally, most of the macrophages infiltrating into the SK03 xenografts were positive for M2 macrophage-specific markers. Regarding the chemoattractant factors, the microarray and quantitative real-time PCR analyses revealed that, of the genes reportedly related to macrophage recruitment, CCL5, CCL3 and CSF1 were significantly upregulated in the SK03 xenograft. These findings suggest that the macrophages recruited into GPC3-overexpressing (with membrane expression) HCC are M2-polarized ones and, more specifically, M2 tumor-associated macrophages which are known to promote tumor progression and metastasis, and CCL5, CCL3 and CSF1 are possible candidate genes for the recruitment of macrophages.

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The observations suggest that the increased macrophages in the GPC3+/C pattern are likely to be recruited macrophages, not resident macrophages, and that the expression of GPC3 in the membrane is involved in macrophage recruitment.

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ABSTRACT. Pneumocystis carinii pneumonia was diagnosed by postmortem examination of a one-year-old Cavalier King Charles Spaniel with four-week history of dyspnea. Cytologic and histologic examination of lung tissues revealed numerous P. carinii trophozoites and cysts, and P. carinii specific DNA was detected by polymerase chain reaction. The dog showed hypogammagloblinemia and extremely low levels of serum IgG. It was considered that P. carinii pneumonia in this case was associated with an immunodeficient condition which has already been reported in Miniature Dachshunds. Pneumocystis carinii (P. carinii) is an organism of uncertain taxonomy. It was thought to be a protozoan but has recently been classified as a fungus. It affects both animals and humans, although infections are usually subclinical. It can cause severe or sometimes fatal pneumonia especially in immunosuppressed hosts such as human patients with acquired immunodeficiency syndrome. In dogs, Pneumocystis pneumonia has been most commonly described in Miniature Dachshunds [3,4,6,7]. Immunological studies have revealed that Pneumocystis pneumonia is associated with immunodeficiency in this breed [7]. This is a first report which describes a case of P.carinii pneumonia in a young Cavalier King Charles Spaniel in Japan.A one-year-old male Cavalier King Charles Spaniel, weighing 7.3 kg, presented at the Veterinary Medical Center of the University of Tokyo with a four-week history of anorexia, coughing and respiratory distress. Treatment with antibiotics and aminophylline by the referring veterinarian had failed. Physical examination revealed tachypnea, dyspnea and cyanosis. Rectal temperature was normal and the submandibular lymph nodes were slightly enlarged. On thoracic auscultation, harsh lung sounds were heard over all lung fields without cardiac murmur. Thoracic radiography showed severe generalized interstitial and alveolar patterns in all lung lobes (Fig. 1). The cardiac silhouette was normal in size and shape. Abnormalities of hematological examinations included mildly increased packed cell volume (51%), high WBC count (31.9 × 10 3 /µl) and neutrophilia (27.0 × 10 3 /µl) with increased nonsegmented neutrophiles. The lymphocyte count was within normal range (2.4 × 10 3 /µl), and total plasma protein concentration was slightly high (9.2 g/dl). Routine plasma biochemical profiles revealed increased activities of alkaline phosphatase (910 IU) and alanine aminotransferase (369 IU). Antibodies against Toxoplasma gondii species were not detected by latex-agglutination assay (Eiken, Tokyo, Japan). Serum protein revealed hypogammaglobulinemia by electrophoresis and the IgG and IgM concentration was determined as 0.72 mg/ml (reference range: 15 ± 5 mg/ml) and 2.3 mg/ml (reference range: 1.5 ± 0.5 mg/ml) [9] by quantitative sandwich enzyme-linked immunosorbent assay (ELISA) kits (Bethyl, Montgomery, TX). Treatment with antibiotics (cefazolin sodium and amikacin sulfate), bronchodilator (aminophylline) and nebulization (gentamicin sulfate with sterile saline...