Pancreatic Acinar Cell Carcinoma with Multiple Liver Metastases Effectively Treated by S-1 Chemotherapy.

A 79-year-old woman was referred for pancreatic tail cancer with multiple liver metastases. The pancreatic tail tumor was diagnosed as acinar cell carcinoma (ACC) histologically by endoscopic ultrasound-guided fine-needle aspiration. Because of multiple liver metastases, S-1 chemotherapy was administered, resulting in a partial response to chemotherapy one year later. After approximately three years, liver atrophy and esophageal varices developed. We suspected S-1 as the cause of the liver cirrhosis. S-1 cessation minimized ascites and improved the esophageal varices. Although S-1 can potentially treat ACC, we should be watchful for liver cirrhosis caused by its long-term administration.

Cellulose acetate beads activate the complement system but inactivate the anaphylatoxins generated.

The generation of anaphylatoxins, particularly C5a, is important in extracorporeal circulation therapies such as granulocyte/monocyte apheresis, which activates the complement system and elevates C5a levels. However, no side effects of granulocyte/monocyte apheresis using cellulose acetate beads have been reported. To investigate the mechanism of complement activation, we prepared plasma from cellulose acetate bead-treated blood (P-CAB) and compared it with zymosan-activated plasma (ZAP). Anaphylaxis activity was measured by skin test, and the activity of carboxypeptidase, which inactivates C5a, was measured by colorimetric assay. Pro-carboxypeptidase R and neutrophil elastase concentrations were measured by enzyme-linked immunosorbent assay. Although C5a was generated in P-CAB, the anaphylaxis activity of P-CAB was lower than that of ZAP. Carboxypeptidase activity and pro-carboxypeptidase R levels were suppressed in P-CAB, but not in ZAP. Furthermore, neutrophil elastase levels increased in P-CAB. The decreases in carboxypeptidase activity and inactivation of anaphylatoxin were inhibited by a neutrophil elastase inhibitor. These results suggest that cellulose acetate beads initiate the activation of carboxypeptidase R via elastase release, thereby inducing the inactivation of anaphylatoxin.

Assessment of rabbit spleen size using ultrasonography.

Assessment of spleen size using the ultrasonography has become a standard practice in human. However, the assessment is not established method in experimental animals. To establish the index to assess the spleen size using ultrasonography, we measured the cross-section image of rabbit spleen during endotoxin shock. The image of the cross-section was appeared as triangle, and the height of the triangular image was defined as the spleen index. This spleen index showed strong correlation with the spleen weight. In conclusion, this method is suitable for observation of changes in rabbit spleen size and may reduce the number of rabbit in the longitudinal studies.

AIDS vaccine: Intranasal immunization using inactivated HIV-1-capturing core-corona type polymeric nanospheres.

Polymeric nanospheres have been widely used in biomedical applications, such as drug, gene and vaccine delivery systems. Nanospheres with entrapped antigens have recently been shown to possess significant potential as vaccine delivery systems and adjuvants. We previously reported that concanavalin A-immobilized polystyrene nanospheres (Con A-NS) could efficiently capture HIV-1 particles and intranasal immunization with inactivated HIV-1-capturing nanospheres (HIV-NS) induced vaginal anti-HIV-1 IgA antibody responses in mice. In addition, vaginal washes from intranasally immunized mice were capable of neutralizing HIV-1. Moreover, simian/human immunodeficiency virus KU-2-capturing nanospheres (SHIV-NS) immunized macaques exhibited partial protection when vaginally and systemically challenged with pathogenic viruses. HIV-NS is suggested to be particularly suitable to enhance antigen delivery to dendritic cells (DCs). In this study, we investigated the mucosal antibody response in mice after the intravaginal or intranasal immunization in detail with using different sized (360, 660, 940 and 1230 nm) HIV-NS. The amount of immobilized Con A to NS was dependent on the surface area of the particle. Moreover, Con A-NS with different sizes could equally capture inactivated HIV-1. Intravaginal or intranasal immunization by HIV-NS with diameters ranging 360 to 1230 nm significantly induced vaginal antibody responses. However, significant differences on vaginal anti-HIV-1 gp120 IgA and IgG antibodies were not found after intravaginal or intranasal immunization with different sized HIV-NS. These results suggest that HIV-NS provides an efficient vaccine delivery system for the induction of a mucosal immune response and the development of a mucosal vaccine.

Induction of dendritic cell-mediated immune responses against HIV-1 by antigen-capturing nanospheres in mice.

Prophylactic vaccines, designed to elicit potent humoral and cellular immune responses to human immunodeficiency virus type 1 (HIV-1) antigens in mucosa, are the important approach to the protection of individuals against HIV-1 infection, since HIV-1 transmission is largely a result of sexual contact. In this study, a novel strategy has been developed to induce HIV-1-specific immune responses, which involves inactivated HIV-1-caputring concanavalin A (Con A)-immobilized nanospheres (HIV-NS) and their interaction with bone marrow (BM)-derived dendritic cells. HIV-NS were taken up by dendritic cells via cytoskeleton-dependent but mannose-binding site-independent phagocytosis. Serial stimulations to unprimed T-cells with HIV-1 gp120-capturing NS-pulsed dendritic cells could induce antigen-specific T-cell response. Intranasal administration of fluorescein isothiocyanate-labeled nanospheres (NS) in mice proved that the particles were taken up into pulmonary dendritic cells. Analysis of mice receiving intranasal immunizations with HIV-NS revealed that the mice efficiently induced the antibodies against HIV-1 in the genital tract and specific cytotoxic T-cells in the spleen. These results suggest that the use of HIV-1-NS may provide a novel and promising approach for the induction of humoral and cellular immune responses to HIV-1.

Induction of HIV-specific antibody response and protection against vaginal SHIV transmission by intranasal immunization with inactivated SHIV-capturing nanospheres in macaques.

We have previously reported that concanavalin A-immobilized polystyrene nanospheres (Con A-NS) could efficiently capture HIV-1 particles and that intranasal immunization with inactivated HIV-1-capturing nanospheres (HIV-NS) induced vaginal anti-HIV-1 IgA antibody response in mice. In this study, to evaluate the protective effect of immunization, each three macaques was intranasally immunized with Con A-NS or inactivated simian/human immunodeficiency virus KU-2-capturing nanospheres (SHIV-NS) and then intravaginally challenged with a pathogenic virus, SHIV KU-2. After a series of six immunizations, vaginal anti-HIV-1 gp120 IgA and IgG antibodies were detected in all SHIV-NS-immunized macaques. After intravaginal challenge, one of the three macaques in each of the Con A-NS- and SHIV-NS-immunized groups was infected. Plasma viral RNA load of infected macaque in SHIV-NS-immunized macaques was substantially less than that in unimmunized control macaque and reached below the detectable level. However, it could not be determined whether intranasal immunization with SHIV-NS is effective in giving complete protection against intravaginal challenge. To explore the effect of the SHIV-NS vaccine, the remaining non-infected macaques were rechallenged intravenously with SHIV KU-2. After intravenous challenge, all macaques became infected. However, SHIV-NS-immunized macaques had lower viral RNA loads and higher CD4(+) T cell counts than unimmunized control macaques. Plasma anti-HIV-1 gp120 IgA and IgG antibodies were induced more rapidly in the SHIV-NS-immunized macaques than in the controls. The rapid antibody responses having neutralizing activity might contribute to the clearance of the challenge virus. Thus, SHIV-NS-immunized macaques exhibited partial protection to vaginal and systemic challenges with SHIV KU-2.

Mucosal immunization with inactivated HIV-1-capturing nanospheres induces a significant HIV-1-specific vaginal antibody response in mice.

Mucosal secretory IgA is considered to have an important role in the prevention of human immunodeficiency virus type 1 (HIV-1) transmission through sexual intercourse. Therefore, substances that induce HIV-1-specific IgA antibody in the genital tract may become promising candidates for prophylactic vaccine against HIV-1 infection. We have previously reported that concanavalin A-immobilized polystyrene nanospheres (Con A-NS) could efficiently capture HIV-1 particles and gp120 antigens on their surface and that intravaginal immunization with inactivated HIV-1-capturing nanospheres (HIV-NS) induced vaginal anti-HIV-1 IgA antibody in mice. In this study, various strategies for immunization with HIV-NS were undertaken to induce HIV-1-specific IgA response in the mouse genital tract. HIV-NS were administered intravaginally, orally, intranasally or intraperitoneally to mice. Progesterone treatment enhanced the anti-HIV-1 IgA response to intravaginal immunization significantly, but intranasal immunization with HIV-NS was more effective compared with other immunization routes in terms of vaginal IgA response. In addition, vaginal washes from intranasally immunized mice were capable of neutralizing HIV-1(IIIB). Thus, application of HIV-NS is a practical approach to promote HIV-1-specific IgA response by the vaginal mucosa in the mouse and intranasal appears to be an effective immunization route in this animal model. Intranasal immunization with HIV-NS should be further pursued for its potential as an HIV-1 prophylactic vaccine.

Induction of mucosal IgA following intravaginal administration of inactivated HIV-1-capturing nanospheres in mice.

Concanavalin A-immobilized polystyrene nanospheres (Con A-NS) were developed for the HIV-1 vaccine capable of preventing sexual transmission. Con A-NS could capture efficiently HIV-1 irrespective of their cell tropism (R5 or X4). Furthermore, Con A-NS captured equally infectious and heat-inactivated HIV-1. Inactivated HIV-1-capturing Con A-NS (HIV-NS) were intravaginally administered to mice. Heat-inactivated HIV-1 alone and Con A-NS alone were also administered as control immunogens. Vaginal fluids were collected during and after immunization and analyzed for their anti-HIV-1 antibody levels. Although the anti-HIV-1 IgG antibody was undetectable in any groups, increased anti-HIV-1 IgA antibody response was identified in the vaginal fluids of immunized mice with HIV-NS. The vaginal fluids obtained from the HIV-NS-administered mice showed neutralizing activity against the immunizing HIV-1 strain. A marked difference in vaginal distribution was observed between HIV-NS and other immunogens, and the toxicity of Con A was reduced by conjugation with nanospheres. Thus, HIV-NS may have great potential as a prophylactic HIV-1 vaccine and should be examined further for its efficacy in non-human primates.