Remote visualization of underwater oil using a flash Raman lidar system.

We propose and experimentally demonstrate a new, to the best of our knowledge, underwater monitoring system that incorporates Raman spectroscopy based on a flash lidar. We have visualized underwater oil at a 5 m distance by illuminating the area of around 15 cm diameter with an expanding laser beam at 532 nm and detecting the oil and water Raman images. By calibrating the oil Raman image with the water Raman image, the detection limit of liquid oil thickness has been estimated to be about 0.27 mm. Thus, the proposed technique provides the capability of effectively detecting oil leaks in underwater sea areas.

Integration of humoral and cellular HLA-specific immune responses in cord blood allograft rejection.

In allo-stem cell transplantation (SCT), it is unclear whether donor-specific anti-HLA Abs (DSAs) can actually mediate graft rejection or if they are simply surrogate markers for the cellular immunity that causes graft rejection. Here, we first analyzed a case of cord blood allograft rejection in which DSA and cytotoxic T lymphocyte (CTL) specific for donor HLA-B*54:01 were detected at the time of graft rejection. Both the DSA and CTL inhibited colony formation by unrelated bone marrow mononuclear cells sharing HLA-B*54:01, suggesting that the humoral and cellular immune responses were involved in the graft rejection. Interestingly, the DSA and CTL were also detected in cryopreserved pre-transplant patient blood, raising a hypothesis that the presence of anti-HLA Abs could be an indicator for corresponding HLA-specific T cells. We then evaluated the existence of HLA-specific CD8(+) T cells in other patient blood specimens having anti-HLA class I Abs. Interferon-γ enzyme-linked immunospot assays clearly confirmed the existence of corresponding HLA-specific T-cell precursors in three of seven patients with anti-HLA Abs. In conclusion, our data demonstrate that integrated humoral and cellular immunity recognizing the same alloantigen of the donor can mediate graft rejection in DSA-positive patients undergoing HLA-mismatched allo-SCT. Further studies generalizing our observation are warranted.

A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases.

Signal transduction and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate cell proliferation, apoptosis, differentiation, development and the immune response. Aberrant signals of STAT induce uncontrolled cell proliferation and apoptosis resistance and are strongly involved in cancer. STAT has been identified as a promising target for antitumor drugs, but to date most trials have not been successful. Here, we demonstrated that a novel STAT inhibitor, OPB-31121, strongly inhibited STAT3 and STAT5 phosphorylation without upstream kinase inhibition, and induced significant growth inhibition in various hematopoietic malignant cells. Investigation of various cell lines suggested that OPB-31121 is particularly effective against multiple myeloma, Burkitt lymphoma and leukemia harboring BCR-ABL, FLT3/ITD and JAK2 V617F, oncokinases with their oncogenicities dependent on STAT3/5. Using an immunodeficient mouse transplantation system, we showed the significant antitumor effect of OPB-31121 against primary human leukemia cells harboring these aberrant kinases and its safety for normal human cord blood cells. Finally, we demonstrated a model to overcome drug resistance to upstream kinase inhibitors with a STAT inhibitor. These results suggested that OPB-31121 is a promising antitumor drug. Phase I trials have been performed in Korea and Hong Kong, and a phase I/II trial is underway in Japan.

PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML.

PAX5 is a transcription factor required for B-cell development and maintenance. PML is a tumor suppressor and a pro-apoptotic factor. A fusion gene, PAX5-PML, was found in acute lymphoblastic leukemia (ALL) with chromosomal translocation t(9;15)(p13;q24), but no functional analysis has been reported. Here, we demonstrate that PAX5-PML had a dominant-negative effect on both PAX5 and PML. PAX5-PML dominant negatively inhibited PAX5 transcriptional activity in the luciferase reporter assay and suppressed the expression of the PAX5 transcriptional targets in B-lymphoid cell line. Surprisingly, PAX5-PML hardly showed DNA-binding activity in vitro although it retained the DNA-binding domain of PAX5. Additional experiments, including chromatin immunoprecipitation (ChIP) assay, suggested that PAX5-PML bound to the promoter through the association with PAX5 on the promoter. On the other hand, coexpression of PAX5-PML inhibited PML sumoylation, disrupted PML nuclear bodies (NBs), and conferred apoptosis resistance on HeLa cells. Furthermore, treatment with arsenic trioxide (ATO) induced PML sumoylation and reconstitution of PML NBs, and overcame the anti-apoptotic effect of PAX5-PML in HeLa cells. These data suggest the possible involvement of this fusion protein in the leukemogenesis of B-ALL in a dual dominant-negative manner and the possibility that ALL with PAX5-PML can be treated with ATO.

Malignant fibrous histiocytoma originating from the chest wall: report of a case and collective review of cases.

Malignant fibrous histiocytomas occur principally as a mass of the extremities, abdominal cavity, or retroperitoneum in adults. However, they only rarely occur in the chest wall. A rare case of primary malignant fibrous histiocytoma originating from the chest wall is herein presented. The 36 previously reported cases are also reviewed. Of the 32 patients who underwent a resection as the initial treatment, 10 (31.3%) had a local recurrence. Of the 37 patients with this disease, 9 (25.0%) had subsequent metastases. The majority of the deaths (36.1%) from this disease occurred within the first 12 months. The patients who undergo surgical and adjuvant therapy must therefore be monitored carefully by frequent examinations.

Angiomyolipoma of the liver: case report and collective review of cases diagnosed from fine needle aspiration biopsy specimens.

We experienced a rare case of primary angiomyolipoma (AML) of the liver, preoperatively diagnosed by fine needle aspiration biopsy (FNAB). Radiographic imaging revealed characteristic features of an angiomyolipoma. The diagnosis was confirmed by the presence of epithelioid smooth muscle cells, mature fat cells and blood vessels in the biopsy tissue. Our review of the literature showed this to be the eleventh case to be diagnosed in this way. Despite this preoperative diagnosis, the lesion was resected because of its pleomorphic histological features. Histologically, the epithelioid smooth muscle component included cells with a bizarre appearance and occasional hyperchromatic nuclei, and furthermore, occasional mitotic figures were observed. In own MEDLINE search of the literature we found 11 cases of AML of the liver for which the diagnoses were established by FNAB, and the same features were present in 5 cases for which surgical excision was contemplated.

Delivery of lymph node-targeted adriamycin by gastric submucosal liposomal injection in rabbits.

We investigated the feasibility of specifically delivering adriamycin (ADR) to the regional lymph nodes via gastric submucosal injection of liposomal adriamycin (Lipo-ADR) in a rabbit model. We determined the tissue distribution of ADR for up to 7 days after the gastric submucosal injection of Lipo-ADR (0.4 mg/kg of ADR potency) and i.v. administration of an equal dose of free adriamycin (F-ADR). The area under the ADR concentration-time curve (AUC) of the regional lymph nodes was 85.4 micrograms.day/g after gastric submucosal injection of Lipo-ADR and 8.44 micrograms.day/g after i.v. administration of F-ADR. The targeting index of the regional lymph nodes, defined as the ratio of the AUC after gastric submucosal injection of Lipo-ADR to the AUC after i.v. administration of F-ADR, was 10.1. Gastric submucosal injection of Lipo-ADR enhanced lymph node-specific delivery of ADR compared with i.v. administration of F-ADR. The targeting index was 0.47 for the heart, 0.25 for the bone marrow, and 0.41 for the spleen, indicating that gastric submucosal injection of Lipo-ADR reduced delivery of ADR to these organs, as compared with i.v. administration of F-ADR. These data demonstrate that gastric submucosal injection of Lipo-ADR is well suited for specific delivery of ADR to the regional lymph nodes, suggesting that this method of administration may be useful in delivering preoperative adjuvant chemotherapy for preventing gastric cancer recurrence.

[Antitumor effect of liposome-entrapped carboplatin after intraperitoneal administration in rats].

We examined the distribution in tissue and antitumor effects of freeze-dried liposome-entrapped carboplatin (Lipo-CBDCA) after intraperitoneal administration to rats bearing AH 130 tumors. Liposomes composed of egg lecithin and cholesterol were used as drug carriers. The serum concentration of platinum was decreased for a short time after the intraperitoneal administration of Lipo-CBDCA. After at least 3 hours, the serum concentration of platinum was higher with free CBDCA intraperitoneal or intravenous administration. The antitumor effects of Lipo-CBDCA were determined in rats with peritoneal dissemination due to AH 130 tumors. Intraperitoneal Lipo-CBDCA prolonged the life span of the tumor-bearing rats. No side effects of the chemotherapy were demonstrated in biochemical and histological studies in the liver, kidney, spleen and small intestine. These results indicate that intraperitoneal chemotherapy with Lipo-CBDCA may be more effective than that with free CBDCA managing in peritoneal dissemination, and may be therapeutically useful without toxic side effects.

[Efficacy of preoperative adjuvant chemotherapy using adriamycin targeting the regional lymph nodes for gastric cancer--lymph node-targeting delivery of adriamycin in rabbits].

Chemotherapy targeting the regional lymph nodes for gastric cancer may be more effective preoperatively than postoperatively since anticancer drugs can be transported to the regional lymph nodes via the lymphatic flow through the stomach. Distribution of Adriamycin (ADR) among the various organs was assessed following its intravenous injection in rabbits. The delivery index of the drug to each organ was assessed by the ratio of the area under the concentration-time curve (AUC) of each organ to the AUC of the regional lymph nodes following the intravenous administration. The delivery index was 0.14 for the stomach, 0.11 for the heart, 0.53 for bone marrow, 0.74 for the spleen, and 0.14 for the liver. These data suggest that preoperative adjuvant chemotherapy by intravenous administration of ADR may be effective in targeting ADR at the regional lymph nodes. Tissue ADR concentrations in the regional lymph nodes were assessed following gastric submucosal administration of ADR in rabbits. The targeting index for the regional lymph nodes was 8.20, measured by the ratio of AUC following a gastric submucosal injection to AUC after the intravenous injection of ADR. This suggests that it may be possible to selectively target chemotherapy to regional lymph nodes by employing a gastric submucosal administration of ADR.

[Endoscopic injection of liposomal adriamycin targeting lymph node metastasis of gastric cancer].

Gastric submucosal injection of 5 mg liposomal adriamycin (L-ADM) close to the main gastric cancer tumor was done in 15 patients by endoscopy. This approach was based on the idea that preoperative adjuvant chemotherapy targeting lymph node metastasis in patients with gastric cancer may be effective for prevention of lymph node recurrence. ADM concentrations in the regional lymph nodes were assessed and compared with those in patients who were administered 5 mg of free adriamycin (F-ADM) i.v. preoperatively. ADM concentrations in Group 7 lymph nodes (according to the General Rules for Gastric Cancer Study) were: After 2 days; 7.21 +/- 5.98 micrograms/g (n = 2) in the L-ADM group and 0.59 +/- 0.23 micrograms/g (n = 3) in the F-ADM group. After 4 days; 4.93 +/- 3.93 micrograms/g (n = 2) in the L-ADM group and 0.36 +/- 0.0 micrograms/g (n = 2) in the F-ADM group. After 6 days; 2.08 +/- 0.49 micrograms/g (n = 2) in the L-ADM group and 0.05 +/- 0.05 micrograms/g (n = 3) in the F-ADM group. L-ADM group: those who had L-ADM injected into the side of the lesser curvature of the stomach. F-ADM group: those who had F-ADM administered i.v. These data demonstrate that gastric submucosal injection of L-ADM is well suited for specific delivery to the regional lymph nodes, suggesting that this type of administration may prevent lymph node recurrence of gastric cancer by targeting lymph node metastasis.

[Clinical application of chemotherapy via the portal vein with liposome-encapsulated adriamycin in inoperable metastatic liver cancer].

We studied the effects of liposome-entrapped adriamycin (L-ADM) administered via the portal vein and the clinical application of this treatment in the therapy and inhibition of liver metastasis, experimentally and clinically. Liposomes composed of egg phosphatidylcholine (cholesterol 50 mol%) were used as drug carriers. We examined the distribution in tissues and antitumor effect of freeze-dried L-ADM administered via the portal vein to rabbits bearing VX2 tumors. The liver concentration of ADM increased after delivery and cardiac uptake decreased compared with free drug treatment. The life span was prolonged by L-ADM treatment compared with the control group and the free ADM group. This L-ADM administration was confirmed to be safe and revealed a decrease in the heart toxicities compared with free adriamycin. Nineteen cases were studied from Jan. 1986 to May 1991 via the portal vein and the clinical effects were evaluated. From Mar. 1988 to date, 10 cases were treated with L-ADM (20-30 mg every 2 weeks/body) in patients with inoperable cases using subcutaneously implanted reservoir. The median survival was 450 days; 275 days for colon cancer, 492 days for gastric cancer, and 1,052 days for uterine cancer (range: 136-1,152 days), compared with 141 days (range: 52-253 days) in 9 cases of historical control treated with free-ADM via the portal vein. These results suggest that chemotherapy via the portal vein with L-ADM for metastatic liver cancer may increase survival time.

Antitumor effect of liposome-entrapped adriamycin administered via the portal vein.

We examined the distribution in tissues and antitumor effect of freeze-dried liposome-entrapped adriamycin (Lipo-ADM) administered via the portal vein to rabbits bearing VX2 tumors. Liposomes composed of egg phosphatidylcholine (cholesterol 50 mol%) were used as drug carriers. The liver concentration of ADM increased after delivery and cardiac uptake decreased compared with free drug treatment. The in vivo antitumor effect of Lipo-ADM was determined in rabbits inoculated with VX2 tumor. Repeated injections of free ADM via the portal vein prolonged the life span of tumor-bearing rabbits. The life span was further prolonged by Lipo-ADM treatment compared with the control group and the free ADM group. Histological examination revealed that the damage to the liver caused by Lipo-ADM administered via the portal vein did not differ from that observed in animals treated with free ADM. These results indicate that portal vein administration of Lipo-ADM may be more effective in dealing with liver metastases than treatment with free ADM and may be therapeutically useful without toxic side effects.