Geometry and Segmentation of Cerberus Fossae, Mars: Implications for Marsquake Properties.

The NASA InSight mission to Mars successfully landed on 26 November 2018 in Elysium Planitia. It aims to characterize the seismic activity and aid in the understanding of the internal structure of Mars. We focus on the Cerberus Fossae region, a giant fracture network ∼1,200 km long situated east of the InSight landing site where M ∼3 marsquakes were detected during the past 2 years. It is formed of five main fossae located on the southeast of the Elysium Mons volcanic rise. We perform a detailed mapping of the entire system based on high-resolution satellite images and Digital Elevation Models. The refined cartography reveals a range of morphologies associated with dike activity at depth. Width and throw measurements of the fossae are linearly correlated, suggesting a possible tectonic control on the shapes of the fossae. Widths and throws decrease toward the east, indicating the long-term direction of propagation of the dike-induced graben system. They also give insights into the geometry at depth and how the possible faults and fractures are rooted in the crust. The exceptional preservation of the fossae allows us to detect up to four scales of segmentation, each formed by a similar number of 3-4 segments/subsegments. This generic distribution is comparable to continental faults and fractures on Earth. We anticipate higher stress and potential marsquakes within intersegment zones and at graben tips.

Exogenous expression of Fas-ligand or CrmA prolongs the survival in rat liver transplantation.

Modulation of donor organs by transfection of a gene encoding immmunosuppresive molecules has been recognized as a less toxic approach to prevent allograft rejection. Fas-ligand (FasL) plays a critical role in activation-induced cell death of activated cytotoxic lymphocytes. This may provide a potential for induction of "immune privileged sites" to escape the host immune surveillance system. Cytokine response modifier A (CrmA), a gene product of cowpox virus, blocks caspase as well as perforin/granzyme-mediated apoptotic pathways. Therefore, it may suppress intragraft apoptosis. The aim of the present study was to investigate whether transfection of FasL or CrmA genes prolonged the survival of rat liver allografts. Using the high responder rat combination of DA (RT-1(a)) donor to LEW (RT-1(1)) recipient, we performed orthotopic liver transplantation with subsequent delivery of adenoviral vectors containing FasL, CrmA, or LacZ, at a dose of 1 x 10(9) pfu via a recipient tail vein using a Cre-mediated gene expression system. Recipient survival was assessed as well as immunohistochemical examination of the grafts for anti-CD2, TUNEL, and H&E staining. Statistical analysis was performed with the Mann-Whitney U test. The therapeutic groups showed significantly prolonged recipient survival compared with the LacZ-treated control group. Histologic analysis revealed reduced hepatocyte apoptosis in the CrmA-treated group and increased apoptosis of infiltrating mononuclear cells in the FasL-treated group. These data suggested that FasL and CrmA may be potent genes to prolong rat liver allograft survival.

Comparison of the vector systems for gene transduction into rat dendritic cells and peritoneal exudate cells.

Specialized antigen-presenting cells (APC), known as dendritic cells (DC), play a pivotal role in initiating primary immune responses. It has been reported that several vector systems, including adenoviral vectors, retroviral vectors, Hemagglutinating Virus of Japan (HVJ)-related vectors, and electroporation, are able to transduce genes into mouse and human DC. This has not been achieved for rat DC. To our knowledge, there is no direct evidence to support the view that the currently used vector systems are able to transduce genes into mature DC. Because most, if not all, gene transfer studies investigating DC or DC-related cell populations are carried out using heterogeneous groups of cells, it is therefore very important to determine to what extent gene transduction occurs in rat DC, and also selected mature DC (CD161a+ fully mature DC). In this study, we provide evidence that none of 4 vector systems are able to transfer genes into fully mature rat DC, which are derived from bone marrow cells (BMC), driven by Flt3/Flk2 ligand and interleukin (IL)-6, and purified by CD161a. Nevertheless, the most efficient gene transduction was observed in the developing DC progenitor cells during the long-term culture of rat BMC, and its gene expression was successfully achieved after 2 weeks of culture only with a human immunodeficiency virus (HIV)-based lentiviral vector system. The most critical time point for lentiviral gene transduction was around the 7th day from the beginning of culture with lentiviral vectors. Rat peritoneal exudate cells (PEC) and another cell line (K562) were easily transducted by adenoviral vectors and lentiviral vectors.

[Locoregional adoptive immunotherapy using LAK cells and IL-2 against liver metastases from digestive tract cancer].

We investigated the clinical efficacy of locoregional and systemic adoptive immunotherapy (AIT) with or without interleukin-2 (IL-2) against solid metastatic lesions from digestive tract cancer. Eighteen patients, who were treated with more than 10(10) lymphokine-activated killer (LAK) cells, were enrolled in this study. Seven of the 18 patients received hepatic arterial infusion (HAI) of LAK cells with or without IL-2 against metastatic liver tumors (locoregional therapy group). The remaining 11 patients received systemic transfer of LAK cells with IL-2 against metastatic lesions located in organs other than the liver (systemic therapy group). Three of 7 locoregional therapy group patients showed clinically significant tumor regressions that were evaluated as being equivalent to partial response (PR). Two of the 11 systemic therapy group patients showed significant tumor regressions, but this response rate was much lower than that of the locoregional therapy group. The 2 effective cases in the systemic therapy group were esophageal cancer patients. Locoregional AIT with or without IL-2 against liver metastases from digestive tract cancer could be an effective therapeutic modality in some patients who are refractory to conventional therapies (e.g., chemotherapy and radiotherapy). It is necessary to find a new way to augment the anti-tumor effect of this therapy in combination with prior or concomitant chemotherapy.

Antitumor effect of alpha-galactosylceramide (KRN7000) on spontaneous hepatic metastases requires endogenous interleukin 12 in the liver.

Hepatic metastasis is a major clinical problem in cancer treatment. We examined antitumor activity of alpha-galactosylceramide (KRN7000) on mice with spontaneous liver metastases of reticulum cell sarcoma M5076 tumor cells (spontaneous metastasis model). In this model, all mice that were s.c. challenged with one million tumor cells developed a solid s.c. mass by day 7 and died of hepatic metastases. In the current study, we administered 100 microg/kg of KRN7000 to the model mice on days 7, 11, and 15. This treatment suppressed the growth of established liver metastases and resulted in the prolongation of survival time. Fluorescence-activated cell sorter analysis of phenotypes of spleen cells, hepatic lymphocytes, and regional lymph node cells around the s.c. tumor revealed that CD3+NK1.1+ (NKT) cells increased in hepatic lymphocytes of the KRN7000-treated mice. Cytotoxic activity and IFN-gamma production of hepatic lymphocytes were augmented in comparison with those of spleen cells and regional LN cells. At the same time, interleukin (IL)-12 production of hepatic lymphocytes was markedly enhanced. Neutralization of IL-12 using a blocking monoclonal antibody diminished the prolonged survival time. These results showed that the in vivo antitumor effects of KRN7000 on spontaneous liver metastases were dependent on the endogenous IL-12 production, where NKT cells in the liver are suggested to be involved. Adjuvant immunotherapy using KRN7000 could be a promising modality for the prevention of postoperative liver metastases.

Mumps virus can suppress the effective augmentation of HPC-induced apoptosis by IFN-gamma through disruption of IFN signaling in U937 cells.

Cells of the human promonocytic cell line U937 were found to be sensitive to hexadecylphosphocholine (HPC), which is a potential anticancer drug. Induction of apoptosis was found in U937 cells after treatment with HPC for 24 to 48 hr. The apoptosis in U937 cells exposed to HPC was increased significantly in the presence of interferon-gamma (IFN-gamma). The augmentation of HPC-induced apoptosis by IFN-gamma is repressed in cells (U937-MP) persistently infected with mumps virus. A persistently infected cell line, U937-MP, showed poor induction of signal transducers and activators of transcription-1alpha (STAT-alpha), STAT-2, p48 and IFN-regulatory factor-1 (IRF-1), which are closely correlated with interferon-alpha (IFN-alpha) and IFN-gamma signaling pathways. Expression of MHC class-I or class-II was augmented by IFN-alpha or IFN-gamma in U937 cells, but not in persistently infected cells. Therefore, it is suggested that the IFN-gamma signaling pathway plays an important role in the augmentation of HPC-induced apoptosis. Mumps virus can suppress the IFN-gamma signaling pathway and subsequent development of apoptosis.

Augmentation of local antitumor immunity in the liver by tumor vaccine modified to secrete murine interleukin 12.

Minimal residual lesions have been a major problem in surgical management of cancer. We transfected M5076 with murine IL-12 gene by a retroviral vector, established a stable transfectant secreting IL-12 and investigated its antitumor effects on a spontaneous liver metastasis murine model of M5076 reticulum cell sarcoma. Subcutaneous vaccination of the irradiated transfectant into the remote skin following the amputation of the tumor-bearing limb improved survival when compared with the vaccination of irradiated parental cells (control). Cytotoxic activities against parental M5076 were significantly stronger in the hepatic lymphocytes from the mice vaccinated with the IL-12 transfectant than those from the control. IFN-gamma production of hepatic lymphocytes when they were cocultured with the parental cells was significantly augmented in mice vaccinated with the IL-12 transfectant compared with the control. On the other hand, both cytotoxic activity and IFN-gamma production of spleen cells in the M5076-vaccinated and transfectant-vaccinated mice were at similar levels. Immunophenotypic analysis revealed the selective increase of CD3+NK1+ population in the liver from the transfectant-vaccinated mice. These results suggest that tumor vaccines genetically modified to secrete IL-12 continuously at a relatively low level preferentially augment local antitumor activity in the liver rather than systemic immune responses. This strategy warrants further investigation as an adjuvant modality in the management of postoperative residual tumors.

Clinical application of adoptive immunotherapy and IL-2 for the treatment of advanced digestive tract cancer.

BACKGROUND/AIMS: We investigated the clinical efficacy of systemic and locoregional adoptive immunotherapy (AIT) with or without interleukin-2 (IL-2) against solid metastatic lesions from digestive tract cancer, which are refractory to conventional chemotherapy or radiotherapy. METHODOLOGY: Seven of 18 patients received hepatic arterial infusion (HAI) of lymphokine-activated killer (LAK) cells with or without IL-2 against metastatic liver tumors (local therapy group). The remaining 11 patients received systemic transfer of LAK cells with IL-2 against metastatic lesions located in organs other than the liver (systemic therapy group). RESULTS: Three of the 7 local therapy group patients showed clinically significant tumor regressions and this was evaluated as being equivalent to partial response (PR) (response rate: 43%). Two of the 11 systemic therapy group patients showed tumor regression which was evaluated as being equivalent to either complete response (CR) or PR (response rate: 18%). These 2 effective cases in the systemic therapy group were esophageal cancer patients. CONCLUSIONS: Locoregional AIT with or without IL-2 against liver metastases of digestive tract cancer could be an effective therapeutic modality in some patients who are refractory to conventional therapies. However, clinical efficacy of systemic AIT with IL-2 against metastases of digestive tract cancer would not be an effective modality except for the metastases of esophageal cancer.

Systemic administration of rIL-12 synergistically enhances the therapeutic effect of a TNF gene-transduced cancer vaccine.

Interleukin-12 (IL-12) is a potent antitumor cytokine, which induces and enhances the activity of natural killer (NK) cells, lymphokine activated killer (LAK) cells and cytotoxic T lymphocytes (CTL). IL-12 also stimulates IFN-gamma production from both T cells and NK cells. In this study, we transfected methylcholanthrene-induced fibrosarcoma (MCA-D) with TNF gene and investigated the therapeutic effect of TNF gene-transduced cancer vaccine and whether the vaccination effect is enhanced by systemic administration of recombinant IL-12 (rIL-12), in a murine model. TNF gene-transduced cancer vaccine or systemic administration of rIL-12 showed slight or moderate inhibition of pre-established tumor. However, simultaneous application of the vaccine and rIL-12 resulted in complete eradication. The cytotoxicity of CTL against parental tumor cells was enhanced with the combination of the vaccine and rIL-12, and IFN-gamma production from spleen cells also increased synergistically. Our findings show that synergistic enhancement of CTL activity and IFN-gamma production could play an important role in the antitumor effect of combination therapy using TNF gene-transduced cancer vaccine and rIL-12.

[Recent advances in Alzheimer's disease research--amyloid precursor protein trafficking, processing, and mutations in Alzheimer's disease linked genes].

Recent advances in Alzheimer's disease (AD) research were briefly reviewed. The AD affected brain is characterized by numerous amyloid plaques, neurofibrillary tangles, and neuronal losses. The amyloid is composed of amyloid beta peptide (A beta), a 40-42 amino acid fragment of large membrane protein, amyloid precursor protein (APP). A beta is cleaved by proteolytic enzyme, beta, and gamma secretase yielding N and C terminus of the A beta. Considerable effort has been directed to identify these enzymes, and to find the intracellular compartments where A beta is generated. Endosome, lysosomal pathway, or related acidic compartment is one of the candidates for A beta generation. Biochemical and immunopathological data implicate that A beta 42 is more important than A beta 40 in the pathogenesis of AD. On the other hand, many missence mutations in APP gene and other gene, S182 (presenilin1), and STM2 (presenilin2) were identified in familial AD. Neuropathology in these FAD appear basically quite similar, and AD is regarded as cerebral A beta amyloidosis. It was established that missense mutations in the genes encoding APP, presenilin1, and presenilin2, all treated APP processing, leading to increased production of A beta 42. AD amyloid is composed of many other proteins than A beta, designated as amyloid associated proteins, It should be a key issue to determine the precise mechanism, by which A beta is generated, and the alteration of APP trafficking resulting in increased A beta 42 generation with these mutant genes.

Borrelia burgdorferi sensu lato in an endemic environment: wild sika deer (Cervus nippon yesoensis) with infected ticks and antibodies.

Ticks and blood samples were collected from wild sika deer (Cervus nippon yesoensis) during a hunting season (August to October) of 1991 at a selected location in Hokkaido, Japan. Ixodes persulcatus (adult and nymph) and I. ovatus (adult) were the common ticks on sika deer. Spirochetes were detected in the midgut of the ticks by the indirect peroxidase-conjugated antibody staining method and by dark-field microscopy after cultivation. By the reactive pattern of monoclonal antibodies, isolates were considered to belong to Borrelia garinii or B. japonica. In an antibody test, the percentage of seropositive deer was 69.0%. Most of the adult sika deer were positive for antibodies to the spirochetes. There are significant age-dependency in antibody level and seropositive rate. The surveillance of deer should be valuable in monitoring the transmission risk of B. burgdorferi sensu lato in nature.

[Giant left atrium in mitral valve disease: a new plication procedure to relieve the compressions of left ventricular wall left bronchus and right lung].

The giant left atrium associated with mitral valve disease frequently produces postoperative hazardness in relation to hemodynamic and respiratory management. We have defined the most serious disorders induced by the presence of giant left atrium in three categories as follows. First, hemodynamic disturbance by the compression of left ventricular wall by downward extension of left atrium (type I), secondly, respiratory disturbance yielded by the compression of left main bronchus by upward extension of left atrium (type II), thirdly, compression of right middle lobe by rightward extension of left atrium (type III). A new procedure of para-annular, superior and right-side plication methods were derived as the procedure to relieve those compressions induced by giant left atrium. Up to the present, 47 patients with giant left atrium underwent surgery, twelve of valvular procedure only and thirty-five of valvular as well as plication procedure. The incidence of postoperative low output syndrome and respiratory failure were evaluated. The plication procedure showed marked decrease in the incidence of low output syndrome and respiratory failure postoperatively, eventual significant decrease in mortality rate. We conclude that plication procedure is very effective for the treatment of compression in the presence of giant left. atrium.