Community structures of soil animals and survival of land snails on an island of the Ogasawara Archipelago

On Chichijima, one of the Ogasawara (Bonin) Islands located in the Western Pacific Ocean, land snails have declined, the suggested cause being predation pressure by an invasive flatworm (Platydemus manokwari). Soil fauna were investigated in areas where the snail survives, and where it has become extinct. Much of the fauna, dominated by introduced earthworms and ants, was undiminished, however, one undescribed but endemic carabid (Badister sp.), which selectively feeds on land snails, was absent in snail-extinct areas. The invasive flatworm P. manokwari has been reported to feed also on the carcasses of earthworms, as well as on live snails, and is therefore expected to occur in most parts of Chichijima Island. Among other groups, the density of isopods (also dominated by exotic species) was very low, in comparison with the reported ones 30 years ago. Community structure is currently reflected by dominance of earthworms and ants, decline of endemic isopods, and a high frequency of introduced or alien species.

Limited telomere shortening in hematopoietic stem cells after transplantation.

The number of cell divisions in hematopoietic stem cells (HSCs) following transplantation of bone marrow or mobilized peripheral blood into myelo-ablated recipients is unknown. This number is expected to depend primarily on the number of transplanted stem cells, assuming that stem cells do not differ in engraftment potential and other functional properties. In a previous study, we found that the telomere length in circulating granulocytes in normal individuals shows a biphasic decline with age, most likely reflecting age-related changes in the turnover of HSCs. In order to study HSCs' proliferation kinetics following stem cells transplantation, we analyzed the telomere length in donor-derived nucleated blood cells in four HLA-matched bone marrow transplant recipients relative to comparable cells from the sibling donors. In each case, the telomeres in granulocytes were shorter in the recipient than in the donor. This difference was established in the first year post transplantation and did not change after that. The telomere length in naïve and memory T cells showed marked differences after transplantation, complicating the interpretation of telomere length data using unseparated nucleated blood cells. Interestingly, the telomere length in naïve T cells that were first observed six months post transplantation was very similar in donor and recipient pairs. Our observations are compatible with a limited number of additional cell divisions in stem cell populations after bone marrow transplantations and support the idea that different populations of stem cells contribute to short-term myeloid and long-term lympho myeloid hematopoiesis.

Loss of insulin synthesis and beta cell survival induced by oxidized LDL require activation of reticulum endoplasmic stress: a mechanism countered by HDL

Elevated circulating concentrations in modified LDL-cholesterol particles (e.g. oxidised LDL) and low levels in HDL increase not only the risk for diabetic patients to develop cardiovascular diseases but also may contribute to development and progression of diabetes by directly having adverse effects on β-cells. Chronic exposure of β-cells to 2 mM human oxidised LDL-cholesterol (oxLDL) increases the rate of apoptosis, reduce insulin biosynthesis and the secretory capacity of the cells in response to nutrients. In line with the protective role, HDL efficiently antagonised the harmful effects of ox- LDL, suggesting that low levels of HDL would be inefficient to protect β-cells against oxLDL attack in patients. Activation of endoplasmic reticulum (ER) stress is pointed out to contribute to β-cell dysfunction elicited by environmental stressors. In this study we investigated whether activation of ER stress is required for oxLDL to mediate detrimental effects on β-cells and we tested the potential antagonist properties of HDL: The mouse MIN6 insulin-secreting cells were cultured with 2 mM of LDL-cholesterol preparation (native or in vitro oxidized) in the presence or absence of 1 mM of HDL-cholesterol or the ER stress inhibitor 4-phenylbutyrate (4-PBA): Prolonged exposure of MIN6 cells to 2 mM oxLDL-cholesterol for 48 hours led to an increase in expression of ER stress markers such as ATF4, CHOP and p58 and stimulated the splicing of XBP-1 whereas, induction of these markers was not observable in the cells cultured with native LDL. Treatment of the cells with the 4-PBA chemical chaperone molecule efficiently blocked activation of the ER stress markers induced by oxLDL. The latter mediates β-cell dysfunction and apoptosis by diminishing the expression of islet brain 1 (IB1) and Bcl2. The levels of these two proteins were preserved in the cells that were co-treated with oxLDL and the 4-PBA. Consistent with this result we found that blockade of ER stress activation alleviated the loss of insulin synthesis and abolished apoptosis evoked by oxLDL. However incubation of the cells with 4-PBA did not prevent impairment of insulin secretion elicited by oxLDL, indicating that ER stress is not responsible for the oxLDL-mediated defect of insulin secretion. Co-incubation of the cells with HDL mimicked the effects of 4-PBA on the expression of IB1 and Blc2 and thereby counteracted oxLDL attacks on insulin synthesis and cell survivals. We found that HDL efficiently inhibited activation of the ER stress mediated by oxLDL: These data highlight the contribution of the ER stress in the defects of insulin synthesis and cell survivals induced by oxLDL and emphasize the potent role of HDL to counter activation of the oxLDL-mediated ER-stress activation:

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-kappaB activation and endothelial cell survival.

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine exerting pleiotropic effects on endothelial cells. Depending on the vascular context it can induce endothelial cell activation and survival or death. The microenvironmental cues determining whether endothelial cells will survive or die, however, have remained elusive. Here we report that integrin ligation acts permissive for TNF-induced protein kinase B (PKB/Akt) but not nuclear factor (NF)-kappaB activation. Concomitant activation of PKB/Akt and NF-kappaB is essential for the survival of endothelial cells exposed to TNF. Active PKB/Akt strengthens integrin-dependent endothelial cell adhesion, whereas disruption of actin stress fibers abolishes the protective effect of PKB/Akt. Integrin-mediated adhesion also represses TNF-induced JNK activation, but JNK activity is not required for cell death. The alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 sensitizes endothelial cells to TNF-dependent cytotoxicity and active PKB/Akt attenuates this effect. Interferon gamma synergistically enhanced TNF-induced endothelial cell death in all conditions tested. Taken together, these observations reveal a novel permissive role for integrins in TNF-induced PKB/Akt activation and prevention of TNF-induced death distinct of NF-kappaB, and implicate the actin cytoskeleton in PKB/Akt-mediated cell survival. The sensitizing effect of EMD121974 on TNF cytotoxicity may open new perspectives to the therapeutic use of TNF as anticancer agent.

Consolidation with Radioimmunotherapy May Prolong Survival in First Remission of Mantle Cell Lymphoma Patients Uneligible for Stem Cell Transplantation, An Analysis of the International RIT-Network

Background: Mantle cell lymphoma (MCL) is a rare subtype (3-9%) of Non Hodgkin Lymphoma (NHL) with a relatively poor prognosis (5-year survival < 40%). Although consolidation of first remission with autologous stem cell transplantation (ASCT) is regarded as "golden standard", less than half of the patients may be subjected to this intensive treatment due to advanced age and co-morbidities. Standard-dose non-myeloablative radioimmunotherapy (RIT) seems to be a very efficient approach for treatment of certain NHL. However, there are almost no data available on the efficacy and safety of RIT in MCL. Methods and Patients: In the RIT-Network, a web-based international registry collecting real observational data from RIT-treated patients, 115 MCL patients treated with ibritumomab tiuxetan were recorded. Most of the patients were elderly males with advanced stage of the disease: median age - 63 (range 31-78); males - 70.4%, stage III/IV - 92%. RIT (i.e. application of ibritumomab tiuxetan) was a part of the first line therapy in 48 pts. (43%). Further 38 pts. (33%) received ibritumomab tiuxetan after two previous chemotherapy regimens, and 33 pts. (24%) after completing 3-8 lines. In 75 cases RIT was applied as a consolidation of chemotherapy induced response; the rest of the patients received ibritumomab tiuxetan because of relapse/refractory disease. At the moment follow up data are available for 74 MCL patients. Results: After RIT the patients achieved high response rate: CR 60.8%, PR 25.7%, and SD 2.7%. Only 10.8% of the patients progressed. For survival analysis many data had to be censored since the documentation had not been completed yet. The projected 3-year overall survival (OAS, fig.1 - image 001.gif) after radioimmunotherapy was 72% for pts. subjected to RIT consolidation versus 29% for those treated in relapse/refractory disease (p=0.03). RIT was feasible for almost all patients; only 3 procedure-related deaths were reported in the whole group. The main adverse event was hematological toxicity (grade III/IV cytopenias) showing a median time of recovery of Hb, WBC and Plt of 45, 40 and 38 days respectively. Conclusion: Standard-dose non-myeloablative RIT is a feasible and safe treatment modality, even for elderly MCL pts. Consolidation radioimmunotherapy with ibritumomab tiuxetan may prolong survival of patients who achieved clinical response after chemotherapy. Therefore, this consolidation approach should be considered as a treatment strategy for those, who are not eligible for ASCT. RIT also has a potential role as a palliation therapy in relapsing/resistant cases.

mTORC2 is an important signaling intermediary in VEGF-mediated endothelial cell proliferation, survival and migration

Objective: The vascular endothelial growth factor (VEGF) is a prominent¦contributor of tumor angiogenesis. VEGF induces endothelial cell migration,¦proliferation and survival, which are critical steps for the development of new¦blood vessels, through the activation of the Mek/Erk and PI3K/Akt signaling¦pathways. Recent findings have demonstrated that mTORC2 regulates Akt and¦Erk in endothelial cells. The role of mTORC2 in VEGF-mediated endothelial¦cell responses has however not been characterized.¦Methods: We used human umbilical vein endothelial cells (HUVEC). The¦effects of VEGF on the Mek/Erk and PI3K/Akt pathway were analyzed by¦Western blot. Inhibition of mTORC2 was achieved using small interfering¦RNAs to rictor. Cell proliferation rate was assessed by BrdU incorporation and¦immunocytofluorescence. Apoptosis rate was determined by ELISA as well as¦propidium iodine staining and FACS analysis. Migration of endothelial cells¦was evaluated using a modified Boyden chamber assay.¦Results:Wefound thatVEGF activatesmTORC2 in endothelial cells. Indeed,¦treatment of endothelial cells with VEGF increases Akt phosphorylation, a¦downstream effector of mTORC2. We have further determined the role¦of mTORC2 in VEGF signaling by knocking down rictor, a component¦of mTORC2. We observed that VEGF failed to activate Akt and Erk in¦endothelial cells transfected with rictor siRNA. To next analyze the functional¦significance of mTORC2 inhibition on VEGF-mediated endothelial cell¦responses we performed proliferation, survival and migration assays. We found¦that VEGF failed to induce endothelial cell proliferation, survival and migration¦in endothelial cell lacking mTORC2 activity.¦Conclusion: These results show that mTORC2 is an important signaling¦intermediary in VEGF-induced endothelial cell responses and thus represents¦an interesting target to block VEGF-induced angiogenesis.

Ectopic lymphoid-organ development occurs through interleukin 7-mediated enhanced survival of lymphoid-tissue-inducer cells.

Development of Peyer's patches and lymph nodes requires the interaction between CD4+ CD3- IL-7Ralpha+ lymphoid-tissue inducer (LTi) and VCAM-1+ organizer cells. Here we showed that by promoting their survival, enhanced expression of interleukin-7 (IL-7) in transgenic mice resulted in accumulation of LTi cells. With increased IL-7 availability, de novo formation of VCAM-1+ Peyer's patch anlagen occurred along the entire fetal gut resulting in a 5-fold increase in Peyer's patch numbers. IL-7 overexpression also led to formation of multiple organized ectopic lymph nodes and cecal patches. After immunization, ectopic lymph nodes developed normal T cell-dependent B cell responses and germinal centers. Mice overexpressing IL-7 but lacking either RORgamma, a factor required for LTi cell generation, or lymphotoxin alpha1beta2 had neither Peyer's patches nor ectopic lymph nodes. Therefore, by controlling LTi cell numbers, IL-7 can regulate the formation of both normal and ectopic lymphoid organs.

Bayesian genetic parameters for body weight and survival of Nile tilapia farmed in Brazil

The objective of this study was to estimate genetic parameters for survival and weight of Nile tilapia (Oreochromis niloticus), farmed in cages and ponds in Brazil, and to predict genetic gain under different scenarios. Survival was recorded as a binary response (dead or alive), during harvest time in the 2008 grow-out period. Genetic parameters were estimated using a Bayesian mixed linear-threshold animal model via Gibbs sampling. The breeding population consisted of 2,912 individual fish, which were analyzed together with the pedigree of 5,394 fish. The heritabilities estimates, with 95% posterior credible intervals, for tagging weight, harvest weight and survival were 0.17 (0.09-0.27), 0.21 (0.12-0.32) and 0.32 (0.22-0.44), respectively. Credible intervals show a 95% probability that the true genetic correlations were in a favourable direction. The selection for weight has a positive impact on survival. Estimated genetic gain was high when selecting for harvest weight (5.07%), and indirect gain for tagging weight (2.17%) and survival (2.03%) were also considerable.

Empirical study of correlated survival times for recurrent events with proportional hazards margins and the effect of correlation and censoring.

Background: In longitudinal studies where subjects experience recurrent incidents over a period of time, such as respiratory infections, fever or diarrhea, statistical methods are required to take into account the within-subject correlation. Methods: For repeated events data with censored failure, the independent increment (AG), marginal (WLW) and conditional (PWP) models are three multiple failure models that generalize Cox"s proportional hazard model. In this paper, we revise the efficiency, accuracy and robustness of all three models under simulated scenarios with varying degrees of within-subject correlation, censoring levels, maximum number of possible recurrences and sample size. We also study the methods performance on a real dataset from a cohort study with bronchial obstruction. Results: We find substantial differences between methods and there is not an optimal method. AG and PWP seem to be preferable to WLW for low correlation levels but the situation reverts for high correlations. Conclusions: All methods are stable in front of censoring, worsen with increasing recurrence levels and share a bias problem which, among other consequences, makes asymptotic normal confidence intervals not fully reliable, although they are well developed theoretically.

Survival impact of lung transplantation for COPD

La bronchopneumopathie chronique obstructive (BPCO) est l'indication la plus fréquente de la transplantation pulmonaire. Néanmoins, le bénéfice de survie dans cette indication est toujours débattu. Le but de cette étude était d'analyser l'impact de la transplantation pulmonaire sur la survie de patients BPCO à l'aide d'une nouvelle méthode utilisant l'index de BODE, un indice validé dans la prédiction de la survie de patients BPCO. L'index de BODE est composé de 4 variables (indice de masse corporelle, obstruction bronchique, dyspnée, capacité d'effort) et son score s'échelonne de 0 à 10, une valeur élevée signifiant une maladie plus sévère et donc une probabilité de survie moindre.Cette étude rétrospective a porté sur 54 patients BPCO ayant consécutivement bénéficié d'une transplantation pulmonaire (unilatérale ou bilatérale) au Centre Hospitalier Universitaire Vaudois et aux Hôpitaux Universitaires de Genève entre 1994 et 2007, avec un suivi jusqu'au 30 juin 2009. Le score de BODE avant transplantation a été calculé pour chaque patient, à partir duquel une survie prédite a été dérivée. Cette survie prédite a été comparée à la survie réelle des patients transplantés.Une majorité de patient (67%) a présenté un bénéfice individuel de survie suite à la transplantation pulmonaire. Ceci s'est vérifié aussi bien dans le sous-groupe de patients avec un score de BODE > 7 que dans celui avec un score de BODE < 7. La survie médiane était significativement améliorée par la transplantation pulmonaire dans la cohorte totale et dans le sous-groupe avec un score de BODE > 7, mais pas dans celui avec un score de BODE < 7. De plus, 4 ans après la transplantation, un bénéfice de survie ne peut être escompté que chez les patients présentant un score de BODE > 7.Dans notre cohorte, la transplantation pulmonaire a donc conduit à un bénéfice individuel de survie chez la majorité des patients, quel que soit leur score de BODE avant l'intervention. Toutefois, un bénéfice global de survie n'a pu être démontré que dans le groupe de patients ayant la maladie la plus sévère. Chez les patients moins sévèrement atteints, les risques liés à l'intervention sont plus importants que le bénéfice de survie escompté à long terme. Ces résultats confortent l'utilisation de l'index de BODE comme critère de sélection pour la transplantation pulmonaire chez les patients BPCO.