Differential effects of Cbl and 70Z/3 Cbl on T cell receptor-induced phospholipase Cγ-1 activity

AbstractWe demonstrate that the differential effects Cbl and oncogenic 70Z/3 Cbl have on Ca2+/Ras-sensitive NF-AT reporters is partially due to their opposing ability to regulate phospholipase Cγ1 (PLCγ1) activation as demonstrated by analysis of the activation of an NF-AT reporter construct and PLCγ1-mediated inositol phospholipid (PI) hydrolysis. Cbl over-expression resulted in reduced T cell receptor-induced PI hydrolysis, in the absence of any effect on PLCγ1 tyrosine phosphorylation. In contrast, expression of 70Z/3 Cbl led to an increase in basal and OKT3-induced PLCγ1 phosphorylation and PI hydrolysis. These data indicate that Cbl and 70Z/3 Cbl differentially regulate PLCγ1 phosphorylation and activation. The implications of these data on the mechanism of Cbl-mediated signaling regulation are discussed

MEIOTIC ORIGIN OF TRISOMY IN NEOPLASM: EVIDENCE IN A CASE OF ERYTROLEUKAEMIA

Trisomic cells in neoplasms may represent abnormal clones originated from a tissue-confined mosaicism, and arise therefore by a meiotic error. We report on a 16-month-old child with erythroleukaemia (AML-M6), whose marrow karyotype at onset was 48,XX,del(13)(q12q14),del(14)(q22q32),+21,+21. The parental origin of the supernumerary chromosomes 21 was investigated by comparing 10 polymorphic loci scattered along the whole chromosome on the patient's marrow and her parents' leukocytes. Three loci were informative for the presence of three alleles, two of which were of maternal origin; two further loci showed a maternal allele of higher intensity. Lymphocytes and skin fibroblasts showed a normal karyotype, and molecular analysis on leukocytes at remission, buccal smear and urinary sediment cells consistently showed only one maternal allele, whereas neonatal blood from Guthrie spot showed two maternal alleles as in the marrow. An accurate clinical re-evaluation confirmed a normal phenotype. Our results indicate that tetrasomy 21 arose from a marrow clone with trisomy 21 of meiotic origin. To the best of our knowledge, this is the first evidence that supernumerary chromosomes in neoplastic clones may in fact be present due to a meiotic error. This demonstrates that a tissue-confined constitutional mosaicism for a trisomy may indeed represent the first event in multistep carcinogenesis

Tailoring CD19xCD3-DART exposure enhances T-cells to eradication of B-cell neoplasms.

Many patients with B-cell malignancies can be successfully treated, although tumor eradication is rarely achieved. T-cell-directed killing of tumor cells using engineered T-cells or bispecific antibodies is a promising approach for the treatment of hematologic malignancies. We investigated the efficacy of CD19xCD3 DART bispecific antibody in a broad panel of human primary B-cell malignancies. The CD19xCD3 DART identified 2 distinct subsets of patients, in which the neoplastic lymphocytes were eliminated with rapid or slow kinetics. Delayed responses were always overcome by a prolonged or repeated DART exposure. Both CD4 and CD8 effector cytotoxic cells were generated, and DART-mediated killing of CD4+ cells into cytotoxic effectors required the presence of CD8+ cells. Serial exposures to DART led to the exponential expansion of CD4 + and CD8 + cells and to the sequential ablation of neoplastic cells in absence of a PD-L1-mediated exhaustion. Lastly, patient-derived neoplastic B-cells (B-Acute Lymphoblast Leukemia and Diffuse Large B Cell Lymphoma) could be proficiently eradicated in a xenograft mouse model by DART-armed cytokine induced killer (CIK) cells. Collectively, patient tailored DART exposures can result in the effective elimination of CD19 positive leukemia and B-cell lymphoma and the association of bispecific antibodies with unmatched CIK cells represents an effective modality for the treatment of CD19 positive leukemia/lymphoma

Effects of feeding low fishmeal diets with increasing soybean meal levels on growth, gut histology and plasma biochemistry of sea bass

The aquaculture industry depends upon the development of sustainable protein sources to replace fishmeal (FM) in aquafeeds and the products derived from soybeans are some of the most studied plant feedstuffs. A key area of investigation for continuing to improve modern aquafeeds includes the evaluation of varying proportions and combinations of plant ingredients to identify mixtures that are more efficiently utilized by the fish. This study investigated the effects of increasing soybean meal (SBM) by replacing a mix of plant ingredients in low FM (20%) diets on growth, blood biochemistry profile and gut histology on European sea bass. Five isonitrogenous and isolipidic experimental diets were formulated: four diets containing increasing SBM levels (0, 10, 20 and 30%; 0SBM, 10SBM, 20SBM and 30SBM, respectively) with a low content of FM (20%) and one control diet (0% SBM; 35% FM). Diets containing SBM brought to comparable performance and protein utilization, while 0SBM had negative impact on feed conversion rate and protein utilization. Blood parameters suggested an optimal nutritional status under all feeding treatments, even though slightly decreased values were reported at increasing dietary SBM. Histology examination did not show any changes indicative of soy-induced enteritis. We can conclude that for European sea bass: (i) different blends of plant protein did not affect feed intake despite the 20% FM dietary level; (ii) the inclusion of SBM maintains optimal growth and feed utilization in low FM diets; (iii) blood biochemistry profile showed a good nutritional status under all feeding regimes; (iv) no evidence of soy-induced enteritis was reported in any group fed low FM diets. For formulation of practical diets in on-growing of European sea bass, SBM up to 30% can be successfully incorporated into feeds containing low FM inclusion

Les bulles « robustes »:Pourquoi il faut construire des logements en région parisienne

« Bulle » ou « pas bulle » ? La question taraude les observateurs et les acteurs du marché immobilier français. Nous examinons dans cet article les éléments empiriques et théoriques qui expliquent la hausse des prix récente et sa résistance aux retournements conjoncturels. En combinant la notion de bulle économique, les arguments de l’économie spatiale et une analyse d’économie politique, nous suggérons que la valorisation importante de l’immobilier en France est le résultat d’une logique rationnelle et conforte les intérêts des acteurs locaux. Dès lors, la forte valorisation peut être considérée comme une « bulle robuste », à même de résister à des chocs importants. Cette bulle organise un transfert intergénérationnel et peut avoir des effets positifs. Elle peut également renforcer la ségrégation spatiale, alimenter les inégalités territoriales et empêcher d’exploiter les économies d’agglomération possibles. L’analyse est détaillée sur la région Ile-de-France où ces phénomènes sont particulièrement marqués

Charm in Deep-Inelastic Scattering

We show how to extend systematically the FONLL scheme for inclusion of heavy quark mass effects in DIS to account for the possible effects of an intrinsic charm component in the nucleon. We show that when there is no intrinsic charm, FONLL is equivalent to S-ACOT to any order in perturbation theory, while when an intrinsic charm component is included FONLL is identical to ACOT, again to all orders in perturbation theory. We discuss in detail the inclusion of top and bottom quarks to construct a variable flavour number scheme, and give explicit expressions for the construction of the structure functions $F^c_2$, $F^c_L$ and $F^c_3$ to NNLO

Delayed intracardial shunting and hypoxemia after massive pulmonary embolism in a patient with a biventricular assist device

We describe the interdisciplinary management of a 34-year-old woman with dilated cardiomyopathy three months postpartum on a cardiac biventricular assist device (BVAD) as bridge to heart transplantation with delayed onset of intracardial shunting and subsequent hypoxemia due to massive pulmonary embolism. After emergency surgical embolectomy pulmonary function was highly compromised (PaO2/FiO2 54) requiring bifemoral veno-venous extracorporeal membrane oxygenation. Transesophageal echocardiography detected atrial level hypoxemic right-to-left shunting through a patent foramen ovale (PFO). Percutaneous closure of the PFO was achieved with a PFO occluder device. After placing the PFO occluder device oxygenation increased significantly (Δ paO2 119 Torr). The patient received heart transplantation 20 weeks after BVAD implantation and was discharged from ICU 3 weeks after transplantation

NLL soft and Coulomb resummation for squark and gluino production at the LHC

We present predictions of the total cross sections for pair production of squarks and gluinos at the LHC, including the stop-antistop production process. Our calculation supplements full fixed-order NLO predictions with resummation of threshold logarithms and Coulomb singularities at next-to-leading logarithmic (NLL) accuracy, including bound-state effects. The numerical effect of higher-order Coulomb terms can be as big or larger than that of soft-gluon corrections. For a selection of benchmark points accessible with data from the 2010-2012 LHC runs, resummation leads to an enhancement of the total inclusive squark and gluino production cross section in the 15-30 % range. For individual production processes of gluinos, the corrections can be much larger. The theoretical uncertainty in the prediction of the hard-scattering cross sections is typically reduced to the 10 % level.Comment: 45 pages, 16 Figures, LaTex. v2: published version. Grids with numerical results for the NLL cross sections for squark and gluino production at the 7/8 TeV LHC are included in the submission and are also available at http://omnibus.uni-freiburg.de/~cs1010/susy.htm