Composição isotópica de Nd na componente terrígena de sedimentos como marcador de eventos de Heinrich:estudo de um caso na margem continental NW Ibérica

The OMEX core KC 024-19 was studied aiming at to assess the influence of climate changes on the origin and transport of the sediments of the Galician continental slope, in the last 40 ka. The results show that sea level variation played a major role in the supply of the terrigenous sediments coming from the nearby continental areas, whose basement has a Variscan age. Additionally, coarse-grained clastic materials, corresponding to ice-rafted debris (IRD), were deposited through melting of icebergs during the Heinrich events (HE), in the last glaciation. The last four HE were identified in the core. The measured Nd isotope ratios reveal that there was a strong contribution of continental crustal sources significantly older than the Variscan basement for HE 1, 2 and 4. The most likely provenance of the coarse clasts deposited during these three events lie in NE America or Greenland, and the carrier icebergs should be fragments of the Laurentide Ice Sheet. In contrast, the HE 3 layer displays εNd values in the range of the compositions of the most common sediments in the core and, therefore, its IRD should have European source(s), which supports previous results obtained in other places of the European Atlantic margin.O core OMEX KC 024-19 foi estudado tendo em vista avaliar o papel das mudanças climáticas nos processos de transporte e nas fontes de sedimentos depositados no talude continental da Galiza, durante os últimos 40 ka. Os resultados obtidos, usando diferentes metodologias, apontam para uma grande influência das mudanças do nível do mar no fornecimento de sedimentos terrígenos a partir das áreas continentais próximas, cujo soco é de idade varisca. Para além disso, nos eventos de Heinrich (HE), ocorridos durante a última glaciação, foram recebidos nesta área materiais detríticos grosseiros transportados por icebergues em fusão (IRD). Foram identificados, neste core, os quatro últimos HE. As razões isotópicas de Nd revelam que durante os HE 1, 2 e 4 houve contribuição importante de fontes de crusta continental significativamente mais antiga do que a ibérica. A origem provável dos IRD desses três eventos estará no NE da América ou na Gronelândia, podendo os icebergues que os transportaram ter origem na LIS (Laurentide Ice Sheet). Já o HE 3, não se distingue, em termos de εNd, dos sedimentos mais comuns no core, pelo que os IRD correspondentes deverão ter origem europeia, o que corrobora resultados obtidos noutros locais da margem atlântica europeia

Reduced cytotoxicity by mutation of lysine 590 of Pseudomonas exotoxin can be restored in an optimized, lysine-free immunotoxin

Immunotoxins, which are fusion proteins of an antibody fragment and a fragment of a bacterial or a plant toxin, induce apoptosis in target cells by inhibition of protein synthesis. ADP-ribosylating toxins often have few lysine residues in their catalytic domain. As they are the target for ubiquitination, the low number of lysines possibly prevents ubiquitin-dependent degradation of the toxin in the cytosol. To reduce this potential degradation, we aimed to generate a lysine-free (noK), Pseudomonas exotoxin (PE)-based immunotoxin. The new generation 24 kDa PE, which lacks all but the furin-cleavage site of domain II, was mutated at lysine 590 (K590) and at K606 in a CD22-targeting immunotoxin and activity was determined against various B cell malignancies in vitro and in vivo. On average, K590 mutated to arginine (R) reduced cytotoxicity by 1.3-fold and K606R enhanced cytotoxicity by 1.3-fold compared to wild type (wt). Mutating K590 to histidine or deleting K590 did not prevent this loss in cytotoxicity. Neither stability nor internalization rate of K590R could explain reduced cytotoxicity. These results highlight the relevance of lysine 590 for PE intoxication. In line with in vitro results, the K606R mutant was more than 1.8-fold more active than the other variants in vivo suggesting that this single mutation may be beneficial when targeting CD22-positive malignancies. Finally, reduced cytotoxicity by K590R was compensated for by K606R and the resulting lysine-free variant achieved wt-like activity in vitro and in vivo. Thus, PE24-noK may represent a promising candidate for down-stream applications that would interfere with lysines

Case Report: IBD-like colitis following CAR T cell therapy for diffuse large B cell lymphoma

Chimeric antigen receptor (CAR) T cell therapy has become a new mainstay in the treatment of several hematologic malignancies, but the spectrum of associated complications is still incompletely defined. Here, we report the case of a 70-year-old female patient treated with tisagenlecleucel for diffuse large B cell lymphoma (DLBCL), who developed chronic diarrhea with characteristics of inflammatory bowel disease (IBD)-like colitis. CAR T cells were substantially enriched in the colon lamina propria and other diagnoses were ruled out. Thus, we conclude that IBD-like colitis in this patient was associated to CAR T cell therapy and needs to be considered as a rare potential complication

Whole-Body Electromyostimulation Combined With Individualized Nutritional Support Improves Body Composition in Patients With Hematological Malignancies – A Pilot Study

Patients undergoing the complex treatment for hematological malignancies are exposed to a high physiological and psychological distress inducing fatigue and physical inactivity. In line with cancer-related metabolic changes patients are predisposed for skeletal muscle mass loss that leads to a functional decline, affects therapeutic success, and quality of life. Benefits of physical exercise and nutritional interventions on muscle maintenance are observed in solid cancer patients, but marginally investigated in patients with hematological cancer. We here studied the effects of a combined supportive exercise and nutrition intervention using whole-body electromyostimulation (WB-EMS) training and individualized nutritional support in patients actively treated for hematological malignancy. In a controlled pilot trial, 31 patients (67.7% male; 58.0 ± 16.7 years) with various hematological cancers were allocated to a control group (n = 9) receiving nutritional support of usual care regarding a high protein intake (>1.0 g/kg/d) or to a physical exercise group (n = 22) additionally performing WB-EMS training twice weekly for 12 weeks. Bodyweight and body composition assessed by bioelectrical impedance analysis were measured every 4 weeks. Physical function, blood parameters, quality of life and fatigue were assessed at baseline and after 12 weeks. No WB-EMS-related adverse effects occurred. Patients attending the exercise program presented a higher skeletal muscle mass than controls after 12-weeks (1.51 kg [0.41, 2.60]; p = 0.008). In contrast, patients of the control group showed a higher fat mass percentage than patients of the WB-EMS group (-4.46% [-7.15, -1.77]; p = 0.001) that was accompanied by an increase in serum triglycerides in contrast to a decrease in the WB-EMS group (change ± SD, control 36.3 ± 50.6 mg/dl; WB-EMS -31.8 ± 68.7 mg/dl; p = 0.064). No significant group differences for lower limb strength, quality of life, and fatigue were detected. However, compared to controls the WB-EMS group significantly improved in physical functioning indicated by a higher increase in the 6-min-walking distance (p = 0.046). A combined therapeutic intervention of WB-EMS and protein-rich nutritional support seems to be safe and effective in improving skeletal muscle mass and body composition in hematological cancer patients during active oncological treatment. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02293239

Genetic Variants in P-Selectin and C-Reactive Protein Influence Susceptibility to Cognitive Decline After Cardiac Surgery

ObjectivesWe hypothesized that candidate gene polymorphisms in biologic pathways regulating inflammation, cell matrix adhesion/interaction, coagulation-thrombosis, lipid metabolism, and vascular reactivity are associated with postoperative cognitive deficit (POCD).BackgroundCognitive decline is a common complication of coronary artery bypass graft (CABG) surgery and is associated with a reduced quality of life.MethodsIn a prospective cohort study of 513 patients (86% European American) undergoing CABG surgery with cardiopulmonary bypass, a panel of 37 single-nucleotide polymorphisms (SNPs) was genotyped by mass spectrometry. Association between these SNPs and cognitive deficit at 6 weeks after surgery was tested using multiple logistic regression accounting for age, level of education, baseline cognition, and population structure. Permutation analysis was used to account for multiple testing.ResultsWe found that minor alleles of the CRP1059G/C SNP (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.16 to 0.78; p = 0.013) and the SELP1087G/A SNP (OR 0.51, 95% CI 0.30 to 0.85; p = 0.011) were associated with a reduction in cognitive deficit in European Americans (n = 443). The absolute risk reduction in the observed incidence of POCD was 20.6% for carriers of the CRP1059C allele and 15.2% for carriers of the SELP1087A allele. Perioperative serum C-reactive protein (CRP) and degree of platelet activation were also significantly lower in patients with a copy of the minor alleles, providing biologic support for the observed allelic association.ConclusionsThe results suggest a contribution of P-selectin and CRP genes in modulating susceptibility to cognitive decline after cardiac surgery, with potential implications for identifying populations at risk who might benefit from targeted perioperative antiinflammatory strategies

Whole-Body Electromyostimulation Combined With Individualized Nutritional Support Improves Body Composition in Patients With Hematological Malignancies – A Pilot Study

Patients undergoing the complex treatment for hematological malignancies are exposed to a high physiological and psychological distress inducing fatigue and physical inactivity. In line with cancer-related metabolic changes patients are predisposed for skeletal muscle mass loss that leads to a functional decline, affects therapeutic success, and quality of life. Benefits of physical exercise and nutritional interventions on muscle maintenance are observed in solid cancer patients, but marginally investigated in patients with hematological cancer. We here studied the effects of a combined supportive exercise and nutrition intervention using whole-body electromyostimulation (WB-EMS) training and individualized nutritional support in patients actively treated for hematological malignancy. In a controlled pilot trial, 31 patients (67.7% male; 58.0 ± 16.7 years) with various hematological cancers were allocated to a control group (n = 9) receiving nutritional support of usual care regarding a high protein intake (>1.0 g/kg/d) or to a physical exercise group (n = 22) additionally performing WB-EMS training twice weekly for 12 weeks. Bodyweight and body composition assessed by bioelectrical impedance analysis were measured every 4 weeks. Physical function, blood parameters, quality of life and fatigue were assessed at baseline and after 12 weeks. No WB-EMS-related adverse effects occurred. Patients attending the exercise program presented a higher skeletal muscle mass than controls after 12-weeks (1.51 kg [0.41, 2.60]; p = 0.008). In contrast, patients of the control group showed a higher fat mass percentage than patients of the WB-EMS group (-4.46% [-7.15, -1.77]; p = 0.001) that was accompanied by an increase in serum triglycerides in contrast to a decrease in the WB-EMS group (change ± SD, control 36.3 ± 50.6 mg/dl; WB-EMS -31.8 ± 68.7 mg/dl; p = 0.064). No significant group differences for lower limb strength, quality of life, and fatigue were detected. However, compared to controls the WB-EMS group significantly improved in physical functioning indicated by a higher increase in the 6-min-walking distance (p = 0.046). A combined therapeutic intervention of WB-EMS and protein-rich nutritional support seems to be safe and effective in improving skeletal muscle mass and body composition in hematological cancer patients during active oncological treatment.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02293239

AAV2-Mediated Combined Subretinal Delivery of IFN-α and IL-4 Reduces the Severity of Experimental Autoimmune Uveoretinitis

We previously showed that adeno-associated virus 2 (AAV2) mediated subretinal delivery of human interferon-alpha (IFN-α) could effectively inhibit experimental autoimmune uveoretinitis (EAU). In this study we investigated whether subretinal injection of both AVV2.IFN-α and AAV2.IL-4 had a stronger inhibition on EAU activity. B10RIII mice were subretinally injected with AAV2.IFN-α alone (1.5×107 vg), AAV2.IL-4 alone (3.55×107 vg), and AAV2.IFN-α combined with AAV2.IL-4. PBS, AAV2 vector encoding green fluorescent protein (AAV2.GFP) (5×107 vg) was subretinally injected as a control. IFN-α and IL-4 were effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2 vectors either alone or following combined administration and significantly attenuated EAU activity clinically and histopathologically. AAV2.IL-4 showed a better therapeutic effect as compared to AAV2.IFN-α. The combination of AAV2.IL-4 and AAV2.IFN-α was not significantly different as compared to AAV2.IL-4 alone. There was no difference concerning DTH (delayed-type hypersensitivity) reaction, lymphocyte proliferation and IL-17 production among the investigated treatment groups, suggesting that local retinal gene delivery did not affect the systemic immune response

CD137 (4-1BB) stimulation leads to metabolic and functional reprogramming of human monocytes/macrophages enhancing their tumoricidal activity

Abstract Immunotherapies have heralded a new era in the cancer treatment. In addition to checkpoint inhibitors, agonistic antibodies against co-stimulatory immune receptors hold the potential to invoke efficient antitumor immunity. Targeting CD137 has gained momentum based on its ability to drive NK- and T-cell-based responses. CD137-engaging mAbs have already entered clinical trials for different types of tumors showing promising results. Despite the efforts to translate CD137-mediated immunotherapy into clinical practice, little remains known regarding the role of CD137 in human monocytes/macrophages. We found CD137 being expressed on monocytes of healthy controls and at even higher levels in patients with multiple myeloma or CLL. CD137HI(GH) monocytes displayed a distinct phenotypic, transcriptomic, and metabolic profile. They possessed an increased phagocytic capacity enabling superior antibody-dependent phagocytosis (ADPC) of multiple myeloma and lymphoma cells that were treated with anti-CD38 or anti-CD20 mAbs. Triggering CD137 promoted both metabolic and tumoricidal activity in an extracellular signal-regulated kinase (ERK)-dependent fashion. In addition, we observed a phenotypic, transcriptomic, and functional skewing towards a M1-like phenotype. Overall, we introduce CD137 as a positive immune checkpoint on human monocytes/macrophages, which can have therapeutic implications especially in view of synergistic effects when combining CD137 agonists with tumor-targeting antibodies