A key role of the WEE1-CDK1 axis in mediating TKI-therapy resistance in FLT3-ITD positive acute myeloid leukemia patients.

The insertion site of the internal tandem duplications (ITDs) in the FLT3 gene affects the sensitivity to tyrosine kinase inhibitors (TKIs) therapy in acute myeloid leukemia (AML). Patients with the ITD in the tyrosine kinase domain lack effective therapeutic options. Here, to identify genotype-driven strategies increasing the TKI therapy efficacy, we developed SignalingProfiler, a strategy supporting the integration of high-sensitive mass spectrometry-based (phospho)proteomics, RNA sequencing datasets with literature-derived signaling networks. The approach generated FLT3-ITD genotype-specific predictive models and revealed a conserved role of the WEE1-CDK1 axis in TKIs resistance. Remarkably, pharmacological inhibition of the WEE1 kinase synergizes and strengthens the pro-apoptotic effect of TKIs therapy in cell lines and patient-derived primary blasts. Finally, we propose a new molecular mechanism of TKIs resistance in AML and suggest the combination of WEE1 inhibitor and TKI as a therapeutic option to improve patients clinical outcome.

Building a small fire database for Sub-Saharan Africa from Sentinel-2 high-resolution images.

Coarse resolution sensors are not very sensitive at detecting small fire patches, making current estimations of global burned areas (BA) very conservative. Using medium or high-resolution sensors to generate BA products becomes then a priority, particularly in areas where fires tend to be small and frequent. Building on previous work that developed a small fire dataset (SFD) for Sub-Saharan Africa for 2016, this paper presents a new version of the dataset for 2019 using the two Sentinel-2 satellites (A and B) and VIIRS active fires. Total estimated BA was 4.8 Mkm2. This value was much higher than estimations from two global, coarser-spatial resolution BA products based on MODIS data for the same area and period: 80 % greater than estimates from FireCCI51 (based on MODIS 250 m bands) and 120 % larger than MCD64A1 (based on MODIS 500 m bands). The main differences were observed in those months with higher fire occurrence (November to January for the Northern Hemisphere regions and June to September for the Southern Hemisphere ones). Accuracy assessment of the SFD product was based on a novel sampling strategy designed to obtain independent fire reference perimeters. Validation results showed remarkable high accuracy values comparing to existing global BA products. Overall omission errors (OE) were estimated as 8.5 %, commission errors (CE) as 15.0 %, with a Dice Coefficient of 87.7 %. All of these estimations implied significant improvements over the global, coarser spatial resolution BA products (OE > 50 % and CE > 20 % for the same area and period), as well as over the previous SFD product for 2016 of the same area, generated from a single Sentinel-2 satellite and MODIS active fires (OE = 26.5 % and CE = 19.3 %). Temporal accuracies greatly increased as well with the new product, with 92.5 % of fires detected within the first 10 days of occurrence.

Tim-3 is dispensable for allergic inflammation and respiratory tolerance in experimental asthma.

T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) has been described as a transmembrane protein, expressed on the surface of various T cells as well as different cells of innate immunity. It has since been associated with Th1 mediated autoimmune diseases and transplantation tolerance studies, thereby indicating a possible role of this receptor in counter-regulation of Th2 immune responses. In the present study we therefore directly examined the role of Tim-3 in allergic inflammation and respiratory tolerance. First, Tim-3-/- mice and wild type controls were immunized and challenged with the model allergen ovalbumin (OVA) to induce an asthma-like phenotype. Analysis of cell numbers and distribution in the bronchoalveolar lavage (BAL) fluid as well as lung histology in H&E stained lung sections demonstrated a comparable degree of eosinophilic inflammation in both mouse strains. Th2 cytokine production in restimulated cell culture supernatants and serum IgE and IgG levels were equally increased in both genotypes. In addition, cell proliferation and the distribution of different T cell subsets were comparable. Moreover, analysis of both mouse strains in our respiratory tolerance model, where mucosal application of the model allergen before immunization, prevents the development of an asthma-like phenotype, revealed no differences in any of the parameters mentioned above. The current study demonstrates that Tim-3 is dispensable not only for the development of allergic inflammation but also for induction of respiratory tolerance in mice in an OVA-based model.

B Cell Speed and B-FDC Contacts in Germinal Centers Determine Plasma Cell Output via Swiprosin-1/EFhd2.

Plasma cells secreting affinity-matured antibodies develop in germinal centers (GCs), where B cells migrate persistently and directionally over defined periods of time. How modes of GC B cell migration influence plasma cell development remained unclear. Through genetic deletion of the F-actin bundling protein Swiprosin-1/EF-hand domain family member 2 (EFhd2) and by two-photon microscopy, we show that EFhd2 restrains B cell speed in GCs and hapten-specific plasma cell output. Modeling the GC reaction reveals that increasing GC B cell speed promotes plasma cell generation. Lack of EFhd2 also reduces contacts of GC B cells with follicular dendritic cells in vivo. Computational modeling uncovers that both GC output and antibody affinity depend quantitatively on contacts of GC B cells with follicular dendritic cells when B cells migrate more persistently. Collectively, our data explain how GC B cells integrate speed and persistence of cell migration with B cell receptor affinity.

The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer.

Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT-TFs to target these factors simultaneously.

IL-10 mediates plasmacytosis-associated immunodeficiency by inhibiting complement-mediated neutrophil migration.

BACKGROUND: Plasmacytosis (ie, an expansion of plasma cell populations to much greater than the homeostatic level) occurs in the context of various immune disorders and plasma cell neoplasia. This condition is often associated with immunodeficiency that causes increased susceptibility to severe infections. Yet a causative link between plasmacytosis and immunodeficiency has not been established. OBJECTIVE: Because recent studies have identified plasma cells as a relevant source of the immunosuppressive cytokine IL-10, we sought to investigate the role of IL-10 during conditions of polyclonal and neoplastic plasmacytosis for the regulation of immunity and its effect on inflammation and immunodeficiency. METHODS: We used flow cytometry, IL-10 reporter (Vert-X) and B cell-specific IL-10 knockout mice, migration assays, and antibody-mediated IL-10 receptor blockade to study plasmacytosis-associated IL-10 expression and its effect on inflammation and Streptococcus pneumoniae infection in mice. ELISA was used to quantify IL-10 levels in patients with myeloma. RESULTS: IL-10 production was a common feature of normal and neoplastic plasma cells in mice, and IL-10 levels increased with myeloma progression in patients. IL-10 directly inhibited neutrophil migration toward the anaphylatoxin C5a and suppressed neutrophil-dependent inflammation in a murine model of autoimmune disease. MOPC.315.BM murine myeloma leads to an increased incidence of bacterial infection in the airways, which was reversed after IL-10 receptor blockade. CONCLUSION: We provide evidence that plasmacytosis-associated overexpression of IL-10 inhibits neutrophil migration and neutrophil-mediated inflammation but also promotes immunodeficiency.

Overactive bladder syndrome: an underestimated long-term problem after treatment of patients with localized prostate cancer?

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? In this study we observed courses of micturition symptoms and differentiated degrees of symptoms for each point in time while also considering the impact of bothersomeness. Our data show that not only significantly more patients who have undergone BT suffer from OAB than those who have undergone RP, but also that those affected show significantly higher values for severity of OAB symptoms throughout the whole observation period of 36 months. Our data analysis further shows that variability of OAB symptoms as well as fluctuation of severity of OAB symptoms vary to a significantly higher degree after BT than after RP. Looking only at mean figures at a given point in time clearly underestimates the underlying problem. This fact is not reflected in the literature. OBJECTIVE: • To look at individual courses of postoperative micturition symptoms, especially urgency, in patients treated either with radical prostatectomy (RP) or with brachytherapy (BT). PATIENTS AND METHODS: • In a prospective longitudinal study we investigated individual changes in micturition symptoms before treatment, and 6, 12, 24 and 36 months after treatment. • All patients received the European Organization for the Research and Treatment of Cancer quality-of-life questionnaire, QLQ-C30, and the International Continence Society male questionnaire at each assessment. • We looked at long-term results as well as changes in time using repeated measures analysis of variance. We further analysed fluctuation of symptoms using sum of changes. RESULTS: • Of the 389 patients treated consecutively in our clinic over the last few years, 99 patients with a mean (sd) age of 65 (6.3) years had completed all five questionnaires and thus were further analysed. Of these, 66 (66.7%) were treated with RP and 33 (33.3%) with BT. • With the exception of age, no significant difference was found between the treatment groups either in physical functioning or in prevalence and severity of overactive bladder (OAB) symptoms. • Adjusted for age and pretreatment symptoms in analysis of covariance, we found that there were statistically more symptoms of OAB 36 months after BT compared with those patients treated with RP (P < 0.025). Whereas 30% of patients complained about severe symptoms of urgency after BT, only 11% did so after RP. • Changes of severity of OAB symptoms over the course of time (P < 0.007) using analysis of repeated measures as well as variability of OAB symptoms (P < 0.033) using the two-sided Wilcoxon t-test were significantly higher in patients treated with BT than in patients treated with RP. CONCLUSIONS: • Independently of age and physical functioning, BT is significantly associated with higher rates of long-term urgency symptoms, even after 3 years. • Repeated measurements show that OAB symptoms are highly fluctuating and that in patients treated with BT, severity of symptoms as well as variability of symptoms was significantly higher than in those patients treated with RP. • Persistent OAB seems to be an underestimated problem after treatment for localized prostate cancer, especially in patients treated with BT.