B cell-specific conditional expression of Myd88(p.L252P) leads to the development of diffuse large B cell lymphoma in mice

The adaptor protein MYD88 is critical to relay activation of Toll-like receptor signaling to NF-{kappa}B activation.MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B cell malignancies, including diffuse large B cell lymphoma (DLBCL). 29% of activated B cell (ABC)-type DLBCL, which is characterized by constitutive activation of the NF-{kappa}B pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2. Here, we generated a novel mouse model, in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P)(the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These animals develop a lympho-proliferative disease, and occasional transformation into clonal lymphomas. The clonal disease displays morphological and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression ofBCL2 Cross-validation experiments in human DLBCL samples revealed that bothMYD88andCD79Bmutations are substantially enriched in ABC-DLBCL, compared to germinal center B cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occur with MYD88 mutations, further validating our approach. Lastly,in silicoexperiments revealed that particularly MYD88-mutant ABC-DLBCL cells display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL, which could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL

Wetlands for wastewater treatment and subsequent recycling of treated effluent : a review

Due to water scarcity challenges around the world, it is essential to think about non-conventional water resources to address the increased demand in clean freshwater. Environmental and public health problems may result from insufficient provision of sanitation and wastewater disposal facilities. Because of this, wastewater treatment and recycling methods will be vital to provide sufficient freshwater in the coming decades, since water resources are limited and more than 70% of water are consumed for irrigation purposes. Therefore, the application of treated wastewater for agricultural irrigation has much potential, especially when incorporating the reuse of nutrients like nitrogen and phosphorous, which are essential for plant production. Among the current treatment technologies applied in urban wastewater reuse for irrigation, wetlands were concluded to be the one of the most suitable ones in terms of pollutant removal and have advantages due to both low maintenance costs and required energy. Wetland behavior and efficiency concerning wastewater treatment is mainly linked to macrophyte composition, substrate, hydrology, surface loading rate, influent feeding mode, microorganism availability, and temperature. Constructed wetlands are very effective in removing organics and suspended solids, whereas the removal of nitrogen is relatively low, but could be improved by using a combination of various types of constructed wetlands meeting the irrigation reuse standards. The removal of phosphorus is usually low, unless special media with high sorption capacity are used. Pathogen removal from wetland effluent to meet irrigation reuse standards is a challenge unless supplementary lagoons or hybrid wetland systems are used

Virtual mono-energetic images and iterative image reconstruction: abdominal vessel imaging in the era of spectral detector CT

AIM: To compare the quality of virtual mono-energetic (VMI) and polychromatic images reconstructed with hybrid iterative (PCIHIR) or model-based reconstruction (PCIMBR) derived from dual-layer spectral detector computed tomography (SDCT) in arterial phase images to visualise the aorta and abdominal main branches. MATERIAL AND METHODS: A retrospective review of 50 patients with abdominal arterial phase scans was undertaken. Attenuation, intraluminal noise, and signal-/contrast-to-noise ratio (S-/CNR) were assessed in the PCIHIR, PCIMBR and VMI40keV, VMI70keV, and VMI100keV images. Contrast, noise, and visualization of soft-plaque, and macro-/micro-calcifications were scored in a blinded reading by two radiologists. RESULTS: VMI40keV yielded highest S-/CNR (p = 0.999) and yielded higher SNR than PCIHIR. VMI70keV yielded higher CNR than PCIHIR (p0.999), while VMI40keV scored second best for depiction of soft-plaque (p<0.020). CONCLUSIONS: VMI40keV and VMI70keV yield better S-/CNR than PCIHIR and PCIMBR; however, PCIMBR visualized arteriosclerotic plaques best, followed by VMI40keV for depiction of soft-plaque and VMI100keV for macro- and micro-calcification. Based on the present findings, PCIMBR on conventional CT and VMI40keV supplemented by VMI100keV on SDCT are recommended for the diagnostic assessment of abdominal arteries. (C) 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved

Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) remains an incurable disease. Two recurrent cytogenetic aberrations, namely del(17p), affecting TP53, and del(11q), affecting ATM, are associated with resistance against genotoxic chemotherapy (del17p) and poor outcome (del11q and del17p). Both del(17p) and del(11q) are also associated with inferior outcome to the novel targeted agents, such as the BTK inhibitor ibrutinib. Thus, even in the era of targeted therapies, CLL with alterations in the ATM/p53 pathway remains a clinical challenge. Here we generated two mouse models of Atm- and Trp53-deficient CLL. These animals display a significantly earlier disease onset and reduced overall survival, compared to controls. We employed these models in conjunction with transcriptome analyses following cyclophosphamide treatment to reveal that Atm deficiency is associated with an exquisite and genotype-specific sensitivity against PARP inhibition. Thus, we generate two aggressive CLL models and provide a preclinical rational for the use of PARP inhibitors in ATM-affected human CLL