High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, mostly known as double-hit lymphoma (DHL), is a rare entity characterized by morphologic and molecular features between ...Burkitt lymphoma and the clinically manageable diffuse large B-cell lymphoma (DLBCL). DHL patients usually undergo a rapidly progressing clinical course associated with resistance to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival inferior to 1 year. ABT-199 (venetoclax) is a potent and selective small-molecule antagonist of BCL-2 recently approved for the treatment of a specific subtype of lymphoid neoplasm. In this study, we demonstrate that single-agent ABT-199 efficiently displaces BAX from BCL-2 complexes but fails to maintain a significant antitumor activity over time in most MYC+/BCL2+DHL cell lines and primary cultures, as well as in a xenograft mouse model of the disease. We further identify the accumulation of the BCL2-like protein BFL-1 to be a major mechanism involved in acquired resistance to ABT-199. Noteworthy, this phenomenon can be counteracted by the BET bromodomain inhibitor CPI203, since gene expression profiling identifies BCL2A1, the BFL-1 coding gene, as one of the top apoptosis-related gene modulated by this compound. Upon CPI203 treatment, simultaneous downregulation of MYC and BFL-1 further overcomes resistance to ABT-199 both in vitro and in vivo, engaging synergistic caspase-mediated apoptosis in DHL cultures and tumor xenografts. Together, these findings highlight the relevance of BFL-1 in DH lymphoma-associated drug resistance and support the combined use of a BCL-2 antagonist and a BET inhibitor as a promising therapeutic strategy for patients with aggressive DHL.
A Metal-Organic Framework (MOF), iron-benzenetricarboxylate (Fe(BTC)), has been studied for the adsorptive removal of azo-dye Orange II from aqueous solutions, where the effect of various parameters ...was tested and isotherm and kinetic models were suggested. The adsorption capacities of Fe(BTC) were much higher than those of an activated carbon. The experimental data can be best described by the Langmuir isotherm model (R² > 0.997) and revealed the ability of Fe(BTC) to adsorb 435 mg of Orange II per gram of adsorbent at the optimal conditions. The kinetics of Orange II adsorption followed a pseudo-second-order kinetic model, indicating the coexistence of physisorption and chemisorption, with intra-particle diffusion being the rate controlling step. The thermodynamic study revealed that the adsorption of Orange II was feasible, spontaneous and exothermic process (-25.53 kJ·mol
). The high recovery of the dye showed that Fe(BTC) can be employed as an effective and reusable adsorbent for the removal of Orange II from aqueous solutions and showed the economic interest of this adsorbent material for environmental purposes.
Although the emergence of multi-parametric magnetic resonance imaging (mpMRI) has had a profound impact on the diagnosis of prostate cancers (PCa), analyzing these images remains still complex even ...for experts. This paper proposes a fully automatic system based on Deep Learning that performs localization, segmentation and Gleason grade group (GGG) estimation of PCa lesions from prostate mpMRIs. It uses 490 mpMRIs for training/validation and 75 for testing from two different datasets: ProstateX and Valencian Oncology Institute Foundation. In the test set, it achieves an excellent lesion-level AUC/sensitivity/specificity for the GGGFormula: see text2 significance criterion of 0.96/1.00/0.79 for the ProstateX dataset, and 0.95/1.00/0.80 for the IVO dataset. At a patient level, the results are 0.87/1.00/0.375 in ProstateX, and 0.91/1.00/0.762 in IVO. Furthermore, on the online ProstateX grand challenge, the model obtained an AUC of 0.85 (0.87 when trained only on the ProstateX data, tying up with the original winner of the challenge). For expert comparison, IVO radiologist's PI-RADS 4 sensitivity/specificity were 0.88/0.56 at a lesion level, and 0.85/0.58 at a patient level. The full code for the ProstateX-trained model is openly available at https://github.com/OscarPellicer/prostate_lesion_detection . We hope that this will represent a landmark for future research to use, compare and improve upon.
Copy number variants (CNVs) are a substantial source of human genetic diversity, influencing the variable susceptibility to multifactorial disorders. Schizophrenia is a complex illness thought to be ...caused by a number of genetic and environmental effects, few of which have been clearly defined. Recent reports have found several low prevalent CNVs associated with the disease. We have used a multiplex ligation-dependent probe amplification-based (MLPA) method to target 140 previously reported and putatively relevant gene-containing CNV regions in 654 schizophrenic patients and 604 controls for association studies. Most genotyped CNVs (95%) showed very low (<1%) population frequency. A few novel rare variants were only present in patients suggesting a possible pathogenic involvement, including 1.39 Mb overlapping duplications at 22q11.23 found in two unrelated patients, and duplications of the somatostatin receptor 5 gene (SSTR5) at 16p13.3 in three unrelated patients. Furthermore, among the few relatively common CNVs observed in patients and controls, the combined analysis of gene copy number genotypes at two glutathione S-transferase (GST) genes, GSTM1 (glutathione S-transferase mu 1) (1p13.3) and GSTT2 (glutathione S-transferase theta 2) (22q11.23), showed a statistically significant association of non-null genotypes at both loci with an additive effect for increased vulnerability to schizophrenia (odds ratio of 1.92; P=0.0008). Our data provide complementary evidences for low prevalent, but highly penetrant chromosomal variants associated with schizophrenia, as well as for common CNVs that may act as susceptibility factors by disturbing glutathione metabolism.
Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of ...the first Bruton's kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents.
We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma.
IQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest.
These results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR-targeting therapies.
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