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Any low-cost quickly implementable physical rehabilitation intervention clinically boosts gait implying much better variation to lessen arm or leg prosthesis: a new randomized clinical study.
A growth arrest caused by the TbCAE knockdown was rescued by the expression of the cytosolic isoform of yeast CAE, even though it was not imported into mitochondria. This finding indicated that the yeast enzyme complements the essential function of TbCAE by adding CCA to the primary tRNA transcripts. Of note, ablation of the mitochondrial TbCAE activity, which likely has a repair function, only marginally affected growth. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this difference, inhibitors of metastasis must account for each migration mode. However, the role of Vimentin in amoeboid migration has not been determined. Since amoeboid, Leader Bleb-Based Migration (LBBM) occurs in confined spaces and Vimentin is known to strongly influence cell mechanical properties, we hypothesized that a flexible Vimentin network is required for fast amoeboid migration. To this end, here we determined the precise role of the Vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial-to-mesenchymal transition and is therefore an ideal target for a metastasis inhibitor. Using a previously developed PDMS slab-based approach to confine cells, RNAi-based Vimentin silencing, Vimentin over-expression, pharmacological treatments, and measurements of cell stiffness, we found that RNAi-mediated depletion of Vimentin increases LBBM by ~50% compared with control cells and that Vimentin over-expression and Simvastatin-induced Vimentin bundling inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Our results indicate that a flexible Vimentin intermediate filament network promotes LBBM of amoeboid cancer cells in confined environments and that Vimentin bundling perturbs cell mechanical properties and thereby inhibits the invasive properties of cancer cells. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Conopeptides are neurotoxic peptides in the venom of marine cone snails and have broad therapeutic potential for managing pain and other conditions. Here, we identified the single-disulfide peptides Czon1107 and Cca1669 from the venoms of Conus zonatus and Conus caracteristicus, respectively. We observed that Czon1107 strongly inhibits the human α3β4 (IC50 15.7 ± 3.0 μM) and α7 (IC50 77.1 ± 0.05 μM) nicotinic acetylcholine receptor (nAChR) subtypes, but the activity of Cca1669 remains to be identified. Czon1107 acted at a site distinct from the orthosteric receptor site. Solution NMR experiments revealed that Czon1107 exists in equilibrium between conformational states that are the result of a key Ser4-Pro5 cis-trans isomerization. Moreover, we found that the X-Pro amide bonds in the inter-cysteine loop are rigidly constrained to cis conformations. Structure-activity experiments of Czon1107 and its variants at positions P5 and P7 revealed that the conformation around the X-Pro bonds (cis-trans) plays an important role in receptor subtype selectivity. The cis conformation at the Cys6-Pro7 peptide bond was essential for α3β4 nAChR subtype allosteric selectivity. In summary, we have identified an unique single disulfide conopeptide with a non-competitive, potentially allosteric inhibitory mechanism at the nAChRs. The small size and rigidity of the Czon1107 peptide could provide a scaffold for rational drug design strategies for allosteric nAChR modulation. This new paradigm in the "conotoxinomic" structure-function space provides an impetus to screen venom from other Conus species for similar, short bioactive peptides that allosterically modulate ligand-gated receptor function. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.PURPOSE Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. Wntagonist1 We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens. EXPERIMENTAL DESIGN A total of 549 adults with T-LBL from 27 medical centers were included in the analysis. Using the Illumina Methylation 850K Beadchip, 44 relapse-related CpGs were identified from 49 T-LBL samples by two algorithms, Least Absolute Shrinkage and Selector Operation (LASSO) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE). We built a four-CpG classifier using LASSO Cox regression based on association between the methylation level of CpGs and relapse-free survival (RFS) in the training cohort (n=160).The four-CpG classifier was validated in the internal testing cohort (n=68) and independent validation cohort (n=321) Results The four-CpG-based classifier discriminated T-LBL patients at high risk of relapse in the training cohort from those at low risk (p less then 0.001).This classifier also showed good predictive value in the internal testing cohort (p less then 0.001) and the independent validation cohort(p less then 0.001). A nomogram incorporating 5 independent prognostic factors including the CpG-based classifier, lactate dehydrogenase levels, ECOG-PS, central nervous system involvement and NOTCH1/FBXW7 status showed a significantly higher predictive accuracy than each single variable. Stratification into different subgroups by the nomogram helped identify the subset of patients who most benefited from more intensive chemotherapy and/or sequential hematopoietic stem cell transplantation. CONCLUSIONS Our four-CpG-based classifier could predict disease relapse in patients with T-LBL, and could be used to guide treatment decision. Copyright ©2020, American Association for Cancer Research.PURPOSE Over 60% of melanoma patients respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on BRAF mutation status, but no available agents are available for NRAS, CDKN2A, PTEN, and TP53 mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to BRAF or NRAS mutations, while loss or mutation of cdkn2a occurs in ~40% of melanomas, resulting in unregulated MDM2-mediated ubiquitination and degradation of P53. Here we investigated the therapeutic efficacy of over-riding MDM2-mediated degradation of P53 in melanoma with an MDM2 inhibitor that interrupts MDM2 ubiquitination of P53, treating tumor-bearing mice with the MDM2 inhibitor alone or combined with MAPK-targeted therapy. EXPERIMENTAL DESIGN To characterize the ability of the MDM2 antagonist, KRT-232, to inhibit tumor growth, we established patient-derived xenografts (PDX) from 15 melanoma patients. Mice were treated with KRT-232 or a combination with BRAF and/or MEK inhibitors.
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