In this work, a novel solid-phase processing; namely, shear assisted processing and extrusion (ShAPE) was used to modify the microstructure of AZ31 magnesium alloy, which simultaneously improved ...corrosion resistance along with mechanical properties compared to wrought AZ31 alloys. A noble breakdown potential, higher polarization resistance, and a smaller film thickness after immersion was observed after ShAPE processing. The improved corrosion resistance of ShAPE processed alloy was attributed to grain refinement, homogenized distribution of second phases, and low residual strain in the matrix. Similarly, a tilted basal texture along the ShAPE processed direction contributed towards enhanced ductility and eliminated the tension-compression asymmetry.
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•Improved ductility, strain hardening, and reduced tension-compression asymmetry.•A noble pitting potential and reduced anodic dissolution with the ShAPE processing.•Formed a stable, and integrated oxide layer on the ShAPE processed surface.
Friction stir spot welding (FSSW) of Al alloy 6016-T4 sheet was evaluated using a conventional pin (CP) tool and off-center feature (OC) tool. Tool rotation speed and plunge depth were varied to ...determine the effect of individual process parameter on lap-shear separation load. Maximum separation load of about 3.3kN was obtained by using a 0.2mm shoulder penetration depth with 1500rpm tool rotation speed for the CP tool and 2500rpm for the OC tool. Three different weld separation modes under lap-shear loading were observed: interfacial separation, nugget fracture separation and upper sheet fracture separation. Microhardness profile for weld cross section indicated no direct relationship between microhardness distribution and separation locations.
•Venetoclax resistance is mediated by methylation and silencing of PUMA.•Treatment algorithms should consider the PUMA, MCL1, and BAX status.
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The BCL2 inhibitor venetoclax has been ...approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter’s syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.
Two complementary articles shed new light on resistance to venetoclax in lymphoid malignancies. Thijssen et al use single-cell studies to reveal the multilayered nature of the mechanisms underpinning the recurrence of chronic lymphocytic leukemia in patients on long-term venetoclax, identifying a range of recurring genetic and epigenetic changes in apoptotic regulators. Overlying this heterogeneity, heightened expression of MCL1 driven by NF-κB is ubiquitous but reversible upon drug discontinuation. Thomalla and colleagues use B-lineage cell lines and patient samples to elegantly demonstrate how methylation and silencing of PUMA, a pro-apoptotic, causes failure of venetoclax. Both articles provide clinically applicable suggestions for circumventing emergent resistance to venetoclax.
The purpose of this study was to objectively characterize in vivo glenohumeral joint laxity using an instrumented shoulder
arthrometer. Secondary objectives were to examine the relationship of ...glenohumeral joint laxity with passive range of motion
and generalized joint laxity. Fifty-one recreational athletes with no history of shoulder injury or long-term participation
in overhead sports participated in this study. Anterior and posterior laxity data were obtained at displacement forces of
67, 89, 111, and 134 N. Bilateral passive shoulder range of motion measures were obtained, and a modified Beighton Mobility
Score was used to quantify generalized joint laxity. There were no significant differences in glenohumeral joint laxity between
the right and left shoulders ( P values = 0.14 to 0.73). No significant differences in laxity were seen between directions (F (1,400) = 1.35, P = 0.25). However, significant differences were observed between force levels (F (3,400) = 27.17, P < 0.0001). No moderate or stronger correlations between laxity, passive range of motion, and generalized joint laxity were
seen. These data confirm the presence of a wide spectrum of symmetric laxity in subjects that fails to correlate strongly
with passive range of motion or generalized joint laxity.
Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is ...heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL IPS-E). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.
•IPS-E is a simple and robust prognostic model for early-stage CLL.•IPS-E can be helpful in patients' counseling and design of clinical trials.
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T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number ...(CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.
In chronic lymphocytic leukemia (CLL), epigenetic alterations are considered to centrally shape the transcriptional signatures that drive disease evolution and underlie its biological and clinical ...subsets. Characterizations of epigenetic regulators, particularly histone-modifying enzymes, are very rudimentary in CLL. In efforts to establish effectors of the CLL-associated oncogene T-cell leukemia 1A (TCL1A), we identified here the lysine-specific histone demethylase KDM1A to interact with the TCL1A protein in B cells in conjunction with an increased catalytic activity of KDM1A. We demonstrate that KDM1A is upregulated in malignant B cells. Elevated KDM1A and associated gene expression signatures correlated with aggressive disease features and adverse clinical outcomes in a large prospective CLL trial cohort. Genetic Kdm1a knockdown in Eμ-TCL1A mice reduced leukemic burden and prolonged animal survival, accompanied by upregulated p53 and proapoptotic pathways. Genetic KDM1A depletion also affected milieu components (T, stromal, and monocytic cells), resulting in significant reductions in their capacity to support CLL-cell survival and proliferation. Integrated analyses of differential global transcriptomes (RNA sequencing) and H3K4me3 marks (chromatin immunoprecipitation sequencing) in Eμ-TCL1A vs iKdm1aKD;Eμ-TCL1A mice (confirmed in human CLL) implicate KDM1A as an oncogenic transcriptional repressor in CLL which alters histone methylation patterns with pronounced effects on defined cell death and motility pathways. Finally, pharmacologic KDM1A inhibition altered H3K4/9 target methylation and revealed marked anti-B-cell leukemic synergisms. Overall, we established the pathogenic role and effector networks of KDM1A in CLL via tumor-cell intrinsic mechanisms and its impacts in cells of the microenvironment. Our data also provide rationales to further investigate therapeutic KDM1A targeting in CLL.
This study assessed shoulder laxity using an instrumented arthrometer. We compared anterior and posterior translations at various force levels to determine the reliability of our measurement ...technique and to provide normative data in healthy shoulders. Fifty shoulders were assessed for glenohumeral joint laxity in two directions (anterior and posterior) and at four force levels (67, 89, 111, and 134 N). The dependent measure was joint displacement. Laxity values were widely, yet normally, distributed in our group of healthy shoulders. Intraclass correlation coefficients revealed excellent between-trial reliability (0.92) and fair between-session (0.73) and between-examiner (0.74) reliability. The average standard error of measurement between trials (0.56 mm), sessions (1.5 mm), and examiners (1.7 mm) demonstrated an unprecedentedly high degree of precision for quantifying glenohumeral joint laxity. Paired t tests revealed no significant laxity differences between sides (P>0.05), indicating bilateral symmetry. A 2 (direction) x 4 (force) analysis of variance revealed significant differences in laxity between directions (P<0.0001) and force levels (P<0.0001). Our results show that our instrumented technique for quantifying glenohumeral joint laxity is precise and reproducible. Posterior translation was significantly greater than anterior, and a significant increase in translation was observed between increasing levels of force.
Although +12 chronic lymphocytic leukemia comprises about 20% of cases, relatively little is known about its pathophysiology. These cases often demonstrate atypical morphologic and immunophenotypic ...features, high proliferative rates, unmutated immunoglobulin heavy chain variable region genes, and a high frequency of NOTCH1 mutation. Patients with +12 chronic lymphocytic leukemia have an intermediate prognosis, and show higher incidences of thrombocytopenia, Richter's transformation, and other second cancers. Despite these important differences, relatively few transcriptional profiling studies have focused on identifying dysregulated pathways that characterize +12 chronic lymphocytic leukemia, and most have used a hierarchical cytogenetic classification in which cases with more than one recurrent abnormality are categorized according to the abnormality with the poorest prognosis. In this study, we sought to identity protein-coding genes whose expression contributes to the unique pathophysiology of +12 chronic lymphocytic leukemia. To exclude the likely confounding effects of multiple cytogenetic abnormalities on gene expression, our +12 patient cohort had +12 as the sole abnormality. We profiled samples obtained from 147 treatment-naive patients. We compared cases with +12 as the sole cytogenetic abnormality to cases with sole del(13q), del(11q), or diploid cytogenetics using independent discovery (n=97) and validation (n=50) sets. We demonstrate that chronic lymphocytic leukemia cases with +12 as the sole abnormality express a unique set of activated pathways compared to other cytogenetic subtypes. Among these pathways, we identify the NFAT signaling pathways and the immune checkpoint molecule, NT5E (CD73), which may represent new therapeutic targets.
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