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BACKGROUND: l-Asparaginase (ASP) plays a crucial role in the treatment of childhood acute lymphoblastic leukemia (ALL). Currently, different ASP products are available in the market, including both native and pegylated drugs. Several biogeneric Escherichia coli ASP (GEN-ASP) products have been developed in response to shortages and expensiveness of the native E. coli ASP innovator compounds, but some concerns have been raised about their quality. Recently, a number of generic pegylated ASP products (GEN-PEG-ASP) have been marketed to substitute for the innovator product (PEG-ASP). METHODS: Clinical courses and serum asparaginase activity (SAA) levels were monitored in 12 children with ALL, who were treated in our institution with two doses of a GEN-PEG-ASP product, given IV at 2500 IU/m2 during the remission induction phase. Results were compared with those obtained in a reference cohort of 35 patients treated in our institution, who received the innovator PEG-ASP product at same dosage and within the same chemotherapy background. RESULTS: Compared to the reference cohort treated with PEG-ASP, SAA levels were significantly lower in the 12 patients receiving GEN-PEG-ASP (p < .0001); a higher proportion of ASP-associated hypersensitivity reactions (2/12 vs. 0/35; p = .061) and silent inactivation (3/12 vs. 0/35; p = .014) were observed in comparison with the reference cohort. CONCLUSIONS: Our results highlighted different pharmacological profiles and different rates of hypersensitivity reactions and silent inactivation in the GEN-PEG-ASP cohort compared to those treated with the innovator product. Our findings suggest that a rigorous clinical attention and a thorough pharmacological monitoring are advisable in patients treated with GEN-PEG-ASP products.

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This study aimed to compare the occlusal morphology and fracture behavior of lithium disilicate ceramic dental crowns on 12 human participants' premolar #45 designed by a knowledge-based AI (CEREC, biogeneric individual function, BI) and different human personnel (experienced technician, TD, and trained dental students, AD) using CAD software. Digital datasets of crown design were best-fit aligned with the original teeth to evaluate profile and volume discrepancies of the occlusal morphology, and difference in the functional cuspal angle. Milled and sintered lithium disilicate crowns were resin-luted to 3D-printed dental casts and were subjected to axial load-to-fracture test. The fracture loads and failure modes were recorded and examined. Repeated measures ANOVA with LSD post-hoc test, Kruskal-Wallis test, Pearson's correlation coefficient, paired t-test, and chi-square exact test were used for statistical analyses (α = 0.05). BI-generated crowns showed the highest occlusal profile discrepancy (0.3677 ± 0.0388 mm), whereas human-CAD designed crowns showed higher conformity to the original teeth (0.3254 ± 0.0515 mm for TD, 0.3571 ± 0.0820 for AD; z-difference method; p < 0.001). Cusp angle values were significantly different in all groups except BI and TD (54.76 ± 3.81° for the original teeth, 70.84 ± 4.31° for BI, 67.45 ± 5.30° for TD, and 62.30 ± 7.92° for AD; p < 0.001). Although all three groups of crown designs could achieve clinically acceptable fracture resistance (1556.09 ± 525.68 N for BI, 1486.00 ± 520.08 N for TD, 1425.77 ± 433.34 for AD; p = 0.505) such that no significant difference in fracture strength was found, most crowns presented catastrophic bulk fracture that was not clinically restorable because of the substrate fracture. Group BI had a significantly higher percentage of restorable substrate damage than TD (p = 0.014) and AD (p < 0.001). In conclusion, in designing lithium disilicate dental crown, CAD design with human may be better than knowledge-based AI.

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BACKGROUND: The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli-derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low-middle-income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes. PROCEDURE: Seven biogeneric EcASNases (P1-P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m2 /dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug-related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R). RESULTS: In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (<100 U/L) was observed in 66% (46/70) of trough timepoints (72 hours postdose) during induction. Twelve patients (19%), 11 with high-risk ALL, developed hypersensitivity. Isoforms of EcASNase were identified in all seven biogenerics. All generic products contained impurities with batch-to-batch variability. These included high levels of protein aggregates and host cell protein contamination. In vitro assays of EcASNase activity and leukaemia cell line cytotoxicity were not discriminatory. CONCLUSIONS: Our findings confirm widespread concerns over the unsatisfactory quality and therapeutic activity of native EcASNase biogenerics marketed in LMICs. Appropriate use of these products requires monitored studies to identify clinical suitability and determine appropriate dosing and schedule. For large parts of the world, assured access to high-quality asparaginases remains an unmet therapeutic need.

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[This corrects the article DOI: 10.3389/fphys.2019.00702.].

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John Bonner presented a provocative conjecture that the means by which organisms evolve has itself evolved. The elements of his postulated nonuniformitarianism in the essay under discussion-the emergence of sex, the enhanced selection pressures on larger multicellular forms-center on a presumed close mapping of genotypic to phenotypic change. A different view emerges from delving into earlier work of Bonner's in which he proposed the concept of "neutral phenotypes" and "neutral morphologies" allied to D'Arcy Thompson's analysis of physical determinants of form and studied the conditional elicitation of intrinsic organizational properties of cell aggregates in social amoebae. By comparing the shared and disparate mechanistic bases of morphogenesis and developmental outcomes in the embryos of metazoans (animals), closely related nonmetazoan holozoans, more distantly related dictyostelids, and very distantly related volvocine algae, I conclude, in agreement with Bonner's earlier proposals, that understanding the evolution of multicellular evolution requires knowledge of the inherent forms of diversifying lineages, and that the relevant causative factors extend beyond genes and adaptation to the physics of materials.

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I discuss recent work on the origins of morphology and cell-type diversification in Metazoa - collectively the animals - and propose a scenario for how these two properties became integrated, with the help of a third set of processes, cellular pattern formation, into the developmental programs seen in present-day metazoans. Inherent propensities to generate familiar forms and cell types, in essence a parts kit for the animals, are exhibited by present-day organisms and were likely more prominent in primitive ones. The structural motifs of animal bodies and organs, e.g., multilayered, hollow, elongated and segmented tissues, internal and external appendages, branched tubes, and modular endoskeletons, can be accounted for by the properties of mesoscale masses of metazoan cells. These material properties, in turn, resulted from the recruitment of "generic" physical forces and mechanisms - adhesion, contraction, polarity, chemical oscillation, diffusion - by toolkit molecules that were partly conserved from unicellular holozoan antecedents and partly novel, distributed in the different metazoan phyla in a fashion correlated with morphological complexity. The specialized functions of the terminally differentiated cell types in animals, e.g., contraction, excitability, barrier function, detoxification, excretion, were already present in ancestral unicellular organisms. These functions were implemented in metazoan differentiation in some cases using the same transcription factors as in single-celled ancestors, although controlled by regulatory mechanisms that were hybrids between earlier-evolved processes and regulatory innovations, such as enhancers. Cellular pattern formation, mediated by released morphogens interacting with biochemically responsive and excitable tissues, drew on inherent self-organizing processes in proto-metazoans to transform clusters of holozoan cells into animal embryos and organs.

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This study evaluates the symmetry of initial proposals for anterior tooth restorations delivered by the Cerec software. By using a symmetric preparation model and a special angulation gauge for restoration axes, the study proves that the restoration proposals are symmetric with respect to the median sagittal plane.

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Objective:To fabricate an all-ceramic crown which copies the morphology of preoperative tooth in one patient with only small occlusal dentin defects with completely digital design (CDD)technology,and to find a more precise and feasible solution to fix the tooth detect.Methods:The tooth treated with root canal therapy had the complete axial surface and small occlusal dentin defects.In order to keep the morphology of preoperative tooth,the digitized crown was designed with the information of preoperative tooth by oral scanning with CS3500 and using the"Biogeneric Copy"function of exocad design software,then the digitized information of the teeth was collected and transformed and the simulate zirconia crown was mode by 3D colloidal deposition technique.The patient's comfort and satisfaction were investigated by observing the morphology,the interproximal contacts,and the occlusion of crown.Results:The morphology of definitive restoration was similar to the preoperative tooth,which presented good interproximal contact and occlusion,and the patient was greatly satisfied without discomfort and foreign body sensation.Conclusion: A more accurate and personalized restoration approach can be implemented with the application of CDD to fabricate new ceramic crowns which copy the preoperative tooth.