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Over the last two decades, the number of gene/protein sequences gleaned from sequencing projects of individual genomes and environmental DNA has grown exponentially. Only a tiny fraction of these predicted proteins has been experimentally characterized, and the function of most proteins remains hypothetical or only predicted based on sequence similarity. Despite the development of postgenomic methods, such as transcriptomics, proteomics, and metabolomics, the assignment of function to protein sequences remains one of the main challenges in modern biology. As in all classes of proteins, the growing number of predicted carbohydrate-active enzymes (CAZymes) has not been accompanied by a systematic and accurate attribution of function. Taking advantage of the CAZy database, which groups CAZymes into families and subfamilies based on amino acid similarities, we recombinantly produced 564 proteins selected from subfamilies without any biochemically characterized representatives, from distant relatives of characterized enzymes and from nonclassified proteins that show little similarity with known CAZymes. Screening these proteins for activity on a wide collection of carbohydrate substrates led to the discovery of 13 CAZyme families (two ofwhich were also discovered by others during the course of our work), revealed three previously unknown substrate specificities, and assigned a function to 25 subfamilies.

Several scoring systems have been developed to assess suitability of individual patients for intensive acute myeloid leukemia (AML) therapy. We sought to compare the performance of these scores in a cohort of 428 consecutive adults with AML who received conventional induction chemotherapy in five academic centers in France. All scoring systems identified a subset of patients with increased 28 and 56-day mortality although the prediction accuracy was overall limited with C-statistics of ranging from 0.61 to 0.71 Overall survival (OS) prediction was more limited and restricted to scoring systems that include AML-related parameters. The outcome of 104 patients (24%) considered unsuitable for intensive chemotherapy based on criteria used in recent randomized trials was similar to that of the other 324 patients (28-day mortality, odds ratio [OR] = 1.88, P = 0.2; 56-day mortality, OR = 1.71, P = 0.21; event-free survival, hazard ratio [HR] = 1.08, P = 0.6; OS, HR = 1.25, P = 0.14) with low discrimination (C-statistic: 0.57, 0.56, 0.50, and 0.52 for 28-day, 56-day mortality, EFS, and OS, respectively). Together, our findings indicate that the accuracy of currently available approaches to identify patients at increased risk of early mortality and shortened survival after intensive AML therapy is relatively limited. Caution regarding the use of available scoring systems should be warranted in clinical decision-making.

Relapse is the leading cause of transplant failure, and the prognosis of these patients is poor with a 2-year survival rate of less than 20%, especially in patients with early relapse after alloHCT (within 6 months). In a randomized trial evaluating ivosidenib in combination with azacitidine in newly diagnosed AML ineligible for intensive chemotherapy, there was a better overall response (52.8% vs. 17.6%) and overall survival (median overall survival [OS] 24 vs. 7 months) with the combination compared to azacitidine alone. Statistical analysis was performed using SAS version 9.4 (SAS Institute Inc.). Age Median age (years) 54.9 (45.9–61.2) ≤65 years old, n (%) 19 (86.4) >65 years old, n (%) 3 (13.6) Hematologic malignancies, n (%) Acute myeloid leukemia 21 (95) Myelodysplastic syndrome 1 (5) Risk (ELN 2022), n (%) Favorable 5 (22.7) Intermediate 9 (45) Adverse 6 (27.3) Donor, n (%) Sibling 5 (22.7) Unrelated 11 (50) Unrelated 11 (50) Haploidentical 6 (27.3) Response before alloHCT, n (%) Complete response 17 (77.4) Relapse 1 (5) Primary induction failure 1 (5) Missing 3 (13.6) Conditioning, n (%) MAC 9 (45) RIC/NMA 13 (55) Stem cell source, n (%) Bone marrow 3 (13.6) Peripheral blood 19 (86.4) GvHD, n (%) Acute GvHD 8 (36.4) Chronic GvHD 8 (36.4) Relapse after alloHCT, n (%) ≤6 months 12 (54.5) >6 months 10 (45.5) Type of relapse, n (%) Morphologic 16 (72.7) Extramedullary 3 (13.6) Molecular 3 (13.6) Response to ivosidenib Median study follow-up time (months) [95% CI] 27.4 [19.4–28.7] Overall response, n (%) 9 (40.9) CR, n (%) 8 (36.4) Median duration of response (months) [95% CI] 18.3 [8.2–26.4] Time to treatment (months) [95% CI] 1.7 [1–4.7] Time to response (days) [95% CI] 40 [30–77] Ivosidenib discontinuation, n (%) 17 (77.3) Reason for discontinuation Death, n (%) 8 (47.1) Progression, n (%) 6 (35.3) Relapse, n (%) 2 (11.8) Second alloHCT, n (%) 1 (5.9) Other treatments DLI, n (%) 6 (27) Azacitidine, n (%) 9 (40.9) Venetoclax, n (%) 4 (18.2) [IMAGE OMITTED. From ivosidenib introduction, with a median follow-up of 27.4 months [95% CI: 19.4–28.7], median OS was 10.3 months [95% CI: 3.1–not evaluable (NE)] and survival rate at 18 months was 45.5% (Figure ).

Microbial mannanases are biotechnologically important enzymes since they target the hydrolysis of hemicellulosic polysaccharides of softwood biomass into simple molecules like manno-oligosaccharides and mannose. In this study, we have implemented a strategy of molecular engineering in the yeast Yarrowia lipolytica to improve the specific activity of two fungal endo-mannanases, PaMan5A and PaMan26A, which belong to the glycoside hydrolase (GH) families GH5 and GH26, respectively. Following random mutagenesis and two steps of high-throughput enzymatic screening, we identified several PaMan5A and PaMan26A mutants that displayed improved kinetic constants for the hydrolysis of galactomannan. Examination of the three-dimensional structures of PaMan5A and PaMan26A revealed which of the mutated residues are potentially important for enzyme function. Among them, the PaMan5A-G311S single mutant, which displayed an impressive 8.2-fold increase in kcat /KM due to a significant decrease of KM, is located within the core of the enzyme. The PaMan5A-K139R/Y223H double mutant revealed modification of hydrolysis products probably in relation to an amino-acid substitution located nearby one of the positive subsites. The PaMan26A-P140L/D416G double mutant yielded a 30% increase in kcat /KM compared to the parental enzyme. It displayed a mutation in the linker region (P140L) that may confer more flexibility to the linker and another mutation (D416G) located at the entrance of the catalytic cleft that may promote the entrance of the substrate into the active site. Taken together, these results show that the directed evolution strategy implemented in this study was very pertinent since a straightforward round of random mutagenesis yielded significantly improved variants, in terms of catalytic efiiciency (kcat/KM).

Acute myeloid leukemia (AML) can lead to life-threatening complications that may require intensive care unit (ICU) management. It has been advocated that early preemptive (ePE) ICU admission, before the onset of organ failure, could benefit some high-risk patients such as those with hyperleukocytosis. The aim of this study was to retrospectively analyze the outcome of newly diagnosed AML patients who required ICU admission in five academic centers with a special focus on patients with an ePE admission strategy, i.e., those transferred to the ICU without any organ failure (modified SOFA score ≤ 2 [omitting thrombocytopenia] and no life-sustaining intervention in the first 24 h following ICU admission) before the start of induction therapy. Between January 2017 and December 2019, 428 patients were included among which 101 were admitted to the ICU. Among patients requiring life-sustaining interventions (n = 83), 18 (22%) died while in the ICU but ICU survivors had the same survival as those not admitted to the ICU. Patients with an ePE admission (n = 18) had more comorbidities and high-risk disease features such as hyperleukocytosis but required no life-sustaining interventions while in the ICU. In a subgroup analysis of patients with hyperleukocytosis ≥ 50 G/l at diagnosis (n = 85), patients not admitted to the ICU and those admitted with an ePE strategy had similar outcomes. This study provides encouraging results about ICU outcome in AML patients during induction therapy but the potential benefit of an ePE strategy must be confirmed prospectively.

Between March to December 2024, we observed a PEG-IFNα2a shortage in France for MPN patients. We identified and followed 90 patients from our center and observed 80% of difficulties obtaining the drug, and 61 patients among all (67.8%) did not receive their prescribed drug on time (impacted group). Twenty-one patients need to reduce the dosage of PEG-IFNα2a and 27 stopped the drug. Ten clinical events were identified with nine in the impacted group ( p =0.04). No hematological or only partial responses were more frequent in the impacted group ( p =0.01). The allelic burden variations were also studied during this period; 17 patients obtained a VAF <10%. Eight patients stopped the drug because of VAF <4% and remained with molecular response. Three-quarters of the patients experimented with psychological and financial impacts of shortage. This study is the first one to explore a shortage of cytoreductive drugs happened in MPN. Much informations will be helpful for clinicians.

Background Three different scoring systems have been developed to assess pre‐transplant comorbidity in allogeneic hematopoietic stem cell transplantation (Allo‐HSCT): the Hematopoietic Cell Transplantation‐Specific Comorbidity Index, the Comorbidity/Age index, and the Augmented Comorbidity/Age index. All were devised to predict overall survival (OS) and disease‐free survival (DFS) survivals and non‐relapse mortality (NRM) in patients receiving HLA‐matched Allo‐HSCT, but their performance has scarcely been studied in the haploidentical Allo‐HSCT setting with post‐transplant cyclophosphamide, a procedure in constant expansion worldwide. Methods To address this issue, their impact on survivals and NRM was examined in a cohort of 223 patients treated with haploidentical Allo‐HSCT in four different centers. Results With a median follow‐up of 35.6 months, 3‐year OS, DFS, and NRM were 48.1% ± 4%, 46.3% ± 4%, and 30.0% ± 3%, respectively. No impact was found for any of the three comorbidity scores in univariate analysis. In multivariate analyses, the only three factors associated with lower OS were DRI (p < 0.001), an older age of recipients (≥55 years old, p = 0.02) and of donors (≥40 years old, p = 0.005). Older donor age was also associated with lower DFS and higher NRM. Conclusion The comorbidity scores do not predict survivals nor NRM in haploidentical Allo‐HSCT with PTCY, suggesting that pre‐transplant comorbidities should not be a contra‐indication to this procedure. Three different scoring systems have been developed to assess pre‐transplant comorbidity in allogeneic hematopoietic stem cell transplantation: the Hematopoietic Cell Transplantation‐Specific Comorbidity Index, the Comorbidity/Age index, and the Augmented Comorbidity/Age index, but their performance has scarcely been studied in the haploidentical stem cell transplantation setting with post‐transplant cyclophosphamide, a procedure in constant expansion worldwide. To address this issue, their impact was examined in a cohort of 223 patients from four French centers treated with haploidentical stem cell transplantation. No impact was found for any of the three comorbidity scores in this study, suggesting that pre‐transplant comorbidities should not be a contra‐indication to this procedure.

This study explores the hypothesis that genetic differences related to an ethnic factor may underlie differences in phenotypic expression of myelodysplastic syndrome (MDS). First, to identify clear ethnic differences, we systematically compared the epidemiology, and the clinical, biological and genetic characteristics of MDS between Asian and Western countries over the last 20 years. Asian MDS cases show a 2- to 4-fold lower incidence and a 10-year younger age of onset compared to the Western cases. A higher proportion of Western MDS patients fall into the very low- and low-risk categories while the intermediate, high and very high-risk groups are more represented in Asian MDS patients according to the Revised International Prognostic Scoring System. Next, we investigated whether differences in prognostic risk scores could find their origin in differential cytogenetic profiles. We found that 5q deletion (del(5q)) aberrations and mutations in TET2, SF3B1, SRSF2 and IDH1/2 are more frequently reported in Western MDS patients while trisomy 8, del(20q), U2AF1 and ETV6 mutations are more frequent in Asian MDS patients. Treatment approaches differ between Western and Asian countries owing to the above discrepancies, but the overall survival rate within each prognostic group is similar for Western and Asian MDS patients. Altogether, our study highlights greater risk MDS in Asians supported by their cytogenetic profile.

β-Mannans are a heterogeneous group of polysaccharides with a common main chain of β-1,4-linked mannopyranoside residues. The cleavage of β-mannan chains is catalyzed by glycoside hydrolases called β-mannanases. In the CAZy database, β-mannanases are grouped by sequence similarity in families GH5, GH26, GH113 and GH134. Family GH113 has been under-explored so far with six enzymes characterized, all from the Firmicutes phylum. We undertook the functional characterization of 14 enzymes from a selection of 31 covering the diversity of the family GH113. Our observations suggest that GH113 is a family with specificity towards mannans, with variations in the product profiles and modes of action. We were able to assign mannanase and mannosidase activities to four out of the five clades of the family, increasing by 200% the number of characterized GH113 members, and expanding the toolbox for fine-tuning of mannooligosaccharides.

Background Filamentous fungi are potent biomass degraders due to their ability to thrive in ligno(hemi)cellulose-rich environments. During the last decade, fungal genome sequencing initiatives have yielded abundant information on the genes that are putatively involved in lignocellulose degradation. At present, additional experimental studies are essential to provide insights into the fungal secreted enzymatic pools involved in lignocellulose degradation. Results In this study, we performed a wide analysis of 20 filamentous fungi for which genomic data are available to investigate their biomass-hydrolysis potential. A comparison of fungal genomes and secretomes using enzyme activity profiling revealed discrepancies in carbohydrate active enzymes (CAZymes) sets dedicated to plant cell wall. Investigation of the contribution made by each secretome to the saccharification of wheat straw demonstrated that most of them individually supplemented the industrial Trichoderma reesei CL847 enzymatic cocktail. Unexpectedly, the most striking effect was obtained with the phytopathogen Ustilago maydis that improved the release of total sugars by 57% and of glucose by 22%. Proteomic analyses of the best-performing secretomes indicated a specific enzymatic mechanism of U. maydis that is likely to involve oxido-reductases and hemicellulases. Conclusion This study provides insight into the lignocellulose-degradation mechanisms by filamentous fungi and allows for the identification of a number of enzymes that are potentially useful to further improve the industrial lignocellulose bioconversion process.