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Abstract This narrative review seeks to summarize chemotherapeutic regimens commonly used for patients with newly diagnosed Philadelphia (Ph) chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in the frontline setting and to describe the latest clinical research using the bispecific T-cell–engaging immunotherapy blinatumomab in the first-line treatment setting. Current standard-of-care chemotherapeutic backbones for newly diagnosed Ph-negative BCP-ALL are based on the same overarching treatment principle: to reduce disease burden to undetectable levels and maintain lasting remission. The adult treatment landscape has progressively evolved following the adoption of pediatric-inspired regimens. However, these intense regimens are not tolerated by all, and high-risk patients still have inferior outcomes. Therefore, designing more effective and less toxic strategies remains key to further improving efficacy and safety outcomes. Overall, the treatment landscape is evolving in the frontline, and integration of blinatumomab into different standard frontline regimens may improve overall outcomes with a favorable safety profile.

Abstract Leukemias with ambiguous lineage comprise several loosely defined entities, often without a clear mechanistic basis. Here, we extensively profile the epigenome and transcriptome of a subgroup of such leukemias with CpG Island Methylator Phenotype. These leukemias exhibit comparable hybrid myeloid/lymphoid epigenetic landscapes, yet heterogeneous genetic alterations, suggesting they are defined by their shared epigenetic profile rather than common genetic lesions. Gene expression enrichment reveals similarity with early T-cell precursor acute lymphoblastic leukemia and a lymphoid progenitor cell of origin. In line with this, integration of differential DNA methylation and gene expression shows widespread silencing of myeloid transcription factors. Moreover, binding sites for hematopoietic transcription factors, including CEBPA, SPI1 and LEF1, are uniquely inaccessible in these leukemias. Hypermethylation also results in loss of CTCF binding, accompanied by changes in chromatin interactions involving key transcription factors. In conclusion, epigenetic dysregulation, and not genetic lesions, explains the mixed phenotype of this group of leukemias with ambiguous lineage. The data collected here constitute a useful and comprehensive epigenomic reference for subsequent studies of acute myeloid leukemias, T-cell acute lymphoblastic leukemias and mixed-phenotype leukemias.

Abstract Mitapivat is an investigational, oral, small‐molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3‐DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3‐DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator‐initiated, open‐label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019‐003438‐18), untargeted metabolomics was used to explore the overall metabolic effects of 8‐week treatment with mitapivat in the dose‐finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate‐adjusted p

Abstract Water security is at stake today. While climate changes influence water availability, urbanization and agricultural activities have led to increasing water demand as well as pollution, limiting safe water use. We conducted a global assessment of future clean-water scarcity for 2050s by adding the water pollution aspect to the classical water quantity-induced scarcity assessments. This was done for >10,000 sub-basins focusing on nitrogen pollution in rivers by integrating land-system, hydrological and water quality models. We found that water pollution aggravates water scarcity in >2000 sub-basins worldwide. The number of sub-basins with water scarcity triples due to future nitrogen pollution worldwide. In 2010, 984 sub-basins are classified as water scarce when considering only quantity-induced scarcity, while 2517 sub-basins are affected by quantity & quality-induced scarcity. This number even increases to 3061 sub-basins in the worst case scenario in 2050. This aggravation means an extra 40 million km2 of basin area and 3 billion more people that may potentially face water scarcity in 2050. Our results stress the urgent need to address water quality in future water management policies for the Sustainable Development Goals.

Abstract Background We recently reported results of the prospective, open‐label HOVON‐100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first‐line treatment with or without clofarabine (CLO). No improvement of event‐free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. Aim In order to investigate the effects of CLO in more depth, two multi‐state models were developed to identify why CLO did not show a long‐term survival benefit despite more MRD‐negativity. Methods The first model evaluated the effect of CLO on going off‐protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment‐related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. Results Overall, patients receiving CLO went off‐protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13–3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08–7.50], p = 0.035). Going off‐protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD‐negativity compared with control patients (HR MRD‐negativity: 1.35 [0.95–1.91], p = 0.10), which did not translate into a significant survival benefit. Conclusion We conclude that the intermediate states, i.e., going off‐protocol and MRD‐negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.

In vitro production (IVP) embryos have a reduced quality and poor cryotolerance in comparison to in vivo embryos. This study investigated whether free fatty acid (FFA) conditions, fatty acid free (FAF)- synthetic oviduct fluid (SOF) without or with 25 μM of saturated stearic (C18:0) or unsaturated oleic (C18:1) acid during the first 5 IVP days, relate to quality and cryosurvival of day 8 blastocysts. Apart from the blastocyst scores, both 1) number and size of lipid droplets of fresh blastocysts and 2) total number and apoptotic and necrotic cells, before and after freezing-thawing, were scored by confocal microscopy. Blastocyst rates were significantly lower in the FAF SOF condition in comparison to other groups. Interestingly, blastocysts originating from the C18:1 group, with a significantly higher lipid content, and blastocysts from the FAF SOF group demonstrated a high cryosurvival rate (70.1 and 67.4%, respectively) comparable with in vivo blastocysts (68%), in contrast to the poor cryosurvival of C18:0 exposed embryos (17.6%). In all freeze-thawed embryos the average amount of apoptotic and necrotic cells increased albeit that the C18:0 condition rates were higher (43.2%) when compared to C18:1 (26.0%) and FAF SOF conditions (26.5%). The current data show that FFA administered during early embryonic development significantly affect the cryotolerance of blastocysts.

Omiganan is an indolicidin analog with antimicrobial properties that could be beneficial for patients with atopic dermatitis. In this randomized, double‐blind, placebo‐controlled, phase II trial we explored the efficacy, pharmacodynamics, and safety of topical omiganan once daily in 36 patients with mild to moderate atomic dermatitis. Patients were randomized to apply topical omiganan 1%, omiganan 2.5%, or vehicle gel to one target lesion once daily for 28 consecutive days. Small but significant improvements in local objective SCORing Atopic Dematitis index and morning itch were observed in the omiganan 2.5% group compared with the vehicle gel group (−18.5%; 95% confidence interval, −32.9 to −1.0; P = 0.04; and −8.2; 95% confidence interval, −16.3 to −0.2; P = 0.05, respectively). A shift from lesional to nonlesional skin microbiota was observed in both omiganan treatment groups, in contrast to the vehicle group. Thus, treatment with topical omiganan improved dysbiosis in patients with mild to moderate atopic dermatitis, and small but statistically significant improvements in clinical scores were detected. Our findings warrant further exploration in future clinical trials.