Treatment of Relapsed/Refractory AML —Novel Treatment Options Including Immunotherapy

ABSTRACT Acute myeloid leukemia is a molecularly heterogenous disease caused by the rapid expansion and impaired differentiation of malignant myeloid progenitors. Overall, outcomes remain poor, and more than half of patients develop relapsed or refractory disease after front‐line therapy. Allogeneic hematopoietic stem cell transplant (HCT) remains the best chance for cure for eligible patients, and the development of novel therapies including BCL2, FLT3, IDH1/2 and menin inhibitors, which are efficacious yet generally more tolerable, have enabled better bridging to prompt HCT. Despite the early success of targeted therapies, more generalized and efficacious therapeutic approaches remain in need, and numerous targeted immunotherapeutic agents (including CAR‐T, bispecific and trispecific antibody therapies) are currently under investigation.

Poor Engraftment After Posttransplant Cyclophosphamide Graft‐Versus‐Host Disease Prophylaxis in Patients With Myelofibrosis

ABSTRACT Patients with myelofibrosis (MF) often have impaired engraftment after allogeneic hematopoietic cell transplantation (alloHCT). To determine whether posttransplant cyclophosphamide (PTCY) exerts a detrimental impact on engraftment, we compared clinical outcomes of all patients receiving PTCY ( N  = 49) and no‐PTCY ( N  = 89) regimens as GVHD prophylaxis after first alloHCT for MF from 2016 to 2023. Median age was 64 in both groups, and baseline characteristics were balanced except that the PTCY group received more haploidentical transplants and were more likely to have secondary MF. Among engrafted individuals, median time to neutrophil engraftment was D + 18 for PTCY and D + 15 for no‐PTCY ( p  < 0.0001). Median time to platelet recovery was D + 33.5 and D + 26 for PTCY and no‐PTCY, respectively ( p  = 0.0006). The graft failure rate was higher for PTCY but did not reach statistical significance (27% for PTCY and 15% for non‐PTCY, p  = 0.095). The need for donor lymphocyte infusion, CD34 boost, or second transplant was significantly higher for PTCY (33% vs. 13% at 1‐year, respectively, p  = 0.004). Most cases of graft failure in both cohorts were due to prolonged cytopenias in the absence of relapse. While T‐cell chimerism at D + 30 and D + 100 was robust after PTCY, the proportion of patients with granulocyte chimerism ≥ 90% at Day + 100 was significantly lower in PTCY (76% vs. 98.2%, respectively, p  = 0.0028). All other outcomes were similar except for a significantly lower chronic GVHD rate in PTCY compared with no‐PTCY ( p  = 0.0002). GVHD prophylaxis with PTCY in patients with MF is associated with delayed engraftment, lower donor granulocyte chimerism, and increased need for additional donor cell infusions after transplant without compromising survival.

Reversal of Glomerular Hyperfiltration Following Hematopoietic Stem Cell Transplantation in Children With Sickle‐Cell Anemia

A Preliminary Investigation of Associations Between Traumatic Events Experienced During Pregnancy and Salivary Diurnal Cortisol Levels of Brazilian Adolescent Mothers and Infants

ABSTRACT Introduction Interpersonal violence against women is a major global health problem that may have intergenerational effects. This study investigated associations between maternal experiences of interpersonal violence and other traumatic events and maternal and infant salivary diurnal cortisol in a cohort of adolescent mothers in São Paulo, Brazil. Method Adolescent mothers (14–19 years) participating in a home‐visiting intervention were interviewed retrospectively about lifetime and pregnancy violence and trauma exposure. Mothers collected saliva at waking and before bedtime from themselves ( n  = 23) and their infants ( n  = 32) at 12 months postpartum. Multivariable regression models were used to examine associations between trauma history variables and salivary diurnal cortisol. Results Adjusting for the intervention group, infant sex, maternal age, non‐supplement medication use, and sample collection time, we found that higher‐than‐average lifetime trauma exposure was associated with maternal evening cortisol ( b  = 0.472, p ‐value = 0.028). Lifetime assaultive violence exposure was also associated with maternal evening cortisol ( b  = 0.196, p ‐value = 0.02). Maternal exposure to traumatic events in pregnancy was positively associated with bedtime cortisol levels of infants ( b  = 0.21, p  = 0.01). Trauma variables were not associated with maternal or infant morning cortisol levels. Conclusion Results suggest that maternal trauma history influences both maternal and infant postnatal cortisol regulation as indexed by evening cortisol levels. These results are consistent with models of fetal programming; however, future studies should investigate potential postnatal psychobiological pathways. Lifetime trauma exposure may also become embedded in the maternal hypothalamic–adrenal–pituitary axis regulation. Future studies are needed to consider other biological pathways in the intergenerational transmission of trauma.

Health and Mortality in the 19th‐Century Rural United States: The Second Epidemiological Transition in Madison County, New York

ABSTRACT Objectives A number of studies have examined changes in mortality and health during industrialization in both the United States and Western Europe; however, most of this work has focused on urban communities. Despite theories regarding differences between rural and urban patterns of mortality at this time, few analyses of data from rural communities have been done. Our goal is to examine trends in mortality, c . 1850–1880, for a rural county in central New York State at a time when farming, the economic base of this county, was becoming commercialized and industrialization was impacting the wider region. Materials and Methods Using census mortality records from Madison County, NY (1850–1880), we examine trends in hazards of death, survivorship, and cause of death. In order to contribute a rural perspective to this area of study, we examine trends from the mortality records at several scales: town‐specific, groups of towns based on population density, and the county as a whole. Results Our results suggest that the hazards of death decreased and survivorship increased at the county level across this 30‐year period. In general, the rates of communicable diseases decreased and the rates of non‐communicable diseases increased. Individual towns had variable outcomes, and higher population density towns had better apparent outcomes than those with medium and lower densities. Conclusions Overall, mortality patterns changed noticeably during this period. These changes were likely at least partially a result of changing economic conditions, but may also have been affected by socio‐spatial factors and access to healthcare, both of which continue to impact rural communities today.

Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia

ABSTRACT Variation in the non‐coding genome represents an understudied mechanism of disease and it remains challenging to predict if single nucleotide variants, small insertions and deletions, or structural variants in non‐coding genomic regions will be detrimental. Our approach using complementary RNA‐seq and targeted long‐read DNA sequencing can prioritize identification of non‐coding variants that lead to disease via alteration of gene splicing or expression. We have identified a patient with primary ciliary dyskinesia with a pathogenic coding variant on one allele of the SPAG1 gene, while the second allele appears normal by whole exome sequencing despite an autosomal recessive inheritance pattern. RNA sequencing revealed reduced SPAG1 transcript levels and exclusive allele specific expression of the known pathogenic allele, suggesting the presence of a non‐coding variant on the second allele that impacts transcription. Targeted long‐read DNA sequencing identified a heterozygous 3 kilobase deletion of the 5′ untranslated region of SPAG1 , overlapping the promoter and first non‐coding exon. This non‐coding deletion was missed by whole exome sequencing and gene‐specific deletion/duplication analysis, highlighting the importance of investigating the non‐coding genome in patients with “missing” disease‐causing variation. This paradigm demonstrates the utility of both RNA and long‐read DNA sequencing in identifying pathogenic non‐coding variants in patients with unexplained genetic disease.

AP2M1 Is a Candidate Gene for Microcephaly and Intellectual Disability in 3q27.1 Deletions

ABSTRACT Deletions of the 3q26.33q27.2 region appear to correlate with a distinct phenotype, although there are few reported cases. Here, we present seven previously unreported individuals carrying de novo 3q27 deletions (under 5 Mb), which include the AP2M1 (adaptor‐related protein complex 2, mu‐1 subunit) gene and summarize data from 12 previously reported cases from the literature. The overall cohort of 19 individuals demonstrates almost universal intrauterine growth restriction, intellectual disability, and post‐natal microcephaly, along with common features of hypotonia, post‐natal short stature, and facial dysmorphisms. Newly identified features include bicuspid aortic valve, atrial septal defect, congenital malformation of the mesentery, and metopic craniosynostosis, present in a subset of individuals. These seven newly identified individuals allow narrowing of the previously reported smallest region of overlap to 430 kb at 3q27.1. This region includes 20 protein coding genes. We propose AP2M1 as the most likely contributor to the neurodevelopmental phenotype, based on its predicted intolerance to haploinsufficiency, functional evidence in murine models, and similar phenotypes associated with other adaptor‐protein‐complex‐family members. Furthermore, we report the first individual with a de novo loss‐of‐function nonsense single nucleotide variant in AP2M1 with neurodevelopmental features including severe epilepsy. We discuss the implications of this finding in the context of previously reported epileptic encephalopathy in individuals with the recurrent p.Arg170Trp variant in AP2M1 . In conclusion, our study expands the phenotypic spectrum of 3q27 microdeletions and highlights the potential importance of AP2M1 in its clinical presentation.

A Transcriptome‐Wide Mendelian Randomization Study in Isolated Human Immune Cells Highlights Risk Genes Involved in Viral Infections and Potential Drug Repurposing Opportunities for Schizophrenia

ABSTRACT Schizophrenia is a neurodevelopmental psychiatric disorder characterized by symptoms of psychosis, thought disorder, and flattened affect. Immune mechanisms are associated with schizophrenia, though the precise nature of this relationship (causal, correlated, consequential) and the mechanisms involved are not fully understood. To elucidate these mechanisms, we conducted a transcriptome‐wide Mendelian randomization study using gene expression exposures from 29 human cis ‐eQTL data sets encompassing 11 unique immune cell types, available from the eQTL catalog. These analyses highlighted 196 genes, including 67 located within the human leukocyte antigen (HLA) region. Enrichment analyses indicated an overrepresentation of immune genes, which was driven by the HLA genes. Stringent validation and replication steps retained 61 candidate genes, 27 of which were the sole causal signals at their respective loci, thereby representing strong candidate effector genes at known risk loci. We highlighted L3HYPDH as a potential novel schizophrenia risk gene and DPYD and MAPK3 as candidate drug repurposing targets. Furthermore, we performed follow‐up analyses focused on one of the candidate effectors, interferon regulatory transcription factor 3 ( IRF3 ), which coordinates interferon responses to viral infections. We found evidence of shared genetic etiology between schizophrenia and autoimmune diseases at the IRF3 locus, and a significant enrichment of IRF3 chromatin binding at known schizophrenia risk loci. Our findings highlight a novel schizophrenia risk gene, potential drug repurposing opportunities, and provide support for IRF3 as a schizophrenia hub gene, which may play critical roles in mediating schizophrenia‐autoimmune comorbidities and the impact of infections on schizophrenia risk.

CURE ID : A Platform to Collect Real‐World Treatment Data for Drug Repurposing in Rare Genetic Disorders

ABSTRACT Rare diseases collectively affect millions of Americans, but less than 5% have approved treatments, and new drug development remains limited. For such diseases, drug repurposing may be an effective strategy to find new treatment options. In the rare genetic disorder community, drugs are frequently prescribed off‐label. This information is rarely available for research, but if captured, could be leveraged to accelerate the identification of candidate drugs to be evaluated for safety and efficacy of the treatment of rare diseases. CURE ID is a publicly available treatment registry that collects real‐world treatment data directly from healthcare providers, patients, and care partners in a consistent format. By aggregating this information, CURE ID can generate hypotheses for follow‐up targeted research of repurposed drugs, potentially leading to the approval of these drugs for new indications. The success of the platform is predicated on its adoption in the rare disease community and routinely reporting treatment experiences to CURE ID.

Access to Syn α‐Amino‐β‐Hydroxyesters by N−H Insertion on O ‐Protected α‐Diazo‐β‐Hydroxyesters

Abstract The N−H insertion reaction is a versatile method for creating C−N bonds under mild conditions, providing in particular an efficient access to both natural and non‐natural α‐amino acid derivatives. In this field, the direct N−H insertion on α‐diazo‐β‐hydroxyesters has not yet been investigated and constitutes a significant challenge, due to competitive migration processes. We report herein the first N−H insertions on O ‐protected α‐diazo‐β‐aryl‐β‐hydroxyesters, enabling to synthesize a wide range of α‐amino‐β‐hydroxyesters by tuning the nature of the amine and the aryl substituent. Overall, 28 N−H insertion products have been isolated, with moderate to good yields in most cases, and diastereoisomeric ratios up to 8.0 : 1 in favor of the syn diastereoisomer.