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Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband’s de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.

Introduction:The prevention of heart failure (HF) is an essential issue in patients treated with anthracyclines, however, existing treatments have demonstrated modest effects. Metformin (MET), widely used to treat diabetes, protects from anthracyclines-induced cardiotoxicity in vitro and in murine models. However, there is no research investigating the cardioprotective effects of MET in patients treated with anthracyclines.Hypothesis:MET is cardioprotective in patients treated with anthracyclines.Methods:Out of 5655 patients undergoing new anthracyclines therapy at a tertiary center between 2008-2021, 260 patients were treated with MET. The clinical characteristics associated with the use of MET were identified and a propensity-score (gender, diabetes, type of cancer, kidney and cerebrovascular disease) used to match 200 patients treated with MET to 200 patients without MET. The primary outcome was new-onset symptomatic HF defined by the AHA/ACC guidelines occurring within 1 year of the initiation of anthracyclines. Proportional hazard analysis was used to identify characteristics associated with HF.Results:Patients were 65 years old [57-70], 34% male. No differences were noted in age, cardiovascular risk factors, history, use of beta-blockers and ACE inhibitors between the MET and non MET groups. Six patients (3%) treated with MET and 20 matched patients (10%) developed HF within 1 year of anthracyclines initiation (P=0.004, Figure). Use of MET ([HR]: 0.27; 95% CI: 0.1 to 0.64; p = 0.002), use of insulin (HR: 2.27; 95% CI: 1.05 to 5; p = 0.04), coronary artery disease (HR: 4.69; 95% CI: 2.06 to 10.2; p < 0.001), and chronic kidney disease (HR: 2.65; 95% CI: 1.21 to 5.77 p = 0.02) were associated with incident HF.Conclusions:MET significantly reduced the risk for HF in patients treated with anthracyclines. Our findings are consistent with previous experimentalstudies and suggest a new therapeutic option in the prevention of cardiotoxicity.

Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2and TPM1variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.

Introduction

Leight: Amgen: Current Employment.

No relevant conflicts of interest to declare.

The gene that encodes DNA methyltransferase 3A (DNMT3A) is mutated in nearly 40% of normal karyotype acute myeloid leukemia (AML) patients. More importantly, DNMT3Amutations are almost invariably the initiating event for the disease; however, the mechanisms by which they contribute to AML initiation are not yet clear [1, 2]. Regardless, ancestral clones containing the DNMT3Amutation are hard to eradicate, and often persist in clinical remission [3, 4]. We have recently shown that the most common DNMT3Amutation in AML patients (R882H; R878H in mice)is a dominant negative mutation that causes a focal, canonical pattern of DNA hypomethylation that is present in pre-leukemic hematopoietic cells, and appears to evolve further in fully transformed AML cells [5]. However, it is not yet clear how the DNMT3AR882Hmutation can cause the clonal expansion of HSPCs, or how it makes HSPCs more susceptible to transformation by secondary mutations.

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The title compound has a complex framework structure in which pairs of Nd atoms are linked by four p-XBP4 ligands to form ‘lanterns’ which are further connected by interwoven Nd–(p-XBP4)–Nd bridges, and yet again by non-coordinated p-XBP4 molecules hydrogen bonded to aqua ligands on the Nd centres.

Despite aggressive chemotherapy and a high remission induction rate, approximately one third of children with acute myeloid leukemia (AML) relapse. Therefore, novel and more effective treatments are urgently needed. Survivin is an inhibitor-of-apoptosis protein that plays a key role in regulating cell division, proliferation and apoptosis (Altieri et al, Nat Rev Cancer, 2008). Furthermore, high expression of survivin and its splice variants have been shown to be associated with poor clinical outcome in AML (Moore et al, ASH Abstract 3555, 2011; Carter et al, Blood, 2012). The small-molecule survivin suppressant YM155 (sepantronium bromide) has been demonstrated to have pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited, particularly in pediatric models. Therefore, we undertook a comprehensive pre-clinical evaluation of YM155 in AML, with a focus on pediatric disease.

No relevant conflicts of interest to declare.