Stevensoncoates4843

We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML.Thalidomide analogs exert their therapeutic effects by binding to the CRL4CRBN E3 ubiquitin ligase, promoting ubiquitination and subsequent proteasomal degradation of specific protein substrates. Epigenetic inhibitor Drug-induced degradation of IKZF1 and IKZF3 in B-cell malignancies demonstrates the clinical utility of targeting disease-relevant transcription factors for degradation. Here, we found that avadomide (CC-122) induces CRBN-dependent ubiquitination and proteasomal degradation of ZMYM2 (ZNF198), a transcription factor involved in balanced chromosomal rearrangements with FGFR1 and FLT3 in aggressive forms of hematologic malignancies. The minimal drug-responsive element of ZMYM2 is a zinc-chelating MYM domain and is contained in the N-terminal portion of ZMYM2 that is universally included in the derived fusion proteins. We demonstrate that avadomide has the ability to induce proteasomal degradation of ZMYM2-FGFR1 and ZMYM2-FLT3 chimeric oncoproteins, both in vitro and in vivo. Our findings suggest that patients with hematologic malignancies harboring these ZMYM2 fusion proteins may benefit from avadomide treatment.Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations useable for CHIP detection by performing a data mining analysis of 48 somatic mutation studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with hematologic malignancies. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole exome sequencing data from 4,538 persons belonging to three non-cancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and pre-cancer surveillance for both children and adults.Emerging clonal complexity has brought into question the way in which we perceive and, in turn, treat disorders of the hematopoietic system. Former models of cell-intrinsic clonal dominance driven by acquisition of driver genes in a stereotypic sequence are often insufficient in explaining observations such as clonal hematopoiesis, and new paradigms are in order. Here, we review the evidence both within the hematologic malignancy field and also borrow from perspectives rooted in evolutionary biology to reframe pathogenesis of hematologic disorders as dynamic processes involving complex interplays of genetic and non-genetic subclones and the tissue microenvironment in which they reside.In this issue of Blood Cancer Discovery, Brück et al applied unsupervised and supervised machine learning to bone marrow histopathology images from Myelodysplastic Syndrome (MDS) patients. Their study provides new insights into the pathobiology of MDS and paves the way for increased use of artificial intelligence for the assessment and diagnosis of hematological malignancies.

To compare outcomes at Mizan-Tepi University Teaching Hospital to national and regional data and to plan quality improvement and research studies based on the results.

This study was a prospective hospital-based cross-sectional analysis of a convenience sample of 1, 000 women who delivered at Mizan-Tepi University Teaching Hospital.

Our convenience sample was young (median age 24 years) with a primarily school level or less of education (68.6%). Only about 5% of women had a history of prior cesarean birth, 2.1% reported they were human immunodeficiency virus seropositive, and the median number of prenatal visits was four. Women were commonly admitted in spontaneous labor (84.5%), transferred from another facility (49.2%; 96.8% of which were referred from a health center), and had their fetal heart rate auscultated on admission (94.7%). Only 5.2% of women did not deliver within twenty-four hours and the cesarean birth prevalence was 23.4%. Many women were delivered by midwives (73.2%; all unassisted vaginal births), 89.2% were term deliveries, and 92.5% of neonatal birthweights were 2500 grams or heavier. Less than five percent of women delivered stillbirths (4.3%) and 5.7% of livebirths experienced neonatal death by the day of discharge. There were no maternal deaths in the cohort.

The prevalence of stillbirth and neonatal death were the most notable findings, while there was no maternal death in the cohort.

The prevalence of stillbirth and neonatal death were the most notable findings, while there was no maternal death in the cohort.There has been a resurgence in the illicit use of 2,4-dinitrophenol by people wishing to achieve rapid weight loss. Despite its availability, the drug is banned for human consumption as it is toxic and can have fatal consequences. We present the case of a 23-year-old man who regularly consumed 2,4-dinitrophenol to generate fat loss without apparent ill effect. He was involved in a high-speed road traffic collision and sustained limb-threatening injuries. The combination of emergency surgery, trauma and 2,4-dinitrophenol consumption culminated in deterioration under anaesthesia, with subsequent death from multiorgan failure in the intensive care unit 48 h later. Previous cases have reported death from 2,4-dinitrophenol toxicity alone. We believe this is the first reported case of 2,4-dinitrophenol toxicity triggered by the additional physiological stress of polytrauma and emergency surgery.I contracted SARS-CoV-2 early in the first wave of the COVID-19 pandemic in the UK and, following nine days of mechanical ventilation, was one of the first few patients to be accepted for venovenous extracorporeal membrane oxygenation. I remained in hospital for 150 days, 34 of which I spent with full extracorporeal respiratory support. I have no recollection of my time on extracorporeal membrane oxygenation, but liberation from it was not the end of my story; I had to overcome numerous physical and mental challenges during recovery and rehabilitation. I hope my story is read by others who are recovering from COVID-19 or critical illness more generally, and that it provides hope that the challenges of rehabilitation can be overcome. This reflection is a personal view of my illness as a patient. link2 In it, I focus upon the aspects of my care that I can remember, predominantly around the time I became unwell but also during the recovery and rehabilitation period, which remains ongoing despite my discharge from hospital and subsequent return to work as a general practitioner.Guidelines for the management of hip fractures recommend timely identification, analgesia and optimisation, in order to facilitate prompt surgical repair. In achieving these aims, multidisciplinary care is essential. In this case series, we present five patients who received bedside pericapsular nerve group (PENG) blocks by emergency physicians in collaboration with the anaesthesia team for pain management following hip fracture. The PENG block is a novel motor- and opioid-sparing technique, which offers long-lasting analgesia and requires less volume than other blocks. In all of the cases in this series, the blocks were performed successfully in a short period of time, without complication. All patients reported a clinically important reduction in pain scores. Patients with hip fracture are often medically complex, and while early surgery is not always possible, pain management should be addressed from an early point in their hospital admission. Multidisciplinary input into peri-operative pathways can enhance the provision of analgesia in the emergency department, by allowing anaesthetists and emergency physicians to work together for the benefit of these often-frail patients.Mutations in the isocitrate dehydrogenase-1 and -2 (IDH1/2) genes were first identified in glioma and acute myeloid leukemia (AML), and subsequently found in multiple other tumor types. These neomorphic mutations convert the normal product of enzyme, α-ketoglutarate (αKG), to the oncometabolite 2-hydroxyglutarate (2HG). Our group recently demonstrated that 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state referred to as 'BRCAness', which confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we sought to elucidate sensitivity of IDH1/2-mutant cells to DNA damage response (DDR) inhibitors and, whether combination therapies could enhance described synthetic lethal interactions. Here, we report that ATR (ataxia telangiectasia and Rad3-related protein kinase) inhibitors are active against IDH1/2-mutant cells, and that this activity is further potentiated in combination with PARP inhibitors. We demonstrate this interaction across multiple cell line models with engineered and endogenous IDH1/2 mutations, with robust anti-tumor activity in vitro and in vivo. Mechanistically, we found ATR and PARP inhibitor treatment induces premature mitotic entry, which is significantly elevated in the setting of IDH1/2-mutations. These data highlight the potential efficacy of targeting HR defects in IDH1/2-mutant cancers and support the development of this combination in future clinical trials.Cancer evolves through the accumulation of somatic mutations over time. Although several methods have been developed to characterize mutational processes in cancers, these have not been specifically designed to identify mutational patterns that predict patient prognosis. link3 Here we present CLICnet, a method that utilizes mutational data to cluster patients by survival rate. CLICnet employs Restricted Boltzmann Machines, a type of generative neural network, which allows for the capture of complex mutational patterns associated with patient survival in different cancer types. For some cancer types, clustering produced by CLICnet also predicts benefit from anti-PD1 immune checkpoint blockade therapy, whereas for other cancer types, the mutational processes associated with survival are different from those associated with the improved anti-PD1 survival benefit. Thus, CLICnet has the ability to systematically identify and catalogue combinations of mutations that predict cancer survival, unveiling intricate associations between mutations, survival, and immunotherapy benefit.