Proctorkromann1966

Inhibition of the H3K79 histone methyltransferase DOT1L has exhibited encouraging preclinical and early clinical activity in KMT2A (MLL)-rearranged leukemia, supporting the development of combinatorial therapies. Here, we investigated two novel combinations dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination with a protein synthesis inhibitor. EZH2 is the catalytic subunit in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has been reported to have preclinical activity in KMT2A-r leukemia. When combined with DOT1L inhibition, however, we observed both synergistic and antagonistic effects. Interestingly, antagonistic effects were not due to PRC2-mediated de-repression of HOXA9. HOXA cluster genes are key canonical targets of both KMT2A and the PRC2 complex. The independence of the HOXA cluster from PRC2 repression in KMT2A-r leukemia thus affords important insights into leukemia biology. Further studies revealed that EZH2 inhibition counteracted the effect of DOT1L inhibition on ribosomal gene expression. We thus identified a previously unrecognized role of DOT1L in regulating protein production. Decreased translation was one of the earliest effects measurable after DOT1L inhibition and specific to KMT2A-rearranged cell lines. H3K79me2 chromatin immunoprecipitation sequencing patterns over ribosomal genes were similar to those of the canonical KMT2A-fusion target genes in primary AML patient samples. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (omacetaxine), supporting further preclinical/clinical development of this combination. In summary, we discovered a novel epigenetic regulation of a metabolic process-protein synthesis-that plays a role in leukemogenesis and affords a combinatorial therapeutic opportunity.Context Historically, the focus of prehospital care has been life-saving treatment. Absent a Non-Hospital Do Not Resuscitate (NHDNR) order, prehospital providers have been compelled to begin and continue resuscitation unless or until it was certain that the situation was futile; they have faced conflict when caregivers objected. Objectives The purpose of the study was to explore prehospital providers' perspectives on how legally binding documents (NHDNR/Medical Orders for Life Sustaining Treatment [MOLST]) informed end-of-life decision-making and care. Methods This exploratory study employed mixed methods in a sequential non-dominant, two-stage convergent QUAN-QUAL design. Phase I involved the collection of survey data. Phase II involved in-person semi-structured interviews. Results Surveys were completed by 239 participants and 50 follow-up interviews were conducted. Survey data suggested that 73.7% felt confident when there was a DNR order and they did not initiate resuscitation and 58.2% felt confident working through family disagreement when CPR was requested but there was a DNR; 66.1% felt confident explaining the dying process when death was imminent and 55.7% felt comfortable telling a family that a patient was dying. Four themes emerged (1) Changing Standards of Care; (2) Eliminating False Hope; (3) Transitioning Care from Patient to Family; and (4) Transferring Care after Death. Conclusion Prehospital providers provide support and care when they tell families that someone has died. Being able to comfort and be present with acute grief on scene is an important and evolving role for prehospital providers who manage death in the field.The ongoing wreaking global outbreak of the novel human beta coronavirus (CoV) pathogen was presumed to be from a seafood wholesale market in Wuhan, China, belongs to the Coronaviridae family in the Nidovirales order. The virus is highly contagious with potential human-human transmission which was named as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread across six continents and emerged as a global pandemic in short span with alarming levels of spread and severity. This virus associated symptoms and infectious respiratory illness is designated as coronavirus disease 19 (COVID-19). The SARS-CoV-2 possesses enveloped club-like spike protein projections with positive-sense large RNA genome and has a unique replication strategy. This virus was believed to have zoonotic origin with genetical identity to bat and pangolin CoV. In the current review, we introduce a general overview about the human CoVs and the associated diseases, the origin, structure, replication and key clinical events that occur in the COVID-19 pathogenicity. Furthermore, we focused on possible therapeutic options such as repurposing drugs including antimalarials, antivirals, antiparasitic drugs, and anti-HIV drugs, as well as monoclonal antibodies, vaccines as potential treatment options. Also we have summarized the latest research progress on the usage of stem cell therapy, human convalescent serum, interferon's, in the treatment of COVID-19.Objective Fetal macrosomia is known to increase maternal and neonatal complications, but 20%-50% of the macrosomic fetuses are prenatally undiagnosed. Our objective was to identify specific factors associated with undiagnosed fetal macrosomia in women without diabetes. Methods Retrospective case-control study in a tertiary maternity unit between January 1st and December 31st, 2016. Inclusion of all women delivering after 37 weeks of a single live-born macrosomic infant, i.e., with a birth weight ≥ 90th percentile for gestational age (GA). Women with pre-existing or gestational diabetes were excluded. To identify specific factors associated with undiagnosed foetal macrosomia, we compared risk factors for macrosomia, maternal characteristics, father's body mass index (BMI) and prenatal follow up between two groups depending on whether macrosomia was prenatally diagnosed or not. Results Among 428 macrosomic newborns, 224 (52.3 %) were prenatally undiagnosed. Known risk factors for macrosomia, maternal characteristics (such as low socio-economic level, low education level) and father's BMI were similar between the two groups. The prenatal follow up was comparable between the two groups. buy Mardepodect Ultrasound estimated foetal weight during the 3rd trimester was lower in the undiagnosed macrosomic foetuses compared to diagnosed macrosomic foetuses (2130 ± 279 vs 2445 ± 333, p less then 0.001). Conclusions No specific factor of undiagnosed macrosomia was identified, and women with prenatally undiagnosed fetal macrosomia had the same risk factors than women with diagnosed macrosomia. Our study suggests that our groups have different growth curves. This hypothesis has yet to be studied.