University of Massachusetts Medical School Larkin, Anne Campbell; Fischer, Melissa A
Academic medicine,
2020-September, Letnik:
95, Številka:
9S A Snapshot of Medical Student Education in the United States and Canada: Reports From 145 Schools
Journal Article
Suppression of apoptosis by expression of antiapoptotic BCL2 family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL1), an ...antiapoptotic BCL2 family member, is commonly upregulated in AML cells and is often a primary mode of resistance to treatment with the BCL2 inhibitor venetoclax. Here, we describe VU661013, a novel, potent, selective MCL1 inhibitor that destabilizes BIM/MCL1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient-derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples and drug-sensitivity testing
accurately predicted cellular responses to selective inhibitors of MCL1 or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and MCL1 inhibitors in sequence or in combination in AML clinical trials. SIGNIFICANCE: Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and MCL1 is a critical antiapoptotic oncoprotein. Armed with novel MCL1 inhibitors and the potent BCL2 inhibitor venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML.
.
.
Abstract Objectives The objective of this study was to gain knowledge and ascertain challenges about periviability counseling among obstetricians to inform curricular development. Methods Focus ...groups were utilized. A series of open-ended questions was posed to each group of obstetricians; responses were audio recorded and transcribed. Transcriptions were analyzed by two coders using thematic analysis. Results Four focus groups were convened. Prominent themes included: (1) Obstetrician knowledge about neonatal outcomes is limited, (2) Periviability counseling is both time intensive and time-challenged, (3) Patient processing of information relies on the content, delivery and patient readiness, and (4) Obstetrician bias is toward advocating for maternal safety, which may run counter to parental instinct to “do everything.” The last theme was specifically focused on the role of cesarean delivery. Conclusions Curricula focused on improving obstetrician periviability counseling should focus on neonatal outcomes, the role of cesarean delivery, and utilization of shared decision-making.
Recent advances in personality theory indicate that there are distinct constructs that dispose individuals to rash action and risky behavior, as opposed to one broad trait of impulsivity. Two are ...emotion based, two represent deficits in conscientiousness, and one is sensation seeking. Previous studies of impulsivity and its relationship to bulimia nervosa have yielded mixed findings. The authors applied this advance in personality theory to the study of bulimia nervosa (BN) to test the hypothesis that the emotion-based disposition of negative urgency (the tendency to act rashly when distressed) relates most strongly to BN symptoms. A meta-analysis of 50 articles indicated the following. Negative urgency had by far the largest effect size (weighted
r
=
.38), followed by sensation seeking (weighted
r
=
.16); lack of planning (weighted
r
=
.16) and lack of persistence (weighted
r
=
.08). Methodological moderators of the effect of distinct traits on BN symptoms were the use of scales that precisely measured one construct as opposed to general impulsivity scales that measured several constructs, clinical vs. non-clinical samples, and whether or not the personality scale was translated from its original language or not. Negative urgency appears especially important for BN; more broadly, researchers should consider the role of emotion-based dispositions to rash acts in their risk theories.
Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create ...high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3′ to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.
Display omitted
•BET inhibitors impair the release of promoter-proximal paused RNA polymerases•BET inhibitors repress KIT transcription through its downstream enhancer•BET inhibitors repress MCL1-targeting microRNAs MIR29C and MIR29B2•Inhibition of MCL1 triggers cell death in BET-inhibitor-treated AML cells
Zhao et al. use PRO-seq to generate high-resolution genomic maps of all active RNA polymerases and identify direct transcriptional targets of BET inhibitors within 15 min of treatment. They find that KIT and MCL1 inhibitors are potential therapeutic targets for combination therapies for acute myeloid leukemia along with BET inhibitors.
In 3 studies, the authors developed and began to validate a
measure of the propensity to act rashly in response to
positive affective states (
positive
urgency
). In Study 1, they developed a
...content-valid 14-item scale, showed that the measure was
unidimensional, and showed that positive urgency was
distinct from impulsivity-like constructs identified in 2
models of impulsive behavior. In Study 2, they showed that
positive urgency explained variance in risky behavior not
explained by measures of other impulsivity-like constructs,
differentially explained positive mood-based risky behavior,
differentiated individuals at risk for problem gambling from
those not at risk, and interacted with drinking motives and
expectancies as predicted to explain problem drinking
behavior. In Study 3, they confirmed the hypothesis that
positive urgency differentiated alcoholics from both
eating-disordered and control individuals.
In retinas where Müller glia have been stimulated to become progenitor cells, reactive microglia are always present. Thus, we investigated how the activation or ablation of microglia/macrophage ...influences the formation of Müller glia‐derived progenitor cells (MGPCs) in the retina in vivo. Intraocular injections of the Interleukin‐6 (IL6) stimulated the reactivity of microglia/macrophage, whereas other types of retinal glia appear largely unaffected. In acutely damaged retinas where all of the retinal microglia/macrophage were ablated, the formation of proliferating MGPCs was greatly diminished. With the microglia ablated in damaged retinas, levels of Notch and related genes were unchanged or increased, whereas levels of ascl1a, TNFα, IL1β, complement component 3 (C3) and C3a receptor were significantly reduced. In the absence of retinal damage, the combination of insulin and Fibroblast growth factor 2 (FGF2) failed to stimulate the formation of MGPCs when the microglia/macrophage were ablated. In addition, intraocular injections of IL6 and FGF2 stimulated the formation of MGPCs in the absence of retinal damage, and this generation of MGPCs was blocked when the microglia/macrophage were absent. We conclude that the activation of microglia and/or infiltrating macrophage contributes to the formation of proliferating MGPCs, and these effects may be mediated by components of the complement system and inflammatory cytokines. GLIA 2014;62:1608–1628
Main Points
Reactive microglia stimulate the formation of proliferating Müller glia‐derived progenitors in damaged retinas.
Reactive microglia stimulate the formation of proliferating Müller glia‐derived progenitors in FGF2‐treated retinas in the absence of damage.
The loss of microglia diminishes levels of ascl1a, components of the complement system, proinflammatory cytokines and enhance levels p38 MAPK coincident with diminished formation of Müller glia‐derived progenitors.
We have recently described a novel type of glial cell that is scattered across the inner layers of the avian retina 1. These cells are stimulated by insulin-like growth factor 1 (IGF1) to ...proliferate, migrate distally into the retina, and up-regulate the nestin-related intermediate filament transition. These changes in glial activity correspond with increased susceptibility of neurons to excitotoxic damage. This novel cell-type has been termed the Non-astrocytic Inner Retinal Glia-like (NIRG) cells. The purpose of the study was to investigate whether the retinas of non-avian species contain cells that resemble NIRG cells. We assayed for NIRG cells by probing for the expression of Sox2, Sox9, Nkx2.2, vimentin and nestin. NIRG cells were distinguished from astrocytes by a lack of expression for Glial Fibrilliary Acidic Protein (GFAP). We examined the retinas of adult mice, guinea pigs, dogs and monkeys (Macaca fasicularis). In the mouse retina and optic nerve head, we identified numerous astrocytes that expressed GFAP, S100beta, Sox2 and Sox9; however, we found no evidence for NIRG-like cells that were positive for Nkx2.2, nestin, and negative for GFAP. In the guinea pig retina, we did not find astrocytes or NIRG cells in the retina, whereas we identified astrocytes in the optic nerve. In the eyes of dogs and monkeys, we found astrocytes and NIRG-like cells scattered across inner layers of the retina and within the optic nerve. We conclude that NIRG-like cells are present in the retinas of canines and non-human primates, whereas the retinas of mice and guinea pigs do not contain NIRG cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens ...can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity.
INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines.
efficacy was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples
and
while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models.
INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes,
and
, and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity.
Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen.
Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and lack of effective clinical therapies. Dysregulation of apoptosis is observed across MDS subtypes ...regardless of mutations and represents an attractive therapeutic opportunity. Venetoclax (VEN), a selective inhibitor of anti-apoptotic protein B-cell lymphoma- 2 (BCL2), has yielded impressive responses in older patients with acute myeloid leukemia (AML) and high risk MDS. BCL2 family anti-apoptotic proteins BCL-XL and induced myeloid cell leukemia 1 (MCL1) are implicated in leukemia survival, and upregulation of MCL1 is seen in VEN-resistant AML and MDS. We determined in vitro sensitivity of MDS patient samples to selective inhibitors of BCL2, BCL-XL and MCL1. While VEN response positively correlated with MDS with excess blasts, all MDS subtypes responded to MCL1 inhibition. Treatment with combined VEN + MCL1 inhibtion was synergistic in all MDS subtypes without significant injury to normal hematopoiesis and reduced MDS engraftment in MISTRG6 mice, supporting the pursuit of clinical trials with combined BCL2 + MCL1 inhibition in MDS.
PDF
