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.
Diffusion tensor imaging can provide unique and detailed information about white matter anatomy following stroke. Fiber tract reconstruction using tract-based techniques and cross-sectional region of ...interest delineation are two common approaches to quantify white matter integrity. After stroke, white matter tract integrity can be affected both locally and distally to the primary lesion location. It has been shown that tract disruption is associated with degree of functional impairment and response to skill training in participants with stroke. However, the reliability and validity of these approaches has not been systematically evaluated nor have the two approaches been directly compared in individuals with chronic stroke.
Ten well-recovered individuals with chronic, right-sided, ischemic stroke in the sub-cortex and ten age-, gender- and handedness-matched healthy participants were studied. Semi-automated tractography of the ipsi- and contralesional corticospinal tract and cross-sectional region of interest drawing of the posterior limb of the internal capsule were performed bilaterally. Fractional anisotropy (FA) values and the hemispheric asymmetry in FA were the primary measures of tract integrity. Two raters performed each analysis method twice to evaluate inter- and intra-rater reliability. Participants with stroke were compared to healthy individuals to determine validity of each analysis approach. Correlational analyses were conducted to examine the relationships between the two approaches and the association between approaches and upper extremity motor impairment.
Both analyses methods generally demonstrated good to excellent intra- and inter-rater reliability in each group (p<0.05). Stroke participants demonstrated lower mean FA values in both ipsi- and contralesional tract integrity, and larger FA hemispheric asymmetry as compared with healthy individuals (p<0.05). Comparison between the analysis approaches revealed significant associations between approaches across both groups and within each group (p<0.05). In stroke, individual tract integrity was not correlated between approaches for ipsilesional (r=0.26) or contralesional (0.15) tracts, nor was FA hemispheric asymmetry (r=0.18). Additionally, contralesional mean FA quantified with the cross-sectional approach correlated with upper extremity motor impairment (r=0.69).
Importantly, this study is the first to systematically characterize the reliability of tract-based and cross-sectional DTI analysis approaches in well-recovered individuals with chronic stroke and matched healthy participants. Results suggest both tract-based and cross-sectional approaches to evaluate white matter tract integrity are reliable, can differentiate between groups of stroke and healthy participants, and are associated with one another. However, only mean FA values for the contralesional side derived using the cross-sectional approach were related to upper extremity impairment. Our findings suggest that each approach provides complimentary rather than redundant information regarding integrity and support the use of both approaches in combination in future investigations in well-recovered individuals with stroke.
► We conducted two data analysis approaches of white matter integrity in stroke. ► The reliability of these methods was confirmed between two raters and two ratings. ► Approaches differentiated bilateral tract integrity between stroke and healthy individuals. ► Approaches may evaluate different aspects of white matter integrity disruption. ► Good reproducibility of both approaches supports use in future inquiry in stroke and stroke recovery.
Engineered macromolecules such as polymer conjugates, micelles, hydrogels and nanofibers continue to attract interest as drug delivery systems due to their potential to improve therapeutic outcomes. ...One area where engineered macromolecules have considerable potential is in the delivery of endogenous signalling molecules, such as hydrogen sulfide (H
2
S). Until recently the application and investigation of H
2
S was limited to the use of small molecule donors, although the use of macromolecular systems may confer considerable advantages. This mini review provides a brief overview of recent advances in the use of macromolecules as H
2
S donors. In particular, we examine the use of materials that release H
2
S both spontaneously and in response to chemical or physical triggers. In many of the highlighted examples macromolecules are reported to provide precise, controlled and sustained production of H
2
S, demonstrating their potential as advanced platforms for H
2
S delivery.
This mini review highlights recent advances in the design of macromolecular materials that can deliver hydrogen sulfide either spontaneously or in response to chemical and physical triggers.
Experience-dependent structural changes are widely evident in gray matter. Using diffusion weighted imaging (DWI), the neuroplastic effect of motor training on white matter in the brain has been ...demonstrated. However, in humans it is not known whether specific features of white matter relate to motor skill acquisition or if these structural changes are associated to functional network connectivity. Myelin can be objectively quantified in vivo and used to index specific experience-dependent change. In the current study, seventeen healthy young adults completed ten sessions of visuomotor skill training (10,000 total movements) using the right arm. Multicomponent relaxation imaging was performed before and after training. Significant increases in myelin water fraction, a quantitative measure of myelin, were observed in task dependent brain regions (left intraparietal sulcus IPS and left parieto-occipital sulcus). In addition, the rate of motor skill acquisition and overall change in myelin water fraction in the left IPS were negatively related, suggesting that a slower rate of learning resulted in greater neuroplastic change. This study provides the first evidence for experience-dependent changes in myelin that are associated with changes in skilled movements in healthy young adults.
This report describes two hypervirulent
isolates that produced
carbapenemase (KPC), which were identified from a rectal swab and a urine culture upon hospital admission. The patient had recently ...traveled to Greece, where he was hospitalized. The isolates were sequence type 86 and contained an IncHI1B IncFIB
hypervirulent plasmid and an IncFII
plasmid harboring KPC.
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Hydrogen sulfide (H2S) is an important signalling molecule with potential pharmaceutical applications. In pursuit of a suitable delivery system for H2S, herein we apply an amphiphilic ...trisulfide to concomitantly alter the mesophase behaviour of dispersed lipid particles and enable triggered H2S release. Amperometric release studies indicate the trisulfide acts as a sustained H2S donor, with inclusion into the mesophase attenuating release vs neat dispersed trisulfide. Taken together the results highlight the potential for including trisulfide-based additives in stimuli-responsive drug delivery vehicles.
We have identified a Salmonella enterica serotype 4,5,12:i:- containing a mcr-3.2 in a patient who travelled to Thailand 1 month prior to the identification of it in Canada. The isolate was multidrug ...resistant, but remained susceptible to the carbapenems, amikacin and piperacillin/tazobactam. The mcr-3.2 was carried on a 261 Kb variant of the IncHI2 pWJ1. This report provides further evidence of the emergence of a ST34 colistin-resistant clone.
Abstract Concussion is among the least understood neurologic injuries. The impact of concussion on the adolescent brain remains largely unknown. This study sought to establish short-term changes in ...white-matter integrity after sports-related concussion in adolescents, and examine the association between changes in white-matter integrity and a clinical measure of concussion. Twelve adolescents, aged 14-17 years with a sports-related concussion within 2 months, and 10 age-matched adolescents with no history of concussion were evaluated with the Sports Concussion Assessment Tool 2 and diffusion tensor imaging. Two measures compared the two groups: fractional anisotropy and mean diffusivity. Whole-brain fractional anisotropy values significantly increased (F(1,40) = 6.29, P = 0.010), and mean diffusivity values decreased (F(1,40) = 4.75, P = 0.036), in concussed athletes compared with control participants. Total scores on the Sports Concussion Assessment Tool 2 were associated with whole-brain fractional anisotropy. Mean diffusivity values with lower scores were associated with higher fractional anisotropy (R2 = 0.25, P = 0.017) and lower mean diffusivity (R2 = 0.20, P = 0.038). We provide evidence of structural changes in the integrity of white matter in adolescent athletes after sports-related concussion.
Obesity is a chronic disease that affects more than 650 million adults worldwide. Obesity not only is a significant health concern on its own, but predisposes to cardiometabolic comorbidities, ...including coronary heart disease, dyslipidemia, hypertension, type 2 diabetes, and some cancers. Lifestyle interventions effectively promote weight loss of 5% to 10%, and pharmacological and surgical interventions even more, with some novel approved drugs inducing up to an average of 25% weight loss. Yet, maintaining weight loss over the long‐term remains extremely challenging, and subsequent weight gain is typical. The mechanisms underlying weight regain remain to be fully elucidated. The purpose of this Pennington Biomedical Scientific Symposium was to review and highlight the complex interplay between the physiological, behavioral, and environmental systems controlling energy intake and expenditure. Each of these contributions were further discussed in the context of weight‐loss maintenance, and systems‐level viewpoints were highlighted to interpret gaps in current approaches. The invited speakers built upon the science of obesity and weight loss to collectively propose future research directions that will aid in revealing the complicated mechanisms involved in the weight‐reduced state.
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