Highlights • After age, the largest effect on sleep behavior is ethnicity. • Shorter sleep duration and later bedtimes are reported in non-Caucasian children. • The interaction between non-Caucasian ...ethnicity and low socioeconomic increases the risk for short sleep duration.
Proanthocyanidins (PAs) were isolated from the skins, seeds and flesh of commercially ripe grapes, and from wine and marc produced from the same source. In the grape berry, skin PAs accounted for 54% ...of the total extractable PA, while seed and flesh-derived PA accounted for 30% and 15% of the total, respectively. Following fermentation, 25% of the fruit PA was found in the wine, while 27% was found in the pericarp isolated from marc, and 48% was unaccounted for (either remaining in the seed or adsorbed to lees). To investigate the role that cell wall material (CWM) has on PA extraction during fermentation, CWM isolated from skin and flesh were combined with PA in model suspensions. In general, the affinity of flesh CWM for PA increased with increasing PA molecular mass (MM); however, this relationship was not observed for the interaction of skin CWM with skin PA. Subsequent experiments suggest that the differences in the interaction of flesh and skin CWM with PA of higher MM (>15000 g/mol) may be limited by the structure of the CWM. Observed variations in the composition between skin and flesh CWM may explain the differences in PA interaction at high MM. Among wine-derived PA, no higher MM material was detected, suggesting that, during vinification, higher MM PA are nonextractable and/or are removed from the wine by interaction with CWM.
Purpose of Review
Over the past two decades, the introduction of tyrosine kinase inhibitors (TKIs) has transformed the treatment of chronic myeloid leukemia (CML). With four agents currently approved ...for frontline use in chronic-phase (CP) disease, it follows that treatment decision-making has been rendered more challenging. Here we will review recent advances that help inform the selection of a first-line TKI.
Recent Findings
Extended follow-up of the seminal CML trials has demonstrated the long-term efficacy of TKIs, while also highlighting significant differences in their respective toxicity profiles and potency. Dasatinib and nilotinib generate deeper molecular responses than imatinib, particularly among patients with higher risk disease, but this has not translated into a significant survival advantage. Similar results have been obtained at 1 year with bosutinib; its efficacy and toxicity were well balanced at a dose of 400 mg daily, prompting its recent approval for this indication. Lastly, multiple studies have demonstrated that TKIs can be safely discontinued in select individuals who have maintained deep responses for extended periods, establishing treatment-free remission as a novel goal in CP CML.
Summary
The careful consideration of parameters such as disease risk, the potency, and toxicity profile of each TKI, as well as each patient’s unique comorbidities and preferences, enables truly individualized therapeutic decision-making in CP CML, with the goal of ensuring that a high quality of life accompanies the survival advantage conferred by these agents.
We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor ...(MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day −1. All patients received T-cell–replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio HR, 0.69; 95% confidence interval CI, 0.38-1.26; P = .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P = .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.
•TCZ did not significantly reduce the incidence of grade 2-4 aGVHD, although trends were seen in VUD recipients.•Addition of TCZ to standard GVHD prophylaxis did not improve long-term survival.
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Proanthocyanidins were isolated from the skins of Cabernet Sauvignon grapes at different stages of grape development in order to study the effect of proanthocyanidin modification on the interaction ...with grape cell wall material. After veraison, the degree of proanthocyanidin polymerization increased, and thereafter was variable between 24 and 33 subunits as ripening progressed. Affinity of skin cell wall material for proanthocyanidin decreased with proanthocyanidin ripeness following veraison. A significant negative relationship (R 2 = 0.93) was found for average proanthocyanidin molecular mass and the proportion of high molecular mass proanthocyanidin adsorbed by skin cell wall material. This indicated that as proanthocyanidin polymerization increased, the affinity of a component of high molecular mass proanthocyanidins for skin cell wall material declined. This phenomenon was only associated with skin proanthocyanidins from colored grapes, as high molecular mass proanthocyanidins of equivalent subunit composition from colorless mutant Cabernet Sauvignon grapes had a higher affinity for skin cell wall material.
Prior studies with single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) have shown a survival benefit with early revascularization in patients with >10% to 12.5% ...ischemic myocardium. The relationship among positron emission tomography (PET)–derived extent of ischemia, early revascularization, and survival is unknown.
The purpose of this study was to evaluate the association among percent ischemia on PET MPI, revascularization, and survival.
A total of 16,029 unique consecutive patients who were undergoing Rubidium-82 rest-stress PET MPI from 2010 to 2016 were included. Patients with known cardiomyopathy and nondiagnostic perfusion results were excluded. Percent ischemic myocardium was estimated from a 17-segment model. Propensity scoring was used to account for nonrandomized referral to early revascularization (90 days of PET). A Cox model was developed, adjusting for propensity scores for early revascularization and percent ischemia, and an interaction between ischemia and early revascularization was tested.
Median follow-up was 3.7 years. Overall, 1,277 (8%) patients underwent early revascularization and 2,493 (15.6%) died (738 cardiac). Nearly 37% of patients (n = 5,902) had ischemia, with 13.5% (n = 2,160) having ≥10%. In propensity-adjusted analyses, there was a significant interaction between ischemia and early revascularization (p < 0.001 for all-cause and cardiac death), such that patients with greater ischemia had improved survival with early revascularization, with a potential ischemia threshold at 5% (upper limit 95% confidence interval at 10%). There was no differential association between ischemia and early revascularization on death based on history of known coronary artery disease (interaction p = 0.72).
In a contemporary cohort of patients undergoing PET MPI, patients with greater ischemia had a survival benefit from early revascularization. On exploratory analyses, this threshold was lower than that previously reported for SPECT. These findings require future validation in prospective cohorts or trials.
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Acute erythroid leukemia (AEL) is characterized by a distinct morphology, mutational spectrum, lack of preclinical models, and poor prognosis. Here, using multiplexed genome editing of mouse ...hematopoietic stem and progenitor cells and transplant assays, we developed preclinical models of AEL and non-erythroid acute leukemia and describe the central role of mutational cooperativity in determining leukemia lineage. Different combination of mutations in Trp53, Bcor, Dnmt3a, Rb1, and Nfix resulted in the development of leukemia with an erythroid phenotype, accompanied by the acquisition of alterations in signaling and transcription factor genes that recapitulate human AEL by cross-species genomic analysis. Clonal expansion during tumor evolution was driven by mutational cooccurrence, with clones harboring a higher number of founder and secondary lesions (eg, mutations in signaling genes) showing greater evolutionary fitness. Mouse and human AEL exhibited deregulation of genes regulating erythroid development, notably Gata1, Klf1, and Nfe2, driven by the interaction of mutations of the epigenetic modifiers Dnmt3a and Tet2 that perturbed methylation and thus expression of lineage-specific transcription factors. The established mouse leukemias were used as a platform for drug screening. Drug sensitivity was associated with the leukemia genotype, with the poly (ADP-ribose) polymerase inhibitor talazoparib and the demethylating agent decitabine efficacious in Trp53/Bcor–mutant AEL, CDK7/9 inhibitors in Trp53/Bcor/Dnmt3a–mutant AEL, and gemcitabine and bromodomain inhibitors in NUP98-KDM5A leukemia. In conclusion, combinatorial genome editing has shown the interplay of founding and secondary genetic alterations in phenotype and clonal evolution, epigenetic regulation of lineage-specific transcription factors, and therapeutic tractability in erythroid leukemogenesis.
•Combinatorial genome editing of hematopoietic progenitors shows the importance of mutational cooperativity in specifying leukemia lineage.•Combinatorial patterns of mutations are associated with drug sensitivity in preclinical models of erythroleukemia.
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Introduction Pediatric sleep-disordered breathing is a continuum, with primary snoring at one end, and complete upper airway obstruction, hypoxemia, and obstructive hypoventilation at the other. The ...latter gives rise to obstructive sleep apnea. An important predisposing factor in the development and progression of pediatric sleep-disordered breathing might be craniofacial disharmony. The purpose of this systematic review and meta-analysis was to elucidate the association between craniofacial disharmony and pediatric sleep-disordered breathing. Methods Citations to potentially relevant published trials were located by searching PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials. The MetaRegister of controlled trials database was also searched to identify potentially relevant unpublished trials. Additionally, hand-searching, Google Scholar searches, and contact with experts in the area were undertaken to identify potentially relevant published and unpublished studies. Inclusion criteria were (1) randomized controlled trials, case-control trials, or cohort studies with controls; (2) studies in nonsyndromic children 0 to 18 years of age with a diagnosis of sleep-disordered breathing or obstructive sleep apnea by either a sleep disorders unit, screening questionnaire, or polysomnography; and (3) principal outcome measures of craniofacial or upper airway dimensions or proportions with various modalities of imaging for the craniofacial and neck regions. The quality of the studies selected was evaluated by assessing their methodologies. Treatment effects were combined by meta-analysis with the random-effects method. Results Children with obstructive sleep apnea and primary snoring show increased weighted mean differences in the ANB angle of 1.64° ( P <0.0001) and 1.54° ( P <0.00001), respectively, compared with the controls. An increased ANB angle was primarily due to a decreased SNB angle in children with primary snoring by 1.4° ( P = 0.02). Children with obstructive sleep apnea had a distance from the posterior nasal spine to the nearest adenoid tissue measured along the PNS-basion line reduced by 4.17 mm (weighted mean difference) ( P <0.00001) and a distance from the posterior nasal spine to the nearest adenoid tissue measured along the line perpendicular to the sella-basion line reduced by 3.12 mm (weighted mean difference) ( P <0.0001) compared with the controls. Conclusions There is statistical support for an association between craniofacial disharmony and pediatric sleep-disordered breathing. However, an increased ANB angle of less than 2° in children with obstructive sleep apnea and primary snoring, compared with the controls, could be regarded as having marginal clinical significance. Therefore, evidence for a direct causal relationship between craniofacial structure and pediatric sleep-disordered breathing is unsupported by this meta-analysis. There is strong support for reduced upper airway width in children with obstructive sleep apnea. Larger well-controlled trials are required to address the relationship of craniofacial and upper airway morphology to pediatric sleep-disordered breathing in all 3 dimensions.
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