To study mechanisms of therapy resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations.
We performed exome ...sequencing of matched diagnosis, remission, and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters.
Evolutionary patterns correlated with clinical outcome. Gain of mutations was associated with late relapse. Alterations of epigenetic regulators were frequently gained at relapse with recurring alterations of
constituting a mechanism of cytarabine resistance. Low
expression correlated with adverse clinical outcome, particularly in male patients. At complete remission, persistent mutations representing preleukemic lesions were observed in 48% of patients. The persistence of
mutations correlated with shorter time to relapse.
Chemotherapy resistance might be acquired through gain of mutations. Insights into the evolution during therapy and disease progression lay the foundation for tailored approaches to treat or prevent relapse of CN-AML.
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RATIONALE:More than 25 million individuals have heart failure worldwide, with ≈4000 patients currently awaiting heart transplantation in the United States. Donor organ shortage and allograft ...rejection remain major limitations with only ≈2500 hearts transplanted each year. As a theoretical alternative to allotransplantation, patient-derived bioartificial myocardium could provide functional support and ultimately impact the treatment of heart failure.
OBJECTIVE:The objective of this study is to translate previous work to human scale and clinically relevant cells for the bioengineering of functional myocardial tissue based on the combination of human cardiac matrix and human induced pluripotent stem cell–derived cardiomyocytes.
METHODS AND RESULTS:To provide a clinically relevant tissue scaffold, we translated perfusion-decellularization to human scale and obtained biocompatible human acellular cardiac scaffolds with preserved extracellular matrix composition, architecture, and perfusable coronary vasculature. We then repopulated this native human cardiac matrix with cardiomyocytes derived from nontransgenic human induced pluripotent stem cells and generated tissues of increasing 3-dimensional complexity. We maintained such cardiac tissue constructs in culture for 120 days to demonstrate definitive sarcomeric structure, cell and matrix deformation, contractile force, and electrical conduction. To show that functional myocardial tissue of human scale can be built on this platform, we then partially recellularized human whole-heart scaffolds with human induced pluripotent stem cell–derived cardiomyocytes. Under biomimetic culture, the seeded constructs developed force-generating human myocardial tissue and showed electrical conductivity, left ventricular pressure development, and metabolic function.
CONCLUSIONS:Native cardiac extracellular matrix scaffolds maintain matrix components and structure to support the seeding and engraftment of human induced pluripotent stem cell–derived cardiomyocytes and enable the bioengineering of functional human myocardial-like tissue of multiple complexities.
More than a third of patients with epilepsy are treatment resistant, and thus new, more effective therapies to achieve seizure freedom are needed. Cenobamate (YKP3089), an investigational ...antiepileptic drug, has shown broad-spectrum anticonvulsant activity in preclinical studies and seizure models. We aimed to evaluate the safety, efficacy, and tolerability of adjunctive cenobamate in patients with uncontrolled focal (partial)-onset epilepsy.
We did a multicentre, double-blind, randomised, placebo-controlled, dose-response study at 107 epilepsy and neurology centres in 16 countries. Adult patients (aged 18–70 years) with focal seizures despite treatment with 1–3 antiepileptic drugs were randomly assigned (1:1:1:1) via an interactive web response system, by block sizes of 4 within each country, to adjuvant once daily oral cenobamate at dose groups of 100 mg, 200 mg, or 400 mg, or placebo following an 8-week baseline assessment. Patients, investigators, and study personnel were masked to treatment assignment. The study included a 6-week titration phase and 12-week maintenance phase. The primary efficacy outcomes were percentage change in 28-day focal seizure frequency (focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizures) from baseline analysed in the modified intention-to-treat population (≥1 dose and any post-baseline seizure data) and responder rates (≥50% reduction) analysed in the maintenance phase population (≥1 dose in the maintenance phase and any maintenance phase seizure data). The primary efficacy outcomes were analysed using a hierarchal step-down procedure comparing 200 mg versus placebo, 400 mg versus placebo, then 100 mg versus placebo. Safety and tolerability were compared descriptively across treatment groups for all randomised patients. This study is registered with ClinicalTrials.gov, number NCT01866111.
Between July 31, 2013, and June 22, 2015, 437 patients were randomly assigned to either placebo (n=108) or cenobamate 100 mg (n=108), 200 mg (n=110), or 400 mg (n=111). Of these patients, 434 (106 98% in placebo group, 108 100% in 100 mg group, 109 99% in 200 mg group, and 111 100% in 400 mg group) were included in the modified intention-to-treat population, and 397 (102 94% in placebo group, 102 94% in 100 mg group, 98 89% in 200 mg group, and 95 86% in 400 mg group) were included in the modified intention-to-treat maintenance phase population. Median percentage changes in seizure frequency were −24·0% (IQR −45·0 to −7·0%) for the placebo group compared with −35·5% (−62·5 to −15·0%; p=0·0071) for the 100 mg dose group, −55·0% (−73·0 to −23·0%; p<0·0001) for the 200 mg dose group, and −55·0% (−85·0 to −28·0%; p<0·0001) for the 400 mg dose group. Responder rates during the maintenance phase were 25% (26 of 102 patients) for the placebo group compared with 40% (41 of 102; odds ratio 1·97, 95% CI 1·08–3·56; p=0·0365) for the 100 mg dose group, 56% (55 of 98; 3·74, 2·06–6·80; p<0·0001) for the 200 mg dose group, and 64% (61 of 95; 5·24, 2·84–9·67; p<0·0001) for the 400 mg dose group. Treatment-emergent adverse events occurred in 76 (70%) of 108 patients in the placebo group, 70 (65%) of 108 in the 100 mg group, 84 (76%) of 110 in the 200 mg group, and 100 (90%) of 111 in the 400 mg group. Treatment-emergent adverse events led to discontinuation in five (5%) patients in the placebo group, 11 (10%) in the 100 mg dose group, 15 (14%) in the 200 mg dose group, and 22 (20%) in the 400 mg dose group. One serious case of drug reaction with eosinophilia and systemic symptoms occurred in the 200 mg cenobamate group. No deaths were reported.
Adjunctive cenobamate reduced focal (partial)-onset seizure frequency, in a dose-related fashion. Treatment-emergent adverse events were most frequent in the highest dose group. Cenobamate appears to be an effective treatment option in patients with uncontrolled focal seizures.
SK Life Science.
Therapies developed for adult patients with heart failure have been shown to be ineffective in pediatric clinical trials, leading to the recognition that new pediatric-specific therapies for heart ...failure must be developed. Administration of the recombinant growth factor neuregulin-1 (rNRG1) stimulates regeneration of heart muscle cells (cardiomyocytes) in adult mice. Because proliferation-competent cardiomyocytes are more abundant in growing mammals, we hypothesized that administration of rNRG1 during the neonatal period might be more effective than in adulthood. If so, neonatal rNRG1 delivery could be a new therapeutic strategy for treating heart failure in pediatric patients. To evaluate the effectiveness of rNRG1 administration in cardiac regeneration, newborn mice were subjected to cryoinjury, which induced myocardial dysfunction and scar formation and decreased cardiomyocyte cell cycle activity. Early administration of rNRG1 to mice from birth to 34 days of age improved myocardial function and reduced the prevalence of transmural scars. In contrast, administration of rNRG1 from 4 to 34 days of age only transiently improved myocardial function. The mechanisms of early administration involved cardiomyocyte protection (38%) and proliferation (62%). We also assessed the ability of rNRG1 to stimulate cardiomyocyte proliferation in intact cultured myocardium from pediatric patients. rNRG1 induced cardiomyocyte proliferation in myocardium from infants with heart disease who were less than 6 months of age. Our results identify an effective time period within which to execute rNRG1 clinical trials in pediatric patients for the stimulation of cardiomyocyte regeneration.
Optical sensing materials for the selective measurement of potassium ions (K+) in water are presented. The indicator dyes are based on an aza‐crown ether as a receptor and borondipyrromethenes ...(BODIPY) dyes as fluorophores. Fluorescence enhancement is caused by the reduction of photoinduced electron transfer (PET) upon complexation with K+ ions. The family of new indicators possesses tuneable optical properties (green to red excitation, red to NIR emission) and PET efficiencies. They exhibit high brightness with quantum yields between 0.20 and 0.47 in the “on” state and a molar absorption coefficient between 30 000 and 290 000 m−1 cm−1. The new indicator dyes are immobilized in biocompatible hydrogel matrices to obtain stable nonleaching and fast responding (t90 ≈ 10 s) sensing materials for continuous measurements of potassium. They are realized in various formats such as planar optodes, fiber‐optic sensors, and water‐dispersible polymer‐based nanoparticles. Apart from fluorescence intensity measurements, self‐referenced read‐out of fluorescence decay time is demonstrated. All sensor materials display a high K+/Na+ selectivity and are not influenced by pH within the physiologically relevant range. Practical applicability of the materials is emphasized by application of a fiber‐optic sensor to quantification of K+ in serum, which shows excellent correlation with the reference measurements.
New fluorescence sensor materials for K+‐ions are prepared by using bright red‐ to NIR‐emitting borondipyrromethene (BODIPY) fluoroionophores with a highly selective crown ether receptor. Incorporation of these indicator dyes into different polymer matrixes yields solid‐state sensing materials as well as water‐dispersible nanoparticles. The sensors show no cross sensitivity to other ions and pH in the physiological range.
A facile route to synthesize hydrophilically or hydrophobically grafted graphitic carbon nitride (g-CN) is reported. For this purpose, functionalized olefinic molecules with a low polymerization ...tendency are utilized for grafting onto the surface to preserve the features of g-CN while improving its dispersibility. One-pot, visible light-induced grafting yields highly dispersible g-CNs either in aqueous or organic media. Moreover, functional groups such as amines can be introduced, which yields pH-dependent dispersibility in aqueous media. Compared with unfunctionalized g-CN, low sonication times are sufficient to redisperse g-CN. In addition, because of increased dispersion stability, higher amounts of functionalized g-CN can be dispersed (up to 10% in aqueous dispersion and 2% in organic dispersion) when compared to unfunctionalized g-CN.
A novel approach for a temperature-sensitive stabilization of water-in-water (W/W) emulsions is described. Specifically, we leveraged the thermal induced conformation change of tailored ...thermoresponsive block copolymers to reversibly stabilize and destabilize water-water interfaces. In addition, we investigated our approach to reversibly tune the reaction kinetics of enzymes compartmentalized within aqueous two-phase systems.
Temperature sensitive water-in-water (W/W) emulsions are described utilizing the thermal induced conformation change of tailored thermoresponsive block copolymers to reversibly stabilize and destabilize water-water interfaces.
Mesocrystalssuperstructures of crystalline nanoparticles that are aligned in a crystallographic fashionare of increasing interest for formation of inorganic materials with complex and sophisticated ...morphologies to tailor properties without changing chemical composition. Here we report morphogenesis of a novel mesocrystal consisting of nanoscale metal–organic frameworks (MOF) by using double hydrophilic block copolymer (DHBC) as a crystal modulator. DHBC selectively prefers the metastable hexagonal kinetic polymorph and promotes anisotropic crystal growth to generate hexagonal rod mesocrystals via oriented attachment and mesoscale assembly. The metastable nature of hexagonal mesocrystals enables further hierarchical morphogenesis by a solvent-mediated polymorphic transformation toward stable tetragonal mesocrystals that retain the outer hexagonal particle morphology. Furthermore, synthesis of hybrid MOFs, where hexagonal mesocrystals are vertically aligned on specific surfaces of cubic MOFs, is demonstrated. The present strategy opens a new avenue to create MOF mesocrystals and their hybrids with controlled size and morphology that can be designed for various potential applications.
Heart failure (HF) survival has improved, and nowadays, many patients with HF die of noncardiac causes, including cancer. Our aim was to investigate whether a causal relationship exists between HF ...and the development of cancer.
HF was induced by inflicting large anterior myocardial infarction in APC
mice, which are prone to developing precancerous intestinal tumors, and tumor growth was measured. In addition, to rule out hemodynamic impairment, a heterotopic heart transplantation model was used in which an infarcted or sham-operated heart was transplanted into a recipient mouse while the native heart was left in situ. After 6 weeks, tumor number, volume, and proliferation were quantified. Candidate secreted proteins were selected because they were previously associated both with (colon) tumor growth and with myocardial production in post-myocardial infarction proteomic studies. Myocardial gene expression levels of these selected candidates were analyzed, as well as their proliferative effects on HT-29 (colon cancer) cells. We validated these candidates by measuring them in plasma of healthy subjects and patients with HF. Finally, we associated the relation between cardiac specific and inflammatory biomarkers and new-onset cancer in a large, prospective general population cohort.
The presence of failing hearts, both native and heterotopically transplanted, resulted in significantly increased intestinal tumor load of 2.4-fold in APC
mice (all P<0.0001). The severity of left ventricular dysfunction and fibrotic scar strongly correlated with tumor growth ( P=0.002 and P=0.016, respectively). We identified several proteins (including serpinA3 and A1, fibronectin, ceruloplasmin, and paraoxonase 1) that were elevated in human patients with chronic HF (n=101) compared with healthy subjects (n=180; P<0.001). Functionally, serpinA3 resulted in marked proliferation effects in human colon cancer (HT-29) cells, associated with Akt-S6 phosphorylation. Finally, elevated cardiac and inflammation biomarkers in apparently healthy humans (n=8319) were predictive of new-onset cancer (n=1124) independently of risk factors for cancer (age, smoking status, and body mass index).
We demonstrate that the presence of HF is associated with enhanced tumor growth and that this is independent of hemodynamic impairment and could be caused by cardiac excreted factors. A diagnosis of HF may therefore be considered a risk factor for incident cancer.
RATIONALE:Cardiac remodeling and subsequent heart failure remain critical issues after myocardial infarction despite improved treatment and reperfusion strategies. Recently, cardiac regeneration has ...been demonstrated in fish and newborn mice after apex resection or cardiac infarctions. Two key issues remain to translate findings in model organisms to future therapies in humanswhat is the mechanism and can cardiac regeneration indeed occur in newborn humans?
OBJECTIVE:To assess whether human neonatal hearts can functionally recover after myocardial infarction.
METHODS AND RESULTS:Here, we report the case of a newborn child having a severe myocardial infarction due to coronary artery occlusion. The child developed massive cardiac damage as defined by serum markers for cardiomyocyte cell death, electrocardiograms, echocardiography, and cardiac angiography. Remarkably, within weeks after the initial ischemic insult, we observed functional cardiac recovery, which translated into long-term normal heart function.
CONCLUSIONS:These data indicate that, similar to neonatal rodents, newborn humans might have the intrinsic capacity to repair myocardial damage and completely recover cardiac function.
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