Preclinical studies have suggested that the oral antifungal agent itraconazole specifically inhibits proliferation, migration, and tube formation of endothelial cells. Itraconazole has potent ...antiangiogenic activity and enhances the efficacy of cytotoxic chemotherapy in multiple primary xenograft lung cancer models. On the basis of these data, we performed an exploratory clinical study, assessing the efficacy of itraconazole with cytotoxic chemotherapy in the treatment of patients with advanced lung cancer.
The study enrolled patients with progressive nonsquamous non–small-cell lung cancer after one prior cytotoxic therapy for metastatic disease, randomized 2:1 to intravenous administration of pemetrexed 500 mg/m2 on day 1, with or without itraconazole 200 mg orally daily, on a 21-day cycle. Outcome measures included percent progression-free at 3 months, progression-free survival, overall survival, and observed toxicity.
A total of 23 patients were enrolled; the study was stopped early because of increasing use of pemetrexed in the first-line setting. At 3 months, 67% of the patients on itraconazole plus pemetrexed were progression-free versus 29% on the control arm of pemetrexed alone (p = 0.11). Median progression-free survivals were 5.5 months (itraconazole) versus 2.8 months (control) (hazard ratio = 0.399, p = 0.089). Overall survival was longer in patients receiving itraconazole (median 32 months) versus control (8 months) (hazard ratio = 0.194, p = 0.012). There were no evident differences in toxicity between the study arms.
Itraconazole is well tolerated in combination with pemetrexed. Consistent with our preclinical data, daily itraconazole administration is associated with trends suggestive of improved disease control in patients receiving chemotherapy for advanced lung cancer.
IL-9 is an important mediator of allergic disease that is critical for mast cell-driven diseases. IL-9 is produced by many cell types, including T cells, basophils, and mast cells. Yet, how IL-9 is ...regulated in mast cells or basophils is not well characterized. In this report, we tested the effects of deficiency of a mouse
gene regulatory element (
CNS-25) in these cells in vivo and in vitro. In mast cells stimulated with IL-3 and IL-33, the
CNS-25 enhancer is a potent regulator of mast cell
gene transcription and epigenetic modification at the
locus. Our data show preferential binding of STAT5 and GATA1 to CNS-25 over the
promoter in mast cells and that T cells and mast cells have differing requirements for the induction of IL-9 production.
CNS-25 is required for IL-9 production from T cells, basophils, and mast cells in a food allergy model, and deficiency in IL-9 expression results in decreased mast cell expansion. In a
infection model, we observed a similar decrease in mast cell accumulation. Although decreased mast cells correlated with higher parasite egg burden and delayed clearance in vivo, T cell deficiency in IL-9 also likely contributes to the phenotype. Thus, our data demonstrate IL-9 production in mast cells and basophils in vivo requires
CNS-25, and that
CNS-25-dependent IL-9 production is required for mast cell expansion during allergic intestinal inflammation.
Deaggregation of oxidized ultradispersed diamond (UDD) in dimethylsulfoxide followed by reaction with glycidol monomer, purification via aqueous dialysis, and dispersion in ethylene glycol (EG) base ...fluid affords nanodiamond (ND)-poly(glycidol) polymer brush:EG nanofluids exhibiting 12% thermal conductivity enhancement at a ND loading of 0.9 vol %. Deaggregation of UDD in the presence of oleic acid/octane followed by dispersion in light mineral oil and evaporative removal of octane gives ND·oleic acid:mineral oil dispersions exhibiting 11% thermal conductivity enhancement at a ND loading of 1.9 vol %. Average particle sizes of ND additives, determined by dynamic light scattering, are, respectively, ca. 11 nm (in H2O) and 18 nm (in toluene). Observed thermal conductivity enhancements outperform enhancement effects calculated using Maxwell's effective medium approximation by 2- to 4-fold. Covalent ND surface modification gives 2-fold greater thermal conductivity enhancement than ND surface modification via hydrogen-bonding interactions at similar concentrations. Stable, static ND:mineral oil dispersions are reported for the first time.
Prolonged chronic stress has deleterious effects on immune function and is associated with numerous negative health outcomes. The spleen harbors one-fourth of the body's lymphocytes and mediates both ...innate and adaptive immune responses. However, the subset of splenic lymphocytes that respond, either adaptively or maladaptively, to various stressors remains largely unknown. Here we investigated the effects of unpredictable chronic mild stress (CMS) exposure on spleen composition in male mice housed in two different caging conditions: standard caging (Cntl) and enriched environment (EE). EE-caged mice exhibited the greatest absolute number of splenocytes and CMS exposure significantly lowered splenocyte numbers in both caging conditions. Glucocorticoid production, measured by mean fecal corticosterone metabolites (FCM), was significantly lower in EE-caged mice vs. Cntl-caged mice. Surprisingly, CMS exposure resulted in an increase in mean FCM in EE-caged mice, but no significant change in Cntl-caged mice. CMS altered the splenic B:T lymphocyte ratio; it reduced the frequency of B cells, but increased the frequency of T cells in EE-caged mice. Splenocyte number and B:T lymphocyte ratio showed a negative relationship with mean FCM. EE-caged mice had a lower frequency of immature and germinal B cells than Cntl-caged mice. CMS markedly increased the frequency of immature and marginal zone B cells, but decreased the frequency of follicular B cells in both caging conditions. Mean FCM correlated positively with frequency of immature, marginal zone and germinal center B cells, but negatively with frequency of follicular B cells. To conclude, splenic immune cells, particularly B lymphocyte composition, are modulated by caging environment and stress and may prime mice differently to respond to immune challenges.
The mechanism behind transgenerational epigenetic inheritance is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by ...the Mtrr hypomorphic mutation results in transgenerational epigenetic inheritance of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. Here, we use genome-wide approaches to reveal genetic stability in the Mtrr model and genome-wide differential DNA methylation in the germline of Mtrr mutant maternal grandfathers. We observe that, while epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional changes that correlate with germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos for at least three wildtype generations in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.
Training in working memory tasks is associated with lasting changes in prefrontal cortical activity. To assess the neural activity changes induced by training, we recorded single units, multi-unit ...activity (MUA) and local field potentials (LFP) with chronic electrode arrays implanted in the prefrontal cortex of two monkeys, throughout the period they were trained to perform cognitive tasks. Mastering different task phases was associated with distinct changes in neural activity, which included recruitment of larger numbers of neurons, increases or decreases of their firing rate, changes in the correlation structure between neurons, and redistribution of power across LFP frequency bands. In every training phase, changes induced by the actively learned task were also observed in a control task, which remained the same across the training period. Our results reveal how learning to perform cognitive tasks induces plasticity of prefrontal cortical activity, and how activity changes may generalize between tasks.
We demonstrate rapid imaging based on four-wave mixing (FWM) by assessing the quality of advanced materials through measurement of their nonlinear response, exciton dephasing, and exciton lifetimes. ...We use a WSe
monolayer grown by chemical vapor deposition as a canonical example to demonstrate these capabilities. By comparison, we show that extracting material parameters such as FWM intensity, dephasing times, excited state lifetimes, and distribution of dark/localized states allows for a more accurate assessment of the quality of a sample than current prevalent techniques, including white light microscopy and linear micro-reflectance spectroscopy. We further discuss future improvements of the ultrafast FWM techniques by modeling the robustness of exponential decay fits to different spacing of the sampling points. Employing ultrafast nonlinear imaging in real-time at room temperature bears the potential for rapid in-situ sample characterization of advanced materials and beyond.
Next‐generation nanoelectronics based on 2D materials ideally will require reliable, flexible, transparent, and versatile dielectrics for transistor gate barriers, environmental passivation layers, ...capacitor spacers, and other device elements. Ultrathin amorphous boron nitride of thicknesses from 2 to 17 nm, described in this work, may offer these attributes, as the material is demonstrated to be universal in structure and stoichiometric chemistry on numerous substrates including flexible polydimethylsiloxane, amorphous silicon dioxide, crystalline Al2O3, other 2D materials including graphene, 2D MoS2, and conducting metals and metal foils. The versatile, large area pulsed laser deposition growth technique is performed at temperatures less than 200 °C and without modifying processing conditions, allowing for seamless integration into 2D device architectures. A device‐scale dielectric constant of 5.9 ± 0.65 at 1 kHz, breakdown voltage of 9.8 ± 1.0 MV cm−1, and bandgap of 4.5 eV were measured for various thicknesses of the ultrathin a‐BN material, representing values higher than previously reported chemical vapor deposited h‐BN and nearing single crystal h‐BN.
Ultrathin amorphous boron nitride films of thicknesses as low as 2 nm are deposited by low temperature pulsed laser deposition. Wafer‐scale process scalability with growth temperatures below 200 °C, film structure and chemistry invariance for numerous prospective substrates, and exceptional dielectric performance open up exciting possibilities to integrate a‐BN films in next‐generation 2D nanoelectronic material constructs.
Alzheimer's disease (AD) represents a pressing global health challenge, with an anticipated surge in diagnoses over the next two decades. This progressive neurodegenerative disorder unfolds ...gradually, with observable symptoms emerging after two decades of imperceptible brain changes. While traditional therapeutic approaches, such as medication and cognitive therapy, remain standard in AD management, their limitations prompt exploration into novel integrative therapeutic approaches. Recent advancements in AD research focus on entraining gamma waves through innovative methods, such as light flickering and electromagnetic fields (EMF) stimulation. Flickering light stimulation (FLS) at 40 Hz has demonstrated significant reductions in AD pathologies in both mice and humans, providing improved cognitive functioning. Additionally, recent experiments have demonstrated that APOE mutations in mouse models substantially reduce tau pathologies, with microglial modulation playing a crucial role. EMFs have also been demonstrated to modulate microglia. The exploration of EMFs as a therapeutic approach is gaining significance, as many recent studies have showcased their potential to influence microglial responses. Th article concludes by speculating on the future directions of AD research, emphasizing the importance of ongoing efforts in understanding the complexities of AD pathogenesis through a holistic approach and developing interventions that hold promise for improved patient outcomes.
Acetylcholine in the neocortex is critical for executive function 1–3. Degeneration of cholinergic neurons in aging and Alzheimer’s dementia is commonly treated with cholinesterase inhibitors 4–7; ...however, these are modestly effective and are associated with side effects that preclude effective dosing in many patients 8. Electrical activation of the nucleus basalis (NB) of Meynert, the source of neocortical acetylcholine 9, 10, provides a potential method of improving cholinergic activation 11, 12. Here we tested whether NB stimulation would improve performance of a working memory task in a nonhuman primate model. Unexpectedly, intermittent stimulation proved to be most beneficial (60 pulses per second, for 20 s every minute), whereas continuous stimulation often impaired performance. Pharmacological experiments confirmed that the effects depended on cholinergic activation. Donepezil, a cholinesterase inhibitor, restored performance in animals impaired by continuous stimulation but did not improve performance further during intermittent stimulation. Intermittent stimulation was rendered ineffective by either nicotinic or muscarinic receptor antagonists. In the months after stimulation began, performance also improved in sessions without stimulation. Our results reveal that intermittent NB stimulation can improve working memory, a finding that has implications for restoring cognitive function in aging and Alzheimer’s dementia.
•Intermittent stimulation of nucleus basalis (NB) improves working memory performance•Continuous NB stimulation degrades performance in young adult monkeys•Donepezil provided no greater improvement than intermittent stimulation•Effects were blocked by nicotinic and muscarinic receptor antagonists
Liu et al. show that an intermittent train of electrical stimulation in the nucleus basalis improves working memory in adult monkeys. The improvement depends on cholinergic receptors. The finding reveals a new mechanism to improve cognitive performance in conditions that compromise cholinergic action, including aging and Alzheimer’s disease.
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