Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent ...cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.
Abstract
Objectives
Vitamin D deficiency was previously correlated with incidence and severity of coronavirus disease 2019 (COVID-19). We investigated the association between serum 25-hydroxyvitamin ...D (25(OH)D) level on admission and radiologic stage and outcome of COVID-19 pneumonia.
Methods
A retrospective observational trial was done on 186 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected individuals hospitalized from March 1, 2020, to April 7, 2020, with combined chest computed tomography (CT) and 25(OH)D measurement on admission. Multivariate regression analysis was performed to study if vitamin D deficiency (25(OH)D <20 ng/mL) correlates with survival independently of confounding comorbidities.
Results
Of the patients with COVID-19, 59% were vitamin D deficient on admission: 47% of females and 67% of males. In particular, male patients with COVID-19 showed progressively lower 25(OH)D with advancing radiologic stage, with deficiency rates increasing from 55% in stage 1 to 74% in stage 3. Vitamin D deficiency on admission was not confounded by age, ethnicity, chronic lung disease, coronary artery disease/hypertension, or diabetes and was associated with mortality (odds ratio OR, 3.87; 95% confidence interval CI, 1.30-11.55), independent of age (OR, 1.09; 95% CI, 1.03-1.14), chronic lung disease (OR, 3.61; 95% CI, 1.18-11.09), and extent of lung damage expressed by chest CT severity score (OR, 1.12; 95% CI, 1.01-1.25).
Conclusions
Low 25(OH)D levels on admission are associated with COVID-19 disease stage and mortality.
Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, ...such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop.
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Formulating poorly water soluble drugs using ordered mesoporous silica materials is an emerging approach to tackle solubility-related bioavailability problems. The current study was ...conducted to assess the bioavailability-enhancing potential of ordered mesoporous silica in man. In this open-label, randomized, two-way cross-over study, 12 overnight fasted healthy volunteers received a single dose of fenofibrate formulated with ordered mesoporous silica or a marketed product based on micronized fenofibrate. Plasma concentrations of fenofibric acid, the pharmacologically active metabolite of fenofibrate, were monitored up to 96h post-dose. The rate (Cmax/dose increased by 77%; tmax reduced by 0.75h) and extent of absorption (AUC0–24h/dose increased by 54%) of fenofibrate were significantly enhanced following administration of the ordered mesoporous silica based formulation. The results of this study serve as a proof of concept in man for this novel formulation approach.
Impairments in motor automaticity cause patients with Parkinson's disease to rely on attentional resources during gait, resulting in greater motor variability and a higher risk of falls. Although ...dopaminergic circuitry is known to play an important role in motor automaticity, little evidence exists on the neural mechanisms underlying the breakdown of locomotor automaticity in Parkinson's disease. This impedes clinical management and is in great part due to mobility restrictions that accompany the neuroimaging of gait. This study therefore utilized a virtual reality gait paradigm in conjunction with functional MRI to investigate the role of dopaminergic medication on lower limb motor automaticity in 23 patients with Parkinson's disease that were measured both on and off dopaminergic medication. Participants either operated foot pedals to navigate a corridor (‘walk’ condition) or watched the screen while a researcher operated the paradigm from outside the scanner (‘watch’ condition), a setting that controlled for the non-motor aspects of the task. Step time variability during walk was used as a surrogate measure for motor automaticity (where higher variability equates to reduced automaticity), and patients demonstrated a predicted increase in step time variability during the dopaminergic “off” state. During the “off” state, subjects showed an increased blood oxygen level-dependent response in the bilateral orbitofrontal cortices (walk>watch). To estimate step time variability, a parametric modulator was designed that allowed for the examination of brain regions associated with periods of decreased automaticity. This analysis showed that patients on dopaminergic medication recruited the cerebellum during periods of increasing variability, whereas patients off medication instead relied upon cortical regions implicated in cognitive control. Finally, a task-based functional connectivity analysis was conducted to examine the manner in which dopamine modulates large-scale network interactions during gait. A main effect of medication was found for functional connectivity within an attentional motor network and a significant condition by medication interaction for functional connectivity was found within the striatum. Furthermore, functional connectivity within the striatum correlated strongly with increasing step time variability during walk in the off state (r=0.616, p=0.002), but not in the on state (r=−0.233, p=0.284). Post-hoc analyses revealed that functional connectivity in the dopamine depleted state within an orbitofrontal-striatal limbic circuit was correlated with worse step time variability (r=0.653, p<0.001). Overall, this study demonstrates that dopamine ameliorates gait automaticity in Parkinson's disease by altering striatal, limbic and cerebellar processing, thereby informing future therapeutic avenues for gait and falls prevention.
•Parkinson's disease patients performed a virtual reality gait task during fMRI.•The role of dopamine on gait automaticity impairments was investigated.•Limbic interference and poor striatal and cerebellar processing impair automaticity.•Dopamine ameliorates gait automaticity impairments in Parkinson's disease.
Controlling chimeras Bick, Christian; Martens, Erik A
New journal of physics,
03/2015, Letnik:
17, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Coupled phase oscillators model a variety of dynamical phenomena in nature and technological applications. Non-local coupling gives rise to chimera states which are characterized by a distinct part ...of phase-synchronized oscillators while the remaining ones move incoherently. Here, we apply the idea of control to chimera states: using gradient dynamics to exploit drift of a chimera, it will attain any desired target position. Through control, chimera states become functionally relevant; for example, the controlled position of localized synchrony may encode information and perform computations. Since functional aspects are crucial in (neuro-)biology and technology, the localized synchronization of a chimera state becomes accessible to develop novel applications. Based on gradient dynamics, our control strategy applies to any suitable observable and can be generalized to arbitrary dimensions. Thus, the applicability of chimera control goes beyond chimera states in non-locally coupled systems.
Gait is a large component and indicator of health. Many factors affect gait including age, disease, and even mood disorders. Few studies have looked at the influence of emotional states on gait. This ...study aimed to investigate the influence of emotional states on walking performance to understand whether an emotional state may be an important factor to consider when evaluating gait. Thirty-six young adults were recruited (23F, 13M) and performed a neutral baseline condition of walking which included six passes of walking across an 8m walkway (a total of 48m of walking). Participants then completed 6 pseudo-randomized emotional state induction conditions while immersive 360-degree videos were used to induce the following emotional conditions: happiness, excitement, sadness, fear, and anger. Participants viewed the emotion elicitation videos using a virtual reality head-mounted display (HMD), then rated their emotional state using self-assessment manikins and walked (without the HMD) over a pressure sensor walkway. One-way repeated measures ANOVA and pairwise comparisons were used to examine differences in gait parameters across the emotional conditions. Participants walked with significantly reduced step length and speed during the sadness condition compared to the other emotional conditions and the neutral condition. Furthermore, participants adjusted the timing of their walking during the sadness condition and walked with significantly increased step, stance, and swing times compared to other emotional conditions, but not the neutral condition. Step time was significantly reduced during the conditions of excitement and fear compared to the neutral condition. Emotions may impact variety of gait parameters involving pace and rhythm, however have little influence on gait variability and postural control. These results indicate that perhaps the emotions of sadness and excitement should be taken into account as potential confounds for future gait analysis.
The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer’s disease (AD) and several other neurodegenerative conditions, including Lewy body dementia (LBD). The ...three APOE alleles encode protein isoforms that differ from one another only at amino acid positions 112 and 158: apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158). Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways. Here, we propose a novel “ApoE Cascade Hypothesis” in AD and age-related cognitive decline, which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately impacting aging-related pathogenic conditions including AD. As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade.
In this review, Martens et al. propose a novel “ApoE Cascade Hypothesis,” which states that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels, ultimately leading to Alzheimer’s disease and age-related cognitive decline.
Ammonia is an industrial large‐volume chemical, with its main application in fertilizer production. It also attracts increasing attention as a green‐energy vector. Over the past century, ammonia ...production has been dominated by the Haber–Bosch process, in which a mixture of nitrogen and hydrogen gas is converted to ammonia at high temperatures and pressures. Haber–Bosch processes with natural gas as the source of hydrogen are responsible for a significant share of the global CO2 emissions. Processes involving plasma are currently being investigated as an alternative for decentralized ammonia production powered by renewable energy sources. In this work, we present the PNOCRA process (plasma nitrogen oxidation and catalytic reduction to ammonia), combining plasma‐assisted nitrogen oxidation and lean NOx trap technology, adopted from diesel‐engine exhaust gas aftertreatment technology. PNOCRA achieves an energy requirement of 4.6 MJ mol−1 NH3, which is more than four times less than the state‐of‐the‐art plasma‐enabled ammonia synthesis from N2 and H2 with reasonable yield (>1 %).
The PNOCRA (non‐thermal plasma nitrogen oxidation and catalytic reduction to ammonia) process allows decentralized ammonia production from water, air and renewable energy through nitrogen oxidation and subsequent catalytic reduction in a lean NOx trap (LNT). The related energy cost of 4.61 MJ mol−1 NH3 is more than four times less than the current best available technology for plasma‐based ammonia production.
Previous studies demonstrated that circulating microRNA-375 (miR-375) is a suitable plasma biomarker for real-time detection of beta cell death. The present study evaluated the use of this biomarker ...to assess the beta cytoprotective effect of phenylpropenoic acid glucoside (PPAG), which was previously demonstrated to protect beta cells against various types of injury, and of exendin-4, which is an established antidiabetic drug.
PPAG or exendin-4 were administered in mice treated with streptozotocin (STZ) to acutely induce beta cell death. Beta cell mass and apoptotic death were measured in pancreatic tissue sections. Circulating miR-375 was measured in blood plasma by RT-qPCR. The release of miR-375 was also measured in vitro by MIN-6 beta cells.
Administration of STZ resulted in measurable circulating levels of miR-375, a decrease in beta cell mass and increase in frequency of apoptotic beta cells. In vitro, there was a good correlation between miR-375 release and the extent of beta cell death. Treatment of mice with PPAG or exendin-4 significantly attenuated STZ-induced loss of beta cell mass and beta cell apoptosis, and normalized the blood level of miR-375.
These findings show the potential use of serological miR-375 measurements to evaluate the beta cytoprotective effect of (potential) antidiabetic drugs in vivo.
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