Therapeutic radiation has conflicting immune effects: radiation therapy (RT)-induced immunogenic cell death can contribute to immune response, but lymphocytes are also sensitive to RT. It is unknown ...whether palliative RT leads to lymphopenia in patients treated with immune checkpoint inhibitors (ICIs) and whether this affects outcomes. As such, we sought to assess the impact of palliative RT on circulating lymphocyte count and neutrophil-to-lymphocyte ratio in patients being treated with PD-1-directed ICI and associations with survival.
We identified patients from 5 radiation oncology centers, treated with palliative RT and either pembrolizumab or nivolumab with non-small cell lung cancer, metastatic melanoma, and renal cell carcinoma. Patients who received intervening cytotoxic chemotherapy were excluded. We recorded absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio before and after palliative RT and at the start of ICI. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models.
One hundred ten patients received 225 courses of palliative RT. Median change in ALC after RT was -161 cells/mL. Decreases in ALC were greater with RT to the spine, lung/mediastinum, and chest wall compared with the brain, extremity, or abdomen/pelvis (P = .002) and after courses >5 fractions (P = .003). Extracranial and >5-fraction RT was associated with increased odds of severe lymphopenia (ALC <500) at the end of RT (odds ratio OR, 3.7; P = .001; and OR, 3.9; P = .001, respectively). Patients who developed RT-induced severe lymphopenia were more likely to have severe lymphopenia when ICI was initiated (OR, 6.4; P = .0001), particularly when RT was administered in the previous 3 months (OR, 189; P < .0001). Severe lymphopenia at onset of ICI therapy was associated with increased mortality on multivariable analysis (hazard ratio, 2.1; P = .03).
Extracranial or prolonged courses of RT increase the risk of severe lymphopenia, which is associated with poorer survival in patients treated with ICI.
This article discusses current concepts of the role of sleep in cellular energy metabolism, the processes of neuroplasticity, and cleansing of the cerebral parenchyma from metabolic products. ...Numerous studies have demonstrated that prolonged waking poses a challenge to the brain, both energetically and physiologically. This article outlines the kinetics of the biochemical processes responsible for replenishing energy reserves during sleep. The roles of ATP, adenosine, and glycogen in these processes are noted. Depletion of the substrates of cellular energy metabolism leads to stress on the endoplasmic reticulum and protein-unfolding reactions. These changes are paralleled by increases in synaptic conductivity, which aggravates energy disorders because increases in the size and number of synapses imply increases in energy costs. The level of glymphatic clearance during waking is significantly lower than that during sleep, and metabolic products cannot be eliminated at the necessary rate.
Transformations of the low-energy vibrational spectra are associated with structural changes in an analyte and closely related to the instability of weak chemical bounds. Terahertz (THz)/far-infrared ...optical spectroscopy is commonly used to probe such transformation, aimed at characterization of the underlying solid-phase chemical reactions in organic compounds. However, such studies usually provide quite qualitative information about the temperature- and time-dependent parameters of absorption peaks in dielectric spectra of an analyte. In this paper, an approach for quantitative analyses of the solid-phased chemical reactions based on the THz pulsed spectroscopy was developed. It involves studying an evolution of the sample optical properties, as a function of the analyte temperature and reaction time, and relies on the classical oscillator model, the sum rule, and the Arrhenius theory. The method allows one to determine the temperature-dependent reaction rate V
(T) and activation energy E
. To demonstrate the practical utility of this method, it was applied to study α-lactose monohydrate during its temperature-induced molecular decomposition. Analysis of the measured THz spectra revealed the increase of the reaction rate in the range of V
≃ ~9 × 10
-10
min
, when the analyte temperature rises from 313 to 393 K, while the Arrhenius activation energy is E
≃ ~45.4 kJ/mol. Thanks to a large number of obtained physical and chemical parameters, the developed approach expands capabilities of THz spectroscopy in chemical physics, analytical chemistry, and pharmaceutical industry.
Abstract
In this work, we compared the samples obtained by additive technologies. Samples for the study were printed on two different printers using similar DMLS and DMLM technologies. Printing was ...carried out according to the CAD model data. The printing was performed using the manufacturer’s recommended print settings. For printing, we used powders recommended by the manufacturer for these printer models. In the course of the work, the structure and roughness parameters in the initial state were compared. The heat treatment mode was selected. The effect of vacuum annealing on the structure as well as mechanical properties such as uniaxial tension, KCU and fatigue strength was investigated. Based on the results of the work, a conclusion was made about the improvement of 3D printing, as a result of which the products obtained using additive technologies after heat treatment are not inferior in properties to products obtained using industrial technology from a similar alloy.
Objectives.
To establish the relationship between the extent of white matter lesions and the degree of reductions in cognitive functions with periodic limb movements (PLM) in patients with cerebral ...microangiopathy (CMA).
Materials and methods.
A total of 34 patients with established diagnoses of CMA (12 men, 22 women, mean age 66.9 years) were studied. The investigation protocol included nocturnal actigraphy and cardiorespiratory monitoring of nocturnal sleep, neuropsychological testing, and assessment of neuroimaging markers of CMA using brain MRI scan data. Depending on the PLM index, study (PLM index ≥15 episodes/h) and control (PLM index <15 episodes/h) groups were formed.
Results and conclusions.
Statistically signifi cant differences were found between the study and control groups in performance levels on neuropsychological tests involving regulatory functions (
p
= 0.0025 for the Frontal Assessment Battery,
p
= 0.036 for the Trail Making Test part B (TMT-B),
p
= 0.009 for the Digit Symbol Substitution Test), and in the volume of juxtacortical white matter lesions (
p
= 0.009). Positive correlations were found between the main features of PLM and the total volume and the volume of the periventricular hypertensive white matter and negative correlations with the results of neuropsychological tests, especially for regulatory functions.
A continuously-tunable terahertz (THz) bandpass filter based on the resonant electromagnetic-wave transmission through a metal-hole array featuring a gradually changing period was developed and ...fabricated on a silicon substrate using optical lithography. A gradient geometry of the metal-hole array yields a wide tunability of the filter transmission, when operating with a focussed THz beam. The filter was studied numerically, using the finite element method, and experimentally, using the THz pulsed spectroscopy. We find that the central wavelength of the filter transmission band can be tuned in the wide range of λ c = 400–800 μ m with the relative bandwidth of Δ λ / λ c ≃ ~0.4. Finally, Kapton-based anti-reflection coating was applied to the filter flat side, in order to suppress an interference pattern in the filter transmission spectrum. We believe that the developed filter holds strong potential for multispectral THz imaging and sensing due to its conceptual simplicity and case of operation. Moreover, the presented filter concept can be translated to other spectral ranges, where appropriate technologies are available for the fabrication of gradient sub-wavelength metal-hole arrays.
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Messenger RNA (mRNA) has recently emerged as a promising class of nucleic acid therapy, with the potential to induce protein production to treat and prevent a range of diseases. ...However, the widespread use of mRNA as a therapeutic requires safe and effective in vivo delivery technologies. Libraries of ionizable lipid nanoparticles (LNPs) have been designed to encapsulate mRNA, prevent its degradation, and mediate intracellular delivery. However, these LNPs are typically characterized and screened in an in vitro setting, which may not fully replicate the biological barriers that they encounter in vivo. Here, we designed and evaluated a library of engineered LNPs containing barcoded mRNA (b-mRNA) to accelerate the screening of mRNA delivery platforms in vivo. These b-mRNA are similar in structure and function to regular mRNA, and contain barcodes that enable their delivery to be quantified via deep sequencing. Using a mini-library of b-mRNA LNPs formulated via microfluidic mixing, we show that these different formulations can be pooled together, administered intravenously into mice as a single pool, and their delivery to multiple organs (liver, spleen, brain, lung, heart, kidney, pancreas, and muscle) can be quantified simultaneously using deep sequencing. In the context of liver and spleen delivery, LNPs that exhibited high b-mRNA delivery also yielded high luciferase expression, indicating that this platform can identify lead LNP candidates as well as optimal formulation parameters for in vivo mRNA delivery. Interestingly, LNPs with identical formulation parameters that encapsulated different types of nucleic acid barcodes (b-mRNA versus a DNA barcode) altered in vivo delivery, suggesting that the structure of the barcoded nucleic acid affects LNP in vivo delivery. This platform, which enables direct barcoding and subsequent quantification of a functional mRNA, can accelerate the in vivo screening and design of LNPs for mRNA therapeutic applications such as CRISPR-Cas9 gene editing, mRNA vaccination, and other mRNA-based regenerative medicine and protein replacement therapies.
Background:
Cerebrovascular diseases are the leading cause of cognitive decline and dementia. Therefore, the investigation of the potential ways to slow down the disease progression is an important ...research field. Periodic limb movements in sleep (PLMS) are known to be associated with transient changes in heart rate and blood pressure. These changes might influence the course of cerebral small vessel disease (cSVD). Nevertheless, the clinical significance of PLMS, particularly its influence on cardiovascular diseases course, is still controversial and underinvestigated.
Methods/design:
Patients from 60 to 75 years old diagnosed with cSVD will undergo nocturnal polysomnography. Subjects with apnea/hypopnea index under 5 will be enrolled. Sleep quality and daytime functioning will be assessed at baseline with self-reported questionnaires. Brain MRI and cognitive assessment will be performed at baseline and in the 2-year follow-up. Progression of cSVD markers and cognitive dysfunction will be compared between patients with PLMS index (PLMI) equal to or more than 15 movements per hour of sleep and controls (PLMI <15/h).
Discussion:
The negative role of PLMS in cSVD progression and related cognitive decline is expected. We suppose that patients with PLMS tend to worsen in cognitive performance more rapidly than age-, gender-, and comorbidity-matched controls. We also expect them to have more rapid white matter hyperintensities and other cSVD marker progression. The limitations of the study protocol are the short follow-up period, the absence of a treatment group, and inability to make a conclusion about causality.
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