Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe ...immune-related (ir) adverse events (AEs). Here, we report the clinical and immune–biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.
Peripheral-immune-checkpoint blockade (P-ICB) with mAbs to PD-1 (nivolumab and pembrolizumab) or PD-L1 (atezolizumab, durvalumab, avelumab) alone or combination with chemotherapy represents a novel ...active treatment for mNSCLC patients. However, this therapy can be associated to immune-related adverse events (irAEs) and high cost. Therefore, finding reliable biomarkers of response and irAEs is strongly encouraged to accurately select patients who may potentially benefit from the immuno-oncological treatment. This is a retrospective multi-institutional analysis performed on ninety-five mNSCLC patients who received real-world salvage therapy with nivolumab or atezolizumab between December 2015 and April 2020. The outcome of these patients in term of PFS and OS was evaluated in comparison with different serum levels of C-reactive protein (CRP), Erythrocyte Sedimention Rate (ESR) and Procalcitonin (PCT) by performing Kaplan–Meier and Log-rank test and multivariate analysis. We found that high baseline levels of CRP, ESR, and PCT were strongly predictive of poor outcome (P <0.05) with the worse prognosis detected in those patients with a baseline levels of both ESR and PCT over the pre-established cut off (median OS recorded in patients with no marker over the cut off
vs
. those with just one marker over the cut off
vs
. those with both markers over the cut off: 40 ± 59
vs
. 15.5 ± 5.5
vs
. 5.5 ± 1.6 months, respectively; P <0.0001). Our results suggest the predictive value of systemic inflammation and suggest a potential role of PCT in predicting a poor outcome in mNSCLC receiving PD-1/PD-L1 blocking mAbs. This finding also suggests a potential role of subclinical bacterial infections in defining the response to PD-1/PD-L1 blocking mAbs that deserves further and more specific investigations.
We developed and investigated a particular geometry of transducers, emulating the shape of bats' cochlea, to transmit and receive ultrasounds in the air. Their design involved the use of ...polyvinylidene fluoride (PVDF) as a piezoelectric material, thanks to its excellent conformability and flexibility. This material offers the primary requirements for sensing devices in applications such as sonar system or energy harvesting technology
The piezo film was folded according to both the Archimedean and Fibonacci spirals, and their performances were investigated in the frequency range from 20 kHz up to more than 80 kHz. The finite element analysis (FEA) of the proposed transducers highlighted the presence of multiple resonance vibrations, proved by the experimental measurements of the equivalent electric impedance and frequency response. Far-field radiation patterns demonstrated, horizontally and vertically
omnidirectional properties both as transmitters and receivers. All was enough to establish the best validity of the spiral shaped transducers for applications based on the bio sonar principle.
Missing value issue is often encountered in international Neuroscience and Neuroimaging databases. As many statistical methods and Machine Learning (ML) algorithms are not designed to work with ...missing data, usually all variables associated with these records are removed, losing information and negatively affecting performance of neurodegenerative diseases classification such as Dementia. A reliable alternative is to employ imputation to substitute missing values, for example with the mean (I mean ), which is widely applied. Recently, missForest (MF), a Random Forest based algorithm - became popular for handling missing data in biomedical research. Thus, we aimed at assessing the reliability of MF in solving the missingness problem in a cohort of Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD) patients from international database Alzheimer's Disease Neuroimaging Initiative (ADNI), with clinical, cognitive and neuroimaging features. First, we amputed the complete dataset with increasing percentage of missing data (from 10% to 80 % ) by applying Missing Completely At Random (MCAR). Then, we used I mean and MF approaches on amputed datasets and we compared their imputation error (RSME, NRSME, MAE). When average error on all features was considered, MF showed better performance than I mean in each amputation percentage. However, when comparing error on single features, MF had slight performance decrease compared with I mean on cognitive features ADAS, RAVLT and MMSE, regardless of the amputation percentage. We conclude that missForest resulted to be a reliable imputation algorithm for handling missing neuroscience data, although it should be used with caution on highly skewed variables, such as cognitive scores.
Tumor-infiltrating T cell rescue by programmed cell death receptor-1 (PD-1)/PD-1 ligand-1 (PD-L1) immune checkpoint blockade is a recommended treatment for malignant diseases, including metastatic ...non-small-cell lung cancer (mNSCLC), malignant melanoma (MM), head and neck, kidney, and urothelial cancer. Monoclonal antibodies (mAbs) against either PD-1 or PD-L1 are active agents for these patients; however, their use may be complicated by unpredictable immune-related adverse events (irAEs), including immune-related pneumonitis (IRP). We carried out a retrospective multi-institutional statistical analysis to investigate clinical and biological parameters correlated with IRP rate on a cohort of 256 patients who received real-world treatment with PD-1/PD-L1 blocking mAbs. An independent radiological review board detected IRP in 29 patients. We did not find statistical IRP rate correlation with gender, tumor type, specific PD-1 or PD-L1 blocking mAbs, radiation therapy, inflammatory profile, or different irAEs. A higher IRP risk was detected only in mNSCLC patients who received metronomic chemotherapy +/- bevacizumab compared with other treatments prior PD-1/PD-L1 blockade. Moreover, we detected a strong correlation among the IRP rate and germinal expression of HLA-B*35 and DRB1*11, alleles associated to autoimmune diseases. Our findings may have relevant implications in predicting the IRP rate in mNSCLC patients receiving PD-1/PD-L1 blockade and need to be validated on a larger patient series.
Peripheral immune-checkpoint blockade with mAbs to programmed cell death receptor-1 (PD-1) (either nivolumab or pembrolizumab) or PD-Ligand-1 (PD-L1) (atezolizumab, durvalumab, or avelumab) alone or ...in combination with doublet chemotherapy represents an expanding treatment strategy for metastatic non-small cell lung cancer (mNSCLC) patients. This strategy lays on the capability of these mAbs to rescue tumor-specific cytotoxic T lymphocytes (CTLs) inactivated throughout PD-1 binding to PD-L1/2 in the tumor sites. This inhibitory interactive pathway is a physiological mechanism of prevention against dangerous overreactions and autoimmunity in case of prolonged and/or repeated CTL response to the same antigen peptides. Therefore, we have carried out a retrospective bioinformatics analysis by single-cell flow cytometry to evaluate if PD-1/PD-L1-blocking mAbs modulate the expression of specific peripheral immune cell subsets, potentially correlated with autoimmunity triggering in 28 mNSCLC patients. We recorded a treatment-related decline in CD4
+
T-cell and B-cell subsets and in the neutrophil-to-lymphocyte ratio coupled with an increase in natural killer T (NKT), CD8
+
PD1
+
T cells, and eosinophils. Treatment-related increase in autoantibodies mainly antinuclear antibodies (ANAs) and extractable nuclear antigen (ENA) antibodies as well as the frequency of immune-related adverse events were associated with the deregulation of specific immune subpopulations (e.g., NKT cells). Correlative biological/clinical studies with deep immune monitoring are badly needed for a better characterization of the effects produced by PD-1/PD-L1 immune-checkpoint blockade.
The development of even more compact, inexpensive, and highly sensitive gas sensors is widespread, even though their performances are still limited and technological improvements are in continuous ...evolution. Zeolite is a class of material which has received particular attention in different applications due to its interesting adsorption/desorption capabilities. The behavior of a zeolite 4A modified capacitor has been investigated for the adsorption of nitrogen (N
), nitric oxide (NO) and 1,1-Difluoroethane (C
H
F
), which are of interest in the field of chemical, biological, radiological, and nuclear threats. Sample measurements were carried out in different environmental conditions, and the variation of the sensor electric capacitance was investigated. The dielectric properties were influenced by the type and concentration of gas species in the environment. Higher changes in capacitance were shown during the adsorption of dry air (+4.2%) and fluorinated gas (+7.3%), while lower dielectric variations were found upon exposure to N
(-0.4%) and NO (-0.5%). The proposed approach pointed-out that a simple fabrication process may provide a convenient and affordable fabrication of reusable capacitive gas sensor.
Low frequency ultrasounds in air are widely used for real-time applications in short-range communication systems and environmental monitoring, in both structured and unstructured environments. One of ...the parameters widely evaluated in pulse-echo ultrasonic measurements is the time of flight (TOF), which can be evaluated with an increased accuracy and complexity by using different techniques. Hereafter, a nonstandard cross-correlation method is investigated for TOF estimations. The procedure, based on the use of template signals, was implemented to improve the accuracy of recursive TOF evaluations. Tests have been carried out through a couple of 60 kHz custom-designed polyvinylidene fluoride (PVDF) hemicylindrical ultrasonic transducers. The experimental results were then compared with the standard threshold and cross-correlation techniques for method validation and characterization. An average improvement of 30% and 19%, in terms of standard error (SE), was observed. Moreover, the experimental results evidenced an enhancement in repeatability of about 10% in the use of a recursive positioning system.
Introduction
The functional connectivity patterns in the brain are highly heritable; however, it is unclear how genetic factors influence the directionality of such “information flows.” Studying the ...“directionality” of the brain functional connectivity and assessing how heritability modulates it can improve our understanding of the human connectome.
Methods
Here, we investigated the heritability of “directed” functional connections using a state‐space formulation of Granger causality (GC), in conjunction with blind deconvolution methods accounting for local variability in the hemodynamic response function. Such GC implementation is ideal to explore the directionality of functional interactions across a large number of networks. Resting‐state functional magnetic resonance imaging data were drawn from the Human Connectome Project (total n = 898 participants). To add robustness to our findings, the dataset was randomly split into a “discovery” and a “replication” sample (each with n = 449 participants). The two cohorts were carefully matched in terms of demographic variables and other confounding factors (e.g., education). The effect of shared environment was also modeled.
Results
The parieto‐ and prefronto‐cerebellar, parieto‐prefrontal, and posterior‐cingulate to hippocampus connections showed the highest and most replicable heritability effects with little influence by shared environment. In contrast, shared environmental factors significantly affected the visuo‐parietal and sensory‐motor directed connectivity.
Conclusion
We suggest a robust role of heritability in influencing the directed connectivity of some cortico‐subcortical circuits implicated in cognition. Further studies, for example using task‐based fMRI and GC, are warranted to confirm the asymmetric effects of genetic factors on the functional connectivity within cognitive networks and their role in supporting executive functions and learning.
We investigated the heritability of ‘directed’ functional connections using a state‐space formulation of Granger causality on resting‐state functional magnetic resonance imaging data from the Human Connectome Project. The parieto‐cerebellar, parieto‐prefrontal, and posterior‐cingulate to hippocampus connections showed the highest and most replicable heritability effects with little influence by the shared environment. In contrast, shared environmental factors significantly affected the visuo‐parietal and sensory‐motor directed connectivity.
We suggest a robust role of heritability in influencing the function of some cortico‐subcortical circuits consistently implicated in cognition.
•Both PSP and PD patients show corpus callosum (CC) involvement.•The CC damage is more severe and widespread in PSP than in PD patients.•Unsteady PD patients had CC genu microstructural alterations ...compared to steady ones.•The mean diffusivity (MD) was the CC genu metric most associated with instability.
Postural instability (PI) is a common disabling symptom in Parkinson’s disease (PD) patients, but the brain alterations underlying this sign are not fully understood yet. This study aimed to investigate the association between PI and callosal damage in PD and progressive supranuclear palsy (PSP) patients, using multimodal MR imaging.
One-hundred and two PD patients stratified according to the presence/absence of PI (PD-steady N=58; PD-unsteady N=44), 69 PSP patients, and 38 healthy controls (HC) underwent structural and diffusion 3T brain MRI. Thickness, fractional anisotropy (FA) and mean diffusivity (MD) were calculated over 50 equidistant points covering the whole midsagittal profile of the corpus callosum (CC) and compared among groups. Associations between imaging metrics and postural instability score were investigated using linear regression.
Both PSP and PD-unsteady patient groups showed CC involvement in comparison with HC, while no difference was found between PD-steady patients and controls. The CC damage was more severe and widespread in PSP than in PD patients. The CC genu was the regions most damaged in PD-unsteady patients compared with PD-steady patients, showing significant microstructural alterations of MD and FA metrics. Linear regression analysis pointed at the MD in the CC genu as the main contributor to PI among the considered MRI metrics.
This study identified callosal microstructural alterations associated with PI in unsteady PD and PSP patients, which provide new insights on PI pathophysiology and might serve as imaging biomarkers for assessing postural instability progression and treatment response.
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