Cancer cell sedimentation in 3D cultures reveals active migration regulated by self-generated gradients and adhesion sites.

Cell sedimentation in 3D hydrogel cultures refers to the vertical migration of cells towards the bottom of the space. Understanding this poorly examined phenomenon may allow us to design better protocols to prevent it, as well as provide insights into the mechanobiology of cancer development. We conducted a multiscale experimental and mathematical examination of 3D cancer growth in triple negative breast cancer cells. Migration was examined in the presence and absence of Paclitaxel, in high and low adhesion environments and in the presence of fibroblasts. The observed behaviour was modeled by hypothesizing active migration due to self-generated chemotactic gradients. Our results did not reject this hypothesis, whereby migration was likely to be regulated by the MAPK and TGF-ß pathways. The mathematical model enabled us to describe the experimental data in absence (normalized error<40%) and presence of Paclitaxel (normalized error<10%), suggesting inhibition of random motion and advection in the latter case. Inhibition of sedimentation in low adhesion and co-culture experiments further supported the conclusion that cells actively migrated downwards due to the presence of signals produced by cells already attached to the adhesive glass surface.

Real-Time Abnormal Event Detection for Enhanced Security in Autonomous Shuttles Mobility Infrastructures.

Autonomous vehicles (AVs) are already operating on the streets of many countries around the globe. Contemporary concerns about AVs do not relate to the implementation of fundamental technologies, as they are already in use, but are rather increasingly centered on the way that such technologies will affect emerging transportation systems, our social environment, and the people living inside it. Many concerns also focus on whether such systems should be fully automated or still be partially controlled by humans. This work aims to address the new reality that is formed in autonomous shuttles mobility infrastructures as a result of the absence of the bus driver and the increased threat from terrorism in European cities. Typically, drivers are trained to handle incidents of passengers' abnormal behavior, incidents of petty crimes, and other abnormal events, according to standard procedures adopted by the transport operator. Surveillance using camera sensors as well as smart software in the bus will maximize the feeling and the actual level of security. In this paper, an online, end-to-end solution is introduced based on deep learning techniques for the timely, accurate, robust, and automatic detection of various petty crime types. The proposed system can identify abnormal passenger behavior such as vandalism and accidents but can also enhance passenger security via petty crimes detection such as aggression, bag-snatching, and vandalism. The solution achieves excellent results across different use cases and environmental conditions.

Clinical, neuroimaging and histopathological features of gliomatosis cerebri: a systematic review based on synthesis of published individual patient data.

INTRODUCTION: Gliomatosis cerebri (GC) is a rare fatal widespread infiltrating CNS tumor. As consistent disease features have not been established, the tumor comprises a diagnostic challenge. METHODS: We conducted a systematic literature search for published case reports and case series on patients with histologically confirmed GC. Clinical, diagnostic, neuroimaging, histopathological, and molecular data on individual or summary patient level were extracted and analyzed. RESULTS: A total of 274 studies were identified, including 866 patients with individual-level data and 782 patients with summary data (58.9% males, mean age 43.6 years). Seizures (49.8%) were the most common presenting symptom followed by headache (35.9%), cognitive decline (32.2%), and focal motor deficits (32%). Imaging studies showed bilateral hemisphere involvement in 65%, infratentorial infiltration in 29.9% and a focal contrast-enhanced mass (type II GC) in 31.1% of cases. MRI (extensive hyperintensities in T2/FLAIR sequences) and MR spectroscopy (elevated choline, creatinine, and myoinositol levels; decreased NAA levels) showed highly consistent findings across GC patients. Low-grade and anaplastic astrocytoma were the most prevalent diagnostic categories, albeit features of any histology (astrocytic, oligodendroglial, oligoastrocytic) and grade (II-IV) were also reported. Among molecular aberrations, IDH1 mutation and MGMT promoter methylation were the most commonly reported. Increasing time elapsed from symptom onset to diagnosis comprised the only independent determinant of the extent of CNS infiltration. CONCLUSION: A distinct clinical, neuroimaging, histopathological, or molecular GC phenotype is not supported by current evidence. MRI and MR spectroscopy are important tools for the diagnosis of the tumor before confirmation with biopsy.

Adult-Onset Foveomacular Vitelliform Dystrophy With Unilateral Presentation: A Case Series.

Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a rare condition affecting the macula that presents diagnostic and management challenges due to its varied manifestations and clinical overlap with other retinal disorders. As vitelliform lesions can occur in various conditions, such as Best disease and age-related macular degeneration, clinical presentation, multimodal imaging findings, and genetic testing can aid in accurate diagnosis. Although AOFVD typically affects both eyes, unilateral involvement can occur. This study presents four cases of unilateral AOFVD in female patients aged 43 to 66 years. Each patient was monitored for two years with fundoscopy and multimodal imaging, including color fundus photography, optical coherence tomography (OCT), OCT-angiography, fluorescein angiography, and fundus autofluorescence (FAF). All patients presented with a characterized solitary, subfoveal, yellow lesion on fundoscopy. FAF revealed intense hyperautofluorescence corresponding with the lesions. OCT revealed the accumulation of homogenous hyperreflective material between the retinal pigment epithelium and photoreceptors. No abnormal findings were observed in the fellow eyes. Subfoveal choroidal thickness was measured at 355 µm, 545 µm, 486 µm, and 669 µm in the affected eyes. While AOFVD typically manifests bilaterally, these cases demonstrate a unique unilateral presentation, highlighting the importance of comprehensive examination and differential diagnosis. Distinguishing cases with unilateral presentation from other conditions can be more challenging, so awareness of this unusual phenotype and its clinical characteristics must be raised. Choroidal thickness measurements provide additional insights into AOFVD pathophysiology, suggesting a potential association with the pachychoroid spectrum.

Quantifying the Morphology and Mechanisms of Cancer Progression in 3D In-Vitro Environments: Integrating Experiments and Multiscale Models.

Mathematical models of cancer growth have become increasingly more accurate both in the space and time domains. However, the limited amount of data typically available has resulted in a larger number of qualitative rather than quantitative studies. In the present study, we provide an integrated experimental-computational framework for the quantification of the morphological characteristics and the mechanistic modelling of cancer progression in 3D environments. The proposed framework allows for the calibration of multiscale, spatiotemporal models of cancer growth using state-of-the-art 3D cell culture data, and their validation based on the resulting experimental morphological patterns using spatial point-pattern analysis techniques. We applied this framework to the study of the development of Triple Negative Breast Cancer cells cultured in Matrigel scaffolds, and validated the hypothesis of chemotactic migration using a multiscale, hybrid Keller-Segel model. The results revealed transient, non-random spatial distributions of cancer cells that consist of clustered, and dispersion patterns. The proposed model was able to describe the general characteristics of the experimental observations and suggests that chemotactic migration together with random motion was found to be a plausible mechanism leading to accumulation, during the examined time period of development. The developed framework enabled us to pursue two goals; first, the quantitative description of the morphology of cancer growth in 3D cultures using point-pattern analysis, and second, the relation of tumour morphology with underlying biophysical mechanisms that govern cancer growth and migration.

Detection and Spatiotemporal Analysis of In-vitro 3D Migratory Triple-Negative Breast Cancer Cells.

The invasion of cancer cells into the surrounding tissues is one of the hallmarks of cancer. However, a precise quantitative understanding of the spatiotemporal patterns of cancer cell migration and invasion still remains elusive. A promising approach to investigate these patterns are 3D cell cultures, which provide more realistic models of cancer growth compared to conventional 2D monolayers. Quantifying the spatial distribution of cells in these 3D cultures yields great promise for understanding the spatiotemporal progression of cancer. In the present study, we present an image processing and segmentation pipeline for the detection of 3D GFP-fluorescent triple-negative breast cancer cell nuclei, and we perform quantitative analysis of the formed spatial patterns and their temporal evolution. The performance of the proposed pipeline was evaluated using experimental 3D cell culture data, and was found to be comparable to manual segmentation, outperforming four alternative automated methods. The spatiotemporal statistical analysis of the detected distributions of nuclei revealed transient, non-random spatial distributions that consisted of clustered patterns across a wide range of neighbourhood distances, as well as dispersion for larger distances. Overall, the implementation of the proposed framework revealed the spatial organization of cellular nuclei with improved accuracy, providing insights into the 3 dimensional inter-cellular organization and its progression through time.

Treatment of Patients with Multiple Sclerosis Transitioning Between Relapsing and Progressive Disease.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating and neurodegenerative disease of the central nervous system with a wide variety of clinical phenotypes. In spite of the phenotypic classification of MS patients, current data provide evidence that diffuse neuroinflammation and neurodegeneration coexist in all MS forms, the latter gaining increasing clinical relevance in progressive phases. Given that the transition phase of relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS) is not well defined, and widely accepted criteria for SPMS are lacking, randomised controlled trials (RCTs) specifically designed for the transition phase have not been conducted. This review summarizes primary and secondary analyses and reports derived from phase III prospective clinical RCTs listed in PubMed of compounds authorised through the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of MS. The best data are available for interferon beta-1a (IFNb-1a) subcutaneous (s.c.), IFNb-1b s.c., mitoxantrone and siponimod, the latter being the most modern compound with likely the best risk-to-effect ratio. Moreover, there is a labels discrepancy for many disease-modifying treatments (DMTs) between the FDA and EMA, which have to be taken into consideration when opting for a specific DMT.

Bioprinted Multicomponent Hydrogel Co-culture Tumor-Immune Model for Assessing and Simulating Tumor-Infiltrated Lymphocyte Migration and Functional Activation.

The immune response against a tumor is characterized by the interplay among components of the immune system and neoplastic cells. Here, we bioprinted a model with two distinct regions containing gastric cancer patient-derived organoids (PDOs) and tumor-infiltrated lymphocytes (TILs). The initial cellular distribution allows for the longitudinal study of TIL migratory patterns concurrently with multiplexed cytokine analysis. The chemical properties of the bioink were designed to present physical barriers that immune T-cells must breech during infiltration and migration toward a tumor with the use of an alginate, gelatin, and basal membrane mix. TIL activity, degranulation, and regulation of proteolytic activity reveal insights into the time-dependent biochemical dynamics. Regulation of the sFas and sFas-ligand present on PDOs and TILs, respectively, and the perforin and granzyme longitudinal secretion confirms TIL activation when encountering PDO formations. TIL migratory profiles were used to create a deterministic reaction-advection diffusion model. The simulation provides insights that decouple passive from active cell migration mechanisms. The mechanisms used by TILs and other adoptive cell therapeutics as they infiltrate the tumor barrier are poorly understood. This study presents a pre-screening strategy for immune cells where motility and activation across ECM environments are crucial indicators of cellular fitness.

Visually Evoked Potential as Prognostic Biomarker for Neuroaxonal Damage in Multiple Sclerosis From a Multicenter Longitudinal Cohort.

BACKGROUND AND OBJECTIVES: With the increasing use of visually evoked potentials (VEPs) as quantitative outcome parameters for myelin in clinical trials, an in-depth understanding of longitudinal VEP latency changes and their prognostic potential for subsequent neuronal loss will be required. In this longitudinal multicenter study, we evaluated the association and prognostic potential of VEP latency for retinal neurodegeneration, measured by optical coherence tomography (OCT), in relapsing-remitting MS (RRMS). METHODS: We included 293 eyes of 147 patients with RRMS (age [years, median ± SD] 36 ± 10, male sex 35%, F/U [years, median {IQR} 2.1 {1.5-3.9}]): 41 eyes had a history of optic neuritis (ON) ≥6 months before baseline (CHRONIC-ON), and 252 eyes had no history of ON (CHRONIC-NON). P100 latency (VEP), macular combined ganglion cell and inner plexiform layer volume (GCIPL), and peripapillary retinal nerve fiber layer thickness (pRNFL) (OCT) were quantified. RESULTS: P100 latency change over the first year predicted subsequent GCIPL loss (36 months) across the entire chronic cohort (p = 0.001) and in (and driven by) the CHRONIC-NON subset (p = 0.019) but not in the CHRONIC-ON subset (p = 0.680). P100 latency and pRNFL were correlated at baseline (CHRONIC-NON p = 0.004, CHRONIC-ON p < 0.001), but change in P100 latency and pRNFL were not correlated. P100 latency did not differ longitudinally between protocols or centers. DISCUSSION: VEP in non-ON eyes seems to be a promising marker of demyelination in RRMS and of potential prognostic value for subsequent retinal ganglion cell loss. This study also provides evidence that VEP may be a useful and reliable biomarker for multicenter studies.

Case report: First case of neuromelioidosis in Europe: CNS infection caused by Burkholderia pseudomallei.

Neuromelioidosis is a rare CNS infection caused by Burkholderia pseudomallei and is characterized by high morbidity and mortality. Our report presents the diagnostic and therapeutic approach of the first case of neuromelioidosis confirmed in Europe. A 47-year-old man with a medical history of recurrent otitis with otorrhea and fever after tympanoplasty and radical cavity revision operation on the left ear was admitted with headache, decreased level of consciousness, dysarthria, left-sided hemiparesis, and urinary incontinence. After extensive investigations including MRI, microbiological, serological, and CSF analyses, and, ultimately, brain biopsy, a diagnosis of neuromelioidosis was established. Despite antibiotic treatment, the patient showed no clinical improvement and remained in a severely compromised neurological state under mandatory mechanical ventilation. Neuromelioidosis can pose a diagnostic challenge requiring an extensive diagnostic evaluation because of its uncommon clinical and radiological presentations.

DARLENE - Improving situational awareness of European law enforcement agents through a combination of augmented reality and artificial intelligence solutions.

Background: Augmented reality (AR) and artificial intelligence (AI) are highly disruptive technologies that have revolutionised practices in a wide range of domains, including the security sector. Several law enforcement agencies (LEAs) employ AI in their daily operations for forensics and surveillance. AR is also gaining traction in security, particularly with the advent of affordable wearable devices. Equipping police officers with the tools to facilitate an elevated situational awareness (SA) in patrolling and tactical scenarios is expected to improve LEAs' safety and capacity to deliver crucial blows against terrorist and/or criminal threats. Methods: In this paper we present DARLENE, an ecosystem incorporating novel AI techniques for activity recognition and pose estimation tasks, combined with a wearable AR framework for visualization of the inferenced results via dynamic content adaptation according to the wearer's stress level and operational context. The concept has been validated with end-users through co-creation workshops, while the decision-making mechanism for enhancing LEAs' SA has been assessed with experts. Regarding computer vision components, preliminary tests of the instance segmentation method for humans' and objects' detection have been conducted on a subset of videos from the RWF-2000 dataset for violence detection, which have also been used to test a human pose estimation method that has so far exhibited impressive results, constituting the basis of further developments in DARLENE. Results: Evaluation results highlight that target users are positive towards the adoption of the proposed solution in field operations, and that the SA decision-making mechanism produces highly acceptable outcomes. Evaluation of the computer vision components yielded promising results and identified opportunities for improvement. Conclusions: This work provides the context of the DARLENE ecosystem and presents the DARLENE architecture, analyses its individual technologies, and demonstrates preliminary results, which are positive both in terms of technological achievements and user acceptance of the proposed solution.

Gender-affirming hormone treatment and cognitive function in transgender young adults: a systematic review and meta-analysis.

BACKGROUND: Previous studies have examined whether steroid hormone treatment in transgender individuals may affect cognitive function; yet, their limited power does not allow firm conclusions to be drawn. We leveraged data from to-date literature aiming to explore the effect of gender-affirming hormone administration on cognitive function in transgender individuals. METHODS: A search strategy of MEDLINE was developed (through June 1, 2019) using the key terms transgender, hormone therapy and cognitive function. Eligible were (i) cohort studies examining the longitudinal effect of hormone therapy on cognition, and (ii) cross-sectional studies comparing the cognitive function between treated and non-treated individuals. Standardized mean differences (Hedges' g) were pooled using random-effects models. Study quality was evaluated using the Newcastle-Ottawa Scale. OUTCOMES: Ten studies (seven cohort and three cross-sectional) were eligible representing 234 birth-assigned males (aM) and 150 birth-assigned females (aF). The synthesis of cohort studies (n = 5) for visuospatial ability following hormone treatment showed a statistically significant enhancement among aF (g = 0.55, 95% confidence intervals [CI]: 0.29, 0.82) and an improvement with a trend towards statistical significance among aM (g = 0.28, 95%CI: -0.01, 0.58). By contrast, no adverse effects of hormone administration were shown. No heterogeneity was evident in most meta-analyses. INTERPRETATION: Current evidence does not support an adverse impact of hormone therapy on cognitive function, whereas a statistically significant enhancing effect on visuospatial ability was shown in aF. New longitudinal studies with longer follow-up should explore the long-term effects of hormone therapy, especially the effects on younger individuals, where there is greater scarcity of data.

Prediction of Gold Nanoparticle and Microwave-Induced Hyperthermia Effects on Tumor Control via a Simulation Approach.

Hyperthermia acts as a powerful adjuvant to radiation therapy and chemotherapy. Recent advances show that gold nanoparticles (Au-NPs) can mediate highly localized thermal effects upon interaction with laser radiation. The purpose of the present study was to investigate via in silico simulations the mechanisms of Au-NPs and microwave-induced hyperthermia, in correlation to predictions of tumor control (biological endpoints: tumor shrinkage and cell death) after hyperthermia treatment. We also study in detail the dependence of the size, shape and structure of the gold nanoparticles on their absorption efficiency, and provide general guidelines on how one could modify the absorption spectrum of the nanoparticles in order to meet the needs of specific applications. We calculated the hyperthermia effect using two types of Au-NPs and two types of spherical tumors (prostate and melanoma) with a radius of 3 mm. The plasmon peak for the 30 nm Si-core Au-coated NPs and the 20 nm Au-NPs was found at 590 nm and 540 nm, respectively. Considering the plasmon peaks and the distribution of NPs in the tumor tissue, the induced thermal profile was estimated for different intervals of time. Predictions of hyperthermic cell death were performed by adopting a three-state mathematical model, where "three-state" includes (i) alive, (ii) vulnerable, and (iii) dead states of the cell, and it was coupled with a tumor growth model. Our proposed methodology and preliminary results could be considered as a proof-of-principle for the significance of simulating accurately the hyperthermia-based tumor control involving the immune system. We also propose a method for the optimization of treatment by overcoming thermoresistance by biological means and specifically through the targeting of the heat shock protein 90 (HSP90), which plays a critical role in the thermotolerance of cells and tissues.

Albuminuria in Association with Cognitive Function and Dementia: A Systematic Review and Meta-Analysis.

OBJECTIVES: Cerebral microvascular disease is considered to contribute to cognitive dysfunction. We opted to explore whether albuminuria, a marker of systemic microangiopathy, is associated with cognitive impairment, dementia, and cognitive function. DESIGN: Systematic review; independent reviewers screened 2359 articles, derived through the search strategy, for identification of observational studies quantifying an association of albuminuria with the outcomes of interest, abstracted data on study characteristics and results and evaluated studies on quality using the Newcastle-Ottawa scale. SETTING: Community. PARTICIPANTS: Adults. MESUREMENTS: Cognitive impairment and dementia, defined by validated neuropsychological tests or clinical guidelines, respectively, and cognitive function, assessed by validated instruments. RESULTS: Thirty-two eligible studies were identified. Albuminuria was associated with cognitive impairment (Odds Ratio (OR): 1.35, 95% Confidence Interval (CI): 1.19-1.53; 7,852 cases), dementia (OR: 1.35, 95% CI: 1.10-1.65; 5,758 cases), clinical Alzheimer's disease (OR: 1.37, 95% CI: 1.11-1.69; 629 cases) and vascular dementia (OR: 1.96, 95% CI: 1.16-3.31; 186 cases); the effect remained significant among longitudinal, population-based and high quality studies. Time-to-event analysis on prospective studies of non-demented at baseline individuals also showed a significant association with incident dementia (Risk Ratio: 1.52, 95% CI: 1.16-1.99; 971 cases). Worse global cognitive performance (Hedge's g: -0.13, 95% CI: -0.18, -0.09; 68,348 subjects) and accelerated cognitive decline (g: -0.20, 95% CI: -0.34, -0.07; 31,792 subjects) were noted among subjects with albuminuria, who also scored lower in executive function, processing speed, verbal fluency, and verbal memory. CONCLUSIONS: Albuminuria was independently associated with cognitive impairment, dementia and cognitive decline. The stronger effects for vascular dementia and cognitive performance in domains primarily affected by microvascular disease support that the association could be mediated by shared microvascular pathology in the kidney and the brain.

Gold nanoparticles, radiations and the immune system: Current insights into the physical mechanisms and the biological interactions of this new alliance towards cancer therapy.

Considering both cancer's serious impact on public health and the side effects of cancer treatments, strategies towards targeted cancer therapy have lately gained considerable interest. Employment of gold nanoparticles (GNPs), in combination with ionizing and non-ionizing radiations, has been shown to improve the effect of radiation treatment significantly. GNPs, as high-Z particles, possess the ability to absorb ionizing radiation and enhance the deposited dose within the targeted tumors. Furthermore, they can convert non-ionizing radiation into heat, due to plasmon resonance, leading to hyperthermic damage to cancer cells. These observations, also supported by experimental evidence both in vitro and in vivo systems, reveal the capacity of GNPs to act as radiosensitizers for different types of radiation. In addition, they can be chemically modified to selectively target tumors, which renders them suitable for future cancer treatment therapies. Herein, a current review of the latest data on the physical properties of GNPs and their effects on GNP circulation time, biodistribution and clearance, as well as their interactions with plasma proteins and the immune system, is presented. Emphasis is also given with an in depth discussion on the underlying physical and biological mechanisms of radiosensitization. Furthermore, simulation data are provided on the use of GNPs in photothermal therapy upon non-ionizing laser irradiation treatment. Finally, the results obtained from the application of GNPs at clinical trials and pre-clinical experiments in vivo are reported.