Miracle-dz/UniFAR-FTUs huggingface dataset:
The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma

Simple Summary Patients with malignant melanoma have an increased risk of being affected by kidney cancer and vice versa. Lifestyle risk factors contributing to these cancers differ. Instead, our study aims to assess whether common genetic predispositions may be at play. Here we reveal the clinical and germline genetic characteristics of a series of 125 patients diagnosed with both malignant melanoma and renal cell carcinoma (RCC), the most common type of kidney cancer. Clinical testing of known predisposing genes only explains a minority of either or both cancer occurrences. Instead, a wide exploration of all coding genes identified 13 novel susceptibility candidates more prone to rare deleterious germline mutations than expected in cancer-free controls, and converging to a common signaling pathway. This research highlights methods to better characterize cancer (co-)heritability. It also provides a basis to better understand and diagnose melanoma and RCC, which is essential for adequate clinical management. Abstract Background: Malignant melanoma and RCC have different embryonic origins, no common lifestyle risk factors but intriguingly share biological properties such as immune regulation and radioresistance. An excess risk of malignant melanoma is observed in RCC patients and vice versa. This bidirectional association is poorly understood, and hypothetic genetic co-susceptibility remains largely unexplored. Results: We hereby provide a clinical and genetic description of a series of 125 cases affected by both malignant melanoma and RCC. Clinical germline mutation testing identified a pathogenic variant in a melanoma and/or RCC predisposing gene in 17/125 cases (13.6%). This included mutually exclusive variants in MITF (p.E318K locus, N = 9 cases), BAP1 (N = 3), CDKN2A (N = 2), FLCN (N = 2), and PTEN (N = 1). A subset of 46 early-onset cases, without underlying germline variation, was whole-exome sequenced. In this series, thirteen genes were significantly enriched in mostly exclusive rare variants predicted to be deleterious, compared to 19,751 controls of similar ancestry. The observed variation mainly consisted of novel or low-frequency variants (<0.01%) within genes displaying strong evolutionary mutational constraints along the PI3K/mTOR pathway, including PIK3CD, NFRKB, EP300, MTOR, and related epigenetic modifier SETD2. The screening of independently processed germline exomes from The Cancer Genome Atlas confirmed an association with melanoma and RCC but not with cancers of established differing etiology such as lung cancers. Conclusions: Our study highlights that an exome-wide case-control enrichment approach may better characterize the rare variant-based missing heritability of multiple primary cancers. In our series, the co-occurrence of malignant melanoma and RCC was associated with germline variation in the PI3K/mTOR signaling cascade, with potential relevance for early diagnostic and clinical management.
Korean Childcare Providers’ Knowledge, Attitudes, Concerns, and Practices of Febrile Convulsions

With the increase in the number of childcare facilities, childcare providers’ coping skills to take quick action in emergencies have become crucial. This study was to examine Korean childcare providers’ knowledge, attitudes, concerns, and practices regarding febrile convulsions (FCs), and to identify factors influencing their management of FCs. A cross-sectional study was conducted using a questionnaire of 216 Korean childcare providers. Descriptive statistics were used to describe the sample characteristics and FC questionnaires. The differences in the FC practice by demographic variables were assessed using t-test and one-way analysis of variance. The relationships between FC practice and other variables were investigated using Pearson correlations and regression analysis. The childcare providers showed unfavorable levels of outcomes regarding FCs with a low percentage of correct answers on FC knowledge and recommended practices as well as negative attitudes and concerns toward FCs. Additionally, results indicated that the knowledge, education, attitudes toward, and actual experiences of FCs were related to FC practices. The current findings provide important evidence to develop interventions targeting childcare providers.
Chronic Ingestion of Bicarbonate-Rich Water Improves Anaerobic Performance in Hypohydrated Elite Judo Athletes: A Pilot Study

In combat sports, anaerobic power and anaerobic capacity determine sport performance and the dominant metabolic pathways. The decline in performance during exercise that is attributed to the cumulative effects of fatigue, including excessive accumulation of metabolites, depletion of energy substrates, and water and electrolyte disturbances, seems to be of greatest significance. In our experiment, we evaluated the effectiveness of three weeks of bicarbonate-rich water ingestion on anaerobic performance in a state of hydration and dehydration in elite judo athletes. Eight male, elite judo athletes participated in two single-blind, repeated-measures trials. They were assigned to two hydration protocols, ingesting low mineralized table water and bicarbonate-rich water. Anaerobic performance was evaluated by two 30 s Wingate tests for lower and upper limbs, respectively, under conditions of hydration as well as exercise-induced dehydration. Resting, post-ingestion, and post-exercise concentrations of bicarbonate (HCO3), urine osmolality (UOSM), urine specific gravity (UGRAV), and lactate (La) were measured. The current investigation assessed two related factors that impair anaerobic performance—hypohydration and buffering capacity. High-bicarbonate water ingestion improved buffering capacity, and we demonstrated the potential role of this mechanism and its phenomenon in masking the adverse effects of dehydration in the context of repeated high-intensity anaerobic exercise (HIAE).
Study Protocol of a Multicenter Randomized Controlled Trial to Tackle Obesity through a Mediterranean Diet vs. a Traditional Low-Fat Diet in Adolescents: The MED4Youth Study

Youth obesity is a strong predictor of adult obesity, which has well-known negative health consequences. Thus, addressing adult obesity requires tackling youth obesity. MED4Youth’s main objective is to strengthen the link between the Mediterranean Diet (MD) and the health benefits against youth obesity and associated cardiovascular disease (CVD) risk factors, identifying positive effects exerted by an MD including sourdough bread and healthy products from the Mediterranean basis (chickpeas/hummus, nuts, and pomegranate juice). For this purpose, a multicenter randomized controlled trial in which an MD-based intervention will be compared to a traditional low-fat diet intervention will be carried out with 240 overweight and obese adolescents (13–17 years) from Spain, Portugal, and Italy. Both interventions will be combined with an educational web-application addressed to engage the adolescents through a learning-through-playing approach, using both educational materials and games. To assess the interventions, adherence to the MD, dietary records, physical activity, food frequency, sociodemographic, and quality of life questionnaires as well as classical anthropometric and biochemical parameters will be evaluated. Furthermore, an omics approach will be performed to elucidate whether the interventions can shape the gut microbiota and gut-derived metabolites to gain knowledge on the mechanisms through which the MD can exert its beneficial effects.
IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

Simple Summary In the current study, we delineate the molecular mechanisms of acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib and taselisib, in human papillomavirus positive head and neck cell lines. By comparing RNA sequencing of isiPI3K-sensitive tumor cells and their corresponding isiPI3K-acquired-resistant tumor cells, we found that overexpression of insulin growth factor 2 (IGF2) is associated with the resistance phenotype. We further demonstrated by gain and loss of function studies that IGF2 plays a causative role in limiting the sensitivity of human papillomavirus-positive head and neck cell lines. Moreover, we show that blocking IGF2 stimulation activity, using an inhibitor of the IGF1 receptor (IGF1R), enhances isiPI3K efficacy and displays a synergistic anti-tumor effect in vitro and superior anti-tumor activity ex vivo and in vivo. Abstract Over 50% of human papilloma positive head-and-neck cancer (HNCHPV+) patients harbor genomic-alterations in PIK3CA, leading to hyperactivation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway. Nevertheless, despite PI3K pathway activation in HNCHPV+ tumors, the anti-tumor activities of PI3K pathway inhibitors are moderate, mostly due to the emergence of resistance. Thus, for potent and long-term tumor management, drugs blocking resistance mechanisms should be combined with PI3K inhibitors. Here, we delineate the molecular mechanisms of the acquisition of resistance to two isoform-selective inhibitors of PI3K (isiPI3K), alpelisib (BYL719) and taselisib (GDC0032), in HNCHPV+ cell lines. By comparing the transcriptional landscape of isiPI3K-sensitive tumor cells with that of their corresponding isiPI3K-acquired-resistant tumor cells, we found upregulation of insulin growth factor 2 (IGF2) in the resistant cells. Mechanistically, we show that upon isiPI3K treatment, isiPI3K-sensitive tumor cells upregulate the expression of IGF2 to induce cell proliferation via the activation of the IGF1 receptor (IGF1R). Stimulating tumor cells with recombinant IGF2 limited isiPI3K efficacy and released treated cells from S phase arrest. Knocking-down IGF2 with siRNA, or blocking IGF1R with AEW541, resulted in superior anti-tumor activity of isiPI3K in vitro and ex vivo. In vivo, the combination of isiPI3K and IGF1R inhibitor induced stable disease in mice bearing either tumors generated by the HNCHPV+ UM-SCC47 cell line or HPV+ patient-derived xenografts. These findings indicate that IGF2 and the IGF2/IGF1R pathway may constitute new targets for combination therapies to enhance the efficacy of PI3K inhibitors for the treatment of HNCHPV+.
Pure Ion Chromatograms Combined with Advanced Machine Learning Methods Improve Accuracy of Discriminant Models in LC–MS-Based Untargeted Metabolomics

Untargeted metabolomics based on liquid chromatography coupled with mass spectrometry (LC–MS) can detect thousands of features in samples and produce highly complex datasets. The accurate extraction of meaningful features and the building of discriminant models are two crucial steps in the data analysis pipeline of untargeted metabolomics. In this study, pure ion chromatograms were extracted from a liquor dataset and left-sided colon cancer (LCC) dataset by K-means-clustering-based Pure Ion Chromatogram extraction method version 2.0 (KPIC2). Then, the nonlinear low-dimensional embedding by uniform manifold approximation and projection (UMAP) showed the separation of samples from different groups in reduced dimensions. The discriminant models were established by extreme gradient boosting (XGBoost) based on the features extracted by KPIC2. Results showed that features extracted by KPIC2 achieved 100% classification accuracy on the test sets of the liquor dataset and the LCC dataset, which demonstrated the rationality of the XGBoost model based on KPIC2 compared with the results of XCMS (92% and 96% for liquor and LCC datasets respectively). Finally, XGBoost can achieve better performance than the linear method and traditional nonlinear modeling methods on these datasets. UMAP and XGBoost are integrated into KPIC2 package to extend its performance in complex situations, which are not only able to effectively process nonlinear dataset but also can greatly improve the accuracy of data analysis in non-target metabolomics.
The Effects of Random Porosities in Resonant Frequencies of Graphene Based on the Monte Carlo Stochastic Finite Element Model

With the distinguished properties in electronics, thermal conductivity, optical transparence and mechanics, graphene has a powerful potential in nanosensors, nano-resonators, supercapacitors, batteries, etc. The resonant frequency of graphene is an important factor in its application and working environment. However, the random dispersed porosities in graphene evidently change the lattice structure and destroy the integrity and geometrical periodicity. This paper focuses on the effects of random porosities in resonant frequencies of graphene. Monte Carlo simulation is applied to propagate the porosities in the finite element model of pristine graphene. The statistical results and probability density distribution of porous graphene with atomic vacancy defects are computed based on the Monte Carlo finite element model. The results of porous graphene with atomic vacancy defects are compared and discussed with the results of graphene with bond vacancy defects. The enhancement effects of atomic vacancy defects are confirmed in porous graphene. The influences of atomic vacancy defects on displacement and rotation vector sums of porous graphene are more concentrated in local places.
Death Processes in Bovine Theca and Granulosa Cells Modelled and Analysed Using a Systems Biology Approach

In this paper, newly discovered mechanisms of atresia and cell death processes in bovine ovarian follicles are investigated. For this purpose the mRNA expression of receptor interacting protein kinases 1 and 3 (RIPK1 and RIPK3) of the granulosa and theca cells derived from healthy and atretic follicles are studied. The follicles were assigned as either healthy or atretic based on the estradiol to progesterone ratio. A statistically significant difference was recorded for the mRNA expression of a RIPK1 and RIPK3 between granulosa cells from healthy and atretic follicles. To further investigate this result a systems biology approach was used. The genes playing roles in necroptosis, apoptosis and atresia were chosen and a network was created based on human genes annotated by the IMEx database in Cytoscape to identify hubs and bottle-necks. Moreover, correlation networks were built in the Cluepedia plug-in. The networks were created separately for terms describing apoptosis and programmed cell death. We demonstrate that necroptosis (RIPK—dependent cell death pathway) is an alternative mechanism responsible for death of bovine granulosa and theca cells. We conclude that both apoptosis and necroptosis occur in the granulosa cells of dominant follicles undergoing luteinisation and in the theca cells from newly selected follicles.
A Balanced Algorithm for In-City Parking Allocation: A Case Study of Al Madinah City

Parking in heavily populated areas has been considered one of the main challenges in the transportation systems for the past two decades given the limited parking resources, especially in city centres. Drivers often waste long periods of time hunting for an empty parking spot, which causes congestion and consumes energy during the process. Thus, finding an optimal parking spot depends on several factors such as street traffic congestion, trip distance/time, the availability of a parking spot, the waiting time on the lot gate, and the parking fees. Designing a parking spot allocation algorithm that takes those factors into account is crucial for an efficient and high-availability parking service. We propose a smart routing and parking algorithm to allocate an optimal parking space given the aforementioned limiting factors. This algorithm supports choosing the appropriate travel route and parking lot while considering the real-time street traffic and candidate parking lots. A multi-objective function is introduced, with varying weights of the five factors to produce the optimal parking spot with the least congested route while achieving a balanced utilization for candidate parking lots and a balanced traffic distribution. A queueing model is also developed to investigate the availability rate in candidate parking lots while considering the arrival rate, departure rate, and the lot capacity. To evaluate the performance of the proposed algorithm, simulation scenarios have been performed for different cases of high and low traffic intensity rates. We have tested the algorithm on in-city parking facility in the city of Al Madinah as a case study. The results show that the proposed algorithm is effective in achieving a balanced utilization of the parking lots, reducing traffic congestion rates on all routes to candidate parking lots, and minimizing the driving time to the assigned parking spot. Additionally, the proposed algorithm outperforms the MADM algorithm in terms of the selected three metrics for the five periods.
Choline Chloride–Lactic Acid-Based NADES As an Extraction Medium in a Response Surface Methodology-Optimized Method for the Extraction of Phenolic Compounds from Hazelnut Skin

Deep eutectic solvents (DESs) are promising green solvents for the extraction of compounds from food byproducts. Hazelnut (Corylus avellana L.) is one of the most commonly cultivated tree nuts worldwide. The skin represents one of the major byproducts of the hazelnut industry and accounts for 2.5% of the total hazelnut kernel weight. It is a rich source of phenolic compounds like flavan-3-ols, flavonols, dihydrochalcones, and phenolic acids. In this work, fifteen DESs based on choline chloride and betaine, with different compositions, were studied in order to test their phenolic compounds extraction efficiency through the determination of their total concentration via Folin–Ciocalteu assay. A qualitative analysis of extracted phenolic compounds was assessed by HPLC with UV and MS detection. Using the DES with the best extraction efficiency, a new ultrasound-assisted solid liquid extraction (UA-SLE) method was optimized though the response surface methodology (RSM), taking into account some extraction parameters. Efficient recovery of extracted phenolic compounds was achieved using a 35% water solution of choline chloride and lactic acid (molar ratio 1:2) as an extraction solvent, working at 80 °C and with a solid-to-solvent ratio of 1:25 gmL−1. The optimized conditions made it possible to recover 39% more phenolic compounds compared to a classic organic solvent.
Blood Particulate Analogue Fluids: A Review

Microfluidics has proven to be an extraordinary working platform to mimic and study blood flow phenomena and the dynamics of components of the human microcirculatory system. However, the use of real blood increases the complexity to perform these kinds of in vitro blood experiments due to diverse problems such as coagulation, sample storage, and handling problems. For this reason, interest in the development of fluids with rheological properties similar to those of real blood has grown over the last years. The inclusion of microparticles in blood analogue fluids is essential to reproduce multiphase effects taking place in a microcirculatory system, such as the cell-free layer (CFL) and Fähraeus–Lindqvist effect. In this review, we summarize the progress made in the last twenty years. Size, shape, mechanical properties, and even biological functionalities of microparticles produced/used to mimic red blood cells (RBCs) are critically exposed and analyzed. The methods developed to fabricate these RBC templates are also shown. The dynamic flow/rheology of blood particulate analogue fluids proposed in the literature (with different particle concentrations, in most of the cases, relatively low) is shown and discussed in-depth. Although there have been many advances, the development of a reliable blood particulate analogue fluid, with around 45% by volume of microparticles, continues to be a big challenge.
NFAT5-Mediated Signalling Pathways in Viral Infection and Cardiovascular Dysfunction

The nuclear factor of activated T cells 5 (NFAT5) is well known for its sensitivity to cellular osmolarity changes, such as in the kidney medulla. Accumulated evidence indicates that NFAT5 is also a sensitive factor to stress signals caused by non-hypertonic stimuli such as heat shock, biomechanical stretch stress, ischaemia, infection, etc. These osmolality-related and -unrelated stimuli can induce NFAT5 upregulation, activation and nuclear accumulation, leading to its protective role against various detrimental effects. However, dysregulation of NFAT5 expression may cause pathological conditions in different tissues, leading to a variety of diseases. These protective or pathogenic effects of NFAT5 are dictated by the regulation of its target gene expression and activation of its signalling pathways. Recent studies have found a number of kinases that participate in the phosphorylation/activation of NFAT5 and related signal proteins. Thus, this review will focus on the NFAT5-mediated signal transduction pathways. As for the stimuli that upregulate NFAT5, in addition to the stresses caused by hyperosmotic and non-hyperosmotic environments, other factors such as miRNA, long non-coding RNA, epigenetic modification and viral infection also play an important role in regulating NFAT5 expression; thus, the discussion in this regard is another focus of this review. As the heart, unlike the kidneys, is not normally exposed to hypertonic environments, studies on NFAT5-mediated cardiovascular diseases are just emerging and rapidly progressing. Therefore, we have also added a review on the progress made in this field of research.
Viral Proteins as Emerging Cancer Therapeutics

Simple Summary This review is focused on enlisting viral proteins from different host sources, irrespective of their origin, that may act as future cancer curatives. Unlike the viral proteins that are responsible for tumor progression, these newly emerged viral proteins function as tumor suppressors. Their ability to regulate various cell signaling mechanisms specifically in cancer cells makes them interesting candidates to explore their use in cancer therapy. The discussion about such viral components may provide new insights into cancer treatment in the absence of any adverse effects to normal cells. The study also highlights avian viral proteins as a substitute to human oncolytic viruses for their ability to evade pre-existing immunity. Abstract Viruses are obligatory intracellular parasites that originated millions of years ago. Viral elements cover almost half of the human genome sequence and have evolved as genetic blueprints in humans. They have existed as endosymbionts as they are largely dependent on host cell metabolism. Viral proteins are known to regulate different mechanisms in the host cells by hijacking cellular metabolism to benefit viral replication. Amicable viral proteins, on the other hand, from several viruses can participate in mediating growth retardation of cancer cells based on genetic abnormalities while sparing normal cells. These proteins exert discreet yet converging pathways to regulate events like cell cycle and apoptosis in human cancer cells. This property of viral proteins could be harnessed for their use in cancer therapy. In this review, we discuss viral proteins from different sources as potential anticancer therapeutics.