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Growing scientific evidence suggests a link between the expression of toll-like receptor 4 (TLR4) and cervical cancer carcinogenesis. Specifically, a close relation between TLR4 expression and FIGO stage, lymph node metastases, and tumor size has been reported in cervical cancer. In the present study, we aimed to evaluate the relationship between TLR4 expression levels and human papillomavirus (HPV) infection and/or high-risk (hr) HPV integration status in patients with a histological diagnosis of high-grade squamous intraepithelial lesion (H-SIL), and squamous cell carcinoma (SCC) of the uterine cervix. Sixty biopsies of cervical neoplasia, comprising H-SIL (n = 20) and SCC (n = 40), were evaluated for TLR4 expression by immunohistochemistry. All samples were positive for high-risk HPV as confirmed by in situ hybridization (ISH) and broad-spectrum PCR followed by Sanger sequencing analysis. The intensity of TLR4 staining was higher in tissues negative for intraepithelial lesion or malignancy (NILM) than in H-SIL, and further reduced in SCC. Moreover, statistically significant differences have been observed in the percentage of TLR4 expression between NILM and H-SIL and between H-SIL and SCC, with higher percentages of expression in H-SIL than in SCC. Our results showed a significant downregulation of TLR4 in HPV-related H-SIL and SCC, compared to NILM. These data support the hypothesis that TLR4 expression is suppressed in HPV-driven oncogenesis.

The electrospinning process is an effective technique for creating micro- and nanofibers from synthetic and natural polymers, with significant potential for biomedical applications and drug delivery systems due to their high drug-loading capacity, large surface area, and tunable release times. Poly(L-lactic acid) (PLLA) stands out for its excellent thermo-mechanical properties, biodegradability, and bioabsorbability. Electrospun PLLA nanofibrous structures have been extensively investigated as wound dressings, sutures, drug delivery carriers, and tissue engineering scaffolds. This study aims to create and characterize electrospun PLLA membranes loaded with spironolactone (SP), mimicking active compounds of Ganoderma lucidum (GL), to develop a biodegradable patch for topical wound-healing applications. GL, a medicinal mushroom, enhances dermal wound healing with its bioactive compounds, such as polysaccharides and ganoderic acids. Focusing on GL extracts-obtained through green extraction methods-and innovative drug delivery, we created new fibers for wound-healing potential applications. To integrate complex mixtures of bioactive compounds into the fibers, we developed a prototype using a single pure substance representing the extract mixture. This painstaking work presents the results of the fabricating, wetting, moisture properties, material resilience, and full characterization of the product, providing a robust rationale for the fabrication of fibers imbued with more complex extracts.

Nowadays, there is considerable attention toward the use of food waste from food processing as possible sources of compounds with health properties, such as anticancer activity. An example is tomato processing, which is responsible for generating a remarkable amount of waste (leaves, peel, seeds). Therefore, our goal was to evaluate the potential anticancer property of tomato extracts, in particular " Datterino " tomato (DT) and " Piccadilly " tomato (PT), and to study their phytochemical composition. Liquid chromatography with tandem mass spectrometry (LC/MS-MS) results showed that these extracts are rich in alkaloids, flavonoids, fatty acids, lipids, and terpenes. Furthermore, their potential anticancer activity was evaluated in vitro by MTT assay. In particular, the percentage of cell viability was assessed in olfactory ensheathing cells (OECs), a particular glial cell type of the olfactory system, and in SH-SY5Y, a neuroblastoma cell line. All extracts (aqueous and ethanolic) did not lead to any significant change in the percentage of cell viability on OECs when compared with the control. Instead, in SH-SY5Y we observed a significant decrease in the percentage of cell viability, confirming their potential anticancer activity; this was more evident for the ethanolic extracts. In conclusion, tomato leaves extracts could be regarded as a valuable source of bioactive compounds, suitable for various applications in the food, nutraceutical, and pharmaceutical fields.

Tomato by-products represent a good source of phytochemical compounds with health properties, such as the steroidal glycoalkaloid α-tomatine (α-TM) and its aglycone tomatidine (TD). Both molecules have numerous beneficial properties, such as potential anticancer activity. Unfortunately, their therapeutic application is limited due to stability and bioavailability issues. Therefore, a valid strategy seems to be their encapsulation into Solid Lipid Nanoparticles (SLN). The nanoformulations containing α-TM (α-TM-SLN) and TD (TD-SLN) were prepared by solvent-diffusion technique and subsequently characterized in terms of technological parameters (particle size, polydispersity index, zeta potential, microscopy, and calorimetric studies). To assess the effect of α-TM and TD on the percentage of cellular viability in Olfactory Ensheathing Cells (OECs), a peculiar glial cell type of the olfactory system used as normal cells, and in SH-SY5Y, a neuroblastoma cancer cell line, an MTT test was performed. In addition, the effects of empty, α-TM-SLN, and TD-SLN were tested. Our results show that the treatment of OECs with blank-SLN, free α-TM (0.25 µg/mL), and TD (0.50 µg/mL) did not induce any significant change in the percentage of cell viability when compared with the control. In contrast, in SH-SY5Y-treated cells, a significant decrease in the percentage of cell viability when compared with the control was found. In particular, the effect appeared more evident when SH-SY5Y cells were exposed to α-TM-SLN and TD-SLN. No significant effect in blank-SLN-treated SH-SY5T cells was observed. Therefore, SLN is a promising approach for the delivery of α-TM and TD.

Human Activity Recognition (HAR) is a complex problem in deep learning, and One-Dimensional Convolutional Neural Networks (1D CNNs) have emerged as a popular approach for addressing it. These networks efficiently learn features from data that can be utilized to classify human activities with high performance. However, understanding and explaining the features learned by these networks remains a challenge. This paper presents a novel eXplainable Artificial Intelligence (XAI) method for generating visual explanations of features learned by one-dimensional CNNs in its training process, utilizing t-Distributed Stochastic Neighbor Embedding (t-SNE). By applying this method, we provide insights into the decision-making process through visualizing the information obtained from the model's deepest layer before classification. Our results demonstrate that the learned features from one dataset can be applied to differentiate human activities in other datasets. Our trained networks achieved high performance on two public databases, with 0.98 accuracy on the SHO dataset and 0.93 accuracy on the HAPT dataset. The visualization method proposed in this work offers a powerful means to detect bias issues or explain incorrect predictions. This work introduces a new type of XAI application, enhancing the reliability and practicality of CNN models in real-world scenarios.

Due to wearables' popularity, human activity recognition (HAR) plays a significant role in people's routines. Many deep learning (DL) approaches have studied HAR to classify human activities. Previous studies employ two HAR validation approaches: subject-dependent (SD) and subject-independent (SI). Using accelerometer data, this paper shows how to generate visual explanations about the trained models' decision making on both HAR and biometric user identification (BUI) tasks and the correlation between them. We adapted gradient-weighted class activation mapping (grad-CAM) to one-dimensional convolutional neural networks (CNN) architectures to produce visual explanations of HAR and BUI models. Our proposed networks achieved 0.978 and 0.755 accuracy, employing both SD and SI. The proposed BUI network achieved 0.937 average accuracy. We demonstrate that HAR's high performance with SD comes not only from physical activity learning but also from learning an individual's signature, as in BUI models. Our experiments show that CNN focuses on larger signal sections in BUI, while HAR focuses on smaller signal segments. We also use the grad-CAM technique to identify database bias problems, such as signal discontinuities. Combining explainable techniques with deep learning can help models design, avoid results overestimation, find bias problems, and improve generalization capability.

Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated the PPARγ selectivity, epithelial permeability, and lung tissue binding of three types of TZDs in vitro (rosiglitazone (RGZ), pioglitazone, and DRF-2546), followed by an in vivo study in preterm rabbits exposed to hyperoxia (95% oxygen) to investigate the pharmacokinetics and the pulmonary outcomes of daily RGZ administration. In addition, blood lipids and a comparative lung proteomics analysis were also performed on Day 7. All TZDs showed high epithelial permeability through Caco-2 monolayers and high plasma and lung tissue binding; however, RGZ showed the highest affinity for PPARγ. The pharmacokinetic profiling of RGZ (1 mg/kg) revealed an equivalent biodistribution after either intratracheal or intraperitoneal administration, with detectable levels in lungs and plasma after 24 h. However, daily RGZ doses of 1 mg/kg did not improve lung function in preterm rabbits exposed to hyperoxia, and daily 10 mg/kg doses were even associated with a significant lung function worsening, which could be partially explained by the upregulation of lung inflammation and lipid metabolism pathways revealed by the proteomic analysis. Notably, daily postnatal RGZ produced an aberrant modulation of serum lipids, particularly in rabbit pups treated with the 10 mg/kg dose. In conclusion, daily postnatal RGZ did not improve lung function and caused dyslipidemia in preterm rabbits exposed to hyperoxia.

Background: Acute stroke care has greatly improved in recent decades. However, the increasing stroke mortality in low-to-middle income countries suggests that progress has not been reached completely by these populations. Here we present the analysis of the hospital phase of the first population-based stroke surveillance study. Methods: A daily hospital surveillance method was used to identify adult patients with acute stroke during 18 months in six hospitals. We abstracted data on demographics, vascular risk factors, neuroimaging-confirmed stroke types, and clinical data. Results: A total of 1361 adults with acute stroke were identified (mean age 69.2 years; 52% women) with transient ischemic attack (5.5%), acute ischemic stroke (68.6%), intracerebral hemorrhage (23.1%), cerebral venous thrombosis (0.2%), and undetermined stroke (2.6%). The main risk factors were hypertension (80.7%) and diabetes mellitus (47.6%). The usage rate of thrombolysis was 3.6%, in spite of the fact that 37.2% of acute ischemic stroke patients arrived in <4.5 h. The 30-day case fatality rate was 32.6%, higher in hemorrhagic than ischemic stroke. Conclusion: We identified limitations in acute stroke care in the Mexico City, including neuroimaging availability and thrombolysis usage. The door-to-door phase will help to depict the acute stroke burden in Mexico.

Toll-like receptors (TLRs) regulate innate and adaptive immune responses. Moreover, TLRs can induce a pro-survival and pro-proliferation response in tumor cells. This study aims to investigate the expression of TLR4 in the epithelium surrounding oral squamous cell carcinomas (OSCC) in relation to its inflammatory microenvironment. This study included 150 human samples: 30 normal oral control (NOC), 38 non-lichenoid epithelium surrounding OSCC (NLE-OSCC), 28 lichenoid epithelium surrounding OSCC (LE-OSCC), 30 OSCC ex-non oral lichenoid lesion (OSCC Ex-NOLL), and 24 OSCC ex-oral lichenoid lesion (OSCC Ex-OLL). TLR4 expression was investigated by immunohistochemistry and the percentage of positive cells was quantified. In addition, a semiquantitative analysis of staining intensity was performed. Immunohistochemical analysis revealed that TLR4 is strongly upregulated in LE-OSCC as compared to normal control epithelium and NLE-OSCC. TLR4 expression was associated with the inflammatory environment, since the percentage of positive cells increases from NOC and NLE-OSCC to LE-OSCC, reaching the highest value in OSCC Ex-OLL. TLR4 was detected in the basal third of the epithelium in NLE-OSCC, while in LE-OSCC, TLR4 expression reached the intermediate layer. These results demonstrated that an inflammatory microenvironment can upregulate TLR4, which may boost tumor development.

Fault tolerance in IoT systems is challenging to overcome due to its complexity, dynamicity, and heterogeneity. IoT systems are typically designed and constructed in layers. Every layer has its requirements and fault tolerance strategies. However, errors in one layer can propagate and cause effects on others. Thus, it is impractical to consider a centralized fault tolerance approach for an entire system. Consequently, it is vital to consider multiple layers in order to enable collaboration and information exchange when addressing fault tolerance. The purpose of this study is to propose a multi-layer fault tolerance approach, granting interconnection among IoT system layers, allowing information exchange and collaboration in order to attain the property of dependability. Therefore, we define an event-driven framework called FaTEMa (Fault Tolerance Event Manager) that creates a dedicated fault-related communication channel in order to propagate events across the levels of the system. The implemented framework assist with error detection and continued service. Additionally, it offers extension points to support heterogeneous communication protocols and evolve new capabilities. Our empirical results show that introducing FaTEMa provided improvements to the error detection and error resolution time, consequently improving system availability. In addition, the use of Fatema provided a reliability improvement and a reduction in the number of failures produced.

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets.

In this paper, we study the basic problem of a charged particle in a stochastic magnetic field. We consider dichotomous fluctuations of the magnetic field where the sojourn time in one of the two states are distributed according to a given waiting-time distribution either with Poisson or non-Poisson statistics, including as well the case of distributions with diverging mean time between changes of the field, corresponding to an ergodicity breaking condition. We provide analytical and numerical results for all cases evaluating the average and the second moment of the position and velocity of the particle. We show that the field fluctuations induce diffusion of the charge with either normal or anomalous properties, depending on the statistics of the fluctuations, with distinct regimes from those observed, e.g., in standard Continuous-Time Random Walk models.

Non-coding RNA transcripts originating from Ultraconserved Regions (UCRs) have tissue-specific expression and play relevant roles in the pathophysiology of multiple cancer types. Among them, we recently identified and characterized the ultra-conserved-transcript-8+ (uc.8+), whose levels correlate with grading and staging of bladder cancer. Here, to validate uc.8+ as a potential biomarker in bladder cancer, we assessed its expression and subcellular localization by using tissue microarray on 73 human bladder cancer specimens. We quantified uc.8+ by in-situ hybridization and correlated its expression levels with clinical characteristics and patient survival. The analysis of subcellular localization indicated the simultaneous presence of uc.8+ in the cytoplasm and nucleus of cells from the Low-Grade group, whereas a prevalent cytoplasmic localization was observed in samples from the High-Grade group, supporting the hypothesis of uc.8+ nuclear-to-cytoplasmic translocation in most malignant tumor forms. Moreover, analysis of uc.8+ expression and subcellular localization in tumor-surrounding stroma revealed a marked down-regulation of uc.8+ levels compared to the paired (adjacent) tumor region. Finally, deep machine-learning approaches identified nucleotide sequences associated with uc.8+ localization in nucleus and/or cytoplasm, allowing to predict possible RNA binding proteins associated with uc.8+, recognizing also sequences involved in mRNA cytoplasm-translocation. Our model suggests uc.8+ subcellular localization as a potential prognostic biomarker for bladder cancer.

Background: The Anaplastic Lymphoma Kinase (ALK) gene is known to be affected by several genetic alterations, such as rearrangement, amplification and point mutation. The main goal of this study was to comprehensively analyze ALK amplification ( ALK -A) and ALK gene copy number gain ( ALK-CNG ) in a large cohort of non-small-cell lung cancer (NSCLC) patients in order to evaluate the effects on mRNA and protein expression. Methods: ALK locus number status was evaluated in 578 NSCLC cases by fluorescence in situ hybridization (FISH). In addition, ALK immunohistochemistry and ALK mRNA in situ hybridization were performed. Results: Out of 578 cases, 17 cases showed ALK -A. In addition, 14 cases presented AL K-CNG and 72 cases presented chromosome 2 polyploidy. None of those carrying ALK -A and -CNG showed either ALK immunohistochemical expression or ALK mRNA expression through in situ hybridization. We observed a high frequency of extra copies of the ALK gene. Conclusions : Our findings demonstrated that ALK -A is not involved in mRNA production and consequently is not involved in protein production; these findings support the hypothesis that ALK -A might not play a role in the pathogenesis of NSCLC, underlining the absence of a specific clinical application.

Structural health monitoring for offshore wind turbines is imperative. Offshore wind energy is progressively attained at greater water depths, beyond 30 m, where jacket foundations are presently the best solution to cope with the harsh environment (extreme sites with poor soil conditions). Structural integrity is of key importance in these underwater structures. In this work, a methodology for the diagnosis of structural damage in jacket-type foundations is stated. The method is based on the criterion that any damage or structural change produces variations in the vibrational response of the structure. Most studies in this area are, primarily, focused on the case of measurable input excitation and vibration response signals. Nevertheless, in this paper it is assumed that the only available excitation, the wind, is not measurable. Therefore, using vibration-response-only accelerometer information, a data-driven approach is developed following the next steps: (i) the wind is simulated as a Gaussian white noise and the accelerometer data are collected; (ii) the data are pre-processed using group-reshape and column-scaling; (iii) principal component analysis is used for both linear dimensionality reduction and feature extraction; finally, (iv) two different machine-learning algorithms, k nearest neighbor ( k -NN) and quadratic-kernel support vector machine (SVM), are tested as classifiers. The overall accuracy is estimated by 5-fold cross-validation. The proposed approach is experimentally validated in a laboratory small-scale structure. The results manifest the reliability of the stated fault diagnosis method being the best performance given by the SVM classifier.

Aim: Musashi 2 (MSI2), which is an RNA-binding protein, plays a fundamental role in the oncogenesis of several cancers. The aim of this study is to investigate the expression of MSI2 in Oral Squamous Cell Carcinoma (OSCC) and evaluate its correlation to clinic-pathological variables and prognosis., Materials and Methods: A bioinformatic analysis was performed on data downloaded from The Cancer Genome Atlas (TCGA) database. The MSI2 expression data were analysed for their correlation with clinic-pathological and prognostic features. In addition, an immmunohistochemical evaluation of MSI2 expression on 108 OSCC samples included in a tissue microarray and 13 healthy mucosae samples was performed., Results: 241 patients' data from TCGA were included in the final analysis. No DNA mutations were detected for the MSI2 gene, but a hyper methylated condition of the gene emerged. MSI2 mRNA expression correlated with Grading ( p = 0.009) and overall survival ( p = 0.045), but not with disease free survival ( p = 0.549). Males presented a higher MSI2 mRNA expression than females. The immunohistochemical evaluation revealed a weak expression of MSI2 in both OSCC samples and in healthy oral mucosae. In addition, MSI2 expression directly correlated with Cyclin-D1 expression (p = 0.022). However, no correlation has been detected with prognostic outcomes (overall and disease free survival)., Conclusions: The role of MSI2 expression in OSCC seems to be not so closely correlated with prognosis, as in other human neoplasms. The correlation with Cyclin-D1 expression suggests an indirect role that MSI2 might have in the proliferation of OSCC cells, but further studies are needed to confirm such results.

Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs.

lncRNAs participate in many cellular processes, including regulation of gene expression at the transcriptional and post-transcriptional levels. In addition, many lncRNAs can contribute to the development of different human diseases including cancer. The tumor microenvironment (TME) plays an important role during tumor growth and metastatic progression, and most of these lncRNAs have a key function in TME intracellular signaling. Among the numerous identified lncRNAs, several experimental evidences have shown the fundamental role of the lncRNA HOTAIR in carcinogenesis, also highlighting its use as a circulating biomarker. In this review we described the contribution of HOTAIR in the TME modulation, highlighting its relation with cellular and non-cellular components during tumor evolution and progression.

Survivin is a well-known protein involved in the inhibition of apoptosis in many different cancer types. The aim of this study was to perform an integrated bioinformatic and histologic analysis in order to study the expression and prognostic role of Survivin and its related gene BIRC5 in oral cancer. Publicly available databases were accessed via Gene Expression Omnibus and Oncomine, in addition raw data from The Cancer Genome Atlas (TCGA) were also obtained in order to analyze the rate of gene mutation, expression and methylation in patients with oral squamous cells carcinoma (OSCC). Immunohistochemistry (IHC) was also performed in order to evaluate the nuclear and cytoplasmic expression of Survivin and their correlation with cell proliferation in samples from OSCC patients. Results of this study revealed that Survivin is rarely mutated in OSCC samples and upregulated when compared to non-cancerous tissue. A negative correlation between the methylation of the island cg25986496 and BIRC5 mRNA expression was detected from TCGA data. IHC staining revealed that cytoplasmic (and not nuclear) expression of Survivin is associated with poor overall survival in OSCC patients, while the nuclear expression correlates with higher proliferation rate. In addition, data from TCGA database revealed that BIRC5 gene expression is an independent prognostic factor for OSCC patients.

The role of sex hormone receptors in human cancer development and progression has been well documented in numerous studies, as has the success of sex hormone antagonists in the biological therapy of many human tumors. In salivary gland tumors (SGTs), little and conflicting information about the role of the estrogen receptor alpha (ERα), progesterone receptor (PgR) and androgen receptor (AR) has been described and in most cases the use of sex hormone antagonists is not contemplated in clinical practice. In this study, we analyzed a panel of sex hormone receptors that have not been widely investigated in SGTs-ERα, PgR, AR, but also ERβ and GPR30-to define their expression pattern and their prognostic and predictive value in a case series of 69 benign and malignant SGTs. We showed the aberrant expression of AR in mucoepidermoid and oncocytic carcinoma, a strong relation between cytoplasmic ERβ expression and tumor grade, and a strong correlation between nuclear GPR30 expression and disease-free survival (DFS) of SGT patients., Competing Interests: The authors declare no conflict of interest.