Explainable prediction model for the human papillomavirus status in patients with oropharyngeal squamous cell carcinoma using CNN on CT images.

Several studies have emphasised how positive and negative human papillomavirus (HPV+ and HPV-, respectively) oropharyngeal squamous cell carcinoma (OPSCC) has distinct molecular profiles, tumor characteristics, and disease outcomes. Different radiomics-based prediction models have been proposed, by also using innovative techniques such as Convolutional Neural Networks (CNNs). Although some of these models reached encouraging predictive performances, there evidence explaining the role of radiomic features in achieving a specific outcome is scarce. In this paper, we propose some preliminary results related to an explainable CNN-based model to predict HPV status in OPSCC patients. We extracted the Gross Tumor Volume (GTV) of pre-treatment CT images related to 499 patients (356 HPV+ and 143 HPV-) included into the OPC-Radiomics public dataset to train an end-to-end Inception-V3 CNN architecture. We also collected a multicentric dataset consisting of 92 patients (43 HPV+ , 49 HPV-), which was employed as an independent test set. Finally, we applied Gradient-weighted Class Activation Mapping (Grad-CAM) technique to highlight the most informative areas with respect to the predicted outcome. The proposed model reached an AUC value of 73.50% on the independent test. As a result of the Grad-CAM algorithm, the most informative areas related to the correctly classified HPV+ patients were located into the intratumoral area. Conversely, the most important areas referred to the tumor edges. Finally, since the proposed model provided additional information with respect to the accuracy of the classification given by the visualization of the areas of greatest interest for predictive purposes for each case examined, it could contribute to increase confidence in using computer-based predictive models in the actual clinical practice.

αV-Integrin-Dependent Inhibition of Glioblastoma Cell Migration, Invasion and Vasculogenic Mimicry by the uPAcyclin Decapeptide.

Among the deadliest human cancers is glioblastoma (GBM) for which new treatment approaches are urgently needed. Here, the effects of the cyclic decapeptide, uPAcyclin, are investigated using the U87-MG, U251-MG, and U138-MG human GBM and C6 rat cell models. All GBM cells express the αV-integrin subunit, the target of uPAcyclin, and bind specifically to nanomolar concentrations of the decapeptide. Although peptide exposure affects neither viability nor cell proliferation rate, nanomolar concentrations of uPAcyclin markedly inhibit the directional migration and matrix invasion of all GBM cells, in a concentration- and αV-dependent manner. Moreover, wound healing rate closure of U87-MG and C6 rat glioma cells is reduced by 50% and time-lapse videomicroscopy studies show that the formation of vascular-like structures by U87-MG in three-dimensional matrix cultures is markedly inhibited by uPAcyclin. A strong reduction in the branching point numbers of the U87-MG, C6, and U251-MG cell lines undergoing vasculogenic mimicry, in the presence of nanomolar peptide concentrations, was observed. Lysates from matrix-recovered uPAcyclin-exposed cells exhibit a reduced expression of VE-cadherin, a prominent factor in the acquisition of vascular-like structures. In conclusion, these results indicate that uPAcyclin is a promising candidate to counteract the formation of new vessels in novel targeted anti-GBM therapies.

Sonic enhancement of virtual exhibits.

Museums have widely embraced virtual exhibits. However, relatively little attention is paid to how sound may create a more engaging experience for audiences. To begin addressing this lacuna, we conducted an online experiment to explore how sound influences the interest level, emotional response, and engagement of individuals who view objects within a virtual exhibit. As part of this experiment, we designed a set of different soundscapes, which we presented to participants who viewed museum objects virtually. We then asked participants to report their felt affect and level of engagement with the exhibits. Our results show that soundscapes customized to exhibited objects significantly enhance audience engagement. We also found that more engaged audience members were more likely to want to learn additional information about the object(s) they viewed and to continue viewing these objects for longer periods of time. Taken together, our findings suggest that virtual museum exhibits can improve visitor engagement through forms of customized soundscape design.

Role of Chemoradiation in the Adjuvant Treatment of Radically Resected Pancreatic Cancer Patients: A Mono-Institutional Retrospective Analysis.

INTRODUCTION: Pancreatic cancer (PC) represents an unfavorable prognosis condition, even in patients with resectable disease. The aim of this series was to investigate the role of treatment intensification with adjuvant chemoradiation (CRT) in radically resected PC patients. METHODS: Data from PC patients who underwent radical surgery, adjuvant chemotherapy (CT), and CRT throughout a 20-year period were retrospectively collected. Actuarial local control (LC) and the overall survival (OS) were the primary endpoints, with disease-free survival and metastasis-free survival (MFS) representing secondary endpoints. RESULTS: The analysis included 108 PC patients treated with adjuvant CRT and CT from January 2000 to August 2019. Median age was 66 years (range: 40-83), and all patients underwent radical surgical resection with adjuvant CT (88, 81.5%) plus concomitant CRT (101, 93.5%) or radiotherapy alone (7, 6.5%). The median dose delivered to the tumor bed was 50.4 Gy (range: 45-50.6 Gy), while median dose to regional lymphatic drainage stations was 39.6 Gy (range 39.6-45 Gy). Concomitant CT was a gemcitabine-based regimen in the vast majority of patients (87, 80.6%). Median follow-up time was 21 months; the 2- and 5-year LC rates were 75.8% and 59.1%, respectively. Perineural invasion at pathological assessment was found significantly associated with LC (p = 0.028). Median OS was 40 months with 2- and 5-year OS rates of 73.9% and 41.6%, respectively. CONCLUSIONS: The outcomes of this series suggest to investigate the possible impact of adding adjuvant CRT to CT in PC patients. Timing and combination of modern CRT with new systemic therapies need to be further investigated to personalize therapy and optimize clinical advantages.

Modulation of Cellular Function by the Urokinase Receptor Signalling: A Mechanistic View.

Urokinase-type plasminogen activator receptor (uPAR or CD87) is a glycosyl-phosphatidyl-inositol anchored (GPI) membrane protein. The uPAR primary ligand is the serine protease urokinase (uPA), converting plasminogen into plasmin, a broad spectrum protease, active on most extracellular matrix components. Besides uPA, the uPAR binds specifically also to the matrix protein vitronectin and, therefore, is regarded also as an adhesion receptor. Complex formation of the uPAR with diverse transmembrane proteins, including integrins, formyl peptide receptors, G protein-coupled receptors and epidermal growth factor receptor results in intracellular signalling. Thus, the uPAR is a multifunctional receptor coordinating surface-associated pericellular proteolysis and signal transduction, thereby affecting physiological and pathological mechanisms. The uPAR-initiated signalling leads to remarkable cellular effects, that include increased cell migration, adhesion, survival, proliferation and invasion. Although this is beyond the scope of this review, the uPA/uPAR system is of great interest to cancer research, as it is associated to aggressive cancers and poor patient survival. Increasing evidence links the uPA/uPAR axis to epithelial to mesenchymal transition, a highly dynamic process, by which epithelial cells can convert into a mesenchymal phenotype. Furthermore, many reports indicate that the uPAR is involved in the maintenance of the stem-like phenotype and in the differentiation process of different cell types. Moreover, the levels of anchor-less, soluble form of uPAR, respond to a variety of inflammatory stimuli, including tumorigenesis and viral infections. Finally, the role of uPAR in virus infection has received increasing attention, in view of the Covid-19 pandemics and new information is becoming available. In this review, we provide a mechanistic perspective, via the detailed examination of consolidated and recent studies on the cellular responses to the multiple uPAR activities.

Investigating the effects of supercritical antisolvent process and food models on antioxidant capacity, bioaccessibility and transepithelial transport of quercetin and rutin.

In the present study, the effects of the Supercritical Anti-Solvent (SAS) process and food models on the antioxidant capacity, bioaccessibility and transport dynamics of flavonol-loaded polyvinylpyrrolidone (PVP) based microparticles were investigated using a combined in vitro gastrointestinal digestion/Caco-2 cell culture model. SAS-processed and unprocessed flavonols were supplied in two different food models: 10% ethanol for an aqueous hydrophilic food simulant and 3% acetic acid for an acidic food simulant. The SAS processing of quercetin and rutin resulted in a much higher recovery of these bioactives as well as greater retention of antioxidant capacity after gastrointestinal digestion in both hydrophilic and acidic food models. The present study also demonstrates that SAS coprecipitation has a positive effect on the stability and transport of bioactives across the epithelial cell layer. It can be deduced from the results that the SAS process can be a useful method in pharmaceutical and nutraceutical applications with high stability, bioaccessibility, bioavailability and thus enhanced nutritional value.

Does restaging MRI radiomics analysis improve pathological complete response prediction in rectal cancer patients? A prognostic model development.

PURPOSE: Our study investigated the contribution that the application of radiomics analysis on post-treatment magnetic resonance imaging can add to the assessments performed by an experienced disease-specific multidisciplinary tumor board (MTB) for the prediction of pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). MATERIALS AND METHODS: This analysis included consecutively retrospective LARC patients who obtained a complete or near-complete response after nCRT and/or a pCR after surgery between January 2010 and September 2019. A three-step radiomics features selection was performed and three models were generated: a radiomics model (rRM), a multidisciplinary tumor board model (yMTB) and a combined model (CM). The predictive performance of models was quantified using the receiver operating characteristic (ROC) curve, evaluating the area under curve (AUC). RESULTS: The analysis involved 144 LARC patients; a total of 232 radiomics features were extracted from the MR images acquired post-nCRT. The yMTB, rRM and CM predicted pCR with an AUC of 0.82, 0.73 and 0.84, respectively. ROC comparison was not significant (p = 0.6) between yMTB and CM. CONCLUSION: Radiomics analysis showed good performance in identifying complete responders, which increased when combined with standard clinical evaluation; this increase was not statistically significant but did improve the prediction of clinical response.

Porous Aerogels and Adsorption of Pollutants from Water and Air: A Review.

Aerogels are open, three-dimensional, porous materials characterized by outstanding properties, such as low density, high porosity, and high surface area. They have been used in various fields as adsorbents, catalysts, materials for thermal insulation, or matrices for drug delivery. Aerogels have been successfully used for environmental applications to eliminate toxic and harmful substances-such as metal ions or organic dyes-contained in wastewater, and pollutants-including aromatic or oxygenated volatile organic compounds (VOCs)-contained in the air. This updated review on the use of different aerogels-for instance, graphene oxide-, cellulose-, chitosan-, and silica-based aerogels-provides information on their various applications in removing pollutants, the results obtained, and potential future developments.

Supercritical Carbon Dioxide-Based Processes in Photocatalytic Applications.

Conventional methods generally used to synthesize heterogeneous photocatalysts have some drawbacks, mainly the difficult control/preservation of catalysts' morphology, size or structure, which strongly affect the photocatalytic activity. Supercritical carbon dioxide (scCO2)-assisted techniques have recently been shown to be a promising approach to overcome these limitations, which are still a challenge. In addition, compared to traditional methods, these innovative techniques permit the synthesis of high-performance photocatalysts by reducing the use of toxic and polluting solvents and, consequently, the environmental impact of long-term catalyst preparation. Specifically, the versatility of scCO2 allows to prepare catalysts with different structures (e.g., nanoparticles or metal-loaded supports) by several supercritical processes for the photocatalytic degradation of various compounds. This is the first updated review on the use of scCO2-assisted techniques for photocatalytic applications. We hope this review provides useful information on different approaches and future perspectives.

Contact Lenses as Ophthalmic Drug Delivery Systems: A Review.

Ophthalmic drugs used for the treatment of various ocular diseases are commonly administered by eye drops. However, due to anatomical and physiological factors, there is a low bioavailability of the active principle. In order to increase the drug residence time on the cornea to adequate levels, therapeutic contact lenses have recently been proposed. The polymeric support that constitutes the contact lens is loaded with the drug; in this way, there is a direct and effective pharmacological action on the target organ, promoting a prolonged release of the active principle. The incorporation of ophthalmic drugs into contact lenses can be performed by different techniques; nowadays, the soaking method is mainly employed. To improve the therapeutic performance of drug-loaded contact lenses, innovative methods have recently been proposed, including the impregnation with supercritical carbon dioxide. This updated review of therapeutic contact lenses production and application provides useful information on the most effective preparation methodologies, recent achievements and future perspectives.

Polycaprolactone/polyethylene-glycol capsules made by injection molding: A drug release modeling.

Polycaprolactone (PCL)/Polyethylene-glycol (PEG) capsules are prepared by injection molding with the aim of producing Colon-specific Drug Delivery Systems (CDDS). PCL, being a gastroresistant polymer, is suitable for this kind of delivery; however, the release from PCL devices is too slow. For this reason, in this paper, different percentages of PEG (10, 20 and 30 w/w %) have been added to obtain blends able to modulate the release from PCL-based capsules. The drug release rate from PCL/PEG capsules increases with the PEG percentage; using PCL/PEG 70/30 w/w capsules, the drug release is suitable for CDDS. The experimental data have been modelled, accounting for three steps: the penetration of the release medium into the capsule, the drug dissolution in the release medium, and the drug migration from the capsule to the medium. The model accurately describes the data, showing a mass transfer coefficient strongly dependent on the PEG percentage.

Could the conservative approach be considered safe in the treatment of locally advanced rectal cancer in case of a clinical near-complete or complete response? A retrospective analysis.

BACKGROUND: Conservative approach has emerged as an option for the management of rectal cancer (RC) patients with a near or complete clinical response after neoadjuvant chemoradiotherapy (nCRT). The aim of this study is to assess the impact of the conservative approach by comparing patients' survival outcomes and quality of life with those who had surgical resection. METHODS: A single-institution and retrospective study including RC patients who reached a near complete or complete clinical response after nCRT from January 2010 to September 2019. Conservative approaches included local excision or watch and wait strategy; surgery approaches included anterior resection or abdominal-perineal resection.Local regrowth (LR), overall survival, disease free survival, metastasis free survival and colostomy free survival were evaluated through Kaplan-Meier curves and compared trough log-rank tests. Quality of life was measured by the following validated questionnaires: EORTC QLC30, EORTC QLQ - CR29 and Fecal Incontinence Quality of Life scale. RESULTS: Overall 157 patients were analyzed: 105 (66,9%) underwent radical surgery and 52 (33,1%) had a conservative approach. With a median follow-up of 51 months, 2 patients in the surgical group had a local recurrence and 8 in the conservative group had a LR, respectively. Distance metastasis occurred in 7 and 1 patients of surgical and conservative group, respectively. No differences were detected in terms of survival outcomes except for colostomy free survival (p: 0,01). The conservative group showed better intestinal (p < 0.01) and sexual (p: 0,04) function and emotional status (p: 0,02). CONCLUSIONS: Conservative approach seems to be safe in terms of survival outcomes with a significant advantage on quality of life in RC patients who achieved clinical complete response after nCRT.

Formation of Rutin-ß-Cyclodextrin Inclusion Complexes by Supercritical Antisolvent Precipitation.

In this work, rutin (RUT)-ß-cyclodextrin (ß-CD) inclusion complexes are prepared by Supercritical AntiSolvent (SAS) precipitation. Well-defined composite microparticles are obtained at guest:host ratios equal to 1:2 and 1:1 mol:mol. The dimensions of composite particles range between 1.45 ± 0.88 µm and 7.94 ± 2.12 µm. The formation of RUT-ß-CD inclusion complexes has been proved by different analyses, including Fourier transform infrared spectroscopy, Differential Scanning Calorimetry, X-ray diffraction, and UV-vis spectroscopy. The dissolution tests reveal a significant improvement in the release rate of RUT from inclusion complexes. Indeed, compared to the unprocessed RUT, the dissolution rate is about 3.9 and 2.4 times faster in the case of the complexes RUT-ß-CD 1:2 and 1:1 mol:mol, respectively. From a pharmaceutical/nutraceutical point of view, CD-based inclusion complexes allow the reduction of the polymer amount in the SAS composite formulations.

Breast Tumor Cell Invasion and Pro-Invasive Activity of Cancer-Associated Fibroblasts Co-Targeted by Novel Urokinase-Derived Decapeptides.

Among peritumoral cells, cancer-associated fibroblasts (CAFs) are major facilitators of tumor progression. This study describes the effects of two urokinase-derived, novel decapeptides, denoted as Pep 1 and its cyclic derivative Pep 2. In a mouse model of tumor dissemination, using HT1080 fibrosarcoma cells, Pep 2 reduced the number and size of lung metastases. Specific binding of fluoresceinated Pep 2 to HT1080 and telomerase immortalised fibroblasts (TIF) cell surfaces was enhanced by αv overexpression or abolished by excess vitronectin, anti-αv antibodies or silencing of ITGAV αv gene, identifying αv-integrin as the Pep 2 molecular target. In 3D-organotypic assays, peptide-exposed TIFs and primary CAFs from breast carcinoma patients both exhibited a markedly reduced pro-invasive ability of either HT1080 fibrosarcoma or MDA-MB-231 mammary carcinoma cells, respectively. Furthermore, TIFs, either exposed to Pep 2, or silenced for αv integrin, were impaired in their ability to chemoattract cancer cells and to contract collagen matrices, exhibiting reduced α-smooth muscle actin (α-SMA) levels. Finally, peptide exposure of αv-expressing primary CAFs led to the downregulation of α-SMA protein and to a dramatic reduction of their pro-invasive capability. In conclusion, the ability of the novel decapeptides to interfere with tumor cell invasion directly and through the down-modulation of CAF phenotype suggests their use as lead compounds for co-targeting anti-cancer strategies.

The Use of Poly(N-vinyl pyrrolidone) in the Delivery of Drugs: A Review.

Polyvinylpyrrolidone (PVP) is a hydrophilic polymer widely employed as a carrier in the pharmaceutical, biomedical, and nutraceutical fields. Up to now, several PVP-based systems have been developed to deliver different active principles, of both natural and synthetic origin. Various formulations and morphologies have been proposed using PVP, including microparticles and nanoparticles, fibers, hydrogels, tablets, and films. Its versatility and peculiar properties make PVP one of the most suitable and promising polymers for the development of new pharmaceutical forms. This review highlights the role of PVP in drug delivery, focusing on the different morphologies proposed for different polymer/active compound formulations. It also provides detailed information on active principles and used technologies, optimized process parameters, advantages, disadvantages, and final applications.

Eudragit: A Novel Carrier for Controlled Drug Delivery in Supercritical Antisolvent Coprecipitation.

In this work, the supercritical antisolvent (SAS) process was used to coprecipitate Eudragit L100-55 (EUD) with diclofenac (DICLO) and theophylline (THEOP), with the aim of obtaining composite microparticles with a prolonged drug release for oral delivery. Working at the optimized conditions in terms of pressure and overall concentration in the liquid solution (10.0 MPa and 50 mg/mL), microparticles of EUD/DICLO 20/1 and 10/1 w/w were produced with a mean size of 2.92 µm and 1.53 µm, respectively. For the system EUD/THEOP, well-defined spherical microspheres with a mean diameter ranging from 3.75 µm and 5.93 µm were produced at 12.0 MPa. The produced composite systems were characterized by various techniques, such as scanning electron microscopy, differential scanning calorimetry, X-ray microanalysis, FT-IR and UV-vis spectroscopy. Dissolution studies showed the potential of EUD to prolong the drug release, significantly, up to a few days.

PCL/Mesoglycan Devices Obtained by Supercritical Foaming and Impregnation.

In this work, a one-shot process for the simultaneous foaming of polycaprolactone (PCL) and impregnation of mesoglycan (MSG) into the porous structure was successfully attempted. Supercritical carbon dioxide plays the role of the foaming agent with respect to PCL and of the solvent with respect to MSG. The main objective is to produce an innovative topical device for application on skin lesions, promoting prolonged pro-resolving effects. The obtained device offers a protective barrier to ensure a favorable and sterilized environment for the wound healing process. The impregnation kinetics revealed that a pressure of 17 MPa, a temperature of 35 °C, and a time of impregnation of 24 h assured a proper foaming of PCL in addition to the impregnation of the maximum amount of MSG; i.e., 0.22 mgMSG/mgPCL. After a preliminary study conducted on PCL granules used as brought, the MSG impregnation was performed at the optimized process conditions also on a PCL film, produced by compression molding, with the final goal of producing medical patches. Comparing the dissolution profiles in phosphate buffered saline solution (PBS) of pure MSG and MSG impregnated on foamed PCL, it was demonstrated that the release of MSG was significantly prolonged up to 70 times. Next, we performed functional assays of in vitro wound healing, cell invasion, and angiogenesis to evaluate the biological effects of the PCL-derived MSG. Interestingly, we found the ability of this composite system to promote the activation of human keratinocytes, fibroblasts, and endothelial cells, as the main actors of tissue regeneration, confirming what we previously showed for the MSG alone.

Paracrine recruitment and activation of fibroblasts by c-Myc expressing breast epithelial cells through the IGFs/IGF-1R axis.

Fibroblasts are among the most abundant stromal cells in the tumor microenvironment (TME), progressively differentiating into activated, motile, myofibroblast-like, protumorigenic cells referred to as Cancer-Associated Fibroblasts (CAFs). To investigate the mechanisms by which epithelial cells direct this transition, the early stages of tumorigenesis were exemplified by indirect cocultures of WI-38 or human primary breast cancer fibroblasts with human mammary epithelial cells expressing an inducible c-Myc oncogene (MCF10A-MycER). After c-Myc activation, the conditioned medium (CM) of MCF10A-MycER cells significantly enhanced fibroblast activation and mobilization. As this was accompanied by decreased insulin-like growth factor binding protein-6 (IGFBP-6) and increased insulin-like growth factor-1 and IGF-II (IGF-I, IGF-II) in the CM, IGFs were investigated as key chemotactic factors. Silencing IGFBP-6 or IGF-I or IGF-II expression in epithelial cells or blocking Insulin-like growth factor 1 receptor (IGF-1R) activity on fibroblasts significantly altered fibroblast mobilization. Exposure of WI-38 fibroblasts to CM from induced MCF10A-MycER cells or to IGF-II upregulated FAK phosphorylation on Tyr397 , as well as the expression of α-smooth muscle actin (α-SMA), features associated with CAF phenotype and increased cell migratory/invasive behavior. In three-dimensional (3D)-organotypic assays, WI-38 or human primary fibroblasts, preactivated with either CM from MCF10A-MycER cells or IGFs, resulted in a permissive TME that enabled nontransformed MCF10A matrix invasion. This effect was abolished by inhibiting IGF-1R activity. Thus, breast epithelial cell oncogenic activation and stromal fibroblast transition to CAFs are linked through the IGFs/IGF-1R axis, which directly promotes TME remodeling and increases tumor invasion.

Annexin A1 Contained in Extracellular Vesicles Promotes the Activation of Keratinocytes by Mesoglycan Effects: An Autocrine Loop Through FPRs.

We have recently demonstrated that mesoglycan, a fibrinolytic compound, may be a promising pro-healing drug for skin wound repair. We showed that mesoglycan induces migration, invasion, early differentiation, and translocation to the membrane of keratinocytes, as well as the secretion of annexin A1 (ANXA1), further involved in keratinocytes activation. These events are triggered by the syndecan-4 (SDC4)/PKCα pathway. SDC4 also participates to the formation and secretion of microvesicles (EVs) which may contribute to wound healing. EVs were isolated from HaCaT cells, as human immortalized keratinocytes, and then characterised by Western blotting, Field Emission-Scanning Electron Microscopy, and Dynamic Light Scattering. Their autocrine effects were investigated by Wound-Healing/invasion assays and confocal microscopy to analyse cell motility and differentiation, respectively. Here, we found that the mesoglycan increased the release of EVs which amplify its same effects. ANXA1 contained in the microvesicles is able to promote keratinocytes motility and differentiation by acting on Formyl Peptide Receptors (FPRs). Thus, the extracellular form of ANXA1 may be considered as a link to intensify the effects of mesoglycan. In this study, for the first time, we have identified an interesting autocrine loop ANXA1/EVs/FPRs in human keratinocytes, induced by mesoglycan.