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Abstract Background The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls. Methods A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment. Results The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p < 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p < 0.001). The addition of both markers further increased the AUC to 0.90 (p < 0.001). Conclusions The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD.

Background/Objectives: The present work proposes a mathematical model able to describe the dissolution of poly-disperse drug spherical particles in a solution (Dissolution Rate Test—DRT). DRT is a pivotal test performed in the pharmaceutical field to qualitatively assess drug bioavailability. Methods: The proposed mathematical model relies on the key hallmarks of DRT, such as particle size distribution, solubility, wettability, hydrodynamic conditions in the dissolving liquid of finite dimensions, and possible re-crystallization during the dissolution process. The spherical shape of the drug particles was the only cue simplification applied. Two model drugs were considered to check model robustness: theophylline (both soluble and wettable) and praziquantel (both poorly soluble and wettable). Results: The DRT data analysis within the proposed model allows us to understand that for theophylline, the main resistance to dissolution is due to the boundary layer surrounding drug particles, whereas wettability plays a negligible role. Conversely, the effect of low wettability cannot be neglected for praziquantel. These results are validated by the determination of drug wettability performed while measuring the solid–liquid contact angle on four liquids with decreasing polarities. Moreover, the percentage of drug polarity was determined. Conclusions: The proposed mathematical model confirms the importance of the different physical phenomena leading the dissolution of poly-disperse solid drug particles in a solution. Although a comprehensive mathematical model was proposed and applied, the DRT data of theophylline and praziquantel was successfully fitted by means of just two fitting parameters.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive disease for which no curative treatment is currently available. Objective: This study aimed to investigate whether cortico-spinal transcranial direct current stimulation (tDCS) could mitigate symptoms in ALS patients via a randomized, double-blind, sham-controlled trial, followed by an open-label phase. Methods: Thirty-one participants were randomized into two groups for the initial controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS), while Group 2 received cortico-spinal stimulation (real tDCS) for five days/week for two weeks (T1), with an 8-week (T2) follow-up (randomized, double-blind, sham-controlled phase). At the 24-week follow-up (T3), all participants (Groups 1 and 2) received a second treatment of anodal bilateral motor cortex and cathodal spinal stimulation (real tDCS) for five days/week for two weeks (T4). Follow-up evaluations were performed at 32-weeks (T5) and 48-weeks (T6) (open-label phase). At each time point, clinical assessment, blood sampling, and intracortical connectivity measures using transcranial magnetic stimulation (TMS) were evaluated. Additionally, we evaluated survival rates. Results: Compared to sham stimulation, cortico-spinal tDCS significantly improved global strength, caregiver burden, and quality of life scores, which correlated with the restoration of intracortical connectivity measures. Serum neurofilament light levels decreased among patients who underwent real tDCS but not in those receiving sham tDCS. The number of completed 2-week tDCS treatments significantly influenced patient survival. Conclusions: Cortico-spinal tDCS may represent a promising therapeutic and rehabilitative approach for patients with ALS. Further larger-scale studies are necessary to evaluate whether tDCS could potentially impact patient survival. Clinical trial registration: NCT04293484.

Background: The identification of novel therapeutic strategies for ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with the cysteine-dependent deubiquitinating enzyme (DUB) UCHL5, thus affecting the ubiquitin-proteasome-dependent degradation of proteins. Methods: 2c phenotypic/molecular effects were studied in two OC 2D/3D culture models and in a mouse xenograft model. Furthermore, we propose an in silico model of 2c interaction with DUB-UCHL5. Finally, we have tested the effect of 2c conjugated to several linkers to generate 2c/derivatives usable for improved drug delivery. Results: 2c effectively impairs the OC cell line and primary tumor cell viability in both 2D and 3D conditions. The effectiveness is confirmed in a xenograft mouse model of OC. We show that 2c impairs proteasome activity and triggers apoptosis, most likely by interacting with DUB-UCHL5. We also propose a mechanism for the interaction with DUB-UCHL5 via an in silico evaluation of the enzyme-inhibitor complex. 2c also reduces cell growth by down-regulating the level of the transcription factor E2F1. Eventually, 2c activity is often retained after the conjugation with linkers. Conclusion: Our data strongly support the potential therapeutic value of 2c/derivatives in OC.

Agarose is a natural polysaccharide known for its ability to form thermoreversible hydrogels. While the effects of curing temperature and polysaccharide concentration on mechanical properties have been discussed in the literature, the role of ionic strength has been less studied. In the present manuscript, we investigate the effects of supporting salt concentration and the role of cation (i.e. Na+ or Li+, neighbors in the Hofmeister series), on the setting and performance of agarose hydrogels. Compressive and rheological measurements show that the supporting salts reduce the immediate elastic response of agarose hydrogels, with Li+ showing a stronger effect than Na+ at high ionic strength, while they significantly increase the extent of linear stress-strain response (i.e., linear elasticity). The presence of increasing amounts of added supporting salt also leads to a reduction in hysteresis during mechanical deformation due to loading and unloading cycles, which is more pronounced with Li+ than with Na+. The combination of rheological measurements and NMR relaxometry shows a mesh size in agarose hydrogels in the order of 6–17 nm, with a thickness of the water layer bound to the biopolymer of about 3 nm. Of note, the different structuring of the water within the hydrogel network due to the different alkali seems to play a role for the final performance of the hydrogels.

Abstract Background Pathway enrichment analysis is extensively used in high-throughput experimental studies to gain insight into the functional roles of pre-defined subsets of genes, proteins and metabolites. Methods that leverages information on the topology of the underlying pathways outperform simpler methods that only consider pathway membership, leading to improved performance. Among all the proposed software tools, there’s the need to combine high statistical power together with a user-friendly framework, making it difficult to choose the best method for a particular experimental environment. Results We propose SEMgsa, a topology-based algorithm developed into the framework of structural equation models. SEMgsa combine the SEM p values regarding node-specific group effect estimates in terms of activation or inhibition, after statistically controlling biological relations among genes within pathways. We used SEMgsa to identify biologically relevant results in a Coronavirus disease (COVID-19) RNA-seq dataset (GEO accession: GSE172114) together with a frontotemporal dementia (FTD) DNA methylation dataset (GEO accession: GSE53740) and compared its performance with some existing methods. SEMgsa is highly sensitive to the pathways designed for the specific disease, showing low p values ( $$< 0.001$$ < 0.001 ) and ranking in high positions, outperforming existing software tools. Three pathway dysregulation mechanisms were used to generate simulated expression data and evaluate the performance of methods in terms of type I error followed by their statistical power. Simulation results confirm best overall performance of SEMgsa. Conclusions SEMgsa is a novel yet powerful method for identifying enrichment with regard to gene expression data. It takes into account topological information and exploits pathway perturbation statistics to reveal biological information. SEMgsa is implemented in the R package SEMgraph, easily available at https://CRAN.R-project.org/package=SEMgraph .

Scleroglucan (Sclg) and Guar Gum (GG) are both capable to give gels in the presence of borax and this study is focused on how a mixed system of the two polysaccharides can be affected by the addition of borax. The anisotropic swelling behavior of tablets obtained by compression of the freeze-dried new gel system is also investigated and compared to that of Sclg and GG alone. Rheological characterization evidences a synergistic effect in terms of critical time, mesh size, as well as crosslinking density. Also creep recovery experiments, carried out in the presence of borax, show a synergistic effect: when the polymers are mixed, a quite low compliance was estimated in comparison to that of Sclg and GG. On the other side, the flexible chains of GG induce the self-healing properties of the mixed gel system, since the rigid triple helix of Sclg does not show such peculiar characteristics. The deep insight of the physico-chemical properties of the new hydrogel system can play a fundamental role for the optimization of its practical application (e.g., in drug delivery, cosmetic products, human tissue repair, wound dressing and food staff).

A cryogel is a cross-linked polymer network with different properties that are determined by its manufacturing technique. The formation of a cryogel occurs at low temperatures and results in a porous structure whose pore size is affected by thermal conditions. The adjustable pore sizes of cryogels make them attractive for diverse applications. In this study, the influence of the external operational temperature, which affects the cooling and freezing rates, on the production of cryogels with 2% w/w agarose is investigated. Moreover, a mathematical model is developed to simulate the cryogel production process and provide an initial estimate of the pore size within the structure. The predictions of the model, supported by qualitative light microscopy images, demonstrate that cryogels produced at higher process temperatures exhibit larger pore sizes. Moreover, the existence of pore size distribution within the gel structure is confirmed. Finally, stress relaxation tests, coupled with an image analysis, validates that cryogels produced at lower temperatures possess a higher stiffness and slower water release rates.

The design of multi-stimuli-responsive vehicles for the controlled and localized release of drugs is a challenging issue increasingly catching the attention of many research groups working on the advanced treatment of hard-to-close wounds. In this work, a thermo- and pH-responsive hydrogel (P-CHP407) was prepared from an ad hoc synthesized amphiphilic poly(ether urethane) (CHP407) exposing a significant amount of –COOH groups (8.8 ± 0.9 nmol/gpolymer). The exposure of acid moieties in P-CHP407 hydrogel led to slightly lower initial gelation temperature (12.1 °C vs. 14.6 °C, respectively) and gelation rate than CHP407 hydrogel, as rheologically assessed. Nanoscale hydrogel characterization by Low Field NMR (LF-NMR) spectroscopy suggested that the presence of carboxylic groups in P-CHP407 caused the formation of bigger micelles with a thicker hydrated shell than CHP407 hydrogels, as further proved by Dynamic Light Scattering analyses. In addition, P-CHP407 hydrogel showed improved capability to change its internal pH compared to CHP407 one when incubated with an alkaline buffer (pH 8) (e.g., pHchange_5min = 3.76 and 1.32, respectively). Moreover, LF-NMR characterization suggested a stronger alkaline-pH-induced interaction of water molecules with micelles exposing –COOH groups. Lastly, the hydrogels were found biocompatible according to ISO 10993 and able to load and release Ibuprofen: delivery kinetics of Ibuprofen was enhanced by P-CHP407 hydrogels at alkaline pH, suggesting their potential use as smart delivery systems in the treatment of chronic infected wounds.

Objective: To evaluate the performance of a Random Forest (RF) classifier on Transcranial Magnetic Stimulation (TMS) measures in patients with Mild Cognitive Impairment (MCI). Methods: We applied a RF classifier on TMS measures obtained from a multicenter cohort of patients with MCI, including MCI-Alzheimer’s Disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), and healthy controls (HC). All patients underwent TMS assessment at recruitment (index test), with application of reference clinical criteria, to predict different neurodegenerative disorders. The primary outcome measures were the classification accuracy, precision, recall and F1-score of TMS in differentiating each disorder. Results: 160 participants were included, namely 64 patients diagnosed as MCI-AD, 28 as MCI-FTD, 14 as MCI-DLB, and 47 as healthy controls (HC). A series of 3 binary classifiers was employed, and the prediction model exhibited high classification accuracy (ranging from 0.72 to 0.86), high precision (0.72–0.90), high recall (0.75–0.98), and high F1-scores (0.78–0.92), in differentiating each neurodegenerative disorder. By computing a new classifier, trained and validated on the current cohort of MCI patients, classification indices showed even higher accuracy (ranging from 0.83 to 0.93), precision (0.87–0.89), recall (0.83–1.00), and F1-scores (0.85–0.94). Conclusions: TMS may be considered a useful additional screening tool to be used in clinical practice in the prodromal stages of neurodegenerative dementias.

Hepatocellular carcinoma (HCC) remains a global health challenge, representing the third leading cause of cancer deaths worldwide. Although therapeutic advances have been made in the few last years, the prognosis remains poor. Thus, there is a dire need to develop novel therapeutic strategies. In this regard, two approaches can be considered: (1) the identification of tumor-targeted delivery systems and (2) the targeting of molecule(s) whose aberrant expression is confined to tumor cells. In this work, we focused on the second approach. Among the different kinds of possible target molecules, we discuss the potential therapeutic value of targeting non-coding RNAs (ncRNAs), which include micro interfering RNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). These molecules represent the most significant RNA transcripts in cells and can regulate many HCC features, including proliferation, apoptosis, invasion and metastasis. In the first part of the review, the main characteristics of HCC and ncRNAs are described. The involvement of ncRNAs in HCC is then presented over five sections: (a) miRNAs, (b) lncRNAs, (c) circRNAs, (d) ncRNAs and drug resistance and (e) ncRNAs and liver fibrosis. Overall, this work provides the reader with the most recent state-of-the-art approaches in this field, highlighting key trends and opportunities for more advanced and efficacious HCC treatments.

The aim of this theoretical paper is to develop a mathematical model for describing the dissolution process, in a finite liquid environment, of an ensemble of poly-dispersed drug particles, in form of sphere, cylinder and parallelepiped that can undergo solubility reduction due to phase transition induced by dissolution. The main result of this work consists in its simplicity as, whatever the particular particles size distribution, only two ordinary differential equations are needed to describe the dissolution process. This, in turn, reflects in a very powerful and agile theoretical tool that can be easily implemented in electronic sheets, a widespread tool among the research community. Another model advantage lies on the possibility of determining its parameters by means of common independent techniques thus enabling the evaluation of the importance of solid wettability on the dissolution process.

Despite the progress made in the diagnoses and therapy of gastrointestinal cancers, these diseases are still plagued by a high mortality. Thus, novel therapeutic approaches are urgently required. In this regard, small interfering RNA (siRNA), double-stranded RNA molecules able to specifically target the mRNA of pathological genes, have the potential to be of therapeutic value. To be effective in the human body, siRNAs need to be protected against degradation. Additionally, they need to target the tumor, leaving the normal tissue untouched in an effort to preserve organ function. To accomplish these tasks, siRNAs have been formulated with smart delivery systems such has polymers and lipids. While siRNA protection is not particularly difficult to achieve, their targeting of tumor cells remains problematic. Here, after introducing the general features of gastrointestinal cancers, we describe siRNA characteristics together with representative delivery systems developed for gastrointestinal cancers. Afterward, we present a selection of research papers employing siRNAs against upper- and lower- gastrointestinal cancers. For the liver, we also consider papers using siRNAs to combat liver cirrhosis, a relevant risk factor for liver cancer development. Finally, we present a brief description of clinical trials employing siRNAs for gastrointestinal cancers.

Background and Purpose Migraine has been shown to increase cerebral excitability, promote rapid infarct expansion into tissue with perfusion deficits, and result in larger infarcts in animal models of focal cerebral ischemia. Whether these effects occur in humans has never been properly investigated. Methods In a series of consecutive patients with acute ischemic stroke, enrolled in the setting of the Italian Project on Stroke at Young Age, we assessed acute as well as chronic infarct volumes by volumetric magnetic resonance imaging, and compared these among different subgroups identified by migraine status. Results A cohort of 591 patients (male, 53.8%; mean age, 37.5±6.4 years) qualified for the analysis. Migraineurs had larger acute infarcts than non-migraineurs (median, 5.9 cm3 [interquartile range (IQR), 1.4 to 15.5] vs. 2.6 cm3 [IQR, 0.8 to 10.1], P

The treatment of urological cancers has been significantly improved in recent years. However, for the advanced stages of these cancers and/or for those developing resistance, novel therapeutic options need to be developed. Among the innovative strategies, the use of small interfering RNA (siRNA) seems to be of great therapeutic interest. siRNAs are double-stranded RNA molecules which can specifically target virtually any mRNA of pathological genes. For this reason, siRNAs have a great therapeutic potential for human diseases including urological cancers. However, the fragile nature of siRNAs in the biological environment imposes the development of appropriate delivery systems to protect them. Thus, ensuring siRNA reaches its deep tissue target while maintaining structural and functional integrity represents one of the major challenges. To reach this goal, siRNA-based therapies require the development of fine, tailor-made delivery systems. Polymeric nanoparticles, lipid nanoparticles, nanobubbles and magnetic nanoparticles are among nano-delivery systems studied recently to meet this demand. In this review, after an introduction about the main features of urological tumors, we describe siRNA characteristics together with representative delivery systems developed for urology applications; the examples reported are subdivided on the basis of the different delivery materials and on the different urological cancers.

Due to its hydroxyl terminal groups, Poloxamer® 407 (P407), a commercially available poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymer can be used as macrodiol for the synthesis of high molecular weight amphiphilic poly(ether urethane)s (PEUs). This work was aimed at studying the effect of P407 purification by removing PEO-PPO diblock copolymer by-products on the chemical properties of PEU polymer and the physical properties of PEU hydrogels. Removal of PEO-PPO diblock copolymers (P407_P) was found to preserve the thermo-responsiveness of resulting hydrogels, although slightly lower gelation onset temperature (Tonset) was found for P407_P (15.3°C) vs. P407 (16.7°C) hydrogels (25% w/V) as assessed through temperature ramp test. P407 and P407_P were then reacted with 1,6-diisocyanatohexane and 1,4-cyclohexanedimethanol to synthesize two different PEUs, coded as CHP407 and CHP407_P, respectively. Lower Number Average Molecular Weight (Mn¯) and higher polydispersity Index (D) was measured for CHP407 (Mn¯: 34 kDa, D: 1.6) respect to CHP407_P (Mn¯: 40 kDa, D: 1.4) as a consequence of macrodiol purification. CHP407_P hydrogels formed bigger micelles (43.9 ± 4.1 nm vs. 28.7 ± 4 nm) while showed similar critical micellar temperatures (22.1°C vs. 21.6°C) respect to CHP407 formulations. Sol-to-gel transition of CHP407 and CHP407_P hydrogels was similar while CHP407_P gelation time at 37°C was longer as assessed by tube inverting test. The rheological analysis showed slightly lower Tonset for CHP407_P hydrogels (15% w/V), probably due to larger micelle size, promoting micellar assembly. However, CHP407_P hydrogels showed a significantly lower critical strain than CHP407 hydrogels, as assessed by strain sweep test, suggesting their higher brittleness due to a lower density of intermicellar bridge chains. Nano-scale hydrogel characterization by Low-Field Nuclear Magnetic Resonance spectroscopy supported previous findings, showing lower spin-spin relaxation time (i.e., 1,259 ms) for CHP407_P than for CHP407 hydrogels (i.e., 1,560 ms) at 37°C, which suggested the formation of a more tightly packed network for CHP407_P than CHP407 hydrogel. Finally, lower swelling capability and resistance against dissolution were measured for CHP407_P hydrogels. Overall, the here‐reported results suggested that the heterogeneous structure in the CHP407 hydrogel network caused by the presence of diblock copolymer-based macrodiols improved PEU hydrogel properties in light of their applicability in the biomedical field.

The focus of this paper is on the theoretical interpretation of Low Field Nuclear Magnetic Resonance (LF-NMR) data regarding hydrogels architecture and on the most interesting applications of LF-NMR presented by this research group at the 6th IAPC Symposium held in Zagreb (HR) on September 2017. Particular attention is devoted to the determination of the mesh size distribution of gels polymeric network and the determination of the pore size distribution of microporous systems such as scaffolds, bones, and porous gels. In addition, we report on a very recent application of LF-NMR for monitoring lung functioning in patients suffering from chronic pulmonary diseases like cystic fibrosis. The main findings of this work consist in providing a very simple and accurate approximation of a general theory devoted to evaluating the relation existing among four fundamental polymeric network parameters, i.e. the polymer volume fraction inside the hydrogel, mesh size, hydraulic radius, and the radius of the cylinder ideally embedding each polymeric network chain. Furthermore, we demonstrated the potentiality of LF-NMR in the characterization of different polymeric systems among which the sputum of patients suffering from chronic pulmonary diseases appears the most innovative application for its simplicity, rapidity, effectiveness, and potential impact in the everyday clinic.

Hepatocellular carcinoma (HCC) is the sixth most common type of tumor and the second leading cause of tumor-related death worldwide. Liver cirrhosis is the most important predisposing factor for HCC. Available therapeutic approaches are not very effective, especially for advanced HCC, which is the most common form of the disease at diagnosis. New therapeutic strategies are therefore urgently needed. The use of animal models represents a relevant tool for preclinical screening of new molecules/strategies against HCC. However, several issues, including animal husbandry, limit the use of current models (rodent/pig). One animal model that has attracted the attention of the scientific community in the last 15 years is the zebrafish. This freshwater fish has several attractive features, such as short reproductive time, limited space and cost requirements for husbandry, body transparency and the fact that embryos do not show immune response to transplanted cells. To date, two different types of zebrafish models for HCC have been developed: the transgenic zebrafish and the zebrafish xenograft models. Since transgenic zebrafish models for HCC have been described elsewhere, in this review, we focus on the description of zebrafish xenograft models that have been used in the last five years to test new molecules/strategies against HCC.

Brain functional disruption and cognitive shortfalls as consequences of neurodegeneration are among the most investigated aspects in current clinical research. Traditionally, specific anatomical and behavioral traits have been associated with neurodegeneration, thus directly translatable in clinical terms. However, these qualitative traits, do not account for the extensive information flow breakdown within the functional brain network that deeply affect cognitive skills. Behavioural variant Frontotemporal Dementia (bvFTD) is a neurodegenerative disorder characterized by behavioral and executive functions disturbances. Deviations from the physiological cognitive functioning can be accurately inferred and modeled from functional connectivity alterations. Although the need for unbiased metrics is still an open issue in imaging studies, the graph-theory approach applied to neuroimaging techniques is becoming popular in the study of brain dysfunction. In this work, we assessed the global connectivity and topological alterations among brain regions in bvFTD patients using a minimum spanning tree (MST) based analysis of resting state functional MRI (rs-fMRI) data. Whilst several graph theoretical methods require arbitrary criteria (including the choice of network construction thresholds and weight normalization methods), MST is an unambiguous modeling solution, ensuring accuracy, robustness, and reproducibility. MST networks of 116 regions of interest (ROIs) were built on wavelet correlation matrices, extracted from 41 bvFTD patients and 39 healthy controls (HC). We observed a global fragmentation of the functional network backbone with severe disruption of information-flow highways. Frontotemporal areas were less compact, more isolated, and concentrated in less integrated structures, respect to healthy subjects. Our results reflected such complex breakdown of the frontal and temporal areas at both intra-regional and long-range connections. Our findings highlighted that MST, in conjunction with rs-fMRI data, was an effective method for quantifying and detecting functional brain network impairments, leading to characteristic bvFTD cognitive, social, and executive functions disorders.

The influence of the physical, rheological, and process parameters on the cellulose nanocrystal (CNC) drops before and after external gelation in a CaCl2 solution was investigated. The dominant role of the CNC’s colloidal suspension properties, such as the viscous force, inertial, and surface tension forces in the fluid dynamics was quantitatively evaluated in the formation of drops and jellified beads. The similarity and difference between the behavior of carbohydrate polymers and rod-like crystallites such as CNC were enlightened. Pump-driven and centrifugally-driven external gelation approaches were followed to obtain CNC hydrogel beads with tunable size and regular shape. A superior morphological control—that is, a more regular shape and smaller dimension of the beads—were obtained by centrifugal force-driven gelation. These results suggest that even by using a simple set-up and a low-speed centrifuge device, the extrusion of a colloidal solution through a small nozzle under a centrifugal field is an efficient approach for the production of CNC hydrogel beads with good reproducibility, control over the bead morphology and size monodispersion.

Frontotemporal Dementia (FTD) is the form of neurodegenerative dementia with the highest prevalence after Alzheimer's disease, equally distributed in men and women. It includes several variants, generally characterized by behavioural instability and language impairments. Although few mendelian genes (MAPT, GRN, and C9orf72) have been associated to the FTD phenotype, in most cases there is only evidence of multiple risk loci with relatively small effect size. To date, there are no comprehensive studies describing FTD at molecular level, highlighting possible genetic interactions and signalling pathways at the origin FTD-associated neurodegeneration. In this study, we designed a broad FTD genetic interaction map of the Italian population, through a novel network-based approach modelled on the concepts of disease-relevance and interaction perturbation, combining Steiner tree search and Structural Equation Model (SEM) analysis. Our results show a strong connection between Calcium/cAMP metabolism, oxidative stress-induced Serine/Threonine kinases activation, and postsynaptic membrane potentiation, suggesting a possible combination of neuronal damage and loss of neuroprotection, leading to cell death. In our model, Calcium/cAMP homeostasis and energetic metabolism impairments are primary causes of loss of neuroprotection and neural cell damage, respectively. Secondly, the altered postsynaptic membrane potentiation, due to the activation of stress-induced Serine/Threonine kinases, leads to neurodegeneration. Our study investigates the molecular underpinnings of these processes, evidencing key genes and gene interactions that may account for a significant fraction of unexplained FTD aetiology. We emphasized the key molecular actors in these processes, proposing them as novel FTD biomarkers that could be crucial for further epidemiological and molecular studies.

This paper focuses on a physiologically-oriented mathematical model aimed at studying the in vivo drug release, absorption, distribution, metabolism and elimination (ADME). To this purpose, the model accounts for drug delivery from an ensemble of non-eroding poly-disperse polymeric particles and the subsequent ADME processes. The model outcomes are studied with reference to three widely used drugs: theophylline, temazepam and nimesulide. One of the most important results of this study is the quantitative evaluation of the interplay between the release kinetics and the subsequent ADME processes. Indeed, it is usually assumed that in vivo drug release coincides with in vitro so that the effect exerted by the ADME processes is neglected. In addition, the proposed model may be an important tool for the design of delivery systems since, through proper changes, it could also account for different oral delivery systems.

The unmet need for novel therapeutic options for ovarian cancer (OC) deserves further investigation. Among the different novel drugs, small interfering RNAs (siRNAs) are particularly attractive because of their specificity of action and efficacy, as documented in many experimental setups. However, the fragility of these molecules in the biological environment necessitates the use of delivery materials able to protect them and possibly target them to the cancer cells. Among the different delivery materials, those based on polymers and lipids are considered very interesting because of their biocompatibility and ability to carry/deliver siRNAs. Despite these features, polymers and lipids need to be engineered to optimize their delivery properties for OC. In this review, we concentrated on the description of the therapeutic potential of siRNAs and polymer-/lipid-based delivery systems for OC. After a brief description of OC and siRNA features, we summarized the strategies employed to minimize siRNA delivery problems, the targeting strategies to OC, and the preclinical models available. Finally, we discussed the most interesting works published in the last three years about polymer-/lipid-based materials for siRNA delivery.

Background: The new concepts of personalized and precision medicine require the design of more and more refined delivery systems. In this frame, hydrogels can play a very important role as they represent the best surrogate of soft living tissues for what concerns rheological properties. Thus, this paper focusses on a global theoretical approach able to describe how hydrogel polymeric networks can affect the release kinetics of drugs characterized by different sizes. The attention is focused on a case study dealing with an interpenetrated hydrogel made up by alginate and poly(N-vinyl-2-pyrrolidone). Methods: Information about polymeric network characteristics (mesh size distribution and polymer volume fraction) is deduced from the theoretical interpretation of the rheological and the low field Nuclear Magnetic Resonance (NMR) characterization of hydrogels. This information is then, embodied in the mass balance equation whose resolution provides the release kinetics. Results: Our simulations indicate the influence of network characteristics on release kinetics. In addition, the reliability of the proposed approach is supported by the comparison of the model outcome with experimental release data. Conclusions: This study underlines the necessity of a global theoretical approach in order to design reliable delivery systems based on hydrogels.

Despite the advances in anticancer therapies, their effectiveness for many human tumors is still far from being optimal. Significant improvements in treatment efficacy can come from the enhancement of drug specificity. This goal may be achieved by combining the use of therapeutic molecules with tumor specific effects and delivery carriers with tumor targeting ability. In this regard, nucleic acid-based drug (NABD) and particularly small interfering RNAs (siRNAs), are attractive molecules due to the possibility to be engineered to target specific tumor genes. On the other hand, polymeric-based delivery systems are emerging as versatile carriers to generate tumor-targeted delivery systems. Here we will focus on the most recent findings in the selection of siRNA/polymeric targeted delivery systems for hepatocellular carcinoma (HCC), a human tumor for which currently available therapeutic approaches are poorly effective. In addition, we will discuss the most attracting and, in our opinion, promising siRNA-polymer combinations for HCC in relation to the biological features of HCC tissue. Attention will be also put on the mathematical description of the mechanisms ruling siRNA-carrier delivery, this being an important aspect to improve effectiveness reducing the experimental work.

In this paper we have concentrated on the characterization of calcium alginate hydrogels loaded with a model drug (myoglobin) by means of a mechanical approach; in addition, release tests of myoglobin from alginate hydrogels were performed. At a fixed temperature, relaxation tests (mechanical study) were carried out on matrices constituted by different polymer concentrations. The interpretation of the relaxation behavior of the different matrices was conducted using the generalized Maxwell model; as a result of this investigation it was possible to conclude that for polymer concentrations greater than 0.5 g/ 100 mL the matrices behaved as solid materials. In addition, it was observed that the mechanical properties of the matrices increased with polymer concentration. With regard to the release tests, the diffusion coefficient of myoglobin in the matrix in relation to polymer concentrations was determined. The mechanical and release data where then analyzed by Flory’s theory and by a modified free-volume theory, respectively, to estimate the network mesh size ξ. The comparison between the mesh sizes obtained by the two approaches showed a satisfactory agreement for polymer concentrations greater than 0.5 g/100 mL. It should be noted that the approach proposed here to determine the polymeric network meshes is absolutely general and can be advantageously applied to the characterization of other similar polymeric systems.

Stefano Nava1, Carmen Santoro1, Mario Grassi2, Nicholas Hill31Respiratory Unit, Fondazione S Maugeri, I R C C S Istituto Scientifico di Pavia, Pavia, Italy; 2Department of Health Sciences, Section of Medical Statistics and Epidemiology, University of Pavia, Pavia, Italy; 3Pulmonary and Critical Care Division, Tufts University, New England Medical Center, Boston, MA, USABackground: The decision whether or not to undertake cardiopulmonary resuscitation (CPR) is a major ethical challenge. Patient preferences may be influenced by multiple factors, including information given by the media.Objectives: We wanted to assess whether patients’ knowledge about CPR survival and outcomes was related to presentation by the media.Methods: 100 consecutive patients with COPD and chronic respiratory failure (CRF) and 100 patients at their first hospital admission for respiratory problems were enrolled. A questionnaire was administered to the patients seeking to ascertain their exposure to health information from the media, and to obtain their opinions on 1) the probability of survival after CPR, 2) the maximal length of time from collapse to CPR that allows a reasonable chance of survival, and 3) long-term outcomes of CPR survivors.Results: The patients overestimated the success rate of CPR (63% of them estimated a hospital survival >40%), while the estimate of long-term outcome and timing of the procedure were more realistic. Bivariate correlations analysis showed significant correlation between the rate of correct responses and the viewing of educational television programs (p = 0.039), but not medical stories, reading of health-oriented newspapers, use of the internet, age, educational level, and the presence of CRF.Conclusions: In conclusion, we have shown that both COPD and “newly admitted” patients’ estimate of survival after CPR is much higher than reported by the current literature. A correct knowledge of CPR procedures and outcomes is significantly correlated with the exposure to “educational” medical TV programs, but not medical stories, newspapers, or internet sources.Keywords: cardiopulmonary resuscitation, chronic respiratory failure, chronic obstructive pulmonary disease, media, television

Scleroglucan is a natural polysaccharide, produced by fungi of the genus Sclerotium, that has been extensively studied for various commercial applications (secondary oil recovery, ceramic glazes, food, paints, etc.) and also shows several interesting pharmacological properties. This review focuses its attention on the use of scleroglucan, and some derivatives, in the field of pharmaceutics and in particular for the formulation of modified-release dosage forms. The reported investigations refer mainly to the following topics: natural scleroglucan suitable for the preparation of sustained release tablets and ocular formulations; oxidized and crosslinked scleroglucan used as a matrix for dosage forms sensitive to environmental conditions; co-crosslinked scleroglucan/gellan whose delivery rate can be affected by calcium ions. Furthermore, a novel hydrogel obtained with this polysaccharide and borate ions is described, and the particular structure of this hydrogel network has been interpreted in terms of conformational analysis and molecular dynamics. Profound attention is devoted to the mechanisms involved in drug release from the tested dosage forms that depend, according to the specific preparation, on swelling and/or diffusion. Experimental data are also discussed on the basis of a mathematical approach that allows a better understanding of the behavior of the tested polymeric materials.

The effects that an increase of environmental pH has on the triple helix of scleroglucan (Sclg) and on the Sclg/borax hydrogel are reported. Rheological experiments show that the hydrogel is less sensitive to pH increase than Sclg alone, while at pH = 14 a dramatic viscosity decrease takes place for both systems. This effect is evidenced also by the reduced water uptake and anisotropic elongation detected, at pH = 14, by the swelling behaviour of tablets prepared with the Sclg/borax system. On the opposite, a different behaviour was observed with guar gum and locust bean gum tablets, tested as reference polysaccharides. The effect of pH on the structure of Sclg and Sclg/borax was investigated also by means of spectroscopic approaches based on the interaction between Congo red (CR) and the Sclg triple helix. Obtained results indicated that the CR absorbance maximum is shifted as a function of pH and by the presence of borax. Principal component analysis allowed very precise identification of the pH value at which the Sclg helix collapses. Molecular dynamics simulations of the Sclg/borax–CR complex indicated that, at physiological pH, only a few ordered configurations are populated, according to the induced circular dichroism (CD) spectrum evidence.