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Abstract Metabolic rate, the rate of energy use, underpins key ecological traits of organisms, from development and locomotion to interaction rates between individuals. In a warming world, the temperature-dependence of metabolic rate is anticipated to shift predator-prey dynamics. Yet, there is little real-world evidence on the effects of warming on trophic interactions. We measured the respiration rates of aquatic larvae of three insect species from populations experiencing a natural temperature gradient in a large-scale mesocosm experiment. Using a mechanistic model we predicted the effects of warming on these taxa’s predator-prey interaction rates. We found that species-specific differences in metabolic plasticity lead to mismatches in the temperature-dependence of their relative velocities, resulting in altered predator-prey interaction rates. This study underscores the role of metabolic plasticity at the species level in modifying trophic interactions and proposes a mechanistic modelling approach that allows an efficient, high-throughput estimation of climate change threats across species pairs.

BackgroundAlzheimer’s and other neurodegenerative forms of dementia affect 8 million Europeans. Assistive technologies are suggested to reduce the burden of care and improve the quality of life of person living with dementia. Nonetheless, the acceptance and attitudes toward technological interventions pose challenges not only for people living with dementia and caregivers but also for healthcare workers. This review specifically aims to investigate how these key groups perceive and accept technology in European dementia care settings.MethodsThis systematic review was conducted to identify studies, published between 2013 and 2023, that examined the acceptance and attitude of assistive technologies in Alzheimer’s and other dementia European settings, following the PRISMA guidelines. Rayyan AI was used for data extraction, and bias was assessed using the Mixed Methods Appraisal Tool.ResultsAmong the 1,202 identified articles, 13 met the inclusion criteria, revealing a prevailing positivity toward technological interventions in dementia care. Nonetheless, several barriers to adoption, including technological unfamiliarity, and specific dementia-related symptoms that complicate usage were identified. They also unveiled varying attitudes, influenced by factors such as familiarity with technologies, perceived usefulness, and the broader context of the COVID-19 pandemic which accelerated telemedicine and digital solution acceptance during restricted mobility and social distancing.ConclusionUnderstanding attitudes toward technology in dementia care is crucial as it influences the adoption and utilization of tech-based interventions, impacting symptom management and quality of life. Addressing these attitudes through tailored interventions and education can enhance well-being and quality of life for people living with dementia, caregivers, and healthcare professionals.

Background: We aim to provide up-to-date real-world evidence on the persistence, adherence, healthcare resource utilization, and costs of multiple sclerosis (MS) by comparing ocrelizumab to other disease-modifying treatments (DMTs) and within different DMT sequences. Methods: We included 3371 people with MS who first received or switched DMT prescriptions from January 2018 to December 2022; they were identified through hospital discharge records, drug prescriptions, and exemption codes from the Campania Region (South Italy). We calculated persistence (time from the first prescription to discontinuation or switching to another DMT), adherence (proportion of days covered (PDC)), DMT costs, and MS hospital admissions and related costs. Results: The most frequently prescribed DMT was dimethyl fumarate (n = 815; age 38.90 ± 11.91 years; 69.5% females), followed by ocrelizumab (n = 682; age 46.46 ± 11.29 years; 56.3%); 28.8% of the patients treated with ocrelizumab were naïve to DMTs. Using ocrelizumab as a statistical reference, the risk of discontinuation was higher for other highly active (HR = 6.32; 95%CI = 3.16, 12.63; p < 0.01) and low-/medium-efficacy DMTs (HR = 10.10; 95%CI = 5.10, 19.77; p < 0.01); adherence was lower for other highly active DMTs (Coeff = −0.07; 95%CI = −0.10, −0.04; p < 0.01) and low-/medium-efficacy DMTs (Coeff = −0.16; 95%CI = −0.19, −0.14; p < 0.01). monthly DMT costs were higher for other highly active DMTs (Coeff = 77.45; 95%CI = 29.36, 125.53; p < 0.01) but lower for low-/medium-efficacy DMTs (Coeff = −772.31; 95%CI = −816.95, −727.66; p < 0.01). The hospital admissions and related costs of MS were similar between ocrelizumab, other highly active DMTs, and other low-/medium-efficacy DMTs, and with ocrelizumab as the first-line DMT after other highly active DMTs and after low-/medium-efficacy DMTs, which was possibly due to the low number of observations. Conclusions: From 2018 to 2022, ocrelizumab was among the most frequently prescribed DMTs, with 28.8% prescriptions to incident MS patients, confirming its relevance in clinical practice. Ocrelizumab was associated with the highest persistence and adherence, pointing towards its favorable benefit–risk profile. The costs of ocrelizumab were lower than those of other highly active DMTs.

Abstract Multiple oncogenic alterations contribute to breast cancer development. Metabolic reprogramming, deeply contributing to tumor microenvironment (TME) education, is now widely recognized as a hallmark of cancer. The reverse Warburg effect induces cancer-associated fibroblasts (CAFs) to produce and secrete L-lactate, enhancing malignant characteristics such as neoangiogenesis, metastatic dissemination, and treatment resistance. Monocarboxylate transporter (MCT) 4 is involved in lactate efflux from CAFs into stromal and epithelial cells. Here, we first assess the expression of miR-425-5p and its target MCT4 in breast cancer CAFs and normal fibroblasts. We analyzed the metabolic changes induced by miR-425-5p in CAFs and its role in the education of breast cancer epithelial cells. We show that miR-425-5p-induced MCT4 knockdown decreased lactate extrusion from CAFs and its availability in the TME. miR-425-5p overexpression induced profound metabolic transformation in CAFs, ultimately influencing breast cancer metabolism. Furthermore, miR-425-5p impaired the capacity of CAFs to sustain vessel formation and breast cancer cell migration, viability, and proliferation. These findings emphasize the key role of miR-425-5p in breast cancer metabolism and aggressiveness, and its possible importance for breast cancer therapy and monitoring.

Nonobstetric vaginal or vulva trauma is an extremely rare occurrence, with an incidence of < 0.2% of traumas. CT represents the gold standard in the diagnosis of gunshot lesions due to its ability to detect and stage injuries with very high sensitivity and specificity. A standardized protocol for penetrating trauma is still under debate for the use of intravenous contrast only or also rectal and oral contrast. Herein, we report a case of gunshot vaginal trauma in a 43-year-old patient presenting with vaginal bleeding. In our case, the protocol was “patient's tailored,” the intravaginal selective use of air was administered due to symptoms (vaginal bleeding) and CT findings, this 2-step protocol increased diagnostic confidence and allow a correct and challenging diagnosis.

Abstract Pore fluids are ubiquitous throughout the lithosphere and are commonly invoked as the cause of induced seismicity and slow earthquakes. We perform lab experiments to address these questions for drained fault conditions and low pore pressure. We shear simulated faults at effective normal stress σn′ of 20 MPa and pore pressures Pp from 1 to 4 MPa. We document the full range of lab earthquake behaviors from slow slip to elasto‐dynamic rupture and show that slow slip can be explained by the slip rate dependence of the critical rheologic stiffness without dilatancy hardening or other fluid effects. Our fault permeabilities ranges from 10−18 to 10−17 m2 with an initial porosity of 0.1 and estimated fluid diffusion time ≈1 s. Slow slip and quasi‐dynamic fault motion may arise from high Pp at higher pressures but dilatancy strengthening is not a general requirement.

Abstract Background Intra-tumor heterogeneity (ITH) results from the continuous accumulation of mutations during disease progression, thus impacting patients’ clinical outcome. How the ITH evolves across papillary thyroid carcinoma (PTC) different tumor stages is lacking. Methods We used the whole-exome sequencing data from The Cancer Genome Atlas Thyroid Cancer (TCGA-THCA) cohort to track the ITH and assessed its relationship with clinical features through different stages of the PTC progression. We further assayed the expression levels of the specific genes in papillary thyroid cancer cell lines compared to an immortalized normal thyroid epithelial cell line by qRT-PCR. Results We revealed the timing of mutational processes and the dynamics of the temporal acquisition of somatic events during the lifetime of the PTC. ITH significantly influences the PTC patient’s survival rate and, as genetic heterogeneity increases, the prognosis gets worse in advanced tumor stages. ITH also affects the mutational architecture of each clinical stage which is subject to periodic fluctuations. Different mutational processes may cooperate to shape a stage-specific mutational spectrum during the progression from early to advanced tumor stages. Moreover, different evolutionary paths characterize PTC progression across pathological stages due to both mutations recurrently occurring in all stages in hotspot positions and distinct codon changes dominating in different stages. A different expression level of specific genes also exists in different thyroid cancer cell lines. Conclusions Our findings suggest ITH as a potential unfavorable prognostic factor in PTC and highlight the dynamic changes in different clinical stages of PTC, providing some clues for the precision medicine and suggesting different diagnostic decisions depending on the clinical stages of patients. Finally, complete clear guidelines to define risk stratification of PTC patients are lacking; thus, this work could contribute to defining patients who need more aggressive treatments and, in turn, could reduce the social burden of this cancer.

Cesarean scar pregnancies (CSPs) are a type of ectopic pregnancy that occur when an embryo implants within the fibrous scar tissue of a previous cesarean surgery. If not promptly detected and treated, CSPs can result in serious maternal complications, such as uterine rupture and hemorrhage. TVUS (transvaginal ultrasonography) represents the imaging of choice for the diagnosis of CSPs; however, recent studies proposed a complementary role of MRI due to its capability in soft tissue characterization that may impact the therapeutical decision-making process. The purpose of our study was to explore the role of MRI in the diagnosis and its impact on therapeutical options in CSPs. Our experience showed that MRI has a complementary role to TVSU in correctly diagnosing CSPs, identifying the type, and guiding the therapeutical approach.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. TNBC progression is sustained by recruitment of a strong tumor microenvironment (TME) mainly composed of cancer-associated fibroblasts (CAFs) able to endorse tumor hallmarks. Increasing evidences demonstrate that exosomes mediate the crosstalk between cancer cells and the TME. We examined TNBC-derived exosomes and their microRNA (miRNA) cargo in activation of normal fibroblasts (NFs) toward CAFs. We demonstrated that TNBC cell-derived exosomes increased NF collagen contraction and migration alongside CAF molecular markers. Exosome-activated fibroblasts promoted the invasion potential of normal breast epithelial cells, as assessed by an organotypic co-culture assay that resembled the in vivo context. We also investigated TNBC cell-derived exosome cargo in activating NFs to CAFs by performing small RNA sequencing. We found that the synergistic action of miR-185-5p, miR-652-5p, and miR-1246 boosted fibroblast migration and contraction, promoting specific CAF subspecialization toward a pro-migratory functional state. These data highlight the role of breast cancer cells in re-education of the TME and their contribution to tumor evolution.

Acute coronary syndrome (ACS) is the most severe clinical manifestation of coronary heart disease. We performed an epigenome-wide analysis of circulating CD4+ and CD8+ T cells isolated from ACS patients and healthy subjects (HS), enrolled in the DIANA clinical trial, by reduced-representation bisulphite sequencing (RRBS). In CD4+ T cells, we identified 61 differentially methylated regions (DMRs) associated with 57 annotated genes (53% hyper- and 47% hypo-methylated) by comparing ACS patients vs HS. In CD8+ T cells, we identified 613 DMRs associated with 569 annotated genes (28% hyper- and 72% hypo-methylated) in ACS patients as compared to HS. In CD4+ vs CD8+ T cells of ACS patients we identified 175 statistically significant DMRs associated with 157 annotated genes (41% hyper- and 59% hypo-methylated). From pathway analyses, we selected six differentially methylated hub genes (NFATC1, TCF7, PDGFA, PRKCB, PRKCZ, ABCA1) and assessed their expression levels by q-RT-PCR. We found an up-regulation of selected genes in ACS patients vs HS (P

In the Anthropocene, ecosystems are changing along with their capacity to support human well‐being. Monitoring ecosystem services (ESs) is required to assess the changing state of human–nature interactions. To standardize the monitoring of multiple facets of ESs, the Group on Earth Observations Biodiversity Observation Network (GEO BON) recently proposed the essential ecosystem service variables (EESVs), which are organized into six classes: Ecological Supply, Use, Demand, Anthropogenic Contribution, Instrumental Value, and Relational Value. We apply the EESV framework to three case studies in British Columbia, Canada, each targeting a single ES. Using trend and intervention analysis, we show how EESVs are changing and affected by policy. We discuss key challenges and solutions while providing guidance on how to quantify EESVs. Finally, we demonstrate the potential of EESVs to harmonize metrics across conceptual frameworks, monitor ES change, and provide decision support to assess progress under various international policy conventions. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is a long-term inflammatory process, with atherosclerosis as its underlying pathophysiological mechanism. Endothelial dysfunction is the first step towards atherosclerosis, where damaged endothelial cells release large amounts of pro-inflammatory cytokines and mediators, thus promoting vascular inflammation and disease progression. However, the correlation between serum cytokines and CAD severity remains to be defined. Serum samples from patients performing cardiac computed tomography for suspected CAD (n = 75) were analyzed with a multiplex bead-based immunoassay panel for simultaneous assessment of the concentration of 11 cytokines using flow cytometric technology. The analysis showed statistically significant increases in sRAGE, CCL2_MCP1, FLT1, and IL6 levels in CAD patients compared with healthy subjects and a gradual increase trend towards a more severe form of the disease for most cytokines (e.g., sCD40L, FLT1, sRAGE, CCL2-MCP1, TNFα). Lastly, we explored the performance of cytokines in predicting the diagnosis of CAD and found that an increase in IL6 levels will increase the odds of being non-obstructive CAD-positive. In contrast, an increase in CCL2-MCP1 or FLT1 levels will increase the probability of being obstructive CAD-positive. These results suggest that the combination of serum cytokines may contribute to the not-invasive stratification risk for patients with suspected CAD.

Hypoxia plays a crucial role in tumorigenesis and drug resistance, and it is recognised as a major factor affecting patient clinical outcome. Therefore, the detection of hypoxic areas within the tumour micro-environment represents a useful way to monitor tumour growth and patients’ responses to treatments, properly guiding the choice of the most suitable therapy. To date, non-invasive hypoxia imaging probes have been identified, but their applicability in vivo is strongly limited due to an inadequate resistance to the low oxygen concentration and the acidic pH of the tumour micro-environment. In this regard, nucleic acid aptamers represent very powerful tools thanks to their peculiar features, including high stability to harsh conditions and a small size, resulting in easy and efficient tumour penetration. Here, we describe a modified cell-SELEX (Systematic Evolution of Ligands by EXponential enrichment) approach that allows the isolation of specific RNA aptamers for the detection of the hypoxic phenotype in breast cancer (BC) cells. We demonstrated the effectiveness of the proposed method in isolating highly stable aptamers with an improved and specific binding to hypoxic cells. To our knowledge, this is the first example of a cell-SELEX approach properly designed and modified to select RNA aptamers against hypoxia-related epitopes expressed on tumour cell surfaces. The selected aptamers may provide new effective tools for targeting hypoxic areas within the tumour with great clinical potential.

Objectives: Four-dimensional (4D) flow cardiac magnetic resonance (CMR) represents an emerging technique for non-invasive evaluation of the aortic flow. The aim of this study was to investigate a 4D-flow CMR sequence for the assessment of thoracic aorta comparing different vendors and different magnetic fields of MR scanner in fifteen healthy volunteers. Methods: CMR was performed on three different MRI scanners: one at 1.5 T and two at 3 T. Flow parameters and planar wall shear stress (WSS) were extracted from six transversal planes along the full thoracic aorta by three operators. Inter-vendor comparability as well as scan–rescan, intra- and interobserver reproducibility were examined. Results: A high heterogeneity was found in the comparisons for each operator and for each scanner in the six transversal planes analysis (Friedman rank-sum test; p-value ≤ 0.05). Among all, the most reproducible measures were extracted for the sinotubular junction plane and for the flow parameters. Conclusions: Our results suggest that standardized procedures have to be defined to make more comparable and reproducible 4D-flow parameters and mainly, clinical impactfulness. Further studies on sequences development are needed to validate 4D-flow MRI assessment across vendors and magnetic fields also compared to a missing gold standard.

The frictional velocity dependence and healing behavior of subduction fault zones play key roles in the nucleation of stick‐slip instabilities at convergent margins. Diagenetic to low‐grade metamorphic processes such as pressure solution are proposed to be responsible for the change in frictional properties of fault materials along plate interfaces; pressure solution also likely contributes to the acceleration of healing according to previous studies. Here, we report friction studies for temperatures of 20–100°C and normal stresses from 20 to 125 MPa on samples collected from ancient subduction fault zones, the Lower Mugi and Makimine mélanges of the Cretaceous Shimanto belt. The two mélanges correspond to the updip and downdip limits of the seismogenic zone and include deformation features that indicate lower and higher degrees of pressure solution. Our data show that the Lower Mugi mélange exhibits velocity‐weakening to velocity‐neutral frictional behavior under low normal stress and that the Makimine mélange sample shows velocity‐strengthening behavior under high normal stress. We suggest that mineralogical changes due to diagenesis and metamorphism influence fault slip behavior. We measure frictional healing in slide‐hold‐slide experiments for the Lower Mugi mélange sample and document the role of pressure solution in fault healing. Our results show that frictional healing increases at higher temperatures. The microstructures related to pressure solution found in the post‐experimental gouges support the idea that the enhanced healing is related to pressure solution. Plain Language Summary: Investigating the mechanical properties of rock materials in plate boundary faults is crucial for the understanding of subduction zone earthquakes. The nucleation of earthquakes along the plate boundary occurs in a zone where friction drops during slip and fault strength rebuilds after an earthquake. The mechanical properties of fault materials in this zone are likely influenced by local diffusion of mobile elements during the interseismic period. Here, we perform friction experiments using two samples of ancient plate boundary faults that were near the updip and downdip limits of the zone, respectively. The first set of experiments reveals a variation in frictional response to slip under an experimental setup analogous to subduction zone conditions. Variation in the magnitude of interseismic pressure solution strain preserved in the samples is likely the cause of varying responses that lead to the nucleation and cessation of earthquakes. We conduct another series of experiments under varying hydrothermal conditions that reveal a faster restrengthening of the fault material at elevated temperatures. This is likely related to the temperature dependence of pressure solution, which is found to be an operative deformation mechanism based on the examination of post‐experimental materials. Key Points: Mélanges bounding the upper and lower limits of the seismogenic zone show changes in frictional velocity‐dependence with normal stressMicrostructures of the sheared samples suggest that temperature dependence of healing occurs via diffusive mass transferThermally‐activated deformation mechanisms can modulate frictional velocity‐dependence and healing behavior of plate boundary faults [ABSTRACT FROM AUTHOR]

Abstract Analysis of large-scale omics data along with biomedical images has gaining a huge interest in predicting phenotypic conditions towards personalized medicine. Multiple layers of investigations such as genomics, transcriptomics and proteomics, have led to high dimensionality and heterogeneity of data. Multi-omics data integration can provide meaningful contribution to early diagnosis and an accurate estimate of prognosis and treatment in cancer. Some multi-layer data structures have been developed to integrate multi-omics biological information, but none of these has been developed and evaluated to include radiomic data. We proposed to use MultiAssayExperiment (MAE) as an integrated data structure to combine multi-omics data facilitating the exploration of heterogeneous data. We improved the usability of the MAE, developing a Multi-omics Statistical Approaches (MuSA) tool that uses a Shiny graphical user interface, able to simplify the management and the analysis of radiogenomic datasets. The capabilities of MuSA were shown using public breast cancer datasets from TCGA-TCIA databases. MuSA architecture is modular and can be divided in Pre-processing and Downstream analysis. The pre-processing section allows data filtering and normalization. The downstream analysis section contains modules for data science such as correlation, clustering (i.e., heatmap) and feature selection methods. The results are dynamically shown in MuSA. MuSA tool provides an easy-to-use way to create, manage and analyze radiogenomic data. The application is specifically designed to guide no-programmer researchers through different computational steps. Integration analysis is implemented in a modular structure, making MuSA an easily expansible open-source software.

Despite the benefits associated with radiotherapy and chemotherapy for glioblastoma (GBM) treatment, most patients experience a relapse following initial therapy. Recurrent or progressive GBM usually does not respond anymore to standard therapy, and this is associated with poor patient outcome. GBM stem cells (GSCs) are a subset of cells resistant to radiotherapy and chemotherapy and play a role in tumor recurrence. The targeting of GSCs and the identification of novel markers are crucial issues in the development of innovative strategies for GBM eradication. By differential cell SELEX (systematic evolution of ligands by exponential enrichment), we have recently described two RNA aptamers, that is, the 40L sequence and its truncated form A40s, able to bind the cell surface of human GSCs. Both aptamers were selective for stem-like growing GBM cells and are rapidly internalized into target cells. In this study, we demonstrate that their binding to cells is mediated by direct recognition of the ephrin type-A receptor 2 (EphA2). Functionally, the two aptamers were able to inhibit cell growth, stemness, and migration of GSCs. Furthermore, A40s was able to cross the blood-brain barrier (BBB) and was stable in serum in in vitro experiments. These results suggest that 40L and A40s represent innovative potential therapeutic tools for GBM.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Despite progress in surgical and medical neuro-oncology, prognosis for GBM patients remains dismal, with a median survival of only 14–15 months. The modest benefit of conventional therapies is due to the presence of GBM stem cells (GSCs) that cause tumor relapse and chemoresistance and, therefore, that play a key role in GBM aggressiveness and recurrence. So far, strategies to identify and target GSCs have been unsuccessful. Thus, the development of an approach for GSC detection and targeting would be fundamental for improving the survival of GBM patients. Here, using the cell-systematic evolution of ligand by exponential (SELEX) methodology on human primary GSCs, we generated and characterized RNA aptamers that selectively bind GSCs versus undifferentiated GBM cells. We found that the shortened version of the aptamer 40L, which we have called A40s, costained with CD133-labeled cells in human GBM tissue, suggestive of an ability to specifically recognize GSCs in fixed human tissues. Of note, both 40L and A40s were rapidly internalized by cells, allowing for the delivery of the microRNA miR-34c and the anti-microRNA anti-miR-10b, demonstrating that these aptamers can serve as selective vehicles for therapeutics. In conclusion, the aptamers 40L and A40s can selectively target GSCs. Given the crucial role of GSCs in GBM recurrence and therapy resistance, these aptamers represent innovative drug delivery candidates with a great potential in the treatment of GBM. Keywords: aptamer, cancer stem cell, glioblastoma, microRNA, delivery

The biological function and clinical values of Chromobox (CBX) family proteins in renal cell carcinoma (RCC) are still poorly investigated. This study aimed to compare the expression profiles and clinical relevance of CBXs between the two most frequent subtypes of RCC, clear cell renal cell carcinomas (ccRCC) and papillary renal cell carcinomas (pRCC), and to investigate whether CBXs would play a more or less similar role in the pathogenesis and progression of these RCC subtypes. Considering these two RCC populations in the TCGA database, we built a bioinformatics framework by integrating a computational pipeline with several online tools. CBXs showed a similar trend in ccRCC and pRCC tissues but with some features specific for each subtype. Specifically, the relative expressions of CBX3 and CBX2 were, respectively, the highest and lowest among all CBXs in both RCC subtypes. These data also found confirmation in cellular validation. Except for CBX4 and CBX8, all others were deregulated in the ccRCC subtype. CBX1, CBX6, and CBX7 were also significantly associated with the tumor stage. Further, low expression levels of CBX1, CBX5, CBX6, CBX7, and high expression of CBX8 were associated with poor prognosis. Otherwise, in the pRCC subtype, CBX2, CBX3, CBX7, and CBX8 were deregulated, and CBX2, CBX6, and CBX7 were associated with the tumor stage. In addition, in pRCC patients, low expression levels of CBX2, CBX4, and CBX7 were associated with an unfavorable prognosis. Similarly, CBX3, CBX6, and CBX7 presented the highest alteration rate in both subtypes and were found to be functionally related to histone binding, nuclear chromosomes, and heterochromatin. Furthermore, CBX gene expression levels correlated with immune cell infiltration, suggesting that CBXs might reflect the immune status of RCC subtypes. Our results highlight similarities and differences of CBXs within the two major RCC subtypes, providing new insights for future eligible biomarkers or possible molecular therapeutic targets for these diseases.

Preeclampsia is a leading cause of perinatal maternal-foetal mortality and morbidity. This study aims to identify the key microRNAs (miRNA) in preeclampsia and uncover their potential functions. We downloaded the miRNA expression profile of GSE119799 for plasma and GSE177049 for the placenta. Each dataset consisted of five patients (PE) and five controls (N). From a technical point of view, we analysed the counts per million (CPM) for both datasets, highlighting 358 miRNAs in common, 78 unique for plasma and 298 unique for placenta. At the same time, we performed an expression differential analysis (|logFC| ≥ 1|and FDR ≤ 0.05) to evaluate the biological impact of the miRNAs. This approach allowed us to highlight 321 miRNAs in common between plasma and placenta, within which four were upregulated in plasma. Furthermore, the same analysis revealed five miRNAs expressed exclusively in plasma; these were also upregulated. In conclusion, the in-depth bioinformatics analysis conducted during our study will allow us, on the one hand, to verify the targets of each of the nine identified miRNAs; on the other hand, to use them both as new non-invasive biomarkers and as therapeutic targets for the development of personalised treatments.

Background: We aim to provide up-to-date real-world evidence on the persistence, adherence, healthcare resource utilization, and costs of multiple sclerosis (MS) by comparing ocrelizumab to other disease-modifying treatments (DMTs) and within different DMT sequences. Methods: We included 3371 people with MS who first received or switched DMT prescriptions from January 2018 to December 2022; they were identified through hospital discharge records, drug prescriptions, and exemption codes from the Campania Region (South Italy). We calculated persistence (time from the first prescription to discontinuation or switching to another DMT), adherence (proportion of days covered (PDC)), DMT costs, and MS hospital admissions and related costs. Results: The most frequently prescribed DMT was dimethyl fumarate (n = 815; age 38.90 ± 11.91 years; 69.5% females), followed by ocrelizumab (n = 682; age 46.46 ± 11.29 years; 56.3%); 28.8% of the patients treated with ocrelizumab were naïve to DMTs. Using ocrelizumab as a statistical reference, the risk of discontinuation was higher for other highly active (HR = 6.32; 95%CI = 3.16, 12.63; p < 0.01) and low-/medium-efficacy DMTs (HR = 10.10; 95%CI = 5.10, 19.77; p < 0.01); adherence was lower for other highly active DMTs (Coeff = −0.07; 95%CI = −0.10, −0.04; p < 0.01) and low-/medium-efficacy DMTs (Coeff = −0.16; 95%CI = −0.19, −0.14; p < 0.01). monthly DMT costs were higher for other highly active DMTs (Coeff = 77.45; 95%CI = 29.36, 125.53; p < 0.01) but lower for low-/medium-efficacy DMTs (Coeff = −772.31; 95%CI = −816.95, −727.66; p < 0.01). The hospital admissions and related costs of MS were similar between ocrelizumab, other highly active DMTs, and other low-/medium-efficacy DMTs, and with ocrelizumab as the first-line DMT after other highly active DMTs and after low-/medium-efficacy DMTs, which was possibly due to the low number of observations. Conclusions: From 2018 to 2022, ocrelizumab was among the most frequently prescribed DMTs, with 28.8% prescriptions to incident MS patients, confirming its relevance in clinical practice. Ocrelizumab was associated with the highest persistence and adherence, pointing towards its favorable benefit–risk profile. The costs of ocrelizumab were lower than those of other highly active DMTs. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are key regulators of different human processes that represent a new promising class of cancer therapeutics or therapeutic targets. Indeed, in several tumor types, including non-small-cell lung carcinoma (NSCLC), the deregulated expression of specific miRNAs has been implicated in cell malignancy. As expression levels of the oncosuppressor miR-34c-3p are decreased in NSCLC compared to normal lung, we show that reintroduction of miR-34c-3p reduces NSCLC cell survival in vitro. Further, in order to deliver the miR-34c-based therapeutic selectively to tumor cells, we took advantage of a reported nucleic acid aptamer (GL21.T) that binds and inhibits the AXL transmembrane receptor and is rapidly internalized in the target cells. By applying methods successfully used in our laboratory, we conjugated miR-34c to the GL21.T aptamer as targeting moiety for the selective delivery to AXL-expressing NSCLC cells. We demonstrate that miR-34c-3p and the GL21.T/miR-34c chimera affect NSCLC cell proliferation and are able to overcome acquired RTK-inhibitor resistance by targeting AXL receptor. Thus, the GL21.T/miR-34c chimera exerts dual inhibition of AXL at functional and transcriptional levels and represents a novel therapeutic tool for the treatment of NSCLC. Keywords: miRNA, aptamer, NSCLC, lung cancer, therapeutics

BackgroundWe aim to overcome limitations of previous clinical and population-based studies by merging a clinical registry to routinely-collected healthcare data, and to specifically describe differences in clinical outcomes, healthcare resource utilization and costs between interferon beta formulations for multiple sclerosis (MS).MethodsWe included 850 patients with MS treated with interferon beta formulations, from 2015 to 2019, seen at the MS Clinical Care and Research Centre (Federico II University of Naples, Italy) and with linkage to routinely-collected healthcare data (prescription data, hospital admissions, outpatient services). We extracted and computed clinical outcomes (relapses, 6-month EDSS progression using a roving EDSS as reference), persistence (time spent on a specific interferon beta formulation), adherence (medication possession ratio (MPR)), healthcare resource utilization and costs (annualized hospitalization rate (AHR), costs for hospital admissions and DMTs). To evaluate differences between interferon beta formulations, we used linear regression (adherence), Poisson regression (AHR), mixed-effect regression (costs), and Cox-regression models (time varying variables); covariates were age, sex, treatment duration, baseline EDSS and adherence.ResultsLooking at clinical outcomes, rates of relapses and EDSS progression were lower than studies run on previous cohorts; there was no differences in relapse risk between interferon beta formulations. Risk of discontinuation was higher for Betaferon®/Extavia® (HR = 3.28; 95%CI = 2.11, 5.12; pConclusionsWe have showed the feasibility of merging routinely-collected healthcare data to a clinical registry for future MS research, and have confirmed interferon beta formulations play an important role in the management of MS, with positive clinical outcomes. Differences between interferon beta formulations are mostly driven by adherence and healthcare resource utilization.

Breast, ovarian, and endometrial cancers have a major impact on mortality in women. These tumors share hormone-dependent mechanisms involved in female-specific cancers which support tumor growth in a different manner. Integrated computational approaches may allow us to better detect genomic similarities between these different female-specific cancers, helping us to deliver more sophisticated diagnosis and precise treatments. Recently, several initiatives of The Cancer Genome Atlas (TCGA) have encouraged integrated analyses of multiple cancers rather than individual tumors. These studies revealed common genetic alterations (driver genes) even in clinically distinct entities such as breast, ovarian, and endometrial cancers. In this study, we aimed to identify expression similarity signatures by extracting common genes among TCGA breast (BRCA), ovarian (OV), and uterine corpus endometrial carcinoma (UCEC) cohorts and infer co-regulatory protein–protein interaction networks that might have a relationship with the estrogen signaling pathway. Thus, we carried out an unsupervised principal component analysis (PCA)-based computational approach, using RNA sequencing data of 2,015 female cancer and 148 normal samples, in order to simultaneously capture the data heterogeneity of intertumors. Firstly, we identified tumor-associated genes from gene expression profiles. Secondly, we investigated the signaling pathways and co-regulatory protein–protein interaction networks underlying these three cancers by leveraging the Ingenuity Pathway Analysis software. In detail, we discovered 1,643 expression similarity signatures (638 downregulated and 1,005 upregulated genes, with respect to normal phenotype), denoted as tumor-associated genes. Through functional genomic analyses, we assessed that these genes were involved in the regulation of cell-cycle-dependent mechanisms, including metaphase kinetochore formation and estrogen-dependent S-phase entry. Furthermore, we generated putative co-regulatory protein–protein interaction networks, based on upstream regulators such as the ERBB2/HER2 gene. Moreover, we provided an ad-hoc bioinformatics workflow with a manageable list of intertumor expression similarity signatures for the three female-specific cancers. The expression similarity signatures identified in this study might uncover potential estrogen-dependent molecular mechanisms promoting carcinogenesis.