Omic-Scale High-Throughput Quantitative LC-MS/MS Approach for Circulatory Lipid Phenotyping in Clinical Research.

Lipid analysis at the molecular species level represents a valuable opportunity for clinical applications due to the essential roles that lipids play in metabolic health. However, a comprehensive and high-throughput lipid profiling remains challenging given the lipid structural complexity and exceptional diversity. Herein, we present an 'omic-scale targeted LC-MS/MS approach for the straightforward and high-throughput quantification of a broad panel of complex lipid species across 26 lipid (sub)classes. The workflow involves an automated single-step extraction with 2-propanol, followed by lipid analysis using hydrophilic interaction liquid chromatography in a dual-column setup coupled to tandem mass spectrometry with data acquisition in the timed-selective reaction monitoring mode (12 min total run time). The analysis pipeline consists of an initial screen of 1903 lipid species, followed by high-throughput quantification of robustly detected species. Lipid quantification is achieved by a single-point calibration with 75 isotopically labeled standards representative of different lipid classes, covering lipid species with diverse acyl/alkyl chain lengths and unsaturation degrees. When applied to human plasma, 795 lipid species were measured with median intra- and inter-day precisions of 8.5 and 10.9%, respectively, evaluated within a single and across multiple batches. The concentration ranges measured in NIST plasma were in accordance with the consensus intervals determined in previous ring-trials. Finally, to benchmark our workflow, we characterized NIST plasma materials with different clinical and ethnic backgrounds and analyzed a sub-set of sera (n = 81) from a clinically healthy elderly population. Our quantitative lipidomic platform allowed for a clear distinction between different NIST materials and revealed the sex-specificity of the serum lipidome, highlighting numerous statistically significant sex differences.

Stimuli-Responsive Multifunctional Nanomedicine for Enhanced Glioblastoma Chemotherapy Augments Multistage Blood-to-Brain Trafficking and Tumor Targeting.

Minimal therapeutic advances have been achieved over the past two decades for glioblastoma (GBM), which remains an unmet clinical need. Here, hypothesis-driven stimuli-responsive nanoparticles (NPs) for docetaxel (DTX) delivery to GBM are reported, with multifunctional features that circumvent insufficient blood-brain barrier (BBB) trafficking and lack of GBM targeting-two major hurdles for anti-GBM therapies. NPs are dual-surface tailored with a i) brain-targeted acid-responsive Angiopep-2 moiety that triggers NP structural rearrangement within BBB endosomal vesicles, and ii) L-Histidine moiety that provides NP preferential accumulation into GBM cells post-BBB crossing. In tumor invasive margin patient cells, the stimuli-responsive multifunctional NPs target GBM cells, enhance cell uptake by 12-fold, and induce three times higher cytotoxicity in 2D and 3D cell models. Moreover, the in vitro BBB permeability is increased by threefold. A biodistribution in vivo trial confirms a threefold enhancement of NP accumulation into the brain. Last, the in vivo antitumor efficacy is validated in GBM orthotopic models following intratumoral and intravenous administration. Median survival and number of long-term survivors are increased by 50%. Altogether, a preclinical proof of concept supports these stimuli-responsive multifunctional NPs as an effective anti-GBM multistage chemotherapeutic strategy, with ability to respond to multiple fronts of the GBM microenvironment.

Recognizing reflexivity among conservation practitioners.

When deciding how to conserve biodiversity, practitioners navigate diverse missions, sometimes conflicting approaches, and uncertain trade-offs. These choices are based not only on evidence, funders' priorities, stakeholders' interests, and policies, but also on practitioners' personal experiences, backgrounds, and values. Calls for greater reflexivity-an individual or group's ability to examine themselves in relation to their actions and interactions with others-have appeared in the conservation science literature. But what role does reflexivity play in conservation practice? We explored how self-reflection can shape how individuals and groups conserve nature. To provide examples of reflexivity in conservation practice, we conducted a year-long series of workshop discussions and online exchanges. During these, we examined cases from the peer-reviewed and gray literature, our own experiences, and conversations with 10 experts. Reflexivity among practitioners spanned individual and collective levels and informal and formal settings. Reflexivity also encompassed diverse themes, including practitioners' values, emotional struggles, social identities, training, cultural backgrounds, and experiences of success and failure. Reflexive processes also have limitations, dangers, and costs. Informal and institutionalized reflexivity requires allocation of limited time and resources, can be hard to put into practice, and alone cannot solve conservation challenges. Yet, when intentionally undertaken, reflexive processes might be integrated into adaptive management cycles at multiple points, helping conservation practitioners better reach their goals. Reflexivity could also play a more transformative role in conservation by motivating practitioners to reevaluate their goals and methods entirely. Reflexivity might help the conservation movement imagine and thus work toward a better world for wildlife, people, and the conservation sector itself.

Reconocimiento de la reflexividad entre los practicantes de la conservación Resumen Cuando se decide cómo conservar la biodiversidad, quienes la practican sortean varias misiones, algunas veces con enfoques contrastantes y compensaciones inciertas. Estas elecciones no se basan solamente en las evidencias, prioridades de los financiadores, los intereses de los actores y las políticas, sino también en las experiencias personales, formación y valores de los practicantes. En la literatura sobre las ciencias de la conservación han surgido llamados para una mayor reflexividad - la habilidad individual o grupal para examinarse a sí mismo en relación con sus acciones e interacciones con otros. Pero ¿cuál es el papel de la reflexividad en la práctica de la conservación? Para responder esto, exploramos cómo la autorreflexión puede determinar cómo ocurre la conservación individual y grupal de la naturaleza. Realizamos una serie de talleres de discusión e intercambios virtuales durante un año para ejemplificar la reflexividad en la práctica de la conservación. Durante estas sesiones examinamos casos de la literatura gris y revisada por pares, nuestras propias experiencias y conversaciones con diez expertos. La reflexividad de los practicantes abarcó niveles individuales y colectivos y escenarios formales e informales. La reflexividad también comprendió diferentes aspectos de los practicantes, como los valores, conflictos emocionales, identidad social, preparación, contexto cultural y experiencias exitosas y fallidas. Los procesos reflexivos también tienen limitaciones, riesgos y costos. La reflexividad informal e institucionalizada requiere la distribución de tiempo y recursos limitados, puede ser difícil de poner en práctica y no puede resolver los retos de conservación por sí sola. Aun así, cuando se realizan intencionalmente, los procesos reflexivos pueden integrarse a los ciclos de manejo adaptativo en varios puntos, lo que ayuda a quienes practican la conservación a lograr sus metas de mejor manera. La reflexividad también podría tener un papel transformador en la conservación al motivar a los practicantes a reevaluar completamente sus metas y métodos. La reflexividad podría ayudar al movimiento de conservación a imaginar, y por lo tanto trabajar para tener, un mundo mejor para la vida silvestre, las personas y el propio sector de la conservación.

scFv biofunctionalized nanoparticles to effective and safe targeting of CEA-expressing colorectal cancer cells.

Colorectal cancer (CRC) is one of the deadliest cancers worldwide, with the 5 year survival rate in metastatic cases limited to 12%. The design of targeted and effective therapeutics remains a major unmet clinical need in CRC treatment. Carcinoembryonic antigen (CEA), a glycoprotein overexpressed in most colorectal tumors, may constitute a promising molecule for generating novel CEA-targeted therapeutic strategies for CRC treatment. Here, we developed a smart nanoplatform based on chemical conjugation of an anti-CEA single-chain variable fragment (scFv), MFE-23, with PLGA-PEG polymers to deliver the standard 5-Fluorouracil (5-FU) chemotherapy to CRC cells. We confirmed the specificity of the developed CEA-targeted NPs on the internalization by CEA-expressing CRC cells, with an enhance of threefold in the cell uptake. Additionally, CEA-targeted NPs loaded with 5-FU induced higher cytotoxicity in CEA-expressing cells, after 24 h and 48 h of treatment, reinforcing the specificity of the targeted NPs. Lastly, the safety of CEA-targeted NPs loaded with 5-FU was evaluated in donor-isolated macrophages, with no relevant impact on their metabolic activity nor polarization. Altogether, this proof of concept supports the CEA-mediated internalization of targeted NPs as a promising chemotherapeutic strategy for further investigation in different CEA-associated cancers and respective metastatic sites.Authors: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 1 Given name: [Maria José] Last name [Silveira]. Author 7 Given name: [Maria José] Last name [Oliveira]. Also, kindly confirm the details in the metadata are correctokAffiliations: Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary.ok.

Leg ulcers in sickle cell disease patients.

Leg ulcers are the most common cutaneous complication of sickle cell disease. These lesions occur mainly in homozygous forms, are slow to heal and often relapse, causing negative physical, emotional, and economic impacts. In this paper, we discuss the clinical presentation, diagnosis, and pathophysiology of sickle cell leg ulcers and their implications for treatment.

Development of a PEGylated-Based Platform for Efficient Delivery of Dietary Antioxidants Across the Blood-Brain Barrier.

The uptake and transport of dietary antioxidants remains the most important setback for their application in therapy. To overcome the limitations, a PEGylated-based platform was developed to improve the delivery properties of two dietary hydroxycinnamic (HCA) antioxidants-caffeic and ferulic acids. The antioxidant properties of the new polymer-antioxidant conjugates (PEGAntiOxs), prepared by linking poly(ethylene glycol) (PEG) to the cinnamic acids by a one-step Knovenagel condensation reaction, were evaluated. PEGAntiOxs present a higher lipophilicity than the parent compounds (caffeic and ferulic acids) and similar, or higher, antioxidant properties. PEGAntiOxs were not cytotoxic at the tested concentrations in SH-SY5Y, Caco-2, and hCMEC/D3 cells. By contrast, cytotoxic effects in hCMEC/D3 and SH-SY5Y cells were observed, at 50 and 100 µM, for caffeic and ferulic acids. PEGAntiOxs operate as antioxidants against several oxidative stress-cellular inducers in a neuronal cell-based model, and were able to inhibit glycoprotein-P in Caco-2 cells. PEGAntiOxs can cross hCMEC/D3 monolayer cells, a model of the blood-brain barrier (BBB) endothelial membrane. In summary, PEGAntiOxs are valid antioxidant prototypes that can uphold the antioxidant properties of HCAs, reduce their cytotoxicity, and improve their BBB permeability. PEGAntiOxs can be used in the near future as drug candidates to prevent or slow oxidative stress associated with neurodegenerative diseases.

Biodegradation and Detoxification of Sanitary Landfill Leachate by Stabilization Ponds System.

The performance of a pilot stabilization ponds system was evaluated for the treatment of sanitary landfill leachate, focusing on effluent detoxification. Three serial ponds (anaerobic-P1, facultative-P2, and maturation-P3) were evaluated during two different operational conditions: natural condition (period 1) and 24 hours of artificial aeration in P2 (period 2). The ponds system exhibited removal efficiencies of 53% for soluble chemical oxygen demand (SCOD), 81% for filtered biochemical oxygen demand (FBOD), and 84% for NH4+-N during period 1 and 70% for SCOD, 80% for FBOD, and 96% for -N during period 2. Most metals (Fe, Cu, Cd, Zn, Cr, Ni, and Pb) and organic compounds in the leachate were significantly reduced in the treatment system, with greater reductions during period 2. Moreover, toxicity tests demonstrated the capacity of the system to reduce the toxicity of the raw leachate (up to 89% toxicity reduction).

Screening new psychoactive substances in urban wastewater using high resolution mass spectrometry.

Analysis of drug residues in urban wastewater could complement epidemiological studies in detecting the use of new psychoactive substances (NPS), a continuously changing group of drugs hard to monitor by classical methods. We initially selected 52 NPS potentially used in Italy based on seizure data and consumption alerts provided by the Antidrug Police Department and the National Early Warning System. Using a linear ion trap-Orbitrap high resolution mass spectrometer, we designed a suspect screening and a target method approach and compared them for the analysis of 24 h wastewater samples collected at the treatment plant influents of four Italian cities. This highlighted the main limitations of these two approaches, so we could propose requirements for future research. A library of MS/MS spectra of 16 synthetic cathinones and 19 synthetic cannabinoids, for which analytical standards were acquired, was built at different collision energies and is available on request. The stability of synthetic cannabinoids was studied in analytical standards and wastewater, identifying the best analytical conditions for future studies. To the best of our knowledge, these are the first stability data on NPS. Few suspects were identified in Italian wastewater samples, in accordance with recent epidemiological data reporting a very low prevalence of use of NPS in Italy. This study outlines an analytical approach for NPS identification and measurement in urban wastewater and for estimating their use in the population.

Analysis of the genetic ancestry of patients with oral clefts from South American admixed populations.

Increased susceptibility to cleft lip, with or without cleft palate (CL±P) has been observed in South America, as related to Amerindian ancestry, using epidemiological data, uniparental markers, and blood groups. In this study, it was evaluated whether this increased risk remains when Amerindian ancestry is estimated using autosomal markers and considered in the predictive model. Ancestry was estimated through genotyping 62 insertion and deletion (INDEL) markers in sample sets of patients with CL±P, patients with cleft palate (CP), and controls, from Patagonia in southern Argentina and Belém in northern Brazil. The Amerindian ancestry in patients from Patagonia with CL±P was greater than in controls although it did not reach statistical significance. The European ancestry in patients with CL±P from Belém and in patients with CP from Belém and Patagonia was higher than in controls and statistically significant for patients with CP who were from Belém. This high contribution of European genetic ancestry among patients with CP who were from Belém has not been previously observed in American populations. Our results do not corroborate the currently accepted risks for CL±P and CP estimated by epidemiological studies in the North American populations and probably reflect the higher admixture found in South American ethnic groups when compared with the same ethnic groups from the North American populations.

Facilitation as Attenuating of Environmental Stress among Structured Microbial Populations.

There is currently an intense debate in microbial societies on whether evolution in complex communities is driven by competition or cooperation. Since Darwin, competition for scarce food resources has been considered the main ecological interaction shaping population dynamics and community structure both in vivo and in vitro. However, facilitation may be widespread across several animal and plant species. This could also be true in microbial strains growing under environmental stress. Pure and mixed strains of Serratia marcescens and Candida rugosa were grown in mineral culture media containing phenol. Growth rates were estimated as the angular coefficients computed from linearized growth curves. Fitness index was estimated as the quotient between growth rates computed for lineages grown in isolation and in mixed cultures. The growth rates were significantly higher in associated cultures than in pure cultures and fitness index was greater than 1 for both microbial species showing that the interaction between Serratia marcescens and Candida rugosa yielded more efficient phenol utilization by both lineages. This result corroborates the hypothesis that facilitation between microbial strains can increase their fitness and performance in environmental bioremediation.

Phonemic awareness is a more important predictor of orthographic processing than rapid serial naming: Evidence from Russian.

We studied the relationship between rapid serial naming (RSN) and orthographic processing in Russian, an asymmetrically transparent orthography. Ninety-six students (mean age = 13.73) completed tests of word and pseudoword reading fluency, spelling, orthographic choice, phonological choice, PA and RSN. PA was a better predictor of orthographic skills and pseudoword reading accuracy than RSN, which accounted for more variance in word and pseudoword reading fluency. Controlling for pseudoword reading fluency washed out RSN's contribution to word reading fluency. These results extend previous findings questioning the role of RSN as an index of orthographic processing skills and support the idea that RSN taps into automaticity/efficiency of processing print-sound mappings.

Metabarcoding expands knowledge on diversity and ecology of rare actinobacteria in the Brazilian Cerrado.

Rare and unknown actinobacteria from unexplored environments have the potential to produce new bioactive molecules. This study aimed to use 16 s rRNA metabarcoding to determine the composition of the actinobacterial community, particularly focusing on rare and undescribed species, in a nature reserve within the Brazilian Cerrado called Sete Cidades National Park. Since this is an inaccessible area without due legal authorization, it is understudied, and, therefore, its diversity and biotechnological potential are not yet fully understood, and it may harbor species with groundbreaking genetic potential. In total, 543 operational taxonomic units (OTUs) across 14 phyla were detected, with Actinobacteria (41.2%), Proteobacteria (26.5%), and Acidobacteria (14.3%) being the most abundant. Within Actinobacteria, 107 OTUs were found, primarily from the families Mycobacteriaceae, Pseudonocardiaceae, and Streptomycetaceae. Mycobacterium and Streptomyces were the predominant genera across all samples. Seventeen rare OTUs with relative abundance < 0.1% were identified, with 82.3% found in only one sample yet 25.5% detected in all units. Notable rare and transient genera included Salinibacterium, Nocardia, Actinomycetospora_01, Saccharopolyspora, Sporichthya, and Nonomuraea. The high diversity and distribution of Actinobacteria OTUs indicate the area's potential for discovering new rare species. Intensified prospection on underexplored environments and characterization of their actinobacterial diversity could lead to the discovery of new species capable of generating innovative natural products.

Epidemiology of Musculoskeletal Injuries in Golf Athletes: A Championship in Portugal.

Although golf is a low-impact sport without physical contact, its movements are carried out over a large range of motion, and their repetition can predispose athletes to the development of injuries. This study aimed to investigate the epidemiology of musculoskeletal injuries in golf athletes who participated in championships in southern Portugal, determining the types, locations and mechanisms of injury and their associated risk factors. The sample consisted of 140 athletes aged between 18 and 72 years, 133 (95%) being male. The measuring instrument was a questionnaire about sociodemographics, modality and injuries' characteristics. Throughout golf practice, 70 (50%) athletes reported injuries, totaling 133 injuries. In the 12-month period, 43 (30.7%) athletes suffered injuries, totaling 65 injuries. The injury proportion was of 0.31, and the injury rate was of 0.33 injuries per 1000 h of golf training. The most common injury type was muscle sprain or rupture (19; 30.9%), located in the lumbar spine (17; 27%), in which the repetitive movements were the main injury mechanism (42; 66.7%). The athletes who trained 4 times or more per week were 3.5 more likely (CI: 0.97-12.36; p = 0.056) to develop an injury while playing golf. Moderate injury presence was observed, with the high training frequency being an associated risk factor.

Genomic and epidemiological insight of an outbreak of carbapenemase-producing Enterobacterales in a Portuguese hospital with the emergence of the new KPC-124.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) is an increasing problem in healthcare settings. This study aimed to identify the source of a CPE outbreak that occurred in 2022, in a tertiary hospital in the North of Portugal, to identify exposed patients, and to assess the risk of becoming CPE-positive following hospital admission. METHODS: A multi-disciplinary investigation was conducted including descriptive, analytical, and molecular epidemiology, environmental screening, and assessment of infection control measures. Clinical and environmental isolates were analyzed using whole-genome sequencing and phylogenetic analysis. Additionally, a prospective observational cohort study was conducted to further investigate the risk factors associated with the emergence of new cases in cohorts of CPE-negative admitted patients. RESULTS: We observed the presence of multispecies KPC-, IMP-, and/or NDM-producing isolates. Genetically indistinguishable clinical and environmental isolates were found on the same room/ward. The ST45 KPC-3-producing Klebsiella pneumoniae clone was the responsible for the outbreak. During patients' treatment, we detected the emergence of resistance to ceftazidime-avibactam, associated with mutations in the blaKPC-3 gene (blaKPC-46, blaKPC-66 and blaKPC-124, the last variant never previously reported), suggesting a vertical evolutionary trajectory. Patients aged ≥ 75 years, hygiene/feeding-care dependent, and/or subjected to secretion aspiration were risk factors for CPE colonization after hospital admission. Additionally, cases with previous admission to the emergency department suggest that CPE dissemination may occur not only during hospitalization but also in the emergency department. CONCLUSION: Overall, the study highlights that selection pressure with antibiotics, like ceftazidime-avibactam, is a contributing factor to the emergence of new ß-lactamase variants and antibiotic resistance. It also shows that the hospital environment can be a significant source of CPE transmission, and that routine use of infection control measures and real-time molecular epidemiology investigations are essential to ensure the long-term termination of CPE outbreaks and prevent future resurgences.

Do young children spell words syllabically? Evidence from learners of Brazilian Portuguese.

The theory that learners of alphabetic writing systems go through a period during which they treat writing as representing syllables is highly influential, especially as applied to learners of Romance languages. The results of Study 1, a 2-year longitudinal study of 76 Portuguese speakers in Brazil from 4 to 6 years of age, did not support this theory. Although most children produced some spellings of words in which the number of letters matched the number of syllables, few children produced significantly more such spellings than expected on the basis of chance. When such spellings did occur, they appeared to reflect partially successful attempts to represent phonemes rather than attempts to represent syllables. Study 2, with 68 Brazilian 4- and 5-year-olds, found similar results even when children spelled words that contained three or four syllables in which all vowels are letter names--conditions that have been thought to favor syllabic spelling. The influential theory that learners of Romance languages go through a period during which they use writing to represent the level of syllables appears to lack a solid empirical foundation.

Assessment of symptomatic women for early diagnosis of ovarian cancer: results from the prospective DOvE pilot project.

BACKGROUND: Around 90% of deaths from ovarian cancer are due to high-grade serous cancer (HGSC), which is frequently diagnosed at an advanced stage. Several cancer organisations made a joint recommendation that all women with specified symptoms of ovarian cancer should be tested with the aim of making an early diagnosis. In the Diagnosing Ovarian Cancer Early (DOvE) study we investigated whether open-access assessment would increase the rate of early-stage diagnosis. METHODS: Between May 1, 2008, and April 30, 2011, we enrolled women who were aged 50 years or older and who had symptoms of ovarian cancer. They were offered diagnostic testing with cancer antigen (CA-125) blood test and transvaginal ultrasonography (TVUS) at a central and a satellite open-access centre in Montreal, QC, Canada. We compared demographic characteristics of DOvE patients with those of women in the same age-group in the general population of the area, and compared indicators of disease burden with those in patients with ovarian cancer referred through the usual route to our gynaecological oncology clinic (clinic patients). FINDINGS: Among 1455 women assessed, 402 (27·6%) were in the highest-risk age group (≥ 65 years). 239 (16·4%) of 1455 required additional investigations. 22 gynaecological cancers were diagnosed, 11 (50%) of which were invasive ovarian cancers, including nine HGSC. The prevalence of invasive ovarian cancer, therefore, was one per 132 women (0·76%), which is ten times higher than that reported in screening studies. DOvE patients were significantly younger, more educated, and more frequently English speakers than were women in the general population. They also presented with less tumour burden than did the 75 clinic patients (median CA-125 concentration 72 U/mL, 95% CI 12-1190 vs 888 U/mL, 440-1936; p=0·010); Eight (73%) tumours were completely resectable in DOvE patients, compared with 33 (44%) in clinic patients (p=0·075). Seven (78%) of the HGSC in the DOvE group originated outside the ovaries and five were associated with only slightly raised CA-125 concentrations and minimal or no ovarian abnormalities on TVUS. INTERPRETATION: The proportion of HGSC that originated outside the ovaries in this study suggests that early diagnosis programmes should aim to identify low-volume disease rather than early-stage disease, and that diagnostic approaches should be modified accordingly. Although testing symptomatic women may result in earlier diagnosis of invasive ovarian cancer, large-scale implementation of this approach is premature. FUNDING: Canadian Institutes of Health Research, Montreal General Hospital Foundation, Royal Victoria Hospital Foundation, Cedar's Cancer Institute, and La Fondation du Cancer Monique Malenfant-Pinizzotto.

Multi-ligand functionalized blood-to-tumor sequential targeting strategies in the field of glioblastoma nanomedicine.

Glioblastoma (GBM) is an unmet clinical need characterized by a standard of care (SOC) 5-year survival rate of only 5%, and a treatment mostly palliative. Significant hurdles in GBM therapies include an effective penetration of therapeutics through the brain protective barrier, namely the blood-brain barrier (BBB), and a successful therapeutic delivery to brain-invading tumor cells post-BBB crossing. These hurdles, along with the poor prognosis and critical heterogeneity of the disease, have shifted attention to treatment modalities with capacity to precisely and sequentially target (i) BBB cells, inducing blood-to-brain transport, and (ii) GBM cells, leading to a higher therapeutic accumulation at the tumor site. This sequential targeting allows therapeutic molecules to reach the brain parenchyma and compromise molecular processes that support tumor cell invasion. Besides improving formulation and pharmacokinetics constraints of drugs, nanomedicines offer the possibility of being surface functionalized with multiple possibilities of targeting ligands, while delivering the desired therapeutic cargos to the biological sites of interest. Targeting ligands exploit the site-specific expression or overexpression of specific molecules on BBB and GBM cells, triggering brain plus tumor transport. Since the efficacy of single-ligand functionalized nanomedicines is limited due to the GBM anatomical site (brain) and disease complexity, this review presents an overview of multi-ligand functionalized, BBB and GBM sequentially- and dual-targeted nanomedicines reported in literature over the last 10 years. The role of the BBB in GBM progression, treatment options, and the multiple possibilities of currently available targeting ligands will be summarized. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Digging the intercellular crosstalk via extracellular vesicles: May exosomes be the drug delivery solution for target glioblastoma?

Glioblastoma (GBM) is an adult's most aggressive brain tumor. The advances in molecular pathology and cell signaling pathways have deepened researchers' understanding of intercellular communication mechanisms that can induce tumor progression, namely the release of extracellular vesicles. Exosomes are small extracellular vesicles in various biological fluids released by almost all cells, thus carrying various biomolecules specific to their parental cell. Several pieces of evidence indicate that exosomes mediate intercellular communication in the tumor microenvironment and cross the blood-brain barrier (BBB), valuable tools for diagnostic and therapeutic applications under the scope of brain diseases such as brain tumors. This review aims to resume the several biological characteristics and the interplay between glioblastoma and exosomes, describing highlight studies that demonstrate the role of exosomes in the tumor microenvironment of GBM and their potential for non-invasive diagnoses and therapeutic approaches, namely, as nanocarriers for drug or gene delivery and cancer vaccines.

Multifunctional nanomedicine strategies to manage brain diseases.

Brain diseases represent a substantial social and economic burden, currently affecting one in six individuals worldwide. Brain research has been focus of great attention in order to unravel the pathogenesis and complexity of brain diseases at the cellular, molecular, and microenvironmental levels. Due to the intrinsic nature of the brain, the presence of the highly restrictive blood-brain barrier (BBB), and the pathophysiology of most diseases, therapies can hardly be considered successful purely by the administration of one drug to a patient. Apart from improving pharmacokinetic parameters, tailoring biodistribution, and reducing the number of side effects, nanomedicines are able to actively co-target the therapeutics to the brain parenchyma and brain lesions, as well as to achieve the delivery of multiple cargos with therapeutic, diagnostic, and theranostic properties. Among other multivalent effects that can be personalized according to the disease needs, this represents a promising class of novel nanosystems, termed multifunctional nanomedicines. Herein, we review the principal mechanisms of therapeutic resistance of the most prevalent brain diseases, how to overcome this therapeutic resistance through the use of multifunctional nanomedicines that tackle multiple fronts of the disease microenvironment, and the promising therapeutic responses achieved by some of the most cutting-edge multifunctional nanomedicines reported in literature.