Cancer-associated fibroblasts (CAF) are the most abundant cells of the tumor stroma and they critically influence cancer growth through control of the surrounding tumor microenvironment (TME). ...CAF-orchestrated reactive stroma, composed of pro-tumorigenic cytokines and growth factors, matrix components, neovessels, and deregulated immune cells, is associated with poor prognosis in multiple carcinomas, including breast cancer. Therefore, beyond cancer cells killing, researchers are currently focusing on TME as strategy to fight breast cancer. In recent years, nanomedicine has provided a number of smart delivery systems based on active targeting of breast CAF and immune-mediated overcome of chemoresistance. Many efforts have been made both to eradicate breast CAF and to reshape their identity and function. Nano-strategies for CAF targeting profoundly contribute to enhance chemosensitivity of breast tumors, enabling access of cytotoxic T-cells and reducing immunosuppressive signals. TME rearrangement also includes reorganization of the extracellular matrix to enhance permeability to chemotherapeutics, and nano-systems for smart coupling of chemo- and immune-therapy, by increasing immunogenicity and stimulating antitumor immunity. The present paper reviews the current state-of-the-art on nano-strategies to target breast CAF and TME. Finally, we consider and discuss future translational perspectives of proposed nano-strategies for clinical application in breast cancer.
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Sporadic amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which there is no validated blood based biomarker. Extracellular vesicles (EVs) have the potential to solve this unmet ...clinical need. However, due to their heterogeneity and complex chemical composition, EVs are difficult to study. Raman spectroscopy (RS) is an optical method that seems particularly well suited to address this task. In fact, RS provides an overview of the biochemical composition of EVs quickly and virtually without any sample preparation. In this work, we studied by RS small extracellular vesicles (sEVs), large extracellular vesicles (lEVs) and blood plasma of sporadic ALS patients and of a matched cohort of healthy controls. The obtained results highlighted lEVs as a particularly promising biomarker for ALS. In fact, their Raman spectra show that sporadic ALS patients have a different lipid content and less intense bands relative to the aromatic amino acid phenylalanine.
Plasma, large extracellular vesicles (lEVs) and small extracellular vesicles (sEVs) from patients affected by amyotrophic lateral sclerosis (ALS) and from a cohort of matched healthy controls were studied by means of Raman spectroscopy. The results obtained show that Raman spectroscopy is able to identify a specific fingerprint of each specimen and that the lEVs of ALS patients are characterized by a distinct biochemical composition. This study thus paves the road towards the use of lEVs as possible circulating biomarkers of ALS. Display omitted
•Raman detects differences between subtypes of extracellular vesicles (EVs).•Large EVs have a different lipid and protein content in patients with ALS.•Large EVs are a promising biomarker for the diagnosis of ALS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
Preliminary reports suggest that extracellular vesicles (EVs) might be a promising biomarker for breast cancer (BC). However, the quantification of plasmatic levels of EVs is a complex task. ...To overcome these limitations, we developed a new, fast, and easy to use assay for the quantification of EVs directly in plasma based on the use of Single-Molecule Array (SiMoA).
Methods
By using SiMoA to identify CD9+/CD63+ EVs, we analyzed plasma samples of 181 subjects (95 BC and 86 healthy controls, HC). A calibration curve, made of a serial dilution of lyophilized standards from human plasma, was used in each run to ensure the obtainment of quantitative results from the assay. In a subgroup of patients, EVs concentrations were estimated in plasma before and after 30 days from cancer surgery. Additional information on the size of EVs were also acquired using a Nanosight system to obtain a clearer understanding of the mechanism underlying the releases of EVs associated with the presence of cancer.
Results
The measured levels of EVs resulted significantly higher in BC patients (median values 1179.1 ng/µl
vs
613.0 ng/µl,
p
< 0.0001). ROC curve was used to define the optimal cut-off level of the test at 1034.5 ng/µl with an AUC of 0.75 95% CI 0.68–0.82. EVs plasmatic concentrations significantly decreased after cancer surgery compared to baseline values (
p
= 0.014). No correlation was found between EVs concentration and clinical features of BC.
Conclusion
SiMoA assay allows plasmatic EVs levels detection directly without any prior processing. EVs levels are significantly higher in BC patients and significantly decreases after cancer surgery.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Curcumin's pharmacological properties and its possible benefits for neurological diseases and dementia have been much debated. In vitro experiments show that curcumin modulates several key ...physiological pathways of importance for neurology. However, in vivo studies have not always matched expectations. Thus, improved formulations of curcumin are emerging as powerful tools in overcoming the bioavailability and stability limitations of curcumin. New studies in animal models and recent double-blinded, placebo-controlled clinical trials using some of these new formulations are finally beginning to show that curcumin could be used for the treatment of cognitive decline. Ultimately, this work could ease the burden caused by a group of diseases that are becoming a global emergency because of the unprecedented growth in the number of people aged 65 and over worldwide. In this review, we discuss curcumin's main mechanisms of action and also data from in vivo experiments on the effects of curcumin on cognitive decline.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Neurofilament light chains (NfL) are neuron-specific cytoskeletal proteins whose plasmatic concentrations have been explored as a clinically useful marker in several types of dementia. Plasma ...concentrations of NfL are extremely low, and just two assays are commercially available for their study: one based on the SiMoA technology and one based on Ella. We thus studied plasma levels of NfL with both platforms to check the correlation between them and to assess their potential in the diagnosis of neurodegeneration. Plasma NfL levels were measured on 50 subjects: 18 healthy controls, 20 Alzheimer's disease, and 12 frontotemporal dementia patients. Ella returned plasmatic NfL levels significantly higher than SiMoA, however the results were strongly correlated (r = 0.94), and a proportional coefficient of 0.58 between the two assays was calculated. Both assays detected higher plasma NfL levels in patients with dementia than in the control group (p < 0.0001) and allowed their discrimination with excellent diagnostic performance (AUC > 0.95). No difference was found between Alzheimer's and Frontotemporal dementia either using SiMoA or Ella. In conclusion, both the analytical platforms resulted effective in analysing plasma levels of NfL. However, the correct interpretation of results requires the precise knowledge of the assay used.
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Extracellular vesicles (EVs) have mostly been investigated as carriers of biological therapeutics such as proteins and RNA. Nevertheless, small-molecule drugs of natural or synthetic origin have also ...been loaded into EVs, resulting in an improvement of their therapeutic properties. A few methods have been employed for EV cargo loading, but poor yield and drastic modifications of vesicles remain unsolved challenges. We tested a different strategy based on temporary pH alteration through incubation of EVs with alkaline sodium carbonate, which resulted in conspicuous exogenous molecule incorporation. In-depth characterization showed that vesicle size, morphology, composition, and uptake were not affected. Our method was more efficient than gold-standard electroporation, particularly for a potential therapeutic toxin: the plant Ribosome Inactivating Protein saporin. The encapsulated saporin resulted protected from degradation, and was efficiently conveyed to receiving cancer cells and triggered cell death. EV-delivered saporin was more cytotoxic compared to the free toxin. This approach allows both the structural preservation of vesicle properties and the transfer of protected cargo in the context of drug delivery.
Graphic Abstract
Lipofilling (LF) is a largely employed technique in reconstructive and esthetic breast surgery. Over the years, it has demonstrated to be extremely useful for treatment of soft tissue defects after ...demolitive or conservative breast cancer surgery and different procedures have been developed to improve the survival of transplanted fat graft. The regenerative potential of LF is attributed to the multipotent stem cells found in large quantity in adipose tissue. However, a growing body of pre-clinical evidence shows that adipocytes and adipose-derived stromal cells may have pro-tumorigenic potential. Despite no clear indication from clinical studies has demonstrated an increased risk of cancer recurrence upon LF, these observations challenge the oncologic safety of the procedure. This review aims to provide an updated overview of both the clinical and the pre-clinical indications to the suitability and safety of LF in breast oncological surgery. Cellular and molecular players in the crosstalk between adipose tissue and cancer are described, and heterogeneous contradictory results are discussed, highlighting that important issues still remain to be solved to get a clear understanding of LF safety in breast cancer patients.
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Brain metastasis (BM) represents a clinical challenge for patients with advanced HER2 + breast cancer (BC). The monoclonal anti-HER2 antibody trastuzumab (TZ) improves survival of BC patients, but it ...has low central nervous system penetrance, being ineffective in treating BM. Previous studies showed that ferritin nanoparticles (HFn) may cross the blood brain barrier (BBB) through binding to the transferrin receptor 1 (TfR1). However, whether this has efficacy in promoting the trans-BBB delivery of TZ and combating BC BM was not studied yet. Here, we investigated the potential of HFn to drive TZ brain delivery and promote a targeted antitumor response in a murine model of BC BM established by stereotaxic injection of engineered BC cells overexpressing human HER2. HFn were covalently conjugated with TZ to obtain a nanoconjugate endowed with HER2 and TfR1 targeting specificity (H-TZ). H-TZ efficiently achieved TZ brain delivery upon intraperitoneal injection and triggered stable targeting of cancer cells. Treatment with H-TZ plus docetaxel significantly reduced tumor growth and shaped a protective brain microenvironment by engaging macrophage activation toward cancer cells. H-TZ-based treatment also avoided TZ-associated cardiotoxicity by preventing drug accumulation in the heart and did not induce any other major side effects when combined with docetaxel. These results provided in vivo demonstration of the pharmacological potential of H-TZ, able to tackle BC BM in combination with docetaxel. Indeed, upon systemic administration, the nanoconjugate guides TZ brain accumulation, reduces BM growth and limits side effects in off-target organs, thus showing promise for the management of HER2 + BC metastatic to the brain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The goal of this work is to develop an innovative approach for the coating of gold nanoparticles (AuNPs) with a synthetic functional copolymer. This stable coating with a thickness of few nanometers ...provides, at the same time, stabilization and functionalization of the particles. The polymeric coating consists of a backbone of polydimethylacrylamide (DMA) functionalized with an alkyne monomer that allows the binding of azido modified molecules by Cu(I)-catalyzed azide/alkyne 1,3-dipolar cycloaddition (CuAAC, click chemistry). The thin polymer layer on the surface stabilizes the colloidal suspension whereas the alkyne functions pending from the backbone are available for the reaction with azido-modified proteins. The reactivity of the coating is demonstrated by immobilizing an azido modified anti-mouse IgG antibody on the particle surface. This approach for the covalent binding of antibody to a gold-NPs is applied to the development of gold labels in biosensing techniques.
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Immune inflammatory biomarkers are easily obtained and inexpensive blood-based parameters that recently showed prognostic and predictive value in many solid tumors. In this study, we aimed to ...investigate the role of these biomarkers in predicting distant relapse in breast cancer patients treated with neoadjuvant chemotherapy (NACT). All breast cancer patients who referred to our Breast Unit and underwent NACT were retrospectively reviewed. The pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and pan-immune-inflammation value (PIV) were calculated from complete blood counts. The primary outcome was 5-year distant-metastasis-free survival (DMFS). In receiver operating characteristic analyses, the optimal cutoff values for the NLR, PLR, MLR, and PIV were determined at 2.25, 152.46, 0.25, and 438.68, respectively. High levels of the MLR, but not the NLR, PLR, or PIV, were associated with improved 5-year DMSF in the study population using both univariate (HR 0.52, p = 0.03) and multivariate analyses (HR, 0.44; p = 0.02). Our study showed that the MLR was a significant independent parameter affecting DMFS in breast cancer patients undergoing NACT. Prospective studies are required to confirm this finding and to define reliable cutoff values, thus leading the way for the clinical application of this biomarker.
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