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PurposeSecretory breast cancer (SBC) is one of the rarest breast cancer (BC), representing the majority of BC in childhood. Nevertheless, it elicits a lot of interest both for the peculiar morphology and the characteristic genetic features. Currently, there is no consensus on optimal treatment strategy. Therefore, it is useful to report every case in order to establish treatment algorithms.MethodsWe describe the case of a 6-year-old boy diagnosed with a SBC, with peculiar genomic and immunohistochemical features. Moreover, we carried out a review of the literature in order to analyze the present state of knowledge about this rare entity.ResultsTo the best of our knowledge, there are only 120 cases published in literature, only 32 in males and only 2 younger than 6 years. Furthermore, this one had peculiar genomic and immunohistochemical features. Indeed, even if SBC expresses basal-cell markers, our patient had a triple-negative tumor expressing both basal and luminal cell markers. Furthermore, the boy’s genomic profile revealed not only positivity for the typical SBC’s translocation t(12;15), but also for a 3q28 duplication, found in his father (healthy) and paternal grandfather (with a previous BC). None were positive for BRCA mutation. This locus includes only one gene encoding for a growth factor recently linked to Early Infantile Epileptic Encephalopathy-47 and Idiopathic ventricular tachycardia. Even if the literature does not provide evidence of a pathogenic role it is not possible to exclude a cancer-predisposing activity.ConclusionsSBC is a rare type of BC, characterized by triple-negative features with an unexpectedly good prognosis. More data are needed to fully understand the behavior of this cancer and genomic profiling could be helpful in improving its diagnosis and management.

To evaluate the impact of prior adjuvant chemotherapy on response rate (RR), progression-free (PFS) and overall survival (OS) of metastatic breast cancer patients treated with epirubicin/paclitaxel (ET) regimens. In all, 291 patients enrolled in five studies in metastatic breast cancer were analysed: 101 (35%) were chemonaive, 109 (37%) had received adjuvant CMF and 81 (28%) adjuvant anthracyclines. Response rate to ET was 66%. Response rate was 63% for cyclophosphamide plus methotrexate plus 5-fluorouracil (CMF), 67% for prior anthracyclines and 68% in chemonaive patients ( P =0.5). By multivariate analysis, adjusted odds ratio for response was 0.81 (95% CI: 0.37–1.79) for CMF and 0.92 (95% CI 0.43–2.01) for anthracyclines ( P =0.86). The CR rates were 14% for both CMF and anthracyclines and 22% for chemonaive patients ( P =0.2). By multivariate analysis, the relative odds of CR for CMF or anthracyclines were 0.40 and 0.39 as compared to chemonaive patients ( P =0.036). The median PFS was 11.0 months for prior CMF, 10.2 months for anthracyclines and 12.5 months in chemonaive patients ( P =0.33). In multivariate Cox's model, a nonsignificant increase in the risk of progression was seen in patients treated with adjuvant CMF or anthracyclines. The median OS was 23.8 months for CMF, 20.2 months for anthracyclines and 27.5 months in chemonaive patients ( P =0.61). The same, nonsignificant, association was seen in multivariate analysis. The ET regimens provide satisfactory results in metastatic breast cancer, regardless of previous adjuvant chemotherapy.

The study was designed to compare an anthracycline-containing regimen to a regimen combining both anthracycline and paclitaxel as adjuvant therapy for high-risk breast cancer patients. In this multicenter, randomized phase-III trial, node-positive early breast cancer patients were randomly assigned to receive either 6 cycles of FEC (5-fluorouracil 600 mg/m 2 , epirubicin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 , day 1, every 3 weeks) or 4 cycles of EP (epirubicin 90 mg/m 2 and paclitaxel 175 mg/m 2 , day 1, every 3 weeks). The primary endpoint was overall survival (OS). Secondary endpoints included toxicity and event-free survival (EFS). From 1996 to 2001, 1055 patients were enrolled. At a median follow-up of 12.8 years, 335 deaths had been recorded. The 10-year OS was 73 % (95 % CI 69–77) in the FEC arm and 74 % (95 % CI 70–78) in the EP arm ( p  = 0.405). The 10-year EFS was 51 % (95 % CI 45–56) in the FEC arm and 49 % (95 % CI 44–55) in the EP arm ( p  = 0.572). No difference in the hazard of death was observed (HR for EP 0.85, 95 % CI 0.68–1.06, p  = 0.15). Patients treated with FEC experienced more frequently nausea and vomiting, stomatitis, and leukopenia as compared to patients treated with EP. Toxicities which occurred more frequently with EP were anemia, fever, myalgias, and neurotoxicity. Our study failed to demonstrate a superiority of an adjuvant treatment with four EP as compared to six FEC in node-positive breast cancer patients.

The complete amino acid sequence of bothropstoxin-II (BthTX-II), a myotoxin isolated from Bothrops jararacussu snake venom, is reported. The results show that BthTX-II is an Asp-49 phospholipase A2 (PLA2)-like protein composed of a single polypeptide chain of 120 amino acid residues (Mr = 13,976), containing one methionine and 14 half-cystines. Despite a high degree of homology with other PLA2's and the presence of the strategic residues known to compose the Ca2+-binding loop, namely Tyr-28, Gly-30, Gly-32, and especially Asp-49, besides His-48, Tyr-52, and Asp-99, all of them directly or indirectly involved in catalysis, BthTX-II revealed a very low PLA2 activity when assayed on egg yolk phosphatidylcholine. We attribute this low catalytic activity to the existence of extra mutations, e.g., Trp-5 for Phe-5, which points to the need of considering other strategic positions, since only Lys-49 PLA2's have been considered to be devoid of this enzymatic activity.

Experimental evidence indicates that the activation of ionotropic glutamate receptors plays an important role in neurological disorders’ models such as epilepsy, cerebral ischemia and trauma. The glutamate receptor agonist kainic acid (KA) induces seizures and excitotoxic cell death in the CA3 region of the hippocampus. Thymoquinone (TQ) is the most important component of the essential oil obtained from black cumin (Nigella sativa L.) seeds. It has many pharmacological actions including antioxidant, anti-inflammatory, and anti-apoptotic effects. TQ was used in an in vitro experimental model of primary cultures where excitotoxicity was induced. Briefly, rat organotypic hippocampal slices were exposed to 5 µM KA for 24 h. Cell death in the CA3 subregions of slices was quantified by measuring propidium iodide fluorescence. The cross-talk between TQ, ER stress and apoptotic pathways was investigated by Western blot. In untreated slices TQ (10 µM) induced a significant increase on the PSD95 levels and it decreased the excitotoxic injury induced by KA. Additionally, TQ was able to ameliorate the KA-induced increase in unfolded proteins GRP78 and GRP94 expression. Finally, TQ was able to partially rescue the reduction of the KA-induced apoptotic pathway activation. Our results suggest that TQ modulates the processes leading to post-kainate neuronal death in the CA3 hippocampal area.

The complete amino acid sequence of bothropstoxin-II (BthTX-II), a myotoxin isolated from Bothrops jararacussu snake venom, is reported. The results show that BthTX-II is an Asp-49 phospholipase A sub(2) (PLA sub(2))-like protein composed of a single polypeptide chain of 120 amino acid residues (M sub(r) = 13,976), containing one methionine and 14 half-cystines. Despite a high degree of homology with other PLA sub(2)'s and the presence of the strategic residues known to compose the Ca super(2+)-binding loop, namely Tyr-28, Gly-30, Gly-32, and especially Asp-49, besides His-48, Tyr-52, and Asp-99, all of them directly or indirectly involved in catalysis, BthTX-II revealed a very low PLA sub(2) activity when assayed on egg yolk phosphatidylcholine. We attribute this low catalytic activity to the existence of extra mutations, e.g., Trp-5 for Phe-5, which points to the need of considering other strategic positions, since only Lys-49 PLA sub(2)'s have been considered to be devoid of this enzymatic activity.

Cannabis contains over 500 different compounds, including cannabinoids, terpenoids, and flavonoids. Cannabidiol (CBD) is a non-psychoactive constituent, whereas beta-caryophyllene (BCP) is one of most the well-known terpenoids of Cannabis sativa. In recent years, there has been an emerging idea that the beneficial activities of these compounds are greater when they are combined. The aim of this study was to evaluate the anti-inflammatory effect of CBD and BCP using the in vitro model of lipopolysaccharide (LPS)-stimulated human keratinocytes (HaCaT) cells. The vitality of the cells was quantified using LDH and MTT assays. The levels of the following pro-inflammatory proteins and genes were quantified: IL-1β, COX-2, and phospho-NF-κB p65 (p-p65) through Western blotting (WB) and interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) through quantitative real-time polymerase chain reaction (RT-qPCR). When present in the incubation medium, CBD and BCP reduced the increased levels of pro-inflammatory proteins (IL-1β, COX-2, and p-NF-kB) induced by LPS. The anti-inflammatory effects of CBD were blocked by a PPARγ antagonist, whereas a CB2 antagonist was able to revert the effects of BCP. Selected concentrations of CBD and BCP were able to revert the increases in the expression of pro-inflammatory genes (IL-1β, IL-6, and TNFα), and these effects were significant when the drugs were used in combination. Our results suggest that CBD and BCP work in concert to produce a major anti-inflammatory effect with good safety profiles.

Dry eye disease (DED) is a common ocular disorder characterized by an inadequate lubrication of the eye by tears leading to inflammation and the alteration of the ocular surface. Current treatments are often limited due to their side effects and ineffectiveness. Thymoquinone (TQ) is a natural compound present in the essential oil of Nigella sativa L., with anti-inflammatory and antioxidant activities. In this study, conventional and hyaluronic acid-coated liposomes were developed to improve TQ activity at ocular level. In the present study, the cytoprotective effects of TQ or TQ liposomes were assessed against oxidative and inflammatory processes in human corneal epithelial cells (HCE-2). Hyperosmolarity conditions (450 mOsm) were used as a model of DED. Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and tumor necrosis factor (TNFα) were quantified by quantitative real-time polymerase chain reaction (RT-qPCR); COX-2 and Phospho-NF-κB p65 (p-p65) by Western blotting (WB). Moreover, the mitochondrial reactive oxygen species (mtROS) levels were measured by MitoSOX assay. The hyperosmotic treatment induced a significant increase of the proinflammatory genes and proteins expression that were significantly decreased in the liposomes-treated cells. The coincubation with hyaluronic acid-coated liposomes significantly reverted the increase of mtROS production, evidently stimulated by the hyperosmotic stress. Our data suggest that TQ-loaded liposomes have potential as a therapeutic agent in dry eye disease, improving the TQ efficacy.

(1) Background: Andrographolide (AG) is a natural compound effective for the treatment of inflammation-mediated neurodegenerative disorders. The aim of this investigation was the preparation of liposomes to enhance the penetration into the brain of AG, by modifying the surface of the liposomes by adding Tween 80 (LPs-AG) alone or in combination with Didecyldimethylammonium bromide (DDAB) (CLPs-AG). (2) Methods: LPs-AG and CLPs-AG were physically and chemically characterized. The ability of liposomes to increase the permeability of AG was evaluated by artificial membranes (PAMPA) and hCMEC/D3 cells. (3) Results: Based on obtained results in terms of size, homogeneity, ζ-potential and EE%. both liposomes are suitable for parenteral administration. The systems showed excellent stability during a month of storage as suspensions or freeze-dried products. Glucose resulted the best cryoprotectant agent. PAMPA and hCMEC/D3 transport studies revealed that LPs-AG and CLPs-AG increased the permeability of AG, about an order of magnitude, compared to free AG without alterations in cell viability. The caveolae-mediated endocytosis resulted the main mechanism of up-take for both formulations. The presence of positive charge increased the cellular internalization of nanoparticles. (4) Conclusions: This study shows that developed liposomes might be ideal candidates for brain delivery of AG.

Background: Cannabidiol (CBD) is a highly lipophilic compound with potential therapeutic applications in neurological disorders. However, its poor aqueous solubility and bioavailability, coupled with instability in physiological conditions, significantly limit its clinical use. Objectives: This study aimed to develop and characterize nanovesicles incorporating Tween 20 to enhance CBD encapsulation, stability, and the performance across the blood–brain barrier (BBB). Methods: Nanovesicles were prepared via thin-film hydration followed by sonication and optimized for size, polydispersity index, and zeta potential. Stability studies were conducted under physiological conditions and during storage at 4 °C. In vitro release studies employed the dialysis bag method, while permeability across the BBB was assessed using PAMPA-BBB and the hCMEC/D3-BBB cell line, characterized for brain endothelial phenotype and largely employed as a model of human blood–brain barrier (BBB) function. Cytotoxicity was evaluated via MTT and LDH assays. Results: The quantification of CBD was carried out by HPLC-DAD and HPLC-MS/MS. Nanovesicles with Tween 20 (VS-CBD) exhibited smaller size (65.27 ± 1.27 nm vs. 90.7 ± 0.2), lower polydispersity (0.230 ± 0.005 vs. 0.295 ± 0.003), and higher stability compared to conventional liposomes (L-CBD). VS-CBD achieved high encapsulation efficiency (96.80 ± 0.96%) and recovery (99.89 ± 0.52%). Release studies showed sustained CBD release with Higuchi model fitting (R2 = 0.9901). Both PAMPA-BBB and hCMEC/D3-BBB cell lines demonstrated an improved controlled permeability of the formulation compared to free CBD. Cytotoxicity tests confirmed the good biocompatibility of VS-CBD formulations. The addition of Tween 20 to nanovesicles enhanced CBD encapsulation, stability, and controlled release. Conclusions: These nanovesicles represent a promising strategy to improve CBD delivery to the brain, offering sustained therapeutic effects and reduced dosing frequency, potentially benefiting the treatment of neurological disorders.