Shock waves modulate corticospinal excitability: A proof of concept for further rehabilitation purposes?

Background: Focal extracorporeal shock wave therapy (fESWT) is a physical therapy vastly studied and used for various musculoskeletal disorders. However, the effect of fESWT on central nervous system is still to be determined. Objective: To elucidate spinal and supra-spinal mechanisms of fESWT in healthy subjects, in order to widen the spectrum of its clinical applications. Methods: In this quasi-experimental, unblinded, proof-of-concept clinical study, 10 voluntary healthy subjects underwent fESWT and were assessed immediately before (T0), immediately after (T1) and seven days after (T2) the intervention. As neurophysiological outcomes, motor evoked potentials (resting motor threshold, maximal motor evoked potential and maximal compound muscle action potential ratio, cortical silent period, total conduction motor time, direct and indirect central motor conduction time), F-waves (minimal and mean latency, persistence and temporal dispersion) and H-reflex (threshold, amplitude, maximal H reflex and maximal compound muscle action potential ratio, latency) were considered. Results: Resting motor threshold and F-waves temporal dispersion significantly decreased, respectively, from T1 and T2 and from T0 and T2 (for both, p <  0.05). H-reflex threshold increase between T0 and T1. Analysis disclosed a strong negative correlation between Δ3 cortical silent period (i.e., T2 -T1 recordings) and Δ1 Hr threshold (i.e., T1 -T0 recordings) (r = -0.66, p <  0.05), and a positive strong relationship between Δ3 cortical silent period and Δ3 Hr threshold (r = 0.63, p <  0.05). Conclusions: fESWT modulates corticospinal tract excitability in healthy volunteers, possibly inducing an early inhibition followed by a later facilitation after one week.

CytoMatrix for a reliable and simple characterization of lung cancer stem cells from malignant pleural effusions.

Cancer stem cells (CSCs) are a subpopulation with the properties of extensive self-renewal, capability to generate differentiated cancer cells and resistance to therapies. We have previously shown that malignant pleural effusions (MPEs) from patients with non-small-cell lung cancer (NSCLC) represent a valuable source of cancer cells that can be grown as three-dimensional (3D) spheroids enriched for stem-like features, which depend on the activation of the Yes-associated protein-transcriptional coactivator with PDZ-binding motif (YAP-TAZ)/Wnt-ßcatenin/stearoyl-CoA desaturase 1 (SCD1) axis. Here, we describe a novel support, called CytoMatrix, for the characterization of limited amounts of cancer cells isolated from MPEs of patients with NSCLC. Our results show that this synthetic matrix allows an easy and fast characterization of several epithelial cellular markers. The use of CytoMatrix to study CSCs subpopulation confirms that SCD1 protein expression is enhanced in 3D spheroids when compared with 2D adherent cell cultures. YAP/TAZ nuclear-cytoplasmic distribution analysed by CytoMatrix in 3D spheroids is highly heterogeneous and faithfully reproduces what is observed in tumour biopsies. Our results confirm and extend the robustness of our workflow for the isolation and phenotypic characterization of primary cancer cells derived from the lung MPEs and underscore the role of SCD1.

Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma.

Drug resistance imposes severe limitations to the efficacy of targeted therapy in BRAF-mutated metastatic melanoma. Although this issue has been mitigated by the development of combination therapies with BRAF plus MEK inhibitors, drug resistance inevitably occurs with time and results in clinical recurrences and untreatable disease. Hence, there is strong need of developing new combination therapies and non-invasive diagnostics for the early identification of drug-resistant patients. We report here that the development of drug resistance to BRAFi is dominated by a dynamic deregulation of a large population of miRNAs, leading to the alteration of cell intrinsic proliferation and survival pathways, as well as of proinflammatory and proangiogenic cues, where a prominent role is played by the miR-199b-5p/VEGF axis. Significant alterations of miRNA expression levels are detectable in tumor biopsies and plasma from patients after disease recurrence. Targeting these alterations blunts the development of drug resistance.

Bromelain Degrades Aß1-42 Monomers and Soluble Aggregates: An In Vitro Study in Cerebrospinal Fluid of Alzheimer's Disease Patients.

BACKGROUND: Therapeutic approaches targeting amyloid ß42 (Aß42) oligomers may represent a promising neuroprotective strategy for the prevention and treatment of Alzheimer's disease (AD). OBJECTIVE: In this study we evaluated the ability of bromelain, a plant cysteine protease derived from pineapple stems, to interact with synthetic Aß42 monomers and oligomers. We also examined the ability of bromelain to interfere in vitro with synthetic Aß42 aggregates in the cerebrospinal fluid (CSF) of Alzheimer's disease as well as of control patients affected by other neurological diseases. METHOD: Both synthetic monomers and aggregates of Aß42 were incubated in CSF with varying concentrations of bromelain. The effects of digestion were evaluated by Western Blot analysis using the specific monoclonal antibody 4G8 to identify the patterns of residual content of Aß42. We further used rat primary cortical culture neurons (CN) to examine the cytotoxic action of this natural compound. RESULTS: We found that bromelain successfully degraded Aß42 monomers and low and high molecular weight oligomers. Indeed, when bromelain preparations of 3 and 6 mU were added to the CSF, the residual amount of Aß42 monomers and oligomers were significantly reduced when compared to the same standard Aß42 preparations incubated in CSF without bromelain. Moreover, bromelain incubations of 0.1, 0.5, and 1 mU/ml were not toxic to CN, as compared to vehicle treated cells. CONCLUSION: Overall, these results represent an important insight into the action of bromelain on Aß42 oligomers, suggesting its potential use in the therapy of AD.