Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship ...between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta.
Human tumors are stiff and data suggest that the extracellular matrix stiffening is consistent with experimental mammary tumor models in which stiffness drives tumor invasion and metastasis.
Tumors are fibrotic and characterized by abundant, remodeled, and cross-linked collagen that stiffens the extracellular matrix stroma. The stiffened collagenous stroma fosters malignant ...transformation of the tissue by increasing tumor cell tension to promote focal adhesion formation and potentiate growth factor receptor signaling through kinase. Importantly, collagen cross-linking requires fibronectin (FN). Fibrotic tumors contain abundant FN, and tumor cells frequently up-regulate the FN receptor α5β1 integrin. Using transgenic and xenograft models and tunable two- and three-dimensional substrates, we show that FN-bound α5β1 integrin promotes tension-dependent malignant transformation through engagement of the synergy site that enhances integrin adhesion force. We determined that ligation of the synergy site of FN permits tumor cells to engage a zyxin-stabilized, vinculin-linked scaffold that facilitates nucleation of phosphatidylinositol (3,4,5)-triphosphate at the plasma membrane to enhance phosphoinositide 3-kinase (PI3K)-dependent tumor cell invasion. The data explain why rigid collagen fibrils potentiate PI3K activation to promote malignancy and offer a perspective regarding the consistent up-regulation of α5β1 integrin and FN in many tumors and their correlation with cancer aggression.
Extracellular matrix stiffness induces focal adhesion assembly to drive malignant transformation and tumor metastasis. Nevertheless, how force alters focal adhesions to promote tumor progression ...remains unclear. Here, we explored the role of the focal adhesion protein vinculin, a force-activated mechano-transducer, in mammary epithelial tissue transformation and invasion. We found that extracellular matrix stiffness stabilizes the assembly of a vinculin-talin-actin scaffolding complex that facilitates PI3-kinase mediated phosphatidylinositol (3,4,5)-triphosphate phosphorylation. Using defined two and three dimensional matrices, a mouse model of mammary tumorigenesis with vinculin mutants and a novel super resolution imaging approach, we established that ECM stiffness, per se, promotes the malignant progression of a mammary epithelium by activating and stabilizing vinculin and enhancing Akt signaling at focal adhesions. Our studies also revealed that vinculin strongly co-localizes with activated Akt at the invasive border of human breast tumors, where the ECM is stiffest and we detected elevated mechano-signaling. Thus, extracellular matrix stiffness could induce tumor progression by promoting the assembly of signaling scaffolds; a conclusion underscored by the significant association we observed between highly expressed focal adhesion plaque proteins and malignant transformation across multiple types of solid cancer.
Background and purpose
Fifteen percent of patients with myasthenia gravis (MG) are refractory to conventional treatment. Case reports and a few studies show probable benefit of rituximab in these ...cases. Our objective was to assess the efficacy and the safety of rituximab in patients with MG, in a multicentric real‐life study.
Method
Inclusion criteria were: age > 18 years; MG with anti‐acetylcholine receptor (AChR) antibodies, anti‐muscle‐specific kinase (MuSk) antibodies or significant decrement after repetitive nerve stimulation; Myasthenia Gravis Foundation of America (MGFA) class >II; refractory or steroid‐dependent MG; and treatment with rituximab. Efficacy was assessed at 6 months using the MGFA‐post‐intervention status (PIS) score, the myasthenic muscle score (MMS) and the number of patients receiving steroids <10 mg/day. Data on adverse events were collected.
Results
Twenty‐nine patients were included: 20 with anti‐AChR MG, five with anti‐MuSK MG and four with seronegative MG. MGFA‐PIS score was improved or better (improved, minimal manifestations or remission) in 86.2% of patients after 6 months of treatment (P < 0.0001). The mean MMS increased from 68.8 to 83.1 (P < 0.0001). A decrease in steroid dosage (<10 mg/day) was effective in 57.9% of treated patients. In all, 42.8% of patients experienced adverse events: infections (21.4% of patients); infusion reaction (7%); bradycardia (3.7%); and cytopenia (7%).
Conclusion
The present study demonstrates the efficacy and safety of rituximab in patients with MG. Additional studies remain necessary to determine the role of rituximab in the pharmacopeia of MG treatment and to establish precise recommendations for the infusion protocol.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Amyotrophic lateral sclerosis (ALS) is a rare fatal motor neuron disease. Although many potential mechanisms have been proposed, the pathophysiology of the disease remains unknown. Currently ...available treatments can only delay the progression of the disease and prolong life expectancy by a few months. There is still no definitive cure for ALS, and the development of new treatments is limited by a lack of understanding of the underlying biological processes that trigger and promote neurodegeneration. Several scientific results suggest a neurovascular impairment in ALS providing perspectives for the development of new biomarkers and treatments. In this article, we performed a systematic review using PRISMA guidelines including PubMed, EmBase, GoogleScholar, and Web of Science Core Collection to analyze the scientific literature published between 2000 and 2021 discussing the neurocardiovascular involvement and ophthalmologic abnormalities in ALS. In total, 122 articles were included to establish this systematic review. Indeed, microvascular pathology seems to be involved in ALS, affecting all the neurovascular unit components. Retinal changes have also been recently highlighted without significant alteration of the visual pathways. Despite the peripheral location of the retina, it is considered as an extension of the central nervous system (CNS) as it displays similarities to the brain, the inner blood–retinal barrier, and the blood–brain barrier. This suggests that the eye could be considered as a ‘window’ into the brain in many CNS disorders. Thus, studying ocular manifestations of brain pathologies seems very promising in understanding neurodegenerative disorders, mainly ALS. Optical coherence tomography angiography (OCT-A) could therefore be a powerful approach for exploration of retinal microvascularization allowing to obtain new diagnostic and prognostic biomarkers 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
Aims
Histological analysis of brain tissue samples provides valuable information about the pathological processes leading to common neurodegenerative disorders. In this context, the development of ...novel high‐resolution imaging approaches is a current challenge in neuroscience.
Methods
To this end, we used a recent super‐resolution imaging technique called STochastic Optical Reconstruction Microscopy (STORM) to analyse human brain sections. We combined STORM cell imaging protocols with neuropathological techniques to image cryopreserved brain samples from control subjects and patients with neurodegenerative diseases.
Results
This approach allowed us to perform 2D‐, 3D‐ and two‐colour‐STORM in neocortex, white matter and brainstem samples. STORM proved to be particularly effective at visualizing the organization of dense protein inclusions and we imaged with a <50 nm resolution pathological aggregates within the central nervous system of patients with Alzheimer’s disease, Parkinson’s disease, Lewy body dementia and fronto‐temporal lobar degeneration. Aggregated Aβ branches appeared reticulated and cross‐linked in the extracellular matrix, with widths from 60 to 240 nm. Intraneuronal Tau and TDP‐43 inclusions were denser, with a honeycomb pattern in the soma and a filamentous organization in the axons. Finally, STORM imaging of α‐synuclein pathology revealed the internal organization of Lewy bodies that could not be observed by conventional fluorescence microscopy.
Conclusions
STORM imaging of human brain samples opens further gates to a more comprehensive understanding of common neurological disorders. The convenience of this technique should open a straightforward extension of its application for super‐resolution imaging of the human brain, with promising avenues to current challenges in neuroscience.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
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