Multimodal investigations of trans-endothelial cell trafficking under condition of disrupted blood-brain barrier integrity

<p>Abstract</p> <p>Background</p> <p>Stem cells or immune cells targeting the central nervous system (CNS) bear significant promises for patients affected by CNS disorders. Brain or spinal cord delivery of therapeutic cells is limited by the blood-brain barrier (BBB) which remains one of the recognized rate-limiting steps. Osmotic BBB disruption (BBBD) has been shown to improve small molecule chemotherapy for brain tumors, but successful delivery of cells in conjunction with BBBD has never been reported.</p> <p>We have used a clinically relevant model (pig) of BBBD to attempt brain delivery of TALL-104, a human leukemic T cell line. TALL-104 cells are potent tumor killers and have demonstrated potential for systemic tumor therapy. The pig model used is analogous to the clinical BBBD procedure. Cells were injected in the carotid artery after labeling with the MRI T1 contrast agent GdHPDO3A. Contrast CT scans were used to quantify BBBD and MRI was used to detect Gd⁺⁺-loaded cells in the brain. Transcranial Doppler was used to monitor cerebral blood flow. EEG recordings were used to detect seizures. Immunocytochemical detection (Cresyl Violet, anti-human CD8 for TALL-104, Evans Blue for BBB damage, GFAP and NEUN) was performed.</p> <p>Results</p> <p>At the concentration used TALL-104 cells were tolerated. Incomplete BBBD did not allow cell entry into the brain. MRI scans at 24 and 48 hours post-injection allowed visualization of topographically segregated cells in the hemisphere that underwent successful BBBD. Perivascular location of TALL-104 was confirmed in the BBBD hemisphere by Cresyl violet and CD8 immunocytochemistry. No significant alteration in CBF or EEG activity was recorded during cell injections.</p> <p>Conclusions</p> <p>Our data show that targeted CNS cell therapy requires blood-brain barrier disruption. MRI-detectable cytotoxic anti-neoplastic cells can be forced to transverse the BBB and accumulate in the perivascular space. The virtual absence of toxicity, the high anti-tumor activity of TALL-104, and the clinical feasibility of human osmotic BBBD suggest that this approach may be adopted to treat brain or spinal cord tumors. In addition, BBBD may favor CNS entry of other cells that normally lack CNS tropism.</p

Preclinical Tests for Cerebral Stroke

Stroke is the second single highest cause of death in Europe. The low reliability of animal models in replicating the human disease is one of the most serious problems in the field of medical and pharmaceutical research about stroke. The standard models for the study of ischemic stroke are often poorly predictive as they simulate only partially the human disease. This work aims at investigating animal models with diseases typically associated with the onset of stroke in human patients. We have designed and realised a knowledge base for collecting, elaborating, and extracting analytical results of genomic, proteomic, biochemical, morphological investigations from animal models of cerebral stroke. Data analysis techniques are tailored to make the data available for processing and correlation, in order to increase the predictive value of the preclinical data, to perform biosimulation studies, and to support both academic and industrial research in the area of cerebral stroke therapy. A first statistical analysis of the retrieved information leads to the validation of our animal models and suggests a predictive and translational value for parameters related to a specific model. In particular, concerning gene expression data, we have applied a data analysis pipeline that initially takes into account an initial set of 64,000 genes and brings down the focus on a few tens of them

Sisters on the Soapbox: Elizabeth Gurley Flynn and Her Female Free Speech Allies’ Lessons for Contemporary Women Labor Activists

At a moment when U.S. labor seems its most weak and vulnerable, a wave of teacher strikes and demonstrations led and carried out primarily by women shows promise of revitalizing the movement. Critics allege the strikes and demonstrations are &ldquo;unseemly,&rdquo; but popular support for them appears to be growing. Historically, militant strikes and demonstrations have met with significant and sometimes violent resistance from corporate and political entities hostile to labor, and contemporary women in the movement should prepare for pushback. In the past, anti-labor forces have used the law and physical aggression to squeeze labor activists out of public space. Labor has a history of fighting back, beginning with the free speech fights of the Industrial Workers of the World (IWW) in the early twentieth century. These campaigns were the first in U.S. history to claim a First Amendment right to use public space. IWW organizer Elizabeth Gurley Flynn led several of these free speech fights. She and other women free speech fighters played an essential if often overlooked role in popularizing the idea that ordinary people have right to public space. Their tactics and experiences can inform and inspire women at the forefront of a contemporary labor militancy

Cyclic hydroxylamine as psychoactive compounds

A compound of formula (I): in which X represents O or CH2; R3 and R4 each independently represent hydrogen or C1-6 alkyl; p represent 0 or 1; and R represents a five- or six-membered saturated or unsaturated ring selected from: formula (II), (III) and (IV); or R represents a five- or six-membered oxo-substituted unsaturated ring selected from: (V) and (VI); wherein R1 and R2 together represent an oxo group, or R1 and R2 each represent hydrogen, methoxy or ethoxy, or R1 and R2 together with the interjacent carbon atom represent a 1,3-dioxolane or 1,3-dioxane ring, attached via the 2 position and optionally bearing one or more methyl or ethyl groups; or a salt thereof, is suitable for the treatment of anxiety and depression

OTC Derivatives Clearing, Brexit, and the CMU

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Brexit and OTC Derivatives Clearing. The Role of Politics

Contains fulltext : 199654.pdf (publisher's version ) (Open Access)35 p

PE Ranking. La classifica degli operatori e degli Advisor.

Analisi della graduatoria di tutti gli operatori e Advisor operanti nel mercato del private equity. Anatomia di un deal