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

Small Vessel Ischemic Disease of the Brain and Brain Metastases in Lung Cancer Patients

Brain metastases occur commonly in patients with lung cancer. Small vessel ischemic disease is frequently found when imaging the brain to detect metastases. We aimed to determine if the presence of small vessel ischemic disease (SVID) of the brain is protective against the development of brain metastases in lung cancer patients.A retrospective cohort of 523 patients with biopsy confirmed lung cancer who had received magnetic resonance imaging of the brain as part of their standard initial staging evaluation was reviewed. Information collected included demographics, comorbidities, details of the lung cancer, and the presence of SVID of the brain. A portion of the cohort had the degree of SVID graded. The primary outcome measure was the portion of study subjects with and without SVID of the brain who had evidence of brain metastases at the time of initial staging of their lung cancer.109 patients (20.8%) had evidence of brain metastases at presentation and 345 (66.0%) had evidence of SVID. 13.9% of those with SVID and 34.3% of those without SVID presented with brain metastases (p<0.0001). In a model including age, diabetes mellitus, hypertension, hyperlipidemia, and tobacco use, SVID of the brain was found to be the only protective factor against the development of brain metastases, with an OR of 0.31 (0.20, 0.48; p<0.001). The grade of SVID was higher in those without brain metastases.These findings suggest that vascular changes in the brain are protective against the development of brain metastases in lung cancer patients

Abraham C. Ratshesky collection, undated, 1875-1974 (bulk: 1930-1948)

This collection contains personal and professional photographs of family, friends and trips to Czechoslovakia, reports on actions as U.S. Minister, diaries, films, and letters from new First Lady Coolidge following the death of President Harding. Also includes an official report and other data about the Halifax Relief Expedition (1917), of which Ratshesky was Commissioner-in-Charge, appointed by the Governor of Mass. to assist the city after a devastating explosion.Includes also 6 films, 4 of which deal with Czechoslovakia and 2 with Boy Scout activities.Abraham Captain Ratshesky (1864-1943) was a banker by profession who founded the U.S. Trust Company with his brother Israel in 1895, and also served in a variety of political positions, including the Massachusetts State Senate from 1892-1895, delegate to the Republican National Conventions in 1892, 1904, 1908, 1916, and 1924, Assistant Food Administrator for Massachusetts during World War I, and most importantly, United States Minister to Czechoslovakia from 1930-1932. In 1933, Ratshesky was honored with the Order of the White Lion First Class, Czechoslovakia’s highest honor. A noted philanthropist, Ratshesky was involved in relief efforts for the 1917 Halifax Disaster, the donation of the building used for the American Red Cross headquarters in Boston, and the 1925 â€Pennies Campaign” to restore the U.S.S. Constitution. He also founded the A.C. Ratshesky Charity Foundation in 1916, still in operation.NB: Films from Box 9 removed to Treasure Room for proper storage, per HS 9/1993.far031

Relationship between SVID severity and metastatic brain tumor:

<p>The data are presented as % (filled symbols) or as a ratio between SVID severity in the two subsets of patients.</p