In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern. Despite nondetectable CNS leukemia in many cases, prophylactic CNS-directed conventional intrathecal chemotherapy is required for relapse-free survival, indicating subclinical CNS manifestation in most patients. However, CNS-directed therapy is associated with long-term sequelae, including neurocognitive deficits and secondary neoplasms. Therefore, molecular mechanisms and pathways mediating leukemia-cell entry into the CNS need to be understood to identify targets for prophylactic and therapeutic interventions and develop alternative CNS-directed treatment strategies. In this study, we analyzed leukemia-cell entry into the CNS using a primograft ALL mouse model. We found that primary ALL cells transplanted onto nonobese diabetic/severe combined immunodeficiency mice faithfully recapitulated clinical and pathological features of meningeal infiltration seen in patients with ALL. ALL cells that had entered the CNS and were infiltrating the meninges were characterized by high expression of vascular endothelial growth factor A (). Although cellular viability, growth, proliferation, and survival of ALL cells were found to be independent of VEGF, transendothelial migration through CNS microvascular endothelial cells was regulated by VEGF. The importance of VEGF produced by ALL cells in mediating leukemia-cell entry into the CNS and leptomeningeal infiltration was further demonstrated by specific reduction of CNS leukemia on in vivo VEGF capture by the anti-VEGF antibody bevacizumab. Thus, we identified a mechanism of ALL-cell entry into the CNS, which by targeting VEGF signaling may serve as a novel strategy to control CNS leukemia in patients, replacing conventional CNS-toxic treatment.
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http://dx.doi.org/10.1182/blood-2017-03-769315 | DOI Listing |
J Hazard Mater
December 2024
Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fiocruz, Brazil; Laboratory of Ocular Immunology and Transplantation, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States. Electronic address:
Persistent organic pollutants (POPs) are ubiquitous in the environment and display the capacity to bioaccumulate in living organisms, constituting a hazard to both wildlife and humans. Although restrictions have been applied to prohibit the production of several POPs since the 1960s, high levels of these compounds can still be detected in many environmental and biological matrices, due to their chemical properties and significantly long half-lives. Some POPs can be passed from mother to the fetus and can gain entry to the central nervous system (CNS), by crossing the blood-brain barrier (BBB), resulting in significant deleterious effects, including neurocognitive and psychiatric abnormalities, which may lead to long-term socio-economic burdens.
View Article and Find Full Text PDFClin Microbiol Infect
December 2024
Medical Microbiology and Virology, Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark.
Background: Despite established antiviral therapy for herpes simplex (HSV), varicella zoster (VZV) and cytomegalovirus (CMV) encephalitis, outcome remains poor.
Objectives: To assess pharmacokinetic (PK) and -dynamic (PD) data of antiviral drugs in the central nervous system (CNS) to optimize treatment of Herpesviridae encephalitis.
Sources: PUBMED search 1950 to September 2024, terms 1.
J Virol
December 2024
Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA.
Unlabelled: Viral aseptic meningitis is a neuroinflammatory condition that occurs when viruses gain access to the central nervous system (CNS) and induce inflammation. The blood-brain barrier (BBB) is comprised of brain endothelial cells (BECs) that stringently regulate the passage of molecules, toxins, and pathogens from the circulation into the CNS. Through their unique properties, such as complex tight junctions, reduced rates of endocytosis, expression of efflux transporters, and restricted expression of leukocyte adhesion molecules, the BBB is often able to limit pathogen entry into the brain; however, certain neurotropic pathogens, such as coxsackievirus B3 (CVB3) are able to infect the CNS.
View Article and Find Full Text PDFBiopharm Drug Dispos
December 2024
Chitkara College of Pharmacy, Chitkara University, Rajpura, India.
Front Neurol
November 2024
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan.
Background: Paper symptom diaries are a common tool for assessing motor fluctuations in Parkinson's disease (PD) patients, but there are concerns about inaccuracies in the assessment of motor fluctuation due to recall bias and poor compliance. We, therefore, developed an electronic diary with reminder and real-time recording functions.
Objectives And Methods: To evaluate the effectiveness of the electronic diary, we compared compliance and motor fluctuation assessment with a paper diary.
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