A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma.

Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-ß and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.

Malignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells.

Purpose: While the tumor microenvironment has been known to play an integral role in tumor progression, the function of nonresident bone marrow-derived cells (BMDC) remains to be determined in neurologic tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas.Experimental Design: We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet-derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression. Levels of CD11b+/GR1+ BMDCs were analyzed at discrete stages of tumor progression. Using bone marrow transplantation, we determined the unique influence of BMDCs in the transition from low- to high-grade glioma. The functional role of these BMDCs was then examined using a JAK 1/2 inhibitor (AZD1480).Results: CD11b+ myeloid cells were significantly increased during tumor progression in peripheral blood and tumors of glioma patients. Increases in CD11b+/GR1+ cells were observed in murine peripheral blood, bone marrow, and tumors during low-grade to high-grade transformation. Transient blockade of CD11b+ cell expansion using a JAK 1/2 Inhibitor (AZD1480) impaired mobilization of these cells and was associated with a reduction in tumor volume, maintenance of a low-grade tumor phenotype, and prolongation in survival.Conclusions: We demonstrate that impaired recruitment of CD11b+ myeloid cells with a JAK1/2 inhibitor inhibits glioma progression in vivo and prolongs survival in a murine glioma model. Clin Cancer Res; 23(12); 3109-19. ©2016 AACR.

Función corticolímbica en la conducta agresiva impulsiva / Corticolimbic function in impulsive aggressive behavior

En la búsqueda de evidencias indicativas de una lesión en los animales y en el ser humano, los estudios de neuroimagen están identificando de manera creciente anomalías de los circuitos corticolímbicos que intervienen en la conducta agresiva. Esta revisión se centra en 3 sistemas neurales que participan en la agresividad impulsiva/reactiva: a)los sistemas neurales subcorticales responsables de la producción de los impulsos agresivos; b)los circuitos de toma de decisión y los circuitos de procesamiento de información social-emocional, que evalúan las consecuencias de realizar o no una agresión, y c)las regiones frontoparietales que intervienen en la regulación de las emociones y las tendencias motivacionales impulsivas. Revisamos los trastornos psiquiátricos, como el trastorno límite de la personalidad y el trastorno de personalidad antisocial, que se caracterizan por una agresividad reactiva elevada, centrándonos en las anomalías de estos 3 sistemas neurales (AU)

Building on animal and human lesion evidence, neuroimaging studies are increasingly identifying abnormalities in corticolimbic circuits mediating aggressive behavior. This review focuses on three neural systems involved in impulsive/reactive aggression: i)subcortical neural systems that support the production of aggressive impulses; ii)decision-making circuits and social-emotional information processing circuits that evaluate the consequences of aggressing or not aggressing; and iii)frontoparietal regions that are involved in regulating emotions and impulsive motivational urges. We review psychiatric disorders, including borderline personality disorder and antisocial personality disorder, characterized by elevated reactive aggression, focusing on abnormalities in these three neural systems (AU)

The neurochemistry of human aggression.

Various data from scientific research studies conducted over the past three decades suggest that central neurotransmitters play a key role in the modulation of aggression in all mammalian species, including humans. Specific neurotransmitter systems involved in mammalian aggression include serotonin, dopamine, norepinephrine, GABA, and neuropeptides such as vasopressin and oxytocin. Neurotransmitters not only help to execute basic behavioral components but also serve to modulate these preexisting behavioral states by amplifying or reducing their effects. This chapter reviews the currently available data to present a contemporary view of how central neurotransmitters influence the vulnerability for aggressive behavior and/or initiation of aggressive behavior in social situations. Data reviewed in this chapter include emoiric information from neurochemical, pharmaco-challenge, molecular genetic and neuroimaging studies.

Corticolimbic function in impulsive aggressive behavior.

Building on animal and human lesion evidence, neuroimaging studies are increasingly identifying abnormalities in corticolimbic circuits mediating aggressive behavior. This review focuses on three neural systems involved in impulsive/reactive aggression: 1) subcortical neural systems that support the production of aggressive impulses; 2) decision-making circuits and social-emotional information processing circuits that evaluate the consequences of aggressing or not aggressing; and 3) frontoparietal regions that are involved in regulating emotions and impulsive motivational urges. We review psychiatric disorders, including borderline personality disorder and antisocial personality disorder, characterized by elevated reactive aggression, focusing on abnormalities in these three neural systems.

Immunoglobulin-like transcript 3, an inhibitor of T cell activation, is reduced on blood monocytes during multiple sclerosis relapses and is induced by interferon beta-1b.

Immunoglobulin-like transcripts (ILTs) are immunoregulatory proteins that either activate or inhibit immune responses. ILT3 is inhibitory and is expressed preferentially by antigen-presenting cells. When its extracellular domain binds to an unidentified ligand of activated T cells, the T cell is silenced. Our objective was to study the expression of ILT3 on circulating monocytes in RRMS. Freshly isolated peripheral blood mononuclear cells were analyzed by multicolored flow cytometry. The proportion of ILT3(+)CD14(+) monocytes in blood, and ILT3 levels expressed by them, is lower in untreated multiple sclerosis in relapse than in: (1) untreated multiple sclerosis in remission (p < 0.009); (2) stable interferon beta-treated relapsing-remitting multiple sclerosis (p < 0.001) and; (3) healthy controls (p < 0.009). Glatiramer acetate-stimulated CD4( +) T cells, co-cultured with freshly isolated monocytes, proliferate significantly better (p = 0.0017 for multiple sclerosis; p = 0.0015 for controls) when T cell interaction with monocyte-expressed ILT3 is blocked by anti-ILT3 antibody. Interferon beta is beneficial in multiple sclerosis; why so remains unclear. Interferon beta-1b markedly increases ILT3 expression in vitro by monocytes from multiple sclerosis patients and controls. These findings identify a putative novel mechanism for the therapeutic benefit bestowed by Interferon beta and a new target for therapeutic intervention in relapsing-remitting multiple sclerosis.

Fat and neurosurgery: does obesity affect outcome after intracranial surgery?

OBJECTIVE: Obesity has been linked to increased morbidity and mortality after some surgical procedures. The purpose of this study was to determine whether obesity affects outcome after general neurosurgery and subarachnoid hemorrhage (SAH). METHODS: Three data sets were analyzed, including a retrospective review of 404 patients undergoing cranial and spinal neurosurgical procedures, a prospective collection of 100 patients with aneurysmal SAH, and data from 3567 patients with aneurysmal SAH who were entered into randomized clinical trials of tirilazad. For each data set, outcome was assessed by mortality, postoperative morbidity, and Glasgow Outcome Scale score. Prognostic factors, including body weight and body mass index, were tested for their effect on these outcomes using multivariable logistic regression. RESULTS: For patients undergoing general cranial and spinal neurosurgery, independent predictors of morbidity and mortality were age, American Society of Anesthesia class, disseminated malignancy, emergency surgery, and increased duration of surgery. For patients with SAH, score on the Glasgow Outcome Scale was associated with age and admission Glasgow Coma Scale score. In the tirilazad data set, multiple factors were associated with score on the Glasgow Outcome Scale, but, as with the other 2 data sets, body weight had no relationship to outcome. CONCLUSION: Obesity may have less effect on the outcome of patients with mainly cranial neurosurgical disease and aneurysmal SAH than it does on patients undergoing other types of surgery.