scholarly journals Simulating vasogenic brain edema using chronic VEGF infusion

2017 ◽  
Vol 127 (4) ◽  
pp. 905-916 ◽  
Author(s):  
Martin Piazza ◽  
Jeeva Munasinghe ◽  
Roger Murayi ◽  
Nancy Edwards ◽  
Blake Montgomery ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Brain Edema ◽  
Immunohistochemical Analysis ◽  
Abnormal Behavior ◽  
Neurological Deficits ◽  
Rat Serum ◽  
Vasogenic Brain Edema ◽  
Chronic Infusion ◽  
Novel Therapeutic Strategies

OBJECTIVETo study peritumoral brain edema (PTBE), it is necessary to create a model that accurately simulates vasogenic brain edema (VBE) without introducing a complicated tumor environment. PTBE associated with brain tumors is predominantly a result of vascular endothelial growth factor (VEGF) secreted by brain tumors, and VEGF infusion alone can lead to histological blood-brain barrier (BBB) breakdown in the absence of tumor. VBE is intimately linked to BBB breakdown. The authors sought to establish a model for VBE with chronic infusion of VEGF that can be validated by serial in-vivo MRI and histological findings.METHODSMale Fischer rats (n = 182) underwent stereotactic striatal implantation of MRI-safe brain cannulas for chronic infusion of VEGF (2–20 µg/ml). Following a preinfusion phase (4–6 days), the rats were exposed to VEGF or control rat serum albumin (1.5 µl/hr) for as long as 144 hours. Serial MRI was performed during infusion on a high-field (9.4-T) machine at 12–24, 24–36, 48–72, and 120–144 hours. Rat brains were then collected and histological analysis was performed.RESULTSControl animals and animals infused with 2 µg/ml of VEGF experienced no neurological deficits, seizure activity, or abnormal behavior. Animals treated with VEGF demonstrated a significantly larger volume (42.90 ± 3.842 mm3) of T2 hyper-attenuation at 144 hours when compared with the volume (8.585 ± 1.664 mm3) in control animals (mean difference 34.31 ± 4.187 mm3, p < 0.0001, 95% CI 25.74–42.89 mm3). Postcontrast T1 enhancement in the juxtacanalicular region indicating BBB breakdown was observed in rats undergoing infusion with VEGF. At the later time periods (120–144 hrs) the volume of T1 enhancement (34.97 ± 8.99 mm3) was significantly less compared with the region of edema (p < 0.0001). Histologically, no evidence of necrosis or inflammation was observed with VEGF or control infusion. Immunohistochemical analysis demonstrated astrocyte activation, vascular remodeling, and increased claudin-5 expression in juxtacanalicular regions. Aquaporin-4 expression was increased in both control and VEGF animals in the juxtacanalicular regions.CONCLUSIONSThe results of this study show that chronic brain infusion of VEGF creates a reliable model of VBE. This model lacks necrosis and inflammation that are characteristic of previous models of VBE. The model allows for a precise investigation into the mechanism of VBE formation. The authors also anticipate that this model will allow for investigation into the mechanism of glucocorticoid action in abrogating VBE, and to test novel therapeutic strategies targeting PTBE.

High Response Rates and Prolonged Survival in Patients With Corticotroph Pituitary Tumors and Refractory Cushing Disease From Capecitabine and Temozolomide (CAPTEM)

Neurosurgery ◽  
2013 ◽  
Vol 74 (4) ◽  
pp. E447-E455 ◽  
Author(s):  
Brad E. Zacharia ◽  
Anthony P. Gulati ◽  
Jeffrey N. Bruce ◽  
Arthur S. Carminucci ◽  
Sharon L. Wardlaw ◽  
...  
Keyword(s):  
Cranial Nerves ◽  
Case Series ◽  
Pituitary Tumors ◽  
Immunohistochemical Analysis ◽  
Neurological Deficits ◽  
Complete Regression ◽  
Cushing Disease ◽  
Chemotherapeutic Regimen ◽  
Hormonal Therapies

ABSTRACT BACKGROUND AND IMPORTANCE: Rarely, corticotrophic pituitary tumors take on an aggressive form characterized by rapid growth, invasion into local structures, compression of cranial nerves, and possible spread to distant sites. When conventional surgery, radiation therapy, and hormones fail to control progression and symptoms, alternative therapies are needed. A novel chemotherapeutic regimen of capecitabine and temozolomide (CAPTEM), originally designed in our laboratory, demonstrated dramatic antineoplastic effects against corticotrophic pituitary tumors. CLINICAL PRESENTATION: We present a case series of 4 patients with aggressive, adrenocorticotrophic hormone--producing pituitary tumors who had previously depleted all surgical, radiation, and hormonal therapies and were then treated with CAPTEM. Dramatic clinical improvements in neurological deficits and Cushing symptoms were evident in all patients after treatment was initiated. Confirmed by radiographic imaging, 2 of 4 patients demonstrated complete regression of disease, 1 patient had a 75% regression, and the fourth patient has ongoing stable disease for &gt; 4.5 years at the time of this writing. Immunohistochemical analysis of patients' tumor samples showed low O6-methyguanyl methyltransferase expression and adequate levels of mismatch repair enzymes (MLH-1, MSH-2, MSH-6, and PMS-2), which are important for the in vivo efficacy of CAPTEM. CONCLUSION: This is the first report of prolonged antitumor response to and radiographic complete remissions as a result of CAPTEM in patients with aggressive pituitary tumors who had exhausted all other therapies.

Vascular permeability factor in brain metastases: correlation with vasogenic brain edema and tumor angiogenesis

1994 ◽  
Vol 81 (4) ◽  
pp. 560-566 ◽  
Author(s):  
John Strugar ◽  
David Rothbart ◽  
William Harrington ◽  
Gregory R. Criscuolo
Keyword(s):  
Brain Tumors ◽  
Mr Imaging ◽  
Vascular Permeability ◽  
Brain Edema ◽  
Vasogenic Edema ◽  
Metastatic Brain Tumors ◽  
Vascular Permeability Factor ◽  
Tumor Vascularity ◽  
Vasogenic Brain Edema ◽  
Peritumoral Brain Edema

✓ Metastatic brain tumors are almost always associated with vasogenic brain edema, which in turn plays a pivotal role in the evolution of neurological morbidity associated with these lesions. Attention has recently focused on a group of proteinaceous vascular permeability factors (VPF's) that are capable of inducing angiogenesis and promoting increased capillary permeability. To test the hypothesis that metastatic brain tumors expressing VPF's are associated with peritumoral cerebral edema, a rabbit polyclonal immunoglobulin (Ig) G anti-VPF was used to immunostain pathological specimens of metastatic cerebral tumors obtained from 22 patients who underwent surgery at Yale-New Haven Hospital. Magnetic resonance (MR) imaging was used to correlate VPF staining in tumor tissue with the occurrence of peritumoral brain edema. A histological antigen, using two gliosis specimens as controls. Results revealed 21 of 22 tumors stained positively for VPF's; the negative-VPF tumor was a melanoma that exhibited no peritumoral edema. Twenty of 22 tumors had MR imaging-evident vasogenic edema. The presence and intensity of VPF immunostaining of microvascular features were noted and compared. Factor VIII staining demonstrated tumor vascularity to be most abundant in VPF-rich regions of tumor. The authors therefore report a high correlation between the presence of VPF's and the occurrence of peritumoral brain edema associated with cerebral metastases.

Influence of interleukin-6 on the development of peritumoral brain edema in meningiomas

2010 ◽  
Vol 112 (1) ◽  
pp. 73-80 ◽  
Author(s):  
Kyung-Jae Park ◽  
Shin-Hyuk Kang ◽  
Yang-Seok Chae ◽  
Mi-Ok Yu ◽  
Tai-Hyoung Cho ◽  
...  
Keyword(s):  
Brain Edema ◽  
Interleukin 6 ◽  
Immunohistochemical Analysis ◽  
Tumor Location ◽  
Neurological Deficits ◽  
Mr Images ◽  
Edema Volume ◽  
Peritumoral Brain Edema ◽  
Mrna And Protein Expression ◽  
Polymerase Chain

Object Peritumoral brain edema (PTBE) is associated with perioperative neurological deficits in patients with meningiomas. However, the pathogenesis of meningioma-associated edema remains unclear. In the present study, the authors investigated the expression of interleukin-6 (IL-6) and its relationship with PTBE in resected meningiomas. Methods Thirty-six benign meningiomas obtained in 36 patients were studied retrospectively. Edema volume was assessed on MR images, and an edema index (EI) was calculated. Interleukin-6 mRNA and protein expression were examined by real-time reverse transcriptase polymerase chain reaction and immunohistochemical staining. Results Peritumoral brain edema was found in 16 patients (44%). Neither age, sex, histological subtype, nor tumor location were related to PTBE. The level of IL-6 mRNA was 7.72 times greater in the edema group (EI > 0.2) than in the nonedema group (EI < 0.2; p = 0.011). On immunohistochemical analysis, IL-6 protein was found localized in the cytoplasm of the tumor cells, and was detected in 12 (75%) of 16 cases of edematous meningiomas, but in only 6 (30%) of 20 nonedematous cases. There was a significant correlation between the severity of PTBE and IL-6 expression (p = 0.004). Conclusions The authors' results in this study indicate that IL-6 expression may contribute to the development of brain edema associated with meningiomas.

Decreased expression of heparanase in glioblastoma multiforme

2005 ◽  
Vol 102 (3) ◽  
pp. 513-521 ◽  
Author(s):  
Yushi Ueno ◽  
Masaaki Yamamoto ◽  
Israel Vlodavsky ◽  
Iris Pecker ◽  
Kohichi Ohshima ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Brain Tumors ◽  
Brain Tissue ◽  
Cell Lines ◽  
Immunohistochemical Analysis ◽  
Metastatic Brain Tumors ◽  
Content Type ◽  
Fine Print

Object. The authors investigated the presence of endoglycosidase heparanase in human glioblastoma multiforme (GBM) and metastatic brain tumors as well as in healthy brain tissue to explore the relationship between the biological characteristics of GBM and the role of heparanase. Methods. Heparanase messenger (m)RNA was almost undetectable in GBMs in vivo, whereas it was frequently seen in metastatic brain tumors according to results of reverse transcription—polymerase chain reaction (RT-PCR). Immunohistochemical analysis of paraffin-embedded tissue sections showed that neoplastic cells in metastatic brain tumors, especially in cells that invaded blood vessels, exhibit intense heparanase immunoreactivity. Heparanase was present in two highly invasive glioma cell lines, U87MG and U251MG, in vitro. These cell lines did not have metastatic capability, which was tested in an experimental pulmonary metastases model in mice. The activity of heparanase in these cell lines was almost the same as that in the highly metastatic melanoma cell line B16-F1. After nude mice were inoculated with U87MG cells, however, heparanase was no longer detected in subcutaneous or intracerebral experimental glioma in vivo based on results of immunohistochemical analysis. According to results of real-time quantitative PCR, there was a 10-fold increase in heparanase mRNA in U87MG glioma cells in vitro compared with that in experimental U87MG glioma tissue in vivo in nude mice. Conclusions. These results indicate that the expression of heparanase was downregulated in GBM in vivo, which rarely metastasizes to distant organs outside the central nervous system. Heparanase is not implicated in the invasiveness of GBM to surrounding healthy brain tissue in vivo.

Scavenging Free Iron Reduces Arteriolar Microvasospasms After Experimental Subarachnoid Hemorrhage

Stroke ◽  
2021 ◽  
Author(s):  
Hanhan Liu ◽  
Julian Schwarting ◽  
Nicole Angela Terpolilli ◽  
Kathrin Nehrkorn ◽  
Nikolaus Plesnila
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Delayed Cerebral Ischemia ◽  
Neurological Deficits ◽  
Free Iron ◽  
Acute Cerebral Ischemia ◽  
Experimental Subarachnoid Hemorrhage ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

Background and Purpose: Subarachnoid hemorrhage (SAH) is associated with acute and delayed cerebral ischemia resulting in high acute mortality and severe chronic neurological deficits. Spasms of the pial and intraparenchymal microcirculation (microvasospasms) contribute to acute cerebral ischemia after SAH; however, the underlying mechanisms remain unknown. We hypothesize that free iron (Fe 3+ ) released from hemolytic red blood cells into the subarachnoid space may be involved in microvasospasms formation. Methods: Male C57BL/6 mice (n=8/group) received 200 mg/kg of the iron scavenger deferoxamine or vehicle intravenously and were then subjected to SAH by filament perforation. Microvasospasms of pial and intraparenchymal vessels were imaged three hours after SAH by in vivo 2-photon microscopy. Results: Microvasospasms occurred in all investigated vessel categories down to the capillary level. Deferoxamine significantly reduced the number of microvasospasms after experimental SAH. The effect was almost exclusively observed in larger pial arterioles (>30 µm) covered with blood. Conclusions: These results provide proof-of-principle evidence that Fe 3+ is involved in the formation of arteriolar microvasospasms after SAH and that arteriolar and capillary microvasospasms are triggered by different mechanisms. Deciphering the mechanisms of Fe 3+ -induced microvasospasms may result in novel therapeutic strategies for SAH patients.

Molecular iodine synergized and sensitized neuroblastoma cells to the antineoplastic effect of ATRA

2020 ◽  
Vol 27 (12) ◽  
pp. 699-710
Author(s):  
Irasema Mendieta ◽  
Gabriel Rodríguez-Gómez ◽  
Bertha Rueda-Zarazúa ◽  
Julia Rodríguez-Castelán ◽  
Winniberg Álvarez-León ◽  
...  
Keyword(s):  
Residual Disease ◽  
Neuroblastoma Cells ◽  
Survivin Expression ◽  
Body Weight Loss ◽  
Immunohistochemical Analysis ◽  
Molecular Iodine ◽  
Tyrosine Kinase Receptor ◽  
Adjuvant Effect

Neuroblastoma (NB) is the most common solid childhood tumor, and all-trans retinoic acid (ATRA) is used as a treatment to decrease minimal residual disease. Molecular iodine (I2) induces differentiation and/or apoptosis in several neoplastic cells through activation of PPARγ nuclear receptors. Here, we analyzed whether the coadministration of I2 and ATRA increases the efficacy of NB treatment. ATRA-sensitive (SH-SY5Y), partially-sensitive (SK-N-BE(2)), and non-sensitive (SK-N-AS) NB cells were used to analyze the effect of I2 and ATRA in vitro and in xenografts (Foxn1 nu/nu mice), exploring actions on cellular viability, differentiation, and molecular responses. In the SH-SY5Y cells, 200 μM I2 caused a 100-fold (0.01 µM) reduction in the antiproliferative dose of ATRA and promoted neurite extension and neural marker expression (tyrosine hydroxylase (TH) and tyrosine kinase receptor alpha (Trk-A)). In SK-N-AS, the I2 supplement sensitized these cells to 0.1 μM ATRA, increasing the ATRA-receptor (RARα) and PPARγ expression, and decreasing the Survivin expression. The I2 supplement increased the mitochondrial membrane potential in SK-N-AS suggesting the participation of mitochondrial-mediated mechanisms involved in the sensibilization to ATRA. In vivo, oral I2 supplementation (0.025%) synergized the antitumor effect of ATRA (1.5 mg/kg BW) and prevented side effects (body weight loss and diarrhea episodes). The immunohistochemical analysis showed that I2 supplementation decreased the intratumoral vasculature (CD34). We suggest that the I2 + ATRA combination should be studied in preclinical and clinical trials to evaluate its potential adjuvant effect in addition to conventional treatments.

scholarly journals LPTO-06. A NOVEL BRAIN-PERMEANT CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF BREAST CANCER LEPTOMENINGEAL METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i7-i7
Author(s):  
Jiaojiao Deng ◽  
Sophia Chernikova ◽  
Wolf-Nicolas Fischer ◽  
Kerry Koller ◽  
Bernd Jandeleit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Tumors ◽  
Cell Lines ◽  
Chemotherapeutic Agent ◽  
Leptomeningeal Metastasis ◽  
Breast Cancer Cell Lines ◽  
Normal Brain ◽  
Breast Cancers

Abstract Leptomeningeal metastasis (LM), a spread of cancer to the cerebrospinal fluid and meninges, is universally and rapidly fatal due to poor detection and no effective treatment. Breast cancers account for a majority of LMs from solid tumors, with triple-negative breast cancers (TNBCs) having the highest propensity to metastasize to LM. The treatment of LM is challenged by poor drug penetration into CNS and high neurotoxicity. Therefore, there is an urgent need for new modalities and targeted therapies able to overcome the limitations of current treatment options. Quadriga has discovered a novel, brain-permeant chemotherapeutic agent that is currently in development as a potential treatment for glioblastoma (GBM). The compound is active in suppressing the growth of GBM tumor cell lines implanted into the brain. Radiolabel distribution studies have shown significant tumor accumulation in intracranial brain tumors while sparing the adjacent normal brain tissue. Recently, we have demonstrated dose-dependent in vitro and in vivo anti-tumor activity with various breast cancer cell lines including the human TNBC cell line MDA-MB-231. To evaluate the in vivo antitumor activity of the compound on LM, we used the mouse model of LM based on the internal carotid injection of luciferase-expressing MDA-MB-231-BR3 cells. Once the bioluminescence signal intensity from the metastatic spread reached (0.2 - 0.5) x 106 photons/sec, mice were dosed i.p. twice a week with either 4 or 8 mg/kg for nine weeks. Tumor growth was monitored by bioluminescence. The compound was well tolerated and caused a significant delay in metastatic growth resulting in significant extension of survival. Tumors regressed completely in ~ 28 % of treated animals. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, Quadriga’s new agent could be effective as a therapeutic for both primary and metastatic brain tumors such as LM. REF: https://onlinelibrary.wiley.com/doi/full/10.1002/pro6.43

scholarly journals RNF141 interacts with KRAS to promote colorectal cancer progression

Oncogene ◽  
2021 ◽  
Author(s):  
Jiuna Zhang ◽  
Xiaoyu Jiang ◽  
Jie Yin ◽  
Shiying Dou ◽  
Xiaoli Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasma Membrane ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Critical Role ◽  
Ring Finger ◽  
Immunohistochemical Analysis ◽  
Bimolecular Fluorescence Complementation

AbstractRING finger proteins (RNFs) play a critical role in cancer initiation and progression. RNF141 is a member of RNFs family; however, its clinical significance, roles, and mechanism in colorectal cancer (CRC) remain poorly understood. Here, we examined the expression of RNF141 in 64 pairs of CRC and adjacent normal tissues by real-time PCR, Western blot, and immunohistochemical analysis. We found that there was more expression of RNF141 in CRC tissue compared with its adjacent normal tissue and high RNF141 expression associated with T stage. In vivo and in vitro functional experiments were conducted and revealed the oncogenic role of RNF141 in CRC. RNF141 knockdown suppressed proliferation, arrested the cell cycle in the G1 phase, inhibited migration, invasion and HUVEC tube formation but promoted apoptosis, whereas RNF141 overexpression exerted the opposite effects in CRC cells. The subcutaneous xenograft models showed that RNF141 knockdown reduced tumor growth, but its overexpression promoted tumor growth. Mechanistically, liquid chromatography-tandem mass spectrometry indicated RNF141 interacted with KRAS, which was confirmed by Co-immunoprecipitation, Immunofluorescence assay. Further analysis with bimolecular fluorescence complementation (BiFC) and Glutathione-S-transferase (GST) pull-down assays showed that RNF141 could directly bind to KRAS. Importantly, the upregulation of RNF141 increased GTP-bound KRAS, but its knockdown resulted in a reduction accordingly. Next, we demonstrated that RNF141 induced KRAS activation via increasing its enrichment on the plasma membrane not altering total KRAS expression, which was facilitated by the interaction with LYPLA1. Moreover, KRAS silencing partially abolished the effect of RNF141 on cell proliferation and apoptosis. In addition, our findings presented that RNF141 functioned as an oncogene by upregulating KRAS activity in a manner of promoting KRAS enrichment on the plasma membrane in CRC.

scholarly journals Detecting apoptosis as a clinical endpoint for proof of a clinical principle

2020 ◽  
Author(s):  
Piero Zollet ◽  
Timothy E.Yap ◽  
M Francesca Cordeiro
Keyword(s):  
Drug Development ◽  
Therapeutic Response ◽  
Imaging Techniques ◽  
Brain Diseases ◽  
Promising Strategy ◽  
Sight Loss ◽  
Apoptosis Detection ◽  
Novel Therapeutic Strategies

The transparent eye media represent a window through which to observe changes occurring in the retina during pathological processes. In contrast to visualising the extent of neurodegenerative damage that has already occurred, imaging an active process such as apoptosis has the potential to report on disease progression and therefore the threat of irreversible functional loss in various eye and brain diseases. Early diagnosis in these conditions is an important unmet clinical need to avoid or delay irreversible sight loss. In this setting, apoptosis detection is a promising strategy with which to diagnose, provide prognosis, and monitor therapeutic response. Additionally, monitoring apoptosis in vitro and in vivo has been shown to be valuable for drug development in order to assess the efficacy of novel therapeutic strategies both in the pre-clinical and clinical setting. Detection of Apoptosing Retinal Cells (DARC) technology is to date the only tool of its kind to have been tested in clinical trials, with other new imaging techniques under investigation in the fields of neuroscience, ophthalmology and drug development. We summarize the transitioning of techniques detecting apoptosis from bench to bedside, along with the future possibilities they encase.

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