Phosphodiesterase type 5 inhibitors increase Herceptin transport and treatment efficacy in mouse metastatic brain tumor models.

Background: Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment.

Methodology/principal Findings: We examined the effect of phosphodiesterase 5 (PDE5) inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport.

Stem/precursor cell-based CNS therapy: the importance of circumventing immune suppression by transplanting autologous cells.

Stem/precursor cell (SPC) therapy for neurodegeneration and neurotrauma has enormous therapeutic potential, but despite ongoing research efforts the success of clinical trials remains limited. Therapies that utilize immune suppression in combination with SPC transplantation have thus far failed to consider the beneficial role of the immune system in central nervous system (CNS) recovery. Systemic immune suppression may prevent neural repair, and in some cases exacerbate the underlying disorder.

Nanoconjugate Platforms Development Based in Poly(β,L-Malic Acid) Methyl Esters for Tumor Drug Delivery.

New copolyesters derived from poly(β,L-malic acid) have been designed to serve as nanoconjugate platforms in drug delivery. 25% and 50% methylated derivatives (coPMLA-Me(25)H(75) and coPMLA-Me(50)H(50)) with absolute molecular weights of 32 600 Da and 33 100 Da, hydrodynamic diameters of 3.0 nm and 5.

Glioma stem cell research for the development of immunotherapy.

Glioma, especially high-grade glioblastoma multiforme (GBM), is the most common and aggressive type of brain tumor, accounting for about half of all the primary brain tumors. Despite continued advances in surgery, chemotherapy, and radiotherapy, the clinical outcomes remain dismal. The 2-year survival rate of GBM is less than 30%.

Attenuation of AD-like neuropathology by harnessing peripheral immune cells: local elevation of IL-10 and MMP-9.

Immunization with an altered myelin-derived peptide (MOG45D) improves recovery from acute CNS insults, partially via recruitment of monocyte-derived macrophages that locally display a regulatory activity. Here, we investigated the local alterations in the cellular and molecular immunological milieu associated with attenuation of Alzheimer's disease-like pathology following immunotherapy. We found that immunization of amyloid precursor protein/presenilin 1 double-transgenic mice with MOG45D peptide, loaded on dendritic cells, led to a substantial reduction of parenchymal and perivascular amyloid beta (Abeta)-plaque burden and soluble Abeta((1-42)) peptide levels as well as reduced astrogliosis and levels of a key glial scar protein (chondroitin sulphate proteoglycan).

Thymic involution, a co-morbidity factor in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating disease, characterized by extremely rapid loss of motor neurons. Our studies over the last decade have established CD4(+) T cells as important players in central nervous system maintenance and repair. Those results, together with recent findings that CD4(+) T cells play a protective role in mouse models of ALS, led us to the current hypothesis that in ALS, a rapid T-cell malfunction may develop in parallel to the motor neuron dysfunction.

Pituitary adenoma stem cells.

The identification of a subpopulation of brain tumor cells with potent tumorigenic capacity strengthens the cancer stem cell hypothesis of the origin of the tumors that has recently attracted the attention of many researchers. Reports have been published on the identification of tumor cells with stem cells characteristics in different types of tumors (acute myelogenic leukemia, breast cancer, prostate cancer, bone sarcomas, liver cancer, and melanomas). We and other groups have previously reported the isolation of cancer stem cells from adult glioblastoma multiforme.

Alternative Abeta immunotherapy approaches for Alzheimer's disease.

In a seminal report in 1999, Schenk and colleagues demonstrated that vaccination of a mouse model of Alzheimer's disease (AD) with amyloid-beta(1-42) peptide (Abeta(1-42)) and adjuvant resulted in striking mitigation of AD-like pathology - giving rise to the field of AD immunotherapy. Later studies confirmed this result in other mouse models of AD and additionally showed cognitive improvement after Abeta vaccination. Based on these results, early developmental clinical trials ensued to immunize AD patients with Abeta(1-42) plus adjuvant (so-called "active" Abeta immunotherapy; trade name AN-1792; Elan Pharmaceuticals, Dublin, Ireland).

DCVax-Brain and DC vaccines in the treatment of GBM.

Background: DCVax-Brain (Northwest Biotherapeutics, Inc., Bethesda, MD, USA) is a personalized treatment for brain tumors. Its approach of administering autologous tumor antigen-bearing dendritic cells (DCs) has garnered hope for more effective and less toxic therapy for patients with malignant brain tumors including glioblastoma multiforme (GBM).

Spontaneous spinal cerebrospinal fluid leaks as the cause of subdural hematomas in elderly patients on anticoagulation.

Subdural hematoma is a relatively common complication of long-term anticoagulation, particularly in the elderly. The combination of anticoagulation and cerebral cortical atrophy is believed to be sufficient to explain the subdural bleeding. The authors report a series of elderly patients who were on a regimen of anticoagulation and developed chronic subdural hematomas (SDHs) due to a spontaneous spinal CSF leak.

Spontaneous spinal cerebrospinal fluid leak as a cause of coma after craniotomy for clipping of an unruptured intracranial aneurysm.

Spontaneous spinal CSF leaks are best known as a cause of orthostatic headache, but may also be the cause of coma. The authors encountered a unique case of a spontaneous spinal CSF leak causing coma 2 days after craniotomy for clipping of an unruptured aneurysm. This 44-year-old woman with autosomal dominant polycystic kidney disease underwent an uneventful craniotomy for an incidental anterior choroidal artery aneurysm.

Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas.

The identification of brain tumor stem-like cells (BTSCs) has implicated a role of biological self-renewal mechanisms in clinical brain tumor initiation and propagation. The molecular mechanisms underlying the tumor-forming capacity of BTSCs, however, remain unknown. Here, we have generated molecular signatures of glioblastoma multiforme (GBM) using gene expression profiles of BTSCs and have identified both Sonic Hedgehog (SHH) signaling-dependent and -independent BTSCs and their respective glioblastoma surgical specimens.

PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model.

The blood-brain tumor barrier (BTB) significantly limits delivery of therapeutic concentrations of chemotherapy to brain tumors. A novel approach to selectively increase drug delivery is pharmacologic modulation of signaling molecules that regulate BTB permeability, such as those in cGMP signaling. Here we show that oral administration of sildenafil (Viagra) and vardenafil (Levitra), inhibitors of cGMP-specific PDE5, selectively increased tumor capillary permeability in 9L gliosarcoma-bearing rats with no significant increase in normal brain capillaries.

Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.

Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here.

Different effects of KCa and KATP agonists on brain tumor permeability between syngeneic and allogeneic rat models.

The blood-brain tumor barrier (BTB) significantly limits delivery of effective concentrations of chemotherapeutic drugs to brain tumors. Previous studies suggest that BTB permeability may be modulated via alteration in the activity of potassium channels. In this study, we studied the relationship of BTB permeability increase mediated by potassium channel agonists to channel expression in two rat brain tumor models.

Increase in brain tumor permeability in glioma-bearing rats with nitric oxide donors.

Purpose: The blood-brain tumor barrier (BTB) significantly limits the delivery of chemotherapeutics to brain tumors. Nitric oxide (NO) is involved in the regulation of cerebral vascular permeability. We investigated the effects of NO donors, L-arginine and hydroxyurea, on BTB permeability in 9L gliosarcoma-bearing Fischer rats.

Dendritic cell immunotherapy for malignant gliomas.

The prognosis for patients with malignant gliomas remains poor despite advances in surgical technique, chemotherapy and radiation therapy. Median survival for glioblastoma multiforme, the most aggressive and deadliest form of brain cancer, remains only fifteen months even after optimal treatment with surgical resection followed by chemoradiation therapy. The grim prognosis can be attributed to the infiltrative nature of the disease, a central nervous system microenvironment that can escape immune surveillance and resistance of the tumor to chemotherapy.

In vivo gene delivery to proliferating cells in the striatum generated in response to a 6-hydroxydopamine lesion of the nigro-striatal dopamine pathway.

The degeneration of neurons in the mammalian brain is commonly associated with the division of cells located in the damaged area. The aim of the present study has been to characterise the phenotype of newly born cells in the striatum of adult rats following 6-hydroxydopamine lesion of the nigro-striatal pathway. Newborn cells were identified through labelling with either bromodeoxyuridine or retrovirus encoding green fluorescence protein.

Absence of TGFBR2 mutations in patients with spontaneous spinal CSF leaks and intracranial hypotension.

A heritable connective-tissue-disorder often is suspected in patients with spontaneous spinal CSF leaks and intracranial hypotension, but the nature of the disorder remains unknown in most patients. The aim of this study was to assess the gene encoding TGF-beta receptor-2 (TGFBR2) as a candidate gene for spinal CSF leaks. We searched the TGFBR2 gene for mutations in eight patients with spontaneous spinal CSF leaks who also had other features associated with TGFBR2 mutations, i.

Neural stem cells--a promising potential therapy for brain tumors.

Brain tumors can be highly aggressive and debilitating for many patients and lead to an untimely death in just a few months. Unfortunately, due to the location of many brain tumors, therapy with ionizing radiation, chemotherapeutic agents and/or surgery has limited rewards. In addition, the probability of totally removing highly infiltrative tumors, particularly gliomas, is extremely low and rarely provides a cure.

Frequency of spontaneous intracranial hypotension in the emergency department.

Spontaneous intracranial hypotension is considered a rare disorder. We conducted a study on the frequency of spontaneous intracranial hypotension in the emergency department (ED). We identified patients with spontaneous intracranial hypotension evaluated in the ED of a large urban hospital between 1 January 2003 and 31 December 2006.

Upright MRI in spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension.

Orthostatic headaches are the hallmark of spontaneous intracranial hypotension, but MRIs are traditionally obtained in the supine position. We investigated the utility of upright MRI of the brain in 6 patients with spontaneous intracranial hypotension. No discernable differences were noted between the supine and upright images.

Mahaley Clinical Research Award: chemosensitization of glioma through dendritic cell vaccination.

A major reason chemotherapy fails in cancer treatment is drug resistance. New targets against chemotherapy resistance have been developed with the identification of molecular pathways in drug resistance. These targets are proteins that are highly expressed in human gliomas and are known to be tumor antigens.

Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model.

Background: The blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases.

Results: In this study, we examined the function and regulation of calcium-activated potassium (KCa) channels in a rat metastatic brain tumor model.