Toxin-Based Targeted Therapy for Malignant Brain Tumors

Despite advances in conventional treatment modalities for malignant brain tumors—surgery, radiotherapy, and chemotherapy—the prognosis for patients with high-grade astrocytic tumor remains dismal. The highly heterogeneous and diffuse nature of astrocytic tumors calls for the development of novel therapies. Advances in genomic and proteomic research indicate that treatment of brain tumor patients can be increasingly personalized according to the characteristics of the targeted tumor and its environment. Consequently, during the last two decades, a novel class of investigative drug candidates for the treatment of central nervous system neoplasia has emerged: recombinant fusion protein conjugates armed with cytotoxic agents targeting tumor-specific antigens. The clinical applicability of the tumor-antigen-directed cytotoxic proteins as a safe and viable therapy for brain tumors is being investigated. Thus far, results from ongoing clinical trials are encouraging, as disease stabilization and patient survival prolongation have been observed in at least 109 cases. This paper summarizes the major findings pertaining to treatment with the different antiglioma cytotoxins at the preclinical and clinical stages

Imaging of Convection Enhanced Delivery of Toxins in Humans

Drug delivery of immunotoxins to brain tumors circumventing the blood brain barrier is a significant challenge. Convection-enhanced delivery (CED) circumvents the blood brain barrier through direct intracerebral application using a hydrostatic pressure gradient to percolate therapeutic compounds throughout the interstitial spaces of infiltrated brain and tumors. The efficacy of CED is determined through the distribution of the therapeutic agent to the targeted region. The vast majority of patients fail to receive a significant amount of coverage of the area at risk for tumor recurrence. Understanding this challenge, it is surprising that so little work has been done to monitor the delivery of therapeutic agents using this novel approach. Here we present a review of imaging in convection enhanced delivery monitoring of toxins in humans, and discuss future challenges in the field

Effect of imaging and catheter characteristics on clinical outcome for patients in the PRECISE study

The PRECISE study used convection enhanced delivery (CED) to infuse IL13-PE38QQR in patients with recurrent glioblastoma multiforme (GBM) and compared survival to Gliadel Wafers (GW). The objectives of this retrospective evaluation were to assess: (1) catheter positioning in relation to imaging features and (2) to examine the potential impact of catheter positioning, overall catheter placement and imaging features on long term clinical outcome in the PRECISE study. Catheter positioning and overall catheter placement were scored and used as a surrogate of adequate placement. Imaging studies obtained on day 43 and day 71 after resection were each retrospectively reviewed. Catheter positioning scores, catheter overall placement scores, local tumor control and imaging change scores were reviewed and correlated using Generalized Linear Mixed Models. Cox PH regression analysis was used to examine whether these imaging based variables predicted overall survival (OS) and progression free survival (PFS) after adjusting for age and KPS. Of 180 patients in the CED group, 20 patients did not undergo gross total resection. Of the remaining 160 patients only 53% of patients had fully conforming catheters in respect to overall placement and 51% had adequate catheter positioning scores. Better catheter positioning scores were not correlated with local tumor control (P = 0.61) or imaging change score (P = 0.86). OS and PFS were not correlated with catheter positioning score (OS: P = 0.53; PFS: P = 0.72 respectively), overall placement score (OS: P = 0.55; PFS: P = 0.35) or imaging changes on day 43 MRI (P = 0.88). Catheter positioning scores and overall catheter placement scores were not associated with clinical outcome in this large prospective trial

Monitoring Radiographic Brain Tumor Progression

Determining radiographic progression in primary malignant brain tumors has posed a significant challenge to the neuroncology community. Glioblastoma multiforme (GBM, WHO Grade IV) through its inherent heterogeneous enhancement, growth patterns, and irregular nature has been difficult to assess for progression. Our ability to detect tumor progression radiographically remains inadequate. Despite the advanced imaging techniques, detecting tumor progression continues to be a clinical challenge. Here we review the different criteria used to detect tumor progression, and highlight the inherent challenges with detection of progression

センシ

In Persian; foreword in Japanese and EnglishAdded t.p. in Japanese and Englishجلد 2 published in 2006 before جلد 1Two col. maps on folded leaves of plates inserted in جلد 1"Supported by Grant-in-Aid for Scientific Research (Grant-in-Aid for JSPS Fellows, 17-2387, 2005-2008 and Grant-in-Aid for Young Scientists (B), 21720255, 2009)"--Foreword, جلد 1, p. xviiIncludes bibliographical references and inde

Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

The impact of human immunodeficiency virus infection on drug-resistant tuberculosis.

Infection with human immunodeficiency virus (HIV) has been associated with increased rates of single- and multidrug-resistant (MDR) tuberculosis in the New York City area. In order to examine the relationship of HIV infection to drug-resistant tuberculosis in other selected regions of the United States, we established a registry of cases of culture-proven tuberculosis. Data were collected from sites participating in an NIH-funded, community-based HIV clinical trials group. All cases of tuberculosis, regardless of HIV status, which occurred between January 1992 and June 1994 were recorded. Overall, 1,373 cases of tuberculosis were evaluated, including 425 from the New York City area, and 948 from seven other metropolitan areas. The overall prevalence of resistance to one or more drugs was 20.4%, and 5.6% of isolates were resistant to both isoniazid and rifampin (MDR). In the New York City area, HIV-infected patients were significantly more likely than persons not known to be HIV-infected, to have resistance to at least one drug (37% versus 19%) and MDR (19% versus 6%). In other geographic areas, overall drug resistance was 16%, and only 2.2% of isolates were MDR. In multiple logistic regression analyses, HIV infection was shown to be a risk factor for drug-resistant tuberculosis, independent of geographic location, history of prior therapy, age, and race. We concluded that HIV infection is associated with increased rates of resistance to antituberculosis drugs in both the New York City area and other geographic areas. MDR tuberculosis is occurring predominantly in the New York City area and is highly correlated with HIV infection

The impact of human immunodeficiency virus infection on drug-resistant tuberculosis.

Infection with human immunodeficiency virus (HIV) has been associated with increased rates of single- and multidrug-resistant (MDR) tuberculosis in the New York City area. In order to examine the relationship of HIV infection to drug-resistant tuberculosis in other selected regions of the United States, we established a registry of cases of culture-proven tuberculosis. Data were collected from sites participating in an NIH-funded, community-based HIV clinical trials group. All cases of tuberculosis, regardless of HIV status, which occurred between January 1992 and June 1994 were recorded. Overall, 1,373 cases of tuberculosis were evaluated, including 425 from the New York City area, and 948 from seven other metropolitan areas. The overall prevalence of resistance to one or more drugs was 20.4%, and 5.6% of isolates were resistant to both isoniazid and rifampin (MDR). In the New York City area, HIV-infected patients were significantly more likely than persons not known to be HIV-infected, to have resistance to at least one drug (37% versus 19%) and MDR (19% versus 6%). In other geographic areas, overall drug resistance was 16%, and only 2.2% of isolates were MDR. In multiple logistic regression analyses, HIV infection was shown to be a risk factor for drug-resistant tuberculosis, independent of geographic location, history of prior therapy, age, and race. We concluded that HIV infection is associated with increased rates of resistance to antituberculosis drugs in both the New York City area and other geographic areas. MDR tuberculosis is occurring predominantly in the New York City area and is highly correlated with HIV infection

Shifting markers of identity in East London's diasporic religious spaces

This article discusses the historical and geographical contexts of diasporic religious buildings in East London, revealing – contrary both to conventional narratives of immigrant integration, mobility, and succession and to identitarian understandings of belonging – that in such spaces and in the concrete devotional practices enacted in them, markers and boundaries of identity (ritual, spatial, and political) are contested, renegotiated, erased, and rewritten. It draws on a series of case-studies: Fieldgate Street Synagogue in its interrelationship with the East London Mosque; St Antony's Catholic Church in Forest Gate where Hindus and Christians worship together; and the intertwined histories of Methodism and Anglicanism in Bow Road. Exploration of the intersections between ethnicity, religiosity, and class illuminates the ambiguity and instability of identity-formation and expression within East London's diasporic faith spaces