Secretion-mediated STAT3 activation promotes self-renewal of glioma stem-like cells during hypoxia.

High-grade gliomas (HGGs) include the most common and the most aggressive primary brain tumor of adults and children. Despite multimodality treatment, most high-grade gliomas eventually recur and are ultimately incurable. Several studies suggest that the initiation, progression, and recurrence of gliomas are driven, at least partly, by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew. We have identified a hypoxia-induced pathway that utilizes the Hypoxia Inducible Factor 1α (HIF-1α) transcription factor and the JAK1/2-STAT3 (Janus Kinase 1/2 - Signal Transducer and Activator of Transcription 3) axis to enhance the self-renewal of glioma stem-like cells. Hypoxia is a commonly found pathologic feature of HGGs. Under hypoxic conditions, HIF-1α levels are greatly increased in glioma stem-like cells. Increased HIF-1α activates the JAK1/2-STAT3 axis and enhances tumor stem-like cell self-renewal. Our data further demonstrate the importance of Vascular Endothelial Growth Factor (VEGF) secretion for this pathway of hypoxia-mediated self-renewal. Brefeldin A and EHT-1864, agents that significantly inhibit VEGF secretion, decreased stem cell self-renewal, inhibited tumor growth, and increased the survival of mice allografted with S100ß-v-erbB/p53-/- glioma stem-like cells. These agents also inhibit the expression of a hypoxia gene expression signature that is associated with decreased survival of HGG patients. These findings suggest that targeting the secretion of extracellular, autocrine/paracrine mediators of glioma stem-like cell self-renewal could potentially contribute to the treatment of HGGs.

Gallium-67 scan for distinguishing follicular hyperplasia from other AIDS-associated diseases in lymph nodes.

We have studied gallium-67 citrate scan (Ga-67) in the diagnosis of lymphadenopathy in patients with HIV-associated symptoms. Thirty HIV-infected patients with lymphadenopathy, fever and/or weight loss were evaluated with Ga-67. Lymph-node biopsy and/or needle aspirations were done in all patients. Twelve of 17 patients with grade 2 or 3 Ga-67 (uptake equal to or greater than that in the liver) had mycobacteriosis, three had lymphoma, one had Kaposi's sarcoma plus Castleman's disease and one had follicular hyperplasia. The three patients with grade 1 Ga-67 (uptake greater than that in soft tissue but less than that in the liver) had follicular hyperplasia. Of the 10 patients with grade 0 Ga-67 (less than or equal to that in soft tissue), nine had follicular hyperplasia and one had Kaposi's sarcoma. Sixteen of 17 patients with grade 2 or 3 Ga-67 versus one of 13 with Ga-67 grade 1 or 0 had diseases other than follicular hyperplasia (P less than 0.0001). Ga-67 may be a practical diagnostic tool in HIV-infected patients with lymphadenopathy and constitutional symptoms. A grade 1 or 0 Ga-67 suggests the presence of follicular hyperplasia, and lymph-node biopsy may be avoided unless Kaposi's sarcoma is suspected.

Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by genetic deficiency of arylsulfatase A (ARSA) enzyme. Failure in catalyzing the degradation of its major substrate, sulfatide (Sulf), in oligodendrocytes and Schwann cells leads to severe demyelination in the peripheral (PNS) and central nervous system (CNS), and early death of MLD patients. The ARSA knockout mice develop a disease that resembles MLD but is milder, without significant demyelination in the PNS and CNS. We showed that adeno-associated virus serotype 5-mediated gene transfer in the brain of ARSA knockout mice reverses Sulf storage and prevents neuropathological abnormalities and neuromotor disabilities when vector injections are performed at a pre-symptomatic stage of disease. Direct injection of viral particles into the brain of ARSA knockout mice at a symptomatic stage results in sustained expression of ARSA, prevention of Sulf storage and neuropathological abnormalities. Despite these significant corrections, the treated mice continue to develop neuromotor disability. We show that more subtle biochemical abnormalities involving gangliosides and galactocerebroside are in fact not corrected.

Mucosal modulation of immune responses to heat shock proteins in autoimmune arthritis.

Induction of oral tolerance to antigens that are targets of self-reactive immune responses is an attractive approach to antigen-specific immune therapy of autoimmune diseases. Oral tolerization has indeed proven to be safe and effective in amelioration of autoimmune diseases in animal models. In humans, results have been somewhat controversial. The emphasis given to clinical outcome rather than to immunomodulation, and the difficulty in identifying appropriate candidate antigens contribute to the controversy. Heat shock proteins are promising targets for immune intervention. Immune reactivity to heat shock proteins has indeed been correlated with autoimmune arthritis in animal models, and abnormal immune responses to heat shock proteins have been described in human arthritis as well. Despite significant recent progress, little is known at a molecular level regarding the mechanisms which are responsible for a switch from autoimmunity to tolerance in humans. This is particularly true with respect to sequential analysis of several molecular and immunologic markers during both the course and treatment of disease. Novel approaches are currently under way to fill the gaps. We will briefly detail here the experience gained to date, and identify some of the avenues which future research will explore.

Modeling EPR powder spectra using numerical diagonalization of the spin hamiltonian

A new modeling code, ZFSFIT (standing for Zero Field Splitting FITting), written in FORTRAN 77 is proposed. It is designed for computing and fitting EPR powder spectra described by any spin Hamiltonian including second- and fourth-order ZFS terms (S

Ontogeny of synonymous T cell populations with specificity for a self MHC epitope mimicked by a bacterial homologoue: an antigen-specific T cell analysis in a non-transgenic system.

By means of a novel technique for identification and isolation of MHC class II-restricted antigen-specific T cells, we describe here in non-transgenic BALB / c mice physiological positive selection of an oligoclonal population of T cells which recognizes both a self MHC-derived peptide (Ialpha52) and a bacterial homologoue (Hi15). The results support a model for self peptide-mediated generation of T cells which have specificity for microbial antigens through molecular mimicry. This mechanism may be a model for the ontogeny of a physiological T cell response to infectious agents. Loss of control of these circuits may be part of the inciting factors of autoimmunity.

Cell-mediated DNA transport between distant inflammatory sites following intradermal DNA immunization in the presence of adjuvant.

After intradermal genetic immunization, naked DNA is transported from the site of injection to regional lymph nodes. Little is known on how inflammation influences this process and whether DNA is transported beyond local lymph nodes. In the experiments herein reported, we injected naked DNA in the presence of adjuvant to address questions related to 1) the fate of naked DNA in the presence of inflammation; 2) the generation of immune responses to the encoded protein during inflammation; and, more in general, 3) the fate of ingested molecules beyond regional lymph nodes during inflammation. Two sites of inflammation were induced in vivo in mice. Naked DNA was injected in the nape together with adjuvant, and adjuvant only was injected at a distant peritoneal site. Injected DNA, uptaken at the primary dermal site of inflammation, was transported beyond regional lymph nodes to distant organs such as the spleen and to the distant peritoneal site of inflammation. This transport, mediated by CD11b+ cells, was cumulative during chronic inflammation. These results indicate a novel route of transport of DNA beyond regional lymph nodes and may have specific implications for DNA-based immune modulation.

Masa pelviana en paciente con adenocarcinoma de próstata / Pelvic mass in a patient with prostatic adenocarcinoma

Se presenta el caso de un paciente que tras biopsias prostáticas seriadas, por PSA persistentemente elevado, se diagnostica de ADC de próstata. En el estudio de extensión se detectan metástasis hepáticas y una masa abdominal que tras biopsia percutánea, se diagnostica de GIST

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Quistes renales complejos. Diagnóstico diferencial con el cáncer renal: a propósito de dos casos clínicos / Complex renal cysts. Differential diagnosis with renal cancer: two clinical cases

El carcinoma de células renales en un 10% de los casos puede aparecer con un patrón morfológico quístico. Las lesiones quísticas renales pueden dividirse en quistes renales simples, siendo fácilmente diagnosticables por ecografía, y quistes renales complejos, para los cuales existe una clasificación radiológica basada en la TC conocida como clasificación de Bosniak (categorías I,II, IIF, III, IV). Este artículo trata sobre las lesiones quísticas renales de dos casos clínicos. El primero consiste en unquiste complicado Bosniak IV en un varón de 44 años que es tratado con nefrectomía radical (anatomía patológica: carcinoma renal de células claras grado II estadía T1). El segundo, consiste en un quiste simple en mujer de 49 años, tratado con punción-aspiración ecodirigida, con desaparición a los 6 meses. Ante una masa quística renal el principal objetivo de la radiología es diferenciar la masa quirúrgica de la masa no quirúrgica. La ecografía es una prueba realizada habitualmente en nuestro medio por motivos varios y favorece el hallazgo incidental de masas renales de forma precoz. La TX es la prueba más sensible y específica para el diagnóstico de CCR y es la base de la clasificación de Bosniak. Para el estudio densiométrico en la TC se utilizan las Unidades Hunsfield cuyos coeficientes de atenuación a tener en cuenta son: <10 (lesión benigna), 10-15 (lesión sospechosa), >15 (lesión maligna). La RNM se emplea en caso de trombosis venosa, alergia y contraste yodado y alteración de la función renal, siendo sus resultados parecidos a la TC. La actitud a seguir en los quistes renales es la siguiente: Bosniak I no requieren seguimiento; Bosniak II, IIF seguimiento; Bosniak III y IV tratamiento quirúrgico

The carcinoma of renal cells in 10% of the cases can appear with a cystic morphology. The cystic renal lesions can be divided into simple renal systs that you can diagnose with ultrasound, and complex renal cysts, which have a special classification called Bosniak classification (I, II, IIF, III, IV categories). This article is based on two clinical cases of cystic renal mass. The first one is about a Bosniak IV complicated cyst in a 44 years old patient treated with a radical nephrectomy (pathologic anatomy: renal cell carcinoma, II grade, T1 stage). The second consists in a simple cyst in a 49 years old patient, treated with puncture and aspiration of it, which disappears after 6 months. The main objective of radiology with renal cystic mass is to differentiated into surgical and not surgical lesions. The ultrasound is a test realized very often in our locality and helps in finding precocious renal mass. The most sensible and specific proof for the diagnose of RCC is tomography, in which Bosniak Classification is based. Hounsfield units are used to study the densitometric of TC and the important attenuation values are:<10 (benign lesion), 10-15 (suspicious lesion), >15 (malignant lesion). The magnetic nuclear resonance is used in case of venous thrombosis, allergy to iodine contrast and alteration of the renal function; its results are similar to TC. The attitude in the renal cysts is: Bosniak I does not need the following. Bosniak II and IIF needs the following, Bosniak III and IV needs surgical treatment