Characterization of the CXCR4 Signaling in Pancreatic Cancer Cells

CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1α, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.     

Antigens of Mycobacterium tuberculosis Recognized by Antibodies during Incipient, Subclinical Tuberculosis

Serum samples obtained from human immunodeficiency virus (HIV)-infected tuberculosis (TB) patients months prior to clinical TB were used to delineate the profile of Mycobacterium tuberculosis culture filtrate proteins recognized during subclinical TB. A subset of ~12 antigens was recognized by antibodies in these serum samples. Antibodies to two of these antigens (81 [88]-kDa malate synthase [GlcB] and MPT51) were present in serum samples obtained during incipient subclinical TB in 19 (~90%) of the 21 HIV-infected TB patients tested. These antigens will be useful for devising diagnostic tests that can identify HIV-positive individuals who are at a high risk for developing clinical TB.     

Second trimester abortion with ethacridine lactate plus Carboprost—which is the best time to administer the Carboprost?

Extra-amniotic ethacridine lactate plus intramuscular prostaglandin has become a popular method for terminating second trimester pregnancies. In this study, intrauterine pressure was continuously monitored in order to objectively compare the efficacy of 3 different times of administration of Carboprost (15-methyl PGF_2alpha)-at 2 hours, 4 hours and 8 hours after the instillation of ethacridine lactate. The best results were obtained with the administration of Carboprost 8 hours after the instillation of the extra-amniotic ethacridine lactate. The synergistic effect of ethacridine lactate and Carboprost is optimal after this time. This is probably because the ethacridine lactate will have produced sufficient cervical ripening to ensure optimal efficacy of the prostaglandin-induced uterine contractions in expelling the products of conception.

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Resumen Un método popular para terminar un embarazo en el segundo trimestre es el lactato de etacridina extraamniótico más prostaglandina intramuscular. En este estudio la presión intrauterina estuvo registrada continuamente a fin de comparar objetivamente la eficacia a 3 horarios diferentes de administración de Carboprost (15-metilo PGF_2alpha) a las 2 horas, 4 horas y 8 horas después de la instilación de lactato de etacridina. Los mejores resultados fueron obtenidos con la administración de Carboprost 8 horas después de la instilación extraamniótica de lactato de etacridina. Después de este tiempo el efecto sinergístico del lactato de etacridina y Carboprost es óptimo. Probablemente esto se debe a que el lactato de etacridina ha producido ablandamiento cervical suficiente para asegurar la óptima eficacia de las contracciones uterinas inducidas por la prostaglandina para eliminar los productos de la concepción.

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Résumé L'administration associée de lactate d'éthacridine extra-amniotique et de prostaglandine intramusculaire est devenue une méthode courante d'interruption de grossesses au deuxième trimestre. Au cours de cette étude, la pression intra-utérine a été contrôlée en continu afin de pouvoir comparer objectivement l'efficacité à trois moments différents d'administration de Carboprost (15-méthyle PGF_2alpha): 2 heures, 4 heures et 8 heures après l'instillation de lactate d'éthacridine. Les meilleurs résultats one été obtenus lorsque le Carboprost a été administré 8 heures après l'instillation de lactate d'éthacridine extra-amniotique. L'effet conjugué du lactate d'éthacridine et du Carboprost est optimal après ce délai, sans doute parce que le lactate d'éthacridine aura permis alors une maturation cervicale suffisante pour assurer une efficacité optimale aux contractions utérines provoquées par la prostaglandine en vue de l'expulsion des produits de conception.

     

Retinoblastoma. A clinical, immunohistochemical, and electron microscopic case report

A 4-year, 9-month-old boy had a history of leukocoria of the right eye for approximately six months prior to admission. The other eye was normal. There was no family history of retinoblastoma. Funduscopy disclosed a large white mass extending from the nasal pars plana to the mid-pupillary zone and the posterior pole with a near total retinal detachment in the superior temporal quadrant. A B-scan ultrasound showed an echo dense area of the anterior portion of the mass. A CT scan showed intraocular tissue densities with no evidence of optic nerve involvement or extraocular extension. Immunohistochemistry of a fresh frozen portion of tumor revealed reactivity with antibodies directed against interphotoreceptor retinoid-binding-protein (IRBP), neuron-specific enolase, glial fibrillary acidic protein, S-antigen, focal reactivity with opsin, and scattered cytoplasmic staining for cyclic GMP and cyclic GMP phosphodiesterase. Biochemical analysis of fresh frozen tissue samples confirmed the presence of IRBP. Transmission electron microscopy disclosed occasional Flexner-Wintersteiner rosettes connected by zonula adherens-like junctions. These showed inner segment-like structures containing prominent mitochondria, portions of cilia and fragments of outer segment material. These data, along with the immunocytochemistry indicates a predominant neuronal nature of the tumor cells with significant photoreceptor-like differentiation.     

Homogeneously staining region in anthracycline-resistant HL-60/AR cells not associated with MDR1 amplification.

Anthracycline-resistant HL-60/AR cells and their drug-sensitive HL-60/S counterparts were characterized by karyotypic analysis and examined for the overexpression of DNA and mRNA sequences coding for P-glycoprotein (Pgp). The HL-60/S cells were karyotypically stable over a 5-year period of study (1986-1991), except for an additional small Giemsa-positive band noted at 7q22 in cultures harvested in 1987, but not in 1986. This change did not affect drug sensitivity. The drug-resistant HL-60/AR cells examined in 1986, 1987, and 1991 demonstrated a very stable karyotype. The most striking feature was a large homogeneously staining region in the long arm of chromosome 7 (7q11.2), and translocation of the remainder of the long arm to another centromere. Other changes in the HL-60/AR cells included inversion in 9q, partial deletion of the short arm of chromosome 10p, addition of material to the p arm of der(16), loss of chromosome 22, and the appearance of a new marker chromosome. Both HL-60/S and the HL-60/AR cells were found not to amplify DNA or mRNA sequences coding for the Pgp. Thus, although the HL-60/AR cells possess the classical multidrug resistance phenotype and demonstrate a homogeneously staining region near the region of the MDR1 gene, their resistance is due to mechanisms other than those coded for by MDR1.