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.     

Prostatitis and male factor infertility: A review of the literature

Prostatitis and male infertility are frequent disorders, and the role of prostatitis in male infertility has been under discussion for more than 30 years. Many researchers have shown relevant links between the two. Although a causal relationship has not been definitely demonstrated, increasing evidence shows that chronic prostatitis has a relevant negative impact on male fertility potential, at least in certain subgroups. In the following review, we focus on the present state of knowledge on the role of chronic prostatitis as an etiologic factor in male infertility.     

Use of a 585 nm Pulsed Dye Laser for the Treatment of Morphea

INTRODUCTION: The clinical presentation of morphea varies from localized plaques to generalized eruptions. Its cause remains unknown and medical treatments have often proved unsatisfactory. Studies have previously shown that improvement of hypertrophic scars and fibrotic skin can be achieved with the use of a 585 nm pulsed dye laser (PDL). METHODS: A case of plaque-type morphea was treated with 585 nm pulsed dye laser irradiation at an average fluence of 5.0 J/cm2 at bimonthly time intervals. RESULTS: Marked clinical improvement as evidenced by improved pliability and skin coloration was seen after 4 successive PDL treatments. No side effects or complications were encountered. CONCLUSION: Pulsed dye laser therapy is a viable treatment option for morphea. The mechanism of its effect in this condition remains unknown.     

Treatment of the dumping syndrome with the somatostatin analogue SMS 201-995.

In six patients suffering from severe early dumping and six patients with late dumping after peptic ulcer surgery, the effect of the somatostatin analogue SMS 201-995 was compared with placebo. In early dumpers subcutaneous administration of 50 micrograms SMS 201-995 prior to meal ingestion induced a strong improvement of dumping symptoms as reflected by a decrease of the Sigstad dumping score from 12 +/- 2 during placebo to 5 +/- 2 (p less than 0.05). Furthermore, the postprandial increase of pulse rate was abolished; maximum pulse rate decreased from 85 +/- 7 beats/min to 67 +/- 7 beats/min (p less than 0.05). SMS 201-995 did not significantly affect postprandial changes in packed cell volume. In late dumpers 50 micrograms SMS 201-995 reduced peak plasma insulin after oral glucose from 173 +/- 16 mU/L during placebo to 35 +/- 9 mU/L during SMS 201-995 (p less than 0.05) and increased individual plasma glucose nadirs from 1.9 +/- 0.3 mmol/L to 7.5 +/- 3.3 mmol/L (p less than 0.01). Both in early and late dumpers SMS 201-995 improved postprandial expiratory breath hydrogen excretion indicating slowing of gastrointestinal hurry. SMS 201-995 is a powerful therapeutic agent for the management of patients suffering from the dumping syndrome after gastric surgery.     

The Membrane Lipid Cholesterol Modulates Anesthetic Actions on a Human Brain Ion Channel

Background: Molecular theories of general anesthesia often are divided into two categories: (l) Anesthetics may bind specifically to proteins, such as ionic channels, and alter their function directly, and (2) anesthetics may alter the functions of integral membrane proteins indirectly through modification of the physical properties of the membrane. Recent studies have provided evidence that anesthetics can bind to proteins and modify their function directly, bringing into question the role of the membrane in anesthetic interactions. To reexamine the role of membrane lipids in anesthetic interactions, an experimental approach was used in which the membrane lipid composition could be systematically altered and the impact on anesthetic interactions with potential targets examined.

Methods: Sodium channels from human brain cortex were incorporated into planar lipid bilayers with increasing cholesterol content. The anesthetic suppression of these channels by pentobarbital was quantitatively examined by single channel measurements under voltage-clamp conditions.

Results: Changes in cholesterol content had no effect on measured channel properties in the absence of anesthetic. In the presence of pentobarbital, however, cholesterol inhibited anesthetic suppression of channel ionic currents, with 1.9% (weight/weight, corresponding to 3.5 mol%) cholesterol decreasing anesthetic suppression of sodium channels by half.     

Aluminium speciation in cerebrospinal fluid of acutely aluminium-intoxicated dialysis patients before and after desferrioxamine treatment; a step in the understanding of the element's neurotoxicity

Background: The association between aluminium and dialysis encephalopathy and deterioration of the neurological state during desferrioxamine treatment of dialysis patients is well established. At present little is known about the speciation and the mechanisms underlying the element's neurotoxicity. Methods. Aluminium speciation was performed in cerebrospinal fluid samples of acutely aluminium-intoxicated dialysis patients using a recently developed high-performance liquid chromatographic/electro-thermal atomic absorption spectrometric hybrid method. Results: Baseline cerebrospinal fluid aluminium levels of samples taken shortly after the intoxication were low but elevated (5.0±2.0 &mgr;g/l, n=3) as compared to subjects with normal renal function (<1 &mgr;g/l). In contrast to the situation noted in serum and to the iron speciation in cerebrospinal fluid, aluminium was not bound to transferrin but appeared as two distinct compounds, the main fraction eluting at the elution volume of aluminium citrate/silicate. The second compound was not identified. Forty-four hours after desferrioxamine administration the cerebrospinal fluid aluminium levels had increased up to a concentration of 10.3±2.5 &mgr;g/l (n=3). This was accompanied by a change in the speciation profile with aluminium appearing at the elution volume of aluminoxamine. Conclusion: Our findings may contribute to a better understanding of the neurotoxic effects of aluminium and its desferrioxamine chelate in dialysis patients.     

Evolution of the sperm aster after microinjection of isolated human sperm centrosomes into meiotically mature human oocytes

This study examined the feasibility of isolating and transferringthe centrosome-containing region of spermatozoa to mature humanoocytes. The findings demonstrate that individual sperm centrosomescan be transferred and are capable of nucleating maternal tubulinto form a well-developed sperm aster in the recipient oocyte.The results are discussed with respect to centrosome functionin early human development and applications in clinical in-vitrofertilization in the treatment of certain forms of male factorinfertility.