Gene expression patterns and profile changes pre- and post-erlotinib treatment in patients with metastatic breast cancer.

PURPOSE: To delineate gene expression patterns and profile changes in metastatic tumor biopsies at baseline and 1 month after treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib in patients with metastatic breast cancer. EXPERIMENTAL DESIGN: Patients were treated with 150 mg of oral erlotinib daily. Gene expression profiles were measured with Affymetrix U133A GeneChip and immunohistochemistry was used to validate microarray findings. RESULTS: Estrogen receptor (ER) status by immunohistochemistry is nearly coincided with the two major expression clusters determined by expression of genes using unsupervised hierarchical clustering analysis. One of 10 patients had an EGFR-positive tumor detected by both microarray and immunohistochemistry. In this tumor, tissue inhibitor of metalloproteinases-3 and collagen type 1 alpha 2, which are the EGF-down-regulated growth repressors, were significantly increased by erlotinib. Gene changes in EGFR-negative tumors are those of G-protein-linked and cell surface receptor-linked signaling. Gene ontology comparison analysis pretreatment and posttreatment in EGFR-negative tumors revealed biological process categories that have more genes differentially expressed than expected by chance. Among 495 gene ontology categories, the significant differed gene ontology groups include G-protein-coupled receptor protein signaling (34 genes, P = 0.002) and cell surface receptor-linked signal transduction (74 genes, P = 0.007). CONCLUSIONS: ER status reflects the major difference in gene expression pattern in metastatic breast cancer. Erlotinib had effects on genes of EGFR signaling pathway in the EGFR-positive tumor and on gene ontology biological process categories or genes that have function in signal transduction in EGFR-negative tumors.     

Microinjection of an Adenosine A1 Agonist into the Medial Pontine Reticular Formation Increases Tail Flick Latency to Thermal Stimulation

Background: Both pain and the pharmacologic management of pain can cause the undesirable effect of sleep disruption. One goal of basic and clinical neuroscience is to facilitate rational drug development by identifying the brain regions and neurochemical modulators of sleep and pain. Adenosine is thought to be an endogenous sleep promoting substance and adenosinergic compounds can contribute to pain management. In the pontine brain stem adenosine promotes sleep but the effects of pontine adenosine on pain have not been studied. This study tested the hypothesis that an adenosine agonist would cause antinociception when microinjected into pontine reticular formation regions that regulate sleep.

Methods: The tail flick latency (TFL) test quantified the time in seconds for an animal to move its tail away from a thermal stimulus created by a beam of light. TFL measures were used to evaluate the antinociceptive effects of the adenosine A1 receptor agonist N6-p-sulfophenyladenosine (SPA). Pontine microinjection of SPA (0.1 [mu]g/0.25 [mu]l, 0.88 mm) was followed by TFL measures as a function of time after drug delivery and across the sleep-wake cycle.

Results: Compared with saline (control), pontine administration of the adenosine agonist significantly increased latency to tail withdrawal (P < 0.0001). The increase in antinociceptive behavior evoked by the adenosine agonist SPA was blocked by pretreatment with the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 0.75 ng/0.25 [mu]l, 10 [mu]m).     

The Hasty British Ban on Commercial Surrogacy

While commercial surrogate parenting arrangements continue to flourish in the U.S., Britain has made it a criminal offense for third parties to benefit from surrogacy. Voluntary surrogacy, however is still within the law. Banning commercial surrogacy while leaving voluntary surrogacy lawful seems neither logical nor fair. A more equitable solution would be to license stringently and control both commercial and nonprofit agencies to provide these services.     

A randomized multicenter study to determine the efficacy of activity restriction for preterm labor management in patients testing negative for fetal fibronectin.

OBJECTIVE: To assess the impact of activity restriction (AR) on the incidence of preterm birth in women treated for preterm labor testing negative for fetal fibronectin (fFN). STUDY DESIGN: Women who were diagnosed with preterm labor and tocolyzed with magnesium sulfate were concurrently screened with fFN for the purpose of subsequent management. Included were consenting patients with negative fFN, gestational age 23 0/7-33 6/7 weeks, cervical dilation < or =3 cm, and minimal vaginal bleeding. Patients were randomized to AR or no AR. Primary study outcome was incidence of preterm delivery and interval from randomization to delivery. RESULTS: A total of 73 women with negative fFN were randomized (36 with AR, 37 without AR). The overall preterm birth rate was 40%, with 44.4% of patients with AR and 35.1% of patients without AR delivering preterm, p=0.478. CONCLUSION: Maternal AR did not impact pregnancy outcome. The incidence of preterm birth in symptomatic women testing fFN negative was higher than previously reported.     

Effects of decreased insulin-like growth factor-1 stimulation on hypoxia inducible factor 1-α protein synthesis and function during cutaneous repair in diabetic mice

Insulin-like growth factor-1 (Igf-1), a critical mediator of tissue repair, is significantly decreased in diabetic wounds. Furthermore, decreased levels of hypoxia-inducible factor 1-alpha (Hif-1alpha) and its target genes are also associated with impaired wound healing in diabetic mice. The aim of our study was to examine whether the reduced levels of Igf-1 are responsible for the reduction in Hif-1alpha protein synthesis and activity in diabetic wounds. We provide evidence that Igf-1 regulates Hif-1alpha protein synthesis and activity during wound repair. In addition, Igf-1 stimulated phosphytidylinositol 3-kinase activity in diabetic fibroblasts, which, in turn, increased activation of the translational regulatory protein, p70 S6 kinase. Moreover, improved healing of diabetic wounds by addition of recombinant IGF-1 protein was associated with an increase in Hif-1alpha protein synthesis and function in vivo.     

The influence of freezer storage of urine samples on the BONN-Risk-Index for calcium oxalate crystallization.

This study was performed to quantify the effect of a 1-week freezer storage of urine on its calcium oxalate crystallization risk. Calcium oxalate is the most common urinary stone material observed in urolithiasis patients in western and affluent countries. The BONN-Risk-Index of calcium oxalate crystallization risk in human urine is determined from a crystallization experiment performed on untreated native urine samples. We tested the influence of a 1-week freezing on the BONN-Risk-Index value as well as the effect of the sample freezing on the urinary osmolality. In vitro crystallization experiments in 49 native urine samples from stone-forming and non-stone forming individuals were performed in order to determine their calcium oxalate crystallization risk according to the BONN-Risk-Index approach. Comparison of the results derived from original sample investigations with those obtained from the thawed aliquots by statistical evaluation shows that i) no significant deviation from linearity between both results exists and ii) both results are identical by statistical means. This is valid for both, the BONN-Risk-Index and the osmolality data. The differences in the BONN-Risk-Index results of both procedures of BONN-Risk-Index determination, however, exceed the clinically acceptable difference. Thus, determination of the urinary calcium oxalate crystallization risk from thawed urine samples cannot be recommended.     

SDZ 208-911, an amino-ergoline with partial dopamine agonist properties,dose dependently increases cocaine self-administration in the rat

Brain dopamine neurotransmission appears to be an important component of the neural pathways involved in the maintenance of intravenous (IV) cocaine self-administration in rats. The effects of a novel partial dopamine agonist, SDZ 208–911, on intravenous cocaine self-administration in rats was studied. SDZ 208–911 at a dose range of 0.025–1.6 mg/kg SC dose-dependently increased the number of lever presses and drug intake in rats exposed to limited (3-h) daily access to cocaine on a continuous reinforcement schedule (0.75 mg/kg per injection). This behavioral profile is similar to that observed following administration of dopamine antagonist drugs and has been hypothesized to reflect a compensatory increase in drug intake due to a reduction of the reinforcing efficacy of the drug, probably because of functional antagonism at the receptor site. These results suggest that dopamine partial agonists may act as functional dopamine antagonists in the face of pharmacologically induced activation of brain dopamine function.     

Na+ currents near and away from endplates on human fast and slow twitch muscle fibers

Fast and slow twitch muscle fibers have distinct contractile properties. Here we determined that membrane excitability also varies with fiber type. Na⁺ currents (I_NA) were studied with the loose-patch voltage clamp technique on 29 histochemically classified human intercostal skeletal muscle fibers at the endplate border and <200 μm from the endplate (extrajunctional). Fast and slow twitch fibers showed slow inactivation of endplate border and extrajunctional I_NA and had increased I_NA at the endplate border compared to extrajunctional membrane. The voltage dependencies of I_NA were similar on the endplate border and extrajunctional membrane, which suggests thatboth regions have physiclogically similar channels. Fast twitch fibers had larger I_NA on the endplate border and extrajunctional membrane and manifest fast and slow inactivation of I_NA at more negative potentials than slow twitch fibers. For normal muscle, the differences between I_NA on fast and slow twitch fibers might: (1) enable fast twitch fibers to operate at high firing frequencies for brief periods; and (2) enable slow twitch fibers to operate at low firing frequencies for prolonged times. Disorders of skeletal membrane excitability, such as the periodic paralyses and myotonias, may impact fast and slow twitch fibers differently due to the distinctive Na⁺ channel properties of each fiber type. © 1993 John Wiley & Sons, Inc.