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.     

Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans.

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.     

A preliminary report of the short-term effect of carbonated beverage consumption on calcium metabolism in normal women

A variety of nutritional factors influence the bioavailability of calcium and increase a woman's risk of osteoporosis. Eight healthy women completed an 8-week metabolic study designed to investigate the effect of nonalcoholic carbonated beverage consumption on calcium metabolism. Compared with women receiving a control diet, women consuming a diet high in nonalcoholic carbonated beverages demonstrated similar mean serum levels of calcium, ionized calcium, phosphorus, alkaline phosphatase, parathyroid hormone, 1,25-dihydroxyvitamin D3, and osteocalcin. Twenty-four-hour urine volume, creatinine clearance, calcium-creatinine ratio, and phosphorus-creatinine ratio were similar during consumption of the diet high in nonalcoholic carbonated beverages and the control diet. Twenty-four-hour cyclic adenosine monophosphate-creatinine ratio was significantly lower in women consuming the diet high in nonalcoholic carbonated beverage compared with women receiving the control diet (342 +/- 27.4 nmol/mmol vs 409 +/- 22.1 nmol/mmol). Consumption of a diet high in nonalcoholic carbonated beverages on a short-term basis does not appear to affect adversely the serum or urinary markers of calcium metabolism.     

Physical Activity Participation by Parental Language Use in 4th, 8th,and 11th Grade Students in Texas,USA

Research on physical activity (PA) by level of acculturation in Hispanic children is limited and findings have been mixed. We examined PA participation by primary language used with parents in a representative sample of 4th, 8th, and 11th grade Texas public school students. Mixed-effects regression models were conducted using cross-sectional data from the 2004–2005 School Physical Activity and Nutrition Study (n = 22,049). Self-reported PA was compared among three language-ethnic groups: Spanish-Hispanic (SH) (referent); English-Hispanic (EH); and English-Other (EO). EH and/or EO girls were generally between 1.25 and 2.58 [OR] times more likely to participate in PA across grade levels, with the largest differences found for school sports in 8th grade girls. EH and EO 8th grade boys were 1.71 (CI: 1.40, 2.10) and 2.06 (CI: 1.68, 2.51) times, respectively, more likely to participate in school sports. Findings indicate important disparities in Spanish-speaking Hispanic children’s PA participation.     

Levels-of-processing effects in first-degree relatives of individuals with schizophrenia.

BACKGROUND: First-degree relatives of individuals with schizophrenia show cognitive impairments that are similar to but less severe than their ill relatives. We have shown that memory impairments can be improved and prefrontal cortical (PFC) activity increased in individuals with schizophrenia by providing beneficial encoding strategies. The current study used a similar paradigm to determine whether siblings of individuals with schizophrenia (SIBs) also show increases in brain activity when presented with beneficial encoding strategies. METHODS: Twenty-one SIBs and 38 siblings of healthy comparison subjects underwent functional magnetic resonance imaging scans while engaged in deep (abstract/concrete judgments) and shallow (orthographic judgments) encoding. Subjects were then given a recognition memory test. RESULTS: The groups did not differ on encoding or recognition accuracy, and the SIBs benefited from deep encoding to a similar degree as control subjects. The SIBs showed deep encoding-related activity in a number of PFC regions typically activated during semantic processing. However, SIBs showed more activity than control subjects in three subregions of PFC (left BA 44 & BA 47 bilaterally). CONCLUSIONS: Siblings of individuals with schizophrenia benefit from supportive verbal encoding conditions. Like individuals with schizophrenia, SIBs also show increased task-related activity in a larger number of PFC subregions than control subjects during deep verbal encoding.     

Phospho-akt expression is associated with a favorable outcome in non-small cell lung cancer.

Akt, a Serine/Threonine protein kinase, mediates growth factor-associated cell survival. Constitutive activation of Akt (phosphorylated Akt, P-Akt) has been observed in several human cancers, including lung cancer and may be associated with poor prognosis and chemotherapy and radiotherapy resistance. The clinical relevance of P-Akt in non-small cell lung cancer (NSCLC) is not well described. In the present study, we examined 82 surgically resected snap-frozen and paraffin-embedded stage I to IIIA NSCLC samples for P-Akt and Akt by Western blotting and for P-Akt by immunohistochemistry. P-Akt protein levels above the median, measured using reproducible semiquantitative band densitometry, correlated with a favorable outcome (P = 0.007). Multivariate analysis identified P-Akt as a significant independent favorable prognostic factor (P = 0.004). Although associated with a favorable prognosis, high P-Akt levels correlated with high tumor grade (P = 0.02). Adenocarcinomas were associated with low P-Akt levels (P = 0.039). Akt was not associated with either outcome or clinicopathologic variables.Cytoplasmic (CP-Akt) and nuclear (NP-Akt) P-Akt tumor cell staining was detected in 96% and 42% of cases, respectively. Both CP-Akt and NP-Akt correlated with well-differentiated tumors (P = 0.008 and 0.017, respectively). NP-Akt also correlated with nodal metastases (P = 0.022) and squamous histology (P = 0.037).These results suggest P-Akt expression is a favorable prognostic factor in NSCLC. Immunolocalization of P-Akt, however, may be relevant as NP-Akt was associated with nodal metastases, a known poor prognostic feature in this disease. P-Akt may be a potential novel therapeutic target for the management of NSCLC.     

Recombinant and nonrecombinant factor XIII and its effect on bone ingrowth and strength of fixation

Thirty cylindrical, commercially pure, titanium fiber, porous-coated Ti₆Al₄V implants were inserted pressfit into the proximal humeral portion of 30 sheep humeri to determine the systemic effect of recombinant factor XIII and placenta-derived factor XIII concentrate on bone ingrowth and strength of fixation. For both the recombinant factor XIII and the factor XIII concentrate group, the volume of bone ingrowth and the strength of fixation were higher than for the control specimens. However, the difference was only significant for the factor XIII concentrate group.