SummaryBackground and objectives Patients with advanced chronic kidney disease (CKD) are in positive phosphorus balance, but phosphorus levels are maintained in the normal range through phosphaturia induced by increases in fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH). This provides the rationale for recommendations to restrict dietary phosphate intake to 800 mg/d. However, the protein source of the phosphate may also be important. Design, setting, participants, & measurementsWe conducted a crossover trial in nine patients with a mean estimated GFR of 32 ml/min to directly compare vegetarian and meat diets with equivalent nutrients prepared by clinical research staff. During the last 24 hours of each 7-day diet period, subjects were hospitalized in a research center and urine and blood were frequently monitored. ResultsThe results indicated that 1 week of a vegetarian diet led to lower serum phosphorus levels and decreased FGF23 levels. The inpatient stay demonstrated similar diurnal variation for blood phosphorus, calcium, PTH, and urine fractional excretion of phosphorus but significant differences between the vegetarian and meat diets. Finally, the 24-hour fractional excretion of phosphorus was highly correlated to a 2-hour fasting urine collection for the vegetarian diet but not the meat diet.Conclusions In summary, this study demonstrates that the source of protein has a significant effect on phosphorus homeostasis in patients with CKD. Therefore, dietary counseling of patients with CKD must include information on not only the amount of phosphate but also the source of protein from which the phosphate derives.

Achievement of maximal calcium retention during adolescence may influence the magnitude of peak bone mass and subsequently lower the risk of osteoporosis. Calcium retention is generally considered to reach a plateau at a certain calcium intake. To test this hypothesis, calcium balance was measured in 35 females with a mean (+/-SD) age of 12.7 +/- 1.2 y (range: 12-15 y) who consumed from 841 +/- 153 to 2173 +/- 149 mg Ca/d. Subjects ate a basal diet that included a fortified beverage containing different amounts of calcium citrate malate. Twenty-one subjects were studied at two dietary calcium intakes with use of a crossover design. Results from a previous study in 14 subjects who were studied at only one calcium intake were included in the data analysis. Calcium retention was modeled as a nonlinear function of calcium intake that included a parameter representing mean maximal retention. Mean maximal calcium retention was 473 mg/d (95% CI: 245, 701 mg Ca/d). At higher postmenarcheal ages, maximal calcium retention was lower but the intake required to achieve this was not affected. Calcium intake explained 79% and 6%, respectively, of the variation in fecal and urinary calcium excretion. Intake of 1200 mg Ca/d, the recommended dietary allowance for calcium published in 1989, resulted in a mean calcium retention that was 57% of the maximal value (95% CI: 25%, 89%). Intake of 1300 mg Ca/d was the smallest intake that allowed some adolescent females to achieve 100% of maximal calcium retention (95% CI: 26%, 100%). These data support the idea that calcium retention plateaus at a certain calcium intake although it continues to increase at intakes > 2 g/d.

Increased sodium (Na(+)) retention in blacks could be related to the high prevalence of hypertension in adult blacks. Na(+) retention in response to controlled dietary Na(+) has not been rigorously compared in the different race groups. The present study assessed Na(+) retention in 22 black and 14 white girls, 11-15 yr old, during 3 wk on a low (1.3 g, 57 mmol)- and during 3 wk on a high (4 g, 172 mmol)-Na(+) diet in a randomized order, crossover design. Subjects were matched by postmenarcheal age and weight. After a 1-wk equilibration period, the mean daily Na(+) retention was 357 +/- 69 mg (15.5 +/- 3.0 mmol) in blacks and 239 +/- 37 mg (10.4 +/- 1.6 mmol) in whites on the low-Na(+) diet and 991 +/- 138 mg (43.1 +/- 6.0 mmol) in blacks vs. 334 +/- 90 mg (14.5 +/- 3.9 mmol) in whites (P < 0.001) on the high-Na(+) diet. The greater Na(+) retention in blacks was not accompanied by an increase in fecal or sweat Na(+) excretion. Blood pressure and weight did not increase despite the Na(+) retention, and thus, the retained Na(+) appeared to reside in a nonextracellular compartment that we speculate to be bone. In summary, black girls showed greater Na(+) retention compared with white girls. The difference in Na(+) handling may contribute to underlying racial differences in susceptibility to hypertension.

Dietary calcium requirements did not differ with race. Higher calcium retention at all calcium intakes during adolescence may underlie the higher bone mineral content of adult blacks than of adult whites.

Purpose: Agents inhibiting the epidermal growth factor receptor (EGFR) have shown clinical benefit in a subset of non^small cell lung cancer patients expressing amplified or mutationally activated EGFR. However, responsive patients can relapse as a result of selection for EGFR gene mutations that confer resistance to ATP competitive EGFR inhibitors, such as erlotinib and gefitinib.We describe here the activity of EXEL-7647 (XL647), a novel spectrum-selective kinase inhibitor with potent activity against the EGF and vascular endothelial growth factor receptor tyrosine kinase families, against both wild-type (WT) and mutant EGFR in vitro and in vivo. Experimental Design: The activity of EGFR inhibitors against WTand mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB-231 (WT EGFR) and H1975 (L858R andT790M mutant EGFR) xenograft tumors.Results: EXEL-7647 shows potent and long-lived inhibition of the WT EGFR in vivo. In addition, EXEL-7647 inhibits cellular proliferation and EGFR pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation (L858R and T790M) in the EGFR gene. In vivo efficacy studies show that EXEL-7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor EGFR signaling and tumor vessel density. Additionally, EXEL-7647, in contrast to erlotinib, substantially inhibited the growth and vascularization of MDA-MB-231 xenografts, a model which is more reliant on signaling through vascular endothelial growth factor receptors. Conclusions: These studies provide a preclinical basis for clinical trials of XL647 in solid tumors and in patients bearing tumors that are resistant to existing EGFR-targeted therapies.

Self-incompatibility (SI) in Brassica is controlled by a single locus, termed the S locus. There is evidence that two of the S locus genes, SLG , which encodes a secreted glycoprotein, and SRK , which encodes a putative receptor kinase, are required for SI on the stigma side. The current model postulates that a pollen ligand recognizing the SLG/SRK receptors is encoded in the genomic region defined by the SLG and SRK genes. A fosmid contig of ‫ف‬ 65 kb spanning the SLG-910 and SRK-910 genes was isolated from the Brassica napus W1 line. A new gene, SLL3 , was identified using a novel approach combining cDNA subtraction and direct selection. This gene encodes a putative secreted small peptide and exists as multiple copies in the Brassica genome. Sequencing analysis of the 65-kb contig revealed seven additional genes and a transposon. None of these seven genes exhibited features expected of S genes on the pollen side. An ‫ف‬ 88-kb contig of the A14 S region also was isolated from the B. napus T2 line and sequenced. Comparison of the two S regions revealed that (1) the gene organization downstream of SLG in both S haplotypes is highly colinear; (2) the distance between SLG-A14 and SRK-A14 genes is much larger than that between SLG-910 and SRK-910 , with the intervening region filled with retroelements and haplotype-specific genes; and (3) the gene organization downstream of SRK in the two haplotypes is divergent. These observations lead us to propose that the SLG downstream region might be one border of the S locus and that the accumulation of heteromorphic sequences, such as retroelements as well as haplotype-unique genes, may act as a mechanism to suppress recombination between SLG and SRK. INTRODUCTIONSelf-incompatibility (SI) is one of the mechanisms promoting outbreeding that have evolved in higher plants. In Brassica spp, SI is controlled sporophytically by a single Mendelian genetic locus, the S locus (Bateman, 1955). Up to 100 S alleles have been identified in the genus Brassica (Bateman, 1955;Ockendon, 1974; de Nettancourt, 1977). Two genes are known to segregate with the genetically defined S locus; therefore, the term S haplotype has been used to collectively describe the components of each S region. One gene encodes a secreted glycoprotein called the S locus glycoprotein (SLG; Nasrallah et al., 1987). The second gene encodes a protein predicted to consist of an extracellular domain linked to a cytoplasmic kinase domain by a transmembrane domain . This structure resembles the receptor kinases from animals (Ullrich and Schlessinger, 1990) and therefore is called the S receptor kinase (SRK).Both SLG and SRK genes have been shown to be highly expressed in stigmas and at a lower level in anthers (Nasrallah et al., 1985;Stein et al., 1991; Goring and Rothstein, 1992). In the pistil, SLG is expressed predominantly in the surface papillar cells of the stigma (Sato et al., 1991), and its glycoprotein product accumulates to high levels in the walls of these cells (Kandasamy et al., 1989). SRK has been demonstrate...

Self-incompatibility (SI) in Brassica is controlled by a single locus, termed the S locus. There is evidence that two of the S locus genes, SLG , which encodes a secreted glycoprotein, and SRK , which encodes a putative receptor kinase, are required for SI on the stigma side. The current model postulates that a pollen ligand recognizing the SLG/SRK receptors is encoded in the genomic region defined by the SLG and SRK genes. A fosmid contig of ‫ف‬ 65 kb spanning the SLG-910 and SRK-910 genes was isolated from the Brassica napus W1 line. A new gene, SLL3 , was identified using a novel approach combining cDNA subtraction and direct selection. This gene encodes a putative secreted small peptide and exists as multiple copies in the Brassica genome. Sequencing analysis of the 65-kb contig revealed seven additional genes and a transposon. None of these seven genes exhibited features expected of S genes on the pollen side. An ‫ف‬ 88-kb contig of the A14 S region also was isolated from the B. napus T2 line and sequenced. Comparison of the two S regions revealed that (1) the gene organization downstream of SLG in both S haplotypes is highly colinear; (2) the distance between SLG-A14 and SRK-A14 genes is much larger than that between SLG-910 and SRK-910 , with the intervening region filled with retroelements and haplotype-specific genes; and (3) the gene organization downstream of SRK in the two haplotypes is divergent. These observations lead us to propose that the SLG downstream region might be one border of the S locus and that the accumulation of heteromorphic sequences, such as retroelements as well as haplotype-unique genes, may act as a mechanism to suppress recombination between SLG and SRK. INTRODUCTIONSelf-incompatibility (SI) is one of the mechanisms promoting outbreeding that have evolved in higher plants. In Brassica spp, SI is controlled sporophytically by a single Mendelian genetic locus, the S locus (Bateman, 1955). Up to 100 S alleles have been identified in the genus Brassica (Bateman, 1955;Ockendon, 1974; de Nettancourt, 1977). Two genes are known to segregate with the genetically defined S locus; therefore, the term S haplotype has been used to collectively describe the components of each S region. One gene encodes a secreted glycoprotein called the S locus glycoprotein (SLG; Nasrallah et al., 1987). The second gene encodes a protein predicted to consist of an extracellular domain linked to a cytoplasmic kinase domain by a transmembrane domain . This structure resembles the receptor kinases from animals (Ullrich and Schlessinger, 1990) and therefore is called the S receptor kinase (SRK).Both SLG and SRK genes have been shown to be highly expressed in stigmas and at a lower level in anthers (Nasrallah et al., 1985;Stein et al., 1991; Goring and Rothstein, 1992). In the pistil, SLG is expressed predominantly in the surface papillar cells of the stigma (Sato et al., 1991), and its glycoprotein product accumulates to high levels in the walls of these cells (Kandasamy et al., 1989). SRK has been demonstrate...

Calcium retention is significantly greater in black girls than in white girls but is significantly reduced in girls of both races in response to salt loading.