Clinical evidence for overcoming capecitabine resistance in a woman with breast cancer terminating in radiologically occult micronodular pseudo-cirrhosis with portal hypertension: a case report

<p>Abstract</p> <p>Introduction</p> <p>We report a case of stage IV breast cancer terminating in an unusual picture of radiologically occult micronodular pseudo-cirrhosis. Contrast-enhanced computed tomography showed no evidence of metastatic breast cancer within the liver. Unlike the few previously reported cases of intrasinusoidal spread of breast cancer, our patient was palliated with a transjugular intrahepatic portosystemic shunt along with salvage chemohormonal therapy. In addition, our patient demonstrated proof of the principle of the dependence of capecitabine (Xeloda) efficacy on dose scheduling as predicted by laboratory studies based on Gompertzian tumor growth and the Norton-Simon hypothesis.</p> <p>Case presentation</p> <p>We report the case of a 52-year-old Caucasian woman who developed radiological signs of portal hypertension without radiological evidence of hepatic metastasis five years after being diagnosed with metastatic breast cancer. She was receiving chemotherapy for stage IV breast cancer initially thought to be metastatic only to the bones. During salvage therapy with high-dose estradiol (Estradiol valerate), vinorelbine (Navelbine) and bevacizumab (Avastin), she suddenly developed signs of portal hypertension confirmed on computed tomography and by portal and systemic venous pressure measurements. Drug toxicity due to bevacizumab (Avastin) was initially and incorrectly entertained as a cause. The patient underwent palliative transjugular intrahepatic portosystemic shunt and transhepatic venous liver biopsy, which revealed the presence of rapidly progressive and uncontrolled metastatic breast cancer. The new discovery of radiologically occult intrasinusodal hepatic metastases with secondary micronodular cirrhosis was found to be the cause of her sudden onset portal hypertension. The patient's resistance to capecitabine (Xeloda) was reversed by changing the schedule of medication to biweekly 7/7 (7 days ingesting drug alternating with 7 days off drug) from the 14/7 (14 days ingesting drug alternating with a 7 day rest period) day schedule approved by the US Food and Drug Administration.</p> <p>Conclusion</p> <p>This case report demonstrates an unusual presentation of radiographically occult hepatic metastasis from breast cancer palliated with transjugular intrahepatic portosystemic shunt. All patients with advanced breast cancer developing unexpected portal hypertension should be considered candidates for liver biopsy despite normal computed tomography of the liver imaging results. This is the first report of a reversal of clinical resistance to capecitabine (Xeloda) by changing from the schedule of 14/7 day to a biweekly 7/7 day schedule. This suggests that a biweekly schedule may be best for some patients.</p

Bacillus anthracis Peptidoglycan Stimulates an Inflammatory Response in Monocytes through the p38 Mitogen-Activated Protein Kinase Pathway

We hypothesized that the peptidoglycan component of B. anthracis may play a critical role in morbidity and mortality associated with inhalation anthrax. To explore this issue, we purified the peptidoglycan component of the bacterial cell wall and studied the response of human peripheral blood cells. The purified B. anthracis peptidoglycan was free of non-covalently bound protein but contained a complex set of amino acids probably arising from the stem peptide. The peptidoglycan contained a polysaccharide that was removed by mild acid treatment, and the biological activity remained with the peptidoglycan and not the polysaccharide. The biological activity of the peptidoglycan was sensitive to lysozyme but not other hydrolytic enzymes, showing that the activity resides in the peptidoglycan component and not bacterial DNA, RNA or protein. B. anthracis peptidoglycan stimulated monocytes to produce primarily TNFα; neutrophils and lymphocytes did not respond. Peptidoglycan stimulated monocyte p38 mitogen-activated protein kinase and p38 activity was required for TNFα production by the cells. We conclude that peptidoglycan in B. anthracis is biologically active, that it stimulates a proinflammatory response in monocytes, and uses the p38 kinase signal transduction pathway to do so. Given the high bacterial burden in pulmonary anthrax, these findings suggest that the inflammatory events associated with peptidoglycan may play an important role in anthrax pathogenesis

spatially-explicit test of the refuge strategy for delaying insecticide resistance

The refuge strategy is used worldwide to delay the evolution of pest resistance to insecticides that are either sprayed or produced by transgenic Bacillus thuringiensis (Bt) crops. This strategy is based on the idea that refuges of host plants where pests are not exposed to an insecticide promote survival of susceptible pests. Despite widespread adoption of this approach, large-scale tests of the refuge strategy have been problematic. Here we tested the refuge strategy with 8 y of data on refuges and resistance to the insecticide pyriproxyfen in 84 populations of the sweetpotato whitefly (Bemisia tabaci) from cotton fields in central Arizona. We found that spatial variation in resistance to pyriproxyfen within each year was not affected by refuges of melons or alfalfa near cotton fields. However, resistance was negatively associated with the area of cotton refuges and positively associated with the area of cotton treated with pyriproxyfen. A statistical model based on the first 4 y of data, incorporating the spatial distribution of cotton treated and not treated with pyriproxyfen, adequately predicted the spatial variation in resistance observed in the last 4 y of the study, confirming that cotton refuges delayed resistance and treated cotton fields accelerated resistance. By providing a systematic assessment of the effectiveness of refuges and the scale of their effects, the spatially explicit approach applied here could be useful for testing and improving the refuge strategy in other crop-pest systems. pesticide resistance | predictive evolutionary models | pest management | resistance management P opulation growth will continue to favor agricultural intensification for decades. Because agricultural intensification is associated with increased pest pressure, pesticides generally help to increase yield (1-3). Although significant progress has been made to reduce reliance on pesticides (4, 5), an increasing number of insects and mites exhibit field-evolved resistance to synthetic pesticides, Bacillus thuringiensis (Bt) sprays, and transgenic Bt crops (6, 7). Negative consequences of resistance include increased pesticide use, disruption of food webs and ecosystem services, increased risk to human health, and loss of profits for farmers and industry (1, 3). One of the main strategies for delaying resistance promotes survival of susceptible pests by providing refuges, which are areas of host plants where pests are not exposed to an insecticide. Theory predicts that refuges will slow the evolution of resistance by reducing the fitness advantage of resistant individuals (7-9). Refuges can also reduce the heritability of resistance when susceptible individuals mate with resistant individuals surviving exposure to an insecticide (7). Empirical support for the refuge strategy was provided by short-term laboratory and greenhouse experiments (10, 11). Although these experiments test the hypothesis that mating between susceptible and resistant individuals delays the evolution of resistance, they do not consider several factors that affect resistance in the field (7-9), and thus only provide partial support for effectiveness of the refuge strategy in the field. Retrospective analyses of variation in resistance evolution in the field also suggest that refuges have been effective, but these previous tests have been based primarily on comparisons among species, or qualitative comparisons within species based on a limited number of widely separated geographic areas (12, 13). In such tests, factors that vary among species or geographic areas can confound the effects of refuges. Accordingly, large-scale field tests of the refuge strategy for a single species within a geographic area where factors affecting resistance are similar are needed to test the refuge strategy more rigorously. Moreover, tests of predictive refuge strategy models are required to determine if the refuge strategy can delay resistance (14). Furthermore, to improve our ability to develop efficient refuge strategies, empirical approaches are necessary to characterize effects of refuges on resistance evolution (7, 15). Here we tested the refuge strategy using 8 y of data on refuges and resistance to the insecticide pyriproxyfen in 84 populations of the sweetpotato whitefly (Bemisia tabaci) sampled in cotton fields of central Arizona. We studied the B biotype of B. tabaci, also known as the Asia Minor-Middle East 1 species, which is a key pest of cotton and other crops in Arizona and worldwide (16). The insect growth regulators pyriproxyfen (a juvenile hormone analog) and buprofezin (a chitin synthesis inhibitor) are selective insecticides that have been used for whitefly control in Arizona cotton (Gossypium spp.) since 1996 (17, 18). A single application of either insecticide on cotton when B. tabaci populations start to increase has substantially reduced sprays of broad-spectrum insecticides, helped to conserve natural enemies, and restored farmers &apos; profits (18, 19). To deter rapid evolution of resistance, farmers in Arizona generally have not used pyriproxyfen to control B. tabaci on crops other than cotton Although B. tabaci is polyphagous, few whitefly crops other than cotton are available in central Arizona from June to September, when pyriproxyfen is sprayed on cotton. In principle, crops that could act as refuges include spring melons (Citrullus lanatus and Cucumis melo), alfalfa (Medicago sativa) and cotton not treated with pyriproxyfen (referred to hereafter as untreated cotton). B. tabac

Large-scale, spatially-explicit test of the refuge strategy for delaying insecticide resistance

The refuge strategy is used worldwide to delay the evolution of pest resistance to insecticides that are either sprayed or produced by transgenic Bacillus thuringiensis (Bt) crops. This strategy is based on the idea that refuges of host plants where pests are not exposed to an insecticide promote survival of susceptible pests. Despite widespread adoption of this approach, large-scale tests of the refuge strategy have been problematic. Here we tested the refuge strategy with 8 y of data on refuges and resistance to the insecticide pyriproxyfen in 84 populations of the sweetpotato whitefly ( Bemisia tabaci ) from cotton fields in central Arizona. We found that spatial variation in resistance to pyriproxyfen within each year was not affected by refuges of melons or alfalfa near cotton fields. However, resistance was negatively associated with the area of cotton refuges and positively associated with the area of cotton treated with pyriproxyfen. A statistical model based on the first 4 y of data, incorporating the spatial distribution of cotton treated and not treated with pyriproxyfen, adequately predicted the spatial variation in resistance observed in the last 4 y of the study, confirming that cotton refuges delayed resistance and treated cotton fields accelerated resistance. By providing a systematic assessment of the effectiveness of refuges and the scale of their effects, the spatially explicit approach applied here could be useful for testing and improving the refuge strategy in other crop–pest systems

A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees

Bipolar mood disorder (BP) is a debilitating syndrome characterized by episodes of mania and depression. We designed a multistage study to detect all major loci predisposing to severe BP (termed BP-I) in two pedigrees drawn from the Central Valley of Costa Rica, where the population is largely descended from a few founders in the 16th–18th centuries. We considered only individuals with BP-I as affected and screened the genome for linkage with 473 microsatellite markers. We used a model for linkage analysis that incorporated a high phenocopy rate and a conservative estimate of penetrance. Our goal in this study was not to establish definitive linkage but rather to detect all regions possibly harboring major genes for BP-I in these pedigrees. To facilitate this aim, we evaluated the degree to which markers that were informative in our data set provided coverage of each genome region; we estimate that at least 94% of the genome has been covered, at a predesignated threshold determined through prior linkage simulation analyses. We report here the results of our genome screen for BP-I loci and indicate several regions that merit further study, including segments in 18q, 18p, and 11p, in which suggestive lod scores were observed for two or more contiguous markers. Isolated lod scores that exceeded our thresholds in one or both families also occurred on chromosomes 1, 2, 3, 4, 5, 7, 13, 15, 16, and 17. Interesting regions highlighted in this genome screen will be followed up using linkage disequilibrium (LD) methods