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1.  Ceramide and glucosylceramide upregulate expression of the multidrug resistance gene MDR1 in cancer cells 
Biochimica et biophysica acta  2007;1771(12):1407-1417.
In the present study we used human breast cancer cell lines to assess the influence of ceramide and glucosylceramide (GC) on expression of MDR1, the multidrug resistance gene that codes for P-glycoprotein (P-gp), because GC has been shown to be a substrate for P-gp. Acute exposure (72 h) to C8-ceramide (5 µg/ml culture medium), a cell-permeable ceramide, increased MDR1 mRNA levels by 3-and 5-fold in T47D and in MDA-MB-435 cells, respectively. Acute exposure of MCF-7 and MDA-MB-231 cells to C8-GC (10 µg/ml culture medium), a cell-permeable analog of GC, increased MDR1 expression by 2-and 4-fold, respectively. Chronic exposure of MDA-MB-231 cells to C8-ceramide for extended periods enhanced MDR1 mRNA levels 45-and 390-fold at passages 12 and 22, respectively, and also elicited expression of P-gp. High-passage C8-ceramide-grown MDA-MB-231 (MDA-MB-231/C8cer) cells were more resistant to doxorubicin and paclitaxel. Incubation with [1-14C]C6-ceramide showed that cells converted short-chain ceramide into GC, lactosylceramide, and sphingomyelin. When challenged with 5 µg/ml [1-14C]C6-ceramide, MDA-MB-231, MDA-MB-435, MCF-7, and T47D cells took up 31, 17, 21, and 13%, respectively, and converted 82, 58, 62, and 58% of that to short-chain GC. Exposing cells to the GCS inhibitor, ethylenedioxy-P4, a substituted analog of 1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol, prevented ceramide’s enhancement of MDR1 expression. These experiments show that high levels of ceramide and GC enhance expression of the multidrug resistance phenotype in cancer cells. Therefore, ceramide’s role as a messenger of cytotoxic response might be linked to the multidrug resistance pathway.
doi:10.1016/j.bbalip.2007.09.005
PMCID: PMC3569095  PMID: 18035065
Multidrug resistance; Ceramide; Glucosylceramide; P-glycoprotein; Breast cancer
2.  Bilateral cytomegalovirus (CMV) oophoritis mimicking widely metastatic carcinoma: a case report and review of the literature 
Diagnostic Pathology  2007;2:50.
Ovarian cytomegalovirus (CMV) infection is a rare finding reported in autopsy studies of immunocompromised patients. We report the first case of bilateral CMV oophoritis diagnosed in surgical resection specimens from a 63-year-old woman with metastatic brain lesions undergoing whole brain radiation and steroid treatment. The ovarian involvement of CMV infection was an incidental finding during the colectomy and bilateral salpingo-oophorectomy procedure for gastrointestinal bleeding and presumed ovarian metastases. In contrast to the prevailing dogma, a review of the literature found similar prevalence of pre-menopausal and post-menopausal cases. While age related vasculopathy was thought to be the prevailing mechanism for CMV oophoritis, the observation of an inflammation mediated microthrombosis in our case provides a plausible age independent mechanism suggesting that both restrictive and obstructive vascular changes can be involved in the pathogenesis of CMV oophoritis. To avoid misdiagnosis, both pathologists and clinicians should recognize ovarian involvement by CMV as a possibility in the immunocompromised patient.
doi:10.1186/1746-1596-2-50
PMCID: PMC2245911  PMID: 18096056
3.  A high-resolution anatomical ontology of the developing murine genitourinary tract 
Gene expression patterns : GEP  2007;7(6):680-699.
Cataloguing gene expression during development of the genitourinary tract will increase our understanding not only of this process but also of congenital defects and disease affecting this organ system. We have developed a high-resolution ontology with which to describe the subcompartments of the developing murine genitourinary tract. This ontology incorporates what can be defined histologically and begins to encompass other structures and cell types already identified at the molecular level. The ontology is being used to annotate in situ hybridisation data generated as part of the Genitourinary Development Molecular Anatomy Project (GUDMAP), a publicly available data resource on gene and protein expression during genitourinary development. The GUDMAP ontology encompasses Theiler stage (TS) 17 to 27 of development as well as the sexually mature adult. It has been written as a partonomic, text-based, hierarchical ontology that, for the embryological stages, has been developed as a high-resolution expansion of the existing Edinburgh Mouse Atlas Project (EMAP) ontology. It also includes group terms for well-characterised structural and/or functional units comprising several sub-structures, such as the nephron and juxtaglomerular complex. Each term has been assigned a unique identification number. Synonyms have been used to improve the success of query searching and maintain wherever possible existing EMAP terms relating to this organ system. We describe here the principles and structure of the ontology and provide representative diagrammatic, histological, and whole mount and section RNA in situ hybridisation images to clarify the terms used within the ontology. Visual examples of how terms appear in different specimen types are also provided.
doi:10.1016/j.modgep.2007.03.002
PMCID: PMC2117077  PMID: 17452023
genitourinary development; renal development; kidney development; urinary development; reproductive development; kidney; gonad; bladder; ureter; urethra; genital tubercle; ovary; testis; congenital defects; gene expression; ontology; annotation; database; anatomy; atlas of development; partonomic ontology; RNA in situ hybridisation
4.  The cdx Genes and Retinoic Acid Control the Positioning and Segmentation of the Zebrafish Pronephros 
PLoS Genetics  2007;3(10):e189.
Kidney function depends on the nephron, which comprises a blood filter, a tubule that is subdivided into functionally distinct segments, and a collecting duct. How these regions arise during development is poorly understood. The zebrafish pronephros consists of two linear nephrons that develop from the intermediate mesoderm along the length of the trunk. Here we show that, contrary to current dogma, these nephrons possess multiple proximal and distal tubule domains that resemble the organization of the mammalian nephron. We examined whether pronephric segmentation is mediated by retinoic acid (RA) and the caudal (cdx) transcription factors, which are known regulators of segmental identity during development. Inhibition of RA signaling resulted in a loss of the proximal segments and an expansion of the distal segments, while exogenous RA treatment induced proximal segment fates at the expense of distal fates. Loss of cdx function caused abrogation of distal segments, a posterior shift in the position of the pronephros, and alterations in the expression boundaries of raldh2 and cyp26a1, which encode enzymes that synthesize and degrade RA, respectively. These results suggest that the cdx genes act to localize the activity of RA along the axis, thereby determining where the pronephros forms. Consistent with this, the pronephric-positioning defect and the loss of distal tubule fate were rescued in embryos doubly-deficient for cdx and RA. These findings reveal a novel link between the RA and cdx pathways and provide a model for how pronephric nephrons are segmented and positioned along the embryonic axis.
Author Summary
In the kidney, structures known as nephrons are responsible for collecting metabolic waste. Nephrons are composed of a blood filter (glomerulus) followed by a series of specialized tubule regions, or segments, which recover solutes such as salts, and finally terminate with a collecting duct. The genetic mechanisms that establish nephron segmentation in mammals have been a challenge to study because of the kidney's complex organogenesis. The zebrafish embryonic kidney (pronephros) contains two nephrons, previously thought to consist of a glomerulus, short tubule, and long stretch of duct. In this study, we have redefined the anatomy of the zebrafish pronephros and shown that the duct is actually subdivided into distinct tubule segments that are analogous to the proximal and distal segments found in mammalian nephrons. Next, we used the zebrafish pronephros to investigate how nephron segmentation occurs. We found that retinoic acid (RA) induces proximal pronephros segments and represses distal segment fates. Further, we found that the caudal (cdx) transcription factors direct the anteroposterior location of pronephric progenitors by regulating the site of RA production. Taken together, these results reveal that a cdx-RA pathway plays a key role in both establishing where the pronephros forms along the embryonic axis as well as its segmentation pattern.
doi:10.1371/journal.pgen.0030189
PMCID: PMC2042002  PMID: 17953490
5.  The cdx Genes and Retinoic Acid Control the Positioning and Segmentation of the Zebrafish Pronephros 
PLoS Genetics  2007;3(10):e189.
Kidney function depends on the nephron, which comprises a blood filter, a tubule that is subdivided into functionally distinct segments, and a collecting duct. How these regions arise during development is poorly understood. The zebrafish pronephros consists of two linear nephrons that develop from the intermediate mesoderm along the length of the trunk. Here we show that, contrary to current dogma, these nephrons possess multiple proximal and distal tubule domains that resemble the organization of the mammalian nephron. We examined whether pronephric segmentation is mediated by retinoic acid (RA) and the caudal (cdx) transcription factors, which are known regulators of segmental identity during development. Inhibition of RA signaling resulted in a loss of the proximal segments and an expansion of the distal segments, while exogenous RA treatment induced proximal segment fates at the expense of distal fates. Loss of cdx function caused abrogation of distal segments, a posterior shift in the position of the pronephros, and alterations in the expression boundaries of raldh2 and cyp26a1, which encode enzymes that synthesize and degrade RA, respectively. These results suggest that the cdx genes act to localize the activity of RA along the axis, thereby determining where the pronephros forms. Consistent with this, the pronephric-positioning defect and the loss of distal tubule fate were rescued in embryos doubly-deficient for cdx and RA. These findings reveal a novel link between the RA and cdx pathways and provide a model for how pronephric nephrons are segmented and positioned along the embryonic axis.
Author Summary
In the kidney, structures known as nephrons are responsible for collecting metabolic waste. Nephrons are composed of a blood filter (glomerulus) followed by a series of specialized tubule regions, or segments, which recover solutes such as salts, and finally terminate with a collecting duct. The genetic mechanisms that establish nephron segmentation in mammals have been a challenge to study because of the kidney's complex organogenesis. The zebrafish embryonic kidney (pronephros) contains two nephrons, previously thought to consist of a glomerulus, short tubule, and long stretch of duct. In this study, we have redefined the anatomy of the zebrafish pronephros and shown that the duct is actually subdivided into distinct tubule segments that are analogous to the proximal and distal segments found in mammalian nephrons. Next, we used the zebrafish pronephros to investigate how nephron segmentation occurs. We found that retinoic acid (RA) induces proximal pronephros segments and represses distal segment fates. Further, we found that the caudal (cdx) transcription factors direct the anteroposterior location of pronephric progenitors by regulating the site of RA production. Taken together, these results reveal that a cdx-RA pathway plays a key role in both establishing where the pronephros forms along the embryonic axis as well as its segmentation pattern.
doi:10.1371/journal.pgen.0030189
PMCID: PMC2042002  PMID: 17953490

Results 1-5 (5)