Biomedical subjects

Heather Herrington

Publications and source records attributed to Heather Herrington.

4 recordsLinked to original sources

PubMed2006

Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma.

The prognosis of head-and-neck squamous cell carcinoma (HNSCC) has not been improved in the past 20 years. Validation of HNSCC biomarkers for targeted therapy has been hindered by a lack of animal models mimicking human HNSCC at both the pathological and molecular levels. Here we report that overexpression of K-ras or H-ras and loss of transforming growth factor-beta type II receptor (TGFbetaRII) are common events in human HNSCC. Activation of either K-ras or H-ras in combination with TGFbetaRII deletion from mouse head-and-neck epithelia caused HNSCC with complete penetrance, some of which progressed to metastases. These tumors displayed pathology indistinguishable from human HNSCCs and exhibited multiple molecular alterations commonly found in human HNSCCs. Additionally, elevated endogenous TGFbeta1 in these lesions contributed to inflammation and angiogenesis. Our data suggest that targeting common oncogenic pathways in tumor epithelia together with blocking the effect of TGFbeta1 on tumor stroma may provide a novel therapeutic strategy for HNSCC.

Animals↗

PubMed2006

Mouse models for human head and neck squamous cell carcinomas.

Mouse models of human cancer play an important role in understanding the mechanisms of carcinogenesis and have accelerated the search for finding new molecular targets for cancer therapy. However, genetically engineered mouse models for head and neck squamous cell carcinoma (HNSCC) have only recently overcome major technical obstacles and begun to be explored. Here we review the current progress in the development of mouse models for human HNSCC, with emphasis on conditional transgenic and knockout mouse models. These new models faithfully recapitulate human HNSCC at both the pathologic and molecular levels. These animal models will not only be useful to define the roles of specific genes in HNSCC development and progression but will also provide a unique tool for developing and testing new therapeutic approaches.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2004

Excluded volume effect of rat intestinal mucin on taurocholate/phosphatidylcholine mixed micelles.

The interaction of bile salt/phospholipid mixed micelles with an intestinal mucin has been investigated to provide the foundation for the transport of ingested fat and poorly water-soluble drugs through the intestinal mucous layer. Egg phosphatidylcholine (PC) was equilibrated with sodium taurocholate (TC) to generate several series of solutions, which had different intermicellar concentrations of TC. Within each series, each solution had the same IMC and thereby micelle sizes, but varied with respect to micelle concentration. These solutions were combined with isolated rat intestinal mucin, equilibrated, and then separated by centrifugation. The supernatant and mucin pellet were assayed for PC and TC, and the diffusion coefficient of PC was measured in the supernatant by PFG-SE NMR spectroscopy. For each series, four linear relationships were found; TC supernatant concentration plotted as a function of PC supernatant concentration; TC pellet concentration plotted as a function of PC pellet concentration; TC pellet concentration plotted as a function of TC supernatant concentration; and PC pellet concentration plotted as a function of PC supernatant concentration. Theoretical analysis of these results indicated that mucin excludes from 25 to 80% of the bile salt/phospholipid mixed micelles with greater exclusion observed with larger micelle size. There is preferential association of the taurocholate with intestinal mucin, when present in the mixed micelle region of the phase diagram. The association coupled with exclusion would allow mucin to modulate the concentration of bile salt at the epithelial surface.

Animals↗

PubMed2004

Interaction of bile salts with gastrointestinal mucins.

The properties of three mucins were examined to identify the structural features responsible for their functional difterences. Bovine submaxillary mucin (BSM), porcine gastric mucin (PGM), and rat intestinal mucin (RIM) were each characterized, and high carbohydrate contents were found for RIM and PGM. The amino acid compositions were typical of mucin glycoproteins, with over half comprising small, neutral amino acids. Thereafter, each mucin was equilibrated with three different series of concentrations of the bile salts sodium taurocholate, sodium taurodeoxycholate, and sodium taurochenodeoxycholate. Following multiple centrifugations, the supernatant and mucin pellet concentrations of the bile salts were measured. The bile salt pellet concentration was plotted as a function of supernatant concentration, and from the slopes, the excluded volumes were calculated as 25, 29-44, and 28 55 mL/g for BSM, RIM, and PGM, respectively. The intercepts were 8-10, 2-3, and 1-3 mM for BSM, RIM, and PGM, respectively, which represents an estimate of the bound concentration of bile salt. Differences among the bile salts were observed in the excluded volume and amount bound, but no trends were evident. The bile salts may interact as aggregates with the hydrophobic areas and carbohydrate side chains of the mucins, providing favorable sites for association. The binding at low concentrations with exclusion at high concentrations is significant for modulating the absorption of lipid aggregates from the intestine. Finally, the differences among the mucins reflect the unique structure function relationship of these gastrointestinal mucins.

Amino Acids↗