The identity of the transporter responsible for fructose absorption in the intestine in vivo and its potential role in fructose-induced hypertension remain speculative. Here we demonstrate that Glut5 (Slc2a5) deletion reduced fructose absorption by ϳ75% in the jejunum and decreased the concentration of serum fructose by ϳ90% relative to wild-type mice on increased dietary fructose. When fed a control (60% starch) diet, Glut5 ؊/؊ mice had normal blood pressure and displayed normal weight gain. However, whereas Glut5 ؉/؉ mice showed enhanced salt absorption in their jejuna in response to luminal fructose and developed systemic hypertension when fed a high fructose (60% fructose) diet for 14 weeks, Glut5 ؊/؊ mice did not display fructose-stimulated salt absorption in their jejuna, and they experienced a significant impairment of nutrient absorption in their intestine with accompanying hypotension as early as 3-5 days after the start of a high fructose diet. Examination of the intestinal tract of Glut5 ؊/؊ mice fed a high fructose diet revealed massive dilatation of the caecum and colon, consistent with severe malabsorption, along with a unique adaptive up-regulation of ion transporters. In contrast to the malabsorption of fructose, Glut5 ؊/؊ mice did not exhibit an absorption defect when fed a high glucose (60% glucose) diet. We conclude that Glut5 is essential for the absorption of fructose in the intestine and plays a fundamental role in the generation of fructose-induced hypertension. Deletion of Glut5 results in a serious nutrient-absorptive defect and volume depletion only when the animals are fed a high fructose diet and is associated with compensatory adaptive up-regulation of ion-absorbing transporters in the colon.
Alternatively spliced tissue factor (asTF) promotes neovascularization and monocyte recruitment via integrin ligation. While asTF mRNA has been detected in some pancreatic ductal adenocarcinoma (PDAC) cell lines and increased asTF expression can promote PDAC growth in a subcutaneous model, the expression of asTF protein in bona fide PDAC lesions and/or its role in metastatic spread are yet to be ascertained. We here report that asTF protein is abundant in lesional and stromal compartments of the five studied types of carcinoma including PDAC. Analysis of 29 specimens of PDAC revealed detectable asTF in >90% of the lesions with a range of staining intensities. asTF levels in PDAC lesions positively correlated with the degree of monocyte infiltration. In an orthotopic model, asTF-overexpressing high-grade PDAC cell line Pt45P1/asTF+ produced metastases to distal lymph nodes, which stained positive for asTF. PDAC cells stimulated with and/or overexpressing asTF exhibited upregulation of genes implicated in PDAC progression and metastatic spread. Pt45P1/asTF+ cells displayed higher coagulant activity compared to Pt45P1 cells; the same effect was observed for cell-derived microparticles (MPs). Our findings demonstrate that asTF is expressed in PDAC and lymph node metastases and potentiates PDAC spread in vivo. asTF elicits global changes in gene expression likely involved in tumor progression and metastatic dissemination, and it also enhances the pro-coagulant potential of PDAC cells and cell-derived MPs. Thus, asTF may comprise a novel therapeutic target to treat PDAC and, possibly, its thrombotic complications.
Fifty-eight patients with clinical inflammatory breast carcinoma and 15 patients with "occult" inflammatory cancer (dermal lymphatic carcinomatosis without clinical inflammation) are grouped and reviewed to determine whether diagnosis is pathologic or clinical. All cases represent a retrospective study of records from the Ellis Fischel State Cancer Hospital, Columbia, Missouri. Lesions of clinically apparent and occult inflammatory carcinoma demonstrate similar gross and microscopic growth patterns, histologic types, axillary involvement and early widespread metastases. Regardless of pathologic evidence of dermal lymphatic tumor, patients with clinical inflammation had rapid deterioration. Cases with only a pathological diagnosis were slightly less fulminant in progression. Either clinical or pathologic criteria justify use of the term "inflammatory breast carcinoma" to indicate short-term prognosis despite available treatment.
PM from RCC carries a consistently favorable prognosis compared to other pathologies. Surgical resection of PM is a safe and viable option, and, in selected patients, may improve survival. However, a period of expectant management in patients with short DFI may be considered.
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