ABSTRACT
Acute type I aortic dissection is a life-threatening emergency with potentially devastating complications, including end-organ malperfusion. Early detection of malperfusion with intraoperative imaging allows for efficient transition to appropriate interventions. We present a case of a 65-year-old male with acute type I aortic dissection who underwent emergent surgical repair of the aortic root and hemiarch followed by acutely worsening distal malperfusion. The use of intraoperative transesophageal echocardiography played a critical role in visualizing diversion of flow to the false lumen, prompting urgent vascular surgery consultation and life-saving thoracic endovascular aortic repair.
Subject(s)
Aortic Aneurysm, Thoracic , Aortic Dissection , Acute Disease , Aged , Aortic Dissection/diagnosis , Aortic Dissection/diagnostic imaging , Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/diagnostic imaging , Echocardiography, Transesophageal , Humans , Male , Treatment Outcome , Vascular Surgical ProceduresABSTRACT
p16(INK4a) is a major tumor-suppressor protein, but its regulation and settings of fuction remain poorly understood. To explore the notion that p16 is induced in vivo in response to replicative stress, we examined p16 expression in tissues from human ulcerative colitis (UC; n = 25) and normal controls (n = 20). p16 was expressed strongly in UC-associated neoplasms (n = 17), as seen previously in sporadic colonic neoplasms. In non-neoplastic UC epithelium, p16 was expressed in 33% of crypts (the proliferative compartment) compared to < 1% of normal controls. p16 expression did not correlate with degree of inflammation but did correlate with the degree of crypt architecture distortion (P = .002)-a reflection of epithelial regeneration. In coimmunofluorescence studies with Ki67, p16 expression was associated with cell cycle arrest (P < .001). Both UC and normal crypts displayed evidence for the activation of the DNA damage checkpoint pathway, and p16 was induced in primary cultures of normal epithelial cells by ionizing irradiation (IR). However, induction by IR displayed delayed kinetics, implying that p16 is not an immediate target of the checkpoint pathway. These findings support a model in which p16 is induced as an "emergency brake" in cells experiencing sustained replicative stress.
Subject(s)
Colitis, Ulcerative/metabolism , Cyclin-Dependent Kinase Inhibitor p16/biosynthesis , Gene Expression Regulation, Neoplastic , Gene Expression Regulation , DNA Damage , Epithelial Cells/cytology , Epithelium/pathology , Humans , Inflammation , Intestinal Mucosa/pathology , Ki-67 Antigen/biosynthesis , Kinetics , Microscopy, Fluorescence , RegenerationABSTRACT
The Ink4a/Arf tumor suppressor locus is widely inactivated in cancer but little is known about the tumor biology of its two products, p16(Ink4a) (p16) and Arf. Both the p16 and Arf promoters are methylated in a significant fraction of human colon carcinomas, implying a functional role. We have demonstrated previously that Ink4a/Arf-null colon tumors display increased growth and vascularity in C57Bl6 mice carrying the Min (multiple intestinal neoplasia) mutation. We present here an analysis in a mixed genetic background of Min colon tumors (N=215) in mice with or without selective deficiencies in p16 or Arf, respectively. Absence of Arf did not significantly alter tumor formation. In contrast, tumors in mice lacking p16 were moderately larger and redder. Histological analysis demonstrated that these tumors contained significantly more pockets of necrosis (p=0.02), a marker of carcinoma in situ; less apoptosis (p=0.02); and higher red blood cell density (p=0.02, 0.006 within vessels). Biochemical analyses demonstrated increased levels of vascular endothelial cell growth factor (VEGF, p<0.01). Exogenous p16 expression in human colon tumor cells in vitro inhibited VEGF production. These results suggest that p16 constrains colon tumor progression, in part through inhibiting angiogenic signaling.
Subject(s)
Colonic Neoplasms/blood supply , Genes, p16 , Neovascularization, Pathologic/genetics , Signal Transduction , Tumor Suppressor Protein p14ARF/genetics , Animals , Apoptosis , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Disease Progression , HT29 Cells , Humans , Mice , Mice, Inbred C57BL , Necrosis/pathology , Neovascularization, Pathologic/pathology , Tumor Suppressor Protein p14ARF/physiologyABSTRACT
The Ink4a/Arf locus is frequently methylated in colon carcinoma and other common human cancers, suggesting that the locus may play a broad, as yet poorly defined,role inhibiting tumor progression. We examined the influence of the locus in mice with multiple intestinal neoplasia (Min). Colon tumors in 3-month-old Min mice that were null for the Ink4a/Arf locus (-/-) were moderately larger than in Ink4a/Arf-wild-type (+/+) animals (P = 0.032). More strikingly, one-half of the -/- colon tumors were grossly red in color, whereas most of the +/+ tumors were white (P = 0.0025). This color difference remained statistically significant after normalizing for tumor area (P = 0.016). On histological analysis, -/- colon tumors displayed more RBCs near the tumor surface, twice the number of functional vessels, and features of carcinoma in situ not found in +/+ tumors. Biochemical analyses showed that red tumors had higher hemoglobin and vascular endothelial growth factor (VEGF) content than white tumors. Surprisingly, the small intestinal tumor burden was actually lower in -/- animals, and none of these tumors were red, underscoring the importance of tissue context in the function of the locus. These results provide direct evidence that the Ink4a/Arf locus inhibits colon tumor progression. The enhanced vascularity of the -/- tumors is particularly significant in light of the clinical importance of this property in the detection, recurrence, and therapy of colon tumors.
