Left ventricular (LV) hypertrophy (LVH) results in a fetal shift in myocardial creatine kinase (CK) expression. Because CK plays an important role in intracellular energy production, transport, and utilization, this study was performed to characterize changes in CK expression and CK flux in severe pressure-overload LVH. Ascending aortic banding in 8-wk-old dogs resulted in LVH with a 92% increase in relative LV mass. In LVH hearts, CK-M isoform mRNA was decreased by 40% (P = 0.05) and protein was decreased by 50% (P < 0.01), whereas mitochondrial CK protein was decreased by 22% (P < 0.05). CK-B isoform mRNA was undetectable in normal hearts but was prominently expressed in LVH (P < 0.01); CK-B protein was increased by more than 10-fold in LVH (P < 0.01). Despite these changes, total CK activity was normal in LVH. Myocardial CK flux was examined using (31)P magnetic resonance spectroscopy magnetization transfer. The CK forward rate constant was similar in normal and LVH hearts at baseline and did not change in either group during dobutamine treatment. In hearts with LVH, the CK forward flux rate was reduced by approximately 60% (P < 0.05) and decreased further during dobutamine. Thus, although pressure-overload LVH caused alterations of expression of both CK mRNA and protein levels, LV performance and oxygen consumption in response to dobutamine were normal. However, myocardial free ADP was increased in LVH hearts. This finding suggests that the CK alterations result in a need for higher ADP levels to maintain ATP synthesis in the hypertrophied heart.

Clinicopathologic features of sporadic colorectal adenocarcinomas were compared using integrated data from 244 patients subjected to curative resection. Individual steps in the tumorigenesis pathway, that is, adenomatosis polyposis coli (APC), Wnt-activated, base excision repair mutations, mismatch repair defects, RAF-mediated, transforming growth factor (TGF)-b-suppressed, bone morphogenic protein (BMP)-suppressed, and p53 alterations, were examined in terms of genetic and epigenetic changes, as well as protein expression. Genetic and molecular alterations of right colon cancers were distinct from those of left colon and rectal cancers. Rectal cancers showed the attenuated phenotype of left colon cancers. Tumors most frequently displayed either TGF-b-or BMP-suppressed alterations (81.2%), followed by RAF-mediated alterations (78.6%), and mismatch repair defects (38.4%), constituting a total of 24 integrated pathways. Tumors lacking APC mutations or carrying the RAF alteration (V600E) were frequently associated with lymphovascular invasion and lymph node metastasis (P < 0.05). Poorly differentiated or mucinous adenocarcinomas were generally associated with high level microsatellite instability, Axin2 suppression, TGF-b1 or BMPR1A suppression, loss of heterozygosity of D18S46 or D18S474, and absence of base excision repair mutations (P < 0.0001-0.05). T he classical pathway of colorectal tumorigenesis constitutes stepwise or consecutive genetic and molecular changes, commencing with adenomatosis polyposis coli (APC) alterations through RAS family genes, and concluding with p53.(1) Although this model provides a simplified explanation of pathogenesis, numerous crossover or alternative changes also occur in human colorectal cancer. These stepwise alterations are consistently observed in only 6.6% of all colorectal cancers.(2) Two types of molecular and biological characteristics have been identified in hereditary colorectal cancer. Hereditary non-polyposis colorectal cancer is associated with microsatellite instability (MSI), right-sided location, diploid DNA, transforming growth factor-β receptor 2 (TGFBR2) and Bc1-2-associated X protein mutations, and indolent behavior. In contrast, familial adenomatous polyposis displays chromosomal instability, left-sided location, aneuploid DNA, and pathogenic mutations in APC, KRAS, and p53, along with aggressive behavior. Previous investigations of sporadic hereditary colorectal cancer have disclosed various concurrent molecular and genetic changes, that is, APC and Wnt-activated mutations, mismatch repair (MMR) defects, and base excision repair (BER), RAFmediated, transforming growth factor (TGF)-β-and bone morphogenic protein (BMP)-suppressed, and p53 alterations. (3)(4)(5) These mutations are interconnected to generate diverse pathways of tumorigenesis and progression. For example, one study showed that both TGFBR2 mutations and MSI are approximately two-to threefold more prevalent in tumors displaying normal p53, APC, and RAS, compared to those with alterations in these ...