Postoperative 30-day mortality in patients undergoing surgery for colorectal cancer: development of a prognostic model using administrative claims data.

PURPOSE: To develop a prognostic model to predict 30-day mortality following colorectal cancer (CRC) surgery using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data and to assess whether race/ethnicity, neighborhood, and hospital characteristics influence model performance. METHODS: We included patients aged 66 years and older from the linked 2000-2005 SEER-Medicare database. Outcome included 30-day mortality, both in-hospital and following discharge. Potential prognostic factors included tumor, treatment, sociodemographic, hospital, and neighborhood characteristics (census-tract-poverty rate). We performed a multilevel logistic regression analysis to account for nesting of CRC patients within hospitals. Model performance was assessed using the area under the receiver operating characteristic curve (AUC) for discrimination and the Hosmer-Lemeshow goodness-of-fit test for calibration. RESULTS: In a model that included all prognostic factors, important predictors of 30-day mortality included age at diagnosis, cancer stage, and mode of presentation. Race/ethnicity, census-tract-poverty rate, and hospital characteristics were independently associated with 30-day mortality, but they did not influence model performance. Our SEER-Medicare model achieved moderate discrimination (AUC = 0.76), despite suboptimal calibration. CONCLUSIONS: We developed a prognostic model that included tumor, treatment, sociodemographic, hospital, and neighborhood predictors. Race/ethnicity, neighborhood, and hospital characteristics did not improve model performance compared with previously developed models.

Hospital and geographic variability in two colorectal cancer surgery outcomes: complications and mortality after complications.

BACKGROUND: The purpose of this study was to describe hospital and geographic variation in 30-day risk of surgical complications and death among colorectal cancer (CRC) patients and the extent to which patient-, hospital-, and census-tract-level characteristics increased risk of these outcomes. METHODS: We included patients at least 66 years old with first primary stage I-III CRC from the 2000-2005 National Cancer Institute's Surveillance, Epidemiology, and End Results data linked with 1999-2005 Medicare claims. A multilevel, cross-classified logistic model was used to account for nesting of patients within hospitals and within residential census tracts. Outcomes were risk of complications and death after a complication within 30 days of surgery. RESULTS: Data were analyzed for 35,946 patients undergoing surgery at 1,222 hospitals and residing in 12,187 census tracts; 27.2 % of patients developed complications, and of these 13.4 % died. Risk-adjusted variability in complications across hospitals and census tracts was similar. Variability in mortality was larger than variability in complications, across hospitals and across census tracts. Specific characteristics increased risk of complications (e.g., census-tract-poverty rate, emergency surgery, and being African-American). No hospital characteristics increased complication risk. Specific characteristics increased risk of death (e.g. census-tract-poverty rate, being diagnosed with colon (versus rectal) cancer, and emergency surgery), while hospitals with at least 500 beds showed reduced death risk. CONCLUSIONS: Large, unexplained variations exist in mortality after surgical complications in CRC across hospitals and geographic areas. The potential exists for quality improvement efforts targeted at the hospital and/or census-tract levels to prevent complications and augment hospitals' ability to reduce mortality risk.

A mouse model of human familial hypercholesterolemia: markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet.

Mutations in the low density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia, a human disease characterized by premature atherosclerosis and markedly elevated plasma levels of LDL cholesterol and apolipoprotein (apo) B100. In contrast, mice deficient for the LDL receptor (Ldlr-/-) have only mildly elevated LDL cholesterol levels and little atherosclerosis. This difference results from extensive editing of the hepatic apoB mRNA in the mouse, which limits apoB100 synthesis in favor of apoB48 synthesis. We have generated Ldlr-/- mice that cannot edit the apoB mRNA and therefore synthesize exclusively apoB100. These mice had markedly elevated LDL cholesterol and apoB100 levels and developed extensive atherosclerosis on a chow diet. This authentic model of human familial hypercholesterolemia will provide a new tool for studying atherosclerosis.

Differences in effectiveness and use of laparoscopic surgery in locally advanced colon cancer patients.

Patients with locally advanced colon cancer have worse outcomes. Guidelines of various organizations are conflicting about the use of laparoscopic colectomy (LC) in locally advanced colon cancer. We determined whether patient outcomes of LC and open colectomy (OC) for locally advanced (T4) colon cancer are comparable in all colon cancer patients, T4a versus T4b patients, obese versus non-obese patients, and tumors located in the ascending, descending, and transverse colon. We used data from the 2013-2015 American College of Surgeons' National Surgical Quality Improvement Program. Patients were diagnosed with nonmetastatic pT4 colon cancer, with or without obstruction, and underwent LC (n = 563) or OC (n = 807). We used a composite outcome score (mortality, readmission, re-operation, wound infection, bleeding transfusion, and prolonged postoperative ileus); length of stay; and length of operation. Patients undergoing LC exhibited a composite outcome score that was 9.5% lower (95% CI - 15.4; - 3.5) versus those undergoing OC. LC patients experienced a 11.3% reduction in postoperative ileus (95% CI - 16.0; - 6.5) and an average of 2 days shorter length of stay (95% CI - 2.9; - 1.0). Patients undergoing LC were in the operating room an average of 13.5 min longer (95% CI 1.5; 25.6). We found no evidence for treatment heterogeneity across subgroups (p > 0.05). Patients with locally advanced colon cancer who receive LC had better overall outcomes and shorter lengths of stay compared with OC patients. LC was equally effective in obese/nonobese patients, in T4a/T4b patients, and regardless of the location of the tumor.

Molecular cloning of an apolipoprotein B messenger RNA editing protein.

Mammalian apolipoprotein B (apo B) exists in two forms, each the product of a single gene. The shorter form, apo B48, arises by posttranscriptional RNA editing whereby cytidine deamination produces a UAA termination codon. A full-length complementary DNA clone encoding an apo B messenger RNA editing protein (REPR) was isolated from rat small intestine. The 229-residue protein contains consensus phosphorylation sites and leucine zipper domains. HepG2 cell extracts acquire editing activity when mixed with REPR from oocyte extracts. REPR is essential for apo B messenger RNA editing, and the isolation and characterization of REPR may lead to the identification of other eukaryotic RNA editing proteins.

Retinoic acid modulates rat Ito cell proliferation, collagen, and transforming growth factor beta production.

Recent studies suggest that vitamin A plays an inhibitory role with respect to "activation" of the hepatic Ito cell, a likely effector of hepatic fibrogenesis. Ito cell "activation" during fibrogenesis is characterized by a decrease in intracellular vitamin A and an increase in cellular proliferation and collagen production. To explore the hypothesis that retinoids have the capacity to diminish Ito cell activation, cultured Ito cells were exposed to retinoic acid and its effects assessed on three key features: cell proliferation, collagen protein production and mRNA abundance, and transforming growth factor beta protein production. Retinoic acid was 100-1,000X more potent than retinol with respect to inhibition of Ito cell proliferation. Interstitial collagen and transforming growth factor beta production were also reduced by 10(-6) M retinoic acid. The relative abundance of type I collagen mRNA however, was not significantly altered. By contrast, retinoic acid administration to rats caused a marked reduction in the abundance of type I collagen mRNA in both total hepatic and purified Ito cell RNA. The relative abundance of rat hepatic fibronectin or apolipoprotein E mRNA was not significantly altered. These studies demonstrate that retinoic acid can differentially modulate several key features of hepatic fibrogenesis in vitro and in vivo.

Rat intestinal apolipoprotein B gene expression. Evidence for integrated regulation by bile salt, fatty acid, and phospholipid flux.

We previously reported that intestinal apo B48 synthesis in the rat was unaltered by dietary triglyceride intake but demonstrated regulation in response to biliary lipid availability. Studies are now presented in which the mechanisms underlying biliary lipid dependent expression of intestinal apo B48 synthesis have been investigated further. Bile salt replacement was effective in a dose- and structure-dependent manner in reexpressing intestinal apo B48 synthesis after prolonged bile diversion. Further experiments suggested that this effect of bile salt may be related to facilitated uptake of fatty acid. A role for mucosal phospholipid flux was suggested by studies in which infusion of lysolecithin, with or without Na taurocholate, produced complete reexpression of apo B48 synthesis in jejunal enterocytes. Over a four- to sixfold range of apo B48 synthesis rates in both jejunum and ileum, there was no change in apo B mRNA size or abundance as determined by RNA blot hybridization. Analysis of both intestinal mucosa and microsome lipid content in a variety of settings revealed that apo B48 synthesis rates were correlated with microsome triglyceride fatty acid content (r = 0.65, P less than 0.005) but not free fatty acid or phospholipid content. These studies demonstrate a physiologic role for elements of biliary lipid flux in the regulation of apo B gene expression. The data suggest that an integrated mechanism may exist whereby apo B48 synthesis is related to microsome triglyceride flux, particularly at low levels of lumenal substrate availability.

Mutations in the K-ras oncogene induced by 1,2-dimethylhydrazine in preneoplastic and neoplastic rat colonic mucosa.

These experiments were conducted to determine whether point mutations activating K-ras or H-ras oncogenes, induced by the procarcinogen 1,2-dimethylhydrazine (DMH), were detectable in preneoplastic or neoplastic rat colonic mucosa. Rats were injected weekly with diluent or DMH at 20 mg/kg body wt for 5, 10, 15, or 25 wk, killed, and their colons dissected. DNA was extracted from diluent-injected control animals, histologically normal colonic mucosa from carcinogen-treated animals, and from carcinomas. Ras mutations were characterized by differential hybridization using allele-specific oligonucleotide probes to polymerase chain reaction--amplified DNA, and confirmed by DNA sequencing. While no H-ras mutations were detectable in any group, K-ras (G to A) mutations were found in 66% of DMH-induced colon carcinomas. These mutations were at the second nucleotide of codons 12 or 13 or the first nucleotide of codon 59 of the K-ras gene. The same type of K-ras mutations were observed in premalignant colonic mucosa from 2 out of 11 rats as early as 15 wk after beginning carcinogen injections when no dysplasia, adenomas, or carcinomas were histologically evident, suggesting that ras mutation may be an early event in colon carcinogenesis.

Troglitazone action is independent of adipose tissue.

We have investigated the antidiabetic action of troglitazone in aP2/DTA mice, whose white and brown fat was virtually eliminated by fat-specific expression of diphtheria toxin A chain. aP2/DTA mice had markedly suppressed serum leptin levels and were hyperphagic, but did not gain excess weight. aP2/DTA mice fed a control diet were hyperlipidemic, hyperglycemic, and had hyperinsulinemia indicative of insulin-resistant diabetes. Treatment with troglitazone alleviated the hyperglycemia, normalized the tolerance to intraperitoneally injected glucose, and significantly decreased elevated insulin levels. Troglitazone also markedly decreased the serum levels of cholesterol, triglycerides, and free fatty acids both in wild-type and aP2/DTA mice. The decrease in serum triglycerides in aP2/DTA mice was due to a marked reduction in VLDL- and LDL-associated triglyceride. In skeletal muscle, triglyceride levels were decreased in aP2/DTA mice compared with controls, but glycogen levels were increased. Troglitazone treatment decreased skeletal muscle, but not hepatic triglyceride and increased hepatic and muscle glycogen content in wild-type mice. Troglitazone decreased muscle glycogen content in aP2/DTA mice without affecting muscle triglyceride levels. The levels of peroxisomal proliferator-activated receptor gamma mRNA in liver increased slightly in aP2/DTA mice and were not changed by troglitazone treatment. The results demonstrate that insulin resistance and diabetes can occur in animals without significant adipose deposits. Furthermore, troglitazone can alter glucose and lipid metabolism independent of its effects on adipose tissue.

An AU-rich sequence element (UUUN[A/U]U) downstream of the edited C in apolipoprotein B mRNA is a high-affinity binding site for Apobec-1: binding of Apobec-1 to this motif in the 3' untranslated region of c-myc increases mRNA stability.

Apobec-1, the catalytic subunit of the mammalian apolipoprotein B (apoB) mRNA-editing enzyme, is a cytidine deaminase with RNA binding activity for AU-rich sequences. This RNA binding activity is required for Apobec-1 to mediate C-to-U RNA editing. Filter binding assays, using immobilized Apobec-1, demonstrate saturable binding to a 105-nt apoB RNA with a K(d) of approximately 435 nM. A series of AU-rich templates was used to identify a high-affinity ( approximately 50 nM) binding site of consensus sequence UUUN[A/U]U, with multiple copies of this sequence constituting the high-affinity binding site. In order to determine whether this consensus site could be functionally demonstrated from within an apoB RNA, circular-permutation analysis was performed, revealing one major (UUUGAU) and one minor (UU) site located 3 and 16 nucleotides, respectively, downstream of the edited base. Secondary-structure predictions reveal a stem-loop flanking the edited base with Apobec-1 binding to the consensus site(s) at an open loop. A similar consensus (AUUUA) is present in the 3' untranslated regions of several mRNAs, including that of c-myc, that are known to undergo rapid degradation. In this context, it is presumed that the consensus motif acts as a destabilizing element. As an independent test of the ability of Apobec-1 to bind to this sequence, F442A cells were transfected with Apobec-1 and the half-life of c-myc mRNA was determined following actinomycin D treatment. These studies demonstrated an increase in the half-life of c-myc mRNA from 90 to 240 min in control versus Apobec-1-expressing cells. Apobec-1 expression mutants, in which RNA binding activity is eliminated, failed to alter c-myc mRNA turnover. Taken together, the data establish a consensus binding site for Apobec-1 embedded in proximity to the edited base in apoB RNA. Binding to this site in other target RNAs raises the possibility that Apobec-1 may be involved in other aspects of RNA metabolism, independent of its role as an apoB RNA-specific cytidine deaminase.

Differences in Effectiveness and Use of Robotic Surgery in Patients Undergoing Minimally Invasive Colectomy.

BACKGROUND: We compared patient outcomes of robot-assisted surgery (RAS) and laparoscopic colectomy without robotic assistance for colon cancer or nonmalignant polyps, comparing all patients, obese versus nonobese patients, and male versus female patients. METHODS: We used the 2013-2015 American College of Surgeons National Surgical Quality Improvement Program data to examine a composite outcome score comprised of mortality, readmission, reoperation, wound infection, bleeding transfusion, and prolonged postoperative ileus. We used propensity scores to assess potential heterogeneous treatment effects of RAS by patient obesity and sex. RESULTS: In all, 17.1% of the 10,844 of patients received RAS. Males were slightly more likely to receive RAS. Obese patients were equally likely to receive RAS as nonobese patients. In comparison to nonRAS, RAS was associated with a 3.1% higher adverse composite outcome score. Mortality, reoperations, wound infections, sepsis, pulmonary embolisms, deep vein thrombosis, myocardial infarction, blood transfusions, and average length of hospitalization were similar in both groups. Conversion to open surgery was 10.1% lower in RAS versus nonRAS patients, but RAS patients were in the operating room an average of 52.4 min longer. We found no statistically significant differences (p > 0.05) by obesity status and gender. CONCLUSIONS: Worse patient outcomes and no differential improvement by sex or obesity suggest more cautious adoption of RAS.

K-ras mutations in 1,2-dimethylhydrazine-induced colonic tumors: effects of supplemental dietary calcium and vitamin D deficiency.

Recent studies from our laboratory have demonstrated that dietary supplemental calcium had no significant effect on the incidence of 1,2-dimethylhydrazine-induced colonic tumors, but did decrease the number of rats with multiple tumors and reduced tumor size. Moreover, concomitant vitamin D deficiency appeared to abolish these protective effects of calcium on colonic tumors in this experimental model. To date, however, the mechanism(s) involved in these phenomena remain unclear. In order to address these important issues, 1,2-dimethylhydrazine-induced colonic tumors from animals on control, Ca(2+)-supplemented, vitamin D-sufficient, and Ca(2+)-supplemented, vitamin D-deficient diets were examined for the presence of ras oncogene mutations. DNA was extracted from each of these tumors. Targeted areas of K-ras and H-ras genes were amplified by the polymerase chain reaction and analyzed for point mutations using allele-specific oligonucleotide hybridization and subsequent DNA sequencing. The results of these studies demonstrated that: (a) approximately one-third of 1,2-dimethylhydrazine-induced colonic carcinomas in the control group had K-ras G to A mutations; (b) no mutations, however, were detected in the cancers of the calcium-supplemented group; (c) concomitant vitamin D deficiency abolished the antimutagenic effect of dietary calcium supplementation (e.g., approximately one-third of cancers in this group again had detectable K-ras mutations); and (d) no H-ras point mutations were detected in colonic tumors from any group. These findings suggest that alterations in K-ras mutations may be one possible mechanism by which calcium and vitamin D status influence colonic carcinogenesis in this experimental model.

Decreased PKC-alpha expression increases cellular proliferation, decreases differentiation, and enhances the transformed phenotype of CaCo-2 cells.

Previous studies have shown that PKC-alpha protein expression is decreased in sporadic human colon cancers, as well as in colonic tumors of rats induced by chemical carcinogens. To elucidate the potential role of PKC-alpha on several phenotypic characteristics of colon cancer cells, we have transfected cDNAs for PKC-alpha in sense or antisense orientations into CaCo-2 cells, a human colonic adenocarcinoma cell line. Transfected clones were isolated that demonstrated approximately 3-fold increases (sense transfectants) and approximately 95% decreases (antisense transfectants) in PKC-alpha expression with no significant alterations in other PKC isoforms. Transfection of CaCo-2 cells with PKC-alpha in the antisense orientation resulted in enhanced proliferation and decreased differentiation, as well as in a more aggressive transformed phenotype compared with empty vector-transfected control cells. In contrast, cells transfected with PKC-alpha cDNA in the sense orientation demonstrated decreased proliferation, enhanced differentiation, and an attenuated tumor phenotype compared with these control cells. These data show that alterations in the expression of PKC-alpha induce changes in the proliferation, differentiation, and tumorigenicity of CaCo-2 cells. Furthermore, these findings indicate that loss of PKC-alpha expression in sporadic human and chemically induced colonic cancers may confer a relative growth advantage during colonic malignant transformation.

Isolation, characterization and developmental regulation of the human apobec-1 complementation factor (ACF) gene.

Mammalian apolipoprotein B (apo B) mRNA undergoes site-specific C to U deamination which is mediated by a multicomponent enzyme complex containing a minimal core composed of apobec-1 and a complementation factor, ACF. We have isolated and characterized the human ACF gene and examined its tissue-specific and developmental expression. The ACF gene spans approximately 80 kb and contains 15 exons, three of which are non-coding. Multiple alternative splice acceptor sites were found, generating at least nine different transcripts. Of these, the majority (approximately 75-89%) encode functional protein. In order to examine the role of ACF mRNA expression in the regulation of apo B mRNA editing, we examined a panel of fetal intestinal and hepatic mRNAs as well as RNA from an intestinal cell line. A developmental increase in C to U RNA editing has been previously noted in the human intestine. In both instances, the pattern of alternative splicing and overall abundance of ACF mRNA was relatively constant during development in both liver and small intestine. Taken together, the data demonstrate a complex pattern of differential, tissue-specific splicing of ACF mRNA, but suggest that other mechanisms are responsible for the developmental increase noted in intestinal apo B mRNA editing in humans.

Variations in dietary triacylglycerol saturation alter the lipid composition and fluidity of rat intestinal plasma membranes.

Rats were maintained on nutritionally complete diets enriched in unsaturated (corn oil) or saturated (butter fat) triacylglycerols. After 6 weeks, significant differences in the lipid composition and fluidity of a number of intestinal membranes were observed. The corn oil diet (enriched mainly in linoleic acid) increased the overall unsaturation of the acyl chains and enhanced the lipid fluidity, as assessed by the fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene, of enterocyte microvillus and basolateral membranes and of colonocyte basolateral membranes. Concomitantly, the cholesterol content and the cholesterol/phospholipid molar ratio were increased in the microvillus but not in the basolateral membranes. The increased cholesterol in ileal microvillus membranes can result from enhanced cellular biosynthesis, since ileal slices from rats fed the unsaturated diet incorporated [14C]octanoate more rapidly into digitonin-precipitable sterol. Increased fluidity of the enterocyte microvillus and basolateral membranes, respectively, enhanced the enzyme specific activities of p-nitrophenylphosphatase and (Na+ + K+)-dependent adenosine triphosphatase. The results indicate that the lipid composition, fluidity and enzyme activities of intestinal plasma membranes can be altered by dietary means. Moreover, rat enterocytes possess regulatory mechanisms which modulate the cholesterol content of the microvillus membranes so as to mitigate changes in lipid fluidity.

Magnesium deficiency modulates hepatic lipogenesis and apolipoprotein gene expression in the rat.

The present study was performed to determine the effects of magnesium (Mg) deficiency upon plasma lipoproteins and hepatic apolipoprotein gene expression in the rat. The most obvious effect of Mg-deficiency on plasma lipids is a marked increase in post-prandial triacylglycerol concentration. This increased triglyceridemia persists in fasted rats. Density gradient ultracentrifugation analysis revealed marked alterations in the distribution of plasma lipoproteins in Mg-deficient rats. An increase in triacylglycerol-rich lipoproteins (TGRLP) was associated with a significant increase in plasma apolipoprotein B (apo B) concentration and was accompanied by selective accumulation of apo B-48. A decrease in high-density lipoproteins (HDL) was accompanied by a corresponding decrease in plasma apo E concentration and a concordant decrease in hepatic apo E mRNA abundance and biosynthesis. Hepatic apo B-100 synthesis was reduced by over 75% in Mg-deficient animals despite an increase in hepatic apo B mRNA abundance. However, this change in hepatic apo B gene expression was not associated with alterations in posttranscriptional apo B mRNA editing. These changes in apolipoprotein gene expression were associated with increased hepatic lipogenesis, despite the observation that net triacylglycerol secretion rates were not different between Mg-deficient and control animals. Taken together, the data demonstrate a complex pattern of alterations in hepatic lipid metabolism and apolipoprotein gene expression in the Mg-deficient rat and suggest a defect in the catabolism rather than secretion of TGLRP as the major factor underlying the altered plasma lipoprotein profile.

TPA causes divergent responses of Ca(2+)-dependent and Ca(2+)-independent isoforms of PKC in the nuclei of Caco-2 cells.

The present studies were undertaken to examine the expression of PKC isoforms within the nucleus of Caco-2 cells, a cell line widely used to investigate intestinal cell growth and differentiation, in order to begin to explore their roles in modulating gene expression. Purified nuclei were, therefore, prepared from Caco-2 cells and found to contain PKC-zeta, but not -alpha. The phorbol ester, 12-O-tetradecanoyl phorbol 13-acetate (TPA) caused an acute redistribution of PKC-alpha to the nucleus, but did not change the distribution of PKC-zeta. Chronic treatment with TPA down-regulated total PKC-alpha, but not -zeta. Moreover, in contrast to acute TPA treatment, after chronic treatment, nuclear PKC-alpha was no longer detectable, whereas nuclear PKC-zeta was unchanged. These studies demonstrate for the first time the constitutive expression and divergent responses to TPA of the Ca(2+)-dependent and Ca(2+)-independent isoforms of PKC in the nuclei of Caco-2 cells and suggest that these specific isoforms may be involved in modulating gene expression.

Apo(a) promotes thrombosis in a vascular injury model by a mechanism independent of plasminogen.

OBJECTIVE: Structural similarity between apolipoprotein(a) [apo(a)], the unique apoprotein of lipoprotein(a), and plasminogen (Plg), the zymogen for plasmin, results in inhibition of functions of Plg by apo(a) in vitro. The objective of this study was to evaluate the interaction of Plg and apo(a) in vivo. METHODS AND RESULTS: Vascular injury was induced in the carotid artery with a perivascular cuff in: (i) wild-type (WT); (ii) Plg deficient (Plg-/-); (iii) apo(a) (6 KIV construct) transgenic [apo(a)tg]; and (iv) apo(a) transgenic and Plg deficient [apo(a):Plg-/-] mice. At 10 days after cuff placement, the media and adventitia area were increased in the injured carotids compared with the uninjured carotids, and collagen deposition was greater in apo(a)tg, Plg-/- and apo(a):Plg-/- mice compared with WT mice. The incidence of a thrombus was greater (P < 0.05) in apo(a):Plg-/- mice (83%) than WT (20%), Plg-/- (12%), and apo(a)tg mice (9%). In the thrombi from apo(a)tg and apo(a):Plg-/- mice, P-selectin and von Willebrand factor immunostaining, indicating a platelet-rich thrombi, was greater than in WT and Plg-/- mice. The presence of fibrin(ogen) in the thrombi was greater in Plg-/- and apo(a):Plg-/- mice than apo(a)tg and WT mice. Of the four genotypes, only the apo(a):Plg-/- mice had both increased platelet and increased fibrin(ogen) deposition. CONCLUSIONS: The major finding of this study is the high incidence of thrombosis after vascular injury in apo(a)transgenic mice in a Plg deficient background, providing strong evidence for a prothrombotic role of apo(a) independent of Plg in vivo.

Apolipoprotein B mRNA editing is modulated by thyroid hormone analogs but not growth hormone administration in the rat.

Recent work has demonstrated that the unique post-transcriptional editing reaction which modifies mammalian apolipoprotein (apo) B100 mRNA, producing an in-frame stop codon in the modified (apo B48) transcript, is modulated in vivo in the rat liver by thyroid hormone (T3). We now report the results of studies undertaken to examine the effects of two synthetic T3 analogs and GH on apo B gene expression together with their effects on hepatic apo A-I, A-IV, C-III, and malic enzyme (ME)mRNAs. The T3 analogs were previously shown to exhibit similar binding to the hepatic nuclear T3 receptor (50% and 38% of native T3) but differing biopotency (18 and less than 3% of native T3). Apo B100 mRNA editing, determined by differential hybridization of polymerase chain reaction amplified apo B cDNA, demonstrated 50-56% unmodified (apo B100) mRNA in control and hypothyroid animals and this proportion was unaltered by GH (61% B100 mRNA), despite a reduction in apo B100 synthesis. Both T3 analogs altered apo B mRNA editing (12-16% B100 mRNA) and no apo B100 synthesis was detectable in vivo. Additionally, both T3 analogs produced a 4- to 10-fold induction in hepatic apo A-I and A-IV mRNA abundance, similar to the effects of native T3. GH produced no alteration in apo A-I or A-IV mRNA abundance and neither T3 analog, GH, or native T3 produced a change in apo C III mRNA abundance.(ABSTRACT TRUNCATED AT 250 WORDS)