[Show abstract][Hide abstract] ABSTRACT: Background:Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Improvements in the understanding of its molecular mechanism and the characterisation of CRC-specific biomarkers facilitating early detection are considered to increase overall survival.Methods:A meta-analysis of microarray and Serial Analysis of Gene Expression (SAGE) has been performed to identify differentially regulated genes in CRC. Dipeptidase 1 (DPEP1/MDP/RDP) and Syntenin-2 (SDCBP2/SITAC18) were found to be differentially expressed in tumour tissue compared with normal mucosa. Expression of DPEP1 was assessed in a validation set of 87 normal mucosa samples, 20 hyperplastic polyps, 46 CR adenomas with low- and high-grade intraepithelial neoplasia (IEN) and 217 well-documented CRCs by immunohistochemistry and partially by immunoblotting and real-time PCR.Results:Expression of DPEP1 was specifically increased in human CRC tissue samples compared with normal mucosa (P<0.0001, Mann-Whitney U-test), showing a striking upregulation in high-grade compared with low-grade IEN. Furthermore, high DPEP1 expression was found to strongly correlate with histological stage (P<0.0001, chi-square test) as well as localisation (P<0.0001, chi-square test) and has been recognised as an independent adverse prognostic factor, showing significant prognostic values with an ROC (receiver operating characteristic)-AUC of 0.9230.Conclusion:Dipeptidase 1 has been identified as an excellent marker of high-grade IEN and CRC, and may thus be applied for screening of early neoplastic lesions and for prognostic stratification.British Journal of Cancer advance online publication, 9 July 2013; doi:10.1038/bjc.2013.363 www.bjcancer.com.
British Journal of Cancer 07/2013; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND & AIMS: The sterolin locus (ABCG5/ABCG8) has been solidly shown to confer susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. METHODS: Genetic mapping utilized patient samples from Germany (2808 cases, 2089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls) and China (280 cases, 244 controls). Analysis of allelic imbalance in cDNA samples from human liver (N=22) was performed using pyrosequencing. Transiently transfected HEK293 cells were used for [3H]-cholesterol export assays, analysis of protein expression and localisation of allelic constructs. RESULTS: Through fine mapping in German and Chilean samples, a ∼250kB disease-associated interval could be defined for this locus. Lack of allelic imbalance or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the search to coding SNPs. Subsequent mutation detection and genotyping yielded two disease-associated variants ABCG5-R50C (p=4.94×10(-9) ) and ABCG8-D19H (p=1.74×10(-10) ) in high pair-wise LD (r(2) =0.95). [3H]-cholesterol export assays of allelic constructs harbouring these genetic candidate variants demonstrated increased transport activity (3.2-fold, p=0.003) only for the ABCG8-19H variant, which was also superior in nested logistic regression models in German (p=0.018), Chilean (p=0.030) and Chinese (p=0.040) patient samples. CONCLUSION: This variant thus provides a molecular basis for biliary cholesterol hypersecretion as the mechanism for cholesterol gallstone formation thereby drawing a link between "post-genomic" and "pre-genomic" pathophysiological knowledge about this common complex disorder. (HEPATOLOGY 2012.).
[Show abstract][Hide abstract] ABSTRACT: PurposeEvaluation of the feasibility, cost-effectiveness, time of surgery, morbidities, and other/additional findings during laparoscopy
for suspected appendicitis.
MethodsProspective evaluation of 148 laparoscopies for suspected acute appendicitis.
ResultsLaparoscopic appendectomy was safe and cost-effective. No appendiceal stump leaks or wound infections occurred. Of the patients,
4.7% developed intra-abdominal abscesses. Mean time of all procedures was 47min: 42min for simple appendectomies (n = 126), 67min for perforated appendicitis (n = 15), and 75min for converted procedures (n = 7). Twenty-one of 148 (14.2%) patients had unexpected findings instead of appendicitis: inflamed epiploic appendices (three
times), inflammatory disorders of intestine (five times), intestinal adhesions (two times), ovarian cysts (six times: one
time with mesenteric lymphadenitis, one time ruptured), tubo-ovarian abscess (one time), tubal necrosis (one time), adnexitis
with mesenteric lymphadenitis (one time), and acute cholecystitis (one time). These diagnoses might have been missed during
conventional open appendectomy and were, if necessary, treated during laparoscopy.
ConclusionsLaparoscopic appendectomy should be recommended as standard procedure for acute appendicitis.
KeywordsLaparoscopic appendectomy-Acute suspected appendicitis-Laparoscopic findings-Cost-effectiveness
Langenbeck s Archives of Surgery 11/2010; 395(8):1069-1076. · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The surgical treatment for cholangiocarcinoma (CCC) is still a challenge. The aim of this study was to evaluate the POSSUM scoring system for preoperative physiological risk adjustment and for the operative risk of postoperative morbidity and mortality.
The operative notes and hospital files of 171 patients with CCC were analyzed retrospectively. The POSSUM scoring system was used to predict morbidity and mortality rates after surgery. The physiological sub score and the operative sub score of the POSSUM score were analyzed with regard to their ability to predict major postoperative complications.
The overall complication rate was 40.9% and the mortality was 11.2%. The morbidity predicted by POSSUM was 63.5% and the prediction for postoperative mortality was 23.7%. Both rates are much higher than the observed morbidity and mortality. High operative severity sub scores correlate with the occurrence of major complications.
The POSSUM scoring system over predicts morbidity and mortality in surgery for CCC. Operative severity and intraoperative parameters have a greater influence on postoperative mortality and morbidity rates than the physiological parameters represented in the POSSUM physiological score. Prospective studies will have to show whether POSSUM can be modified or whether it is necessary to develop a new score for assessing morbidity and mortality in surgery for CCC.
[Show abstract][Hide abstract] ABSTRACT: It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.
British Journal of Cancer 11/2009; 102(2):447-54. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An elevated proteasome activity contributes to tumorigenesis, particularly by providing cancer cells with antiapoptotic protection and efficient clearance from irregular proteins. Still, the underlying mechanisms are poorly known. In this study, we report that in colon cancer patients, higher proteasome activity was detected in tumoral tissue compared with surrounding normal tissue, and also that increased levels of proteasomal subunit proteins, such as S5a/PSMD4 and alpha-5/PSMA5, could be detected. Colon tumors showed higher nuclear levels of nuclear factor E2-related factor 2 (Nrf2), a transcription factor supposed to be involved in the control of proteasomal subunit protein expression. The induction or overexpression of Nrf2 led to stronger S5a and alpha-5 expression in the human colon cancer cell lines, Colo320 and Lovo, as well as in NCM460 colonocytes along with higher proteasome activity. The small interfering RNA (siRNA)-mediated Nrf2 knockdown decreased S5a and alpha-5 expression and reduced proteasome activity. Additionally, Nrf2-dependent S5a and alpha-5 expression conferred protection from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, an effect preceded by an increased nuclear factor (NF)-kappaB activation and higher expression of antiapoptotic NF-kappaB target genes. These findings point to an important role of Nrf2 in the gain of proteasome activity, thereby contributing to colorectal carcinogenesis. Nrf2 may therefore serve as a potential target in anticancer therapy.
[Show abstract][Hide abstract] ABSTRACT: Variation in genes involved in the innate immune response may play a role in the predisposition to colorectal cancer (CRC). Several polymorphisms of the CARD15 gene (caspase activating recruitment domain, member 15) have been reported to be associated with an increased susceptibility to Crohn disease. Since the CARD15 gene product and other CARD proteins function in innate immunity, we investigated the impact of germline variation at the CARD4, CARD8 and CARD15 loci on the risk for sporadic CRC, using a large patient sample from Northern Germany.
A total of 1044 patients who had been operated with sporadic colorectal carcinoma (median age at diagnosis: 59 years) were recruited and compared to 724 sex-matched, population-based control individuals (median age: 68 years). Genetic investigation was carried out following both a coding SNP and haplotype tagging approach. Subgroup analyses for N = 143 patients with early manifestation of CRC (<or=50 age at diagnosis) were performed for all CARD loci and subgroup analyses for diverse age strata were carried out for CARD15 mutations R702W, G908R and L1007fs. In addition, all SNPs were tested for association with disease presentation and family history of CRC.
No significant differences were observed between the patient and control allelic or haplotypic spectra of the three genes under study for the total cohort (N = 1044 patients). None of the analysed SNPs was significantly associated with either tumour location or yielded significant association in the familial or non-familial CRC patient subgroups. However, in a patient subgroup (<or=45 age at diagnosis) with early disease manifestation the mutant allele of CARD15 R702W was found to be significantly associated with disease susceptibility (9.7% in cases vs 4.6% in controls; P(allelic) = 0.008, P(genotypic) = 0.0008, OR(allelic) = 2.22 (1.21-4.05) OR(ressessive) = 21.9 (1.96-245.4).
Variation in the innate immunity genes CARD4, CARD8 and CARD15 is unlikely to play a major role in the susceptibility to CRC in the German population. But, we report a significant disease contribution of CARD15 for CRC patients with very early disease manifestation, mainly driven by variant R702W.
[Show abstract][Hide abstract] ABSTRACT: Human chromosome 8q24.21 has been implicated as a susceptibility region for colorectal cancer (CRC) as a result of genome-wide association and candidate gene studies. To assess the impact of molecular variants at 8q24.21 upon the CRC risk of German individuals and to refine the disease-associated region, a total of 2,713 patients with operated CRC (median age at diagnosis: 63 years) were compared with 2,718 sex-matched control individuals (median age at inclusion: 65 years). Information on microsatellite instability in tumors was available for 901 patients. Association analysis of SNPs rs10505477 and rs6983267 yielded allelic p-values of 1.42 x 10(-7) and 2.57 x 10(-7), respectively. For both polymorphisms, the odds ratio was estimated to be 1.50 (95% CI: 1.29-1.75) under a recessive disease model. The strongest candidate interval, outside of which significance dropped by more than 4 orders of magnitude, was delineated by SNPs rs10505477 and rs7014346 and comprised 17 kb. In a subgroup analysis, the disease association was found to be more pronounced in MSI-stable tumors (odds ratio: 1.71). Our study confirms the role of genetic variation at 8q24.21 as a risk factor for CRC and localizes the corresponding susceptibility gene to a 17 kb candidate region.
International Journal of Cancer 11/2008; 124(1):75-80. · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The best treatment option for liver metastases is complete surgical resection. Unfortunately, at the time of diagnosis, not all patients are candidates for complete resection. Electrolytic therapy (ECT) is a novel non-thermal method of tissue destruction. We evaluated its safety and effectiveness in comparison with radiofrequency ablation (RFA).
Tumor mimics were created by injecting a gel into the pig liver. The volume of the lesions was measured by ultrasound before treatment. The tumor mimics were treated with either RFA or electrolytic ablation. 48 h after treatment the liver was fixed in formalin and subjected to histological examination.
Histological investigation confirmed that all lesions were completely surrounded by necrosis after treatment with either ECT or RFA. Two different types of necrosis were identified. After RFA the cell membranes disappeared but the nuclei were still intact, whereas after ECT these structures were completely disrupted. After ECT the necrosis was often surrounded by infiltrating lymphocytes. This inflammatory reaction was not apparent after RFA.
ECT produced predictable and reproducible necrosis in pig livers and was as effective as RFA at destroying a defined target lesion. A local inflammatory reaction after ECT may favour the development of a systemic immune response. Our results indicate that ECT is an alternative treatment option for irresectable liver metastases.
Journal of Surgical Oncology 08/2008; 98(2):135-8. · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.
[Show abstract][Hide abstract] ABSTRACT: Glucocorticoids are among the most potent anti-inflammatory agents that act by inhibiting the synthesis of almost all known cytokines and influencing multiple transduction pathways. Inflammation accompanies most solid cancers including pancreatic ductal adenocarcinoma (PDAC), one of the most fatal cancers with surgery being the only potential curative therapeutic. In the present work we investigated the influence of glucocorticoids on PDAC cells in vitro as well as in vivo in a pancreatic carcinoma resection mouse model.
The influence of dexamethasone (DEX), a synthetic glucocorticoid, on proliferation and IL8 secretion in pancreatic cells (BxPC3, Colo357, PancTuI) was analyzed by cell counting and ELISA. NFkappaB-activity of PancTuI cells treated with DEX was determined by electrophoretic mobility shift assay (EMSA). Furthermore, effects of DEX on the invasiveness were studied by a fibroblast-based invasion assay. In the mouse resection model subtotal pancreatectomy was performed after orthotopic inoculation of human PDAC cells. DEX was administered after resection as an adjuvant treatment regime and 4 weeks later, local recurrent tumor sizes as well as number of liver and spleen metastases were analyzed.
In vitro, DEX did not have an anti-proliferative effect on PDAC cells, but strongly reduced the invasiveness well as the activation of NFkappaB. The secretion of IL-8 into the supernatant of the tumor cells correlated inversely with the reduced activation of NFkappaB. In vivo, we observed a significant reduction of the local recurrent tumor volume and the number of liver and spleen metastases.
DEX has a profound influence on the malignant phenotype of PDAC tumor cells in vitro in terms of inhibition of invasiveness and pro-inflammatory signaling. This was approved in vivo by reduced metastasizing capacity and reduced size of local tumor recurrence. Therefore, DEX-treatment appears to be an interesting therapeutical option in an adjuvant setting after pancreatic cancer resection.
Cancer biology & therapy 05/2008; 7(7):1044-50. · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic inflammation has been implicated in the pathogenesis of many severe autoimmune disorders, as well as in diabetes, pulmonary diseases, and cancer. Inflammation accompanies most solid cancers including pancreatic ductal adenocarcinoma (PDAC), one of the most fatal cancers with surgery being the only curative therapeutic approach currently available. In the present work, we investigated the role of the major proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) in the malignancy of PDAC cells in vitro and in vivo. In vitro, TNFalpha strongly increased invasiveness of Colo357, BxPc3, and PancTuI cells and showed only moderate antiproliferative effect. TNFalpha treatment of mice bearing orthotopically growing PDAC tumors led to dramatically enhanced tumor growth and metastasis. Notably, we found that PDAC cells themselves secrete TNFalpha. Although inhibition of TNFalpha with infliximab or etanercept only marginally affected proliferation and invasiveness of PDAC cells in vitro, both reagents exerted strong antitumoral effects in vivo. In severe combined immunodeficient mice with orthotopically growing Colo357, BxPc3, or PancTuI tumors, human-specific anti-TNF antibody infliximab reduced tumor growth and metastasis by about 30% and 50%, respectively. Importantly, in a PDAC resection model performed with PancTuI cells, we found an even stronger therapeutic effect for both anti-TNF compounds. Infliximab and etanercept reduced the number of liver metastases by 69% and 42%, respectively, as well as volumes of recurrent tumors by 73% and 51%. Thus, tumor cell-derived TNFalpha plays a profound role in malignancy of PDAC, and inhibition of TNFalpha represents a promising therapeutic option particularly in adjuvant therapy after subtotal pancreatectomy.
Cancer Research 04/2008; 68(5):1443-50. · 8.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For patients undergoing oncologic surgery, the quality of life (QoL) is generally accepted as an important outcome parameter in addition to long-term survival, mortality, and complication rates. Our study focused on outcome in terms of QoL in patients with esophageal cancer, comparing the sites of anastomosis (cervical versus thoracic anastomosis).
In a prospective longitudinal single-center study from 1998 to 2005, 105 patients underwent surgery for esophageal cancer. To assess QoL the EORTC-QLQ-C-30 and a tumor-specific module were administered before surgery, at discharge, and three, six, 12, and 24 months after surgery. Clinical data were collected prospectively and follow-up was performed every six months.
The histological type was squamous cell carcinoma in 51.4% of the cases, adenocarcinoma in 41.9%, and some other type in 6.7%. There was no significant difference between cervical and thoracic anastomosis with regard to morbidity, mortality, and survival rates (30% five-year survival rate), whereas tumor stage was a significant (p < 0.001) prognostic factor. Most QoL scores dropped significantly below baseline in the early postoperative period. Even though they recovered slowly during the follow-up period, they never reached preoperative levels again. There was no statistically significant difference in any of the QoL scales between patients with a cervical or a thoracic anastomosis.
Esophageal resections are associated with significant deterioration of QoL, which persists during the follow-up period. The surgical technique and position of the esophagogastrostomy did not affect QoL deterioration.
Annals of Surgical Oncology 02/2008; 15(2):566-75. · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intensive efforts are being made to develop new approaches for adjuvant or neoadjuvant treatment in pancreas carcinoma. Recently, we established an animal model simulating an adjuvant therapeutic treatment setting. In order to additionally mimic a neoadjuvant treatment regime, we further developed the preclinical testing system.
Subtotal pancreatectomy was performed in mice after orthotopic inoculation of human pancreatic cancer cells (PancTu1). Four different settings were investigated: control without chemotherapy, adjuvant, neoadjuvant and extended neoadjuvant treatment protocols employing gemcitabine. All animals were autopsied 28 days after tumor resection.
28 of 32 animals survived the treatment setting. The largest pancreatic tumor masses were seen in animals without any chemotherapy, and the different chemotherapy protocols resulted in a stepwise reduction of the tumor mass. The mean weight of locally recurrent tumors was 553.1 +/- 133.2 mg (control) and 44 +/- 21.8 mg (adjuvant treatment group). Animals in the neoadjuvant treatment group developed larger tumor masses (215 +/- 191.3 mg) but fewer organ metastases. An extended neoadjuvant treatment setting proved to be most effective, resulting in the smallest tumor masses (25.6 +/- 8.8 mg) and the fewest organ metastases.
Murine orthotopic tumor resection is an excellent simulation of the clinical situation and therefore provides a relevant option for preclinical comparative testing of new therapeutic strategies. To our knowledge, this is the first model described, in which all different therapeutic regimes for pancreatic carcinoma were systematically compared with each other in a standardized manner. The extended neoadjuvant regime proved to be superior.
Cancer biology & therapy 09/2007; 6(8):1227-32. · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetic susceptibility contributes to the aetiology of gallbladder diseases as shown by multiple epidemiological studies. A major gallstone susceptibility locus (Lith6) was identified in 2003 by quantitative trait locus mapping in mice. Two attractive positional and functional candidate genes in apolipoprotein B mRNA-editing protein (APOBEC1) and peroxisome proliferator-activated receptor gamma (PPARG) are located in this interval.
To investigate APOBEC1 and PPARG as candidate genes for common symptomatic gallstone disease in humans.
Eight hundred and ten patients who underwent cholecystectomy for symptomatic gallstone disease (median age of onset 50) were compared with 718 sex-matched control individuals. An independent additional sample included 368 gallstone patients and 368 controls. Control individuals were sonographically free of gallstones. Haplotype tagging and all known coding single nucleotide polymorphisms were genotyped for PPARG (N=32) and APOBEC1 (N=11).
The investigated high-risk patient sample provides a power of greater than 80% for the detection of odds ratios down to 1.45. No evidence of association of the two genes in the single-point tagging markers, coding variants and in the sliding window haplotype analysis was detected (all nominal single point P-values >0.04). A logistic regression analysis including age, sex and BMI as covariates was also negative (nominal P-values > or =0.08).
In the investigated German samples, no evidence of association of APOBEC1 and PPARG with gallstone susceptibility was detected. Systematic fine mapping of the complete Lith6 region is required to identify the causative genetic variants for gallstone in mice and humans.
Liver international: official journal of the International Association for the Study of the Liver 09/2007; 27(7):910-9. · 3.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations in DNA repair genes have previously been identified as causative factors for hereditary nonpolyposis colon cancer (HNPCC). Recent evidence also supports an association between DNA sequence variation in these genes and sporadic colorectal carcinoma (CRC). Genetic investigation of DNA repair genes PMS2, MLH1, MSH2, MSH6, MUTYH, OGG1 and MTH1, as possible susceptibility factors for sporadic CRC, was done using both a haplotype tagging and a candidate (i.e. coding) single nucleotide polymorphism (SNP) approach. Some 1,068 patients with operated CRC (median age at diagnosis: 59 years) were compared to 738 sex-matched control individuals (median age: 67 years). Haplotype tagging SNPs, previously reported risk variants and all known coding SNPs with a minor allele frequency >0.005 were genotyped in PMS2 (N = 10), MLH1 (N = 11), MSH2 (N = 18), MSH6 (N = 15), MUTYH (N = 7), OGG1 (N = 11) and MTH1 (N = 3). No evidence for an association between CRC and any of the 7 genes was detected, neither with the tagging or coding SNPs nor in a sliding window haplotype analysis (all nominal p-values >0.05). The previously reported risk variants D132H in MLH1 and R154H in OGG1 were not even observed in the German population. Genetic CRC risk factors so far identified in DNA repair genes seem to be rare and population-specific. Their association with the disease could not be replicated in German CRC samples. It remains to be elucidated by more systematic, large-scale experiments whether common variants in the same genes, but present across populations, represent risk factors for sporadic CRC.
International Journal of Cancer 08/2007; 121(3):555-8. · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With an overall prevalence of 10-20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries. We performed an association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value P(CCA) = 4.1 x 10(-9)), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 x 10(-7)) and 167 Chilean subjects (P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8-2.6, P = 1.4 x 10(-14)) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.