4 Synchronous liver metastases represent 15–25% of all liver metastases from CRC.5–7 The optimal timing of liver surgery for resectable synchronous CLM remains controversial.8 The classical approach is first to resect the primary colorectal tumor followed by liver resection 2–3 months later. In theory, this staged approach allows selection of a biologically favorable group for liver metastases.9 However, recent advances in surgical technique

and anesthesiology of liver resection has prompted some surgeons to resect simultaneously colorectal lesions and liver metastases with a low perioperative morbidity rate, mortality rate of 0–24% and save the patients a second laparotomy.8,10,11 In addition, recent studies have demonstrated the feasibility of synchronous hepatic and colorectal resection with good short-term results.8,10,12–16 Anti-infection Compound Library high throughput The paradigm for the surgical management of synchronous CLM (SCLM) appears to change.10,12,15,16 However, the consensus has not been reached as to the safety and efficacy of simultaneous liver resection compared to staged hepatectomy. We therefore conducted this meta-analysis of published studies to compare the morbidity, mortality, intraoperative blood loss, overall survival (OS), disease-free survival (DFS), length of Tamoxifen in vivo hospital stay in days and

tumor recurrence at follow up of patients who underwent synchronous resection and staged resection and to assess the safety and efficacy of simultaneous resection in the management of SCLM. TO IDENTIFY ALL relevant studies that compared outcomes following simultaneous resection and staged resection for SCLM, electronic searches

were performed of the PubMed, Embase, Ovid and Medline 上海皓元医药股份有限公司 databases from January 1990 to December 2010. The following terms were used: “synchronous”, “colorectal cancer”, “liver metastases”, “simultaneous resection”, “concurrent resection”, “staged resection” and “delayed resection”. Reference lists of all retrieved articles were manually searched for additional studies. No language restrictions were made. The inclusion criteria for study in the meta-analysis were as follows: (i) clearly document indications for simultaneous resection and staged resection for patients with SCLM; (ii) compare outcomes of patients receiving simultaneous resection of liver metastases and the primary colorectal tumor with those of patients receiving staged liver resection for SCLM; (iii) report on at least one of these outcomes: overall survival rate at 1, 3 and 5 years, disease-free survival rate at 1, 3 and 5 years, length of hospital stay, postoperative recurrence, morbidity, mortality and intraoperative blood loss; and (iv) in dual studies reported by the same institution and/or authors, either the one of highest quality or the most recent publication was included in the analysis.

4 Synchronous liver metastases represent 15–25% of all liver metastases from CRC.5–7 The optimal timing of liver surgery for resectable synchronous CLM remains controversial.8 The classical approach is first to resect the primary colorectal tumor followed by liver resection 2–3 months later. In theory, this staged approach allows selection of a biologically favorable group for liver metastases.9 However, recent advances in surgical technique

and anesthesiology of liver resection has prompted some surgeons to resect simultaneously colorectal lesions and liver metastases with a low perioperative morbidity rate, mortality rate of 0–24% and save the patients a second laparotomy.8,10,11 In addition, recent studies have demonstrated the feasibility of synchronous hepatic and colorectal resection with good short-term results.8,10,12–16 Sirolimus concentration The paradigm for the surgical management of synchronous CLM (SCLM) appears to change.10,12,15,16 However, the consensus has not been reached as to the safety and efficacy of simultaneous liver resection compared to staged hepatectomy. We therefore conducted this meta-analysis of published studies to compare the morbidity, mortality, intraoperative blood loss, overall survival (OS), disease-free survival (DFS), length of check details hospital stay in days and

tumor recurrence at follow up of patients who underwent synchronous resection and staged resection and to assess the safety and efficacy of simultaneous resection in the management of SCLM. TO IDENTIFY ALL relevant studies that compared outcomes following simultaneous resection and staged resection for SCLM, electronic searches

were performed of the PubMed, Embase, Ovid and Medline medchemexpress databases from January 1990 to December 2010. The following terms were used: “synchronous”, “colorectal cancer”, “liver metastases”, “simultaneous resection”, “concurrent resection”, “staged resection” and “delayed resection”. Reference lists of all retrieved articles were manually searched for additional studies. No language restrictions were made. The inclusion criteria for study in the meta-analysis were as follows: (i) clearly document indications for simultaneous resection and staged resection for patients with SCLM; (ii) compare outcomes of patients receiving simultaneous resection of liver metastases and the primary colorectal tumor with those of patients receiving staged liver resection for SCLM; (iii) report on at least one of these outcomes: overall survival rate at 1, 3 and 5 years, disease-free survival rate at 1, 3 and 5 years, length of hospital stay, postoperative recurrence, morbidity, mortality and intraoperative blood loss; and (iv) in dual studies reported by the same institution and/or authors, either the one of highest quality or the most recent publication was included in the analysis.

pylori is most common in impoverished areas with overcrowding and poor sanitation. Transmission occurs during childhood through an oral–oral or a fecal–oral route. Dattoli et al. [20]. demonstrated this very well in their study on risk factors, and Cervantes et al. [44], for example, identified early childhood with transmission between siblings as an important mode of transmission of infection. Public health measures

should be targeted to alleviate poor living conditions which will in turn result in decreased transmission and reduction of the reservoir of infection. There is conflicting data on the association of H. pylori infection with anemia. Some studies did not find any associations [22,24] while others did [10,63]. The association between H. pylori infection and anemia selleck chemicals was addressed in recent review articles [64,65]. H. pylori infection has been reported to negatively impact child growth in one study [23], but overall click here data continue to show a lack of such association as pointed out in a review article [66]. Nevertheless, this is of great concern particularly in high prevalence areas as it may impact significantly on the well-being of a community or population. There were two articles that looked at the outcome of H. pylori eradication and the development of gastric cancer, which is the most

serious outcome of H. pylori infection. Kosunen et al. [67] in a large longitudinal cohort follow-up study for 10 years noted a marked decline in gastric cancer incidence following H. pylori

eradication. In a second study from Japan, Take et al. [68] in another cohort follow-up study showed that gastric cancer developed at a rate of 0.30% per year even after H. pylori eradication. This indicates as we have known before that once pre-malignant changes have already developed, a “point of no-return” is reached. medchemexpress In Japan, annual screening gastroscopy for gastric cancer has been implemented for a long time. Mizuno et al. [69] published an important paper which showed that pre-screening high-risk individuals in the population with serum pepsinogen and H. pylori serology can identify those with high risk of developing gastric cancer who can then undergo gastroscopy. In this population-based cohort study, participants were followed up for a total of 9 years and the incident cases of gastric cancer were recorded. Those with H. pylori and atrophy had an 11-fold increased risk of developing gastric cancer, but the highest risk was with those with absent H. pylori but presence of atrophic gastritis indicating a group with longstanding severe gastritis from which H. pylori disappeared. Several review papers addressed the issue of prevention and elimination of gastric cancer in Japan. Asaka et al. [70] in a review paper on “strategies on eliminating gastric cancer” proposed gastric cancer screening by simultaneous measurement of serum pepsinogen and H. pylori antibody as described earlier by Mizuno et al., combined with eradication of H.

Disclosures: Fenglei Huang – Employment: Boehringer Ingelheim Pharmaceuticals, Inc Viktoria Moschetti – Employment: Boehringer Ingelheim Pharma GmbH&Co. KG Benjamin Lang – Employment: Boehringer Ingelheim Pharma GmbH & Co. KG Marc Petersen-Sylla – Employment: CRS-Kiel Mabrouk Elgadi – Employment: Boehringer Ingelheim The following people have nothing to disclose: Atef Halabi, Chan-Loi Yong Ledipasvir (LDV), a potent HCV NS5A inhibitor, is in Phase 3 clinical development for the treatment of chronic HCV infection as a fixed-dose combination tablet with sofosbuvir. LDV is primarily

eliminated in the feces as an unchanged parent drug (∼ 70% of the dose); ∼1 % of the LDV dose is excreted in the urine as metabolites. Since many HCV-infected DNA Damage inhibitor patients may develop impaired hepatic function during the natural history of the disease, this study evaluated the short-term safety and pharmacokinetics (PK) of LDV in subjects with moderate or severe hepatic impairment (HI) versus control subjects with normal hepatic function (NF) to inform dosing recommendations for LDV in this population. Methods Subjects with stable moderate hepatic impairment (N=10) Child-Pugh-Turcotte Selleck GDC-0980 (CPT) Classification B (score 7- 9) and healthy control subjects with normal hepatic

function, matched for age (±10 years), gender, and BMI (±15%) received LDV 30 mg+GS-9451 200 mg daily (N=10) for 12 days each with food. Subjects with stable severe HI (N = 10) CPT C (score 10-15) and matched controls received a single dose (SD) of LDV 90 mg with food. All treatments were followed by intensive pharmacokinetic (PK) sampling. Safety assessments were performed throughout the study. Geometric mean ratios (GMRs: HI:NF) and 90% confidence intervals (CIs) for LDV AUC (tau/inf), Cmax and Ctau (moderate HI only) were calculated using ANOVA model medchemexpress with an exposure increase of at least 100% being considered as clinically relevant. Results All enrolled subjects (N=10/group) completed the study; no subject discontinued due to an adverse event (AE).

One moderate HI subject was excluded from analysis due to a major protocol deviation (disallowed medication). All treatment-emergent AEs were Grade 1 (mild), except for one Grade 2 (moderate) AE (headache: severe HI subject). LDV plasma exposures were similar in subjects with moderate HI and controls; LDV Cmax was modestly lower but AUC remained comparable in subjects with severe HI and normal hepatic function. Conclusions: LDV administration was safe and well tolerated. No clinically relevant changes in overall LDV plasma exposures were observed in subjects with moderate or severe hepatic impairment relative to subjects with normal hepatic function. LDV dose adjustment is therefore not required in patients with chronic HCV infection with mild, moderate or severe hepatic impairment.

” This conference clearly was a step forward towards clarifying the nosology of pediatric hepatobiliary diseases and determining directions in research. In 1978 I received an offer from Bill Schubert to return Selleckchem OTX015 to Cincinnati. We were clearly ready to investigate the immature liver and its diseases, specifically neonatal cholestasis. Schubert offered an environment to carry out these studies and the resources, including

a dedicated mass spectrometer facility. CCHMC had established programs for specialized care of complex patients such as neonates and patients with cardiac disease. In addition, CCHMC had a long history of successful experience as a center for renal and bone MK0683 cell line marrow transplantation. In light of the growing number of children with chronic liver disease in the primary and secondary service areas of CCHMC and the national reputation of the institution in patient care and research, our plan was to establish a formalized Pediatric Liver Care Center (PLCC). The goal of the PLCC was to focus on the evaluation and comprehensive care of patients with liver disease, including medical, surgical,

social service, and institutional support, including transplantation where required. This would be combined with basic and clinical research into the physiologic, biochemical, and immunologic aspects of disease. We hoped to create a network/support group of parents of children with liver disease and we envisioned a training program for clinical and research fellows. The concept of the center, the first of its kind in the United States, was unique because it integrated novel and existing aspects of liver patient care and treatment with intensive ongoing research and education regarding pediatric liver disease. A significant force driving the nascent field of Pediatric Hepatology was the utilization of clinical and research procedures and techniques to investigate the child with presumed

liver disease. An important step was the development of a safe and reliable method to “sample” tissue for examination and analysis; this greatly aided the deciphering of the many potential causes of neonatal liver injury. The percutaneous liver biopsy technique had been developed by Bill Schubert, who with MCE Dick Hong showed the technique to be safe in infants and children. They clearly demonstrated that a diagnosis could be established by assessment of tissue biopsy specimens by light and electron microscopy.[40] In addition, liver tissue samples of adequate size could be obtained to allow biochemical dissection and enzyme analysis, which led to investigation into aspects of disordered hepatic physiology and to a better understanding of metabolic liver disease. “Unique” pediatric liver diseases were therefore uncovered, such as alpha-1-antitrypsin deficiency as a cause of “familial neonatal hepatitis.

Patients with cirrhosis achieved SVR12 of 73% (24w). The adjusted SVR12 rate for 24w in patients with or without cirrhosis was significantly higher than the historical control. Summary of efficacy (FDV+DBV+RBV; ITT) C, patients with cirrhosis. Disclosures: Christoph Sarrazin – Advisory Committees or Review Panels: Boehringer Ingelheim, Vertex, Janssen, Merck/MSD, Gilead, Roche, Boehringer Ingelheim, Achillion, Janssen, Merck/MSD, Gilead, Roche; Consulting: Merck/MSD, Novartis, Merck/MSD, Novartis; Grant/Research Support: Abbott, Intermune, Roche, Merck/MSD, Gilead, Janssen, Abbott, Roche, Merck/MSD, Vertex, Gilead, Janssen; Speaking and Teaching: Bristol-Myers

Squibb, Gilead, Novartis, Abbott, Roche, Merck/MSD, Janssen, Siemens, Falk, Boehringer-Ingelheim,

Bristol-Myers Squibb, Gilead, Novartis, Abbott, Roche, Merck/MSD, Janssen, Siemens, Metformin purchase Falk, Boehringer-Ingelheim Francesco Castelli – Grant/Research Support: Astellas, Pfizer, Abbott; Independent Contractor: BMS, Boheringer Ingheleim, ViiV, Schering, Roche, Janssen Cilag, Novartis Massimo Puoti – Consulting: Abbvie Mitchell L. Shiffman – Advisory Committees or Review Panels: Merck, Gilead, Boehringer-Ingelheim, Bristol-Myers-Squibb, Abbvie, Janssen; Consulting: Roche/ Genentech, Gen-Probe; Grant/Research Support: Merck, Gilead, Boehring-er-Ingelheim, Bristol-Myers-Squibb, GSK, Abbvie, Beckman-Coulter, Achillion, Lumena, Intercept, 上海皓元 Novarit, Gen-Probe; Speaking and Teaching: Roche/Genen-tech, Merck, Gilead, GSK, Janssen, Bayer Xavier Forns – Consulting: Jansen, MSD, Abbvie; Grant/Research Support: Roche, MSD, Gilead Maria Buti www.selleckchem.com/products/forskolin.html – Advisory Committees or Review Panels: Gilead, Janssen, Vertex, MSD; Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead, Janssen, Vertex,

Novartis Eric M. Yoshida – Advisory Committees or Review Panels: Hoffman LaRoche, Gilead Sciences Inc, Vertex Inc; Grant/Research Support: Abbvie, Hoffman LaRo-che, Merck Inc, Pfizer Inc, Norvartis Inc, Vertex Inc, Jannsen Inc, Gilead Sciences Inc, Boeringher Ingleheim Inc, Astellas; Speaking and Teaching: Gilead Sciences Inc, Cangene Corporation, Vertex Inc, Merck Inc Marc Bourlière – Advisory Committees or Review Panels: Schering-Plough, Bohringer inghelmein, Schering-Plough, Bohringer inghelmein; Board Membership: Bristol-Myers Squibb, Gilead, Idenix; Consulting: Roche, Novartis, Tibotec, Abott, glaxo smith kline, Merck, Bristol-Myers Squibb, Novartis, Tibotec, Abott, glaxo smith kline; Speaking and Teaching: Gilead, Roche, Merck, Bristol-Myers Squibb Jerry O. Stern – Employment: Boehringer Ingelheim Wulf O. Boecher – Employment: Boehringer Ingelheim GmbH George Kukolj – Employment: Boehringer Ingelheim Carla Haefner – Employment: Boehringer Ingelheim Pharma GmbH & co. KG Richard Vinisko – Employment: Boehringer-Ingelheim Miguel Garcia – Employment: Boehringer-Ingelheim Federico J.

6E and 7C). Third, increased phosphorylation

of mothers against decapentaplegic homologs 2 and 3, which is downstream of TGF-β signaling, was observed in the spinal cords of SOD1mu mice,47 demonstrating that an activating SOD1 mutation leads to activation MK-8669 cell line of TGF-β signaling (Fig. 7C). The present study demonstrates the interaction between SOD1, NOX1, and NOX4 to generate ROS in HSCs and induce liver fibrosis. Building on the work of us6, 30, 32, 34, 42 and others,8, 35, 36, 48 this study establishes a role for Nox1 and Nox4 in generating oxidative damage to induce liver fibrosis. Treatment with GKT137831, a novel, first-in-class, specific Nox1/Nox4 inhibitor,17 reverses fibrogenic response by inhibiting ROS production and expression of fibrogenic genes in both WT and SOD1mut HSCs. Most important, GKT137831 blocks liver fibrosis and down-regulates markers Adriamycin mouse of oxidative stress, inflammation,

and fibrosis in WT and SOD1mut mice. Taken together, these results indicate that dual inhibition of Nox1 and Nox4 might provide a unique opportunity for the treatment of liver fibrosis and other fibrotic diseases. Additional Supporting Information may be found in the online version of this article. “
“Background and Aim:  Manometric studies on the human lower esophageal sphincter (LES) have shown radial asymmetry of the high-pressure zone (HPZ). The aim of this study was to compare the functional properties of human LES clasp and sling muscles, and to look at their relationship with the expression of muscarinic receptors

and intracellular Ca2+ concentration. Methods:  Muscle strips of sling and clasp fibers from the LES were obtained from patients undergoing subtotal esophagectomy. Isometric tension responses of the strips to acetylcholine were studied. Western blotting and reverse transcription-polymerase chain reaction (RT-PCR) were used to determine the expression of five subtypes of muscarinic receptors. Intracellular Ca2+ ([Ca2+]i) was measured using laser scanning confocal microscopy. Results:  Acetylcholine caused a concentration-dependent increase in the tension of sling and clasp strips, the sling MCE公司 strip being stronger than clasp (P = 0.00). Messenger RNA and protein for the five muscarinic acetylcholine receptor (mAChRs) expressed in the sling and clasp muscles were highest for M2, and then in decreasing levels: M3 > M1 > M4 > M5. Acetylcholine caused significant elevation of [Ca2+]i in sling and clasp muscle cells in the presence of extracellular Ca2+ (1.5 mmol/L), and Ach-induced [Ca2+]i elevation was 1.6 times greater in sling cells than in clasp cells. Conclusion:  Variation of intracellular concentrations of Ca2+ may be the reason for differential responses to acetylcholine for sling versus clasp fibers. However, these differences are not associated with the distribution and the level of expression of the five mAChRs between the two muscle types.

7). On day 3, Kupffer cells expressed higher levels of surface CD40L than they

did at the later stage (day 12) in both groups. Furthermore, Kupffer cells from the CD40+ transgenic mice had higher levels of CD40L than those from the control animals on day 3. These data suggest that CD40 expressed on hepatocytes can activate Kupffer cells in the early stage of an adenovirus infection. The full implication of this interaction, however, requires further investigation. Hepatic CD86 expression is associated with increased T cell activation and retention, which contribute to hepatitis in mice.9 In an attempt to test whether parenchymal CD40 expression affects the regulation of B7 family members in the liver, we used quantitative reverse-transcription

polymerase chain reaction (RT-PCR) and flow cytometry analyses to examine CD80 and CD86 molecules in selleck kinase inhibitor transgenic mice 7 days after AdCre injection. The CD40 transgenic mice displayed 1.63- and 1.82-fold increases in CD80 and CD86 mRNA, respectively, over their wild-type littermates (Fig. 7A,B), although the differences were not statistically significant. Furthermore, purified hepatocytes from transgenic PD0325901 manufacturer mice expressed detectable surface expression of CD80 and CD86 (Fig. 7C-E). The effect of parenchymal CD40 expression was not limited to these two molecules in the B7 superfamily17; in transgenic mice, the relative copy numbers of programmed death ligand 1 (PD-L1; B7-H1) and B7-H4 mRNA were 2.71- (P < 0.01) and 1.84-fold (P > 0.05), respectively, versus those in the nontransgenic mice (Supporting Fig. 9). Blocking the programmed death 1 (PD-1)/PD-L1 pathway with an anti–PD-L1 antibody further enhanced the proliferation (but not IFN-γ expression) of intrahepatic CD8+

T cells (Supporting Fig. 10). In agreement with several previous reports,18 the mRNA levels of several adhesion molecules (especially E-selectin) also appeared to be up-regulated in the CD40 transgenic mice (Supporting Fig. 9). These data 上海皓元 suggest the possible involvement of B7 family members and adhesion molecules in the pathogenesis of adenovirus-induced hepatitis. CD40 is a member of the tumor necrosis factor receptor superfamily and is expressed on the surfaces of professional APCs as well as vascular endothelial cells and parenchymal cells during inflammation.4-7 The binding of CD40 by CD40L induces the up-regulation of MHC and B7 family members on professional APCs and leads to a broad range of immune and inflammatory responses.7, 19, 20 CD40 engagement on vascular endothelial cells induces cell proliferation and expression of adhesion molecules (e.g., E-selectin, vascular cell adhesion molecule 1, and intercellular cell adhesion molecule 1)19, 21 and results in microvasculature changes in patients with inflammatory bowel disease.

In clinical practice, IR is evaluated by the homeostasis model of assessment (HOMA), a rather crude index of IR that does not discriminate the hepatic and peripheral components. Recently other surrogate indices of IR sites have been proposed. We aimed to 1. validate the available IR indexes vs hepatic and peripheral IR assessed by stable isotope tracers in a group of NAFLD subjects and 2. examine the relation of the best performing indexes with histological features in an independent cohort of 126 patients with histological-proven NAFLD. Methods. The validation

cohort consisted of 24 NAFLD patients in which hepatic IR was derived from Endogenous Glucose Production (EGP) and peripheral IR from glucose clearance measured by [6-62-H2] glucose EPZ-6438 nmr in the

basal state and after a 4h-oral glucose tolerance test. Surrogate indexes of hepatic IR (as described by Laakso and De Fronzo) and peripheral IR (oral glucose insulin sensitivity (OGIS) and Matsuda insulin sensitivity index-(ISI)) were computed according to published formulas. Results. Hepatic IR indexes described by Laakso and De Fronzo significantly correlated with hepatic IR calculated as EGPxINS, but the first one had a better performance (r=0.52, P=0.009 and r=0.415, P=0.044, respectively). PD-332991 Glucose clearance by tracer was poorly correlated

with ISI (r=0.298, P=0,166) and almost significantly related to OGIS (r=0.374, P=0.078). In the larger NAFLD cohort, the prevalence of basal IR according to HOMA (values >75th percentile of normal) was 57.8%, peripheral IR according to OGIS (<25th percentile) was 67.8% and hepatic IR according to Laakso (>75th percentile) was 87.2%. In a multivariate model, peripheral IR (OGIS) was the best predictor of severe fibrosis (p=0.0023) and of NASH (p=0.0019), independent of age, BMI, steatosis, HOMA-R and Laakso index. Conversely, hepatic IR (Laakso) was the best predictor of ste-atosis (p=0.0055), independently of age, MCE公司 BMI, HOMA-R and OGIS. Logistic regression analysis confirmed the strong association of hepatic IR with steatosis (p=0.0002) and of peripheral IR with fibrosis (p=0.001). Conclusion. Laakso and OGIS are the most appropriate surrogate indexes to measure respectively hepatic and peripheral IR. They can be used as non-invasive predictors of the severity of steatosis (Laakso) and of fibrosis (OGIS) in NAFLD patients. Funded by FP7/2007-2013 under grant agreement n° HEALTH-F2-2009-241762 for the project FLIP and by PRIN 2009ARYX4T.

9% saline) at postnatal days 12-15 and allowed to grow until 8 months of age. At 8 months these mice were divided into two groups and treated with either TAM (6 μg/mouse) or corn oil and sacrificed

2 months later at 10 months of age. Liver and serum samples were obtained and processed this website as described.19 Liver and body weights of mice were noted at the time of sacrifice and used to determine liver/body weight ratios. Liver injury and function were determined by serum alanine aminotransferase (ALT), serum bilirubin, and serum glucose levels measured using the Infinity ALT (GPT) and the Infinity Glucose kit (Thermo Scientific; Middletown, VA) according to the manufacturer’s protocol. RIPA extracts obtained from whole liver tissues were used for western blot analysis and western blots were performed using the described protocol.20 The antibodies used in this study were: HNF4α (1:1,000; R&D Systems, Minneapolis, MN; Cat. no. PP-H1415-00), Cyclin D1 (Cat. no. 2978), c-Myc (Cat. no. 5605), and β-Actin (Cat. no. 4970) (1:1,000; Cell Signaling, Danvers, MA). Paraffin-embedded liver sections (4-μm thick) were used for hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), and immunohistochemical

staining of proliferating cell nuclear antigen (PCNA) as described.20 After staining for PCNA, positive cells were quantified by counting four 40× fields per slide for each liver sample (n = 3 per group). Fresh-frozen sections high throughput screening assay (5-μm thick) were used to detect lipid accumulation by staining with Oil Red O and Ki-67 immunofluorescence as described.19, 20 Apoptosis was measured using the In Situ Cell Death Detection Kit, TMR red (Roche Applied Science, Indianapolis, IN; Cat. no. 12156792910) according to the manufacturer’s protocol. Total RNA was isolated from liver tissue using the phenol/chloroform extraction protocol. Integrity of RNA was analyzed by the Microarray Core 上海皓元医药股份有限公司 Facility at KUMC (Kansas City, KS) using an Agilent Bioanalyzer 2100 (Agilent Technologies; Santa Clara, CA). We performed two separate and independent RNA-Seq experiments for the same treatment conditions, Cre+/Tamoxifen, Cre−/Tamoxifen, and Cre+/Corn Oil. In the first

instance (Run1), the total processed RNA extracted from pooled mouse liver samples (3 mice per group) treated with Cre+/Tamoxifen, Cre−/Tamoxifen, and Cre+/Corn Oil was sequenced in an Illumina HiSeq 2000 sequencing machine (Illumina, San Diego, CA). The initial library of 10 nM concentration for each of the three samples was split into two diluted concentrations of 5 pM and 3 pM and sequenced separately at a 2 × 100 basepair (bp) paired-end resolution and the output of the sequencing runs combined for downstream analysis. In order to complement the initial RNA-Seq analysis, we ran a second RNA-seq experiment (Run2) on biological replicate samples (n = 2) of mouse liver treated with Cre+/Tamoxifen, Cre−/Tamoxifen, and Cre+/Corn Oil.