05), and correlated with the degree of fibrosis. PA-induced lipoapoptosis in primary hepatocytes in vitro lead to mtDNA release into the supernatant, and mice with HFD-induced fatty liver were predisposed to greater increases in serum mtDNA in response to thioacetamide-induced liver injury. Intravenous administration of purified mtDNA at physiological doses (10μg/mouse) induced robust upregulation of a-SMA expression in HSC in mice primed with short-term MCD feeding, as determined by in situ immunostaining and immunoblotting of liver lysates 24h post-mtDNA (p<0.05). Activation of HSC was following by 2-3-fold increases in pro-fibrogenic gene expression (TGFp1, procollagen a1(I) and

TIMP-1) 48 hours after mtDNA administration (p<0.05). In vitro, addition of mtDNA (1-5μg/ml) induced significant upregulation of a-SMA expression in primary HSC cultures and pro-inflammatory cytokine XL765 TNFα secretion by murine macrophages in a dose-dependent fashion (p<0.05) CONCLUSIONS: In murine NASH models, mtDNA is released from injured fat-laden hepatocytes, circulates in serum and

correlates with fibrosis progression. Administration this website of purified mtDNA induces pro-inflammatory and pro-fibrogenic responses in liver cells in vivo and in vitro. Our results suggest hepatocyte-derived mtDNA acts as a “danger signal”, promotes progression of NAFLD/NASH and is a potential disease biomarker. Disclosures: Yury Popov – Consulting: Gilead Sciences, Inc; Grant/Research Support: Gilead Sciences, Inc, Takeda The following people have nothing to disclose: Naoki

Ikenaga, Makoto Miyamoto, Susan B. Liu, Zhen-Wei Peng, Shuhei Yoshida, Konstantin Khrapko, Henry Koziel BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and can progress to cirrhosis and hepatocellular cancer (HCC). NAFLD is characterized by steatosis, inflammation, ballooning and pericellular fibrosis. It is also associated with obesity, insulin resistance, hyperglycemia and dyslipidemia. While numerous mouse models of NASH have been described, they do not mimic human disease and do not develop HCC reliably without genetic manipulation. selleck chemicals llc AIMS: To characterize a mouse model of NAFLD that is associated with obesity/insulin resistance and develops increasing fibrosis and HCC. METHODS: A unique isogenic mouse strain derived from a C57Bl/6J and 129Sl/ SvlmJ background was created and maintained with inbreeding. Mice were fed one of four diets: (1) chow diet (Harlan TD.7012), (2) high-fat diet (HFD) with 42% Kcal from fat (Harlan TD.88137) (3) HFD + high fructose-glucose solution (HFS, 23.1g/l d-fructose + 18.9 g/l d-glucose), and (4) chow diet + HFS. Normal tap water was provided ad lib to groups 1 and 2. Histology was assessed from hematoxylin+eosin and trichrome stains.

Because FTCD thymic expression is under Aire control, the invalidation of one copy of the Aire gene in heterozygous B6.129S2-Airetm1.1Doi/J mice induces a thymus-specific reduction of FTCD expression in mice with an otherwise normal phenotype. Xenoimmunization of these B6.129S2-Airetm1.1Doi/J mice induced an AIH with a similar grade of liver inflammation as C57BL/6 mice and exhibited the same sex selleck products bias. Therefore, despite lowered expression of FTCD in the thymus,

male mice are still resistant to AIH, and female mice develop an AIH of similar intensity. This observation and the similar thymic expression level of mFTCD and CYP2D9 in both sexes suggests that central tolerance is likely not the main factor responsible for the observed sex bias in AIH. Peripheral tolerance to AIH autoantigens could be

involved in susceptibility or resistance to AIH. The main mechanisms of peripheral tolerance are (1) the induction of functional unresponsiveness (anergy) or deletion of autoreactive T cells and (2) suppression by regulatory T cells. Because we have no means to directly measure the frequency of circulating AIH-specific CD8+ T cells, peripheral deletion or induction of anergy cannot be excluded as a possible factor in AIH susceptibility. However, male and female C57BL/6 mice express similar levels of AIH autoantigens, implying similar exposure to autoantigens in both sexes. Therefore, C57BL/6 male resistance to AIH is probably not the result of extensive peripheral deletion or induction of anergy of AIH-specific autoreactive Selleck PARP inhibitor T cells. Regulatory T cells are key elements in the control of autoimmunity stemming from molecular mimicry,23 because Tregs have the ability to be click here activated at 10-fold to 100-fold lower antigen concentrations

compared with naïve T cells and in the presence of low levels of CD80/86 and self-peptide/major histocompatibility complex on antigen-presenting cells.24 Furthermore, once activated by specific antigens, Tregs can exert a suppressive action on T cells irrespective of their antigen specificity.24 C57BL/6 male mice showed significantly higher numbers of regulatory T cells in the spleen, peripheral blood mononuclear cells, and liver in response to the xenoimmunization compared with females. In vaccinated female mice, Tregs were virtually absent from liver infiltrates. This parallels the observation by Longhi et al.25 that patients with AIH have decreased numbers of circulating regulatory T cells. In B6.129S2-Airetm1.1Doi/J mice, males also show higher levels of regulatory T cells than females in the spleen, peripheral blood mononuclear cells, and liver after vaccination. Interestingly, the percentage of Tregs in peripheral blood mononuclear cells and liver were higher in male B6.129S2-Airetm1.

Because FTCD thymic expression is under Aire control, the invalidation of one copy of the Aire gene in heterozygous B6.129S2-Airetm1.1Doi/J mice induces a thymus-specific reduction of FTCD expression in mice with an otherwise normal phenotype. Xenoimmunization of these B6.129S2-Airetm1.1Doi/J mice induced an AIH with a similar grade of liver inflammation as C57BL/6 mice and exhibited the same sex BAY 57-1293 mw bias. Therefore, despite lowered expression of FTCD in the thymus,

male mice are still resistant to AIH, and female mice develop an AIH of similar intensity. This observation and the similar thymic expression level of mFTCD and CYP2D9 in both sexes suggests that central tolerance is likely not the main factor responsible for the observed sex bias in AIH. Peripheral tolerance to AIH autoantigens could be

involved in susceptibility or resistance to AIH. The main mechanisms of peripheral tolerance are (1) the induction of functional unresponsiveness (anergy) or deletion of autoreactive T cells and (2) suppression by regulatory T cells. Because we have no means to directly measure the frequency of circulating AIH-specific CD8+ T cells, peripheral deletion or induction of anergy cannot be excluded as a possible factor in AIH susceptibility. However, male and female C57BL/6 mice express similar levels of AIH autoantigens, implying similar exposure to autoantigens in both sexes. Therefore, C57BL/6 male resistance to AIH is probably not the result of extensive peripheral deletion or induction of anergy of AIH-specific autoreactive PD-0332991 supplier T cells. Regulatory T cells are key elements in the control of autoimmunity stemming from molecular mimicry,23 because Tregs have the ability to be click here activated at 10-fold to 100-fold lower antigen concentrations

compared with naïve T cells and in the presence of low levels of CD80/86 and self-peptide/major histocompatibility complex on antigen-presenting cells.24 Furthermore, once activated by specific antigens, Tregs can exert a suppressive action on T cells irrespective of their antigen specificity.24 C57BL/6 male mice showed significantly higher numbers of regulatory T cells in the spleen, peripheral blood mononuclear cells, and liver in response to the xenoimmunization compared with females. In vaccinated female mice, Tregs were virtually absent from liver infiltrates. This parallels the observation by Longhi et al.25 that patients with AIH have decreased numbers of circulating regulatory T cells. In B6.129S2-Airetm1.1Doi/J mice, males also show higher levels of regulatory T cells than females in the spleen, peripheral blood mononuclear cells, and liver after vaccination. Interestingly, the percentage of Tregs in peripheral blood mononuclear cells and liver were higher in male B6.129S2-Airetm1.

066, P < 0.05; Z = 2.074, P < 0.05 respectively). The CXCL12 mRNA expression significantly decreased in group with lymph node metastasis (Z = 4.402, P < 0.05). Conclusion: Up-regulation of LGR5 and CXCR4 gene expression and down-regulation of CXCL12 gene in colorectal cancer tissues may be involved in the growth and metastasis of colorectal cancer. It is expected to be new potential therapeutic targets for cancer stem cells. Key Word(s): 1. Cancer/ Colorectal; 2. Stem Cells; 3. Lgr5;

4. CXCL12/ CXCR4; Presenting Author: YINGYING ZOU Corresponding Author: YINGYING ZOU Affiliations: the Second Affiliated Hospital of Nanchang University Objective: To investigate the effects of transfected XPD gene on the growth of hepatoma cell SMMC-7721 and the expression of ERG gene in the cells. RAD001 cell line Methods: The

selleck screening library XPD gene was transfected into SMMC-7721 cells with Lipofectamine 2000. There were four groups in this study including SMMC-7721 – pEGFP- N2-XPD group (XPD), SMMC-7721-pEGFP-N2 group (N2), Lipofectamine group (Lip) and blank control group. Reverse transcriptase PCR and Western blot were used to measure the expression levels of XPD and ERG mRNAs and proteins, respectively. The cell proliferation was assessed by MTT assay and the cell apoptosis was examined by flow cytometry. Results: Compared with N2 group, Lip group and blank control group, the expression levels of EGR mRNA and protein were significantly declined in XPD group (P < 0.01), however, the expression levels of XPD mRNA and protein were elevated significantly in XPD group (P < 0.01). The proliferation of SMMC-7721 cells was significantly inhibited and the apoptosis of the cells was significantly increased after transfection of XPD (P < 0.01). XPD plays an inhibitory effect on hepatoma proliferation via suppressing

expression of ERG (Ets Related Gene) which is identified being an oncogene. Conclusion: The wild-type XPD could inhibit the expression of ERG, decrease the proliferation of SMMC-7721 cells as well as enhance the apoptosis of the cells in vitro. Key Word(s): 1. liver neoplasms; 2. plasmid; 3. XPD gene; 4. ERG gene; Presenting Author: JIANG CAIFENG selleck chemicals llc Additional Authors: SUN CHANG, SHI JIAN, XIE WEIFEN, CHEN YUEXIANG Corresponding Author: JIANG CAIFENG Affiliations: Changzheng Hospital, Second Military Medical University Objective: Extranodal NK/T-cell lymphoma, nasal type (ENKTCL) is a rare form of lymphoma, and a refractory anorectal ulcer presenting as the earliest clinical manifestation is extremely rare. Methods: Here we report a case of ENKTCL in a 20-year-old girl admitted by an unhealed anorectal ulcer. Results: A smooth swelling lymph node with the size of 1*2*3 cm was found in the left inguinal region through physical examination. Rectal examination revealed a tenderness-evident ulcer with an area of 6*7 cm.

Data are collected using 1 of 3 versions of the Patient Record form. These are completed by medical staff for a random sample of patient visits during a 4-week period. Collected information includes complaints, diagnoses, testing and procedures, medications used, and demographic information. As in the NAMCS, the “Reason for Visit Classification” developed by the American Medical Records Association RG-7388 research buy is used to categorize patient-reported principal reasons for visits. Physician diagnoses are classified using the ICD-9-CM. The AMPP study is a

longitudinal population-based study of Americans with migraine.[6] Previous population-based studies of migraine prevalence, the American Migraine Studies 1 and 2, obtained cross-sectional data on migraine prevalence and disability.7-9 The AMPP began in 2004 with a questionnaire that was mailed to a stratified random sample of US households drawn from a panel maintained by a survey sampling company.[6] The sample was created

to be representative of the US population for key characteristics such as income, number of family members, and age of household head. The survey was mailed to 120,000 household with 257,339 household members. Like NHIS and NHANES, AMPP also uses self-report of symptoms to assign a diagnosis; unlike the NHIS and NHANES questions, those used in AMPP have been validated. The second phase of the survey involved a random sample of 24,000 adults 18 years of age or older from the group who had previously reported having a severe headache. This group http://www.selleckchem.com/products/Deforolimus.html was sent a yearly survey from 2005 to 2009. The surveys collected information on the frequency and severity of headaches as well as symptoms, treatment, disability, and demographic information. The surveys were constructed so that a diagnosis of migraine

could be made based on International Classification of Headache Disorders-II criteria (ICHD-II citation); a previous study estimated this method to have a sensitivity of 100% and specificity of 82.3%.[6] this website Kalaydjian and Merikangas analyzed data from 6 years of NHANES spanning the period of 1999-2004.[10] In the sample of 15,322 adults aged 20 or older who were interviewed, 3045 reported severe headache or migraine in the previous 3 months for an overall prevalence of 22.7% (27.6% in females and 14.8% in males). Overall, the odds of having severe headache/migraine were 2.32 higher for females compared with males (95% confidence interval [CI] 2.08-2.39). Prevalence did not differ substantially by race or ethnicity. More frequent health care usage was associated with headache, with 43.32% of those with headache reporting 4 or more health care visits in the last year (vs 22.7% for those without headache). The odds of being diagnosed with a comorbid physical or psychiatric condition were, respectively, 2.8 and 2.3 times greater in those with headaches compared with those without severe headache after controlling for demographic variables.

Data are collected using 1 of 3 versions of the Patient Record form. These are completed by medical staff for a random sample of patient visits during a 4-week period. Collected information includes complaints, diagnoses, testing and procedures, medications used, and demographic information. As in the NAMCS, the “Reason for Visit Classification” developed by the American Medical Records Association Doxorubicin mw is used to categorize patient-reported principal reasons for visits. Physician diagnoses are classified using the ICD-9-CM. The AMPP study is a

longitudinal population-based study of Americans with migraine.[6] Previous population-based studies of migraine prevalence, the American Migraine Studies 1 and 2, obtained cross-sectional data on migraine prevalence and disability.7-9 The AMPP began in 2004 with a questionnaire that was mailed to a stratified random sample of US households drawn from a panel maintained by a survey sampling company.[6] The sample was created

to be representative of the US population for key characteristics such as income, number of family members, and age of household head. The survey was mailed to 120,000 household with 257,339 household members. Like NHIS and NHANES, AMPP also uses self-report of symptoms to assign a diagnosis; unlike the NHIS and NHANES questions, those used in AMPP have been validated. The second phase of the survey involved a random sample of 24,000 adults 18 years of age or older from the group who had previously reported having a severe headache. This group Tamoxifen price was sent a yearly survey from 2005 to 2009. The surveys collected information on the frequency and severity of headaches as well as symptoms, treatment, disability, and demographic information. The surveys were constructed so that a diagnosis of migraine

could be made based on International Classification of Headache Disorders-II criteria (ICHD-II citation); a previous study estimated this method to have a sensitivity of 100% and specificity of 82.3%.[6] learn more Kalaydjian and Merikangas analyzed data from 6 years of NHANES spanning the period of 1999-2004.[10] In the sample of 15,322 adults aged 20 or older who were interviewed, 3045 reported severe headache or migraine in the previous 3 months for an overall prevalence of 22.7% (27.6% in females and 14.8% in males). Overall, the odds of having severe headache/migraine were 2.32 higher for females compared with males (95% confidence interval [CI] 2.08-2.39). Prevalence did not differ substantially by race or ethnicity. More frequent health care usage was associated with headache, with 43.32% of those with headache reporting 4 or more health care visits in the last year (vs 22.7% for those without headache). The odds of being diagnosed with a comorbid physical or psychiatric condition were, respectively, 2.8 and 2.3 times greater in those with headaches compared with those without severe headache after controlling for demographic variables.

Successful isolation of human embryonic stem cells and, more recently, development of induced pluripotent stem cells (iPSCs) has created the ability to generate cells representing almost any lineage with the hope of modeling diseases in vitro as well as developing new therapies. This potential has been validated through the generation of PSC-derived cells with characteristics of cardiomyocytes, pancreatic check details beta cells, blood vessels, hematopoietic cells, neurons, and hepatocytes, to name just a few. It is now possible to envision a time when cells could be generated for transplantation to correct genetic abnormalities or replace

damaged parenchymal cells. Despite significant progress over the last decade in deriving hepatocytes from PSCs, differentiation to a fully mature phenotype has remained elusive. Though human iPSC-derived hepatocytes recapitulate many characteristics of adult

hepatocytes, some critical ones, such as mature inducible cytochrome P450 (CYP)450-metabolizing capacity (e.g., CYP3A4), appropriate selleck products responsiveness to hepatic proliferation signals in immune-deficient mouse models, and the ability to correct liver disease have not been demonstrated. Furthermore, most forms of cell therapy, other than hematopoietic stem cell transplantation, have not yet proven to be effective in the clinic, and whether hepatocyte transplantation could treat degenerative liver disease remains questionable. As a result, a major aspiration click here for PSCs has been the generation of donor organs, where limited availability has been a major barrier to transplantation. Toward this end, Takebe et al., in a recent article in Nature,[1] attempted to create an iPSC-derived organ by generating an “embryonic liver bud” in vitro from PSCs. Subsequent to transplantation in immune-deficient mice, the liver bud-like structure became quickly vascularized and exhibited many human hepatocyte functions

for a period of weeks. Takebe et al. generated hepatocyte-specific definitive endoderm, expressing the liver-enriched transcription factor, hepatocyte nuclear factor 4 alpha, from human iPSCs using previously published protocols.[2] The resulting cells were then cultured with human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSCs). Such cells have previously been shown to be important for organogenesis,[3, 4] and aggregates formed in culture containing these cells have been shown to improve the survival and physiological function of iPSC-derived cardiomyocytes and pancreatic cells.[5, 6] The mixture of cells formed into three-dimensional clusters in vitro, where iPSC-derived cells stained for alpha-fetoprotein (AFP) and albumin, and expressed many liver-specific genes by quantitative polymerase chain reaction, indicating that cluster formation supported maturation toward a hepatocyte phenotype.

Successful isolation of human embryonic stem cells and, more recently, development of induced pluripotent stem cells (iPSCs) has created the ability to generate cells representing almost any lineage with the hope of modeling diseases in vitro as well as developing new therapies. This potential has been validated through the generation of PSC-derived cells with characteristics of cardiomyocytes, pancreatic learn more beta cells, blood vessels, hematopoietic cells, neurons, and hepatocytes, to name just a few. It is now possible to envision a time when cells could be generated for transplantation to correct genetic abnormalities or replace

damaged parenchymal cells. Despite significant progress over the last decade in deriving hepatocytes from PSCs, differentiation to a fully mature phenotype has remained elusive. Though human iPSC-derived hepatocytes recapitulate many characteristics of adult

hepatocytes, some critical ones, such as mature inducible cytochrome P450 (CYP)450-metabolizing capacity (e.g., CYP3A4), appropriate selleckchem responsiveness to hepatic proliferation signals in immune-deficient mouse models, and the ability to correct liver disease have not been demonstrated. Furthermore, most forms of cell therapy, other than hematopoietic stem cell transplantation, have not yet proven to be effective in the clinic, and whether hepatocyte transplantation could treat degenerative liver disease remains questionable. As a result, a major aspiration this website for PSCs has been the generation of donor organs, where limited availability has been a major barrier to transplantation. Toward this end, Takebe et al., in a recent article in Nature,[1] attempted to create an iPSC-derived organ by generating an “embryonic liver bud” in vitro from PSCs. Subsequent to transplantation in immune-deficient mice, the liver bud-like structure became quickly vascularized and exhibited many human hepatocyte functions

for a period of weeks. Takebe et al. generated hepatocyte-specific definitive endoderm, expressing the liver-enriched transcription factor, hepatocyte nuclear factor 4 alpha, from human iPSCs using previously published protocols.[2] The resulting cells were then cultured with human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSCs). Such cells have previously been shown to be important for organogenesis,[3, 4] and aggregates formed in culture containing these cells have been shown to improve the survival and physiological function of iPSC-derived cardiomyocytes and pancreatic cells.[5, 6] The mixture of cells formed into three-dimensional clusters in vitro, where iPSC-derived cells stained for alpha-fetoprotein (AFP) and albumin, and expressed many liver-specific genes by quantitative polymerase chain reaction, indicating that cluster formation supported maturation toward a hepatocyte phenotype.

CYP2C19 genotyping (64 subjects) revealed 56.3% rapid metabolizer, 29.7% intermediate metabolizer,

and 14% poor metabolizer. The eradication rate with the 14-day learn more regimen was 100% (95% CI = 93.5–100%) and 92.7% (95% CI = 82–97%) with the 7-day regimen. The difference was related to improved eradication at 14 days in rapid metabolizers (i.e. 100 vs 88.2%). Triple therapy using a 14-day high-dose PPI and long-acting clarithromycin provided an excellent cure rate (100%) regardless of the CYP2C19 genotype. “
“Gastric cancer and peptic ulcer between them cause the death of over a million people each year. A number of articles this year have studied changes in the prevalence of the infection in a variety of countries and ethnic groups. They confirm the known risk factors for infection, principally a low standard of living, poor education, and reduced life span. The prevalence of infection in developed countries is falling, but more slowly now than was the case before, meaning that a substantial number of

the population will remain infected in the years to come. Reinfection is more common in less developed countries. The incidence of gastric cancer is highest in populations with a high prevalence of infection. Population test and treat is a cost-effective means of preventing gastric cancer. Peptic ulcer is the commonest cause of death in patients undergoing emergency surgery. The alleged risk that treatment may cause some to develop reflux esophagitis remains controversial. MK-2206 cost Helicobacter pylori infection is the underlying cause of noncardia gastric cancer, the second commonest cause of death from cancer in the world, it is also responsible for deaths from peptic ulcer. Gastric cancer and peptic

ulcer together cause more than a million deaths per year worldwide, it is therefore a serious public health problem. In spite selleck kinase inhibitor of its being a transmissible infection with a high mortality, no preventive public health measures have been instigated to reduce the burden of Helicobacter infection or to prevent its spread. There are many reasons for this failure. The prevalence of the infection is falling in the developed world, and it is hoped the infection will eventually die out spontaneously. There have been suggestions that infection with H. pylori is “protective” against gastroesophageal reflux disease (GERD), esophageal adenocarcinoma, and possibly some allergic illnesses, so its elimination might cause unexpected problems. No vaccine is available. H. pylori infection is more difficult to cure than it was expected because of the emergence of resistant organisms. The widespread use of antibiotics is generally considered to be undesirable. It is uncertain what the reinfection rate might be in some countries. Public health measures might be unduly expensive. van Blankenstein et al. [1] studied 1550 randomly selected blood donors from four regions in the southern half of the Netherlands, spread over 5- to 10-year age cohorts.

Recent studies have shown that Survivin is involved in carcinogenesis, not only by its antiapoptotic effects, but also by regulation of mitosis and angiogenesis.31 In contrast to Survivin, mRNA expression of other IAP family members (e.g., XIAP, cIAP-1) was not up-regulated in Mcl-1Δhep livers. Further, potentially interesting players of the apoptotic network were studied, but found to be of minor or no relevance for hepatocarcinogenesis in Mcl-1Δhep mice: (1) Absence of Mcl-1 was not compensated by enhanced expression of other antiapoptotic Bcl-2 proteins (Bcl-xL, Bcl-2, or

A1). (2) Moreover, beta-catenin inhibitor the multidomain proapoptotic Bcl-2 members Bax and Bak were not significantly changed, as described in hepatocytes deficient in NEMO/IKKγ.32 (3) Besides, no down-regulation of the BH3-only protein Bid, essential for death receptor-induced activation of mitochondria in hepatocytes,5 or other BH3-only proteins (Noxa, Puma) was observed in of Mcl-1Δhep livers. Persistent apoptosis of hepatocytes could lead to compensatory hepatocyte find more proliferation probably due to an increased activation of hepatic progenitor (oval) cells. Oval cells are located in the periphery of the biliary tract and represent

a constant source to restore the pool of hepatocytes. The finding that most of the liver tumors from Mcl-1Δhep mice lacked A6+ cells argues against a prominent involvement of oval

cells and liver tumor formation in Mcl-1Δhep mice. However, it is also possible that A6 positivity of HCC, which demarcates oval cell origin, is lost in the environment of Mcl-1Δhep HCC, and therefore a link between oval cell proliferation and HCC development cannot be absolutely excluded. Remarkably, HCC development in Mcl-1Δhep mice occurred independently of overt hepatitis. This is in contrast to recently published mouse models that link HCC formation to inflammation, e.g., deletion of nuclear factor κB essential modifier/IκB kinase-gamma (NEMO/IKKγ).16, 32 In line with the observed absence of morphologically overt inflammation, we could also not detect learn more an up-regulation of IFNγ or IL1β in livers of Mcl-1Δhep mice when compared to WT controls. Only a slightly increased expression of the proinflammatory cytokine IL6 was found in livers of Mcl-1Δhep mice. Increased levels of IL6 in Mcl-1Δhep livers are very likely to be produced by activated Kupffer cells, the main source of cytokines in the liver.33 IL6 may also co-contribute to hepatocarcinogenesis in Mcl-1Δhep mice, as described in other HCC models. For example, in dimethylnitrosamine-induced HCC in mice, triggering of IL6 production is considered a key mechanism for chemically induced hepatocarcinogenesis.