Adipose tissue is a rich, ubiquitous and easily acces-sible source for multipotent stromal/stem cells and has, therefore, several advantages compared to other sourc-es of mesenchymal stromal/stem cells. Several studie...Adipose tissue is a rich, ubiquitous and easily acces-sible source for multipotent stromal/stem cells and has, therefore, several advantages compared to other sourc-es of mesenchymal stromal/stem cells. Several studies have tried to identify the origin of the stromal/stem cell population within adipose tissue in situ. This is a complicated attempt because no marker has currently been described which unambiguously identifies native adipose-derived stromal/stem cells(ASCs). Isolated and cultured ASCs are a non-uniform preparation consisting of several subsets of stem and precursor cells. Cultured ASCs are characterized by their expression of a panel of markers(and the absence of others), whereas their in vitro phenotype is dynamic. Some markers were ex-pressed de novo during culture, the expression of some markers is lost. For a long time, CD34 expression was solely used to characterize haematopoietic stem and progenitor cells, but now it has become evident that it is also a potential marker to identify an ASC subpopula-tion in situ and after a short culture time. Nevertheless, long-term cultured ASCs do not express CD34, perhaps due to the artificial environment. This review gives an update of the recently published data on the origin and phenotype of ASCs both in vivo and in vitro. In addition, the composition of ASCs(or their subpopula-tions) seems to vary between different laboratories andpreparations. This heterogeneity of ASC preparationsmay result from different reasons. One of the main problems in comparing results from different laborato-ries is the lack of a standardized isolation and culture protocol for ASCs. Since many aspects of ASCs, suchas the differential potential or the current use in clinical trials, are fully described in other recent reviews, this review further updates the more basic research issues concerning ASCs' subpopulations, heterogeneity andculture standardization.展开更多
Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstric...Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstriction(functional component).PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding.Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns(PAMPs)that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways.Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability:The intestinal barrier function is affected by impaired microcirculation,neoangiogenesis,and abnormal vascular and mucosal permeability.The close bidirectional relationship between the gut and the liver has been termed“gut-liver axis”.Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function,intestinal barrier integrity,as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects.The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments,however,further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed.In this review,we summarize the clinical impact of PHT on the course of liver disease,discuss the underlying pathophysiological link of PHT to gut-liver axis signaling,and provide insight into molecular mechanisms that may represent novel therapeutic targets.展开更多
Cardiac dysfunction is frequently observed in patients with cirrhosis, and has long been linked to the direct toxic effect of alcohol. Cirrhotic cardiomyopathy(CCM) has recently been identified as an entity regardless...Cardiac dysfunction is frequently observed in patients with cirrhosis, and has long been linked to the direct toxic effect of alcohol. Cirrhotic cardiomyopathy(CCM) has recently been identified as an entity regardless of the cirrhosis etiology. Increased cardiac output due to hyperdynamic circulation is a pathophysiological hallmark of the disease. The underlying mechanisms involved in pathogenesis of CCM are complex and involve various neurohumoral and cellular pathways, including the impaired β-receptor and calcium signaling, altered cardiomyocyte membrane physiology, elevated sympathetic nervous tone and increased activity of vasodilatory pathways predominantly through the actions of nitric oxide, carbon monoxide and endocannabinoids. The main clinical features of CCM include attenuated systolic contractility in response to physiologic or pharmacologic strain, diastolic dysfunction, electrical conductance abnormalities and chronotropic incompetence. Particularly the diastolic dysfunction with impaired ventricularrelaxation and ventricular filling is a prominent feature of CCM.The underlying mechanism of diastolic dysfunction in cirrhosis is likely due to the increased myocardial wall stiffness caused by myocardial hypertrophy,fibrosis and subendothelial edema,subsequently resulting in high filling pressures of the left ventricle and atrium.Currently,no specific treatment exists for CCM.The liver transplantation is the only established effective therapy for patients with end-stage liver disease and associated cardiac failure.Liver transplantation has been shown to reverse systolic and diastolic dysfunction and the prolonged QT interval after transplantation.Here,we review the pathophysiological basis and clinical features of cirrhotic cardiomyopathy,and discuss currently available limited therapeutic options.展开更多
Despite progress in the treatment of advanced and metastatic pancreatic cancer （PC）, the outcome of this disease remains dismal for the majority of patients. Given the moderate efficacy of treatment, prognostic fact...Despite progress in the treatment of advanced and metastatic pancreatic cancer （PC）, the outcome of this disease remains dismal for the majority of patients. Given the moderate efficacy of treatment, prognostic factors may help to guide treatment decisions. Several trials identified baseline performance status as an important prognostic factor for survival. Unfit patients with a Kamofsky performance status （KPS） below 70% only have a marginal benefit from chemotherapy with gemcitabine （Gem） and may often benefit more from optimal supportive care. Once, however, the decision is taken to apply chemotherapy, KPS may be used to select either mono- or combination chemotherapy. Patients with a good performance status （KPS = 90%-100%） may have a significant and clinically relevant survival benefit from combination chemotherapy. By contrast, patients with a poor performance status （KPS ≤ 80%） have no advantage from intensified therapy and should rather receive single-agent treatment.展开更多
Alcoholic liver disease(ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options...Alcoholic liver disease(ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.展开更多
AIM: To study the effect of gelatinases (especially MMP-9) on migration of tissue inhibitor of metalloproteinase (TIMP-1) overexpressing hepatoma cells. METHODS: Wild type HepG2 cells, cells stably transfected with TI...AIM: To study the effect of gelatinases (especially MMP-9) on migration of tissue inhibitor of metalloproteinase (TIMP-1) overexpressing hepatoma cells. METHODS: Wild type HepG2 cells, cells stably transfected with TIMP-1 and TIMP-1 antagonist (MMP-9-H401A, a catalytically inactive matrix metalloproteinase (MMP) which still binds and neutralizes TIMP-1) were incubated in Boyden chambers either with or without Galardin (a synthetic inhibitor of MMP-1, -2, -3, -8, -9) or a specific inhibitor of gelatinases. RESULTS: Compared to wild type HepG2 cells, the cells overexpressing TIMP-1 showed 115% migration (P<0.05) and the cells overexpressing MMP-9-H401A showed 62% migration (P<0.01). Galardin reduced cell migration dose dependently in all cases. The gelatinase inhibitor reduced migration in TIMP-1 overexpressing cells predominantly. Furthermore, we examined intracellular signal transduction pathways of TIMP-1-dependent HepG2 cells. TIMP-1 deactivates cell signaling pathways of MMP-2 and MMP-9 involving p38 mitogen-activated protein kinase. Specific blockade of the ERK pathway suppresses gelatinase expression either in the presence or absence of TIMP-1. CONCLUSION: Overexpressing functional TIMP-1-enhanced migration of HepG2-TIMP-l cells depends on enhanced MMP-activity, especially MMP-9.展开更多
AIM: To study statements and recommendations on psychosocial issues as presented in international evidence-based guidelines on the management of inflammatory bowel diseases (IBD).
The transjugular intrahepatic portosystemic stent-shunt (TIPS) has successfully been used in the management of refractory variceal bleeding and ascites in patients with portal hypertension. Major drawbacks are the ind...The transjugular intrahepatic portosystemic stent-shunt (TIPS) has successfully been used in the management of refractory variceal bleeding and ascites in patients with portal hypertension. Major drawbacks are the induction of hepatic encephalopathy and shunt dysfunction. We present a 59-year-old woman with alcoholic liver cirrhosis who received a TIPS because of recurrent bleeding from esophageal varices. Stent occlusion occurred 4 mo after placement of the TIPS. Laboratory testing revealed resistance to activated protein C (APC). Combination therapy with low-dose enoxaparin and clopidogrel could not prevent her recurrent stent occlusion. Finally, therapy with high-dose enoxaparin was sufficient to prevent further shunt complications up to now (follow-up period of 1 year). In conclusion, early occlusion of a TIPS warrants testing for thrombophilia. If risk factors are confirmed,anticoagulation should be intensified. There are currently no evidence-based recommendations regarding the best available anticoagulant therapy and surveillance protocol for patients with TIPS.展开更多
AIM:To investigate the systemic availability of budesonide in a patient with Child A cirrhosis due to autoimmune hepatitis (AIH) and primary hepatocellular carcinoma,who developed serious side effects. METHODS:Serum l...AIM:To investigate the systemic availability of budesonide in a patient with Child A cirrhosis due to autoimmune hepatitis (AIH) and primary hepatocellular carcinoma,who developed serious side effects. METHODS:Serum levels of budesonide,6β-OH-budesonide and 16α-OH-prednisolon were measured by HPLC/MS/MS; portosystemic shunt-index (SI) was determined by 99mTc nuclear imaging.All values were compared with a matched control patient without side effects. RESULTS:Serum levels of budesonide were 13-fold increased in the index patient.The ratio between serum levels of the metabolites 6β-OH-budesonide and 16α-OH- prednisolone,respectively,and serum levels of budesonide was diminished (1.0 vs.4.0 for 6β-OH-budesonide,4.2 vs. 10.7 for 16α-OH-prednisolone).Both patients had portosystemic SI (5.7 % and 3.1%) within the range of healthy subjects.CONCLUSION:Serum levels of budesonide Vary uP to 13-fold in AIH Patients with Child A eirrhosis in the absenee ofrelevant Portosystemic shunting.Redueed hePatiemetabolism,as indicated by redueed metabolite-to-drugratio,rather than Portosystemie shunting may explainsystemic side effects of this drug in cirrhosis展开更多
High-sensitivity cardiac troponin(hs-cTn) assays are increasingly being used in many countries worldwide,however,a generally accepted definition of high-sen-sitivity is still pending.These assays enable cTn mea-sureme...High-sensitivity cardiac troponin(hs-cTn) assays are increasingly being used in many countries worldwide,however,a generally accepted definition of high-sen-sitivity is still pending.These assays enable cTn mea-surement with a high degree of analytical sensitivity with a low analytical imprecision at the low measuring range of cTn assays(coefficient of variation of < 10% at the 99th percentile upper reference limit).One of the most important advantages of these new assays is that they allow novel,more rapid approaches to rule in or rule out acute coronary syndromes(ACSs) than with previous cTn assay generations which are still more commonly used in practice worldwide.hs-cTn is also more sensitive for the detection of myocardial damage unrelated to acute myocardial ischemia.Therefore,the increase in early diagnostic sensitivity of hs-cTn assays for ACS comes at the cost of a reduced ACS specificity,because more patients with other causes of acute or chronic myocardial injury without overt myocardial isch-emia are detected than with previous cTn assays.As hs-cTn assays are increasingly being adopted in clinical practice and more hs-cTn assays are being developed,this review attempts to synthesize the available clinical data to make recommendations for their everyday clini-cal routine use.展开更多
New endoscopic techniques for hemostasis in nonvariceal bleeding were introduced and known methods further improved. Hemospray and Endoclot are two new compounds for topical treatment of bleeding. Initial studies in t...New endoscopic techniques for hemostasis in nonvariceal bleeding were introduced and known methods further improved. Hemospray and Endoclot are two new compounds for topical treatment of bleeding. Initial studies in this area have shown a good hemostatic effect, especially in active large scale oozing bleeding, e.g., tumor bleedings. For further evaluation larger prospective studies comparing the substanced with other methods of endoscopic hemostasis are needed. For localized active arterial bleeding primary injection therapy in the area of bleeding as well as in the four adjacent quadrants offers a good method to reduce bleeding activity. The injection is technically easy to learn and practicable. After bleeding activity is reduced the bleeding source can be localized more clearly for clip application. Today many different through-thescope(TTS) clips are available. The ability to close and reopen a clip can aid towards good positioning at the bleeding site. Even more important is the rotatability of a clip before application. Often multiple TTS clips are required for secure closure of a bleeding vessel. One model has the ability to use three clips in series without changing the applicator. Severe arterial bleeding from vessels larger than 2 mm is often unmanageable with these conventional methods. Here is the over-the-scopeclip system another newly available method. It is similar to the ligation of esophageal varices and involves aspiration of tissue into a transparent cap before closure of the clip. Thus a greater vascular occlusion pressure can be achieved and larger vessels can be treated endoscopically. Patients with severe arterial bleeding from the upper gastrointestinal tract have a very high rate of recurrence after initial endoscopic treatment. These patients should always be managed in an interdisciplinary team of interventional radiologist and surgeons.展开更多
AIM: To evaluate the use of translumenal pancreatography with placement of endoscopic ultrasonography(EUS)-guided drainage of the pancreatic duct.METHODS: This study enrolled all consecutive patients between June 2002...AIM: To evaluate the use of translumenal pancreatography with placement of endoscopic ultrasonography(EUS)-guided drainage of the pancreatic duct.METHODS: This study enrolled all consecutive patients between June 2002 and April 2014 who underwent EUSguided pancreatography and subsequent placement of a drain and had symptomatic retention of fluid in the pancreatic duct after one or more previous unsuccessful attempts at endoscopic retrograde cannulation of the pancreatic duct. In all,94 patients underwent 111 interventions with one of three different approaches:(1) EUS-endoscopic retrograde drainage with a rendezvous technique;(2) EUS-guided drainage of the pancreatic duct; and(3) EUS-guided,internal,antegrade drainage of the pancreatic duct.RESULTS: The mean duration of the interventions was 21 min(range,15-69 min). Mean patient age was 54 years(range,28-87 years); the M:F sex ratio was 60:34. The technical success rate was 100%,achieving puncture of the pancreatic duct including pancreatography in 94/94 patients. In patients requiring drainage,initial placement of a drain wassuccessful in 47/83 patients(56.6%). Of these,26 patients underwent transgastric/transbulbar positioning of a stent for retrograde drainage; plastic prostheses were used in 11 and metal stents in 12. A ring drain(antegrade internal drainage) was placed in three of these 26 patients because of anastomotic stenosis after a previous surgical intervention. The remaining 21 patients with successful drain placement had transpapillary drains using the rendezvous technique; the majority(n = 19) received plastic prostheses,and only two received metal stents(covered self-expanding metal stents). The median follow-up time in the 21 patients with transpapillary drainage was 28 mo(range,1-79 mo),while that of the 26 patients with successful transgastric/transduodenal drainage was 9.5 mo(range,1-82 mo). Clinical success,as indicated by reduced or absence of further pain after the EUS-guided intervention was achieved in 68/83 patients(81.9%),including several who improved without drainage,but with manipulation of the access route.CONCLUSION: EUS-guided drainage of the pancreatic duct is a safe,feasible alternative to endoscopic retrograde drainage when the papilla cannot be reached endoscopically or catheterized.展开更多
AIM Evaluate the association between phase angle and the development of hepatic encephalopathy in the longterm follow-up of cirrhotic patients.METHODS This was a prospective cohort study. Clinical, nutritional and bio...AIM Evaluate the association between phase angle and the development of hepatic encephalopathy in the longterm follow-up of cirrhotic patients.METHODS This was a prospective cohort study. Clinical, nutritional and biochemical evaluations were performed. MannWhitney's U and χ2 tests were used as appropriate. Kaplan-Meier curves and Cox proportional Hazards analysis were used to evaluate the prediction and incidence of hepatic encephalopathy.RESULTS Two hundred and twenty were included; the most frequent etiology of cirrhosis was hepatitis C infection, 52% of the patients developed hepatic encephalopathy(18.6% covert and 33.3% overt); the main precipitating factors were infections and variceal bleeding. KaplanMeier curves showed a higher proportion of HE in the group with low phase angle(39%) compared to the normal phase angle group(13%)(P = 0.012). Furthermore, creatinine and phase angle remained independently associated to hepatic encephalopathy in the Cox regression multivariate analysis [hazard ratio = 1.80(1.07-3.03)]. CONCLUSION In our cohort of patients low phase angle was associated with an increased incidence of hepatic encephalopathy. Phase angle is a useful nutritional marker that evaluates cachexia and could be used as a part of the integral assessment in patients with cirrhosis.展开更多
In patients with history of coronary artery disease angina pectoris is usually attributed to the progression of atherosclerotic lesions. However,in patients with previous coronary artery bypass graft operation(CABG) u...In patients with history of coronary artery disease angina pectoris is usually attributed to the progression of atherosclerotic lesions. However,in patients with previous coronary artery bypass graft operation(CABG) using internal mammary artery grafts,great vessel disease should also be considered. Herein we present two patients with history of CABG whose symptoms were suspicious for coronary ischemia. During cardiac catheterization reverse blood flow was observed from the left artery disease to the left internal mammary artery(LIMA) graft in both cases. After angioplasty and stent implantation of the left subclavian artery antegrade flow was restored in the LIMA grafts and both patients had complete resolution of symptoms.展开更多
AIM: To study the interleukin-1(IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4^(-/-)(Abcb4^(-/-)) mouse model.METHODS: Female and male Abcb4...AIM: To study the interleukin-1(IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4^(-/-)(Abcb4^(-/-)) mouse model.METHODS: Female and male Abcb4^(-/-) mice from 6 to 13 mo of age were analysed for the degree of cholestasis(liver serum tests), extent of liver fibrosis(hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the IL-1 pathway [quantitative polymerase chain reaction(q PCR)]. For in vivo experiments, murine hepatic stellate cells(HSCs) were isolated via pronasecollagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/m L IL-1β with or without 2.5 μg/m L Anakinra, an IL-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the Brd U assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis(FDH) assay. In vivo 8-wk-old Abcb4^(-/-) mice with an already fully established hepatic phenotype were treated with Anakinra(1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, q PCR, hydroxyproline content and Sirius red staining. RESULTS: Liver fibrosis was less pronounced in males than in female Abcb4^(-/-) animals as defined by a lower hydroxyproline content(274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P < 0.001; MannWhitney U-test) and lower m RNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1(TIMP)(1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P < 0.05; Mann-Whitney U-test). Reduced liver fibrosis was associated with significantly lower levels of F4/80 m RNA expression(1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P < 0.05; Mann-Whitney U-test) and significantly lower IL-1β m RNA expression levels(1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P < 0.001; Mann-Whitney U-test). No gender differences in the serum liver parameters [bilirubin; alanine aminotransferase(ALT); aspartate aminotransferase and alkaline phosphatase(AP)] were found. In vitro, the administration of IL-1β resulted in a significant increase in HSC proliferation [0.94 ± 0.72 arbitrary units(A.U.) in untreated controls, 1.12 ± 0.80 A.U. at an IL-1β concentration of 0.1 ng/m L and 1.18 ± 0.73 A.U. at an IL-1β concentration of 1 ng/m L in samples from n = 6 donor animals; P < 0.001; analyses of variance(ANOVA)]. Proliferation was reduced significantly by the addition of 2.5 μg/m L Anakinra(0.81 ± 0.60 A.U. in untreated controls, 0.92 ± 0.68 A.U. at an IL-1β concentration of 0.1 ng/m L, and 0.91 ± 0.69 A.U. at an IL-1β concentration of 1 ng/m L; in samples from n = 6 donor animals; P < 0.001; ANOVA) suggesting an anti-proliferative effect of this clinically approved IL-1 receptor antagonist. The FDH assay showed this dose to be non-toxic in HSCs. In vivo, Anakinra had no effect on the hepatic hydroxyprolinecontent, liver serum tests(ALT and AP) and profibrotic(collagen 1α1, collagen 1α2, transforming growth factor-β, and TIMP-1) and anti-fibrotic [matrix metalloproteinase 2(MMP2), MMP9 and MMP13 ] gene expression after 4 wk of treatment. Furthermore, the hepatic IL-1β and F4/80 m RNA expression levels were unaffected by Anakinra treatment.CONCLUSION: IL-1β expression is associated with the degree of liver fibrosis in Abcb4^(-/-) mice and promotes HSC proliferation. IL-1 antagonism shows antifibrotic effects in vitro but not in Abcb4^(-/-) mice.展开更多
Endoglin, also known as cluster of differentiation CD105, was originally identified 25 years ago as a novel marker of endothelial cells. Later it was shown that endoglin is also expressed in pro-fibrogenic cells inclu...Endoglin, also known as cluster of differentiation CD105, was originally identified 25 years ago as a novel marker of endothelial cells. Later it was shown that endoglin is also expressed in pro-fibrogenic cells including mesangial cells, cardiac and scleroderma fibroblasts, and hepatic stellate cells. It is an integral membranebound disulfide-linked 180 kDa homodimeric receptor that acts as a transforming growth factor-β(TGF-β) auxiliary co-receptor. In humans, several hundreds of mutations of the endoglin gene are known that give rise to an autosomal dominant bleeding disorder that is characterized by localized angiodysplasia and arteriovenous malformation. This disease is termed hereditary hemorrhagic telangiectasia type Ⅰ and induces various vascular lesions, mainly on the face, lips, hands and gastrointestinal mucosa. Two variants of endoglin(i.e., S- and L-endoglin) are formed by alternative splicing that distinguishes from each other in the length of their cytoplasmic tails. Moreover, a soluble form of endoglin, i.e.,sol-Eng, is shedded by the matrix metalloprotease-14 that cleaves within the extracellular juxtamembrane region. Endoglin interacts with the TGF-β signaling receptors and influences Smad-dependent and-independent effects. Recent work has demonstrated that endoglin is a crucial mediator during liver fibrogenesis that critically controls the activity of the different Smad branches. In the present review, we summarize the present knowledge of endoglin expression and function, its involvement in fibrogenic Smad signaling, current models to investigate endoglin function, and the diagnostic value of endoglin in liver disease.展开更多
Pancreatic ductal adenocarcinoma(PDA) is one of the major causes for cancer death worldwide. Treatment of metastatic disease remains challenging as only certain patients benefit from advances made with the intensified...Pancreatic ductal adenocarcinoma(PDA) is one of the major causes for cancer death worldwide. Treatment of metastatic disease remains challenging as only certain patients benefit from advances made with the intensified chemotherapy regimen folinic acid, irinotecan and oxaliplatin, the epidermal growth factor receptor inhibitor erlotinib or the recently FDA-approved nab-paclitaxel. Up to date, no established approach for prediction of treatment response or specific treatment allocation exists. Translational research was able to identify a number of potential biomarkers that might help to improve the dismal prognosis of PDA by facilitating upfront treatment allocation. This topic highlight is focused on current evidence on potential biomarkers for tumor biology, prognosis and prediction of treatment efficacy.展开更多
AIM： To investigate the prevalence, risk factors, and selection of the study population for cholecystolithiasis in an urban population in Germany, in relation to our own findings and to the results in the internation...AIM： To investigate the prevalence, risk factors, and selection of the study population for cholecystolithiasis in an urban population in Germany, in relation to our own findings and to the results in the international literature. METHODS： A total of 2 147 persons （1 111 females, age 42.8 ＋ 12.7 years; 1 036 males, age 42.3 ＋ 13.1 years） participating in an investigation on the prevalence of Echinococcus rnultilocularis were studied for risk factors and prevalence of gallbladder stone disease. Risk factors were assessed by means of a standardized interview and calculation of body mass index （BMI）. A diagnostic ultrasound examination of the gallbladder was performed. Data were analyzed by multiple logistic regression, using the SAS statistical software package. RESULTS： Gallbladder stones were detected in 171 study participants （8.0%, n = 2 147）. Risk factors for the development of gallbladder stone disease included age, sex, BMI, and positive family history. In a separate analysis of female study participants, pregnancy （yes/no） and number of pregnancies did not exert any influence. CONCLUSION： Findings of the present study confirm that age, female sex, BMI, and positive family history are risk factors for the development of gallbladder stone disease. Pregnancy and the number of pregnancies, however, could not be shown to be risk factors. There seem to be no differences in the respective prevalence for gallbladder stone disease in urban and rural populations.展开更多
BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear geno...BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear genotype-phenotype correlations exist in WD.Protein-truncating nonsense,frame-shift,or splice-site variants may be associated with more severe disease.In contrast,missense variants may be associated with late-onset,less severe disease,and more neurological manifestations.Recently,a gene variant(HSD17B13:TA,rs72613567)with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed.The clinical manifestations(ALF with non-immune hemolytic anemia or other less severe forms),laboratory parameters,copper metabolism,ATP7B variants,and the HSD17B13:TA(rs72613567)variant were reviewed to analyze the possible genotype-phenotype correlations.RESULTS We analyzed the data of 51 patients with WD,26 females(50.98%),with the mean age at the diagnosis of 12.36±3.74 years.ALF and Coombs-negative hemolytic anemia was present in 8 children(15.67%),all adolescent girls.The Kayser-Fleisher ring was present in 9 children(17.65%).The most frequent variants of the ATP7B gene were p.His1069Gln(c.3207A>G)in 38.24% of all alleles,p.Gly1341Asp(c.4021G>A)in 26.47%,p.Trp939Cys(c.2817G>T)in 9.80%,and p.Lys844Ter(c.2530A>T)in 4.90%.In ALF with hemolytic anemia,p.Trp939Cys(c.2817G>T)and p.Lys844Ter(c.2530A>T)variants were more frequent than in other less severe forms,in which p.His1069Gln(c.3207A>G)was more frequent.p.Gly1341Asp(c.4021G>A)has a similar frequency in all hepatic forms.For 33 of the patients,the HSD17B13 genotype was evaluated.The overall HSD17B13:TA allele frequency was 24.24%.Its frequency was higher in patients with less severe liver disease(26.92%)than those with ALF and hemolytic anemia(14.28%).CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients.In children with ALF and hemolytic anemia,the missense variants other than p.His1069Gln(c.3207A>G)and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants.As genetic analysis is usually time-consuming and the results are late,the importance at the onset of the ALF is questionable.If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease,this could be essential to predict a possible severe evolution.展开更多
The mammalian target of rapamycin(mTOR)acts in two structurally and functionally distinct protein complexes,mTOR complex 1(mTORC1)and mTOR complex 2(mTORC2).Upon deregulation,activated mTOR signaling is associated wit...The mammalian target of rapamycin(mTOR)acts in two structurally and functionally distinct protein complexes,mTOR complex 1(mTORC1)and mTOR complex 2(mTORC2).Upon deregulation,activated mTOR signaling is associated with multiple processes involved in tumor growth and metastasis.Compared with mTORC1,much less is known about mTORC2 in cancer,mainly because of the unavailability of a selective inhibitor.However,existing data suggest that mTORC2 with its two distinct subunits Rictor and mSin1 might play a more important role than assumed so far.It is one of the key effectors of the PI3K/AKT/mTOR pathway and stimulates cell growth,cell survival,metabolism,and cytoskeletal organization.It is not only implicated in tumor progression,metastasis,and the tumor microenvironment but also in resistance to therapy.Rictor,the central subunit of mTORC2,was found to be upregulated in different kinds of cancers and is associated with advanced tumor stages and a bad prognosis.Moreover,AKT,the main downstream regulator of mTORC2/Rictor,is one of the most highly activated proteins in cancer.Primary and secondary liver cancer are major problems for current cancer therapy due to the lack of specific medical treatment,emphasizing the need for further therapeutic options.This review,therefore,summarizes the role of mTORC2/Rictor in cancer,with special focus on primary liver cancer but also on liver metastases.展开更多
文摘Adipose tissue is a rich, ubiquitous and easily acces-sible source for multipotent stromal/stem cells and has, therefore, several advantages compared to other sourc-es of mesenchymal stromal/stem cells. Several studies have tried to identify the origin of the stromal/stem cell population within adipose tissue in situ. This is a complicated attempt because no marker has currently been described which unambiguously identifies native adipose-derived stromal/stem cells(ASCs). Isolated and cultured ASCs are a non-uniform preparation consisting of several subsets of stem and precursor cells. Cultured ASCs are characterized by their expression of a panel of markers(and the absence of others), whereas their in vitro phenotype is dynamic. Some markers were ex-pressed de novo during culture, the expression of some markers is lost. For a long time, CD34 expression was solely used to characterize haematopoietic stem and progenitor cells, but now it has become evident that it is also a potential marker to identify an ASC subpopula-tion in situ and after a short culture time. Nevertheless, long-term cultured ASCs do not express CD34, perhaps due to the artificial environment. This review gives an update of the recently published data on the origin and phenotype of ASCs both in vivo and in vitro. In addition, the composition of ASCs(or their subpopula-tions) seems to vary between different laboratories andpreparations. This heterogeneity of ASC preparationsmay result from different reasons. One of the main problems in comparing results from different laborato-ries is the lack of a standardized isolation and culture protocol for ASCs. Since many aspects of ASCs, suchas the differential potential or the current use in clinical trials, are fully described in other recent reviews, this review further updates the more basic research issues concerning ASCs' subpopulations, heterogeneity andculture standardization.
文摘Portal hypertension(PHT)in advanced chronic liver disease(ACLD)results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition(structural component)and intrahepatic vasoconstriction(functional component).PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding.Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns(PAMPs)that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways.Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability:The intestinal barrier function is affected by impaired microcirculation,neoangiogenesis,and abnormal vascular and mucosal permeability.The close bidirectional relationship between the gut and the liver has been termed“gut-liver axis”.Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function,intestinal barrier integrity,as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects.The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments,however,further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed.In this review,we summarize the clinical impact of PHT on the course of liver disease,discuss the underlying pathophysiological link of PHT to gut-liver axis signaling,and provide insight into molecular mechanisms that may represent novel therapeutic targets.
文摘Cardiac dysfunction is frequently observed in patients with cirrhosis, and has long been linked to the direct toxic effect of alcohol. Cirrhotic cardiomyopathy(CCM) has recently been identified as an entity regardless of the cirrhosis etiology. Increased cardiac output due to hyperdynamic circulation is a pathophysiological hallmark of the disease. The underlying mechanisms involved in pathogenesis of CCM are complex and involve various neurohumoral and cellular pathways, including the impaired β-receptor and calcium signaling, altered cardiomyocyte membrane physiology, elevated sympathetic nervous tone and increased activity of vasodilatory pathways predominantly through the actions of nitric oxide, carbon monoxide and endocannabinoids. The main clinical features of CCM include attenuated systolic contractility in response to physiologic or pharmacologic strain, diastolic dysfunction, electrical conductance abnormalities and chronotropic incompetence. Particularly the diastolic dysfunction with impaired ventricularrelaxation and ventricular filling is a prominent feature of CCM.The underlying mechanism of diastolic dysfunction in cirrhosis is likely due to the increased myocardial wall stiffness caused by myocardial hypertrophy,fibrosis and subendothelial edema,subsequently resulting in high filling pressures of the left ventricle and atrium.Currently,no specific treatment exists for CCM.The liver transplantation is the only established effective therapy for patients with end-stage liver disease and associated cardiac failure.Liver transplantation has been shown to reverse systolic and diastolic dysfunction and the prolonged QT interval after transplantation.Here,we review the pathophysiological basis and clinical features of cirrhotic cardiomyopathy,and discuss currently available limited therapeutic options.
文摘Despite progress in the treatment of advanced and metastatic pancreatic cancer （PC）, the outcome of this disease remains dismal for the majority of patients. Given the moderate efficacy of treatment, prognostic factors may help to guide treatment decisions. Several trials identified baseline performance status as an important prognostic factor for survival. Unfit patients with a Kamofsky performance status （KPS） below 70% only have a marginal benefit from chemotherapy with gemcitabine （Gem） and may often benefit more from optimal supportive care. Once, however, the decision is taken to apply chemotherapy, KPS may be used to select either mono- or combination chemotherapy. Patients with a good performance status （KPS = 90%-100%） may have a significant and clinically relevant survival benefit from combination chemotherapy. By contrast, patients with a poor performance status （KPS ≤ 80%） have no advantage from intensified therapy and should rather receive single-agent treatment.
基金the MINECO Retos,No.SAF2016-78711 and SAF2017-87919REXOHEP-CM,No.S2017/BMD-3727+8 种基金the AMMF Cholangiocarcinoma Charity,No.2018/117the COST Action,No.CA17112Ramón y Cajal,No.RYC-2014-15242 and No.RYC-2015-17438grant of ERAB,No.EA 14/18Gilead Liver Research Scholar 2018,No.44/2018Ministerio de Sanidad,Servicios Sociales e Igualdad,No.2017I065the UCM group “Lymphocyte Immunobiology”,No.920631(imas12-associated,Ref.IBL-6)German Research Foundation(SFB/TRR57/P04 and DFG NE 2128/2-1)Interdisciplinary Center for Clinical Research from the Faculty of Medicine at RWTH Aachen University(IZKF/E8-2)
文摘Alcoholic liver disease(ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.
基金Supported by grants from the Federal Ministry of Education Research of Germany, Deutsche Forschungsgemeinschaft (DFG), and Aachen University
文摘AIM: To study the effect of gelatinases (especially MMP-9) on migration of tissue inhibitor of metalloproteinase (TIMP-1) overexpressing hepatoma cells. METHODS: Wild type HepG2 cells, cells stably transfected with TIMP-1 and TIMP-1 antagonist (MMP-9-H401A, a catalytically inactive matrix metalloproteinase (MMP) which still binds and neutralizes TIMP-1) were incubated in Boyden chambers either with or without Galardin (a synthetic inhibitor of MMP-1, -2, -3, -8, -9) or a specific inhibitor of gelatinases. RESULTS: Compared to wild type HepG2 cells, the cells overexpressing TIMP-1 showed 115% migration (P<0.05) and the cells overexpressing MMP-9-H401A showed 62% migration (P<0.01). Galardin reduced cell migration dose dependently in all cases. The gelatinase inhibitor reduced migration in TIMP-1 overexpressing cells predominantly. Furthermore, we examined intracellular signal transduction pathways of TIMP-1-dependent HepG2 cells. TIMP-1 deactivates cell signaling pathways of MMP-2 and MMP-9 involving p38 mitogen-activated protein kinase. Specific blockade of the ERK pathway suppresses gelatinase expression either in the presence or absence of TIMP-1. CONCLUSION: Overexpressing functional TIMP-1-enhanced migration of HepG2-TIMP-l cells depends on enhanced MMP-activity, especially MMP-9.
文摘AIM: To study statements and recommendations on psychosocial issues as presented in international evidence-based guidelines on the management of inflammatory bowel diseases (IBD).
文摘The transjugular intrahepatic portosystemic stent-shunt (TIPS) has successfully been used in the management of refractory variceal bleeding and ascites in patients with portal hypertension. Major drawbacks are the induction of hepatic encephalopathy and shunt dysfunction. We present a 59-year-old woman with alcoholic liver cirrhosis who received a TIPS because of recurrent bleeding from esophageal varices. Stent occlusion occurred 4 mo after placement of the TIPS. Laboratory testing revealed resistance to activated protein C (APC). Combination therapy with low-dose enoxaparin and clopidogrel could not prevent her recurrent stent occlusion. Finally, therapy with high-dose enoxaparin was sufficient to prevent further shunt complications up to now (follow-up period of 1 year). In conclusion, early occlusion of a TIPS warrants testing for thrombophilia. If risk factors are confirmed,anticoagulation should be intensified. There are currently no evidence-based recommendations regarding the best available anticoagulant therapy and surveillance protocol for patients with TIPS.
文摘AIM:To investigate the systemic availability of budesonide in a patient with Child A cirrhosis due to autoimmune hepatitis (AIH) and primary hepatocellular carcinoma,who developed serious side effects. METHODS:Serum levels of budesonide,6β-OH-budesonide and 16α-OH-prednisolon were measured by HPLC/MS/MS; portosystemic shunt-index (SI) was determined by 99mTc nuclear imaging.All values were compared with a matched control patient without side effects. RESULTS:Serum levels of budesonide were 13-fold increased in the index patient.The ratio between serum levels of the metabolites 6β-OH-budesonide and 16α-OH- prednisolone,respectively,and serum levels of budesonide was diminished (1.0 vs.4.0 for 6β-OH-budesonide,4.2 vs. 10.7 for 16α-OH-prednisolone).Both patients had portosystemic SI (5.7 % and 3.1%) within the range of healthy subjects.CONCLUSION:Serum levels of budesonide Vary uP to 13-fold in AIH Patients with Child A eirrhosis in the absenee ofrelevant Portosystemic shunting.Redueed hePatiemetabolism,as indicated by redueed metabolite-to-drugratio,rather than Portosystemie shunting may explainsystemic side effects of this drug in cirrhosis
文摘High-sensitivity cardiac troponin(hs-cTn) assays are increasingly being used in many countries worldwide,however,a generally accepted definition of high-sen-sitivity is still pending.These assays enable cTn mea-surement with a high degree of analytical sensitivity with a low analytical imprecision at the low measuring range of cTn assays(coefficient of variation of < 10% at the 99th percentile upper reference limit).One of the most important advantages of these new assays is that they allow novel,more rapid approaches to rule in or rule out acute coronary syndromes(ACSs) than with previous cTn assay generations which are still more commonly used in practice worldwide.hs-cTn is also more sensitive for the detection of myocardial damage unrelated to acute myocardial ischemia.Therefore,the increase in early diagnostic sensitivity of hs-cTn assays for ACS comes at the cost of a reduced ACS specificity,because more patients with other causes of acute or chronic myocardial injury without overt myocardial isch-emia are detected than with previous cTn assays.As hs-cTn assays are increasingly being adopted in clinical practice and more hs-cTn assays are being developed,this review attempts to synthesize the available clinical data to make recommendations for their everyday clini-cal routine use.
文摘New endoscopic techniques for hemostasis in nonvariceal bleeding were introduced and known methods further improved. Hemospray and Endoclot are two new compounds for topical treatment of bleeding. Initial studies in this area have shown a good hemostatic effect, especially in active large scale oozing bleeding, e.g., tumor bleedings. For further evaluation larger prospective studies comparing the substanced with other methods of endoscopic hemostasis are needed. For localized active arterial bleeding primary injection therapy in the area of bleeding as well as in the four adjacent quadrants offers a good method to reduce bleeding activity. The injection is technically easy to learn and practicable. After bleeding activity is reduced the bleeding source can be localized more clearly for clip application. Today many different through-thescope(TTS) clips are available. The ability to close and reopen a clip can aid towards good positioning at the bleeding site. Even more important is the rotatability of a clip before application. Often multiple TTS clips are required for secure closure of a bleeding vessel. One model has the ability to use three clips in series without changing the applicator. Severe arterial bleeding from vessels larger than 2 mm is often unmanageable with these conventional methods. Here is the over-the-scopeclip system another newly available method. It is similar to the ligation of esophageal varices and involves aspiration of tissue into a transparent cap before closure of the clip. Thus a greater vascular occlusion pressure can be achieved and larger vessels can be treated endoscopically. Patients with severe arterial bleeding from the upper gastrointestinal tract have a very high rate of recurrence after initial endoscopic treatment. These patients should always be managed in an interdisciplinary team of interventional radiologist and surgeons.
文摘AIM: To evaluate the use of translumenal pancreatography with placement of endoscopic ultrasonography(EUS)-guided drainage of the pancreatic duct.METHODS: This study enrolled all consecutive patients between June 2002 and April 2014 who underwent EUSguided pancreatography and subsequent placement of a drain and had symptomatic retention of fluid in the pancreatic duct after one or more previous unsuccessful attempts at endoscopic retrograde cannulation of the pancreatic duct. In all,94 patients underwent 111 interventions with one of three different approaches:(1) EUS-endoscopic retrograde drainage with a rendezvous technique;(2) EUS-guided drainage of the pancreatic duct; and(3) EUS-guided,internal,antegrade drainage of the pancreatic duct.RESULTS: The mean duration of the interventions was 21 min(range,15-69 min). Mean patient age was 54 years(range,28-87 years); the M:F sex ratio was 60:34. The technical success rate was 100%,achieving puncture of the pancreatic duct including pancreatography in 94/94 patients. In patients requiring drainage,initial placement of a drain wassuccessful in 47/83 patients(56.6%). Of these,26 patients underwent transgastric/transbulbar positioning of a stent for retrograde drainage; plastic prostheses were used in 11 and metal stents in 12. A ring drain(antegrade internal drainage) was placed in three of these 26 patients because of anastomotic stenosis after a previous surgical intervention. The remaining 21 patients with successful drain placement had transpapillary drains using the rendezvous technique; the majority(n = 19) received plastic prostheses,and only two received metal stents(covered self-expanding metal stents). The median follow-up time in the 21 patients with transpapillary drainage was 28 mo(range,1-79 mo),while that of the 26 patients with successful transgastric/transduodenal drainage was 9.5 mo(range,1-82 mo). Clinical success,as indicated by reduced or absence of further pain after the EUS-guided intervention was achieved in 68/83 patients(81.9%),including several who improved without drainage,but with manipulation of the access route.CONCLUSION: EUS-guided drainage of the pancreatic duct is a safe,feasible alternative to endoscopic retrograde drainage when the papilla cannot be reached endoscopically or catheterized.
基金supported by CONACYT/UNAMsupported by Fundación para la Salud y Educación "Salvador Zubirán". Francisco Javier Cubero is a Ramón y Cajal Researcher (RYC-2014-15242)
文摘AIM Evaluate the association between phase angle and the development of hepatic encephalopathy in the longterm follow-up of cirrhotic patients.METHODS This was a prospective cohort study. Clinical, nutritional and biochemical evaluations were performed. MannWhitney's U and χ2 tests were used as appropriate. Kaplan-Meier curves and Cox proportional Hazards analysis were used to evaluate the prediction and incidence of hepatic encephalopathy.RESULTS Two hundred and twenty were included; the most frequent etiology of cirrhosis was hepatitis C infection, 52% of the patients developed hepatic encephalopathy(18.6% covert and 33.3% overt); the main precipitating factors were infections and variceal bleeding. KaplanMeier curves showed a higher proportion of HE in the group with low phase angle(39%) compared to the normal phase angle group(13%)(P = 0.012). Furthermore, creatinine and phase angle remained independently associated to hepatic encephalopathy in the Cox regression multivariate analysis [hazard ratio = 1.80(1.07-3.03)]. CONCLUSION In our cohort of patients low phase angle was associated with an increased incidence of hepatic encephalopathy. Phase angle is a useful nutritional marker that evaluates cachexia and could be used as a part of the integral assessment in patients with cirrhosis.
文摘In patients with history of coronary artery disease angina pectoris is usually attributed to the progression of atherosclerotic lesions. However,in patients with previous coronary artery bypass graft operation(CABG) using internal mammary artery grafts,great vessel disease should also be considered. Herein we present two patients with history of CABG whose symptoms were suspicious for coronary ischemia. During cardiac catheterization reverse blood flow was observed from the left artery disease to the left internal mammary artery(LIMA) graft in both cases. After angioplasty and stent implantation of the left subclavian artery antegrade flow was restored in the LIMA grafts and both patients had complete resolution of symptoms.
基金Supported by The Münchener Medizinische Wochenschrift(MMW)B.Braun-Stiftung(to Reiter FP)the Deutsche Forschungsgemeinschaft(HO 4460/2-1 to Hohenester S and RU 742/6-1 to Rust C)
文摘AIM: To study the interleukin-1(IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4^(-/-)(Abcb4^(-/-)) mouse model.METHODS: Female and male Abcb4^(-/-) mice from 6 to 13 mo of age were analysed for the degree of cholestasis(liver serum tests), extent of liver fibrosis(hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the IL-1 pathway [quantitative polymerase chain reaction(q PCR)]. For in vivo experiments, murine hepatic stellate cells(HSCs) were isolated via pronasecollagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/m L IL-1β with or without 2.5 μg/m L Anakinra, an IL-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the Brd U assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis(FDH) assay. In vivo 8-wk-old Abcb4^(-/-) mice with an already fully established hepatic phenotype were treated with Anakinra(1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, q PCR, hydroxyproline content and Sirius red staining. RESULTS: Liver fibrosis was less pronounced in males than in female Abcb4^(-/-) animals as defined by a lower hydroxyproline content(274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P < 0.001; MannWhitney U-test) and lower m RNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1(TIMP)(1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P < 0.05; Mann-Whitney U-test). Reduced liver fibrosis was associated with significantly lower levels of F4/80 m RNA expression(1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P < 0.05; Mann-Whitney U-test) and significantly lower IL-1β m RNA expression levels(1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P < 0.001; Mann-Whitney U-test). No gender differences in the serum liver parameters [bilirubin; alanine aminotransferase(ALT); aspartate aminotransferase and alkaline phosphatase(AP)] were found. In vitro, the administration of IL-1β resulted in a significant increase in HSC proliferation [0.94 ± 0.72 arbitrary units(A.U.) in untreated controls, 1.12 ± 0.80 A.U. at an IL-1β concentration of 0.1 ng/m L and 1.18 ± 0.73 A.U. at an IL-1β concentration of 1 ng/m L in samples from n = 6 donor animals; P < 0.001; analyses of variance(ANOVA)]. Proliferation was reduced significantly by the addition of 2.5 μg/m L Anakinra(0.81 ± 0.60 A.U. in untreated controls, 0.92 ± 0.68 A.U. at an IL-1β concentration of 0.1 ng/m L, and 0.91 ± 0.69 A.U. at an IL-1β concentration of 1 ng/m L; in samples from n = 6 donor animals; P < 0.001; ANOVA) suggesting an anti-proliferative effect of this clinically approved IL-1 receptor antagonist. The FDH assay showed this dose to be non-toxic in HSCs. In vivo, Anakinra had no effect on the hepatic hydroxyprolinecontent, liver serum tests(ALT and AP) and profibrotic(collagen 1α1, collagen 1α2, transforming growth factor-β, and TIMP-1) and anti-fibrotic [matrix metalloproteinase 2(MMP2), MMP9 and MMP13 ] gene expression after 4 wk of treatment. Furthermore, the hepatic IL-1β and F4/80 m RNA expression levels were unaffected by Anakinra treatment.CONCLUSION: IL-1β expression is associated with the degree of liver fibrosis in Abcb4^(-/-) mice and promotes HSC proliferation. IL-1 antagonism shows antifibrotic effects in vitro but not in Abcb4^(-/-) mice.
基金Supported by Deutsche Forschungsgemeinschaft SFB/TRR57,P13 and P26A grant from the Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the RWTH Aachen University IZKF Aachen,Project E6-11,to Weiskirchen R
文摘Endoglin, also known as cluster of differentiation CD105, was originally identified 25 years ago as a novel marker of endothelial cells. Later it was shown that endoglin is also expressed in pro-fibrogenic cells including mesangial cells, cardiac and scleroderma fibroblasts, and hepatic stellate cells. It is an integral membranebound disulfide-linked 180 kDa homodimeric receptor that acts as a transforming growth factor-β(TGF-β) auxiliary co-receptor. In humans, several hundreds of mutations of the endoglin gene are known that give rise to an autosomal dominant bleeding disorder that is characterized by localized angiodysplasia and arteriovenous malformation. This disease is termed hereditary hemorrhagic telangiectasia type Ⅰ and induces various vascular lesions, mainly on the face, lips, hands and gastrointestinal mucosa. Two variants of endoglin(i.e., S- and L-endoglin) are formed by alternative splicing that distinguishes from each other in the length of their cytoplasmic tails. Moreover, a soluble form of endoglin, i.e.,sol-Eng, is shedded by the matrix metalloprotease-14 that cleaves within the extracellular juxtamembrane region. Endoglin interacts with the TGF-β signaling receptors and influences Smad-dependent and-independent effects. Recent work has demonstrated that endoglin is a crucial mediator during liver fibrogenesis that critically controls the activity of the different Smad branches. In the present review, we summarize the present knowledge of endoglin expression and function, its involvement in fibrogenic Smad signaling, current models to investigate endoglin function, and the diagnostic value of endoglin in liver disease.
文摘Pancreatic ductal adenocarcinoma(PDA) is one of the major causes for cancer death worldwide. Treatment of metastatic disease remains challenging as only certain patients benefit from advances made with the intensified chemotherapy regimen folinic acid, irinotecan and oxaliplatin, the epidermal growth factor receptor inhibitor erlotinib or the recently FDA-approved nab-paclitaxel. Up to date, no established approach for prediction of treatment response or specific treatment allocation exists. Translational research was able to identify a number of potential biomarkers that might help to improve the dismal prognosis of PDA by facilitating upfront treatment allocation. This topic highlight is focused on current evidence on potential biomarkers for tumor biology, prognosis and prediction of treatment efficacy.
文摘AIM： To investigate the prevalence, risk factors, and selection of the study population for cholecystolithiasis in an urban population in Germany, in relation to our own findings and to the results in the international literature. METHODS： A total of 2 147 persons （1 111 females, age 42.8 ＋ 12.7 years; 1 036 males, age 42.3 ＋ 13.1 years） participating in an investigation on the prevalence of Echinococcus rnultilocularis were studied for risk factors and prevalence of gallbladder stone disease. Risk factors were assessed by means of a standardized interview and calculation of body mass index （BMI）. A diagnostic ultrasound examination of the gallbladder was performed. Data were analyzed by multiple logistic regression, using the SAS statistical software package. RESULTS： Gallbladder stones were detected in 171 study participants （8.0%, n = 2 147）. Risk factors for the development of gallbladder stone disease included age, sex, BMI, and positive family history. In a separate analysis of female study participants, pregnancy （yes/no） and number of pregnancies did not exert any influence. CONCLUSION： Findings of the present study confirm that age, female sex, BMI, and positive family history are risk factors for the development of gallbladder stone disease. Pregnancy and the number of pregnancies, however, could not be shown to be risk factors. There seem to be no differences in the respective prevalence for gallbladder stone disease in urban and rural populations.
文摘BACKGROUND Wilson’s disease(WD)is a rare autosomal recessive inherited disorder of copper metabolism.Acute liver failure(ALF)and hemolytic anemia represent the most severe presentation of WD in children.No clear genotype-phenotype correlations exist in WD.Protein-truncating nonsense,frame-shift,or splice-site variants may be associated with more severe disease.In contrast,missense variants may be associated with late-onset,less severe disease,and more neurological manifestations.Recently,a gene variant(HSD17B13:TA,rs72613567)with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed.The clinical manifestations(ALF with non-immune hemolytic anemia or other less severe forms),laboratory parameters,copper metabolism,ATP7B variants,and the HSD17B13:TA(rs72613567)variant were reviewed to analyze the possible genotype-phenotype correlations.RESULTS We analyzed the data of 51 patients with WD,26 females(50.98%),with the mean age at the diagnosis of 12.36±3.74 years.ALF and Coombs-negative hemolytic anemia was present in 8 children(15.67%),all adolescent girls.The Kayser-Fleisher ring was present in 9 children(17.65%).The most frequent variants of the ATP7B gene were p.His1069Gln(c.3207A>G)in 38.24% of all alleles,p.Gly1341Asp(c.4021G>A)in 26.47%,p.Trp939Cys(c.2817G>T)in 9.80%,and p.Lys844Ter(c.2530A>T)in 4.90%.In ALF with hemolytic anemia,p.Trp939Cys(c.2817G>T)and p.Lys844Ter(c.2530A>T)variants were more frequent than in other less severe forms,in which p.His1069Gln(c.3207A>G)was more frequent.p.Gly1341Asp(c.4021G>A)has a similar frequency in all hepatic forms.For 33 of the patients,the HSD17B13 genotype was evaluated.The overall HSD17B13:TA allele frequency was 24.24%.Its frequency was higher in patients with less severe liver disease(26.92%)than those with ALF and hemolytic anemia(14.28%).CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients.In children with ALF and hemolytic anemia,the missense variants other than p.His1069Gln(c.3207A>G)and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants.As genetic analysis is usually time-consuming and the results are late,the importance at the onset of the ALF is questionable.If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease,this could be essential to predict a possible severe evolution.
文摘The mammalian target of rapamycin(mTOR)acts in two structurally and functionally distinct protein complexes,mTOR complex 1(mTORC1)and mTOR complex 2(mTORC2).Upon deregulation,activated mTOR signaling is associated with multiple processes involved in tumor growth and metastasis.Compared with mTORC1,much less is known about mTORC2 in cancer,mainly because of the unavailability of a selective inhibitor.However,existing data suggest that mTORC2 with its two distinct subunits Rictor and mSin1 might play a more important role than assumed so far.It is one of the key effectors of the PI3K/AKT/mTOR pathway and stimulates cell growth,cell survival,metabolism,and cytoskeletal organization.It is not only implicated in tumor progression,metastasis,and the tumor microenvironment but also in resistance to therapy.Rictor,the central subunit of mTORC2,was found to be upregulated in different kinds of cancers and is associated with advanced tumor stages and a bad prognosis.Moreover,AKT,the main downstream regulator of mTORC2/Rictor,is one of the most highly activated proteins in cancer.Primary and secondary liver cancer are major problems for current cancer therapy due to the lack of specific medical treatment,emphasizing the need for further therapeutic options.This review,therefore,summarizes the role of mTORC2/Rictor in cancer,with special focus on primary liver cancer but also on liver metastases.
