Hideo A Baba

Publications (85)445.07 Total impact

• Article: Expression of Apoptosis- and Vitamin D Pathway-Related Genes in Hepatocellular Carcinoma.

  Christian D Fingas, Akif Altinbas, Martin Schlattjan, Anja Beilfuss, Jan-Peter Sowa, Svenja Sydor, Lars P Bechmann, Judith Ertle, Hikmet Akkiz, Kerstin Herzer, Andreas Paul, Guido Gerken, Hideo A Baba, Ali Canbay
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  ABSTRACT: Background/Aims: Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and therapeutic options are scarce. As they might represent future targets for cancer therapy, the expression of apoptosis-related genes in HCC is of particular interest. In this pilot study, we further examined apoptosis-related genes in human HCC and also focused on vitamin D signaling as this might be a regulator of HCC cell apoptosis. Methods: We employed tumor tissue and serum samples from 62 HCC patients as well as 62 healthy controls for these studies. Tissue and serum specimens were analyzed by quantitative RT-PCR, immunohistochemistry and ELISA. Results: In HCC patients the apoptosis marker M30 was found to be elevated and several pro-apoptotic (TRAIL, FasL and FasR) as well as anti-apoptotic genes (Mcl-1 and Bcl-2) were simultaneously upregulated in tumor tissue and especially tumor-surrounding tissue as compared to healthy control livers. Moreover, vitamin D serum levels were decreased in HCC patients whereas vitamin D receptor mRNA expression was increased in tumor tissue and tumor-surrounding tissue as compared to healthy livers. Conclusions: In human HCC, M30 serum levels are elevated indicating an increased cell turnover. Modulation of the vitamin D pathway might be a supportive, pro-apoptotic HCC therapy.
  Digestion 04/2013; 87(3):176-181. · 2.05 Impact Factor
• Article: Novel prognostic scoring system after surgery for klatskin tumor.

  Gernot M Kaiser, Andreas Paul, George Sgourakis, Ernesto P Molmenti, Alexander Dechêne, Tanja Trarbach, Martin Stuschke, Hideo A Baba, Guido Gerken, Georgios C Sotiropoulos
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  ABSTRACT: Klatskin tumor is a rare hepatobiliary malignancy whose outcome and prognostic factors are not clearly documented. Between April 1998 and January 2007, 96 patients with hilar cholangiocarcinoma underwent resection. Data were collected prospectively. Thirty-one variables were evaluated for prognostic significance. There were 40 trisectionectomies, 40 hemihepatectomies, five central hepatectomies, and 11 biliary hilar resections. Thirty-seven (n = 37) patients required vascular reconstruction. There were 68 R0, 26 R1, and two R2 resections. Age (P = 0.048), pT status (P = 0.046), R class (P = 0.034), and adjuvant chemoradiation (P = 0.045) showed predictive significance by multivariate Cox proportional hazard regression analysis. A point scoring system was determined as follows: age younger than 62 years:age 62 years or older = 1:2 points; pT1:pT2 to 4 = 1:2 points; R0:R1/2 = 1:2 points; and chemoradiation yes:no = 1:2 points. The only model that reached statistical significance (P = 0.0332) described the following three groups: score 6 or less; score = 7; and score = 8. Median survival for score 6 or less, score = 7, and score = 8 was 26.5, 12, and 2.2 months, respectively (P = 0.032). The corresponding 1- and 3-year survival rates were 73 to 56 per cent, 52 to 38 per cent, and 17 to 0 per cent, respectively. We propose a scoring system predictive of long-term surgical outcome that could potentially improve patient selection for further postoperative oncologic treatment for Klatskin tumors.
  The American surgeon 01/2013; 79(1):90-5. · 1.28 Impact Factor
• Article: Steatosis does not impair liver regeneration after partial hepatectomy.

  Svenja Sydor, Yanli Gu, Martin Schlattjan, Lars P Bechmann, Ursula Rauen, Jan Best, Andreas Paul, Hideo A Baba, Jan-Peter Sowa, Guido Gerken, Ali Canbay
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  ABSTRACT: Hepatic steatosis is a key feature of non-alcoholic fatty liver disease (NAFLD). While storage of lipid droplet-bound triglycerides in simple steatosis is physiologically inert, non-alcoholic steatohepatitis (NASH) is associated with hepatocyte damage and apoptosis. Mitochondrial oxidation of free fatty acids (FFA), derived from lipid droplets and hepatocellular uptake, is a rapid and effective way of energy supply for proliferating cells and FFA esterification provides substrates for lipid synthesis and cell proliferation. Thus, we investigated whether simple steatosis induced by western diet (WD) improves liver regeneration after partial hepatectomy (PHx). WD feeding for 6 weeks caused simple steatosis with hepatic lipid droplet and triglyceride accumulation accompanied by induction of fatty acid transport proteins (FATP), death receptors (DR), pro- and anti-apoptotic genes, hepatocyte growth factor (Hgf) as well as increased serum leptin levels in a mouse model. After PHx, liver cell proliferation was higher in WD-fed mice and associated with FATP and Hgf induction. In addition, Erk1/2 (extracellular-related MAP kinase 1/2) dephosphorylation observed in standard diet (SD) mice was reduced in WD animals. PHx in steatotic livers did not affect hepatocyte apoptosis, despite DR upregulation. WD-induced steatosis enhances liver cell proliferation, which is accompanied by increased Hgf and leptin signaling as well as Erk1/2 phosphorylation. Induction of mild steatosis may therefore be beneficial for surgical outcome of hepatectomies.Laboratory Investigation advance online publication, 15 October 2012; doi:10.1038/labinvest.2012.142.
  Laboratory Investigation 10/2012; · 3.64 Impact Factor
• Article: 55-jährige Patientin mit Thymom und Hypogammaglobulinämie (Good-Syndrom), Colitis ulcerosa sowie CMV-Infektion

  Alisan Kahraman, Michael Miller, Evelyn Maldonado-Lopez, Hideo A. Baba, Ulrich Treichel, Guido Gerken
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  ABSTRACT: Fallbeschreibung: Die Autoren berichten über eine 55-jährige Patientin nach erfolgter R1-Resektion eines Thymoms vom Spindelzelltyp (Typ A nach WHO, Masaoka-Stadium III), die ihnen zur weiteren Therapie einer Colitis ulcerosa zugewiesen wurde. Eine adjuvante Radiochemotherapie war aufgrund der ausgeprägten Aktivität der Colitis ulcerosa vorerst nicht vertretbar. Unter immunsuppressiver Behandlung mit Azathioprin und Steroiden entwickelte die Patientin eine Zytomegalievirus-(CMV-)Enteritis, die durch die azathioprininduzierte Leukopenie begünstigt worden war. Unter Umstellung der Immunsuppression von Azathioprin auf Mycophenolatmofetil (MMF) sowie der Gabe von Cidofovir aufgrund einer Ganciclovirrefraktärität der CMV-Ulzera und einer gleichzeitigen Foscarnet-Natrium-(Foscavir®-)Unverträglichkeit der Patientin kam es zur raschen Besserung der Klinik. Zusätzlich erhielt die Patientin aufgrund ihres Antikörpermangelsyndroms Immunglobuline in 3- bis 4-wöchigen Abständen. Mittlerweile 3,5 Jahre nach erfolgter R1-Resektion ist die Patientin unter Immunsuppression mit MMF weiterhin ohne Anhalt für ein Rezidiv des Thymoms. Zudem zeigt sich auch die Colitis ulcerosa in Remission. Schlussfolgerung: Dieser Fallbericht veranschaulicht eine seltene Erkrankung aus Thymom und Antikörpermangelsyndrom, welche erstmalig von Robert Good beschrieben wurde, und weist auf die Wichtigkeit der immunsuppressiven Behandlung und der Beherrschung opportunistischer Infektionen hin. Case Report: The authors report on a 55-year-old female patient after R1 resection of a malignant thymoma with spindle type epithelial cells (WHO type A, Masaoka stage III) referred for further therapy of an ulcerative colitis. At that time, both adjuvant radiation and cytostatic therapy were not applicable due to severe activity of the ulcerative colitis. Under immunosuppressive treatment with azathioprine and steroids, the patient developed cytomegalovirus (CMV) enteritis which was triggered by therapy-induced leukopenia. After a switch from azathioprine to mycophenolatmofetil (MMF) treatment and administration of cidofovir because of nonresponse to ganciclovir and incompatibility of foscarnet sodium (Foscavir®), the patient clinically improved. In addition, the patient was treated with immunoglobulins every 3–4 weeks because of antibody deficiency. At present, 3.5 years after R1 resection, the patient still has no clues of a remaining tumor mass under current immunosuppressive therapy. Ulcerative colitis is also in complete remission stage. Conclusion: This case indicates the very rare features of a syndrome with thymoma and antibody deficiency which was first described by Robert Good. Furthermore, the impact of immunosuppressive therapy and management of opportunistic infections on the course of this disease is obvious.
  04/2012; 104(2):150-154.
• Article: Modulation of SR Ca2+ release by the triadin-to-calsequestrin ratio in ventricular myocytes.

  Dana Kučerová, Hideo A Baba, Peter Bokník, Larissa Fabritz, Alexander Heinick, Marek Mát'uš, Frank U Müller, Joachim Neumann, Wilhelm Schmitz, Uwe Kirchhefer
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  ABSTRACT: Calsequestrin (CSQ) is a Ca(2+) storage protein that interacts with triadin (TRN), the ryanodine receptor (RyR), and junctin (JUN) to form a macromolecular tetrameric Ca(2+) signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). Heart-specific overexpression of CSQ in transgenic mice (TG(CSQ)) was associated with heart failure, attenuation of SR Ca(2+) release, and downregulation of associated junctional SR proteins, e.g., TRN. Hence, we tested whether co-overexpression of CSQ and TRN in mouse hearts (TG(CxT)) could be beneficial for impaired intracellular Ca(2+) signaling and contractile function. Indeed, the depressed intracellular Ca(2+) concentration ([Ca](i)) peak amplitude in TG(CSQ) was normalized by co-overexpression in TG(CxT) myocytes. This effect was associated with changes in the expression of cardiac Ca(2+) regulatory proteins. For example, the protein level of the L-type Ca(2+) channel Ca(v)1.2 was higher in TG(CxT) compared with TG(CSQ). Sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) expression was reduced in TG(CxT) compared with TG(CSQ), whereas JUN expression and [(3)H]ryanodine binding were lower in both TG(CxT) and TG(CSQ) compared with wild-type hearts. As a result of these expressional changes, the SR Ca(2+) load was higher in both TG(CxT) and TG(CSQ) myocytes. In contrast to the improved cellular Ca(2+), transient co-overexpression of CSQ and TRN resulted in a reduced survival rate, an increased cardiac fibrosis, and a decreased basal contractility in catheterized mice, working heart preparations, and isolated myocytes. Echocardiographic and hemodynamic measurements revealed a depressed cardiac performance after isoproterenol application in TG(CxT) compared with TG(CSQ). Our results suggest that co-overexpression of CSQ and TRN led to a normalization of the SR Ca(2+) release compared with TG(CSQ) mice but a depressed contractile function and survival rate probably due to cardiac fibrosis, a lower SERCA2a expression, and a blunted response to β-adrenergic stimulation. Thus the TRN-to-CSQ ratio is a critical modulator of the SR Ca(2+) signaling.
  AJP Heart and Circulatory Physiology 03/2012; 302(10):H2008-17. · 3.71 Impact Factor
• Article: Gilbert's syndrome--a frequent cause of unconjugated hyperbilirubinemia in children after orthotopic liver transplantation.

  Simone Kathemann, Elke Lainka, Hideo A Baba, Peter F Hoyer, Patrick Gerner
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  ABSTRACT: Gilbert's syndrome is one major cause for unconjugated hyperbilirubinemia in healthy individuals with the prevalence being approximately 3.2-8.6%. It is caused by a mutation in the promoter region of the UGT1A1-gene with a prolonged TAA-repeat coding for the enzyme bilirubin UDP-glucuronosyltransferase (A(TA)(7) TAA allele). After OLT, Gilbert's disease of the transplanted liver can cause unconjugated hyperbilirubinemia. Therefore, we looked for the presence of A(TA)(7) TAA alleles in pediatric liver transplant recipients with unconjugated hyperbilirubinemia. Laboratory results of 106 pediatric liver transplant recipients (aged 0-17 yr) were evaluated for elevated total bilirubin over 2.0 mg/dL (conjugated bilirubin <30%). In these patients, DNA of the liver graft was extracted from paraffin-embedded liver biopsy samples formerly taken for diagnostic reasons. The DNA was analyzed for A(TA)(7) TAA alleles in the promoter region of the UGT1A1-gene. In 4 of 106 pediatric liver transplant recipients we found unconjugated hyperbilirubinemia with total bilirubin above 2.0 mg/dL (conjugated bilirubin <30%). The analysis of the promoter region of the UGT1A1-gene of the liver grafts showed three homozygous A(TA)(7) TAA alleles (homozygous Gilbert's syndrome) and one heterozygous A(TA)(7) TAA allele (heterozygous Gilbert's syndrome). This study shows that pediatric liver transplant recipients with unconjugated hyperbilirubinemia are very likely to have received a liver graft from a donor with Gilbert's syndrome.
  Pediatric Transplantation 03/2012; 16(2):201-4. · 1.48 Impact Factor
• Article: Elevated gamma-glutamyltransferase is associated with mortality in lung transplantation for cystic fibrosis.

  Alexander Wree, Lars P Bechmann, Nevitha Kumarasamy, Urte Sommerwerck, Christoph Jochum, Heinz Jakob, Hideo A Baba, Guido Gerken, Markus Kamler, Ali Canbay
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  ABSTRACT: Cystic fibrosis (CF) is a life-threatening autosomal recessive hereditary disease, affecting multiple organs. In end stage disease, lung transplantation improves the quality of life and prolongs survival. CF liver disease (CFLD) as co-morbidity develops in 8-17% of CF patients. We aimed to investigate the impact of liver injury on prognosis following lung transplantation. Thirty-one patients with CF who underwent double lung transplantation (DLTx) from 1999 to 2009 were included. Post-transplant survival, liver serum parameters as well as INR, creatinine and the MELD-Score were determined preoperatively, 1 day and 4 weeks postoperatively. Prognostic impact of liver function on outcome was analysed. Mean patient age was 25 (15-38) and post-transplant 1 year-survival was 74%, 3 years 71% and 5 years 68%. Patients were grouped according to post-transplant survival, those deceased within the first year as group I (n = 8) and patients who survived longer as group II (n = 23). Group I exhibited significantly elevated gamma-glutamyltransferase (GGT), bilirubin and reduced platelets postoperatively. Low platelet count, increased bilirubin and GGT were associated with mortality after DLTx. Prospective studies are needed to determine a potential use and clinical implications for liver function tests in patients with CF before lung transplantation.
  Transplant International 01/2012; 25(1):78-86. · 2.92 Impact Factor
• Article: Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I.

  Stefan Frantz, Michael Klaiber, Hideo A Baba, Heike Oberwinkler, Katharina Völker, Birgit Gaβner, Barbara Bayer, Marco Abeβer, Kai Schuh, Robert Feil, Franz Hofmann, Michaela Kuhn
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  ABSTRACT: AimsCardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism.Methods and resultsTo circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the [Ca(2+)](i)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser(16), the specific target site for cGKI, resulting in altered myocyte Ca(2+)(i) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, Ca(2+)(i)-handling, and contractility via cGKI.ConclusionThese results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte Ca(2+)(i) handling and contractility.
  European Heart Journal 12/2011; · 10.48 Impact Factor
• Article: Large tumor of the liver and hypoglycemic shock in an 85-year-old patient.

  Sonia Radunz, Hideo A Baba, Georgios C Sotiropoulos
  Gastroenterology 12/2011; 142(2):e10-1. · 11.68 Impact Factor
• Article: Klatskin tumors and the accuracy of the Bismuth-Corlette classification.

  Andreas Paul, Gernot M Kaiser, Ernesto P Molmenti, Tobias Schroeder, Spiridon Vernadakis, Arzu Oezcelik, Hideo A Baba, Vito R Cicinnati, Georgios C Sotiropoulos
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  ABSTRACT: The Bismuth-Corlette (BC) classification is the current preoperative standard to assess hilar cholangiocarcinomas (HC). The aim of this study is to evaluate the accuracy, sensitivity, and prognostic value of the BC classification. Data of patients undergoing resection for HC were analyzed. Endoscopic retrograde cholangiography and standard computed tomography were undertaken in all cases. Additional 3D-CT-reconstructions, magnetic resonance imaging, and percutaneous transhepatic cholangiography were obtained in selected patients. A systematic review and meta-analysis of the literature was performed. Ninety patients underwent resection of the hilar bile duct confluence, with right or left hemihepatectomy in 68 instances. The overall accuracy of the BC classification was 48 per cent. Rates of BC under- and over-estimation were 29 per cent and 23 per cent, respectively. The addition of MRI, 3D-CT-reconstructions, or percutaneous transhepatic cholangiography improved the accuracy to 49 per cent (P = 1.0), 53 per cent (P = 0.074), and 64 per cent (P < 0.001), respectively. Lowest sensitivity rates were for BC Type IIIA/IIIB tumors. Meta-analysis of published BC data corresponding to 540 patients did not reach significance. The BC classification has low accuracy and no prognostic value in cases of HC undergoing resection.
  The American surgeon 12/2011; 77(12):1695-9. · 1.28 Impact Factor
• Article: Long-term follow-up after right hepatectomy for adult living donation and attitudes toward the procedure.

  Georgios C Sotiropoulos, Arnold Radtke, Ernesto P Molmenti, Tobias Schroeder, Hideo A Baba, Andrea Frilling, Christoph E Broelsch, Massimo Malagó
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  ABSTRACT: To determine the long-term health status of donors after right hepatectomy for adult live donor liver transplantation (ALDLT). The long-term outcomes for ALDLT donors are unknown. ALDLT donors undergoing right hepatectomy from April 1998 to June 2007 were invited to complete a questionnaire regarding health status, satisfaction (1-10/worst-best scale), self-esteem, willingness to donate again, and suggestions for improvement. In addition, donor files and cholecystectomy specimens were reviewed. Fisher's exact test, Kaplan-Meier and logistic regression analyses were performed. Eighty-three donors were contacted (median age: 36 years; median follow-up: 69 months). 39 (47%) were free of symptoms. The remaining 44 (53%) reported: intolerance to fatty meals and diarrhea (31%), gastroesophageal reflux associated with left liver hypertrophy (9%), incisional discomfort requiring pain medications (6%), severe depression requiring hospitalization (4%), rib pain affecting lifestyle (2%), and exacerbation of psoriasis (1%). Median satisfaction score was 8. Self-esteem diminished in 5%. Thirty-nine (47%) recommended improvements particularly more detailed informed donor consent and a centralized living donor liver registry. Seventy-eight (94%) were willing to donate again. There were no differences between donors with and without complaints with respect to: donor age, gender, early complications and follow-up time, young-to-old donation, recipient diagnosis of malignancy and death of the recipient. Noninflamed donor cholecystectomy specimens correlated with intolerance to fatty meals and diarrhea (P = 0.001). ALDLT donors are at risk for long-term complaints that are neither reflected nor related to early complications. This information should be included in both the donor evaluation and the ALDLT decision-making process.
  Annals of surgery 11/2011; 254(5):694-700; discussion 700-1. · 7.90 Impact Factor
• Article: AKR1B10 expression is associated with less aggressive hepatocellular carcinoma: a clinicopathological study of 168 cases.

  Klaus J Schmitz, Georgios C Sotiropoulos, Hideo A Baba, Kurt W Schmid, Doris Müller, Andreas Paul, Thomas Auer, Gabriele Gamerith, Judith Loeffler-Ragg
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  ABSTRACT: The detoxification enzyme AKR1B10, a member of the aldo-keto reductase superfamily, is discussed as a new biomarker candidate for hepatocellular carcinoma (HCC). Only rare clinicopathological data on AKRB1B10 in HCC exist. This retrospective study determines the diagnostic and prognostic relevance of AKR1B10 expression in HCC and its relationship to a series of clinicopathological parameters including underlying aetiological factors. A series of 168 patients with HCCs treated either by surgical resection (n=92) or liver transplantation (n=76) were investigated after construction of a tissue micro-array. Immunohistochemically confirmed AKR1B10 expression was correlated with clinicopathologically relevant parameters as well as proliferative activity (indicated by Ki-67 immunostaining) and apoptosis (terminal deoxyribonucleotide transferase-mediated dUTP nick-end labelling). AKR1B10 overexpression is significantly associated with lower pT-classification (P=0.030) and highly statistically associated with an underlying viral hepatitis (P<0.001) and the presence of cirrhosis (P<0.001). In addition, loss of AKR1B10 expression correlates with increased proliferative activity (Ki-67, P=0.001). Kaplan-Meier survival analysis of the resection group reveals a poorer prognosis in patients with AKR1B10-negative HCCs compared with patients with strongly positive HCCs (P=0.046). This study confirms and expands data on the expression of AKR1B10 in HCC, suggesting that this enzyme is a valuable novel biomarker candidate for staging of HCC, especially in patients with underlying virus hepatitis or cirrhosis, and may present a new therapeutic target for multimodal therapy concepts. We confirm its prognostic value and conclude that high expression of AKR1B10 reflects a less aggressive tumour behaviour.
  Liver international: official journal of the International Association for the Study of the Liver 07/2011; 31(6):810-6. · 3.82 Impact Factor
• Article: Clinical, molecular, and genomic changes in response to a left ventricular assist device.

  Jennifer L Hall, David R Fermin, Emma J Birks, Paul J R Barton, Mark Slaughter, Peter Eckman, Hideo A Baba, Jeremias Wohlschlaeger, Leslie W Miller
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  ABSTRACT: The use of left ventricular assist devices in treating patients with end-stage heart failure has increased significantly in recent years, both as a bridge to transplantation and as destination therapy in those who are ineligible for cardiac transplantation. This increase is based largely on the results of several recently completed clinical trials with the new second-generation continuous-flow devices that showed significant improvements in survival, functional capacity, and quality of life. Additional information on the use of the first- and second-generation left ventricular assist devices has come from a recently released report spanning the years 2006 to 2009, from the Interagency Registry for Mechanically Assisted Circulatory Support, a National Heart, Lung, and Blood Institute-sponsored collaboration between the U.S. Food and Drug Administration, the Centers for Medicare and Medicaid Services, and the scientific community. The authors review the latest clinical trials and data from the registry, with tight integration of the landmark molecular, cellular, and genomic research that accompanies the reverse remodeling of the human heart in response to a left ventricular assist device and functional recovery that has been reported in a subset of these patients.
  Journal of the American College of Cardiology 02/2011; 57(6):641-52. · 14.16 Impact Factor
• Chapter: Left Ventricular Assist Device: Morphological, Molecular, and Genetic Changes After Mechanical Support

  Hideo A. Baba, Atsushi Takeda, Nobuakira Takeda, Jeremias Wohlschlaeger
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  ABSTRACT: Left ventricular assist devices (LVADs) are currently used to either “bridge” patients with terminal congestive heart failure (CHF) to cardiac transplantation or optionally for patients with contraindications for transplantation (“destination therapy”). Mechanical support is associated with a marked decrease of cardiac dilation and hypertrophy as well as numerous cellular and molecular changes (“reverse cardiac remodeling”), which can be accompanied by improved cardiac function (“bridge to recovery”) in a relatively small subset of patients. In these patients, heart transplantation is no longer necessary even after removal of the device (“weaning”). In the recent past, novel pharmacological strategies have been developed and are combined with mechanical support, which has increased the percentage of patients with improved clinical status and cardiac performance. Gene expression profiles have demonstrated that individuals who recover after LVADs show different gene expression compared to individuals who do not respond to unloading. This chapter focuses on signal transduction, transcriptional regulation, and aspects of neurohormonal activation in the failing human heart before and after ventricular unloading. KeywordsChromogranin A-Heart failure-Hypertrophy-Myocytes-Natriuretic peptides-Remodeling
  12/2010: pages 235-240;
• Article: Long-term survival after "liver first" approach for locally advanced rectal cancer and synchronous liver metastases.

  Sonia Radunz, Matthias Heuer, Tanja Trarbach, Zoltan Mathe, Hideo A Baba, Andreas Paul, Georgios C Sotiropoulos
  International Journal of Colorectal Disease 12/2010; 26(9):1219-20. · 2.38 Impact Factor
• Article: Losartan reduces mortality in a genetic model of heart failure.

  Sophie Günther, Hideo A Baba, Steffen Hauptmann, Hans-Jürgen Holzhausen, Claudia Grossmann, Karla Punkt, Tina Kusche, Larry R Jones, Ulrich Gergs, Joachim Neumann
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  ABSTRACT: Altered Ca(2+) homoeostasis accompanies heart failure. As a model of heart failure, transgenic mice (TG) with selective overexpression of calsequestrin (CSQ) in the heart were used. CSQ is the main Ca(2+) binding protein in the lumen of the junctional sarcoplasmic reticulum. Overexpression of CSQ leads to hypertrophy, fibrosis, heart failure, cardiac arrhythmias, and ultimately premature death compared to littermate controls (WT). In the present study, cardiac hypertrophy was noted at 2 months of age (relative heart weight 6.4 +/- 0.2 mg/g in WT and 11.2 +/- 0.3 mg/g in TG, n = 7, p < 0.05) which progressed at 5 months of age (relative heart weight 15.5 +/- 1.1 mg/g in TG, n = 11). Furthermore, an increased degree of fibrosis (from 0.29 +/- 0.04 in WT to 0.77 +/- 0.06 in TG, n = 8, p < 0.05) was quantified by sirius red staining. Cardiac function was greatly impaired in TG as exemplified by reduced pressure development and cardiac arrhythmias. It is hypothesized that losartan, an inhibitor of angiotensin II receptors, might be able to attenuate these detrimental effects. Hence, TG and WT were treated for 1 or 4 months perorally with losartan (5 mg/kg/day) or solvent alone (control conditions) starting at 4 weeks of age. Under control conditions, none of the WT died within the observation period whereas all TG died within 9 months. Losartan treatment reduced the mortality of TG: Mean life span was raised from 116 to 193 days (n = 18 end, p < 0.05). Likewise, losartan reduced relative heart weight and the degree of fibrosis. In addition, losartan improved hemodynamic parameters, like left ventricular pressure and its first derivative. However, losartan treatment did not modify overexpression of CSQ in the heart of TG. These results imply that the angiotensin II receptor (type 1) contributes to heart failure due to CSQ overexpression, as its blockade improved survival.
  Archiv für Experimentelle Pathologie und Pharmakologie 09/2010; 382(3):265-78. · 2.65 Impact Factor
• Article: Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation.

  Alexander Dechêne, Jan-Peter Sowa, Robert K Gieseler, Christoph Jochum, Lars P Bechmann, Amr El Fouly, Martin Schlattjan, Fuat Saner, Hideo A Baba, Andreas Paul, Volker Dries, Margarethe Odenthal, Guido Gerken, Scott L Friedman, Ali Canbay
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  ABSTRACT: Acute liver failure (ALF) is associated with massive short-term cell death, whereas chronic liver injury is accompanied by continuous cell death. Hepatic stellate cells (HSCs) contribute to tissue repair and liver fibrosis in chronic liver injury, although their role in ALF remains unexplained. Twenty-nine patients (median age = 43 years, 17 females and 12 males) with ALF according to the Acute Liver Failure Study Group criteria were included. Upon the diagnosis of ALF and after 7 days, we determined liver stiffness (LS) with FibroScan, standard laboratory parameters, and serum levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-9, tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, hyaluronic acid, and markers of overall cell death (M65) and apoptosis (M30). Stellate cell activation and progenitor response were analyzed immunohistochemically in biopsy samples of 12 patients with alpha-smooth muscle actin (alpha-SMA), keratin-17, and keratin-19 staining, respectively. Cell death markers (M30 level = 2243 +/- 559.6 U/L, M65 level = 3732 +/- 839.9 U/L) and fibrosis markers (TIMP-1 level = 629.9 +/- 69.4 U/mL, MMP-2 level = 264 +/- 32.5 U/mL, hyaluronic acid level = 438.5 +/- 69.3 microg/mL) were significantly increased in patients versus healthy controls. This was paralleled by collagen deposition, elevated alpha-SMA expression, and higher LS (25.6 +/- 3.0 kPa). ALF was associated with ductular progenitor proliferation. CONCLUSION: Our results demonstrate HSC activation and a progenitor response in ALF. Positive correlations between LS, the degree of liver cell damage, and the intensity of HSC activation suggest that fibrosis is a response to ALF in an attempt to repair damaged tissue.
  Hepatology 09/2010; 52(3):1008-16. · 11.66 Impact Factor
• Article: Assessment of allograft fibrosis by transient elastography and noninvasive biomarker scoring systems in liver transplant patients.

  Susanne Beckebaum, Speranta Iacob, Christian G Klein, Alexander Dechêne, Joye Varghese, Hideo A Baba, Georgios C Sotiropoulos, Andreas Paul, Guido Gerken, Vito R Cicinnati
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  ABSTRACT: This prospective, monocentric study was designed to assess the efficacy of transient elastography (TE), biochemical tests, and more complex scores in determining fibrosis stage in 157 patients transplanted for hepatitis C virus (HCV) infection or non-HCV-related liver diseases. The optimal TE cutoff values for HCV patients and non-HCV patients were 4.7 and 5.0 kPa for F> or =1, 7.1 and 7.3 kPa for F> or =2, 10.9 kPa and 9.9 kPa for F> or =3, and 17.3 and 12.6 kPa for F=4, respectively. The corresponding area under the receiver operating characteristic (AUROC) curves for F> or =1, F> or =2, F> or =3, and F=4 were 0.95 and 0.86, 0.89 and 0.85, 0.97 and 0.88, and 0.99 and 0.97 for HCV and non-HCV patients, respectively. On the basis of the logistic regression equation, we created a model (FibroTransplant score) to identify advanced fibrosis (F> or =3). The accuracy of this model was tested in a validation group (n=74). AUROCs for diagnosis of F> or =3 in HCV patients and non-HCV patients of the training group were 0.89 and 0.83 (FibroTransplant score), 0.86 and 0.66 (Benlloch score), 0.81 and 0.71 (aspartate aminotransferase-to-platelet ratio index), 0.80 and 0.77 (Hepascore), 0.79 and 0.70 (FibroTest), 0.78 and 0.71 (FIB-4), 0.75 and 0.60 (Forns index), 0.73 and 0.69 (FibroIndex), and 0.70 and 0.59 (Lok score). Among the validation group, AUROCs of the FibroTransplant score for F> or =3 were 0.90 and 0.91, respectively. TE and the FibroTransplant score can be reliably used for diagnosing advanced fibrosis in transplanted patients.
  Transplantation 03/2010; 89(8):983-93. · 4.00 Impact Factor
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  Available from: Alexander Dietrich

  Article: Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2.

  Michael Klaiber, Martin Kruse, Katharina Völker, Juliane Schröter, Robert Feil, Marc Freichel, Andrea Gerling, Susanne Feil, Alexander Dietrich, Juan Eduardo Camacho Londoño, Hideo A Baba, Joel Abramowitz, Lutz Birnbaumer, Josef M Penninger, Olaf Pongs, Michaela Kuhn
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  ABSTRACT: Cardiac atrial natriuretic peptide (ANP) locally counteracts cardiac hypertrophy via the guanylyl cyclase-A (GC-A) receptor and cGMP production, but the downstream signalling pathways are unknown. Here, we examined the influence of ANP on beta-adrenergic versus Angiotensin II (Ang II)-dependent (G(s) vs. G(alphaq) mediated) modulation of Ca(2+) (i)-handling in cardiomyocytes and of hypertrophy in intact hearts. L-type Ca(2+) currents and Ca(2+) (i) transients in adult isolated murine ventricular myocytes were studied by voltage-clamp recordings and fluorescence microscopy. ANP suppressed Ang II-stimulated Ca(2+) currents and transients, but had no effect on isoproterenol stimulation. Ang II suppression by ANP was abolished in cardiomyocytes of mice deficient in GC-A, in cyclic GMP-dependent protein kinase I (PKG I) or in the regulator of G protein signalling (RGS) 2, a target of PKG I. Cardiac hypertrophy in response to exogenous Ang II was significantly exacerbated in mice with conditional, cardiomyocyte-restricted GC-A deletion (CM GC-A KO). This was concomitant to increased activation of the Ca(2+)/calmodulin-dependent prohypertrophic signal transducer CaMKII. In contrast, beta-adrenoreceptor-induced hypertrophy was not enhanced in CM GC-A KO mice. Lastly, while the stimulatory effects of Ang II on Ca(2+)-handling were absent in myocytes of mice deficient in TRPC3/TRPC6, the effects of isoproterenol were unchanged. Our data demonstrate a direct myocardial role for ANP/GC-A/cGMP to antagonize the Ca(2+) (i)-dependent hypertrophic growth response to Ang II, but not to beta-adrenergic stimulation. The selectivity of this interaction is determined by PKG I and RGS2-dependent modulation of Ang II/AT(1) signalling. Furthermore, they strengthen published observations in neonatal cardiomyocytes showing that TRPC3/TRPC6 channels are essential for Ang II, but not for beta-adrenergic Ca(2+) (i)-stimulation in adult myocytes.
  Archiv für Kreislaufforschung 03/2010; 105(5):583-95. · 7.35 Impact Factor
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  Available from: Frank Weber

  Article: Deregulation of HIF1-alpha and hypoxia-regulated pathways in hepatocellular carcinoma and corresponding non-malignant liver tissue--influence of a modulated host stroma on the prognosis of HCC.

  Frank Simon, Maximilian Bockhorn, Christian Praha, Hideo A Baba, Christoph E Broelsch, Andrea Frilling, Frank Weber
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  ABSTRACT: The aim of this study was to elucidate the role of HIF1A expression in hepatocellular carcinoma (HCC) and the corresponding non-malignant liver tissue and to correlate it with the clinical outcome of HCC patients after curative liver resection. HIF1A expression was determined by quantitative RT-PCR in HCC and corresponding non-malignant liver tissue of 53 patients surgically treated for HCC. High-density gene expression analysis and pathway analysis was performed on a selected subset of patients with high and low HIF1A expression in the non-malignant liver tissue. HIF1A over-expression in the apparently non-malignant liver tissue was a predictor of tumor recurrence and survival. The estimated 1-year and 5-year disease-free survival was significantly better in patients with low HIF1A expression in the non-malignant liver tissue when compared to those patients with high HIF1 expression (88.9% vs. 67.9% and 61.0% vs. 22.6%, respectively, p = 0.008). Based on molecular pathway analysis utilizing high-density gene-expression profiling, HIF1A related molecular networks were identified that contained genes involved in cell migration, cell homing, and cell-cell interaction. Our study identified a potential novel mechanism contributing to prognosis of HCC. The deregulation of HIF1A and its related pathways in the apparently non-malignant liver tissue provides for a modulated environment that potentially enhances or allows for HCC recurrence after curative resection.
  Langenbeck s Archives of Surgery 02/2010; 395(4):395-405. · 1.81 Impact Factor