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Peter R Galle

Publications and source records attributed to Peter R Galle.

At least 19 recordsLinked to original sources
PubMed2026

Long-term follow-up of a phase 1/2 trial of anti-GDF-15 antibody visugromab plus anti-PD-1 antibody nivolumab in anti-PD-1/-L1 relapsed/refractory solid tumors.

BACKGROUND: Resistance to anti-PD-1/PD-L1 therapy is a major unmet need. Growth Differentiation Factor 15 (GDF-15) has been identified as a key resistance factor for anti-PD-1/PD-L1 immunotherapy. Visugromab, a neutralizing anti-GDF-15 antibody, plus the anti-PD-1 antibody nivolumab (V+N) was evaluated in the first-in-human phase 1/2a GDFATHER-01 trial in heavily pretreated participants with locally advanced/metastatic non-squamous non-small-cell lung cancer (nsq NSCLC), urothelial carcinoma (UC), or hepatocellular carcinoma (HCC), stringently defined as anti-PD-1/PD-L1-relapsed/refractory, and showed encouraging objective responses. This analysis reports long-term follow-up of these three phase 2 expansion cohorts of the GDFATHER-01 trial. METHODS: Seventy-seven participants with nsq NSCLC (N=22), UC (N=27), and HCC (N=28) received visugromab (10 mg/kg) plus nivolumab (240 mg) every two weeks until disease progression or unacceptable toxicity. RESULTS: Objective response rates (RECIST v1.1) were 18.2% for nsq NSCLC (4/22; 95%CI 5.2-40.3), 18.5% for UC (5/27; 95%CI 6.3-38.1), and 14.3% for HCC (4/28; 95%CI 4.0-32.7). Median duration of response (DoR) was 32.2 months (95%CI 5.5-38.0), 28.8 months (95%CI 7.4-39.4), and 19.4 months (95%CI 5.8-39.7; with protracted recruitment), respectively, with 7/13 responses (53.8%) ongoing. Confirmed complete response or complete metabolic response (CR or CMR) among responders was 61.5% (8/13), with 7/8 ongoing. In addition, 46.2% (6/13) of responders achieved a deeper response on V+N per RECIST v1.1 than with the prior anti-PD-(L)1 therapy; median DoR on V+N was 28.8 months (95%CI 7.4-38.0) versus 12.0 months (95%CI 8.0-24.0) on initial anti-PD-1/PD-L1 treatment. V+N was generally well tolerated. CONCLUSIONS: In heavily pretreated, advanced/metastatic participants with nsq NSCLC, UC, or HCC who were anti-PD-1/PD-L1-relapsed/refractory, V+N achieved deep and durable objective responses. The observed DoR, depth of response, and CR+CMR rate among responders exceeded those reported for their initial anti-PD-1/PD-L1 therapy. These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti-PD-1/PD-L1 responses, and warrant further exploration in randomized trials. REGISTRY: ClinicalTrials.gov, TRN: NCT04725474, Registration date: 25 January 2021; EudraCT, TRN: 2020-002103-19, Registration date 16 Dec 2020.

Humans↗
PubMed2007

Prospective randomized comparison of minilaparoscopy and percutaneous liver biopsy: diagnosis of cirrhosis and complications.

BACKGROUND AND AIMS: Liver cirrhosis represents an advanced stage of hepatic fibrosis characterized by distortion of organ architecture and formation of regenerative nodules. Retrospective series reported percutaneous liver biopsy to miss cirrhosis in about 30%. The aim of this study was to prospectively compare diagnostic sensitivity regarding the detection of cirrhosis and the complication rates of percutaneous versus minilaparoscopic liver biopsy in chronic liver disease. METHODS: Eight hundred fifty-seven patients were randomized to percutaneous (415) or to minilaparoscopic liver biopsy (442). Macroscopic liver evaluation was documented as normal, fibrosis, or cirrhosis. Liver specimens were assessed blindly according to the modified Ishak score. RESULTS: Demographic and clinical data of procedure groups were comparable. Histologic grading alone diagnosed cirrhosis in 22.3% (n=85) of liver specimens obtained by percutaneous route compared with 26.0% (n=98) obtained by minilaparoscopy (P=0.270). By combining macroscopy and histology, minilaparoscopic staging diagnosed a significantly higher rate of liver cirrhoses with 33.8% (n=127) compared with percutaneous route with 22.3% (n=85) (P=0.001). Analysis of minilaparoscopic data revealed that 33 of the 128 cirrhoses were diagnosed by inspection only, suggesting a 26% underestimation of cirrhosis by histology alone. Severe complications occurred in 1.0% (n=4) of percutaneous and in 0.2% (n=1) of minilaparoscopic procedures (P=0.025). CONCLUSIONS: Minilaparoscopic evaluation based upon the combined macroscopic and histologic assessment is more sensitive with regards to the detection of cirrhosis and has a comparable safety profile.

Adult↗
PubMed2006

Expression of chemokine receptor CXCR4 in esophageal squamous cell and adenocarcinoma.

BACKGROUND: Prognosis of esophageal cancer is poor despite curative surgery. The chemokine receptor CXCR4 has been proposed to distinctly contribute to tumor growth, dissemination and local immune escape in a limited number of malignancies. The aim of our study was to evaluate the role of CXCR4 in tumor spread of esophageal cancer with a differentiated view of the two predominant histologic types--squamous cell and adenocarcinoma. METHODS: Esophageal cancer tissue samples were obtained from 102 consecutive patients undergoing esophageal resection for cancer with curative intent. The LSAB+ System was used to detect the protein CXCR4. Tumor samples were classified into two groups based on the homogeneous staining intensity. A cut-off between CXCR4w (= weak expression) and CXCR4s (= strong expression) was set at 1.5 (grouped 0-1.5 versus 2.0-3). Long-term survival rates were calculated using life tables and the Kaplan-Meier method. Using the Cox's proportional hazards analysis, a model of survival prediction was established. RESULTS: The overall expression rate for CXCR4 in esophageal squamous cell carcinoma was 94.1%. Subdividing these samples, CXCR4w was found in 54.9% and CXCR4s in 45.1%. In adenocarcinoma, an overall expression rate of 89.1% was detected with a weak intensitiy in 71.7% compared to strong staining in 29.3% (p = 0.066 squamous cell versus adenocarcinoma). The Cox's proportional hazards analysis identified the pM-category with a hazard ratio (HR) of 1.860 (95% CI: 1.014-3.414) (p = 0.045), the histologic tumor type (HR: 0.334; 95% CI: 0.180-0.618) (p = 0.0001) and the operative approach (transthoracic > transhiatal esophageal resection) (HR: 0.546; 95% CI: 0.324-0.920) (p = 0.023) as independent factors with a possible influence on the long-term prognosis in patients with esophageal carcinoma, whereas CXCR4 expression was statistically not significant (>0.05). CONCLUSION: Expression of the chemokine receptor CXCR4 in esophageal cancer is of major relevance in both histologic entities--squamous cell and adenocarcinoma. Though with lack of statistical significance, strong CXCR4 expression revealed a poorer long-term prognosis following curative esophagectomy in both histologic subtypes. Thus, the exact biological functions of CXCR4 in terms of tumor dissemination of esophageal cancer is yet undetermined. Inhibition of esophageal cancer progression by CXCR4 antagonists might be a promising therapeutic option in the future.

Adenocarcinoma↗
PubMed2006

Genome-wide analysis of factors regulating gene expression in liver.

In recent decades, multiple individual genes have been studied with respect to their level of expression in liver tissue and in many cases substantial progress has been made in identifying individual factors promoting gene expression in liver. However, the overall picture is still undefined and general rules or factors regulating gene expression in liver have not yet been established. Thus, a genome-wide screen for factors regulating gene expression in liver is of high interest, as it may reveal common regulatory mechanisms for most genes highly expressed in liver. These factors represent potential new targets in liver disease associated with differential gene expression. Using a novel bioinformatics approach, we have performed a genome-wide, bioinformatic screen to identify genetic factors regulating gene expression in liver. As the expression of an individual gene is generally driven by its promoter activity, we compared the level of expression to individual promoter sequences. Expression data of 15,704 individual genes in 12 tissues were obtained from a normal tissue microarray dataset. The genes were subsequently divided into two groups, according to whether or not their highest expression level was found in liver tissue. Scanning 1000 bp upstream of the transcription start of each individual gene and using the PromoterScan algorithm, we were able to identify a total of 7042 promoters containing a total of 241,984 transcription factors. To eliminate the possibility that currently unknown transcription factors may be crucial to liver expression regulation, we investigated all possible nucleotide combinations of 8 bp and 10 bp which we reasoned may serve as novel binding sites for transcription factors. In both screens we did not detect any significant, biologically relevant differences in numbers of transcription factors and binding sites between the two groups. Furthermore, we excluded possible differences in distribution of TATA-boxes or CpG islands as well as differences in nucleotide composition of RNA sequences or amino acid composition of transcribed protein sequences. We conclude that the existence of central, superordinated regulatory factors in liver gene expression is unlikely and that expression of individual genes in liver is more likely to be dependent on individual combinations of regulating factors for each gene.

Algorithms↗
PubMed2006

Suppression of Mcl-1 via RNA interference sensitizes human hepatocellular carcinoma cells towards apoptosis induction.

BACKGROUND: Hepatocelluar carcinoma (HCC) is one of the most common cancers worldwide and a major cause of cancer-related mortality. HCC is highly resistant to currently available chemotherapeutic drugs. Defects in apoptosis signaling contribute to this resistance. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 protein family which interferes with mitochondrial activation. In a previous study we have shown that Mcl-1 is highly expressed in tissues of human HCC. In this study, we manipulated expression of the Mcl-1 protein in HCC cells by RNA interference and analyzed its impact on apoptosis sensitivity of HCC cells in vitro. METHODS: RNA interference was performed by transfecting siRNA to specifically knock down Mcl-1 expression in HCC cells. Mcl-1 expression was measured by quantitative real-time PCR and Western blot. Induction of apoptosis and caspase activity after treatment with chemotherapeutic drugs and different targeted therapies were measured by flow cytometry and fluorometric analysis, respectively. RESULTS: Here we demonstrate that Mcl-1 expressing HCC cell lines show low sensitivity towards treatment with a panel of chemotherapeutic drugs. However, treatment with the anthracycline derivative epirubicin resulted in comparatively high apoptosis rates in HCC cells. Inhibition of the kinase PI3K significantly increased apoptosis induction by chemotherapy. RNA interference efficiently downregulated Mcl-1 expression in HCC cells. Mcl-1 downregulation sensitized HCC cells to different chemotherapeutic agents. Sensitization was accompanied by profound activation of caspase-3 and -9. In addition, Mcl-1 downregulation also increased apoptosis rates after treatment with PI3K inhibitors and, to a lower extent, after treatment with mTOR, Raf I and VEGF/PDGF kinase inhibitors. TRAIL-induced apoptosis did not markedly respond to Mcl-1 knockdown. Additionally, knockdown of Mcl-1 efficiently enhanced apoptosis sensitivity towards combined treatment modalities: Mcl-1 knockdown significantly augmented apoptosis sensitivity of HCC cells towards chemotherapy combined with PI3K inhibition. CONCLUSION: Our data suggest that specific downregulation of Mcl-1 by RNA interference is a promising approach to sensitize HCC cells towards chemotherapy and molecularly targeted therapies.

Antineoplastic Agents↗
PubMed2006

Genetic association of autoimmune hepatitis and human leucocyte antigen in German patients.

AIM: To report on our large German collective and updated data of 142 patients with autoimmune hepatitis (AIH) type 1. METHODS: Key investigations performed were liver biopsy, serum autoantibodies as well as serum markers such as IgG and elevated transaminases. Antinuclear antigen (ANA) and smooth muscle antigen (SMA) autoantibodies characterized type 1 AIH. Type 3 (AIH) was solely characterized by the occurrence of soluble liver antigen/liver-pancreas antigen (SLA/LP) autoantibodies either with or without ANA or SMA autoantibodies. RESULTS: Most prevalent HLAs were A2 (68 patients, 48%), B8 (63 patients, 44%), C7 (90 patients, 63%), DR3 (49 patients, 38%), DR4 (49 patients, 38%) and DQ2 (42 patients, 30%). Compared to the Italian and North American patients, we found fewer patients with a DQ2 subtype. Furthermore, the B8-DR3-DQ2 human leucocyte antigen (HLA) was also less prominent compared to the North American patients. However, prevalences of B8, DR3, DR4, DR7, DR11 and DR13 were comparable to the Italian and North American patients. Furthermore, we report on an additional subgroup of patients with SLA/LP positive AIH. Generally, in this subgroup of patients the same HLA subtypes were favoured as the AIH type 1. CONCLUSION: Although HLA subtypes were comparable between these three collectives, the German patients were distinct from the Italian and North American patients with respect to DQ2 and from the North American patients with respect to B8-DR3-DQ2 HLA. A clinical correlation, e.g. difference in severity or treatability of AIH type 1, has yet to be determined.

Autoantigens↗
PubMed2006

Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis.

Although IL-12 and IL-23 share the common p40 subunit, IL-23, rather than IL-12, seems to drive the pathogenesis of experimental autoimmune encephalomyelitis and arthritis, because IL-23/p19 knockout mice are protected from disease. In contrast, we describe in this study that newly created LacZ knockin mice deficient for IL-23 p19 were highly susceptible for the development of experimental T cell-mediated TNBS colitis and showed even more severe colitis than wild-type mice by endoscopic and histologic criteria. Subsequent studies revealed that dendritic cells from p19-deficient mice produce elevated levels of IL-12, and that IL-23 down-regulates IL-12 expression upon TLR ligation. Finally, in vivo blockade of IL-12 p40 in IL-23-deficient mice rescued mice from lethal colitis. Taken together, our data identify cross-regulation of IL-12 expression by IL-23 as novel key regulatory pathway during initiation of T cell dependent colitis.

Animals↗
PubMed2006

Long-term effectiveness of azathioprine in IBD beyond 4 years: a European multicenter study in 1176 patients.

In Crohn's disease the optimal duration of azathioprine treatment is still controversial and for ulcerative colitis only limited data are available to support its efficacy. Charts of 1176 patients with IBD from 16 European centers were analyzed. Flare incidences and steroid dosages were assessed for the time before and during treatment and after discontinuation. Within the first 4 years, azathioprine suppressed flare incidence and steroid consumption in both diseases (P < 0.001). While in CD discontinuation after 3-4 years did not lead to reactivation, this was the case in UC. However, continuation beyond 4 years further improved clinical activity in CD and steroid requirement in both diseases (P < 0.001). Discontinuation of azathioprine may thus be considered after 3-4 years in CD patients in complete remission without steroid requirement. In all other CD patients and for UC patients in general, continuation seems beneficial. These results support a novel differential algorithm for long-term azathioprine therapy in IBD.

Adult↗
PubMed2006

Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27.

The immune response to bacterial infections must be tightly controlled to guarantee pathogen elimination while preventing tissue damage by uncontrolled inflammation. Here, we demonstrate a key role of interleukin (IL)-27 in regulating this critical balance. IL-27 was rapidly induced during murine experimental peritonitis induced by cecal ligation and puncture (CLP). Furthermore, mice deficient for the EBI3 subunit of IL-27 were resistant to CLP-induced septic peritonitis as compared with wild-type controls, and this effect could be suppressed by injection of recombinant single-chain IL-27. EBI3-/- mice displayed significantly enhanced neutrophil migration and oxidative burst capacity during CLP, resulting in enhanced bacterial clearance and local control of infection. Subsequent studies demonstrated that IL-27 directly suppresses endotoxin-induced production of reactive oxygen intermediates by isolated primary granulocytes and macrophages. Finally, in vivo blockade of IL-27 function using a newly designed soluble IL-27 receptor fusion protein led to significantly increased survival after CLP as compared with control-treated mice. Collectively, these data identify IL-27 as a key negative regulator of innate immune cell function in septic peritonitis. Furthermore, in vivo blockade of IL-27 is a novel potential therapeutic target for treatment of sepsis.

Animals↗
PubMed2006

Gemcitabine in combination with EGF-Receptor antibody (Cetuximab) as a treatment of cholangiocarcinoma: a case report.

BACKGROUND: Extensive disease of cholangiocarcinoma (CC) determines the overall outcome and limits curative resection. Despite chemotherapy, which has been introduced to improve the outcome of biliary tract malignancies, the benefit in survival is still marginal. CASE PRESENTATION: We report a 69-year-old patient with non-resectable CC showing hepatic metastasis and peritoneal carcinomatosis. Diagnosis was based on computed tomography, mini-laparoscopy and bioptic specimens. Histology revealed an adenocarcinoma of the biliary tract with expression of epithelial growth factor receptor. After informed consent the patient received experimental gemcitabine (1000 mg/m2) every other week and cetuximab (250 mg/m2) weekly for palliative chemotherapy. During the reported follow up (since time of first presentation) 20 cycles of chemotherapy were administered. Relevant chemotherapy-related toxicity was limited on gemcitabine-associated side effects. Predominantly, haematological toxicity (CTC, grade 3) and neutropenic fever (CTC, grade 3) promoted by catheter-related sepsis were observed. Cetuximab caused only mild skin toxicity (CTC, grade 1). Chemotherapy led to a partial response (> 30% reduction, according to RECIST) of the target lesions and disappearance of the peritoneal carcinomatosis as shown by computed tomography. Partial response occurred after 17 weeks of treatment and remained stable during the entire course of chemotherapy for 9.7 months. In parallel, Ca 19-9 serum levels, which were elevated 5-fold at time of diagnosis, returned to normal after 16 weeks of treatment. The performance status stabilized and intravenous alimentation could be discontinued. CONCLUSION: Our experience from one patient with CC suggests, that a combination of cytotoxic chemotherapy together with cetuximab may show promising efficacy in respect to survival and quality of life. Therefore cetuximab, as a component of palliative chemotherapy in biliary tract cancer, needs further evaluation in prospective randomized trials.

Aged↗
PubMed2006

In vivo histology of Barrett's esophagus and associated neoplasia by confocal laser endomicroscopy.

BACKGROUND & AIMS: Confocal laser endomicroscopy allows subsurface analysis of the intestinal mucosa and in vivo histology during ongoing endoscopy. Here, we have applied this technique to the in vivo diagnosis of Barrett's epithelium and associated neoplasia. METHODS: Fluorescein-aided endomicroscopy was performed by applying the endomicroscope over the whole columnar-lined lower esophagus. Images obtained within 1 cm of the columnar-lined lower esophagus were stored digitally and a targeted biopsy examination or endoscopic mucosal resection of the examined areas was performed. In vivo histology was compared with the histologic specimens. All digitally stored images were re-assessed by a blinded investigator by the confocal Barrett classification system to predict histology. Intraobserver and interobserver variations of the involved endoscopists were evaluated by using kappa statistics. RESULTS: Endomicroscopy allowed distinguishing between different types of epithelial cells and detected cellular and vascular changes in Barrett's epithelium at high resolution during ongoing endoscopy in 63 patients. Barrett's esophagus and associated neoplasia could be predicted with a sensitivity of 98.1% and 92.9% and a specificity of 94.1% and 98.4%, respectively (accuracy, 96.8% and 97.4%). The mean kappa value for interobserver agreement for the prediction of histopathological diagnosis was .843, whereas the intraobserver agreement showed a mean kappa value of .892. CONCLUSIONS: Fluorescence-aided endomicroscopy of Barrett's esophagus allows in vivo histology of the mucosal layer during ongoing endoscopy. Gastric and Barrett's epithelium and Barrett's-associated neoplastic changes can be diagnosed with high accuracy. Thus, endomicroscopy may be helpful in the management of patients with Barrett's esophagus.

Barrett Esophagus↗
PubMed2006

Five cases of de novo inflammatory bowel disease after orthotopic liver transplantation.

Immunosuppression is currently the treatment of choice for severe inflammatory bowel disease (IBD). Thus, it was anticipated that the course of preexisting IBD should improve after orthotopic liver transplantation (OLT). Despite sufficient allograft immunosuppressive therapy, however, exacerbation of IBD or the development of de novo IBD after OLT were described in some cases, primarily in patients transplanted for end-stage primary sclerosing cholangitis (PSC). In addition, the development of de novo IBD in patients undergoing OLT for indications other than PSC was described. Evaluating our collective of 314 liver transplanted patients we found five patients transplanted for various indications other than PSC (autoimmune hepatitis [AIH], acute-on-chronic hepatitis B, Wilson's disease, and cryptogenic cirrhosis) who developed de novo IBD after OLT despite sufficient immunosuppressive therapy with tacrolimus or cyclosporine. PSC was widely excluded in these patients by clinical and histological examinations and there was no sign of an enteric infection. It was remarkable that all patients were suspected to have an autoimmune background. Four of our patients were women and almost all patients showed histologically typical signs of an ulcerative colitis (UC). To prevent allograft rejection, three of five patients were treated with cyclosporine and the other two with tacrolimus. After diagnosis, treatment with aminosalicylates and corticosteroids led to complete clinical and histological remission. However, relapses occurred frequently after termination of specific therapy. In combination with previous reports, our cases indicate an immune dysregulation leading to the development of de novo IBD after OLT under immunosuppressive therapy. Reviewing the literature, it should be considered that apart from the autoimmune background, immunosuppressive therapy may itself play a major role in the development of de novo IBD. From the clinical point of view, it is of critical importance to detect this phenomenon, since diarrhea is an important cause of morbidity and mortality in transplanted patients and therapy for this disorder completely differs from the treatment for other causes of diarrhea. Aminosalicylates and courses of corticosteroids offer an effective treatment.

Adolescent↗
PubMed2006

Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice.

BACKGROUND/AIMS: In hepatic fibrogenesis, stellate cells are activated leading to production and deposition of extracellular matrix. To clarify the role of PDGF-B in liver fibrogenesis, we overexpressed PDGF-B in the liver of transgenic mice. METHODS: Transgenic mice for the conditional overexpression of PDGF-B in the liver under control of an albumin promoter were generated utilising the Cre/loxP system. Constitutive PDGF-B expression was achieved after breeding with mice expressing Cre-recombinase under actin promoter control. Tamoxifen inducible expression was achieved after breeding with mice expressing Cre under transthyretin receptor promoter control. Levels of fibrosis were assessed and the expression of regulators of matrix remodelling was measured. RESULTS: PDGF-B expression caused hepatic stellate cell and myofibroblast activation marked by alpha-smooth muscle actin and PDGFR-beta expression. Liver fibrosis was verified macroscopically, histologically and by collagen I mRNA quantification in 4-6 week-old animals. MMP-2, MMP-9 and TIMP-1 were upregulated whereas TGF-beta expression was unchanged. CONCLUSIONS: We identified PDGF-B as a proliferative and profibrogenic stimulus and potential inducer of stellate cell transdifferentiation in vivo. PDGF-B overexpression causes liver fibrosis without significantly upregulating TGF-beta1, suggesting a TGF-beta-independent mechanism. The established model provides a tool for testing anti-PDGF-B therapeutic strategies in liver fibrosis in vivo.

Animals↗
PubMed2006

Treatment of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause for elevated liver enzymes in the developed nations. Beyond prevention programs which are of particular interest because of the increasing number of overweight children, treatment should be focussed on the most important risk factors, obesity and insulin resistance. As a consequence of elucidating the pathomechanisms of NAFLD, the number of potential therapeutic options increased. However, many studies investigating the therapeutic effect show shortcomings in at least one of the following points: lack of a serial liver biopsy, short term of treatment and limited number of included patients. The second generation insulin sensitizer pioglitazone and rosiglitazone show the most promising improvements in NAFLD, but weight gain and potential hepatotoxicity calls for attention. In conclusion, a general recommendation for the application of specific drugs cannot be given. Besides controlled clinical trials, weight reduction and physical activity to improve insulin sensitivity in obese patients should be the priority objective.

Alanine Transaminase↗
PubMed2006

Nitric oxide promotes resistance to tumor suppression by CTLs.

Many human tumors express inducible NO synthetase (NOS2), but the roles of NO in tumor development are not fully elucidated. An important step during tumor development is the acquisition of apoptosis resistance. We investigated the dose-dependent effects of endogenously produced NO on apoptosis using ecdysone-inducible NOS2 cell lines. Our results show that short-term NOS2 expression enhances CD95-mediated apoptosis and T cell cytotoxicity dose dependently. Furthermore, we could show that during chronic exposure to NO, besides the primary cytotoxic NO effect, there is selection of cell clones resistant to NO that show cross-resistance to CD95-induced apoptosis and the killing by CTLs. We propose that NO production could initially act as an autocrine suicide or paracrine killing mechanism in cells undergoing malignant transformation. However, once failed, the outcome is fatal. NO promotes tumor formation by enhancing the selection of cells that can evade immune attack by acquiring apoptosis resistance.

Apoptosis↗
PubMed2006

Characterization of human gene encoding SLA/LP autoantigen and its conserved homologs in mouse, fish, fly, and worm.

AIM: To approach the elusive function of the SLA/LP molecule, we have characterized genomic organization and conservation of the major antigenic and functional properties of the SLA/LP molecule in various species. METHODS: By means of computational biology, we have characterized the complete SLA/LP gene, mRNA and deduced protein sequences in man, mouse, zebrafish, fly, and worm. RESULTS: The human SLA/LP gene sequence of approximately 39 kb, which maps to chromosome 4p15.2, is organized in 11 exons, of which 10 or 11 are translated, depending on the splice variant. Homologous molecules were identified in several biological model organisms. The various homologous protein sequences showed a high degree of similarity or homology, notably at those residues that are of functional importance. The only domain of the human protein sequence that lacks significant homology with homologous sequences is the major antigenic epitope recognized by autoantibodies from autoimmune hepatitis (AIH) patients. CONCLUSION: The SLA/LP molecule and its functionally relevant residues have been highly conserved throughout the evolution, suggesting an indispensable function of the molecule. The finding that the only non-conserved domain is the dominant antigenic epitope of the human SLA/LP sequence, suggests that SLA/LP autoimmunity is autoantigen-driven rather than being driven by molecular mimicry.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Pregnancy in autoimmune hepatitis: outcome and risk factors.

OBJECTIVE: Autoimmune hepatitis (AIH) may influence pregnancy outcome and pregnancy may affect AIH. We aimed at analyzing the disease course in pregnant AIH patients and at identifying disease-related risk factors for adverse pregnancy outcome. PATIENTS AND METHODS: AIH patients with at least one pregnancy were identified at four liver units. The patients' records and the data obtained by detailed questionnaires were analyzed retrospectively. Forty-two pregnancies of 22 AIH patients were included. RESULTS: The rate of adverse pregnancy outcome was 26%; a medical explanation could be elucidated in only 4 of 11 pregnancies with adverse outcome. Of note, the 7 unexplained adverse pregnancy outcomes were highly associated with the presence of antibodies to SLA/LP (odds ratio 51; p < 0.003) and Ro/SSA (odds ratio 27; p < 0.02). Of 35 live births, 30 children developed normally over a mean observation period of nearly 5 yr. Eleven of these had been exposed to azathioprine in utero. The rate of serious maternal complications was 9% and a high rate (52%) of postpartum flares was noted. CONCLUSIONS: The presence of autoantibodies may be a risk factor for adverse pregnancy outcome in AIH patients. Close monitoring of both mother and fetus seems advisable due to a significant rate of maternal and fetal complications.

Adolescent↗