Publications by authors named "Wolfgang Reindl"

81 Publications

Exploring joint patterns of brain structure and function in inflammatory bowel diseases using multimodal data fusion.

Neurogastroenterol Motil 2020 Dec 28:e14078. Epub 2020 Dec 28.

Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Heidelberg, Germany.

Background: A growing number of neuroimaging studies suggest distinct neural changes in inflammatory bowel diseases (IBDs). Whether such changes may show similar spatial patterns across distinct neural features within and between specific IBD is unclear. To address this question, we used multivariate multimodal data fusion analysis to investigate structure/function modulation in remitted patients with Crohn's disease (CD) and ulcerative colitis (UC).

Methods: Patients with IBD (n = 46; n = 31 with CD, n = 15 with UC) in stable remission and 17 healthy controls (HC) underwent structural magnetic resonance imaging (sMRI) and resting-state functional magnetic resonance imaging (rs-fMRI) as well as cognitive testing. Anxiety, depression, and fatigue were assessed using self-rating questionnaires. sMRI data were analyzed via voxel-based morphometry (VBM) and rs-fMRI data via amplitude of low-frequency fluctuations (ALFFs) and regional homogeneity (ReHo). Detection of cross-information between VBM, ALFF, and ReHo was conducted by means of a joint independent component analysis (jICA), followed by group-inference statistics.

Key Results: Joint independent component analysis detected structural alterations in middle frontal and temporal regions (VBM), and functional changes in the superior frontal gyrus (ReHo) and the medial as well as inferior frontal, inferior temporal, rectal, and subcallosal gyrus (ALFF). One joint component of extracted features of the three modalities differed significantly between IBD patients and controls (p = 0.03), and most distinctly between HC and patients with UC.

Conclusions And Inferences: Using a multivariate data fusion technique, this study provides further evidence to brain alterations in IBD. The data suggest distinct neural differences between CD and UC, particularly in frontotemporal regions.
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http://dx.doi.org/10.1111/nmo.14078DOI Listing
December 2020

MALDI-TOF-Based Affinity Selection Mass Spectrometry for Automated Screening of Protein-Ligand Interactions at High Throughput.

SLAS Discov 2021 Jan 17;26(1):44-57. Epub 2020 Oct 17.

Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.

Demonstration of in vitro target engagement for small-molecule ligands by measuring binding to a molecular target is an established approach in early drug discovery and a pivotal step in high-throughput screening (HTS)-based compound triaging. We describe the setup, evaluation, and application of a ligand binding assay platform combining automated affinity selection (AS)-based sample preparation and label-free matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis. The platform enables mass spectrometry (MS)-based HTS for small-molecule target interactions from single-compound incubation mixtures and is embedded into a regular assay automation environment. Efficient separation of target-ligand complexes is achieved by in-plate size exclusion chromatography (SEC), and small-molecule ligands are subsequently identified by MALDI-TOF analysis. In contrast to alternative HTS-capable binding assay formats, MALDI-TOF AS-MS is capable of identifying orthosteric and allosteric ligands, as shown for the model system protein tyrosine phosphatase 1B (PTP1B), irrespective of protein function. Furthermore, determining relative binding affinities (RBAs) enabled ligand ranking in accordance with functional inhibition and reference data for PTP1B and a number of diverse protein targets. Finally, we present a validation screen of more than 23,000 compounds within 24 h, demonstrating the general applicability of the platform for the HTS-compatible assessment of protein-ligand interactions.
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http://dx.doi.org/10.1177/2472555220959266DOI Listing
January 2021

Long, relapsing, and atypical symptomatic course of COVID-19 in a B-cell-depleted patient after rituximab.

Semin Arthritis Rheum 2020 10 30;50(5):1087-1088. Epub 2020 Jun 30.

Department of Medicine II, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.semarthrit.2020.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833880PMC
October 2020

The Innate Immune Response to Infection Induces Erythropoietin-Dependent Replenishment of the Dendritic Cell Compartment.

Front Immunol 2020 31;11:1627. Epub 2020 Jul 31.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Microbiology, Infectious Diseases and Immunology, Berlin, Germany.

Dendritic cells (DC) play a key role in the adaptive immune response due to their ability to present antigens and stimulate naïve T cells. Many bacteria and viruses can efficiently target DC, resulting in impairment of their immunostimulatory function or elimination. Hence, the DC compartment requires replenishment following infection to ensure continued operational readiness of the adaptive immune system. Here, we investigated the molecular and cellular mechanisms of inflammation-induced DC generation. We found that infection with viral and bacterial pathogens as well as Toll-like receptor 9 (TLR9) ligation with CpG-oligodeoxynucleotide (CpG-ODN) expanded an erythropoietin (EPO)-dependent TER119CD11a cell population in the spleen that had the capacity to differentiate into TER119CD11c and TER119CD11c cells both and . TER119CD11c cells contributed to the conventional DC pool in the spleen and specifically increased in lymph nodes draining the site of local inflammation. Our results reveal a so far undescribed inflammatory EPO-dependent pathway of DC differentiation and establish a mechanistic link between innate immune recognition of potential immunosuppressive pathogens and the maintenance of the DC pool during and after infection.
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http://dx.doi.org/10.3389/fimmu.2020.01627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411349PMC
July 2020

Ultrahigh-Throughput ESI-MS: Sampling Pushed to Six Samples per Second by Acoustic Ejection Mass Spectrometry.

Anal Chem 2020 09 3;92(18):12242-12249. Epub 2020 Sep 3.

Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany.

We present an acoustic ejection mass spectrometry (AEMS) setup for contactless electrospray ionization mass spectrometry (ESI-MS)-based sample injection at a sampling rate faster than current ESI and matrix-assisted laser desorption ionization (MALDI) techniques. For the direct transfer of samples out of 384-well plates into a modified ESI source, an open port interface (OPI) was combined with a modified acoustic droplet ejection (ADE) system. AEMS has the potential to eliminate bottlenecks known from classical MS approaches, such as speed, reproducibility, carryover, ion suppression, as well as sample preparation and consumption. This setup provided a drastically reduced transfer distance between OPI and ESI electrode for optimum throughput performance and broadens the scope of applications for this emerging technique. To simulate label-free applications of drug metabolism and pharmacokinetics (DMPK) analysis and high-throughput screening (HTS) campaigns, two stress tests were performed regarding ion suppression and system endurance in combination with minor sample preparation. The maximum sampling rate was 6 Hz for dextromethorphan and -dextrorphan (each 100 nM) for 1152 injections in 63 s at full width at half-maximum (FWHM) of 105 ms and a relative standard deviation (%RSD) of 7.7/7.5% without internal standard correction. Enzyme assay buffer and crude dog plasma caused signal suppression of 51/73% at %RSD of 5.7/6.7% ( = 120). An HTS endurance buffer was used for >25 000 injections with minor OPI pollution and constant signals (%RSD = 8.5%, FWHM of 177 ms ± 8.5%, = 10 557). The optimized hardware and method setup resulted in high-throughput performance and enables further implementation in a fully automated platform for ESI-MS-based high-throughput screening.
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http://dx.doi.org/10.1021/acs.analchem.0c01632DOI Listing
September 2020

Ustekinumab Inhibits T Follicular Helper Cell Differentiation in Patients With Crohn's Disease.

Cell Mol Gastroenterol Hepatol 2021 15;11(1):1-12. Epub 2020 Jul 15.

Department of Medicine II, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Background & Aims: The pathogenesis of chronic inflammatory bowel diseases (Crohn's disease [CD] and ulcerative colitis) involves dysregulated TH1 and TH17 cell responses, which can be targeted therapeutically by the monoclonal antibody Ustekinumab directed against the joint p40 subunit of IL-12 and IL-23. These cytokines may also regulate the differentiation of T follicular helper (TFH) cells, which promote B cell function in germinal centers. However, the role of TFH cells in CD pathogenesis and impact of Ustekinumab therapy on TFH cell fate in patients are poorly defined.

Methods: Lymphocytes were isolated from peripheral blood (n=45) and intestinal biopsies (n=15) of CD patients or healthy controls (n=21) and analyzed by flow cytometry to assess TFH cell phenotypes and functions ex vivo. In addition, TFH cell differentiation was analyzed in the presence of Ustekinumab in vitro.

Results: TFH cell frequencies in the intestine as well as peripheral blood were associated with endoscopic as well as biochemical evidence of CD activity. CD patients with clinical response to Ustekinumab, but not those with response to anti-TNF antibodies, displayed reduced frequencies of circulating TFH cells in a concentration-dependent manner while the TFH phenotype was not affected by Ustekinumab therapy. In keeping with this notion, TFH cell differentiation was inhibited by Ustekinumab in vitro while TFH cell maintenance was not affected. Moreover, Ustekinumab therapy resulted in reduced germinal center activity in CD patients in vivo.

Conclusions: These data implicate TFH cells in the pathogenesis of CD and indicate that Ustekinumab therapy affects TFH cell differentiation, which may influence TFH-mediated immune functions in UST-treated CD patients.
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http://dx.doi.org/10.1016/j.jcmgh.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593584PMC
July 2020

Tofacitinib in Treatment-Refractory Moderate to Severe Ulcerative Colitis: Real-World Experience from a Retrospective Multicenter Observational Study.

J Clin Med 2020 Jul 10;9(7). Epub 2020 Jul 10.

Department of Gastroenterology and Hepatology, University Hospital Heidelberg, INF 410, 69120 Heidelberg, Germany.

(1) Background: Tofacitinib is approved in Europe for the treatment of adults with moderately to severely active ulcerative colitis since 2018. Real-world efficacy and safety data are currently scarce. (2) Methods: We performed a retrospective multicenter study at three German tertiary outpatient clinics for inflammatory bowel diseases and included all patients who started tofacitinib therapy between August 2018 and March 2020. The primary endpoint was a combined endpoint of steroid-free clinical remission, steroid-free clinical response, or clinical response at week 8. Secondary endpoints were biochemical response at week 8, as well as steroid-free clinical remission, steroid-free clinical response or clinical response at week 24, respectively, adverse events by week 24, and need for colectomy by the end of follow-up. (3) Results: Thirty-eight patients with moderate-to-severe ulcerative colitis were included. Eleven patients (28.9%) achieved steroid-free clinical remission at week 8. Fifty-three percent of the patients were primary non-responders at week 8. Three severe adverse events (pneumonia, hospitalization for aggravation of ulcerative colitis, emergency colectomy due to colon perforation), and 12 adverse events were documented by week 8 of therapy. By the end of follow-up, seven patients (18.4%) had undergone colectomy.
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http://dx.doi.org/10.3390/jcm9072177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408885PMC
July 2020

Review article: bugs, inflammation and mood-a microbiota-based approach to psychiatric symptoms in inflammatory bowel diseases.

Aliment Pharmacol Ther 2020 07 11;52(2):247-266. Epub 2020 Jun 11.

Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong.

Background: Psychiatric co-morbidities including depression and anxiety are common in inflammatory bowel diseases (IBD). Emerging evidence suggests that interactions between the gut microbiota and brain may play a role in the pathogenesis of psychiatric symptoms in IBD.

Aim: To review the literature on microbiota-brain-gut interactions in gut inflammation, psychosocial stress and mental disorders and to discuss the putative mediating role of gut microbiota in the development of psychiatric symptoms or co-morbidities in IBD.

Methods: A literature search was conducted on Ovid and Pubmed to select relevant animal and human studies reporting an association between IBD, mental disorders and gut microbiota.

Results: Gut microbial alterations are frequently reported in subjects with IBD and with mental disorders. Both have been associated with reduced faecal bacterial diversity, decreased taxa within the phylum Firmicutes and increased Gammaproteobacteria. In animal studies, microbial perturbations induce behavioural changes and modulate inflammation in mice. Anxiety- and depression-like behaviours in animals can be transferred via faecal microbiota. In humans, modulation of the gut microbiota with probiotics is associated with behavioural and mood changes. Recent data show correlations in changes of faecal and mucosal microbiota and psychological distress in patients with IBD independent of disease activity.

Conclusion: Both IBD and mental disorders are associated with gut microbial alterations. Preclinical and preliminary human studies have shown a mediating role of the gut microbiota in intestinal inflammation and anxiety, depression and stress. Targeting the gut microbiota may represent a useful therapeutic approach for the treatment of psychiatric co-morbidities in IBD.
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http://dx.doi.org/10.1111/apt.15787DOI Listing
July 2020

MITIGATE-NeoBOMB1, a Phase I/IIa Study to Evaluate Safety, Pharmacokinetics, and Preliminary Imaging of Ga-NeoBOMB1, a Gastrin-Releasing Peptide Receptor Antagonist, in GIST Patients.

J Nucl Med 2020 12 24;61(12):1749-1755. Epub 2020 Apr 24.

Department of Nuclear Medicine, Medical University Innsbruck, Innsbruck, Austria

Gastrin-releasing peptide receptors (GRPRs) are potential molecular imaging targets in a variety of tumors. Recently, a Ga-labeled antagonist to GRPRs, NeoBOMB1, was developed for PET. We report on the outcome of a phase I/IIa clinical trial (EudraCT 2016-002053-38) within the EU-FP7 project Closed-loop Molecular Environment for Minimally Invasive Treatment of Patients with Metastatic Gastrointestinal Stromal Tumors ('MITIGATE') (grant agreement no. 602306) in patients with oligometastatic gastrointestinal stromal tumors (GIST). The main objectives were evaluation of safety, biodistribution, dosimetry, and preliminary tumor targeting of Ga-NeoBOMB1 in patients with advanced tyrosine-kinase inhibitors-treated GIST using PET/CT. Six patients with histologically confirmed GIST and unresectable primary lesion or metastases undergoing an extended protocol for detailed pharmacokinetic analysis were included. Ga-NeoBOMB1 was prepared using a kit procedure with a licensed Ge/Ga generator. Ga-NeoBOMB1 (3 MBq/kg of body weight) was injected intravenously, and safety parameters were assessed. PET/CT included dynamic imaging at 5, 11, and 19 min as well as static imaging at 1, 2, and 3-4 h after injection for dosimetry calculations. Venous blood samples and urine were collected for pharmacokinetic analysis. Tumor targeting was assessed on a per-lesion and per-patient basis. Ga-NeoBOMB1 (50 μg) was prepared with high radiochemical purity (yield > 97%). Patients received 174 ± 28 MBq of the radiotracer, which was well tolerated in all patients over a follow-up period of 4 wk. Dosimetry calculations revealed a mean effective dose of 0.029 ± 0.06 mSv/MBq, with the highest organ dose to the pancreas (0.274 ± 0.099 mSv/MBq). Mean plasma half-life was 27.3 min with primarily renal clearance (mean 25.7% ± 5.4% of injected dose 4 h after injection). Plasma metabolite analyses revealed high stability; metabolites were detected only in the urine. In 3 patients, a significant uptake with increasing maximum SUVs (SUV at 2 h after injection: 4.3-25.9) over time was found in tumor lesions. This phase I/IIa study provides safety data for Ga-NeoBOMB1, a promising radiopharmaceutical for targeting GRPR-expressing tumors. Safety profiles and pharmacokinetics are suitable for PET imaging, and absorbed dose estimates are comparable to those of other Ga-labeled radiopharmaceuticals used in clinical routine.
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http://dx.doi.org/10.2967/jnumed.119.238808DOI Listing
December 2020

Ustekinumab serum concentrations are associated with clinical outcomes in Crohn's disease - a regional multi-center pilot study.

Z Gastroenterol 2020 May 11;58(5):439-444. Epub 2020 Feb 11.

Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background And Aim:  The role of therapeutic drug monitoring (TDM) in ustekinumab (UST) therapy for Crohn's disease (CD) has not been established, as only few studies have analyzed the relationship between UST serum concentrations and clinical outcome. In this pilot study, we retrospectively examined the potential of UST-concentrations (cUST) 8 weeks after induction (cUSTw8) to predict clinical response at week 16.

Methods:  Serum samples and clinical data from patients (n = 72) with moderate to severely active CD who received intravenous induction with UST were retrospectively analyzed. cUST were quantitated using liquid chromatography-tandem mass spectrometry (LC-MSMS). A receiver-operating characteristic (ROC) curve and area under ROC curve (AUROC) was computed to analyze the predictive potential of cUSTw8 for clinical response at week 16 and to determine the minimal therapeutic UST trough concentration.

Results:  Forty-four patients (61 %) achieved clinical response to UST therapy at week 16. cUSTw8 was moderately effective to predict clinical response with a minimal therapeutic cUSTw8 of 2.0 mg/l (AUC 0.72, p = 0.001).

Conclusion:  Trough concentrations of UST 8 weeks after induction predict clinical response to therapy in week 16 with moderate sensitivity and specificity. TDM using LC-MSMS could prove beneficial in personalized UST therapy of patients with CD by identifying individuals with subtherapeutic concentrations who might benefit from dose escalation.
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http://dx.doi.org/10.1055/a-1088-1461DOI Listing
May 2020

Reducing Perioperative Risks of Surgery in Crohn's Disease.

Visc Med 2019 Dec 12;35(6):348-354. Epub 2019 Nov 12.

Abteilung für Allgemein- und Viszeralchirurgie, Theresienkrankenhaus und St. Hedwig-Klinik GmbH Mannheim, Mannheim, Germany.

Background: Approximately one-third of all patients suffering from Crohn's disease (CD) undergo surgery within the first 10 years after diagnosis and another 20% will have a second operation in the 10 years after their first operation. Surgery will remain an essential part of managing CD and therefore it is crucial to prevent perioperative complications by optimizing perioperative management.

Methods: We reviewed the current literature on managing immunomodulating therapy, nutritional support, and thromboembolic prophylaxis in the perioperative situation.

Results: CD patients with serious nutritional deficits (weight loss >10% in the last 3-6 months, body mass index <18.5 kg/m2, or albumin levels <30 g/L) benefit from intensive enteral or parenteral nutritional support, thereby reducing the risk of surgical-site infections and post-operative septic complications. Immunosuppressive therapy with prednisolone doses >20 mg should be avoided. The risk of therapy with anti-TNFα agents, vedolizumab, and ustekinumab for surgical complications has not been fully established. Analysis of currently available data suggests that an interval of 4-8 weeks is prudent to avoid complications and reduce risk by performing protective ostomy in the emergency setting. Finally, due to the high risk of venous thromboembolism, prophylactic therapy with heparin is recommended.

Conclusion: As most cases of CD-related surgery are performed in a non-emergency setting, careful planning and risk management can reduce the rate of surgical complications, increase quality of life, and also reduce costs.
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http://dx.doi.org/10.1159/000504030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944936PMC
December 2019

The Gut Microbiome in Inflammatory Bowel Diseases: Diagnostic and Therapeutic Implications.

Visc Med 2019 Dec 7;35(6):332-337. Epub 2019 Nov 7.

II. Medizinische Klinik, Universitätsmedizin Mannheim, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany.

The incidence of chronic inflammatory bowel diseases (IBD) is rising worldwide, and the interaction between the mucosal immune system and the intestinal microbiota is crucial for the understanding of these diseases. Due to new technologies, the data published on the intestinal microbiota has increased rapidly in the recent years. While many findings are descriptive, reporting associations between disease and microbial populations, recent advancement in technology made it possible to ask and answer more functional questions and to elucidate complex interactions between the intestinal microbiota and the mucosal immune system. In addition, first trials influenced the intestinal microbiota with the intention to treat IBD. This review summarizes aspects of the physiological function as well as the inflammation-induced changes of the gut microbiota and the association between the gut microbiota and pathogenesis in IBD. In addition, diagnostic and therapeutic options for treating IBD are reviewed.
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http://dx.doi.org/10.1159/000504148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944918PMC
December 2019

Inflammatory Bowel Diseases.

Visc Med 2019 Dec 14;35(6):331. Epub 2019 Nov 14.

Klinik für Allgemein-, Viszeral- und Unfallchirurgie, Krankenhaus Porz am Rhein, Cologne, Germany.

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http://dx.doi.org/10.1159/000504149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944929PMC
December 2019

MALDI-TOF Mass Spectrometry-Based High-Throughput Screening for Inhibitors of the Cytosolic DNA Sensor cGAS.

SLAS Discov 2020 04 4;25(4):372-383. Epub 2019 Oct 4.

Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.

Comprehensive and unbiased detection methods are a prerequisite for high-throughput screening (HTS) campaigns within drug discovery research. Label-free matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) has been introduced as an HTS-compatible readout for biochemical test systems to support the drug discovery process. So far, reported HTS applications were based on surface-modified systems or proof-of-concept studies. We present the utilization of a MALDI-TOF-based screening platform to identify inhibitors of human cyclic GMP-AMP synthase (cGAS), a mediator of innate immune response whose aberration has been causally correlated to a number of inflammatory disorders. In this context, the development and validation of a MALDI-TOF-based activity assay is reported to demonstrate fast, robust, and accurate detection of chemical cGAS inhibition by direct quantification of the physiological reaction product cyclic GMP-ATP (cGAMP). Results from a screen of a diverse library of more than 1 million small molecules in 1536-well format against the catalytic cGAS activity are presented with excellent assay performance and data quality. Identified hits were qualified in dose-response experiments and confirmed by RapidFire-MS measurements. Conclusively, the presented data provide the first proof of applicability of direct automated MALDI-TOF MS as a readout strategy for large-scale drug discovery HTS campaigns.
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http://dx.doi.org/10.1177/2472555219880185DOI Listing
April 2020

Comparison of iron-reduced and iron-supplemented semisynthetic diets in T cell transfer colitis.

PLoS One 2019 5;14(7):e0218332. Epub 2019 Jul 5.

Institute for Immunology, Biomedical Center, Ludwig-Maximilians-University Munich, Martinsried, Germany.

Clinical observations in inflammatory bowel disease patients and experimental studies in rodents suggest that iron in the intestinal lumen derived from iron-rich food or oral iron supplementation could exacerbate inflammation and that iron depletion from the diet could be protective. To test the hypothesis that dietary iron reduction is protective against colitis development, the impact of iron reduction in the diet below 10 mg/kg on the course of CD4+ CD62L+ T cell transfer colitis was investigated in adult C57BL/6 mice. Weight loss as well as clinical and histological signs of inflammation were comparable between mice pretreated with semisynthetic diets with either < 10mg/kg iron content or supplemented with 180 mg/kg iron in the form of ferrous sulfate or hemin. Accumulation and activation of Ly6Chigh monocytes, changes in dendritic cell subset composition and induction of proinflammatory Th1/Th17 cells in the inflamed colon were not affected by the iron content of the diets. Thus, dietary iron reduction did not protect adult mice against severe intestinal inflammation in T cell transfer induced colitis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218332PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611680PMC
February 2020

Aberrant brain structural large-scale connectome in Crohn's disease.

Neurogastroenterol Motil 2019 06 14;31(6):e13593. Epub 2019 Apr 14.

Center for Mental Health, Odenwald District Healthcare Centre, Erbach, Germany.

Background: Disturbed brain-gut interactions and a bidirectional relationship between inflammation and psychiatric symptoms such as anxiety and depression are being discussed in patients with inflammatory bowel diseases (IBD). Alterations of brain structure and function in IBD have been reported with heterogeneous results. Whether these changes reflect independent localized deficits or rather a systematic disruption in the anatomical organization of large-scale brain networks remains unclear. The present study investigated the gray matter structural connectome in patients with Crohn's disease (CD).

Methods: Sixty participants (30 with quiescent CD and 30 matched healthy controls [HC]) underwent high-resolution brain MRI at 3 Tesla. Well-established graph theoretical metrics were analyzed at the global and regional network level and compared between groups.

Key Results: The networks in both groups followed a small-world organization, that is, an architecture that is simultaneously highly segregated and integrated. However, transitivity, a measure of global network segregation, was significantly reduced in patients (P = 0.003). Regionally, patients showed a reduction of nodal betweenness centrality in the right insula and cuneus and the left superior frontal cortex and reduced nodal degree within the left-hemispheric cingulate and the left lateral and right medial orbitofrontal cortex.

Conclusion And Inferences: These findings lend support to the hypothesis that CD is accompanied by alterations in both global network organization and regional connectivity. A deeper understanding of neural central networks in IBD may facilitate the development of complementary strategies in the treatment of "extraintestinal" comorbid conditions such as depression or anxiety.
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http://dx.doi.org/10.1111/nmo.13593DOI Listing
June 2019

Meso scale discovery-based assays for the detection of aggregated huntingtin.

PLoS One 2019 26;14(3):e0213521. Epub 2019 Mar 26.

CHDI Management/CHDI Foundation, Los Angeles, CA, United States of America.

Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat domain in the huntingtin (HTT) gene, leading to an expanded poly-glutamine (polyQ) stretch in the HTT protein. This mutant HTT (mHTT) protein is highly prone to intracellular aggregation, causing significant damage and cellular loss in the striatal, cortical, and other regions of the brain. Therefore, modulation of mHTT levels in these brain regions in order to reduce intracellular mHTT and aggregate levels represents a direct approach in the development of HD therapeutics. To this end, assays that can be used to detect changes in HTT levels in biological samples are invaluable tools to assess target engagement and guide dose selection in clinical trials. The Meso Scale Discovery (MSD) ELISA-based assay platform is a robust and sensitive method previously employed for the quantification of HTT. However, the currently available MSD assays for HTT are primarily detecting the monomeric soluble form of the protein, but not aggregated species. In this study, we describe the development of novel MSD assays preferentially detecting mHTT in an aggregated form. Recombinant monomeric HTT(1-97)-Q46, which forms aggregates in a time-dependent manner, was used to characterize the ability of each established assay to distinguish between HTT monomers and HTT in a higher assembly state. Further validation of these assays was performed using brain lysates from R6/2, zQ175 knock-in, and BACHD mouse models, to replicate a previously well-characterized age-dependent increase in brain aggregate signals, as well as a significant reduction of aggregate levels in the striatum following mHTT knockdown with a CAG-directed allele-specific zinc-finger repressor protein (ZFP). Lastly, size exclusion chromatography was used to separate and characterize HTT species from brain tissue lysates to demonstrate specificity of the assays for the fractions containing aggregated HTT. In summary, we demonstrate that the newly developed assays preferentially detect aggregated HTT with improved performance in comparison to previous assay technologies. These assays complement the existing MSD platform assays specific for soluble HTT monomers, allowing for a more comprehensive analysis of disease-relevant HTT species in preclinical models of HD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213521PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435127PMC
December 2019

Infection and Predictors of Outcome of Cirrhotic Patients after Emergency Care Hospital Admission.

Ann Hepatol 2018 Oct;17(6):948-958

2nd Medical Department, Technische Universität München, Klinikum rechts der Isar, Germany.

Introduction And Aims: We aimed to explore the impact of infection diagnosed upon admission and of other clinical baseline parameters on mortality of cirrhotic patients with emergency admissions.

Material And Methods: We performed a prospective observational monocentric study in a tertiary care center. The association of clinical parameters and established scoring systems with short-term mortality up to 90 days was assessed by univariate and multivariable Cox regression analysis. Akaike's Information Criterion (AIC) was used for automated variable selection. Statistical interaction effects with infection were also taken into account.

Results: 218 patients were included. 71.2% were male, mean age was 61.1 ± 10.5 years. Mean MELD score was 16.2 ± 6.5, CLIF-consortium Acute on Chronic Liver Failure-score was 34 ± 11. At 28, 90 and 365 days, 9.6%, 26.0% and 40.6% of patients had died, respectively. In multivariable analysis, respiratory organ failure [Hazard Ratio (HR) = 0.15], albumin substitution (HR = 2.48), non-HCC-malignancy (HR = 4.93), CLIF-C-ACLF (HR = 1.10), HCC (HR = 3.70) and first episode of ascites (HR = 0.11) were significantly associated with 90-day mortality. Patients with infection had a significantly higher 90-day mortality (36.3 vs. 20.1%, p = 0.007). Cultures were positive in 32 patients with resistance to cephalosporins or quinolones in 10, to ampicillin/sulbactam in 14 and carbapenems in 6 patients.

Conclusion: Infection is common in cirrhotic ED admissions and increases mortality. The proportion of resistant microorganisms is high. The predictive capacity of established scoring systems in this setting was low to moderate.
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http://dx.doi.org/10.5604/01.3001.0012.7195DOI Listing
October 2018

Mandatory criteria for the application of variability-based parameters of fluid responsiveness: a prospective study in different groups of ICU patients.

J Zhejiang Univ Sci B 2018 Jul;19(7):515-524

Klinik für Innere Medizin, RoMed Klinik Bad Aibling, Harthauser Straße 16, D-83043 Bad Aibling, Germany.

Background And Objective: Stroke volume variation (SVV) has high sensitivity and specificity in predicting fluid responsiveness. However, sinus rhythm (SR) and controlled mechanical ventilation (CV) are mandatory for their application. Several studies suggest a limited applicability of SVV in intensive care unit (ICU) patients. We hypothesized that the applicability of SVV might be different over time and within certain subgroups of ICU patients. Therefore, we analysed the prevalence of SR and CV in ICU patients during the first 24 h of PiCCO-monitoring (primary endpoint) and during the total ICU stay. We also investigated the applicability of SVV in the subgroups of patients with sepsis, cirrhosis, and acute pancreatitis.

Methods: The prevalence of SR and CV was documented immediately before 1241 thermodilution measurements in 88 patients.

Results: In all measurements, SVV was applicable in about 24%. However, the applicability of SVV was time-dependent: the prevalence of both SR and CV was higher during the first 24 h compared to measurements thereafter (36.1% vs. 21.9%; P<0.001). Within different subgroups, the applicability during the first 24 h of monitoring ranged between 0% in acute pancreatitis, 25.5% in liver failure, and 48.9% in patients without pancreatitis, liver failure, pneumonia or sepsis.

Conclusions: The applicability of SVV in a predominantly medical ICU is only about 25%-35%. The prevalence of both mandatory criteria decreases over time during the ICU stay. Furthermore, the applicability is particularly low in patients with acute pancreatitis and liver failure.
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http://dx.doi.org/10.1631/jzus.B1700243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052358PMC
July 2018

Prevalence of inflammatory bowel disease in alcoholic, non-alcoholic and autoimmune pancreatitis.

Z Gastroenterol 2018 05 7;56(5):469-478. Epub 2018 May 7.

Department of Medicine II, University Medical Center Mannheim, Medical Faculty of the University of Heidelberg, Mannheim, Germany.

Objectives: Patients with inflammatory bowel disease (IBD) frequently reveal features of pancreatic inflammation. However, the prevalence of IBD in patients with alcoholic pancreatitis (AP) and nonalcoholic pancreatitis (NAP) has not yet been determined, and the prevalence of IBD in patients with autoimmune pancreatitis (AiP) from Germany is unknown.

Aims: Thus, we aimed, first, to determine the prevalence of IBD in AP, NAP, and AiP from a tertiary center in Germany and, second, to characterize patients with AiP and IBD.

Methods: We performed a retrospective cross-sectional study to determine the prevalence of IBD in patients with different forms of pancreatitis presenting to our clinic.

Results: Compared to the general population and to a control group with viral hepatitis from our clinic, we observed the most significant increase of IBD in patients with AiP (n = 3/28; p < 0.0001 vs. general population, binomial proportion test; p = 0.0112 vs. hepatitis group, Fisher's exact test), followed by a significant increase in subjects with NAP (n = 11/278; p < 0.0001 vs. general population, binomial proportion test; p = 0.0338 vs. hepatitis group, Fisher's exact test). A review of previous studies on the prevalence of IBD among patients with AiP revealed a combined prevalence of 12 % (n = 43/355). Type 2 AiP is significantly more often associated with IBD than type 1 AiP (n = 28/48, 58 % vs. n = 7/129, 5 %; combined patient cohort, p < 10E - 12; Fisher's exact test).

Conclusions: Immune-mediated mechanisms related to IBD may participate in the development of AiP, especially AiP type 2, and may also increase the risk for the development of other forms of pancreatic inflammation.
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http://dx.doi.org/10.1055/s-0043-123881DOI Listing
May 2018

PPARγ-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant mice.

Oncoimmunology 2018;7(5):e1423168. Epub 2018 Feb 1.

Dept. of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

To identify novel hubs for cancer immunotherapy, we generated J mice with concomitant deletion of the drugable transcription factor PPARγ and transgenic overexpression of the mutant oncogene in enterocytes. Animals developed epithelial hyperplasia, transmural inflammation and serrated adenomas in the small intestine with infiltration of CD3+ FOXP3+ T-cells and macrophages into the lamina propria of the non-malignant mucosa. Within serrated polyps, CD3+ CD8+ T-cells and phosphorylated ERK1/2 were reduced and the senescence marker P21 and macrophage counts up-regulated, indicative of an immunosuppressive tissue microenvironment. Treatment of mutant mice with the PPARγ-agonist rosiglitazone augmented M1 macrophage numbers, reduced IL4 expression and diminished polyp load in mice. Rosiglitazone also promoted M1 polarisation of human THP1-derived macrophages and decreased mRNA in isolated murine lymphocytes. Thus, inhibition of the oncogenic driver mutant RAS by PPARγ in epithelial and immune cell compartments may be a future target for the prevention or treatment of human malignancies associated with intestinal inflammation.
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http://dx.doi.org/10.1080/2162402X.2017.1423168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927516PMC
February 2018

Intrinsic neural network dysfunction in quiescent Crohn's Disease.

Sci Rep 2017 09 14;7(1):11579. Epub 2017 Sep 14.

Department of General Psychiatry, Heidelberg University Hospital, 69115, Heidelberg, Germany.

Psychological factors and comorbidities play an important role in inflammatory bowel diseases. Such comorbidity could be associated with a specific neural phenotype. Brain regions associated with emotion regulation and self-referential processing, including areas assigned to the "default mode network" (DMN), could be promising candidates in this regard. We investigated the functional integrity of multiple intrinsic neural networks in remitted patients with Crohn's disease (CD) and sought to establish relationships between neural network connectivity and psychiatric symptoms. Fifteen CD patients in remission and 14 controls were investigated. We employed resting-state functional magnetic resonance imaging (fMRI) at 3 Tesla followed by a spatial Independent Component Analysis for fMRI data. Abnormal connectivity in CD patients was observed in DMN subsystems only (p < 0.05, cluster-corrected). Increased connectivity was found in the anterior cingulate and left superior medial frontal gyrus (aDMN) and the middle cingulate cortex (pDMN). Middle cingulate activity showed a significant association with anxiety scores in patients (p = 0.029). This study provides first evidence of selectively disrupted intrinsic neural network connectivity in CD and suggests abnormalities of self-referential neural networks. An increased sensitivity to self-related affective and somatic states in CD patients could account for these findings and explain a higher risk for anxiety symptoms.
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http://dx.doi.org/10.1038/s41598-017-11792-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599642PMC
September 2017

Clinical and Histopathologic Features of Colorectal Adenocarcinoma in Crohn's Disease.

J Clin Gastroenterol 2018 08;52(7):635-640

Department of Surgery.

Goals: The aim of this study was to assess the histopathologic characteristics of colorectal carcinomas (CRC) in patients with Crohn's disease (CD).

Background: A higher frequency of microsatellite instability (MSI) is seen in mucinous compared with nonmucinous CRC which suggests that its pathogenesis involves distinct molecular pathways. Several publications reported a higher percentage of mucinous adenocarcinoma in CD patients with CRC. So far, there has been no investigation of MSI in CD patients with mucinous CRC.

Study: The medical records of patients who underwent surgery for CRC were reviewed and those with a history of CD identified. The data of histologic classification and MSI status of the tumor were investigated.

Results: Fourteen patients with CD-associated CRC were identified (5 female, 9 male) resulting in 20 CRC in total. Histologic investigation revealed 7 adenocarcinomas without a mucinous or signet ring cell component. All other CRCs harbored a mucinous (n=11) and/or signet ring cell (n=6) component. All tumors assessed for MSI were found to be microsatellite stable.

Conclusions: Our data indicate that CRCs with signet ring cell and mucinous components were much more common in patients with CD than in patients with sporadic CRC. This observation suggests that CRC in CD represent an own entity with distinct histopathologic and molecular features. This may implicate potential consequences for diagnosis and therapy of CRC in CD in the future as well as new factors to identify patients with an increased risk for developing CRC in CD.
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http://dx.doi.org/10.1097/MCG.0000000000000817DOI Listing
August 2018

Altered Markers of Brain Development in Crohn's Disease with Extraintestinal Manifestations - A Pilot Study.

PLoS One 2016;11(9):e0163202. Epub 2016 Sep 21.

Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background And Objective: Alterations of brain morphology in Crohn's disease have been reported, but data is scarce and heterogenous and the possible impact of disease predisposition on brain development is unknown. Assuming a systemic course of the disease, brain involvement seems more probable in presence of extraintestinal manifestations, but this question has not yet been addressed. The present study examined the relationship between Crohn's disease and brain structure and focused on the connection with extraintestinal manifestations and markers of brain development.

Methods: In a pilot study, brains of 15 patients with Crohn's disease (of which 9 had a history of extraintestinal manifestations, i.e. arthritis, erythema nodosum and primary sclerosing cholangitis) were compared to matched healthy controls using high resolution magnetic resonance imaging. Patients and controls were tested for depression, fatigue and global cognitive function. Cortical thickness, surface area and folding were determined via cortical surface modeling.

Results: The overall group comparison (i.e. all patients vs. controls) yielded no significant results. In the patient subgroup with extraintestinal manifestations, changes in cortical area and folding, but not thickness, were identified: Patients showed elevated cortical surface area in the left middle frontal lobe (p<0.05) and hypergyrification in the left lingual gyrus (p<0.001) compared to healthy controls. Hypogyrification of the right insular cortex (p<0.05) and hypergyrification of the right anterior cingulate cortex (p<0.001) were detected in the subgroup comparison of patients with against without extraintestinal manifestations. P-values are corrected for multiple comparisons.

Conclusions: Our findings lend further support to the hypothesis that Crohn's disease is associated with aberrant brain structure and preliminary support for the hypothesis that these changes are associated with a systemic course of the disease as indicated by extraintestinal manifestations. Changes in cortical surface area and folding suggest a possible involvement of Crohn's disease or its predisposition during brain development.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031401PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163202PLOS
September 2016

Development of Bifunctional Inhibitors of Polo-Like Kinase 1 with Low-Nanomolar Activities Against the Polo-Box Domain.

Chembiochem 2016 Apr 4;17(8):759-67. Epub 2015 Dec 4.

Leipzig University, Institute of Organic Chemistry, Johannisallee 29, 04103, Leipzig, Germany.

Polo-like kinase 1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP-competitive ligand of the enzymatic domain, derived from BI 2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low-nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors.
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http://dx.doi.org/10.1002/cbic.201500535DOI Listing
April 2016

IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity.

J Immunol 2015 Dec 11;195(12):5787-94. Epub 2015 Nov 11.

Institute for Immunology, Biomedical Center Munich, Ludwig Maximilians University, D-82152 Planegg-Martinsried, Germany;

IL-1R-associated kinase (IRAK) 1 is an important component of the IL-1R and TLR signaling pathways, which influence Th cell differentiation. In this study, we show that IRAK1 promotes Th17 development by mediating IL-1β-induced upregulation of IL-23R and subsequent STAT3 phosphorylation, thus enabling sustained IL-17 production. Moreover, we show that IRAK1 signaling fosters Th1 differentiation by mediating T-bet induction and counteracts regulatory T cell generation. Cotransfer experiments revealed that Irak1-deficient CD4(+) T cells have a cell-intrinsic defect in generating Th1 and Th17 cells under inflammatory conditions in spleen, mesenteric lymph nodes, and colon tissue. Furthermore, IRAK1 expression in T cells was shown to be essential for T cell accumulation in the inflamed intestine and mesenteric lymph nodes. Transcriptome analysis ex vivo revealed that IRAK1 promotes T cell activation and induction of gut-homing molecules in a cell-intrinsic manner. Accordingly, Irak1-deficient T cells failed to upregulate surface expression of α4β7 integrin after transfer into Rag1(-/-) mice, and their ability to induce colitis was greatly impaired. Lack of IRAK1 in recipient mice provided additional protection from colitis. Therefore, IRAK1 plays an important role in intestinal inflammation by mediating T cell activation, differentiation, and accumulation in the gut. Thus, IRAK1 is a promising novel target for therapy of inflammatory bowel diseases.
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http://dx.doi.org/10.4049/jimmunol.1501874DOI Listing
December 2015

Patient position and hypoxemia during propofol sedation for colonoscopy: a randomized trial.

Endoscopy 2015 Dec 30;47(12):1159-66. Epub 2015 Jun 30.

II. Medizinische Klinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.

Aim: To evaluate the benefits of the left lateral position in avoiding hypoxemic events in patients undergoing colonoscopy.

Methods: We conducted a randomized, prospective, controlled trial at two study sites in Germany. Patients undergoing colonoscopy under propofol sedation were randomized to either the supine or left lateral position. The primary outcome was oxygen desaturation (SaO2<90%). Secondary outcome measures were apneic events, hypotension, patient satisfaction, propofol dosage, cecal intubation time, and adenoma detection.

Results: A total of 412 patients were randomized 1:1 to undergo colonoscopy in the supine or left lateral position. No severe adverse events were observed in either group. Intention-to-treat analysis revealed no significant difference in the frequency of desaturation in the left lateral arm compared with the supine arm (6.8% vs. 12.1%; P=0.064). Patients in the left lateral arm showed lower apnea rates (9.4% vs. 16.2%; P= .040), but had more episodes of hypotension (12.3% vs. 2.9%; P<0.001). The frequency of repositioning was higher in the left lateral group. No significant differences were observed in patient satisfaction and cooperation, propofol dosage, or adenoma detection rate. Patients who were repositioned to facilitate endoscope passage were excluded from per-protocol analysis. The incidence of hypoxemia was lower for the left lateral than for the supine group in per-protocol analysis (1.8% vs. 11.2%; P=0.003).

Conclusion: The positioning of patients in the left lateral position during propofol sedation for colonoscopy results in lower desaturation rates provided the position can be maintained throughout endoscopy. ClinicalTrials.gov NCT02001792.
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http://dx.doi.org/10.1055/s-0034-1392329DOI Listing
December 2015

Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach.

Genome Biol 2015 Feb 21;16:40. Epub 2015 Feb 21.

Background: An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels.

Results: Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease.

Conclusions: Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.
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http://dx.doi.org/10.1186/s13059-015-0599-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389302PMC
February 2015

Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntington's disease.

J Med Chem 2015 Feb 23;58(3):1159-83. Epub 2015 Jan 23.

Evotec (U.K.) Ltd, 114 Innovation Drive, Milton Park, Abingdon, OX14 4RZ, U.K.

We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.
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http://dx.doi.org/10.1021/jm501350yDOI Listing
February 2015

High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity.

Nature 2014 Oct 31;514(7523):508-12. Epub 2014 Aug 31.

Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany.

Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers. There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota. Moreover, there is now unequivocal evidence linking dysbiosis to cancer development. However, the mechanisms by which high-fat diet (HFD)-mediated changes in the microbial community affect the severity of tumorigenesis in the gut remain to be determined. Here we demonstrate that an HFD promotes tumour progression in the small intestine of genetically susceptible, K-ras(G12Dint), mice independently of obesity. HFD consumption, in conjunction with K-ras mutation, mediated a shift in the composition of the gut microbiota, and this shift was associated with a decrease in Paneth-cell-mediated antimicrobial host defence that compromised dendritic cell recruitment and MHC class II molecule presentation in the gut-associated lymphoid tissues. When butyrate was administered to HFD-fed K-ras(G12Dint) mice, dendritic cell recruitment in the gut-associated lymphoid tissues was normalized, and tumour progression was attenuated. Importantly, deficiency in MYD88, a signalling adaptor for pattern recognition receptors and Toll-like receptors, blocked tumour progression. The transfer of faecal samples from HFD-fed mice with intestinal tumours to healthy adult K-ras(G12Dint) mice was sufficient to transmit disease in the absence of an HFD. Furthermore, treatment with antibiotics completely blocked HFD-induced tumour progression, suggesting that distinct shifts in the microbiota have a pivotal role in aggravating disease. Collectively, these data underscore the importance of the reciprocal interaction between host and environmental factors in selecting a microbiota that favours carcinogenesis, and they suggest that tumorigenesis is transmissible among genetically predisposed individuals.
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http://dx.doi.org/10.1038/nature13398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233209PMC
October 2014