Publications by authors named "Oliver Koch"

104 Publications

Computational Ion Channel Research: from the Application of Artificial Intelligence to Molecular Dynamics Simulations.

Cell Physiol Biochem 2021 Mar;55(S3):14-45

Institute of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität Münster, Münster, Germany,

Although ion channels are crucial in many physiological processes and constitute an important class of drug targets, much is still unclear about their function and possible malfunctions that lead to diseases. In recent years, computational methods have evolved into important and invaluable approaches for studying ion channels and their functions. This is mainly due to their demanding mechanism of action where a static picture of an ion channel structure is often insufficient to fully understand the underlying mechanism. Therefore, the use of computational methods is as important as chemical-biological based experimental methods for a better understanding of ion channels. This review provides an overview on a variety of computational methods and software specific to the field of ion-channels. Artificial intelligence (or more precisely machine learning) approaches are applied for the sequence-based prediction of ion channel family, or topology of the transmembrane region. In case sufficient data on ion channel modulators is available, these methods can also be applied for quantitative structureactivity relationship (QSAR) analysis. Molecular dynamics (MD) simulations combined with computational molecular design methods such as docking can be used for analysing the function of ion channels including ion conductance, different conformational states, binding sites and ligand interactions, and the influence of mutations on their function. In the absence of a three-dimensional protein structure, homology modelling can be applied to create a model of your ion channel structure of interest. Besides highlighting a wide range of successful applications, we will also provide a basic introduction to the most important computational methods and discuss best practices to get a rough idea of possible applications and risks.
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http://dx.doi.org/10.33594/000000336DOI Listing
March 2021

[Planning and Design of a Prospective Randomised Multi-Centre Trial on the Repair of Large Hiatal Hernias with Sutures vs. Pledgeted Sutures vs. Absorbable Mesh].

Zentralbl Chir 2021 Feb 10. Epub 2021 Feb 10.

Universitätsklinik für Allgemein-, Viszeral- und Thoraxchirurgie, Landeskrankenhaus Salzburg - Universitätsklinikum der Paracelsus Medizinischen Privatuniversität, Salzburg, Österreich.

Background: The hernia recurrence rate after surgical treatment of large hiatal hernias is still very high. The optimal technique to reduce the recurrence rate is still under debate. The aim of this work is to clarify whether pledgeted reinforced sutures or a resorbable mesh can reduce the recurrence rate compared to hiatus closure with only sutures.

Materials And Methods: An Austria-wide, multi-centre, prospective, randomised study was planned. The study protocol was prepared by the main test centre (University Clinic for General, Visceral and Thoracic Surgery, Paracelsus Medical University Salzburg). The study includes patients who are scheduled to undergo laparoscopic or robot-assisted surgery for a large symptomatic hiatal hernia. A large hiatal hernia is defined as > 5 cm in manometry or gastroscopy or at least ⅓ of the stomach lying intrathoracically. The primary study endpoint is defined as the hernia recurrence rate, objectively assessed by gastroscopy. After inclusion in the study, patients will be followed up for 6 months, 1 year, 3 years and 5 years after the operation, using standardised questionnaires and gastroscopy. The power calculation showed a requirement of 55 patients per group. Preoperative randomisation and data management are software-based.

Results: The study approval by the leading ethics committee is currently pending and the study itself has been registered on ClinicalTrials.gov since October 2020. The Clinical Trials Registration Number is NCT04591860. Five clinics are participating in the study at the moment and all centres are actively enrolling patients. The duration of the study is set until January 2027.

Conclusion: This study is the world's first prospective randomised study that examines the value of pledgets and resorbable mesh to reduce the recurrence rate after treatment of large hiatal hernias. The results will help to find the optimal technique to close the hiatus of large hiatal hernias.
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http://dx.doi.org/10.1055/a-1369-9694DOI Listing
February 2021

[Reflux Symptoms - No Difference in Severity and Intensity in Patients with and without Functional Verified Gastroesophageal Reflux Disease].

Zentralbl Chir 2021 Feb 8. Epub 2021 Feb 8.

Universitätsklinik für Chirurgie, Landeskrankenhaus Salzburg - Universitätsklinikum der Paracelsus Medizinischen Privatuniversität, Salzburg, Österreich.

Background: Patients with gastroesophageal reflux disease (GERD) often suffer greatly from their symptoms. The aim of this study was to determine if there is a difference in quality of life and gastrointestinal symptom complexes between patients with purely functional complaints and patients with objective GERD.

Material And Methods: We included all patients with typical reflux symptoms, who had a GERD examination in 2017 at our department. All patients underwent high resolution manometry, 24-h-pH-metry impedance measurement and gastroscopy. Quality of life was assessed using the Gastrointestinal Quality of Life Index (GIQLI) and gastrointestinal symptoms were rated by a symptom checklist (SCL), assessing the severity and intensity of 14 different symptoms. Based on the results of the 24-h-pH-metry impedance measurement, patients were divided into 2 groups: patients with functional reflux symptoms and patients with true GERD. These two groups were compared.

Results: Complete data were available in 162 patients, of whom 86 (52.2%) were objectively suffering from reflux (DeMeester score mean: 37.85; SD ± 29.11) and 76 (46.1%) had a normal DeMeester score (Mean: 7.01; SD ± 4.09). No significant difference in quality of life was found between the two groups (mean GIQLI of GERD patients: 94.81, SD ± 22.40, and mean GIQLI of patients with functional reflux symptoms: 95.26, SD ± 20.33, p = 0.988). Furthermore, no significant difference could be found in the evaluated symptoms (mean general SCL score of GERD patients: 46.97; SD ± 29.23; patients with functional reflux symptoms: 48.03; SD ± 29.17, p = 0.827).

Conclusion: Patients with functional complaints suffer just as much from their symptoms as patients with objectively diagnosed GERD. Differentiation between gastroesophageal reflux disease and functional reflux symptoms is only possible by means of functional diagnostic testing.
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http://dx.doi.org/10.1055/a-1333-3910DOI Listing
February 2021

Using Domain-Specific Fingerprints Generated Through Neural Networks to Enhance Ligand-Based Virtual Screening.

J Chem Inf Model 2021 Feb 26;61(2):664-675. Epub 2021 Jan 26.

Institute of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, Münster 48149, Germany.

Similarity-based virtual screening is a fundamental tool in the early drug discovery process and relies heavily on molecular fingerprints. We propose a novel strategy of generating domain-specific fingerprints by training neural networks on target-specific bioactivity datasets and using the activation as a new molecular representation. The neural network is expected to combine information of already known bioactive compounds with unique information of the molecular structure and by doing so enrich the fingerprint. We evaluate this strategy on a large kinase-specific bioactivity dataset. A comparison of five neural network architectures and their fingerprints to the well-established extended-connectivity fingerprint (ECFP) and an autoencoder shows that our neural fingerprint produces better results in the similarity search. Most importantly, the neural fingerprint performs well even when specific targets are not included during training. Surprisingly, while Graph Neural Networks (GNNs) are thought to offer an advantageous alternative, the best performing neural fingerprints were based on traditional fully connected layers using the ECFP4 as the input. The neural fingerprint is freely available at: https://github.com/kochgroup/kinase_nnfp.
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http://dx.doi.org/10.1021/acs.jcim.0c01208DOI Listing
February 2021

Co-staining of K 3.1 Channels in NSCLC Cells with a Small-Molecule Fluorescent Probe and Antibody-Based Indirect Immunofluorescence.

ChemMedChem 2020 Dec 21;15(24):2462-2469. Epub 2020 Oct 21.

Institute for Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University Münster, Corrensstraße 48, 48149, Münster, Germany.

The Ca activated potassium channel 3.1 (K 3.1) is involved in critical steps of the metastatic cascade, such as proliferation, migration, invasion and extravasation. Therefore, a fast and efficient protocol for imaging of K 3.1 channels was envisaged. The novel fluorescently labeled small molecule imaging probes 1 and 2 were synthesized by connecting a dimethylpyrrole-based BODIPY dye with a derivative of the K 3.1 channel inhibitor senicapoc via linkers of different length. Patch-clamp experiments revealed the inhibition of K 3.1 channels by the probes confirming interaction with the channel. Both probes 1 and 2 were able to stain K 3.1 channels in non-small-cell lung cancer (NSCLC) cells following a simple, fast and efficient protocol. Pre-incubation with unlabeled senicapoc removed the punctate staining pattern showing the specificity of the new probes 1 and 2. Staining of the channel with the fluorescently labeled senicapoc derivatives 1 or 2 or with antibody-based indirect immunofluorescence yielded identical or very similar densities of stained K 3.1 channels. However, co-staining using both methods did not lead to the expected overlapping punctate staining pattern. This observation was explained by docking studies showing that the antibody used for indirect immunofluorescence and the probes 1 and 2 label different channel populations. Whereas the antibody binds at the closed channel conformation, the probes 1 and 2 bind within the open channel.
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http://dx.doi.org/10.1002/cmdc.202000652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756743PMC
December 2020

Prospective randomized controlled trial on comparison of standard CO pressure pneumoperitoneum insufflator versus AirSeal®.

Surg Endosc 2020 Aug 7. Epub 2020 Aug 7.

Department of Surgery, Paracelsus Medical University, Salzburg, Austria.

Background: AirSeal® is a valve-free insufflation system that enables a stable pneumoperitoneum with continuous smoke evacuation and CO recirculation during laparoscopic surgery. Comparative evidence on the use of AirSeal® and standard CO insufflator in laparoscopic general surgery procedures is scarce. The aim of this study was to compare surgical outcomes between AirSeal® and standard CO insufflators in patients undergoing the most frequently performed laparoscopic procedures.

Methods: One hundred and ninety-eight patients undergoing elective laparoscopic cholecystectomy, colorectal surgery and hernia repair were randomized to either AirSeal® (group A) or standard pressure CO insufflator (group S). The primary endpoints were operative time and level of postoperative shoulder tip pain (Visual Analog Scale). Secondary outcomes included Clavien-Dindo grade complications, surgical side effect and length of hospital stay.

Results: Patients were randomized to either group A (n = 101) or group S (n = 97) and were analyzed by intention-to-treat. There was no significant difference in mean operative time between the groups (median [IQR]; 71 min [56-94] in group A vs. 69 min [52-93] in group S; p = 0.434). Shoulder tip pain levels were significantly lower in group S (VAS 0 [0-3] in group S vs. 2 [0-4] in group A; p = 0.001). There was no significant difference in complications, surgical side effects (subcutaneous emphysema was not observed in any group) and length of hospital stay.

Conclusion: This randomized controlled trial showed that using the AirSeal® system did not reduce operative time and was associated with a higher postoperative shoulder tip pain compared to standard CO insufflator for short elective surgeries. ClinicalTrials.gov (NCT01740011).
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http://dx.doi.org/10.1007/s00464-020-07846-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412773PMC
August 2020

Interferon-gamma polymorphisms and risk of iron deficiency and anaemia in Gambian children.

Wellcome Open Res 2020 2;5:40. Epub 2020 Jun 2.

Kenya Medical Research Institute (KEMRI) Centre for Geographic Medicine Coast, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.

: Anaemia is a major public health concern especially in African children living in malaria-endemic regions. Interferon-gamma (IFN-γ) is elevated during malaria infection and is thought to influence erythropoiesis and iron status. Genetic variants in the IFN-γ gene ) are associated with increased IFN-γ production. We investigated putative functional single nucleotide polymorphisms (SNPs) and haplotypes of in relation to nutritional iron status and anaemia in Gambian children over a malaria season. We used previously available data from Gambian family trios to determine informative SNPs and then used the Agena Bioscience MassArray platform to type five SNPs from the gene in a cohort of 780 Gambian children aged 2-6 years. We also measured haemoglobin and biomarkers of iron status and inflammation at the start and end of a malaria season. We identified five haplotype-tagging SNPs ( -1616 [rs2069705], +874 [rs2430561], +2200 [rs1861493], +3234 [rs2069718] and +5612 [rs2069728]). The +2200C [rs1861493] allele was associated with reduced haemoglobin concentrations (adjusted β -0.44 [95% CI -0.75, -0.12]; Bonferroni adjusted P = 0.03) and a trend towards iron deficiency compared to wild-type at the end of the malaria season in multivariable models adjusted for potential confounders. A haplotype uniquely identified by +2200C was similarly associated with reduced haemoglobin levels and trends towards iron deficiency, anaemia and iron deficiency anaemia at the end of the malaria season in models adjusted for age, sex, village, inflammation and malaria parasitaemia. We found limited statistical evidence linking polymorphisms with a risk of developing iron deficiency and anaemia in Gambian children. More definitive studies are needed to investigate the effects of genetically influenced IFN-γ levels on the risk of iron deficiency and anaemia in children living in malaria-endemic areas.
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http://dx.doi.org/10.12688/wellcomeopenres.15750.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202087PMC
June 2020

Drive-through testing in COVID-19: experience from NHS Lothian.

Clin Med (Lond) 2020 05 1;20(3):290-291. Epub 2020 May 1.

NHS Lothian, Edinburgh, UK.

The growing epidemic of SARS-CoV-2 challenges healthcare resources globally and mandates innovation. We describe our novel drive-through coronavirus testing which we used for testing of possible cases in the contain phase of UK response and are now using for healthcare worker testing. We found that this system was pragmatic, cost-efficient and favourable for patients. It is easily modifiable for use in future infectious disease outbreaks.
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http://dx.doi.org/10.7861/clinmed.2020-0160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354038PMC
May 2020

Two cases of imported respiratory diphtheria in Edinburgh, Scotland, October 2019.

Epidemiol Infect 2020 05 15;148:e143. Epub 2020 May 15.

Health Protection Team, NHS Lothian, Edinburgh, Scotland.

We report two cases of respiratory toxigenic Corynebacterium diphtheriae infection in fully vaccinated UK born adults following travel to Tunisia in October 2019. Both patients were successfully treated with antibiotics and neither received diphtheria antitoxin. Contact tracing was performed following a risk assessment but no additional cases were identified. This report highlights the importance of maintaining a high index of suspicion for re-emerging infections in patients with a history of travel to high-risk areas outside Europe.
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http://dx.doi.org/10.1017/S0950268820001028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374812PMC
May 2020

Coronavirus disease (COVID-19) Community Testing Team in Scotland: A 14-day review, 6 to 20 February 2020.

Euro Surveill 2020 03;25(12)

NHS Lothian Regional Infectious Diseases Unit, Edinburgh Scotland.

In response to the outbreak of COVID-19, we set up a team to carry out sampling in the community. This enabled individuals to remain in self-isolation in their own homes and to prevent healthcare settings and services from being overwhelmed by admissions for sampling of suspected cases. There is evidence that this is a cost effective, safe and necessary service to complement COVID-19 testing in hospitals.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.12.2000217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118345PMC
March 2020

The index case of SARS-CoV-2 in Scotland.

J Infect 2020 07 21;81(1):147-178. Epub 2020 Mar 21.

NHS Lothian, Regional Infectious Diseases Unit, Edinburgh, EH4 2XU.

Since its identification in December 2019, SARS-CoV-2 has infected 125,048 persons globally with cases identified in 118 countries across all continents. We report on the Scottish index case of SARS-CoV-2 infection, the virus causing COVID-19.
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http://dx.doi.org/10.1016/j.jinf.2020.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118628PMC
July 2020

Synthesis of Small-Molecule Fluorescent Probes for the In Vitro Imaging of Calcium-Activated Potassium Channel K 3.1.

Angew Chem Int Ed Engl 2020 05 17;59(21):8277-8284. Epub 2020 Mar 17.

Institute for Pharmaceutical and Medicinal Chemistry, Westphalian Wilhelms-University Münster, Corrensstraße 48, 48149, Münster, Germany.

Small-molecule probes for the in vitro imaging of K 3.1 channel-expressing cells were developed. Senicapoc, showing high affinity and selectivity for the K 3.1 channels, was chosen as the targeting component. BODIPY dyes 15-20 were synthesized and connected by a Cu -catalyzed azide-alkyne [3+2]cycloaddition with propargyl ether senicapoc derivative 8, yielding fluorescently labeled ligands 21-26. The dimethylpyrrole-based imaging probes 25 and 26 allow staining of K 3.1 channels in NSCLC cells. The specificity was shown by removing the punctate staining pattern by pre-incubation with senicapoc. The density of K 3.1 channels detected with 25 and by immunostaining was identical. The punctate structure of the labeled channels could also be observed in living cells. Molecular modeling showed binding of the senicapoc-targeting component towards the binding site within the ion channel and orientation of the linker with the dye along the inner surface of the ion channel.
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http://dx.doi.org/10.1002/anie.202001201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318252PMC
May 2020

Expression of the microRNA-200 Family, microRNA-205, and Markers of Epithelial-Mesenchymal Transition as Predictors for Endoscopic Submucosal Dissection over Esophagectomy in Esophageal Adenocarcinoma: A Single-Center Experience.

Cells 2020 02 20;9(2). Epub 2020 Feb 20.

Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.

Endoscopic submucosal dissection (ESD) is an effective treatment of early esophageal adenocarcinomas (EACs). The decision of ESD over esophagectomy is based on clinical evaluation of tumor depth and invasion. On a molecular level, tumor invasion is strongly associated with epithelial-to-mesenchymal transition (EMT). Here, we investigated whether localized ESD-resected and surgically resected EAC samples displayed different expression profiles of EMT protein and microRNA markers and whether these different expression profiles were able to retrospectively discriminate localized and surgically resected samples. By doing this, we aimed to evaluate whether preoperative measurement of EMT marker expression might support the decision regarding ESD over surgery. The results showed that ESD-resected samples displayed an epithelial expression profile, i.e., high expression of epithelial protein markers, whereas surgically resected samples displayed high expression of mesenchymal markers. In addition, the anti-EMT microRNA-205 was significantly more expressed in ESD-resected samples, whereas we found no significant differences in the expression levels of microRNA-200 family members. Furthermore, in our retrospective approach, we have demonstrated that measurement of selected EMT markers and microRNA-205 has significant discrimination power to distinguish ESD-resected and surgically resected samples. We suggest that the assessment of EMT status of EAC samples on a molecular level may support clinical evaluation regarding the applicability of ESD.
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http://dx.doi.org/10.3390/cells9020486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072807PMC
February 2020

Case report: meningitis as a presenting feature of anti-NMDA receptor encephalitis.

BMC Infect Dis 2020 Jan 7;20(1):21. Epub 2020 Jan 7.

Centre of Clinical Brain Sciences, The University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.

Background: Meningitis is a very rare atypical presenting feature of anti-NMDA receptor encephalitis. In our case report, we describe an unusual clinical presentation of anti-NMDA receptor encephalitis with a biphasic pattern of meningitis followed by encephalitis and discuss potential mechanisms underlying this presentation. We aim to widen the differential diagnosis to be considered in a patient presenting with clinical meningitis and pyrexia.

Case Presentation: This is a case of a 33-year old Caucasian woman who initially presented with a lymphocytic meningitis attributed to a viral infection. She subsequently developed fluctuating consciousness, agitation, visual hallucinations, dyskinetic movements, a generalized tonic-clonic seizure, and autonomic instability. Investigations revealed a diagnosis of anti-NMDA receptor encephalitis secondary to a previously unidentified ovarian teratoma. She made an excellent recovery with immunotherapy and removal of the teratoma.

Conclusion: Clinicians should consider autoimmune encephalitides in individuals with meningitis, particularly where extensive investigations fail to identify a causative pathogen and there is rapid development of an encephalitic phenotype.
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http://dx.doi.org/10.1186/s12879-020-4761-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947964PMC
January 2020

SCOT: Rethinking the classification of secondary structure elements.

Bioinformatics 2020 04;36(8):2417-2428

Department of Computer Science.

Motivation: Secondary structure classification is one of the most important issues in structure-based analyses due to its impact on secondary structure prediction, structural alignment and protein visualization. There are still open challenges concerning helix and sheet assignments which are currently not addressed by a single multi-purpose software.

Results: We introduce SCOT (Secondary structure Classification On Turns) as a novel secondary structure element assignment software which supports the assignment of turns, right-handed α-, 310- and π-helices, left-handed α- and 310-helices, 2.27- and polyproline II helices, β-sheets and kinks. We demonstrate that the introduction of helix Purity values enables a clear differentiation between helix classes. SCOT's unique strengths are highlighted by comparing it to six state-of-the-art methods (DSSP, STRIDE, ASSP, SEGNO, DISICL and SHAFT). The assignment approaches were compared concerning geometric consistency, protein structure quality and flexibility dependency and their impact on secondary structure element-based structural alignments. We show that only SCOT's combination of hydrogen bonds, geometric criteria and dihedral angles enables robust assignments independent of the structure quality and flexibility. We demonstrate that this combination and the elaborate kink detection lead to SCOT's clear superiority for protein alignments. As the resulting helices and strands are provided in a PDB conform output format, they can immediately be used for structure alignment algorithms. Taken together, the application of our new method and the straight-forward visualization using the accompanying PyMOL scripts enable the comprehensive analysis of regular backbone geometries in proteins.

Availability And Implementation: https://this-group.rocks.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz826DOI Listing
April 2020

Pepsin and oropharyngeal pH monitoring to diagnose patients with laryngopharyngeal reflux.

Laryngoscope 2020 07 11;130(7):1780-1786. Epub 2019 Oct 11.

Department of Surgery, Paracelsus Medical University, Salzburg, Austria.

Objectives: The aim of this study was to compare the diagnostic accuracy of salivary pepsin with oropharyngeal pH monitoring using the Restech measurement system (Dx-pH) for the diagnosis of laryngopharyngeal reflux (LPR).

Study Design: Prospective cohort study.

Methods: Seventy patients with primary symptoms related to LPR underwent gastroscopy, high-resolution manometry, pH throughout 24-hour monitoring (MII-pH), and barium esophagography between October 2015 and May 2018. In addition, an ear, nose, and throat examination was performed, including assessment of Belafsky Reflux Finding Score (RFS). Clinical symptoms were evaluated with the Belafsky Reflux Symptom Index (RSI) and the Gastrointestinal Quality of Life Index (GIQLI). Simultaneous to MII-pH, pepsin determination and Dx-pH were performed.

Results: Of 70 patients, 41 (58.6%) subjects with a pathological DeMeester score showed higher mean values of pepsin (mean value: 216 ng/mL, 95% confidence interval [CI]: 172 to 260), compared to patients with a normal DeMeester score (mean value: 161 ng/mL, 95% CI: 115 to 207). Salivary pepsin showed a specificity of 86.2% and sensitivity of 41.5% for diagnosing LPR using the optimal cutoff value of 216 ng/mL. Furthermore, a significant correlation between the values of salivary pepsin and the RSI score was seen in patients with pathological results in MII-pH (r = 0.344; P = 0.046). However, elevated Dx-pH measurements showed no significant correlation with either MII-pH, RSI score, RFS score, or GIQLI score, or with the results of pepsin measurement.

Conclusion: Pepsin measurement in saliva could be an alternative tool to assist office-based diagnosis of LPR, whereas Dx-pH does not seem to be an adequate test.

Level Of Evidence: 2B Laryngoscope, 130:1780-1786, 2020.
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http://dx.doi.org/10.1002/lary.28320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318637PMC
July 2020

Perioperative chemotherapy versus neoadjuvant chemoradiation for patients with adenocarcinoma of the distal esophagus in Austria: a retrospective analysis.

World J Surg Oncol 2019 Aug 19;17(1):146. Epub 2019 Aug 19.

Department of Visceral and Thoracic Surgery, Paracelsus Medical University, Salzburg, Austria.

Background: The aim of this study was to compare the outcome of patients with adenocarcinoma of the distal esophagus (AEG type I) treated with neoadjuvant chemoradiation or perioperative chemotherapy.

Methods: Eligible patients from four Austrian centers were selected to conduct a retrospective analysis. All patients treated between January 2007 and October 2017 with chemotherapy according to EOX-protocol (Epirubicin, Oxaliplatin, Xeloda) or chemoradiation according to CROSS-protocol (carboplatin/paclitaxel + RTX 41.4 Gy), before esophagectomy were included. Primary outcomes disease-free survival (DFS) and overall survival (OS) as well as secondary outcomes downstaging of T- or N-stage and achievement of pathological complete response pCR (ypT0N0M0) were analyzed. Data of 119 patients were included.

Results: Complete data was available in 104 patients, 53 patients in the chemoradiation group and 51 patients in the chemotherapy group. The mean number of lymph nodes removed was significantly higher in the EOX group (EOX 29 ± 15.5 vs. CROSS 22 ± 8.8; p < 0.05). Median follow-up in the CROSS group was 17 months (CI 95% 8.8-25.2) and in the EOX group 37 months (CI 95% 26.5-47.5). In the chemotherapy group, the OS rate after half a year, - 1, and 3 years was 92%, 75%, and 51%. After chemoradiation, overall survival after half a year was 85 %, after 1 year 66%, and after 3 years 17%. In the EOX group DFS after ½, - 1, and 3 years was 90%, 73%, and 45%, in the chemoradiation group after half a year 81%, after 1 year 55% and after 3 years 15%. Pathological complete response (pCR) was achieved in 23% of patients after CROSS and in 10% after EOX (p < 0.000).

Conclusions: There seem to be clear advantages for chemoradiation, concerning the major response of the primary tumor, whereas a tendency in favor for chemotherapy is seen in regards to systemic tumor control. Furthermore, the type of neoadjuvant treatment has a significant influence on the number of lymph nodes resected.
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http://dx.doi.org/10.1186/s12957-019-1693-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701048PMC
August 2019

Binding site characterization - similarity, promiscuity, and druggability.

Medchemcomm 2019 Jul 6;10(7):1145-1159. Epub 2019 Jun 6.

Faculty of Chemistry and Chemical Biology , TU Dortmund University , Dortmund , Germany.

The elucidation of non-obvious binding site similarities has provided useful indications for the establishment of polypharmacology, the identification of potential off-targets, or the repurposing of known drugs. The concept underlying all of these approaches is promiscuous binding which can be analyzed from a ligand-based or a binding site-based perspective. Herein, we applied methods for the automated analysis and comparison of protein binding sites to study promiscuous binding on a novel dataset of sites in complex with ligands sharing common shape and physicochemical properties. We show the suitability of this dataset for the benchmarking of novel binding site comparison methods. Our investigations also reveal promising directions for further in-depth analyses of promiscuity and druggability in a pocket-centered manner. Drawbacks concerning binding site similarity assessment and druggability prediction are outlined, enabling researchers to avoid the typical pitfalls of binding site analyses.
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http://dx.doi.org/10.1039/c9md00102fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644390PMC
July 2019

Successful reintroduction of tumour necrosis factor-alpha inhibition after treatment of disseminated Lyme borreliosis.

J R Coll Physicians Edinb 2019 Jun;49(2):122-124

Regional Infectious Diseases Unit, Western General Hospital, Edinburgh, Scotland.

The importance of tumour necrosis factor-alpha (TNF-α) in the human immune response to Borrelia burgdorferi is uncertain. Murine models suggest a critical role, including spirochaete reactivation following TNF-α inhibition. Our case, combined with a review of the clinical and scientific literature, provides reassurance that TNF-α inhibition can be safely reinstituted after treatment of disseminated borreliosis with standard duration antimicrobial chemotherapy.
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http://dx.doi.org/10.4997/JRCPE.2019.207DOI Listing
June 2019

Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated.

J Med Chem 2019 05 29;62(9):4426-4443. Epub 2019 Apr 29.

German Cancer Consortium (DKTK) , 69120 Heidelberg , Germany.

The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01936DOI Listing
May 2019

The Development of Target-Specific Machine Learning Models as Scoring Functions for Docking-Based Target Prediction.

J Chem Inf Model 2019 03 18;59(3):1238-1252. Epub 2019 Mar 18.

Faculty of Chemistry and Chemical Biology , TU Dortmund University , Otto-Hahn-Straße 6 , 44227 , Dortmund , Germany.

The identification of possible targets for a known bioactive compound is of the utmost importance for drug design and development. Molecular docking is one possible approach for in-silico protein target prediction, whereas a molecule is docked into several different protein structures to identify potential targets. This reverse docking approach is hampered by the limitation of current scoring functions to correctly discriminate between targets and nontargets. In this work, a development of target-specific scoring functions is described that showed improved prediction performances for the correct target prediction of both actives and decoys on three validation data sets. In contrast to pure ligand-based approaches, that are in general faster and include a greater target space, docking-based approaches can cover also unknown chemical space that lies outside the known bioactivity data. These target-specific scoring functions are based on known bioactivity data retrieved from ChEMBL and supervised machine learning approaches. Neural Networks and Support Vector Machines (SVMs) models were trained for 20 different protein targets. Our protein-ligand interaction fingerprint PADIF (Protein Atom Score Contributions Derived Interaction Fingerprint) represents the input for training, whereas the PADIFs are calculated based on docking poses of active and inactive compounds. Different data sets of previously unseen molecules were used for the final evaluation and analysis of the prediction performance of the created models. For a single-target selectivity data set, the correct target model returns in most of the cases the highest probabilities scores for their active molecules and with statistically significant differences from the other targets. These probability scores were also predicted and successfully used to rank the targets for molecules of a multitarget data set with activity data described simultaneously for two, three, and four to seven protein targets.
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http://dx.doi.org/10.1021/acs.jcim.8b00773DOI Listing
March 2019

A benchmark driven guide to binding site comparison: An exhaustive evaluation using tailor-made data sets (ProSPECCTs).

PLoS Comput Biol 2018 11 8;14(11):e1006483. Epub 2018 Nov 8.

Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany.

The automated comparison of protein-ligand binding sites provides useful insights into yet unexplored site similarities. Various stages of computational and chemical biology research can benefit from this knowledge. The search for putative off-targets and the establishment of polypharmacological effects by comparing binding sites led to promising results for numerous projects. Although many cavity comparison methods are available, a comprehensive analysis to guide the choice of a tool for a specific application is wanting. Moreover, the broad variety of binding site modeling approaches, comparison algorithms, and scoring metrics impedes this choice. Herein, we aim to elucidate strengths and weaknesses of binding site comparison methodologies. A detailed benchmark study is the only possibility to rationalize the selection of appropriate tools for different scenarios. Specific evaluation data sets were developed to shed light on multiple aspects of binding site comparison. An assembly of all applied benchmark sets (ProSPECCTs-Protein Site Pairs for the Evaluation of Cavity Comparison Tools) is made available for the evaluation and optimization of further and still emerging methods. The results indicate the importance of such analyses to facilitate the choice of a methodology that complies with the requirements of a specific scientific challenge.
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http://dx.doi.org/10.1371/journal.pcbi.1006483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224041PMC
November 2018

Overcoming conservation in TALE-DNA interactions: a minimal repeat scaffold enables selective recognition of an oxidized 5-methylcytosine.

Chem Sci 2018 Sep 2;9(36):7247-7252. Epub 2018 Aug 2.

Faculty of Chemistry and Chemical Biology , TU Dortmund University , Otto-Hahn Str. 4a , 44227 Dortmund , Germany . Email:

Transcription-activator-like effectors (TALEs) are repeat-based proteins featuring programmable DNA binding. The repulsion of TALE repeats by 5-methylcytosine (5mC) and its oxidized forms makes TALEs potential probes for their programmable analysis. However, this potential has been limited by the inability to engineer repeats capable of actual, fully selective binding of an (oxidized) 5mC: the extremely conserved and simple nucleobase recognition mode of TALE repeats and their extensive involvement in inter-repeat interactions that stabilize the TALE fold represent major engineering hurdles. We evaluated libraries of alternative, strongly truncated repeat scaffolds and discovered a repeat that selectively recognizes 5-carboxylcytosine (5caC), enabling construction of the first programmable receptors for an oxidized 5mC. In computational studies, this unusual scaffold executes a dual function a critical arginine that provides inter-repeat stabilization and selectively interacts with the 5caC carboxyl group a salt-bridge. These findings argue for an unexpected adaptability of TALE repeats and provide a new impulse for the design of programmable probes for nucleobases beyond A, G, T and C.
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http://dx.doi.org/10.1039/c8sc01958dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148557PMC
September 2018

Austrian consensus guidelines on imaging requirements prior to hepatic surgery and during follow-up in patients with malignant hepatic lesions.

Wien Klin Wochenschr 2018 Nov 30;130(21-22):665-672. Epub 2018 Aug 30.

Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Rapid advances in imaging technology have improved the detection, characterization and staging of colorectal liver metastases, hepatocellular carcinoma and cholangiocarcinoma. A variety of imaging modalities are available and play a pivotal role in the work-up of patients, particularly as imaging findings determine resectability. Surgery often represents the only measure that can render long-term survival possible. Imaging is also indispensable for the assessment of responses to neoadjuvant treatment and for the detection of recurrence. At a consensus meeting held in June 2017 in Vienna, Austria, Austrian experts in the fields of surgery and radiology discussed imaging requirements prior to and after hepatic surgery for malignant liver lesions. This consensus was refined by online voting on a total of 47 items. Generally, the degree of consensus was high. The recommendations relate to the type of preferred preoperative imaging modalities, technical settings with respect to computed tomography and magnetic resonance imaging, use of contrast agents, reporting, postoperative follow-up, and long-term follow-up. Taking local resources into account, these consensus recommendations can be implemented in daily clinical practice at specialized centers as well as outpatient diagnostic institutes in Austria.
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http://dx.doi.org/10.1007/s00508-018-1387-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244807PMC
November 2018

Cancer of the gastroesophageal junction: a diagnosis, classification, and management review.

Ann N Y Acad Sci 2018 12 23;1434(1):132-138. Epub 2018 Aug 23.

Department of Surgery, Royal Marsden Hospital, London, UK.

Management of gastroesophageal junction (GEJ) adenocarcinoma is a controversial topic. The rising incidence of this cancer requires a clear consensus to ensure proper management. Application of oncological principles for tumors of the esophagus or stomach is not possible because of comparative differences in the biology of GEJ adenocarcinoma, leading to different therapeutic options. Staging work-up with endoscopy, endosonography, and PET is essential to inform the choice of neoadjuvant treatment and surgical approach to GEJ adenocarcinoma. Surgery remains the only curative treatment and should be undertaken in specialized centers.
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http://dx.doi.org/10.1111/nyas.13954DOI Listing
December 2018

Conditional Expression of the Small GTPase ArfA Impacts Secretion, Morphology, Growth, and Actin Ring Position in .

Front Microbiol 2018 8;9:878. Epub 2018 May 8.

Department of Applied and Molecular Microbiology, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.

In filamentous fungi, growth and protein secretion occurs predominantly at the tip of long, thread like cells termed hyphae. This requires coordinated regulation of multiple processes, including vesicle trafficking, exocytosis, and endocytosis, which are facilitated by a complex cytoskeletal apparatus. In this study, functional analyses of the small GTPase ArfA from demonstrate that this protein functionally complements the , and that this protein is essential for . Loss-of-function and gain-of-function analyses demonstrate that titration of expression impacts hyphal growth rate, hyphal tip morphology, and protein secretion. Moreover, localization of the endocytic machinery, visualized via fluorescent tagging of the actin ring, was found to be abnormal in ArfA under- and overexpressed conditions. Finally, we provide evidence that the major secreted protein GlaA localizes at septal junctions, indicating that secretion in may occur at these loci, and that this process is likely impacted by expression levels. Taken together, our results demonstrate that ArfA fulfills multiple functions in the secretory pathway of .
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http://dx.doi.org/10.3389/fmicb.2018.00878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952172PMC
May 2018

Complete, Programmable Decoding of Oxidized 5-Methylcytosine Nucleobases in DNA by Chemoselective Blockage of Universal Transcription-Activator-Like Effector Repeats.

J Am Chem Soc 2018 05 26;140(18):5904-5908. Epub 2018 Apr 26.

Faculty of Chemistry and Chemical Biology , Technische Universität Dortmund , Otto-Hahn-Straße 4a , 44227 Dortmund , Germany.

5-Methylcytosine (5mC) and its oxidized derivatives are regulatory elements of mammalian genomes involved in development and disease. These nucleobases do not selectively modulate Watson-Crick pairing, preventing their programmable targeting and analysis by traditional hybridization probes. Transcription-activator-like effectors (TALEs) can be engineered for use as programmable probes with epigenetic nucleobase selectivity. However, only partial selectivities for oxidized 5mC have been achieved so far, preventing unambiguous target binding. We overcome this limitation by destroying and re-inducing nucleobase selectivity in TALEs via protein engineering and chemoselective nucleobase blocking. We engineer cavities in TALE repeats and identify a cavity that accommodates all eight human DNA nucleobases. We then introduce substituents with varying size, flexibility, and branching degree at each oxidized 5mC. Depending on the nucleobase, substituents with distinct properties effectively block TALE-binding and induce full nucleobase selectivity in the universal repeat. Successful transfer to affinity enrichment in a human genome background indicates that this approach enables the fully selective detection of each oxidized 5mC in complex DNA by programmable probes.
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http://dx.doi.org/10.1021/jacs.8b02909DOI Listing
May 2018

Clinical feasibility of a new full-thickness endoscopic plication device (GERDx™) for patients with GERD: results of a prospective trial.

Surg Endosc 2018 05 30;32(5):2541-2549. Epub 2018 Mar 30.

Department of Surgery, Paracelsus Medical University, 5020, Salzburg, Austria.

Background: Previous studies suggest clinical effectiveness of endoscopic full-thickness plication in selected patients with gastroesophageal reflux disease (GERD). The aim of this study was to assess the clinical safety and efficiency of the GERDx™ device by evaluating clinical parameters, reflux symptom scores, and quality of life (QoL).

Methods: Prospective one-arm trial evaluating the outcome of forty patients with GERD subjected to endoscopic plication with the GERDx™ device. We included patients with at least one typical reflux symptom despite treatment with a PPI for > 6 months, pathologic esophageal acid exposure, hiatal hernia of size < 2 cm, and endoscopic Hill grade II-III. Evaluation of Gastrointestinal Quality of Life Index (GIQLI), symptom scores, esophageal manometry, and impedance-pH-monitoring were performed at baseline and at 3 months after surgery. (Trial Registration: ClinicalTrials.gov NCT 01798212.) RESULTS: There were no intraoperative complications. Four out of forty patients experienced postoperative complications requiring intervention. Seven of forty patients were subjected to laparoscopic fundoplication 3 months after endoscopic plication due to persistent symptoms and were lost to further follow-up. Thirty out of forty patients were available at 3-month follow-up. There was an improvement of the GIQLI score, from a mean of 92.45 ± 18.47 to 112.03 ± 13.11 (p < 0.001). The general reflux-specific score increased from a mean of 49.84 ± 24.83 to 23.93 ± 15.63 (p < 0.001), and the DeMeester score from a mean of 46.48 ± 30.83 to 20.03 ± 23.62 (p < 0.001). There was no significant change in manometric data after intervention. Three of thirty patients continued daily antireflux medication.

Conclusions: Endoscopic plication with the GERDx™ device reduced distal acid exposure of the esophagus, reflux-related symptoms, and improved GIQLI scores with minimal side effects in a selected cohort of patients and may be a safe alternative in the treatment of GERD.
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http://dx.doi.org/10.1007/s00464-018-6153-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897467PMC
May 2018

A novel interaction fingerprint derived from per atom score contributions: exhaustive evaluation of interaction fingerprint performance in docking based virtual screening.

J Cheminform 2018 Mar 16;10(1):15. Epub 2018 Mar 16.

Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Str. 6, 44227, Dortmund, Germany.

Protein ligand interaction fingerprints are a powerful approach for the analysis and assessment of docking poses to improve docking performance in virtual screening. In this study, a novel interaction fingerprint approach (PADIF, protein per atom score contributions derived interaction fingerprint) is presented which was specifically designed for utilising the GOLD scoring functions' atom contributions together with a specific scoring scheme. This allows the incorporation of known protein-ligand complex structures for a target-specific scoring. Unlike many other methods, this approach uses weighting factors reflecting the relative frequency of a specific interaction in the references and penalizes destabilizing interactions. In addition, and for the first time, an exhaustive validation study was performed that assesses the performance of PADIF and two other interaction fingerprints in virtual screening. Here, PADIF shows superior results, and some rules of thumb for a successful use of interaction fingerprints could be identified.
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http://dx.doi.org/10.1186/s13321-018-0264-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856854PMC
March 2018

CHIPMUNK: A Virtual Synthesizable Small-Molecule Library for Medicinal Chemistry, Exploitable for Protein-Protein Interaction Modulators.

ChemMedChem 2018 03 20;13(6):532-539. Epub 2018 Feb 20.

Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Straße 6, Dortmund, 44227, Germany.

A common issue during drug design and development is the discovery of novel scaffolds for protein targets. On the one hand the chemical space of purchasable compounds is rather limited; on the other hand artificially generated molecules suffer from a grave lack of accessibility in practice. Therefore, we generated a novel virtual library of small molecules which are synthesizable from purchasable educts, called CHIPMUNK (CHemically feasible In silico Public Molecular UNiverse Knowledge base). Altogether, CHIPMUNK covers over 95 million compounds and encompasses regions of the chemical space that are not covered by existing databases. The coverage of CHIPMUNK exceeds the chemical space spanned by the Lipinski rule of five to foster the exploration of novel and difficult target classes. The analysis of the generated property space reveals that CHIPMUNK is well suited for the design of protein-protein interaction inhibitors (PPIIs). Furthermore, a recently developed structural clustering algorithm (StruClus) for big data was used to partition the sub-libraries into meaningful subsets and assist scientists to process the large amount of data. These clustered subsets also contain the target space based on ChEMBL data which was included during clustering.
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http://dx.doi.org/10.1002/cmdc.201700689DOI Listing
March 2018