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Article ; Online: Interneuron diversity in the rat dentate gyrus: An unbiased in vitro classification.

Degro, Claudius E / Bolduan, Felix / Vida, Imre / Booker, Sam A

2022 Volume 32, Issue 4, Page(s) 310–331

Abstract: Information processing in cortical circuits, including the hippocampus, relies on the dynamic control of neuronal activity by GABAergic interneurons (INs). INs form a heterogenous population with defined types displaying distinct morphological, molecular, ...

Abstract	Information processing in cortical circuits, including the hippocampus, relies on the dynamic control of neuronal activity by GABAergic interneurons (INs). INs form a heterogenous population with defined types displaying distinct morphological, molecular, and physiological characteristics. In the major input region of the hippocampus, the dentate gyrus (DG), a number of IN types have been described which provide synaptic inhibition to distinct compartments of excitatory principal cells (PrCs) and other INs. In this study, we perform an unbiased classification of GABAergic INs in the DG by combining in vitro whole-cell patch-clamp recordings, intracellular labeling, morphological analysis, and unsupervised cluster analysis to better define IN type diversity in this region. This analysis reveals that DG INs divide into at least 13 distinct morpho-physiological types which reflect the complexity of the local IN network and serve as a basis for further network analyses.
MeSH term(s)	Animals ; Dentate Gyrus/physiology ; Hippocampus ; Interneurons/physiology ; Neurons ; Patch-Clamp Techniques ; Rats
Language	English
Publishing date	2022-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1074352-2
ISSN	1098-1063 ; 1050-9631
ISSN (online)	1098-1063
ISSN	1050-9631
DOI	10.1002/hipo.23408
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Article ; Online: Evolving acidic microenvironments during colitis provide selective analgesic targets for a pH-sensitive opioid.

Degro, Claudius E / Jiménez-Vargas, Nestor Nivardo / Tsang, Quentin / Yu, Yang / Guzman-Rodriguez, Mabel / Alizadeh, Elahe / Hurlbut, David / Reed, David E / Lomax, Alan E / Stein, Christoph / Bunnett, Nigel W / Vanner, Stephen J

Pain

2023 Volume 164, Issue 11, Page(s) 2501–2515

Abstract: Abstract: Targeting the acidified inflammatory microenvironment with pH-sensitive opioids is a novel approach for managing visceral pain while mitigating side effects. The analgesic efficacy of pH-dependent opioids has not been studied during the ... ...

Abstract	Abstract: Targeting the acidified inflammatory microenvironment with pH-sensitive opioids is a novel approach for managing visceral pain while mitigating side effects. The analgesic efficacy of pH-dependent opioids has not been studied during the evolution of inflammation, where fluctuating tissue pH and repeated therapeutic dosing could influence analgesia and side effects. Whether pH-dependent opioids can inhibit human nociceptors during extracellular acidification is unexplored. We studied the analgesic efficacy and side-effect profile of a pH-sensitive fentanyl analog, (±)- N -(3-fluoro-1-phenethylpiperidine-4-yl)- N -phenyl propionamide (NFEPP), during the evolution of colitis induced in mice with dextran sulphate sodium. Colitis was characterized by granulocyte infiltration, histological damage, and acidification of the mucosa and submucosa at sites of immune cell infiltration. Changes in nociception were determined by measuring visceromotor responses to noxious colorectal distension in conscious mice. Repeated doses of NFEPP inhibited nociception throughout the course of disease, with maximal efficacy at the peak of inflammation. Fentanyl was antinociceptive regardless of the stage of inflammation. Fentanyl inhibited gastrointestinal transit, blocked defaecation, and induced hypoxemia, whereas NFEPP had no such side effects. In proof-of-principle experiments, NFEPP inhibited mechanically provoked activation of human colonic nociceptors under acidic conditions mimicking the inflamed state. Thus, NFEPP provides analgesia throughout the evolution of colitis with maximal activity at peak inflammation. The actions of NFEPP are restricted to acidified layers of the colon, without common side effects in normal tissues. N -(3-fluoro-1-phenethylpiperidine-4-yl)- N -phenyl propionamide could provide safe and effective analgesia during acute colitis, such as flares of ulcerative colitis.
MeSH term(s)	Mice ; Humans ; Animals ; Analgesics, Opioid/pharmacology ; Analgesics, Opioid/therapeutic use ; Colitis/chemically induced ; Colitis/drug therapy ; Colon ; Analgesics/pharmacology ; Inflammation/pathology ; Visceral Pain/pathology ; Fentanyl/pharmacology ; Fentanyl/therapeutic use ; Hydrogen-Ion Concentration
Chemical Substances	propionamide (QK07G0HP47) ; Analgesics, Opioid ; Analgesics ; Fentanyl (UF599785JZ)
Language	English
Publishing date	2023-06-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	193153-2
ISSN	1872-6623 ; 0304-3959
ISSN (online)	1872-6623
ISSN	0304-3959
DOI	10.1097/j.pain.0000000000002956
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Article: Peptide Signatures for Prognostic Markers of Pancreatic Cancer by MALDI Mass Spectrometry Imaging

Loch, Florian N. / Klein, Oliver / Beyer, Katharina / Klauschen, Frederick / Schineis, Christian / Lauscher, Johannes C. / Margonis, Georgios A. / Degro, Claudius E. / Rayya, Wael / Kamphues, Carsten

Biology. 2021 Oct. 12, v. 10, no. 10

2021

Abstract: Despite the overall poor prognosis of pancreatic cancer there is heterogeneity in clinical courses of tumors not assessed by conventional risk stratification. This yields the need of additional markers for proper assessment of prognosis and multimodal ... ...

Abstract	Despite the overall poor prognosis of pancreatic cancer there is heterogeneity in clinical courses of tumors not assessed by conventional risk stratification. This yields the need of additional markers for proper assessment of prognosis and multimodal clinical management. We provide a proof of concept study evaluating the feasibility of Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify specific peptide signatures linked to prognostic parameters of pancreatic cancer. On 18 patients with exocrine pancreatic cancer after tumor resection, MALDI imaging analysis was performed additional to histopathological assessment. Principal component analysis (PCA) was used to explore discrimination of peptide signatures of prognostic histopathological features and receiver operator characteristic (ROC) to identify which specific m/z values are the most discriminative between the prognostic subgroups of patients. Out of 557 aligned m/z values discriminate peptide signatures for the prognostic histopathological features lymphatic vessel invasion (pL, 16 m/z values, eight proteins), nodal metastasis (pN, two m/z values, one protein) and angioinvasion (pV, 4 m/z values, two proteins) were identified. These results yield proof of concept that MALDI-MSI of pancreatic cancer tissue is feasible to identify peptide signatures of prognostic relevance and can augment risk assessment.
Keywords	desorption ; histopathology ; ionization ; matrix-assisted laser desorption-ionization mass spectrometry ; metastasis ; pancreatic neoplasms ; peptides ; principal component analysis ; prognosis ; resection ; risk assessment
Language	English
Dates of publication	2021-1012
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology10101033
Database	NAL-Catalogue (AGRICOLA)

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Article: Rethinking the TNM Classification Regarding Direct Lymph Node Invasion in Pancreatic Ductal Adenocarcinoma.

Speichinger, Fiona / Dragomir, Mihnea P / Schallenberg, Simon / Loch, Florian N / Degro, Claudius E / Baukloh, Ann-Kathrin / Hartmann, Lisa / Pozios, Ioannis / Schineis, Christian / Margonis, Georgios Antonios / Lauscher, Johannes C / Beyer, Katharina / Kamphues, Carsten

Cancers

2021 Volume 14, Issue 1

Abstract: Mechanisms of lymph node invasion seem to play a prognostic role in pancreatic ductal adenocarcinoma (PDAC) after resection. However, the 8th edition of the TNM classification of the American Joint Committee on Cancer (AJCC) does not consider this. The ... ...

Abstract	Mechanisms of lymph node invasion seem to play a prognostic role in pancreatic ductal adenocarcinoma (PDAC) after resection. However, the 8th edition of the TNM classification of the American Joint Committee on Cancer (AJCC) does not consider this. The aim of this study was to analyse the prognostic role of different mechanisms of lymph node invasion on PDAC. One hundred and twenty-two patients with resected PDAC were examined. We distinguished three groups: direct (per continuitatem, Nc) from the main tumour, metastasis (Nm) without any contact to the main tumour, and a mixed mechanism (Ncm). Afterwards, the prognostic power of the different groups was analysed concerning overall survival (OS). In total, 20 patients displayed direct lymph node invasion (Nc = 16.4%), 44 were classed as Nm (36.1%), and 21 were classed as Ncm (17.2%). The difference in OS was not statistically significant between N0 (no lymph node metastasis,
Language	English
Publishing date	2021-12-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14010201
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Article: Compartmental distribution of GABAB receptor-mediated currents along the somatodendritic axis of hippocampal principal cells.

Degro, Claudius E / Kulik, Akos / Booker, Sam A / Vida, Imre

Frontiers in synaptic neuroscience

2015 Volume 7, Page(s) 6

Abstract: Activity of cortical principal cells is controlled by the GABAergic system providing inhibition in a compartmentalized manner along their somatodendritic axis. While GABAAR-mediated inhibitory synaptic transmission has been extensively characterized in ... ...

Abstract	Activity of cortical principal cells is controlled by the GABAergic system providing inhibition in a compartmentalized manner along their somatodendritic axis. While GABAAR-mediated inhibitory synaptic transmission has been extensively characterized in hippocampal principal cells, little is known about the distribution of postsynaptic effects of GABABRs. In the present study, we have investigated the functional localization of GABABRs and their effector inwardly rectifying potassium (Kir3) channels by combining electrophysiological recordings in acute rat hippocampal slices, high-resolution immunoelectron microscopic analysis and single cell simulations. Pharmacologically isolated slow inhibitory postsynaptic currents were elicited in the three major hippocampal principal cell types by endogenous GABA released by electrical stimulation, photolysis of caged-GABA, as well as the canonical agonist baclofen, with the highest amplitudes observed in the CA3. Spatially restricted currents were assessed along the axis of principal cells by uncaging GABA in the different hippocampal layers. GABABR-mediated currents were present along the entire somatodendritic axis of principal cells, but non-uniformly distributed: largest currents and the highest conductance densities determined in the simulations were consistently found on the distal apical dendrites. Finally, immunocytochemical localization of GABABRs and Kir3 channels showed that distributions overlap but their densities diverge, particularly on the basal dendrites of pyramidal cells. GABABRs current amplitudes and the conductance densities correlated better with Kir3 density, suggesting a bottlenecking effect defined by the effector channel. These data demonstrate a compartmentalized distribution of the GABABR-Kir3 signaling cascade and suggest differential control of synaptic transmission, dendritic integration and synaptic plasticity at afferent pathways onto hippocampal principal cells.
Language	English
Publishing date	2015-03-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2592086-8
ISSN	1663-3563
ISSN	1663-3563
DOI	10.3389/fnsyn.2015.00006
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Article: Peptide Signatures for Prognostic Markers of Pancreatic Cancer by MALDI Mass Spectrometry Imaging.

Loch, Florian N / Klein, Oliver / Beyer, Katharina / Klauschen, Frederick / Schineis, Christian / Lauscher, Johannes C / Margonis, Georgios A / Degro, Claudius E / Rayya, Wael / Kamphues, Carsten

Biology

2021 Volume 10, Issue 10

Abstract	Despite the overall poor prognosis of pancreatic cancer there is heterogeneity in clinical courses of tumors not assessed by conventional risk stratification. This yields the need of additional markers for proper assessment of prognosis and multimodal clinical management. We provide a proof of concept study evaluating the feasibility of Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify specific peptide signatures linked to prognostic parameters of pancreatic cancer. On 18 patients with exocrine pancreatic cancer after tumor resection, MALDI imaging analysis was performed additional to histopathological assessment. Principal component analysis (PCA) was used to explore discrimination of peptide signatures of prognostic histopathological features and receiver operator characteristic (ROC) to identify which specific
Language	English
Publishing date	2021-10-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology10101033
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Article ; Online: Survival rates and prognostic factors in right- and left-sided colon cancer stage I-IV: an unselected retrospective single-center trial.

Degro, Claudius E / Strozynski, Richard / Loch, Florian N / Schineis, Christian / Speichinger, Fiona / Lee, Lucas D / Margonis, Georgios A / Lauscher, Johannes C / Beyer, Katharina / Kreis, Martin E / Kamphues, Carsten

International journal of colorectal disease

2021 Volume 36, Issue 12, Page(s) 2683–2696

Abstract: Purpose: Colorectal cancer revealed over the last decades a remarkable shift with an increasing proportion of a right- compared to a left-sided tumor location. In the current study, we aimed to disclose clinicopathological differences between right- and ...

Abstract	Purpose: Colorectal cancer revealed over the last decades a remarkable shift with an increasing proportion of a right- compared to a left-sided tumor location. In the current study, we aimed to disclose clinicopathological differences between right- and left-sided colon cancer (rCC and lCC) with respect to mortality and outcome predictors. Methods: In total, 417 patients with colon cancer stage I-IV were analyzed in the present retrospective single-center study. Survival rates were assessed using the Kaplan-Meier method and uni/multivariate analyses were performed with a Cox proportional hazards regression model. Results: Our study showed no significant difference of the overall survival between rCC and lCC stage I-IV (p = 0.354). Multivariate analysis revealed in the rCC cohort the worst outcome for ASA (American Society of Anesthesiologists) score IV patients (hazard ratio [HR]: 16.0; CI 95%: 2.1-123.5), CEA (carcinoembryonic antigen) blood level > 100 µg/l (HR: 3.3; CI 95%: 1.2-9.0), increased lymph node ratio of 0.6-1.0 (HR: 5.3; CI 95%: 1.7-16.1), and grade 4 tumors (G4) (HR: 120.6; CI 95%: 6.7-2179.6) whereas in the lCC population, ASA score IV (HR: 8.9; CI 95%: 0.9-91.9), CEA blood level 20.1-100 µg/l (HR: 5.4; CI 95%: 2.4-12.4), conversion to laparotomy (HR: 14.1; CI 95%: 4.0-49.0), and severe surgical complications (Clavien-Dindo III-IV) (HR: 2.9; CI 95%: 1.5-5.5) were identified as predictors of a diminished overall survival. Conclusion: Laterality disclosed no significant effect on the overall prognosis of colon cancer patients. However, group differences and distinct survival predictors could be identified in rCC and lCC patients.
MeSH term(s)	Colonic Neoplasms/pathology ; Humans ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Survival Rate
Language	English
Publishing date	2021-08-26
Publishing country	Germany
Document type	Journal Article
ZDB-ID	84975-3
ISSN	1432-1262 ; 0179-1958
ISSN (online)	1432-1262
ISSN	0179-1958
DOI	10.1007/s00384-021-04005-6
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Article ; Online: Differential surface density and modulatory effects of presynaptic GABA

Booker, Sam A / Althof, Daniel / Degro, Claudius E / Watanabe, Masahiko / Kulik, Ákos / Vida, Imre

Brain structure & function

2017 Volume 222, Issue 8, Page(s) 3677–3690

Abstract: The perisomatic domain of cortical neurons is under the control of two major GABAergic inhibitory interneuron types: regular-spiking cholecystokinin (CCK) basket cells (BCs) and fast-spiking parvalbumin (PV) BCs. CCK and PV BCs are different not only in ... ...

Abstract	The perisomatic domain of cortical neurons is under the control of two major GABAergic inhibitory interneuron types: regular-spiking cholecystokinin (CCK) basket cells (BCs) and fast-spiking parvalbumin (PV) BCs. CCK and PV BCs are different not only in their intrinsic physiological, anatomical and molecular characteristics, but also in their presynaptic modulation of their synaptic output. Most GABAergic terminals are known to contain GABA
MeSH term(s)	Animals ; Cholecystokinin/metabolism ; Cholecystokinin/physiology ; Hippocampus/cytology ; Hippocampus/metabolism ; Hippocampus/physiology ; Inhibitory Postsynaptic Potentials ; Neural Inhibition ; Parvalbumins/metabolism ; Parvalbumins/physiology ; Presynaptic Terminals/physiology ; Pyramidal Cells/cytology ; Pyramidal Cells/metabolism ; Pyramidal Cells/physiology ; Rats, Transgenic ; Rats, Wistar ; Receptor, Cannabinoid, CB1/metabolism ; Receptor, Muscarinic M2/metabolism ; Receptors, GABA-B/metabolism ; Receptors, GABA-B/physiology ; Synapses/physiology
Chemical Substances	Parvalbumins ; Receptor, Cannabinoid, CB1 ; Receptor, Muscarinic M2 ; Receptors, GABA-B ; Cholecystokinin (9011-97-6)
Language	English
Publishing date	2017-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2273162-3
ISSN	1863-2661 ; 1863-2653
ISSN (online)	1863-2661
ISSN	1863-2653
DOI	10.1007/s00429-017-1427-x
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Article ; Online: Accuracy of various criteria for lymph node staging in ductal adenocarcinoma of the pancreatic head by computed tomography and magnetic resonance imaging.

Loch, Florian N / Asbach, Patrick / Haas, Matthias / Seeliger, Hendrik / Beyer, Katharina / Schineis, Christian / Degro, Claudius E / Margonis, Georgios A / Kreis, Martin E / Kamphues, Carsten

World journal of surgical oncology

2020 Volume 18, Issue 1, Page(s) 213

Abstract: Background: Lymph node staging of ductal adenocarcinoma of the pancreatic head (PDAC) by cross-sectional imaging is limited. The aim of this study was to determine the diagnostic accuracy of expanded criteria in nodal staging in PDAC patients.: ... ...

Abstract	Background: Lymph node staging of ductal adenocarcinoma of the pancreatic head (PDAC) by cross-sectional imaging is limited. The aim of this study was to determine the diagnostic accuracy of expanded criteria in nodal staging in PDAC patients. Methods: Sixty-six patients with histologically confirmed PDAC that underwent primary surgery were included in this retrospective IRB-approved study. Cross-sectional imaging studies (CT and/or MRI) were evaluated by a radiologist blinded to histopathology. Number and size of lymph nodes were measured (short-axis diameter) and characterized in terms of expanded morphological criteria of border contour (spiculated, lobulated, and indistinct) and texture (homogeneous or inhomogeneous). Sensitivities and specificities were calculated with histopathology as a reference standard. Results: Forty-eight of 66 patients (80%) had histologically confirmed lymph node metastases (pN+). Sensitivity, specificity, and Youden's Index for the criterion "size" were 44.2%, 82.4%, and 0.27; for "inhomogeneous signal intensity" 25.6%, 94.1%, and 0.20; and for "border contour" 62.7%, 52.9%, and 0.16, respectively. There was a significant association between the number of visible lymph nodes on preoperative CT and lymph node involvement (pN+, p = 0.031). Conclusion: Lymph node staging in PDAC is mainly limited due to low sensitivity for detection of metastatic disease. Using expanded morphological criteria instead of size did not improve regional nodal staging due to sensitivity remaining low. Combining specific criteria yields improved sensitivity with specificity and PPV remaining high.
MeSH term(s)	Breast Neoplasms ; Humans ; Lymph Nodes/diagnostic imaging ; Lymph Nodes/surgery ; Magnetic Resonance Imaging ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Sensitivity and Specificity ; Tomography, X-Ray Computed
Language	English
Publishing date	2020-08-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2118383-1
ISSN	1477-7819 ; 1477-7819
ISSN (online)	1477-7819
ISSN	1477-7819
DOI	10.1186/s12957-020-01951-3
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Article ; Online: Prognostic value of primary tumor sidedness in patients with non-metastatic IBD related CRC - Is it the exception to the rule?

Kamphues, Carsten / Lefevre, Jeremie H / Wang, Jane / Amini, Neda / Beaugerie, Laurent / Kuehn, Florian / Park, Sang Hyoung / Andreatos, Nikolaos / Lauscher, Johannes C / Enea, Diana / Lehmann, Kai S / Peru, Nicolas / Weixler, Benjamin / Kirchgesner, Julien / Degro, Claudius E / Pozios, Ioannis / van Beekum, Cornelius J / Schölch, Sebastian / Zambonin, Daniela /

Surgical oncology

2022 Volume 45, Page(s) 101874

Abstract: Background: Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in ...

Abstract	Background: Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC. Methods: All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence-free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS. Results: A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98). Conclusions: In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC.
MeSH term(s)	Humans ; Prognosis ; Colorectal Neoplasms/pathology ; Retrospective Studies ; Rectal Neoplasms ; Inflammatory Bowel Diseases
Language	English
Publishing date	2022-10-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1107810-8
ISSN	1879-3320 ; 0960-7404
ISSN (online)	1879-3320
ISSN	0960-7404
DOI	10.1016/j.suronc.2022.101874
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