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  1. Article ; Online: Pseudotime dynamics of T cells in pancreatic ductal adenocarcinoma inform distinct functional states within the regulatory and cytotoxic T cells

    Ashwin Jainarayanan / Nithishwer Mouroug-Anand / Edward H. Arbe-Barnes / Adam J. Bush / Rachael Bashford-Rogers / Adam Frampton / Lara Heij / Mark Middleton / Michael L. Dustin / Enas Abu-Shah / Shivan Sivakumar

    iScience, Vol 26, Iss 4, Pp 106324- (2023)

    2023  

    Abstract: Summary: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer and has a 5-year survival of less than 8% owing to its complex biology. As PDAC is refractory to immunotherapy, we need to understand the functional dynamics of T ... ...

    Abstract Summary: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer and has a 5-year survival of less than 8% owing to its complex biology. As PDAC is refractory to immunotherapy, we need to understand the functional dynamics of T cells in the PDAC microenvironment to develop alternative therapeutic strategies. In this study, we performed RNA velocity-based pseudotime analysis on a scRNA-seq dataset from surgically resected human PDAC specimens to gain insight into temporal gene expression patterns that best characterize the cell fates. The tumor microenvironment was seen to encompass a range of terminal states for the T cell trajectories with suppressive and non-tumor-responsive T cells dominating them. However, the results also reveal the existence of a functional branch of the T cell population that was not transitioning to exhausted and senescent states. These findings reveal various microenvironmental signals driving T cell patterns which can be useful in identifying new therapeutic avenues.
    Keywords Immune response ; Bioinformatics ; Cancer systems biology ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2023-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Expression of Checkpoint Molecules in the Tumor Microenvironment of Intrahepatic Cholangiocarcinoma

    Lara Heij / Jan Bednarsch / Xiuxiang Tan / Mika Rosin / Simone Appinger / Konrad Reichel / Dana Pecina / Michail Doukas / Ronald M. van Dam / Juan Garcia Vallejo / Florian Ulmer / Sven Lang / Tom Luedde / Flavio G. Rocha / Shivan Sivakumar / Ulf Peter Neumann

    Cells, Vol 12, Iss 851, p

    Implications for Immune Checkpoint Blockade Therapy

    2023  Volume 851

    Abstract: Background : The tumor microenvironment (TME) in cholangiocarcinoma (CCA) influences the immune environment. Checkpoint blockade is promising, but reliable biomarkers to predict response to treatment are still lacking. Materials and Methods : The levels ... ...

    Abstract Background : The tumor microenvironment (TME) in cholangiocarcinoma (CCA) influences the immune environment. Checkpoint blockade is promising, but reliable biomarkers to predict response to treatment are still lacking. Materials and Methods : The levels of checkpoint molecules (PD-1, PD-L1, PD-L2, LAG-3, ICOS, TIGIT, TIM-3, CTLA-4), macrophages (CD68), and T cells (CD4 and CD8 cells) were assessed by multiplexed immunofluorescence in 50 intrahepatic cases. Associations between marker expression, immune cells, and region of expression were studied in the annotated regions of tumor, interface, sclerotic tumor, and tumor-free tissue. Results : ICCA demonstrated CD4_TIM-3 high densities in the tumor region of interest (ROI) compared to the interface ( p = 0.014). CD8_PD-L1 and CD8_ICOS densities were elevated in the sclerotic tumor compared to the interface ( p = 0.011 and p = 0.031, respectively). In a multivariate model, high expression of CD8_PD-L2 ( p = 0.048) and CD4_ICOS_TIGIT ( p = 0.011) was associated with nodal metastases. Conclusions: High densities of PD-L1 were more abundant in the sclerotic tumor region; this is meaningful for the stratification of immunotherapy. Lymph node metastasis correlates with CD4_ICOS_TIGIT co-expression and CD8_PD-L2 expression, indicating the checkpoint expression profile of patients with a poor prognosis. Also, multiple co-expressions occur, and this potentially suggests a role for combination therapy with different immune checkpoint targets than just PD-1 blockade monotherapy.
    Keywords cholangiocarcinoma ; tumor microenvironment ; checkpoint molecules ; multiplexed imaging ; immunotherapy ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Osteopenia is associated with inferior survival in patients undergoing partial hepatectomy for hepatocellular carcinoma

    Franziska Alexandra Meister / Suekran Verhoeven / Anna Mantas / Wen-Jia Liu / Decan Jiang / Lara Heij / Daniel Heise / Philipp Bruners / Sven Arke Lang / Tom Florian Ulmer / Ulf Peter Neumann / Jan Bednarsch / Zoltan Czigany

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 12

    Abstract: Abstract Osteopenia is known to be associated with clinical frailty which is linked to inferior outcomes in various clinical scenarios. However, the exact prognostic value of osteopenia in patients undergoing curative intent-surgery for hepatocellular ... ...

    Abstract Abstract Osteopenia is known to be associated with clinical frailty which is linked to inferior outcomes in various clinical scenarios. However, the exact prognostic value of osteopenia in patients undergoing curative intent-surgery for hepatocellular carcinoma (HCC) is not completely understood. This retrospective study was conducted in a cohort of 151 patients who underwent partial hepatectomy for HCC in curative intent at a German university medical center (05/2008–12/2019). Preoperative computed tomography-based segmentation was used to assess osteopenia, and the prognostic impact of pathological changes in bone mineral density (BMD) on perioperative morbidity, mortality, and long-term oncological outcome was analyzed. Five-year overall survival of osteopenic patients was significantly worse compared to those with normal BMD (29% vs. 65%, p = 0.014). In line with this, the probability of disease-free survival at 5 years was significantly worse for patients with osteopenia (21% vs. 64%, p = 0.005). In our multivariable model, osteopenia was confirmed as an independent risk-factor for inferior overall survival (Hazard-ratio 7.743, p = 0.002). Concerning perioperative complications, osteopenic patients performed slightly worse, even though no statistical difference was detected (Clavien-Dindo ≥ 3b; 21% vs. 9%, p = 0.139). The present study confirms osteopenia as an independent risk-factor for inferior survival in patients undergoing partial hepatectomy for HCC in a European cohort. Further studies are warranted to validate these findings.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616 ; 610
    Language English
    Publishing date 2022-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: The impact of site-specific digital histology signatures on deep learning model accuracy and bias

    Frederick M. Howard / James Dolezal / Sara Kochanny / Jefree Schulte / Heather Chen / Lara Heij / Dezheng Huo / Rita Nanda / Olufunmilayo I. Olopade / Jakob N. Kather / Nicole Cipriani / Robert L. Grossman / Alexander T. Pearson

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 13

    Abstract: Deep learning models have been trained on The Cancer Genome Atlas to predict numerous features directly from histology, including survival, gene expression patterns, and driver mutations. Here, the authors demonstrate that site-specific histologic ... ...

    Abstract Deep learning models have been trained on The Cancer Genome Atlas to predict numerous features directly from histology, including survival, gene expression patterns, and driver mutations. Here, the authors demonstrate that site-specific histologic signatures can lead to biased estimates of accuracy for such models, and propose a method to minimize such bias.
    Keywords Science ; Q
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Sarcoidosis and Pain Caused by Small-Fiber Neuropathy

    Lara Heij / Albert Dahan / Elske Hoitsma

    Pain Research and Treatment, Vol

    2012  Volume 2012

    Abstract: Sarcoidosis is a chronic inflammatory illness and small-fiber neuropathy (SFN) is one of the disabling and often chronic manifestations of the disease. SFN presents with peripheral pain and symptoms of autonomic dysfunction. The character of the pain can ...

    Abstract Sarcoidosis is a chronic inflammatory illness and small-fiber neuropathy (SFN) is one of the disabling and often chronic manifestations of the disease. SFN presents with peripheral pain and symptoms of autonomic dysfunction. The character of the pain can be burning or shooting. Besides, allodynia and hyperesthesia can exist. Diagnosis is usually made on the basis of clinical features, in combination with abnormal specialized tests. The aim of treatment is often to reduce pain; however, total pain relieve is seldom achieved. The role of TNF-α in the pathogenesis of SFN in sarcoidosis appears interesting to explore. Novel therapeutic agents such as ARA 290, a nonhematopoietic erythropoietin analogue with potent anti-inflammatory and tissue protective properties, are interesting to explore in the treatment of SFN in sarcoidosis.
    Keywords Medicine (General) ; R5-920
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Hindawi Publishing Corporation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Various myosteatosis selection criteria and their value in the assessment of short- and long-term outcomes following liver transplantation

    Franziska Alexandra Meister / Jan Bednarsch / Iakovos Amygdalos / Joerg Boecker / Pavel Strnad / Philipp Bruners / Sven Arke Lang / Tom Florian Ulmer / Lara Heij / Daniel Antonio Morales Santana / Wen-Jia Liu / Georg Lurje / Ulf Peter Neumann / Zoltan Czigany

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 14

    Abstract: Abstract Body composition and myosteatosis affect clinical outcomes in orthotopic liver transplantation (OLT). Here we aimed to compare the value and limitations of various selection criteria to define pre-transplant myosteatosis in the assessment of ... ...

    Abstract Abstract Body composition and myosteatosis affect clinical outcomes in orthotopic liver transplantation (OLT). Here we aimed to compare the value and limitations of various selection criteria to define pre-transplant myosteatosis in the assessment of short- and long-term outcomes following OLT. We retrospectively analyzed the data of 264 consecutive recipients who underwent deceased donor OLT at a German university medical centre. Myosteatosis was evaluated by preoperative computed-tomography-based segmentation. Patients were stratified using muscle radiation attenuation of the whole muscle area (L3Muslce-RA), psoas RA (L3Psoas-RA) and intramuscular adipose tissue content (IMAC) values. L3Muslce-RA, L3Psoas-RA and IMAC performed well without major differences and identified patients at risk for inferior outcomes in the group analysis. Quartile-based analyses, receiver operating characteristic curve and correlation analyses showed a superior association of L3Muslce-RA with perioperative outcomes when compared to L3Psoas-RA and L3IMAC. Long-term outcome did not show any major differences between the used selection criteria. This study confirms the prognostic role of myosteatosis in OLT with a particularly strong value in the perioperative phase. Although, based on our data, L3Muscle-RA might be the most suitable and recommended selection criterion to assess CT-based myosteatosis when compared to L3Psoas-RA and L3IMAC, further studies are warranted to validate these findings.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Perioperative rifaximin is not associated with enhanced functional and volumetric recovery after major liver resection

    Jan Bednarsch / Zoltan Czigany / Sven H. Loosen / Lara Heij / Lorenz Ruckgaber / Henning Maes / Jan-Pit Krause / Matthias Reen / Beata Toteva / Theresa Vosdellen / Philipp Bruners / Sven Arke Lang / Tom Florian Ulmer / Christoph Roderburg / Tom Luedde / Ulf Peter Neumann

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 12

    Abstract: Abstract The objective of this randomized controlled trial (RCT) was to assess the impact of rifaximin on the course of liver function, liver regeneration and volumetric recovery in patients undergoing major hepatectomy. The ARROW trial was an ... ...

    Abstract Abstract The objective of this randomized controlled trial (RCT) was to assess the impact of rifaximin on the course of liver function, liver regeneration and volumetric recovery in patients undergoing major hepatectomy. The ARROW trial was an investigator initiated, single-center, open-label, phase 3 RCT with two parallel treatment groups, conducted at our hepatobiliary center from 03/2016 to 07/2020. Patients undergoing major hepatectomy were eligible and randomly assigned 1:1 to receive oral rifaximin (550 mg twice daily for 7–10 or 14–21 days in case of portal vein embolization preoperatively and 7 days postoperatively) versus no intervention. Primary endpoint was the relative increase in postoperative liver function measured by LiMAx from postoperative day (POD) 4 to 7. Secondary endpoint were the course of liver function and liver volume during the study period as well as postoperative morbidity and mortality. Between 2016 and 2020, 45 patients were randomized and 35 patients (16 individuals in the rifaximin and 19 individuals in the control group) were eligible for per-protocol analysis. The study was prematurely terminated following interim analysis, due to the unlikelihood of reaching a significant primary endpoint. The median relative increase in liver function from POD 4 to POD 7 was 27% in the rifaximin group and 41% in the control group (p = 0.399). Further, no significant difference was found in terms of any other endpoints of functional liver- and volume regeneration or perioperative surgical complications following the application of rifaximin versus no intervention. Perioperative application of rifaximin has no effect on functional or volumetric regeneration after major hepatectomy (NCT02555293; EudraCT 2013-004644-28).
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Ketamine does not produce relief of neuropathic pain in mice lacking the β-common receptor (CD131).

    Maarten Swartjes / Marieke Niesters / Lara Heij / Ann Dunne / Leon Aarts / Carla Cerami Hand / Hyung-Suk Kim / Michael Brines / Anthony Cerami / Albert Dahan

    PLoS ONE, Vol 8, Iss 8, p e

    2013  Volume 71326

    Abstract: Neuropathic pain (NP) is a debilitating condition associated with traumatic, metabolic, autoimmune and neurological etiologies. Although the triggers for NP are diverse, there are common underlying pathways, including activation of immune cells in the ... ...

    Abstract Neuropathic pain (NP) is a debilitating condition associated with traumatic, metabolic, autoimmune and neurological etiologies. Although the triggers for NP are diverse, there are common underlying pathways, including activation of immune cells in the spinal cord and up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Ketamine, a well-known NDMAR antagonist, reduces neuropathic pain in a sustained manner. Recent study has shown that the novel 11-amino acid peptide erythropoietin derivative ARA290 produces a similar, long-lasting relief of NP. Here, we show that both drugs also have similar effects on the expression of mRNA of the NMDAR, as well as that of microglia, astrocytes and chemokine (C-C motif) ligand 2, all-important contributors to the development of NP. Although the effects of ketamine and ARA 290 on NP and its molecular mediators suggest a common mechanism of action, ARA 290 has no affinity for the NMDAR and acts specifically via the innate repair receptor (IRR) involved in tissue protection. We speculated therefore, that the IRR might be critically involved in the action of ketamine on neuropathic pain. To evaluate this, we studied the effects of ketamine and ARA 290 on acute pain, side effects, and allodynia following a spared nerve injury model in mice lacking the β-common receptor (βcR), a structural component of the IRR. Ketamine (50 mg/kg) and ARA 290 (30 µg/kg) produced divergent effects on acute pain: ketamine produced profound antinociception accompanied with psychomotor side effects, but ARA290 did not, in both normal and knock out mice. In contrast, while both drugs were antiallodynic in WT mice, they had no effect on NP in mice lacking the βcR. Together, these results show that an intact IRR is required for the effective treatment of NP with either ketamine or ARA 290, but is not involved in ketamine's analgesic and side effects.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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