Gastroenterology TUM

💬New in Zeitschrift für : ➡️"Evaluation of a to assess the indication for screening colonoscopy for asymptomatic patients"

https://pubmed.ncbi.nlm.nih.gov/37875129/

Veit Phillip, Alexander Hapfelmeier, Benjamin Walter, Roland M Schmid, Sebastian Rasch

PMID: 37875129 DOI: 10.1055/a-2181-1706

Abstract:

Introduction: Colorectal is the second most common cause of cancer death worldwide. Screening is a very effective measure to prevent colorectal cancer and can reduce at the population level. However, the participation rates of screening programs are low. To provide easily accessible information on screening colonoscopy and to increase the participation rates of screening programs, we developed a questionnaire for asymptomatic patients based on the German guidelines to assess the indication for screening colonoscopy. We evaluated the questionnaire with reference to the indications given by specialists in .

Methods: Patients who visited a specialist in gastroenterology in an outpatient clinic of a tertiary hospital for other reasons than a colonoscopy were eligible for the study. A maximum of seven questions to assess the indication for screening colonoscopy were answered by the patients. Afterward, the indication for screening colonoscopy was given or not by a specialist in gastroenterology. The accuracy of the questionnaire was measured in terms of sensitivity, specificity, and predictive values.

Results: In total, 335 patients were included in the analyses, of whom 50 and 285 patients were given and were not given an indication for screening colonoscopy by the specialists, respectively. In 0/50 patients, the questionnaire was false negative and in 8/285 patients false positive. Thus, the questionnaire had a sensitivity of 100% (95% confidence interval: 93-100%), a specificity of 97% (95-99%), a negative predictive value of 100% (99-100%), and a positive predictive value of 86% (75-94%).A subgroup analysis including patients who had never had a colonoscopy (n=109) showed comparable results: sensitivity of 100% (92-100%), specificity of 92% (83-97%), negative predictive value of 100% (94-100%), and positive predictive value of 90% (87-97%).

Conclusion: The self-assessment questionnaire for asymptomatic individuals to assess the recommendation for screening colonoscopy is very sensitive and specific compared to a specialist in gastroenterology. The questionnaire can be found at: https://www.interdisziplinaere-endoskopie.mri.tum.de/de/infos-patienten/index.php.

TU München Ludwig-Maximilians-Universität München Helmholtz Juniors MGC Doctoral Candidates

Evaluation of a questionnaire to assess the indication for screening colonoscopy for asymptomatic patients - PubMed The self-assessment questionnaire for asymptomatic individuals to assess the recommendation for screening colonoscopy is very sensitive and specific compared to a specialist in gastroenterology.The questionnaire can be found at: https://www.interdisziplinaere-endoskopie.mri.tum.de/de/infos-patienten...

Translational Seminar in : We had the pleasure to welcome Elisa Espinet, PhD, University of Barcelona (UB) and Bellvitge Institute of Research in Biomedicine (IDIBELL), Spain, who gave a fantastic talk about epigenetics and microenvironment. A full auditorium of researchers and students listened to an inspiring new developments on biology!

We thank Elisa for sharing all the exciting data and we are already looking forward to next visit!

Save the date – our next seminar

- on 23.05.2024
- with Dr. med. Stephanie Frenz-Wießner, Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU Klinikum München

More information:
https://www.med2.mri.tum.de/en/seminar_series/index.php

TU München Helmholtz Juniors MGC Doctoral Candidates

Save the date

➔ Translational Series,

➔ Thursday, 30.11.2023, 5 to 6 pm

➔ Dr. Rene-Filip Jackstadt, German Cancer Research Center / Deutsches Krebsforschungszentrum (DKFZ), Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH)

➔ Klinikum rechts der Isar der TU München, Ismaninger Straße 22, Auditorium C, 81675

➔ Host: Prof. Maximilian Reichert

https://www.med2.mri.tum.de/en/seminar_series/index.php

For our seminar series we invite scientists from all over the world to present their newest scientific findings and discuss their data.

Participants have the possibiliy to meet the scientists for personal discussion (please contact the host of each seminar).

Registration is not required. We will be happy to welcome you to this talk!

Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors MGC Doctoral Candidates

18/07/2023 - Translational in

Thank you Prof. Chris Halbrook, Department of Molecular Biology and Biochemistry at the University of California, Irvine, USA, for agreeing to present your in Munich!

Dear followers: We invite you all to our seminar

- "Targeting Metabolic Support and Resistance Networks in Pancreatic "
- by Prof. Chris Halbrook
- on Tuesday 18/07/2023, 5 to 6 pm
- Venue: Auditorium C, Klinikum rechts der Isar der TU München, Ismaninger Straße 22, 81675

Host:
Prof. Maximilian Reichert

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ONLINE VIA ZOOM

To our followers from all over the world who cannot be there in Munich: You can join our Translational Gastroenterology Seminar via Zoom.

More information & QR Code:
https://www.med2.mri.tum.de/en/seminar_series/

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Good to know:
Christopher Halbrook, PhD, is an Assistant Professor at the University of California Irvine in the Department of Molecular Biology and Biochemistry, UCI Chao Family Comprehensive Cancer Center, and UCI Institute for Immunology.

Dr. Halbrook’s work focuses on disrupting the pancreatic tumor microenvironment to enable effective therapy. His research has led to seminal findings showing mechanisms of metabolic crosstalk with functional consequences on tumor growth, chemoresistance, and immune suppression in pancreatic cancer. Current work by his team includes contrasting the programming of the primary vs. metastatic tumor niche, targeting metabolic networks supporting proliferation and therapy resistance, and understanding how dysregulation of regenerative programs drives pancreatitis and cancer.

Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors MGC Doctoral Candidates

Account Transfer: from to Gastroenterology@TUM

We would like to continue our journey as Gastroenterology@TUM with the Translational Series.

Here we keep you updated on our seminars and publications in the field of gastroenterology!

Follow us also on :
https://twitter.com/GastroTUM

Your Translational Gastroenterology Team
(Klinik für Innere Medizin II, University Hospital rechts der Isar, Technical University of )
https://www.med2.mri.tum.de/en/research/index.php

TU München Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors MGC Doctoral Candidates

: "Non-canonical functions of drive context-specific progression" - this is our publication in Nature Communications: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9992512/

Contratulations to out team!

Paul, M. C., Schneeweis, C., Falcomata, C., Shan, C., Rossmeisl, D., Koutsouli, S., Klement, C., Zukowska, M., Widholz, S. A., Jesinghaus, M., Heuermann, K. K., Engleitner, T., Seidler, B., Sleiman, K., Steiger, K., Tschurtschenthaler, M., Walter, B., Weidemann, S. A., Pietsch, R., Schnieke, A., Schmid, R. M., Robles, M. S., Andrieux, G., Boerries, M., Rad, R., Schneider, G., and Saur, D. (2023). Nat Commun 14, 1201. doi: 10.1038/s41467-023-36505-0

Abstract:
SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer.

Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL-related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer.

Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16INK4A-independent inactivation of the Retinoblastoma (RB)-restriction checkpoint.

Collectively, our work identifies non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer.

TU München Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors

Non-canonical functions of SNAIL drive context-specific cancer progression SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent ...

" definition of sludge and microlithiasis as a possible cause of " - this is our new in Gut:
https://gut.bmj.com/content/early/2023/04/24/gutjnl-2022-327955

Congratulations to our !

Zorniak, M., Sirtl, S., Beyer, G., Mahajan, U. M., Bretthauer, K., Schirra, J., Schulz, C., Kohlmann, T., Lerch, M. M., Mayerle, J., and Team, L. M. E. S. (2023). Gut [Epub ahead of print]. doi: 10.1136/gutjnl-2022-327955

Abstract

Objective:
In up to 20% of patients, the aetiology of acute pancreatitis (AP) remains elusive and is thus called idiopathic. On more detailed review these cases can often be explained through biliary disease and are amenable to treatment. Findings range from biliary sludge to microlithiasis but their definitions remain fluid and controversial.

Design:
A systematic literature review (1682 reports, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines) analysed definitions of biliary sludge and microlithiasis, followed by an online international expert survey (30 endoscopic ultrasound/hepatobiliary and pancreatic experts; 36 items) which led to definitions of both. These were consented by Delphi voting and clinically evaluated in a retrospective cohort of patients with presumed biliary pancreatitis.

Results:
In 13% of original articles and 19.2% of reviews, microlithiasis and biliary sludge were used synonymously. In the survey, 41.7% of experts described the term 'sludge' and 'microlithiasis' as identical findings. As a consequence, three definitions were proposed, agreed on and confirmed by voting to distinctly discriminate between biliary sludge (hyperechoic material without acoustic shadowing) and microlithiasis (echorich calculi of ≤5 mm with acoustic shadowing) as opposed to larger biliary stones, both for location in gallbladder and bile ducts. In an initial attempt to investigate the clinical relevance in a retrospective analysis in 177 confirmed cases in our hospital, there was no difference in severity of AP if caused by sludge, microlithiasis or stones.

Conclusion:
We propose a consensus definition for the localisation, ultrasound morphology and diameter of biliary sludge and microlithiasis as distinct entities. Interestingly, severity of biliary AP was not dependent on the size of concrements warranting prospective randomised studies which treatment options are adequate to prevent recurrence.

TU München Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors MGC Doctoral Candidates

Consensus definition of sludge and microlithiasis as a possible cause of pancreatitis Objective In up to 20% of patients, the aetiology of acute pancreatitis (AP) remains elusive and is thus called idiopathic. On more detailed review these cases can often be explained through biliary disease and are amenable to treatment. Findings range from biliary sludge to microlithiasis but their...

Reminder for the Translational , (www.sfb1321.de):

- Tomorrow, 3:00 pm

- "Epithelial-Mesenchymal Plasticity in Carcinoma Metastasis"

- by Prof. Jing Yang (University of California, San Diego, USA)

- at Johannes B. Ortner Forum / right part, TranslaTUM, Einsteinstraße 25, 81675 München, Germany

Hosts:
Aris Papargyriou, Prof. Max Reichert

https://sfb1321.med.tum.de/en/jing-yang

For our seminar series we invite scientists from all over the world to present their newest scientific findings and discuss their data. Participants have the possibiliy to meet the scientists for personal discussion (please contact the host of each seminar).

Anyone who is interested is very welcome! There is no registration required.

Good to know about Jing Yang, PhD:
She is a Professor of Pharmacology and Pediatrics at University of California, San Diego. She is also the co-leader of the Cell Biology and Signaling program at UCSD Moores Comprehensive Cancer Center. She did her PhD in cell cycle regulation with Dr. Sally Kornbluth at Duke University and then performed her postdoctoral research on tumor metastasis with Dr. Robert Weinberg at Whitehead Institute. Dr. Yang joined the faculty of University of California, San Diego in 2006.

Dr. Yang’s research focuses on understanding the molecular basis of tumor metastasis. Her pioneering research demonstrates a critical role of the Epithelial-Mesenchymal Transition (EMT) program in tumor metastasis and brought EMT to the forefront of cancer research. Her lab uses (1) functional genomics and cellular and molecular biology approaches in 3D organoid cultures and (2) mouse tumor models to uncover novel signaling pathways in tumor metastasis.

Her group has identified matrix stiffening, epithelial polarity, and invadopodia-mediated extracellular matrix degradation as being critical regulatory mechanisms of EMT and tumor metastasis and continues to address the dynamic involvement of these programs in metastasis.

We look forward to you!

Your research center team
www.sfb1321.de

TU München Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors

News: Congratulations to our team for the publication in "The EMBO Journal"!

"eIF3 mRNA selectivity profiling reveals eIF3k as a -relevant regulator of ribosome content": https://www.embopress.org/doi/full/10.15252/embj.2022112362

Duan, H. R., Zhang, S. Q., Zarai, Y., Ollinger, R., Wu, Y. M., Sun, L., Hu, C., He, Y. H., Tian, G. Y., Rad, R., Kong, X. Q., Cheng, Y. B., Tuller, T., and Wolf, D. A. (2023). EMBO J [Epub ahead of print]. doi: 10.15252/embj.2022112362

Abstract:
eIF3, whose subunits are frequently overexpressed in cancer, regulates mRNA translation from initiation to termination, but mRNA-selective functions of individual subunits remain poorly defined. Using multiomic profiling upon acute depletion of eIF3 subunits, we observed that while eIF3a, b, e, and f markedly differed in their impact on eIF3 holo-complex formation and translation, they were each required for cancer cell proliferation and tumor growth. Remarkably, eIF3k showed the opposite pattern with depletion promoting global translation, cell proliferation, tumor growth, and stress resistance through repressing the synthesis of ribosomal proteins, especially RPS15A. Whereas ectopic expression of RPS15A mimicked the anabolic effects of eIF3k depletion, disruption of eIF3 binding to the 5'-UTR of RSP15A mRNA negated them. eIF3k and eIF3l are selectively downregulated in response to endoplasmic reticulum and oxidative stress. Supported by mathematical modeling, our data uncover eIF3k-l as a mRNA-specific module which, through controlling RPS15A translation, serves as a rheostat of ribosome content, possibly to secure spare translational capacity that can be mobilized during stress.

TU München Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors

eIF3 mRNA selectivity profiling reveals eIF3k as a cancer‐relevant regulator of ribosome content Multiomic profiling upon acute depletion of eIF3 subunits uncovers an mRNA-specific module securing spare translational capacity that can be mobilized during stress.

: In "Nature " we outline single-cell analyses in , discuss their implications on our understanding of the disease and present future perspectives of multimodal approaches to elucidate its biology and response to therapy at the single-cell level. Reading tip!

https://sfb1321.med.tum.de/en/single-cell-profiling-explore-pancreatic-cancer-heterogeneity-plasticity-and-response-therapy

"Single-cell profiling to explore pancreatic cancer heterogeneity, plasticity and response to therapy"

Barthel, S., Falcomata, C., Rad, R., Theis, F. J., and Saur, D. (2023). Nat Cancer [Epub ahead of print]. doi: 10.1038/s43018-023-00526-x

Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer entity characterized by a heterogeneous genetic landscape and an immunosuppressive tumor microenvironment. Recent advances in high-resolution single-cell sequencing and spatial transcriptomics technologies have enabled an in-depth characterization of both malignant and host cell types and increased our understanding of the heterogeneity and plasticity of PDAC in the steady state and under therapeutic perturbation. In this Review we outline single-cell analyses in PDAC, discuss their implications on our understanding of the disease and present future perspectives of multimodal approaches to elucidate its biology and response to therapy at the single-cell level.

More publications of our Pancreatic Cancer Collaborative Research Centre:
https://sfb1321.med.tum.de/en/publications

TU München Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors Deutsches Krebsforschungszentrum (DKFZ)

More : Our , published in "Cell Genomics", constitutes a first survey toward a systems-level understanding of quasi-insufficiency in and gives multifaceted insights into tumor evolution and the tissue-specific effects of non-coding mutations.

"In vivo interrogation of regulatory genomes reveals extensive quasi-insufficiency in cancer evolution"

Fischer, A., Lersch, R., de Andrade Kratzig, N., Strong, A., Friedrich, M. J., Weber, J., Engleitner, T., Ollinger, R., Yen, H. Y., Kohlhofer, U., Gonzalez-Menendez, I., Sailer, D., Kogan, L., Lahnalampi, M., Laukkanen, S., Kaltenbacher, T., Klement, C., Rezaei, M., Ammon, T., Montero, J. J., Schneider, G., Mayerle, J., Heikenwalder, M., Schmidt-Supprian, M., Quintanilla-Martinez, L., Steiger, K., Liu, P., Cadinanos, J., Vassiliou, G. S., Saur, D., Lohi, O., Heinaniemi, M., Conte, N., Bradley, A., Rad, L., and Rad, R. (2023). Cell Genom 3, 100276. doi: 10.1016/j.xgen.2023.100276

Abstract:
In contrast to mono- or biallelic loss of tumor-suppressor function, effects of discrete gene dysregulations, as caused by non-coding (epi)genome alterations, are poorly understood. Here, by perturbing the regulatory genome in mice, we uncover pervasive roles of subtle gene expression variation in cancer evolution. Genome-wide screens characterizing 1,450 tumors revealed that such quasi-insufficiency is extensive across entities and displays diverse context dependencies, such as distinct cell-of-origin associations in T-ALL subtypes. We compile catalogs of non-coding regions linked to quasi-insufficiency, show their enrichment with human cancer risk variants, and provide functional insights by engineering regulatory alterations in mice. As such, kilo-/megabase deletions in a Bcl11b-linked non-coding region triggered aggressive malignancies, with allele-specific tumor spectra reflecting gradual gene dysregulations through modular and cell-type-specific enhancer activities. Our study constitutes a first survey toward a systems-level understanding of quasi-insufficiency in cancer and gives multifaceted insights into tumor evolution and the tissue-specific effects of non-coding mutations.

TU München Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors MGC Doctoral Candidates

In vivo interrogation of regulatory genomes reveals extensive quasi-insufficiency in cancer evolution In contrast to mono- or biallelic loss of tumor-suppressor function, effects of discrete gene dysregulations, as caused by non-coding (epi)genome alte…

Our in Gut - the first population-based study delineating age-adjusted upper reference limits of CBD and PD on MRCP

We showed that up to 18.2% of healthy volunteers would have needed diagnostic workup, if the conventional reference values were used. The utilisation of the adapted reference levels may help to avoid unnecessary investigations and thus to reduce healthcare expenditure and test-related adverse events.

https://sfb1321.med.tum.de/en/definition-age-dependent-reference-values-diameter-common-bile-duct-and-pancreatic-duct-mrcp

Definition of age-dependent reference values for the diameter of the common bile duct and pancreatic duct on MRCP: a population-based, cross-sectional cohort study

Beyer, G., Kasprowicz, F., Hannemann, A., Aghdassi, A., Thamm, P., Volzke, H., Lerch, M. M., Kuhn, J. P., and Mayerle, J. (2023). Gut [Epub ahead of print]. doi: 10.1136/gutjnl-2021-326106

Abstract:

Objective:
Changes of the pancreaticobiliary ducts herald disease. Magnetic resonance cholangiopancreatography (MRCP) allows accurate duct visualisation. Data on reliable upper reference ranges are missing.

Design:
Cross-sectional whole body MRI data from the population-based Study of Health in Pomerania were analysed. The width of the common bile duct (CBD) and the pancreatic duct (PD) was determined. We aimed to describe the distribution of physiological duct diameters on MRCP in a population of healthy subjects and to identify factors influencing duct size.

Results:
After excluding pre-existing pancreaticobiliary conditions, CBD and PD diameters from 938 and 774 healthy individuals, respectively, showed a significant increase with age (p

Proud to share our in Journal of Cell Biology: "TIMP-1 is a novel ligand of Amyloid Precursor Protein and triggers a proinflammatory phenotype in human monocytes"

https://sfb1321.med.tum.de/en/timp-1-novel-ligand-amyloid-precursor-protein-and-triggers-proinflammatory-phenotype-human-monocytes

Eckfeld, C., Schoeps, B., Haussler, D., Fraedrich, J., Bayerl, F., Bottcher, J. P., Knolle, P., Heisz, S., Prokopchuk, O., Hauner, H., Munkhbaatar, E., Demir, I. E., Hermann, C. D., and Kruger, A. (2023). J Cell Biol 222. doi: ARTN e202206095 10.1083/jcb.202206095

Abstract:
The emerging cytokine tissue inhibitor of metalloproteinases-1 (TIMP-1) correlates with the progression of inflammatory diseases, including cancer. However, the effects of TIMP-1 on immune cell activation and underlying molecular mechanisms are largely unknown. Unbiased ligand-receptor-capture-screening revealed TIMP-1-interaction with Amyloid Precursor Protein (APP) family members, namely APP and Amyloid Precursor-like Protein-2 (APLP2), which was confirmed by pull-down assays and confocal microscopy. We found that TIMP-1 triggered glucose uptake and proinflammatory cytokine expression in human monocytes. In cancer patients, TIMP-1 expression positively correlated with proinflammatory cytokine expression and processes associated with monocyte activation. In pancreatic , TIMP-1 plasma levels correlated with the monocyte activation marker sCD163, and the combined use of both clinically accessible plasma proteins served as a powerful prognostic indicator. Mechanistically, TIMP-1 triggered monocyte activation by its C-terminal domain and via APP as demonstrated by in vitro interference, in silico docking, and the employment of recombinant TIMP-1 variants. Identification of TIMP-1 as a trigger of monocyte activation opens new therapeutic perspectives for inflammatory diseases.

Congratulations to our team!

More publications of our Pancreatic Cancer Collaborative Research Centre:
https://sfb1321.med.tum.de/en/publications

TU München Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors MGC Doctoral Candidates

: Excited to share results showing that deep learning in IPMN-EUS images can predict the histological outcome with high accuracy.

Our in Endoscopy:
http://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1971-1274

"Accurate prediction of histological grading of intraductal papillary mucinous neoplasia using deep learning"

Schulz, D., Heilmaier, M., Phillip, V., Treiber, M., Mayr, U., Lahmer, T., Mueller, J., Demir, I. E., Friess, H., Reichert, M., Schmid, R. M., and Abdelhafez, M. (2023). Endoscopy [Epub ahead of print]. doi: 10.1055/a-1971-1274

Abstract:

Background:
Risk stratification and recommendation for surgery for intraductal papillary mucinous neoplasm (IPMN) are currently based on consensus guidelines. Risk stratification from presurgery histology is only potentially decisive owing to the low sensitivity of fine-needle aspiration. In this study, we developed and validated a deep learning-based method to distinguish between IPMN with low grade dysplasia and IPMN with high grade dysplasia/invasive carcinoma using endoscopic ultrasound (EUS) images.

Methods:
For model training, we acquired a total of 3355 EUS images from 43 patients who underwent pancreatectomy from March 2015 to August 2021. All patients had histologically proven IPMN. We used transfer learning to fine-tune a convolutional neural network and to classify "low grade IPMN" from "high grade IPMN/invasive carcinoma." Our test set consisted of 1823 images from 27 patients, recruiting 11 patients retrospectively, 7 patients prospectively, and 9 patients externally. We compared our results with the prediction based on international consensus guidelines.

Results:
Our approach could classify low grade from high grade/invasive carcinoma in the test set with an accuracy of 99.6 % (95 %CI 99.5 %-99.9 %). Our deep learning model achieved superior accuracy in prediction of the histological outcome compared with any individual guideline, which have accuracies between 51.8 % (95 %CI 31.9 %-71.3 %) and 70.4 % (95 %CI 49.8-86.2).

Conclusion:
This pilot study demonstrated that deep learning in IPMN-EUS images can predict the histological outcome with high accuracy.

TU München Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors MGC Doctoral Candidates

Thieme E-Journals - Endoscopy / Abstract Thieme E-Books & E-Journals

Congrats to our for the in PNAS!

"Long-term persistence and functionality of adoptively transferred antigen-specific T cells with genetically ablated PD-1 expression"

Dotsch, S., Svec, M., Schober, K., Hammel, M., Wanisch, A., Gokmen, F., Jarosch, S., Warmuth, L., Barton, J., Cicin-Sain, L., D'Ippolito, E., and Busch, D. H. (2023). Proc Natl Acad Sci U S A 120, e2200626120. doi: 10.1073/pnas.2200626120

Abstract:
Engagement of the inhibitory T cell receptor programmed cell death protein 1 (PD-1) associates with dysfunctional states of pathogen- or tumor-specific T cells. Accordingly, systemic antibody-mediated blockade of PD-1 has become a central target for immunotherapies but is also associated with severe toxicities due to loss of peripheral tolerance. Therefore, selective ablation of PD-1 expression on adoptively transferred T cells through direct genetic knockout (KO) is currently being explored as an alternative therapeutic approach. However, since PD-1 might also be required for the regulation of physiological T cell function and differentiation, the suitability of PD-1 as an engineering target is controversial. In this study, we systematically investigated the maintenance of T cell functionality after CRISPR/Cas9-mediated PD-1 KO in vivo during and after acute and chronic antigen encounter. Under all tested conditions, PD-1 ablation preserved the persistence, differentiation, and memory formation of adoptively transferred receptor transgenic T cells. Functional PD-1 KO T cells expressing chimeric antigen receptors (CARs) targeting CD19 could be robustly detected for over 390 d in a syngeneic immunocompetent mouse model, in which constant antigen exposure was provided by continuous B cell renewal, representing the longest in vivo follow-up of CAR-T cells described to date. PD-1 KO CAR-T cells showed no evidence for malignant transformation during the entire observation period. Our data demonstrate that genetic ablation of PD-1 does not impair functionality and longevity of adoptively transferred T cells per se and therefore may be pursued more generally in engineered T cell-based immunotherapy to overcome a central immunosuppressive axis.

More publications:
https://sfb1321.med.tum.de/en/publications

Important to know:
Modelling and Targeting - Pancreatic is one of the biggest challenges for oncologists and scientists: It belongs to those forms of cancer that are very aggressive and difficult to treat. Every year around 450,000 people around the world receive the diagnosis of pancreatic cancer. Survival in this cancer is still the lowest among all cancers: The overall 5-year survival rate is less than 8%. This has remained almost unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. Pancreatic cancer is predicted to become the second leading cause of cancer death in the next decade.
Our collaborative center is studying biological characteristics of this cancer. We believe that only a profound mechanistic understanding of pancreatic cancer and its extreme and unique characteristics will lead to a sustained improvement of the prognosis for affected patients. Based on this clinical orientation we are determined to improve the therapy options for this specific form of cancer.

TU München Ludwig-Maximilians-Universität München Helmholtz-Munich Helmholtz Juniors MGC Doctoral Candidates