Publications by authors named "Bence Sipos"

164 Publications

FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale.

Front Endocrinol (Lausanne) 2021 12;12:712107. Epub 2021 Aug 12.

Department of Internal Medicine I, Division of Endocrinology/Diabetology, University of Würzburg, Würzburg, Germany.

Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.

Materials And Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.

Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.

Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.
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http://dx.doi.org/10.3389/fendo.2021.712107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406771PMC
August 2021

Development and Characterization of -Propyl Gallate Encapsulated Solid Lipid Nanoparticles-Loaded Hydrogel for Intranasal Delivery.

Pharmaceuticals (Basel) 2021 Jul 19;14(7). Epub 2021 Jul 19.

Institute of Pharmaceutical Technology and Regulatory Affairs, Faculty of Pharmacy, University of Szeged, Eötvös Str. 6, H-6720 Szeged, Hungary.

The objective of the present study was to develop -propyl gallate-loaded solid lipid nanoparticles (PG-SLNs) in a hydrogel (HG) formulation using Transcutol-P (TC-P) as a permeation enhancer. Modified solvent injection technique was applied to produce optimized PG-SLNs via the Quality by Design approach and central composite design. The in vitro mucoadhesion, scavenging activity, drug release, permeation studies of PG from PG-SLNs-loaded HG were evaluated under simulated nasal conditions. Compared with in vitro release behavior of PG from SLNs, the drug release from the PG-SLNs-loaded HG showed a lower burst effect and sustained release profile. The cumulative permeation of PG from PG-SLNs-loaded HG with TC-P was 600 μg/cm within 60 min, which is 3-60-fold higher than PG-SLNs and native PG, respectively. Raman mapping showed that the distribution of PG-SLNs was more concentrated in HG having lower concentrations of hyaluronic acid. The scavenging assay demonstrated increased antioxidant activity at higher concentrations of HG. Due to enhanced stability and mucoadhesive properties, the developed HG-based SLNs can improve nasal absorption by increasing residence time on nasal mucosa. This study provides in vitro proof of the potential of combining the advantages of SLNs and HG for the intranasal delivery of antioxidants.
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http://dx.doi.org/10.3390/ph14070696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308668PMC
July 2021

Development of dexamethasone-loaded mixed polymeric micelles for nasal delivery.

Eur J Pharm Sci 2021 Nov 31;166:105960. Epub 2021 Jul 31.

Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös str. 6., H-6720 Szeged, Hungary. Electronic address:

Our study aimed to formulate a novel dexamethasone (DXM)-loaded, mixed polymeric micelle-based drug delivery system, focusing on the auspicious nose-to-brain pathway, as a key delivery route to treat central nervous system (CNS) associated diseases. Polymeric micelles might be a solution to deliver drugs to the place of action compared to conventional formulations. Due to low Z-average (89.92 ± 2.7 nm), a polydispersity index of 0.216 ± 0.014 and high surface polarity (52.23%), a significant increase in water solubility (14-fold) was experienced. This increase resulted in favourable dissolution profile at nasal and axonal conditions with high in vitro permeability value (14.6×10 cm/s) on polar brain (porcine) lipid extract. Modified Side-bi-side® type diffusion study confirmed rapid and efficient passive diffusion through the nasal mucosa contributed by strong mucoadhesive properties. The final formulation met all the requirements of a nasal drug delivery system with rapid onset of action, meaning DXM can reach the CNS and there it can exert its beneficial effects in pathological conditions.
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http://dx.doi.org/10.1016/j.ejps.2021.105960DOI Listing
November 2021

Combined effects of PNPLA3, TM6SF2 and HSD17B13 variants on severity of biopsy-proven non-alcoholic fatty liver disease.

Hepatol Int 2021 Aug 2;15(4):922-933. Epub 2021 Jun 2.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Objective: Several single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors.

Design: Patients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0-F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study.

Results: 703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3-4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added.

Conclusion: In biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.
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http://dx.doi.org/10.1007/s12072-021-10200-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382644PMC
August 2021

CUX1 Enhances Pancreatic Cancer Formation by Synergizing with KRAS and Inducing MEK/ERK-Dependent Proliferation.

Cancers (Basel) 2021 May 18;13(10). Epub 2021 May 18.

Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, D06120 Halle/Saale, Germany.

The transcription factor CUX1 has been implicated in either tumor suppression or progression, depending on the cancer entity and the prevalent CUX1 isoform. Previously, we could show that CUX1 acts as an important mediator of tumor cell proliferation and resistance to apoptosis in pancreatic cancer cell lines. However, in vivo evidence for its impact on pancreatic carcinogenesis, isoform-specific effects and downstream signaling cascades are missing. We crossbred two different CUX1 isoform mouse models (p200 CUX1 and p110 CUX1) with KC (KrasLSL-G12D/+; Ptf1aCre/+) mice, a genetic model for pancreatic precursor lesions (PanIN). In the context of oncogenic KRASs, both mice KCCux1p200 and KCCux1p110 led to increased PanIN formation and development of invasive pancreatic ductal adenocarcinomata (PDAC). In KCCux1p110 mice, tumor development was dramatically more accelerated, leading to formation of invasive PDAC within 4 weeks. In vitro and in vivo, we could show that CUX1 enhanced proliferation by activating MEK-ERK signaling via an upstream increase of ADAM17 protein, which in turn led to an activation of EGFR. Additionally, CUX1 further enhanced MEK-ERK activation through upregulation of the serine/threonine kinase MOS, phosphorylating MEK in a KRAS-independent manner. We identified p110 CUX1 as major driver of pancreatic cancer formation in the context of mutant KRAS. These results provide the first in vivo evidence for the importance of CUX1 in the development of pancreatic cancer, and highlight the importance of CUX1-dependent signaling pathways as potential therapeutic targets.
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http://dx.doi.org/10.3390/cancers13102462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158495PMC
May 2021

A Systematic, Knowledge Space-Based Proposal on Quality by Design-Driven Polymeric Micelle Development.

Pharmaceutics 2021 May 12;13(5). Epub 2021 May 12.

Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Eötvös Str. 6, H-6720 Szeged, Hungary.

Nanoparticle research and development for pharmaceuticals is a challenging task in the era of personalized medicine. Specialized and increased patient expectations and requirements for proper therapy adherence, as well as sustainable environment safety and toxicology topics raise the necessity of well designed, advanced and smart drug delivery systems on the market. These stakeholder expectations and social responsibility of pharma sector open the space and call new methods on the floor for new strategic development tools, like Quality by Design (QbD) thinking. The extended model, namely the R&D QbD proved to be useful in case of complex and/or high risk/expectations containing or aiming developments. This is the case when we formulate polymeric micelles as promising nanotherapeutics; the risk assessment and knowledge-based quality targeted QbD approach provides a promising tool to support the development process. Based on risk assessment, many factors pose great risk in the manufacturing process and affect the quality, efficacy and safety profile. The quality-driven strategic development pathway, based on deep prior knowledge and an involving iterative risk estimation and management phases has proven to be an adequate tool, being able to handle their sensitive stability issues and make them efficient therapeutic aids in case of several diseases.
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http://dx.doi.org/10.3390/pharmaceutics13050702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150990PMC
May 2021

Platelet-Expressed Synaptophysin (pSyn) as Novel Biomarker in Neuroendocrine Malignancies.

Cancers (Basel) 2021 May 11;13(10). Epub 2021 May 11.

Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, 72076 Tuebingen, Germany.

Neuroendocrine neoplasms (NENs) encompass a heterogeneous group of tumors. Whereas low-grade neuroendocrine tumors (NETs) are histologically well-differentiated, highly aggressive neuroendocrine carcinomas (NECs) are characterized by a high proliferation rate and a worse clinical outcome. Since most NEN patients need monitoring of tumor progress and response to treatment for a long period of time, especially in metastatic disease, reliable, dynamic, and easy-to-assess biomarkers are needed. In this prospective study, we identified platelet-expressed synaptophysin (pSyn) as a novel biomarker in NENs. The level of pSyn in NENs was significantly upregulated compared to healthy donors. pSyn was positively correlated with higher tumor stages, the occurrence of metastasis, histological grading, and higher tumor proliferation (Ki67). Most importantly, high pSyn expression in our NEN cohort was shown to predict shorter progression-free survival (PFS). In conclusion, our data highlight the potential of pSyn as a novel biomarker in NENs reflecting tumor stages, grading, and prognosis.
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http://dx.doi.org/10.3390/cancers13102286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150833PMC
May 2021

Development of In Situ Gelling Meloxicam-Human Serum Albumin Nanoparticle Formulation for Nose-to-Brain Application.

Pharmaceutics 2021 May 1;13(5). Epub 2021 May 1.

Institute of Pharmaceutical Technology and Regulatory Affairs, Faculty of Pharmacy, University of Szeged, Eötvös Str. 6, H-6720 Szeged, Hungary.

The aim of this study was to develop an intranasal in situ thermo-gelling meloxicam-human serum albumin (MEL-HSA) nanoparticulate formulation applying poloxamer 407 (P407), which can be administered in liquid state into the nostril, and to increase the resistance of the formulation against mucociliary clearance by sol-gel transition on the nasal mucosa, as well as to improve drug absorption. Nanoparticle characterization showed that formulations containing 12-15% / P407 met the requirements of intranasal administration. The Z-average (in the range of 180-304 nm), the narrow polydispersity index (PdI, from 0.193 to 0.328), the zeta potential (between -9.4 and -7.0 mV) and the hypotonic osmolality (200-278 mOsmol/L) of MEL-HSA nanoparticles predict enhanced drug absorption through the nasal mucosa. Based on the rheological, muco-adhesion, drug release and permeability studies, the 14% / P407 containing formulation (MEL-HSA-P14%) was considered as the optimized formulation, which allows enhanced permeability of MEL through blood-brain barrier-specific lipid fraction. Cell line studies showed no cell damage after 1-h treatment with MEL-HSA-P14% on RPMI 2650 human endothelial cells' moreover, enhanced permeation (four-fold) of MEL from MEL-HSA-P14% was observed in comparison to pure MEL. Overall, MEL-HSA-P14% can be promising for overcoming the challenges of nasal drug delivery.
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http://dx.doi.org/10.3390/pharmaceutics13050646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147280PMC
May 2021

Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.

Cell Stem Cell 2021 06 28;28(6):1105-1124.e19. Epub 2021 Apr 28.

Institute of Neuroanatomy & Developmental Biology (INDB), Eberhard Karls University Tübingen, Tübingen, Germany.

Personalized in vitro models for dysplasia and carcinogenesis in the pancreas have been constrained by insufficient differentiation of human pluripotent stem cells (hPSCs) into the exocrine pancreatic lineage. Here, we differentiate hPSCs into pancreatic duct-like organoids (PDLOs) with morphological, transcriptional, proteomic, and functional characteristics of human pancreatic ducts, further maturing upon transplantation into mice. PDLOs are generated from hPSCs inducibly expressing oncogenic GNAS, KRAS, or KRAS with genetic covariance of lost CDKN2A and from induced hPSCs derived from a McCune-Albright patient. Each oncogene causes a specific growth, structural, and molecular phenotype in vitro. While transplanted PDLOs with oncogenic KRAS alone form heterogenous dysplastic lesions or cancer, KRAS with CDKN2A loss develop dedifferentiated pancreatic ductal adenocarcinomas. In contrast, transplanted PDLOs with mutant GNAS lead to intraductal papillary mucinous neoplasia-like structures. Conclusively, PDLOs enable in vitro and in vivo studies of pancreatic plasticity, dysplasia, and cancer formation from a genetically defined background.
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http://dx.doi.org/10.1016/j.stem.2021.03.005DOI Listing
June 2021

Exploiting the MUC5AC Antigen for Noninvasive Identification of Pancreatic Cancer.

J Nucl Med 2021 Mar 12. Epub 2021 Mar 12.

Memorial Sloan Kettering Cancer Center, United States.

Pancreatic cancer (PC) remains the 4th leading cause of cancer death; therefore, there is a clinically unmet need for novel therapeutics and diagnostic markers to treat this devastating disease. Physicians often rely on biopsy or CT for diagnosis, but more specific protein biomarkers are highly desired to assess the stage and severity of PC in a noninvasive manner. Serum biomarkers such as CA19.9 are of particular interest as they are commonly elevated in PC but have exhibited suboptimal performance in the clinic. MUC5AC has emerged as a useful serum biomarker that is specific for PC vs. inflammation. We developed RA96, an anti-MUC5AC antibody, to gauge its utility in PC diagnosis through immunohistochemical (IHC) analysis and whole-body PET in PC. In this study, extensive biochemical characterization determined MUC5AC as the antigen for RA96. We then determined the utility of RA96 for MUC5AC IHC on clinical PC and pre-clinical PC. Finally, we radiolabeled RA96 with zirconium-89 to assess its application as a whole-body PET radiotracer for MUC5AC quantification in PC. Immunohistochemical staining with RA96 distinguished chronic pancreatitis (CP), PanIN, and varying grades of pancreatic ductal adenocarcinoma (PDAC) in clinical samples. [Zr]Zr-DFO-RA96 was able to detect MUC5AC with high specificity in mice bearing capan-2 xenografts. Our study demonstrates that RA96 can differentiate between inflammation and PC, improving the fidelity of PC diagnosis. Our immuno-PET tracer [Zr]Zr-DFO-RA96 shows specific detection of MUC5AC+ tumors in vivo, highlighting the utility of MUC5AC targeting for diagnosis of PC.
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http://dx.doi.org/10.2967/jnumed.120.256776DOI Listing
March 2021

Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Institute of Medical Systems Biology, Ulm University, 89081 Ulm, Germany.

Cofilin-1 (CFL1) overexpression in pancreatic cancer correlates with high invasiveness and shorter survival. Besides a well-documented role in actin remodeling, additional cellular functions of CFL1 remain poorly understood. Here, we unraveled molecular tumor-promoting functions of CFL1 in pancreatic cancer. For this purpose, we first show that a knockdown of CFL1 results in reduced growth and proliferation rates in vitro and in vivo, while apoptosis is not induced. By mechanistic modeling we were able to predict the underlying regulation. Model simulations indicate that an imbalance in actin remodeling induces overexpression and activation of CFL1 by acting on transcription factor 7-like 2 (TCF7L2) and aurora kinase A (AURKA). Moreover, we could predict that CFL1 impacts proliferation and apoptosis via the signal transducer and activator of transcription 3 (STAT3). These initial model-based regulations could be substantiated by studying protein levels in pancreatic cancer cell lines and human datasets. Finally, we identified the surface protein CD44 as a promising therapeutic target for pancreatic cancer patients with high CFL1 expression.
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http://dx.doi.org/10.3390/cancers13040725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916621PMC
February 2021

An IgG-based bispecific antibody for improved dual targeting in PSMA-positive cancer.

EMBO Mol Med 2021 Feb 29;13(2):e11902. Epub 2020 Dec 29.

Department of Immunology, Institute for Cell Biology, Eberhard Karls University Tuebingen, German Cancer Consortium (DKTK), Partner Site Tuebingen, Tuebingen, Germany.

The prostate-specific membrane antigen (PSMA) has been demonstrated in numerous studies to be expressed specifically on prostate carcinoma cells and on the neovasculature of several other cancer entities. However, the simultaneous expression of PSMA on both, tumor cells as well as tumor vessels remains unclear, even if such "dual" expression would constitute an important asset to facilitate sufficient influx of effector cells to a given tumor site. We report here on the generation of a PSMA antibody, termed 10B3, which exerts superior dual reactivity on sections of prostate carcinoma and squamous cell carcinoma of the lung. 10B3 was used for the construction of T-cell recruiting bispecific PSMAxCD3 antibodies in Fab- and IgG-based formats, designated Fabsc and IgGsc, respectively. In vitro, both molecules exhibited comparable activity. In contrast, only the larger IgGsc molecule induced complete and durable elimination of established tumors in humanized mice due to favorable pharmacokinetic properties. Upon treatment of three patients with metastasized prostate carcinoma with the IgGsc reagent, marked activation of T cells and rapid reduction of elevated PSA levels were observed.
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http://dx.doi.org/10.15252/emmm.201911902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863392PMC
February 2021

Immunoprofiling in Neuroendocrine Neoplasms Unveil Immunosuppressive Microenvironment.

Cancers (Basel) 2020 Nov 19;12(11). Epub 2020 Nov 19.

Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany.

Checkpoint inhibitors have shown promising results in a variety of tumors; however, in neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), low response rates were reported. We aimed herein to investigate the tumor immune microenvironment in NET/NEC to determine whether checkpoint pathways like programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) might play a role in immune escape and whether other escape mechanisms might need to be targeted to enable a functional antitumor response. Forty-eight NET and thirty NEC samples were analyzed by immunohistochemistry (IHC) and mRNA immunoprofiling including digital spatial profiling. Through IHC, both NET/NEC showed stromal, but less intratumoral CD3+ T cell infiltration, although this was significantly higher in NEC compared to NET. Expression of PD1, PD-L1, and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on immune cells was low or nearly absent. mRNA immunoprofiling revealed low expression of IFNγ inducible genes in NET and NEC without any spatial heterogeneity. However, we observed an increased mRNA expression of chemokines, which attract myeloid cells in NET and NEC, and a high abundance of genes related to immunosuppressive myeloid cells and genes with immunosuppressive functions like CD47 and CD74. In conclusion, NET and NEC lack signs of an activation of the adaptive immune system, but rather show abundance of several immunosuppressive genes that represent potential targets for immunomodulation.
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http://dx.doi.org/10.3390/cancers12113448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699546PMC
November 2020

Elevated Serum Amino Acids Induce a Subpopulation of Alpha Cells to Initiate Pancreatic Neuroendocrine Tumor Formation.

Cell Rep Med 2020 Aug 25;1(5):100058. Epub 2020 Aug 25.

Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

The cellular origin of sporadic pancreatic neuroendocrine tumors (PNETs) is obscure. Hormone expression suggests that these tumors arise from glucagon-producing alpha cells or insulin-producing β cells, but instability in hormone expression prevents linage determination. We utilize loss of hepatic glucagon receptor (GCGR) signaling to drive alpha cell hyperproliferation and tumor formation to identify a cell of origin and dissect mechanisms that drive progression. Using a combination of genetically engineered knockout mice and GCGR-inhibiting antibodies, we show that elevated plasma amino acids drive the appearance of a proliferative population of SLC38A5 embryonic progenitor-like alpha cells in mice. Further, we characterize tumors from patients with rare bi-allelic germline loss-of-function variants and find prominent tumor-cell-associated expression of the SLC38A5 paralog SLC7A8 as well as markers of active mTOR signaling. Thus, progenitor cells arise from adult alpha cells in response to metabolic signals and, when inductive signals are chronically present, drive tumor initiation.
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http://dx.doi.org/10.1016/j.xcrm.2020.100058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659536PMC
August 2020

Targeting interleukin 6 signaling by monoclonal antibody siltuximab on cholangiocarcinoma.

J Gastroenterol Hepatol 2021 May 12;36(5):1334-1345. Epub 2020 Nov 12.

Department of Internal Medicine I, Universitätsklinikum Tübingen, Tübingen, Germany.

Background And Aim: Cholangiocarcinoma has an unimproved prognosis. Interleukin 6 (IL-6) has an oncogenic potential in some cancer diseases. However, the role of IL-6 in cholangiocarcinoma carcinogenesis is not well understood. The current study investigated the role of IL-6 signaling in cholangiocarcinoma carcinogenesis and efficacy of siltuximab treatment on cholangiocarcinoma in vitro and in vivo.

Methods: The expression of IL-6 was analyzed on human cholangiocarcinoma cell lines and murine and human cholangiocarcinoma tissues, using reverse transcription real-time polymerase chain reaction and immunohistochemistry. In addition, the effect of anti-IL-6 chimeric monoclonal antibody, siltuximab, was investigated in vitro by proliferation, migration, and two-dimensional and three-dimensional invasion assays and in vivo by xenograft mouse model. Western blot was applied to study the molecular alteration.

Results: Our result shows high expression of IL-6 in human cholangiocarcinoma cells, and IL-6 stimulants enhance cholangiocarcinoma cell proliferation. In addition, murine and human cholangiocarcinoma tissues express significantly higher levels of IL-6, compared with adjacent non-tumor tissues. On the cholangiocarcinoma engineered mouse model, IL-6 level is associated with tumor volume. Taken together, our data indicate an oncogenic potential of IL-6 in cholangiocarcinoma carcinogenesis. Siltuximab sufficiently abrogates IL-6 signaling and inhibits cholangiocarcinoma progression in vitro and in vivo. The results additionally indicate a relative alteration of IL-6 signaling and its molecular targets, such as STAT3, Wnt/β-catenin, and mesenchymal markers.

Conclusions: Interleukin 6 plays an essential role in cholangiocarcinoma carcinogenesis, and siltuximab has the potential to be considered as a new treatment option for cholangiocarcinoma patients.
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http://dx.doi.org/10.1111/jgh.15307DOI Listing
May 2021

Quality by Design Based Formulation Study of Meloxicam-Loaded Polymeric Micelles for Intranasal Administration.

Pharmaceutics 2020 Jul 24;12(8). Epub 2020 Jul 24.

Faculty of Pharmacy, Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, H-6720 Szeged, Hungary.

Our study aimed to develop an "ex tempore" reconstitutable, viscosity enhancer- and preservative-free meloxicam (MEL)-loaded polymeric micelle formulation, via Quality by Design (QbD) approach, exploiting the nose-to-brain pathway, as a suitable tool in the treatment of neuroinflammation. The anti-neuroinflammatory effect of nose-to-brain NSAID polymeric micelles was not studied previously, therefore its investigation is promising. Critical product parameters, encapsulation efficiency (89.4%), Z-average (101.22 ± 2.8 nm) and polydispersity index (0.149 ± 0.7) and zeta potential (-25.2 ± 0.4 mV) met the requirements of the intranasal drug delivery system (nanoDDS) and the targeted profile liquid formulation was transformed into a solid preservative-free product by freeze-drying. The viscosity (32.5 ± 0.28 mPas) and hypotonic osmolality (240 mOsmol/L) of the reconstituted formulation provides proper and enhanced absorption and probably guarantees the administration of the liquid dosage form (nasal drop and spray). The developed formulation resulted in more than 20 times faster MEL dissolution rate and five-fold higher nasal permeability compared to starting MEL. The prediction of IVIVC confirmed the great potential for in vivo brain distribution of MEL. The nose-to-brain delivery of NSAIDs such as MEL by means of nanoDDS as polymeric micelles offers an innovative opportunity to treat neuroinflammation more effectively.
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http://dx.doi.org/10.3390/pharmaceutics12080697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464185PMC
July 2020

Oncolytic vaccinia virus GLV-1h68 exhibits profound antitumoral activities in cell lines originating from neuroendocrine neoplasms.

BMC Cancer 2020 Jul 6;20(1):628. Epub 2020 Jul 6.

Department of Internal Medicine VIII, Department of Medical Oncology and Pneumology, University Hospital Tuebingen, University of Tuebingen, Otfried-Mueller-Strasse 10, 72076, Tuebingen, Baden-Wuerttemberg, Germany.

Background: Oncolytic virotherapy is an upcoming treatment option for many tumor entities. But so far, a first oncolytic virus only was approved for advanced stages of malignant melanomas. Neuroendocrine tumors (NETs) constitute a heterogenous group of tumors arising from the neuroendocrine system at diverse anatomic sites. Due to often slow growth rates and (in most cases) endocrine non-functionality, NETs are often detected only in a progressed metastatic situation, where therapy options are still severely limited. So far, immunotherapies and especially immunovirotherapies are not established as novel treatment modalities for NETs.

Methods: In this immunovirotherapy study, pancreatic NET (BON-1, QGP-1), lung NET (H727, UMC-11), as well as neuroendocrine carcinoma (NEC) cell lines (HROC-57, NEC-DUE1) were employed. The well characterized genetically engineered vaccinia virus GLV-1 h68, which has already been investigated in various clinical trials, was chosen as virotherapeutical treatment modality.

Results: Profound oncolytic efficiencies were found for NET/NEC tumor cells. Besides, NET/NEC tumor cell bound expression of GLV-1 h68-encoded marker genes was observed also. Furthermore, a highly efficient production of viral progenies was detected by sequential virus quantifications. Moreover, the mTOR inhibitor everolimus, licensed for treatment of metastatic NETs, was not found to interfere with GLV-1 h68 replication, making a combinatorial treatment of both feasible.

Conclusions: In summary, the oncolytic vaccinia virus GLV-1 h68 was found to exhibit promising antitumoral activities, replication capacities and a potential for future combinatorial approaches in cell lines originating from neuroendocrine neoplasms. Based on these preliminary findings, virotherapeutic effects now have to be further evaluated in animal models for treatment of Neuroendocrine neoplasms (NENs).
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http://dx.doi.org/10.1186/s12885-020-07121-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339398PMC
July 2020

Inflammation Associated Pancreatic Tumorigenesis: Upregulation of Succinate Dehydrogenase (Subunit B) Reduces Cell Growth of Pancreatic Ductal Epithelial Cells.

Cancers (Basel) 2019 Dec 21;12(1). Epub 2019 Dec 21.

Institute for Experimental Cancer Research, University of Kiel and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, 24105 Kiel, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is amongst the most fatal malignancies and its development is highly associated with inflammatory processes such as chronic pancreatitis (CP). Since the succinate dehydrogenase subunit B (SDHB) is regarded as tumor suppressor that is lost during cancer development, this study investigated the impact of M1-macrophages as part of the inflammatory microenvironment on the expression as well as function of SDHB in benign and premalignant pancreatic ductal epithelial cells (PDECs). Immunohistochemical analyses on pancreatic tissue sections from CP patients and control individuals revealed a stronger SDHB expression in ducts of CP tissues being associated with a greater abundance of macrophages compared to ducts in control tissues. Accordingly, indirect co-culture with M1-macrophages led to clearly elevated SDHB expression and SDH activity in benign H6c7-pBp and premalignant H6c7-kras PDECs. While siRNA-mediated SDHB knockdown in these cells did not affect glucose and lactate uptake after co-culture, SDHB knockdown significantly promoted PDEC growth which was associated with increased proliferation and decreased effector caspase activity particularly in co-cultured PDECs. Overall, these data indicate that SDHB expression and SDH activity are increased in PDECs when exposed to pro-inflammatory macrophages as a counterregulatory mechanism to prevent excessive PDEC growth triggered by the inflammatory environment.
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http://dx.doi.org/10.3390/cancers12010042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016879PMC
December 2019

A Non-interventional Clinical Trial Assessing Immune Responses After Radiofrequency Ablation of Liver Metastases From Colorectal Cancer.

Front Immunol 2019 19;10:2526. Epub 2019 Nov 19.

Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany.

Radiofrequency ablation (RFA) is an established treatment option for malignancies located in the liver. RFA-induced irreversible coagulation necrosis leads to the release of danger signals and cellular content. Hence, RFA may constitute an endogenous tumor vaccination, stimulating innate and adaptive immune responses, including tumor-antigen specific T cells. This may explain a phenomenon termed abscopal effect, namely tumor regression in untreated lesions evidenced after distant thermal ablation or irradiation. In this study, we therefore assessed systemic and local immune responses in individual patients treated with RFA. For this prospective clinical trial, patients with liver metastasis from colorectal carcinoma (mCRC) receiving RFA and undergoing metachronous liver surgery for another lesion were recruited ( = 9) during a 5-year period. Tumor and non-malignant liver tissue samples from six patients were investigated by whole transcriptome sequencing and tandem-mass spectrometry, characterizing naturally presented HLA ligands. Tumor antigen-derived HLA-restricted peptides were selected by different predefined approaches. Further, candidate HLA ligands were manually curated. Peripheral blood mononuclear cells were stimulated with epitope candidate peptides, and functional T cell responses were assessed by intracellular cytokine staining. Immunohistochemical markers were additionally investigated in surgically resected mCRC from patients treated with ( = 9) or without RFA ( = 7). In all six investigated patients, either induced immune responses and/or pre-existing T cell immunity against the selected targets were observed. Multi-cytokine responses were directed against known tumor antigens such as cyclin D1 but also against a (predicted) mutation contained in ERBB3. Immunohistochemistry did not show a relevant influx of immune cells into distant malignant lesions after RFA treatment ( = 9) as compared to the surgery only mCRC group ( = 7). Using an individualized approach for target selection, RFA induced and/or boosted T cell responses specific for individual tumor antigens were more frequently detectable as compared to previously published observations with well-characterized tumor antigens. However, the witnessed modest RFA-induced immunological effects alone may not be sufficient for the rejection of established tumors. Therefore, these findings warrant further clinical investigation including the assessment of RFA combination therapies e.g., with immune stimulatory agents, cancer vaccination, and/or immune checkpoint inhibitors.
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http://dx.doi.org/10.3389/fimmu.2019.02526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877671PMC
November 2020

SPARC dependent collagen deposition and gemcitabine delivery in a genetically engineered mouse model of pancreas cancer.

EBioMedicine 2019 Oct 6;48:161-168. Epub 2019 Oct 6.

Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Göttingen, Germany. Electronic address:

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterised by extensive matrix deposition that has been implicated in impaired drug delivery and therapeutic resistance. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates collagen deposition and is highly upregulated in the activated stroma subtype with poor prognosis in PDAC patients.

Methods: Kras;p48-Cre;SPARC (KC-SPARC) and Kras;p48-Cre;SPARC (KC-SPARC) were generated and analysed at different stages of carcinogenesis by histological grading, immunohistochemistry for epithelial and stromal markers, survival and preclinical analysis. Pharmacokinetic and pharmacodynamic studies were conducted by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunohistochemistry following gemcitabine treatment (100 mg/kg) in vivo.

Findings: Global genetic ablation of SPARC in a Kras driven mouse model resulted in significantly reduced overall and mature collagen deposition around early and advanced pancreatic intraepithelial neoplasia (PanIN) lesions and in invasive PDAC (p < .001). However, detailed pathological scoring and molecular analysis showed no effects on PanIN to PDAC progression, vessel density (CD31), tumour incidence, grading or metastatic frequency. Despite comparable tumour kinetics, ablation of SPARC resulted in a significantly shortened survival in KC-SPARC mice (280 days versus 485 days, p < .03, log-rank-test). Using LC-MS/MS, we show that SPARC dependent collagen deposition does not affect intratumoural gemcitabine accumulation or immediate therapeutic response in tumour bearing KC-SPARC and KC-SPARCmice.

Interpretation: Global SPARC ablation reduces the collagen-rich microenvironment in murine PDAC. Moreover, global SPARC depletion did not affect tumour growth kinetics, grading or metastatic frequency. Notably, the dense-collagen matrix did not restrict access of gemcitabine to the tumour. These findings may have direct translational implications in clinical trial design.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838446PMC
October 2019

Clonally related duodenal-type follicular lymphoma and follicular neoplasia.

Haematologica 2019 11 1;104(11):e537-e539. Epub 2019 Aug 1.

Institute of Pathology and Neuropathology, University Hospital Tübingen and Comprehensive Cancer Center

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http://dx.doi.org/10.3324/haematol.2019.226142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821625PMC
November 2019

The Oncolytic Herpes Simplex Virus Talimogene Laherparepvec Shows Promising Efficacy in Neuroendocrine Cancer Cell Lines.

Neuroendocrinology 2019 13;109(4):346-361. Epub 2019 Jun 13.

Department of Clinical Tumor Biology, University Hospital, University of Tübingen, Tübingen, Germany,

Metastatic neuroendocrine cancer still constitutes a palliative situation, lacking promising treatment options. Oncolytic virotherapy, a novel type of virus-based immunotherapy, lyses tumor cells using genetically engineered viruses thereby activating the immune system to induce an optimized antitumor response which could bring down tumor masses to a stage of minimal residual tumor disease. The oncolytic vector talimogene laherparepvec (T-VEC, herpes simplex virus [HSV] type 1) has already shown excellent safety profiles in clinical studies and has become the first ever FDA/EMA-approved oncolytic virus (OV). This work presents a first preclinical assessment of this state-of-the-art OV, using a panel of human neuroendocrine tumor/neuroendocrine carcinoma (NET/NEC) cell lines. Cytotoxicity, transgene expression, and viral replication patterns were studied. Furthermore, the antiproliferative activity was compared to the one of mTOR inhibitor Everolimus and also interactions between the OV and Everolimus were evaluated. Moreover, virostatic effects of ganciclovir (GCV) on replication of T-VEC were assessed and electron microscopic pictures were taken to comprehend viral envelopment and details of the replication cycle of T-VEC in human neuroendocrine cancer. It could be shown that T-VEC infects, replicates in, and lyses human NET/NEC cells exhibiting high oncolytic efficiencies already at quite low virus concentrations. Interestingly, Everolimus was not found to have any relevant impact on rates of viral replication, but no additive effects could be proved using a combinatorial therapy regimen. On the other hand, GCV was shown to be able to limit replication of T-VEC, thus establishing an important safety feature for future treatments of NET/NEC patients. Taken together, T-VEC opens up a promising novel treatment option for NET/NEC patients, warranting its further preclinical and clinical development.
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http://dx.doi.org/10.1159/000500159DOI Listing
May 2020

Contrast-enhanced imaging in hepatic epithelioid hemangioendothelioma: retrospective study of 10 patients.

Z Gastroenterol 2019 Jun 15;57(6):753-766. Epub 2019 Apr 15.

Department of Internal Medicine 1, University of Tuebingen, Tuebingen, Germany.

Purpose:  The purpose of this study was to analyze imaging findings in hepatic epithelioid hemangioendothelioma (HEHE) with a particular focus on contrast-enhanced ultrasound (CEUS).

Materials And Methods:  This retrospective multicenter study included 10 patients with histologically proven HEHE from 5 European centers. All existing ultrasound images/videos were independently analyzed by 2 experienced examiners (DEGUM level III, internal medicine) using a standardized evaluation form. Patterns of contrast enhancement were correlated with computed tomography (CT), magnetic resonance imaging (MRI), and pathological findings.

Results:  B-mode ultrasound, CEUS, CT, and MRI were performed in 90 %, 70 %, 100 %, and 90 % of patients, respectively. Multifocal HEHE could be observed in 80 % with affection of both liver lobes in 70 %. Analysis of CEUS revealed 3 characteristic patterns that correlated well with contrast patterns on CT and MRI: (a) peripheral nodular enhancement with centripetal fill-in and wash-out in the portal venous and late venous phase (PVLP), (b) rim-like arterial enhancement with wash-out in the PVLP, and (c) inversed target sign with/without wash-out in the PVLP. Wash-out in the PVLP as a sign suspicious of malignancy was observed in 6/7 patients (85.7 %).

Conclusions:  Knowledge of the different characteristic CEUS patterns is of importance to avoid misdiagnosis due to resemblance of patterns A and B to the much more common focal liver lesions hemangioma and intrahepatic cholangiocarcinoma. Of importance, sonographers should be aware that wash-out in the PVLP might be absent in some patients.
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http://dx.doi.org/10.1055/a-0886-0081DOI Listing
June 2019

Increased SLC38A4 Amino Acid Transporter Expression in Human Pancreatic α-Cells After Glucagon Receptor Inhibition.

Endocrinology 2019 05;160(5):979-988

Regeneron Pharmaceuticals, Inc., Tarrytown, New York.

Plasma amino acids and their transporters constitute an important part of the feedback loop between the liver and pancreatic α-cell function, and glucagon regulates hepatic amino acid turnover. Disruption of hepatic glucagon receptor action activates the loop and results in high plasma amino acids and hypersecretion of glucagon associated with α-cell hyperplasia. In the present study, we report a technique to rescue implanted human pancreatic islets from the mouse kidney capsule. Using this model, we have demonstrated that expression of the amino acid transporter SLC38A4 increases in α-cells after administration of a glucagon receptor blocking antibody. The increase in SLC38A4 expression and associated α-cell proliferation was dependent on mechanistic target of rapamycin pathway. We confirmed increased α-cell proliferation and expression of SLC38A4 in pancreas sections from patients with glucagon cell hyperplasia and neoplasia (GCHN) with loss-of-function mutations in the glucagon receptor. Collectively, using a technique to rescue implanted human islets from the kidney capsule in mice and pancreas sections from patients with GCHN, we found that expression of SLC38A4 was increased under conditions of disrupted glucagon receptor signaling. These data provide support for the existence of a liver-human α-cell endocrine feedback loop.
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http://dx.doi.org/10.1210/en.2019-00022DOI Listing
May 2019

Author Correction: Necroptosis microenvironment directs lineage commitment in liver cancer.

Nature 2018 12;564(7735):E9

Department of Internal Medicine VIII, University Hospital Tuebingen, Tuebingen, Germany.

In this Article, the pCaMIN construct consisted of 'mouse MYC and mouse Nras' instead of 'mouse Myc and human NRAS; and the pCAMIA construct consisted of 'mouse Myc and human AKT1' instead of 'mouse Myc and Akt1' this has been corrected online.
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http://dx.doi.org/10.1038/s41586-018-0723-9DOI Listing
December 2018

The antioxidant transcription factor Nrf2 modulates the stress response and phenotype of malignant as well as premalignant pancreatic ductal epithelial cells by inducing expression of the ATF3 splicing variant ΔZip2.

Oncogene 2019 02 9;38(9):1461-1476. Epub 2018 Oct 9.

Laboratory of Molecular Gastroenterology & Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany.

Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the worst survival rates of all cancers. While death rates show declining trends in the majority of cancers, PDAC registers rising rates. Based on the recently described crosstalk between TGF-β1 and Nrf2 in the PDAC development, the involvement of ATF3 and its splice variant ΔZip2 in TGF-β1- and Nrf2-driven pancreatic tumorigenesis was investigated. As demonstrated here, PDAC (Panc1, T3M4) cells or premalignant H6c7 pancreatic ductal epithelial cells differentially express ΔZip2- and ATF3, relating to stronger Nrf2 activity seen in Panc1 cells and TGF-ß1 activity in T3M4 or H6c7 cells, respectively. Treatment with the electrophile/oxidative stress inducer tBHQ or the cytostatic drug gemcitabine strongly elevated ΔZip2 expression in a Nrf2-dependent fashion. The differential expression of ATF3 and ΔZip2 in response to Nrf2 and TGF-ß1 relates to differential ATF3-gene promoter usage, giving rise of distinct splice variants. Nrf2-dependent ΔZip2 expression confers resistance against gemcitabine-induced apoptosis, only partially relating to interference with ATF3 and its proapoptotic activity, e.g., through CHOP-expression. In fact, ΔZip2 autonomously activates expression of cIAP anti-apoptotic proteins. Moreover, ΔZip2 favors and ATF3 suppresses growth and clonal expansion of PDAC cells, again partially independent of each other. Using a Panc1 tumor xenograft model in SCID-beige mice, the opposite activities of ATF3 and ΔZip2 on tumor-growth and chemoresistance were verified in vivo. Immunohistochemical analyses confirmed ΔZip2 and Nrf2 coexpression in cancerous and PanIN structures of human PDAC and chronic pancreatitis tissues, respectively, which to some extent was reciprocal to ATF3 expression. It is concluded that depending on selective ATF3-gene promoter usage by Nrf2, the ΔZip2 expression is induced in response to electrophile/oxidative (here through tBHQ) and xenobiotic (here through gemcitabine) stress, providing apoptosis protection and growth advantages to pancreatic ductal epithelial cells. This condition may substantially add to pancreatic carcinogenesis driven by chronic inflammation.
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http://dx.doi.org/10.1038/s41388-018-0518-3DOI Listing
February 2019

Necroptosis microenvironment directs lineage commitment in liver cancer.

Nature 2018 10 12;562(7725):69-75. Epub 2018 Sep 12.

Department of Internal Medicine VIII, University Hospital Tuebingen, Tuebingen, Germany.

Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and responses to therapy. However, the regulatory molecules and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here we show that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumorigenesis. Whereas a necroptosis-associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes containing identical oncogenic drivers give rise to HCC if they are surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of mouse HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage-commitment factors, a function that is conserved in humans. Together, our results provide insight into lineage commitment in liver tumorigenesis, and explain molecularly why common liver-damaging risk factors can lead to either HCC or ICC.
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http://dx.doi.org/10.1038/s41586-018-0519-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111790PMC
October 2018

The Expression of Aldolase B in Islets Is Negatively Associated With Insulin Secretion in Humans.

J Clin Endocrinol Metab 2018 12;103(12):4373-4383

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University of Tuebingen, Tübingen, Germany.

Context: Reduced β-cell mass, impaired islet function, and dedifferentiation are considered causal to development of hyperglycemia and type 2 diabetes. In human cohort studies, changes of islet cell-specific expression patterns have been associated with diabetes but not directly with in vivo insulin secretion.

Objective: This study investigates alterations of islet gene expression and corresponding gene variants in the context of in vivo glycemic traits from the same patients.

Methods: Fasting blood was collected before surgery, and pancreatic tissue was frozen after resection from 18 patients undergoing pancreatectomy. Islet tissue was isolated by laser capture microdissection. Islet transcriptome was analyzed using microarray and quantitative RT-PCR. Proteins were examined by immunohistochemistry and western blotting. The association of gene variants with insulin secretion was investigated with oral glucose tolerance test (OGTT)-derived insulin secretion measured in a large cohort of subjects at increased risk of type 2 diabetes and with hyperglycemic clamp in a subset.

Results: Differential gene expression between islets from normoglycemic and hyperglycemic patients was prominent for the glycolytic enzyme ALDOB and the obesity-associated gene FAIM2. The mRNA levels of both genes correlated negatively with insulin secretion and positively with HbA1c. Islets of hyperglycemic patients displayed increased ALDOB immunoreactivity in insulin-positive cells, whereas α- and δ-cells were negative. Exposure of isolated islets to hyperglycemia augmented ALDOB expression. The minor allele of the ALDOB variant rs550915 associated with significantly higher levels of C-peptide and insulin during OGTT and hyperglycemic clamp, respectively.

Conclusion: Our analyses suggest that increased ALDOB expression in human islets is associated with lower insulin secretion.
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http://dx.doi.org/10.1210/jc.2018-00791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915830PMC
December 2018

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Gut 2019 06 1;68(6):1099-1107. Epub 2018 Aug 1.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Objective: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.

Design: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.

Results: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).

Conclusion: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
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http://dx.doi.org/10.1136/gutjnl-2018-316228DOI Listing
June 2019

Impact of surgery in patients with metastatic soft tissue sarcoma: A monocentric retrospective analysis.

J Surg Oncol 2018 Jul 28;118(1):167-176. Epub 2018 Jun 28.

Department of Medical Oncology, Hematology, Immunology, Rheumatology and Pulmonology, University of Tübingen, Tübingen, Germany.

Background And Objectives: The role of local surgical procedures in patients with metastatic soft tissue sarcoma is still undefined. Few retrospective studies have reported survival benefits for patients with pulmonary metastases after complete surgical resection. Treatment decisions are therefore mainly based on personal experiences rather than on reproducible knowledge.

Method: A total of 237 patients with metastatic sarcoma, treated between 1982 and 2015 at the University Hospital Tuebingen, Germany, were eligible for inclusion. Out of the 237 screened patients, 102 patients underwent at least one metastasectomy. Overall survival was defined as the primary endpoint in this study. For association of non-linear relationship to the endpoint, significant prognostic factors were included into a recursive partitioning model. A subgroup analysis for long-term survivors was also performed.

Results: The median overall survival was 64 months. The 3-, 5-, 10-, and 20-years overall survival rates were 70.7%, 50.3%, 24.7%, and 14.8%, respectively. The number of resections and the progression-free intervals were independent prognostic factors in three statistical models.

Conclusion: Repeated resections of metastases from different localizations are a strong predictor for prolonged survival. We suggest that the progression-free interval after metastasectomy should be considered as a predictive factor for benefit from further surgery.
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http://dx.doi.org/10.1002/jso.25115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668010PMC
July 2018
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