Publications by authors named "Thomas Seufferlein"

268 Publications

Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation.

Commun Biol 2021 Nov 17;4(1):1298. Epub 2021 Nov 17.

Institute for Computational Genomics, RWTH Aachen University Medical School, Aachen, Germany.

Cell type specification during pancreatic development is tightly controlled by a transcriptional and epigenetic network. The precise role of most transcription factors, however, has been only described in mice. To convey such concepts to human pancreatic development, alternative model systems such as pancreatic in vitro differentiation of human pluripotent stem cells can be employed. Here, we analyzed stage-specific RNA-, ChIP-, and ATAC-sequencing data to dissect transcriptional and regulatory mechanisms during pancreatic development. Transcriptome and open chromatin maps of pancreatic differentiation from human pluripotent stem cells provide a stage-specific pattern of known pancreatic transcription factors and indicate ONECUT1 as a crucial fate regulator in pancreas progenitors. Moreover, our data suggest that ONECUT1 is also involved in preparing pancreatic progenitors for later endocrine specification. The dissection of the transcriptional and regulatory circuitry revealed an important role for ONECUT1 within such network and will serve as resource to study human development and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-021-02818-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599846PMC
November 2021

A complex intervention to promote prevention of delirium in older adults by targeting caregiver's participation during and after hospital discharge - study protocol of the TRAnsport and DElirium in older people (TRADE) project.

BMC Geriatr 2021 11 16;21(1):646. Epub 2021 Nov 16.

Agaplesion Bethesda Clinic Ulm, Zollernring 26, 89073, Ulm, Germany.

Background: Among potentially modifiable risk factors for delirium, transfers between wards, hospitals and other facilities have been mentioned with low evidence. TRADE (TRAnsport and DElirium in older people) was set up to investigate i) the impact of transfer and/or discharge on the onset of delirium in older adults and ii) feasibility and acceptance of a developed complex intervention targeting caregiver's participation during and after hospital discharge or transfer on cognition and the onset of delirium in older adults.

Methods: The study is designed according to the guidelines of the UK Medical Research Council (MRC) for development and evaluation of complex interventions and comprises two steps: development and feasibility/piloting. The development phase includes i) a multicenter observational prospective cohort study to assess delirium incidence and cognitive decline associated with transfer and discharge, ii) a systematic review of the literature, iii) stakeholder focus group interviews and iv) an expert workshop followed by a Delphi survey. Based on this information, a complex intervention to better and systematically involve family caregivers in discharge and transport was developed. The intervention will be tested in a pilot study using a stepped wedge design with a detailed process and health economic evaluation. The study is conducted at four acute care hospitals in southwest Germany. Primary endpoints are the delirium incidence and cognitive function. Secondary endpoints include prevalence of caregiver companionship, functional decline, cost and cost effectiveness, quality of discharge management and quality of admission management in admitting hospitals or nursing homes. Data will be collected prior to discharge as well as after 3, 7 and 90 days.

Discussion: TRADE will help to evaluate transfer and discharge as a possible risk factor for delirium. In addition, TRADE evaluates the impact and modifiability of caregiver's participation during patient's transfer or discharge on delirium incidence and cognitive decline providing the foundation for a confirmatory implementation study.

Trial Registration: DRKS (Deutsches Register für klinische Studien) DRKS00017828 . Registered on 17th September 2019. Retrospectively registered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12877-021-02585-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594294PMC
November 2021

[Multimodal, interdisciplinary therapeutic concepts for liver metastasized colorectal cancer].

Dtsch Med Wochenschr 2021 Nov 5;146(22):1468-1477. Epub 2021 Nov 5.

About half of all patients with colorectal carcinoma (CRC) develop metastases mainly in the liver during the course of their disease. Metastatic disease is associated with a low 5-year overall survival rate of only 5-7 %, particularly when there is no possibility of local treatment. However, if there is an opportunity to resect the metastases, especially isolated liver metastases, the chance of long-term survival is approximately 15-27 % after both primary resection or secondary resection after neoadjuvant pretreatment. Overall, long-term survival of patients with metastatic CRC has improved significantly in recent years due to a combination of modern systemic therapies, advanced liver surgery and local ablative procedures.Of note, for the vast majority of patients, metastatic resection does not mean cure, but a significant prolongation of overall survival with a good quality of life. Chemotherapy-free intervals after metastasis resection maintain quality of life and can help to reduce toxicity.In this review, we would like to present the "toolbox" for the multidisciplinary treatment of metastatic CRC and give recommendations how the individual modalities should be optimally used, considering tumor-specific characteristics and patient preferences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1391-5273DOI Listing
November 2021

COVID-19 and digestive health: Implications for prevention, care and the use of COVID-19 vaccines in vulnerable patients.

United European Gastroenterol J 2021 11 30;9(9):1091-1095. Epub 2021 Oct 30.

School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ueg2.12173DOI Listing
November 2021

Small Extracellular Vesicles Propagate the Inflammatory Response After Trauma.

Adv Sci (Weinh) 2021 Oct 28:e2102381. Epub 2021 Oct 28.

Department of Internal Medicine I, University Hospital Ulm, Albert-Einstein-Allee 23, Ulm, 89081, Germany.

Trauma is the leading cause of death in individuals under 44 years of age. Thorax trauma (TxT) is strongly associated with trauma-related death, an unbalanced innate immune response, sepsis, acute respiratory distress syndrome, and multiple organ dysfunction. It is shown that different in vivo traumata, such as TxT or an in vitro polytrauma cytokine cocktail trigger secretion of small extracellular nanovesicles (sEVs) from endothelial cells with pro-inflammatory cargo. These sEVs transfer transcripts for ICAM-1, VCAM-1, E-selectin, and cytokines to systemically activate the endothelium, facilitate neutrophil-endothelium interactions, and destabilize barrier integrity. Inhibition of sEV-release after TxT in mice ameliorates local as well as systemic inflammation, neutrophil infiltration, and distant organ damage in kidneys (acute kidney injury, AKI). Vice versa, injection of TxT-plasma-sEVs into healthy animals is sufficient to trigger pulmonary and systemic inflammation as well as AKI. Accordingly, increased sEV concentrations and transfer of similar cargos are observed in polytrauma patients, suggesting a fundamental pathophysiological mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.202102381DOI Listing
October 2021

-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome.

Cancers (Basel) 2021 Oct 13;13(20). Epub 2021 Oct 13.

Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany.

Patient-derived induced pluripotent stem cells (iPSCs) provide a unique platform to study hereditary disorders and predisposition syndromes by resembling germline mutations of affected individuals and by their potential to differentiate into nearly every cell type of the human body. We employed plucked human hair from two siblings with a family history of cancer carrying a pathogenic variant, P16-p.G101W/P14-p.R115L, to generate patient-specific iPSCs in a cancer-prone ancestry for downstream analytics. The differentiation capacity to pancreatic progenitors and to pancreatic duct-like organoids (PDLOs) according to a recently developed protocol remained unaffected. Upon inducible expression of using a transposon system in CDKN2A-mutated PDLOs, we revealed structural and molecular changes in vitro, including disturbed polarity and epithelial-to-mesenchymal (EMT) transition. -mutated PDLO xenotransplants formed either a high-grade precancer lesion or a partially dedifferentiated PDAC-like tumor. Intriguingly, P14/P53/P21 and P16/RB cell-cycle checkpoint controls have been only partly overcome in these grafts, thereby still restricting the tumorous growth. Hereby, we provide a model for hereditary human pancreatic cancer that enables dissection of tumor initiation and early development starting from patient-specific -mutated pluripotent stem cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13205139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533699PMC
October 2021

Systemic Therapy for Metastatic Pancreatic Cancer.

Curr Treat Options Oncol 2021 10 19;22(11):106. Epub 2021 Oct 19.

Department of Internal Medicine I, Ulm University Hospital, Albert-Einstein-Allee 23, 89081, Ulm, Germany.

Opinion Statement: Pancreatic cancer is mainly diagnosed at an advanced, often metastatic stage and still has a poor prognosis. Over the last decades, chemotherapy of metastatic pancreatic cancer (mPDAC) has proven to be superior to a mere supportive treatment with respect to both survival and quality of life. Recently, even sequential treatment of mPDAC could be established. Options for first-line treatment are combination chemotherapy regimens such as FOLFIRINOX and gemcitabine plus nab-paclitaxel when the performance status of the patient is good. For patients with poorer performance status, gemcitabine single-agent treatment is a valid option. Recently, the PARP inhibitor olaparib has been demonstrated to improve progression-free survival when used as a maintenance treatment in the subgroup of patients with mPDAC and a BRCA1/-2 germ line mutation having received at least 16 weeks of platinum-based chemotherapy. This group of patients also benefits from platinum-based chemotherapy combinations. Therefore, the BRCA1/-2 stats should be examined early in patients with mPDAC even when the occurrence of these mutations is only about 5% in the general Caucasian population. After the failure of first-line treatment, patients should be offered a second-line treatment if their ECOG permits further treatment. Here, the combination of 5-FU/FA plus nanoliposomal irinotecan has shown to be superior to 5-FU/FA alone with respect to overall survival. Immune checkpoint inhibitors like PD1/PD-L1 mAbs are particularly efficacious in tumors with high microsatellite instability (MSI-h). Limited data in mPDACs shows that only a part of the already small subgroup of MSI-H mPDACs (frequency about 1%) appears to benefit substantially from a checkpoint inhibitor treatment. The identification of further subgroups, e.g., tumors with DNA damage repair deficiency, gene fusions, as well as novel approaches such as tumor-organoid-informed treatment decisions, may further improve therapeutic efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11864-021-00895-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526424PMC
October 2021

Mutations and variants of ONECUT1 in diabetes.

Nat Med 2021 Nov 18;27(11):1928-1940. Epub 2021 Oct 18.

Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, Commissariat à l'Energie Atomique, Université Paris-Saclay, Evry, France.

Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-021-01502-7DOI Listing
November 2021

Intestinal organoids in co-culture: Redefining the boundaries of gut mucosa ex vivo modeling.

Am J Physiol Gastrointest Liver Physiol 2021 10 13. Epub 2021 Oct 13.

Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.

All-time preservation of an intact mucosal barrier is crucial to ensuring intestinal homeostasis and, hence, the organism's overall health maintenance. This complex process relies on an equilibrated signaling system between the intestinal epithelium and numerous cell populations inhabiting the gut mucosa. Any perturbations of this delicate crosstalk, particularly regarding the immune cell compartment and microbiota, may sustainably debilitate the intestinal barrier function. As a final joint event, a critical rise in epithelial permeability facilitates the exposure of submucosal immunity to microbial antigens, resulting in uncontrolled inflammation, collateral tissue destruction and dysbiosis. Organoid-derived intestinal co-culture models have established themselves as convenient tools to re-enact such pathophysiological events, explore interactions between selected cell populations and assess their roles with a central focus on intestinal barrier recovery and stabilization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpgi.00043.2021DOI Listing
October 2021

Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication.

Cancers (Basel) 2021 Sep 28;13(19). Epub 2021 Sep 28.

Department for Internal Medicine, University Clinic Ulm, 89081 Ulm, Germany.

Even with all recent advances in cancer therapy, pancreatic cancer still has a dismal 5-year survival rate of less than 7%. The most prevalent tumor subtype is pancreatic ductal adenocarcinoma (PDAC). PDACs display an extensive crosstalk with their tumor microenvironment (TME), e.g., pancreatic stellate cells, but also immune cells to regulate tumor growth, immune evasion, and metastasis. In addition to crosstalk in the local TME, PDACs were shown to induce the formation of pre-metastatic niches in different organs. Recent advances have attributed many of these interactions to intercellular communication by small extracellular vesicles (sEVs, exosomes). These nanovesicles are derived of endo-lysosomal structures (multivesicular bodies) with a size range of 30-150 nm. sEVs carry various bioactive cargos, such as proteins, lipids, DNA, mRNA, or miRNAs and act in an autocrine or paracrine fashion to educate recipient cells. In addition to tumor formation, progression, and metastasis, sEVs were described as potent biomarker platforms for diagnosis and prognosis of PDAC. Advances in sEV engineering have further indicated that sEVs might once be used as effective drug carriers. Thus, extensive sEV-based communication and applications as platform for biomarker analysis or vehicles for treatment suggest a major impact of sEVs in future PDAC research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13194844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508300PMC
September 2021

Small Extracellular Vesicles and Metastasis-Blame the Messenger.

Cancers (Basel) 2021 Aug 30;13(17). Epub 2021 Aug 30.

Department for Internal Medicine, University Clinic Ulm, 89081 Ulm, Germany.

Cancer is a complex disease, driven by genetic defects and environmental cues. Systemic dissemination of cancer cells by metastasis is generally associated with poor prognosis and is responsible for more than 90% of cancer deaths. Metastasis is thought to follow a sequence of events, starting with loss of epithelial features, detachment of tumor cells, basement membrane breakdown, migration, intravasation and survival in the circulation. At suitable distant niches, tumor cells reattach, extravasate and establish themselves by proliferating and attracting vascularization to fuel metastatic growth. These processes are facilitated by extensive cross-communication of tumor cells with cells in the primary tumor microenvironment (TME) as well as at distant pre-metastatic niches. A vital part of this communication network are small extracellular vesicles (sEVs, exosomes) with a size of 30-150 nm. Tumor-derived sEVs educate recipient cells with bioactive cargos, such as proteins, and in particular, major nucleic acid classes, to drive tumor growth, cell motility, angiogenesis, immune evasion and formation of pre-metastatic niches. Circulating sEVs are also utilized as biomarker platforms for diagnosis and prognosis. This review discusses how tumor cells facilitate progression through the metastatic cascade by employing sEV-based communication and evaluates their role as biomarkers and vehicles for drug delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13174380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431296PMC
August 2021

Targeting DNA Damage Repair Mechanisms in Pancreas Cancer.

Cancers (Basel) 2021 Aug 24;13(17). Epub 2021 Aug 24.

Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany.

Impaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, , , , , and . Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline -mutated PDAC. Extending this outcome to the significant proportion of human PDACs with somatic or germline mutations in DDR genes beyond might be beneficial, but there is a lack of data, and consequently, no clear recommendations are provided in the field. Therefore, an expert panel was invited by the European Society of Digestive Oncology (ESDO) to assess the current knowledge and significance of DDR as a target in PDAC treatment. The aim of this virtual, international expert meeting was to elaborate a set of consensus recommendations on testing, diagnosis and treatment of PDAC patients with alterations in DDR pathways. Ahead of the meeting, experts completed a 27-question survey evaluating the key issues. The final recommendations herein should aid in facilitating clinical practice decisions on the management of DDR-deficient PDAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13174259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428219PMC
August 2021

The Selective 5-HT1A Agonist SR57746A Protects Intestinal Epithelial Cells and Enteric Glia Cells and Promotes Mucosal Recovery in Experimental Colitis.

Inflamm Bowel Dis 2021 Aug 21. Epub 2021 Aug 21.

Department of Internal Medicine I, University of Ulm, Ulm, Germany.

Background: Neurotrophic growth factors can stabilize the intestinal barrier by preventing the apoptosis of enteric glial cells (EGCs) and enterocytes. We reasoned that a selective 5-HT1A receptor agonist may have neuroprotective properties in the gut and that topical application of SR57746A might be an effective treatment strategy in inflammatory bowel disease (IBD).

Methods: The therapeutic potential of 5-HT1A receptor agonist SR57746A in IBD was evaluated in vitro (nontransformed NCM460 colonic epithelial cells, SW480 colorectal carcinoma cells) and in vivo (murine dextran sulfate sodium [DSS] colitis and CD4-T-cell transfer colitis). In vitro, we analyzed the effect of SR57746A on apoptosis in intestinal epithelial cells (IECs) and EGCs, and upon proliferation, migration, and intracellular signaling in IECs. In vivo, the effect of topical application of SR57746 on disease activity and on histological and endoscopic findings was compared with intraperitoneal infliximab and placebo, respectively.

Results: The SR57746A activates PI3-K/AKT- and ERK-signaling in IECs. Depending on ERK- and AKT activation, SR57746A potently prevents apoptosis of IECs without inducing proliferation or migration in these cells. Moreover, SR57746A prevented apoptosis in EGCs in vitro. Topical SR57746A treatment significantly reduced mucosal injury in 2 experimental murine colitis models and was as effective as intraperitoneal infliximab treatment.

Conclusions: Treatment with SR57746A prevents inflammatory cell damage and apoptosis in IECs and EGCs, similar to the neurotrophic effects of EGCs on IECs. Topical treatment with SR57746A could be a candidate for clinical evaluation in the treatment of IBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ibd/izab191DOI Listing
August 2021

Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration.

Adv Sci (Weinh) 2021 07 13;8(14):2100626. Epub 2021 May 13.

Department of Internal Medicine I University Hospital Ulm Albert-Einstein Allee 23 89081 Ulm Germany.

Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, -null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5 liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical-Wnt-signaling in -null animals. This results in reduced expression of the Hedgehog repressor and increased Hedgehog-signaling activity upon loss. Collectively, these data reveal as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical-Wnt-, and Hedgehog-signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.202100626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292873PMC
July 2021

[COVID-19 pandemic-related burden and SARS-CoV-2 prevalence in care facilities].

Z Gerontol Geriatr 2021 Aug 14;54(5):463-470. Epub 2021 Jul 14.

Klinik für Innere Medizin 1, Universitätsklinikum Ulm, Ulm, Deutschland.

Background: Care facilities are particularly challenged by the COVID-19 pandemic. Besides others this includes human and structural resources.

Objective: This cross-sectional study evaluated the occurrence of infections, psychosocial stress and the different strategies to handle the COVID-19 pandemic in care facilities.

Material And Methods: Data collection took place in 7 care facilities in Baden-Württemberg, Germany between 17 July and 25 August 2020. This included a SARS-CoV‑2 PCR and antibody testing and a questionnaire for residents and staff. Care facilities were questioned on interventions and preventive measures taken.

Results: Out of 829 SARS-CoV‑2 PCR tests all remained negative. Only 2 asymptomatic subjects had detectable SARS-CoV‑2 antibodies. All subjects (n = 6) with a history of positive PCR had no detectable antibodies. Healthcare workers were mainly worried about infecting family, friends and especially residents (54.4%) with less fear to infect themselves (27.2%). Individual stress caused by the COVID-19 pandemic: 17.1% exhaustion, 16% financial burden and 13.1% sleeping disorders. Coping strategies included a moderate increase of harmful behavior (+3.3% alcohol, +4.3% nicotine). This was relevantly more important in staff aged under 35 years (+13% alcohol, +12.7% nicotine). Women reported a 2.4% increased use of medication, 49.8% of respondents reduced their social contacts, 76.8% changed their individual hygiene behavior. Care facilities felt prepared to a limited extent for the challenges faced by the pandemic.

Conclusion: Even with a low prevalence of infections at the time of the survey the COVID-19 pandemic challenged care facilities at multiple levels. This should result in better preventive management and coping strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00391-021-01931-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278814PMC
August 2021

Single-cell-resolved differentiation of human induced pluripotent stem cells into pancreatic duct-like organoids on a microwell chip.

Nat Biomed Eng 2021 08 8;5(8):897-913. Epub 2021 Jul 8.

Helmholtz Pioneer Campus, Helmholtz Zentrum München, Neuherberg, Germany.

Creating in vitro models of diseases of the pancreatic ductal compartment requires a comprehensive understanding of the developmental trajectories of pancreas-specific cell types. Here we report the single-cell characterization of the differentiation of pancreatic duct-like organoids (PDLOs) from human induced pluripotent stem cells (hiPSCs) on a microwell chip that facilitates the uniform aggregation and chemical induction of hiPSC-derived pancreatic progenitors. Using time-resolved single-cell transcriptional profiling and immunofluorescence imaging of the forming PDLOs, we identified differentiation routes from pancreatic progenitors through ductal intermediates to two types of mature duct-like cells and a few non-ductal cell types. PDLO subpopulations expressed either mucins or the cystic fibrosis transmembrane conductance regulator, and resembled human adult duct cells. We also used the chip to uncover ductal markers relevant to pancreatic carcinogenesis, and to establish PDLO co-cultures with stellate cells, which allowed for the study of epithelial-mesenchymal signalling. The PDLO microsystem could be used to establish patient-specific pancreatic duct models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41551-021-00757-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611572PMC
August 2021

Telomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells.

Cancers (Basel) 2021 Jun 23;13(13). Epub 2021 Jun 23.

Department of Internal Medicine I, University Medical Centre Ulm, 89081 Ulm, Germany.

To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the "stemness" maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13133145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268125PMC
June 2021

Digitalization of adverse event management in oncology to improve treatment outcome-A prospective study protocol.

PLoS One 2021 4;16(6):e0252493. Epub 2021 Jun 4.

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

The occurrence of adverse events frequently accompanies tumor treatments. Side effects should be detected and treated as soon as possible to maintain the best possible treatment outcome. Besides the standard reporting system Common Terminology Criteria for Adverse Events (CTCAE), physicians have recognized the potential of patient-reporting systems. These are based on a more subjective description of current patient reporting symptoms. Patient-reported symptoms are essential to define the impact of a given treatment on the quality of life and the patient's wellbeing. They also act against an underreporting of side effects which are paramount to define the actual value of a treatment for the individual patient. Here, we present a study protocol for a clinical trial that assesses the potential of a smartphone application for CTCAE conform symptom reporting and tracking that is adjusted to the standard clinical reporting system rather than symptom oriented descriptive trial tools. The presented study will be implemented in two parts, both lasting over six months. The first part will assess the feasibility of the application with 30 patients non-randomly divided into three equally-sized age groups (<55years, 55-75years, >75years). In the second part 36 other patients will be randomly assigned to two groups, one reporting using the smartphone and one not. This prospective second part will compare the impact of smartphone reported adverse events regarding applied therapy doses and quality of life to those of patients receiving standard care. We aim for early detection and treatment of adverse events in oncological treatment to improve patients' safety and outcomes. For this purpose, we will capture frequent adverse events of chemotherapies, immunotherapies, or other targeted therapies with our smartphone application. The presented trial is registered at the U.S. National Library of Medicine ClinicalTrials.gov (NCT04493450) on July 30, 2020.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252493PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177479PMC
November 2021

A Prospective Feasibility Trial to Challenge Patient-Derived Pancreatic Cancer Organoids in Predicting Treatment Response.

Cancers (Basel) 2021 May 21;13(11). Epub 2021 May 21.

Department of Internal Medicine, University Hospital Ulm, 89081 Ulm, Germany.

Real-time isolation, propagation, and pharmacotyping of patient-derived pancreatic cancer organoids (PDOs) may enable treatment response prediction and personalization of pancreatic cancer (PC) therapy. In our methodology, PDOs are isolated from 54 patients with suspected or confirmed PC in the framework of a prospective feasibility trial. The drug response of single agents is determined by a viability assay. Areas under the curves (AUC) are clustered for each drug, and a prediction score is developed for combined regimens. Pharmacotyping profiles are obtained from 28 PDOs (efficacy 63.6%) after a median of 53 days (range 21-126 days). PDOs exhibit heterogeneous responses to the standard-of-care drugs, and are classified into high, intermediate, or low responder categories. Our developed prediction model allows a successful response prediction in treatment-naïve patients with an accuracy of 91.1% for first-line and 80.0% for second-line regimens, respectively. The power of prediction declines in pretreated patients (accuracy 40.0%), particularly with more than one prior line of chemotherapy. Progression-free survival (PFS) is significantly longer in previously treatment-naïve patients receiving a predicted tumor sensitive compared to a predicted tumor resistant regimen (mPFS 141 vs. 46 days; = 0.0048). In conclusion, generation and pharmacotyping of PDOs is feasible in clinical routine and may provide substantial benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13112539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196829PMC
May 2021

Trailblazing precision medicine in Europe: A joint view by Genomic Medicine Sweden and the Centers for Personalized Medicine, ZPM, in Germany.

Semin Cancer Biol 2021 May 24. Epub 2021 May 24.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Genomic Medicine Sweden (GMS), Sweden.

Over the last decades, rapid technological and scientific advances have led to a merge of molecular sciences and clinical medicine, resulting in a better understanding of disease mechanisms and the development of novel therapies that exploit specific molecular lesions or profiles driving disease. Precision oncology is here used as an example, illustrating the potential of precision/personalized medicine that also holds great promise in other medical fields. Real-world implementation can only be achieved by dedicated healthcare connected centers which amass and build up interdisciplinary expertise reflecting the complexity of precision medicine. Networks of such centers are ideally suited for a nation-wide outreach offering access to precision medicine to patients independent of their place of residence. Two of these multicentric initiatives, Genomic Medicine Sweden (GMS) and the Centers for Personalized Medicine (ZPM) initiative in Germany have teamed up to present and share their views on core concepts, potentials, challenges, and future developments in precision medicine. Together with other initiatives worldwide, GMS and ZPM aim at providing a robust and sustainable framework, covering all components from technology development to clinical trials, ethical and legal aspects as well as involvement of all relevant stakeholders, including patients and policymakers in the field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semcancer.2021.05.026DOI Listing
May 2021

CYP2D6 in the Brain: Potential Impact on Adverse Drug Reactions in the Central Nervous System-Results From the ADRED Study.

Front Pharmacol 2021 7;12:624104. Epub 2021 May 7.

Institute of Clinical Pharmacology, University Hospital of RWTH Aachen, Aachen, Germany.

Cytochrome P450 (CYP) 2D6 is a polymorphic enzyme expressed in the central nervous system (CNS), important in drug metabolism and with a potentially constitutive role in CNS function such as vigilance. This study aimed to analyze variability in CYP2D6 activity linked to vigilance-related adverse drug reactions (ADRs) in the CNS. A dataset of N = 2939 ADR cases of the prospective multicenter observational trial in emergency departments (EDs) (ADRED; trial registration: DRKS-ID: DRKS00008979) was analyzed. Dizziness as the most frequent reported CNS ADR symptom (12.7% of patients, = 372) related to vigilance was chosen as the outcome. The association of dizziness with CYP2D6 activity markers was analyzed. The number of CYP2D6 substrates taken, a CYP2D6 saturation score (no, moderate, and strong saturation), a CYP2D6 saturation/inhibition score (no, weak, moderate, and strong), and composed CYP2D6 activity using a genotyped subsample ( = 740) calculating additive effects of genotype and CYP2D6 saturation by drug exposure were used as CYP2D6 activity markers. Effects were compared to other frequent nonvigilance-related CNS ADR symptoms (syncope and headache). Secondary analyses were conducted to control for other ADR symptoms frequently associated with dizziness (syncope, nausea, and falls). The majority of all patients (64.5%, = 1895) took at least one drug metabolized by CYP2D6. Around a third took a CNS drug (32.5%, = 955). The chance to present with drug-related dizziness to the ED increased with each CYP2D6 substrate taken by OR 1.11 [1.01-1.23]. Presenting with drug-related dizziness was more likely with CYP2D6 saturation and saturation/inhibition (both OR 1.27 [1.00-1.60]). The composed CYP2D6 activity was positively associated with dizziness ( = 0.028), while poorer activity affected patients more often with dizziness as an ADR. In contrast, nonvigilance-related ADR symptoms such as syncope and nausea were not consistently significantly associated with CYP2D6 activity markers. This study shows an association between the number of CYP2D6 substrates, the predicted CYP2D6 activity, and the occurrence of dizziness as a CNS ADR symptom. As dizziness is a vigilance-related CNS symptom, patients with low CYP2D6 activity might be more vulnerable to drug-related dizziness. This study underlines the need for understanding individual drug metabolism activity and individual risks for ADRs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.624104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138470PMC
May 2021

Association between miRNA signatures in serum samples from epidermal growth factor inhibitor treated patients and skin toxicity.

Oncotarget 2021 May 11;12(10):982-995. Epub 2021 May 11.

Institute of Clinical Pharmacology, University Hospital of the RWTH Aachen, Aachen, Germany.

Objective: Epidermal growth factor receptor inhibitors (EGFRI) are used as targeted cancer therapy. On average 70% of patients treated with EGFRIs suffer from skin toxicity. Studies showed a correlation between overall survival and the appearance of a skin rash, which is used as a biomarker for therapy efficacy. Micro RNAs (miRNA) as tumor or resistance biomarkers for cancer therapy are also highly investigated. In our study, we searched for associations of miRNA expression profiles in serum, with the severity of skin rash, in order to identify tentative therapy predictive biomarkers.

Materials And Methods: Five candidate miRNAs were selected, based on an earlier next-generation-sequencing-experiment and after literature search. MiR-21, miR-31, miR-17, miR-106b and miR-520e were investigated in serum samples from patients ( = 254) treated with EGFRI. The quantitative expression of miRNA was tested for association with the occurrence/severity of the rash.

Results: In our cohort of patients treated with EGFR inhibiting monoclonal antibodies, miR-21 and miR-520e serum concentrations were negatively correlated with severity of skin rash (-value 0.000582 and 1.53e-07 linear-trend-test) whereas for miR-31, a positive correlation was observed (-value 9.01e-06 linear-trend-test).

Conclusions: This suggests that miR-21, miR-31 and miR-520e expression might be a treatment dependent marker for EGFRI induced skin rash.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121613PMC
May 2021

Patient Empowerment During the COVID-19 Pandemic by Ensuring Safe and Fast Communication of Test Results: Implementation and Performance of a Tracking System.

J Med Internet Res 2021 06 7;23(6):e27348. Epub 2021 Jun 7.

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

Background: Overcoming the COVID-19 crisis requires new ideas and strategies for online communication of personal medical information and patient empowerment. Rapid testing of a large number of subjects is essential for monitoring and delaying the spread of SARS-CoV-2 in order to mitigate the pandemic's consequences. People who do not know that they are infected may not stay in quarantine and, thus, risk infecting others. Unfortunately, the massive number of COVID-19 tests performed is challenging for both laboratories and the units that conduct throat swabs and communicate the results.

Objective: The goal of this study was to reduce the communication burden for health care professionals. We developed a secure and easy-to-use tracking system to report COVID-19 test results online that is simple to understand for the tested subjects as soon as these results become available. Instead of personal calls, the system updates the status and the results of the tests automatically. This aims to reduce the delay when informing testees about their results and, consequently, to slow down the virus spread.

Methods: The application in this study draws on an existing tracking tool. With this open-source and browser-based online tracking system, we aim to minimize the time required to inform the tested person and the testing units (eg, hospitals or the public health care system). The system can be integrated into the clinical workflow with very modest effort and avoids excessive load to telephone hotlines.

Results: The test statuses and results are published on a secured webpage, enabling regular status checks by patients; status checks are performed without the use of smartphones, which has some importance, as smartphone usage diminishes with age. Stress tests and statistics show the performance of our software. CTest is currently running at two university hospitals in Germany-University Hospital Ulm and University Hospital Tübingen-with thousands of tests being performed each week. Results show a mean number of 10 (SD 2.8) views per testee.

Conclusions: CTest runs independently of existing infrastructures, aims at straightforward integration, and aims for the safe transmission of information. The system is easy to use for testees. QR (Quick Response) code links allow for quick access to the test results. The mean number of views per entry indicates a reduced amount of time for both health care professionals and testees. The system is quite generic and can be extended and adapted to other communication tasks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/27348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189287PMC
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stem.2021.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461636PMC
June 2021

[Heidelberg Milestones Communication (HeiMeKOM) - Experiences, Best Practice Examples and Recommendations from the Final Symposium on January 30 and 31 in 2020].

Gesundheitswesen 2021 Apr 16. Epub 2021 Apr 16.

Abteilung Internistische Onkologie, Thoraxklinik am Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Mitglied des Deutschen Zentrums für Lungenforschung (DZL), Heidelberg, Deutschland.

The National Cancer Plan emphasises the importance of medical communication and calls for its integration into medical education and training. In this context, the Milestone Communication Approach meets the communicative challenges in dealing with lung cancer patients. Interprofessional tandems, consisting of doctors and nurses, conduct structured conversations at defined moments with patients and their relatives. The concept aims at shared decision making, continuity in the care of lung cancer patients and the early integration of palliative care. During the symposium on the Heidelberg Milestone Communication in January 2020, recommendations on the care situation of lung cancer patients in advanced stages were developed. In addition, the further adaptability of HeiMeKOM to other settings and hospitals and to other diseases was discussed as well as the possibility of implementing such a concept in standard care. This article presents the experiences, best practice examples and recommendations discussed during the symposium in order to enable their extrapolation to other similarly oriented projects. The long-term goal is to transfer the milestone concept to other hospital, primarily certified lung cancer centers, and to ensure permanent funding. For further dissemination of the concept and, above all, to have it established in standard care, health policy awareness and support are required in addition to the integration of the concept in competence catalogues of continuing medical and nursing education.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1375-0922DOI Listing
April 2021

A Follow-Up Study of a European IgG4-Related Disease Cohort Treated with Rituximab.

J Clin Med 2021 Mar 23;10(6). Epub 2021 Mar 23.

Department of Internal Medicine 1, Ulm University Hospital, 89081 Ulm, Germany.

Objectives: IgG4-related disease (IgG4-RD) is a chronic fibro-inflammatory disorder affecting virtually any organ. Type 1 autoimmune (type 1 AIP) is its pancreatic manifestation. To date, steroids are considered the first-line pancreatitis treatment. The CD20-binding antibody rituximab (RTX) appears a promising steroid-sparing therapy, although long-term data are lacking. We aimed to bridge this gap with a cohort of IgG4-RD patients treated with RTX and to assess the potential value of the Responder Index (RI) as a discriminatory score for disease activity.

Methods: We retrospectively evaluated 46 patients from a tertiary referral centre who were diagnosed with IgG4-RD and/or type 1 AIP according to the International Consensus Diagnostic Criteria or Unifying-AIP criteria between June 2006 and August 2019.

Results: Patients resembled previous cohorts in terms of characteristics, diagnosis, and therapeutic response. Thirteen of the 46 patients with IgG4-RD/type 1 AIP were treated with RTX pulse therapy due to relapse, adverse reactions to steroids, or high-risk constellations predicting a severe course of disease with multi-organ involvement. Median follow-up after diagnosis was 52 months for all subjects, and 71 months in IgG4-RD patients treated with RTX. While patients in the RTX group showed no significant response to an initial steroid pulse, clinical activity as measured by the RI significantly decreased in the short-term after RTX induction. Within 16 months, 61% of patients relapsed in the RTX group but responded well to re-induction. Clinical and laboratory parameters improved equally in response to RTX.

Conclusion: RTX therapy in patients with IgG4-RD is an effective and safe treatment to induce treatment response and possible long-term remission. Repeated RTX administration after 6-9 months may be of value in reducing the risk of relapse. The RI appears to be a reasonable index to assess disease activity and to identify patients with IgG4-related disease who may benefit from B-cell-depleting therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10061329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004657PMC
March 2021

SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas.

Nat Metab 2021 02 3;3(2):149-165. Epub 2021 Feb 3.

Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany.

Infection-related diabetes can arise as a result of virus-associated β-cell destruction. Clinical data suggest that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), impairs glucose homoeostasis, but experimental evidence that SARS-CoV-2 can infect pancreatic tissue has been lacking. In the present study, we show that SARS-CoV-2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human β-cells express viral entry proteins, and SARS-CoV-2 infects and replicates in cultured human islets. Infection is associated with morphological, transcriptional and functional changes, including reduced numbers of insulin-secretory granules in β-cells and impaired glucose-stimulated insulin secretion. In COVID-19 full-body postmortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the β-cell marker NKX6.1 and are in close proximity to the islets of Langerhans in all four patients investigated. Our data identify the human pancreas as a target of SARS-CoV-2 infection and suggest that β-cell infection could contribute to the metabolic dysregulation observed in patients with COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-021-00347-1DOI Listing
February 2021

RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer.

Cancer Res 2021 04 2;81(7):1758-1774. Epub 2021 Feb 2.

Department of Internal Medicine I, University Medical Centre Ulm, Ulm, Germany.

Pancreatic ductal adenocarcinoma (PDAC) still presents with a dismal prognosis despite intense research. Better understanding of cellular homeostasis could identify druggable targets to improve therapy. Here we propose RAD50-interacting protein 1 (RINT1) as an essential mediator of cellular homeostasis in PDAC. In a cohort of resected PDAC, low RINT1 protein expression correlated significantly with better survival. Accordingly, RINT1 depletion caused severe growth defects associated with accumulation of DNA double-strand breaks (DSB), G cell cycle arrest, disruption of Golgi-endoplasmic reticulum homeostasis, and cell death. Time-resolved transcriptomics corroborated by quantitative proteome and interactome analyses pointed toward defective SUMOylation after RINT1 loss, impairing nucleocytoplasmic transport and DSB response. Subcutaneous xenografts confirmed tumor response by RINT1 depletion, also resulting in a survival benefit when transferred to an orthotopic model. Primary human PDAC organoids licensed RINT1 relevance for cell viability. Taken together, our data indicate that RINT1 loss affects PDAC cell fate by disturbing SUMOylation pathways. Therefore, a RINT1 interference strategy may represent a new putative therapeutic approach. SIGNIFICANCE: These findings provide new insights into the aggressive behavior of PDAC, showing that RINT1 directly correlates with survival in patients with PDAC by disturbing the SUMOylation process, a crucial modification in carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-2633DOI Listing
April 2021
-->