Publications by authors named "R M Schmid"

2,137 Publications

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An Eschar-like souvenir from a journey to Colombia: Ecthyma gangrenosum as a differential diagnosis of tropical diseases in immunocompromised patients - a case report.

BMC Infect Dis 2021 Apr 12;21(1):344. Epub 2021 Apr 12.

German Center for Infection Research (DZIF), partner site Munich, Munich, Germany.

Background: Ecthyma gangrenosum (EG) is a cutaneous infectious disease characterized by eschar-like skin ulcers typically caused by Pseudomonas aeruginosa. Here, we report a case of relapsing EG in a patient who had returned from a trip to Colombia, thus establishing EG as an important differential diagnosis of tropical diseases, and demonstrating that even long-term antibiotic treatment can result in only partial remission of EG.

Case Presentation: A 77-year-old man with underlying chronic lymphocytic leukemia (CLL) on ibrutinib treatment was admitted because of a superinfected mosquito bite on the left ear and multiple partially necrotic skin lesions disseminated all over the entire body five days after returning from a trip to Colombia. The initial clinical suspicion of a tropical disease (leishmaniosis, systemic mycosis, or others) could not be confirmed. During the diagnostic workup, microbiological cultures of the skin biopsies and bronchoalveolar lavage revealed Pseudomonas aeruginosa, leading to a diagnosis of EG. Initial antibiotic treatment resulted in partial remission. However, the patient had to be re-admitted due to a relapse 3-4 weeks after the first episode. Finally, the patient was successfully treated with a combined approach consisting of antibiotics, recurrent surgical incisions, and administration of immunoglobulins.

Conclusions: In conclusion, EG should be considered as a differential diagnosis in immunosuppressed patients presenting with eschar-like skin ulcers. A combined treatment approach seems to be the best choice to achieve clinical cure and avoid relapse.
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http://dx.doi.org/10.1186/s12879-021-05998-9DOI Listing
April 2021

Impact of DNA repair and reactive oxygen species levels on radioresistance in pancreatic cancer.

Radiother Oncol 2021 Apr 8. Epub 2021 Apr 8.

Institute of Radiation Medicine (IRM), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Department of Radiation Oncology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich (TUM), Ismaninger Str. 22, 81675 Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, Munich, Germany. Electronic address:

Purpose: Radioresistance in pancreatic cancer patients remains a critical obstacle to overcome. Understanding the molecular mechanisms underlying radioresistance may achieve better response to radiotherapy and thereby improving the poor treatment outcome. The aim of the present study was to elucidate the mechanisms leading to radioresistance by detailed characterization of isogenic radioresistant and radiosensitive cell lines.

Methods: The human pancreatic cancer cell lines, Panc-1 and MIA PaCa-2 were repeatedly exposed to radiation to generate radioresistant (RR) isogenic cell lines. The surviving cells were expanded, and their radiosensitivity was measured using colony formation assay. Tumor growth delay after irradiation was determined in a mouse pancreatic cancer xenograft model. Gene and protein expression were analyzed using RNA sequencing and Western blot, respectively. Cell cycle distribution and apoptosis (Caspase 3/7) were measured by FACS analysis. Reactive oxygen species generation and DNA damage were analyzed by detection of CM-HDCFDA and γH2AX staining, respectively. Transwell chamber assays were used to investigate cell migration and invasion.

Results: The acquired radioresistance of RR cell lines was demonstrated in vitro and validated in vivo. Ingenuity pathway analysis of RNA sequencing data predicted activation of cell viability in both RR cell lines. RR cancer cell lines demonstrated greater DNA repair efficiency and lower basal and radiation-induced reactive oxygen species levels. Migration and invasion were differentially affected in RR cell lines.

Conclusions: Our data indicate that repeated exposure to irradiation increases the expression of genes involved in cell viability and thereby leads to radioresistance. Mechanistically, increased DNA repair capacity and reduced oxidative stress might contribute to the radioresistant phenotype.
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http://dx.doi.org/10.1016/j.radonc.2021.03.038DOI Listing
April 2021

Important role of Nfkb2 in the Kras-driven carcinogenesis in the pancreas.

Pancreatology 2021 Mar 26. Epub 2021 Mar 26.

Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675, München, Germany; German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. Electronic address:

Background: Oncogenic Kras initiates and drives carcinogenesis in the pancreas by complex signaling networks, including activation of the NFκB pathway. Although recent evidence has shown that oncogenic gains in Nfκb2 collaborate with Kras in the carcinogenesis, no data at the level of genetics for the contribution of Nfκb2 is available so far.

Methods: We used Nfkb2 knock-out mice to decipher the role of the gene in Kras-driven carcinogenesis in vivo.

Results: We show that the Nfkb2 gene is needed for cancer initiation and progression in Kras-driven models and this requirement of Nfkb2 is mechanistically connected to proliferative pathways. In contrast, Nfκb2 is dispensable in aggressive pancreatic ductal adenocarcinoma (PDAC) models relying on the simultaneous expression of the Kras oncogene and the mutated tumor suppressor p53.

Conclusions: Our data add to the understanding of context-dependent requirements of oncogenic Kras signaling during pancreatic carcinogenesis.
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http://dx.doi.org/10.1016/j.pan.2021.03.012DOI Listing
March 2021

BCL3 couples cancer stem cell enrichment with pancreatic cancer molecular subtypes.

Gastroenterology 2021 Apr 2. Epub 2021 Apr 2.

Comprehensive Cancer Center Munich at the Klinikum rechts der Isar (CCCM(TUM)), Technische Universität München, 81675 Munich, Germany. Electronic address:

Backgroung & Aims: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown.

Methods: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical NF-κB signaling member, as differing in pancreatic CSCs. To determine the biological consequences of Bcl3 silencing in vivo and in vitro, we generated Bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models and two independent patient cohorts. We assessed the correlation of BCL3 expression pattern with clinical parameters and subtypes.

Results: BCL3 was significantly downregulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via Bcl3 genetic knockout enhanced tumor burden, metastasis, EMT, and reduced overall survival. FACS analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays all indicated that Bcl3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes.

Conclusions: We demonstrate that Bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker predicting subtype characterization in PDAC thereby, allowing for personalized therapeutic approaches.
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http://dx.doi.org/10.1053/j.gastro.2021.03.051DOI Listing
April 2021

NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma.

Cancers (Basel) 2021 Mar 29;13(7). Epub 2021 Mar 29.

Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.

(1) Inactivation of the tumor suppressor NF2 is believed to play a major role in the pathogenesis of malignant pleural mesothelioma (MPM) by deregulating the Hippo-YAP signaling pathway. However, NF2 has functions beyond regulation of the Hippo pathway, raising the possibility that NF2 contributes to MPM via Hippo-independent mechanisms. (2) We performed weighted gene co-expression analysis (WGCNA) in transcriptomic and proteomic datasets obtained from The Cancer Gene Atlas (TCGA) MPM cohort to identify clusters of co-expressed genes highly correlated with NF2 and phospho (p)-YAP protein, surrogate markers of active Hippo signaling and YAP inactivation. The potential targets are experimentally validated using a cell viability assay. (3) MPM tumors with NF2 loss-of-function are not associated with changes in p-YAP level nor YAP/TAZ activity score, but are characterized by a deficient B-cell receptor (BCR) signaling pathway. Conversely, MPM tumors with YAP activation display exhausted CD8 T-cell-mediated immunity together with significantly upregulated PD-L1, which is validated in an independent MPM cohort, suggesting a potential benefit of immune-checkpoint inhibitors (ICI) in this patient subset. In support of this, mutations in core Hippo signaling components including LATS2, but not NF2, are independently associated with better overall survival in response to ICI in patients. Additionally, based on cancer cell line models, we show that MPM cells with a high Hippo-YAP activity are particularly sensitive to inhibitors of BCR-ABL/SRC, stratifying a unique MPM patient subset that may benefit from BCR-ABL/SRC therapies. Furthermore, we observe that NF2 physically interacts with a considerable number of proteins that are not involved in the canonical Hippo-YAP pathway, providing a possible explanation for its Hippo-independent role in MPM. Finally, survival analyses show that YAP/TAZ scores together with p-YAP protein level, but not NF2, predict the prognosis of MPM patients. (4) NF2 loss-of-function and dysregulated Hippo-YAP pathway define distinct MPM subsets that differ in their molecular features and prognosis, which has important clinical implications for precision oncology in MPM patients.
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http://dx.doi.org/10.3390/cancers13071561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036327PMC
March 2021

Adoptive T Cell Therapy Is Complemented by Oncolytic Virotherapy with Fusogenic VSV-NDV in Combination Treatment of Murine Melanoma.

Cancers (Basel) 2021 Mar 2;13(5). Epub 2021 Mar 2.

Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.

Cancer immunotherapies have made major advancements in recent years and are becoming the prevalent treatment options for numerous tumor entities. However, substantial response rates have only been observed in specific subsets of patients since pre-existing factors determine the susceptibility of a tumor to these therapies. The development of approaches that can actively induce an anti-tumor immune response, such as adoptive cell transfer and oncolytic virotherapy, have shown clinical success in the treatment of leukemia and melanoma, respectively. Based on the immune-stimulatory capacity of oncolytic VSV-NDV virotherapy, we envisioned a combination approach to synergize with adoptive T cell transfer, in order to enhance tumor cell killing. Using the immune-competent B16 melanoma model, we demonstrate that combination treatment has beneficial effects on the suppressive microenvironment through upregulation of MHC-I and maintaining low expression levels of PD-L1 on tumor cells. The approach led to additive cytotoxic effects and improved the recruitment of T cells to virus-infected tumor cells in vitro and in vivo. We observed substantial delays in tumor growth and evidence of abscopal effects, as well as prolongation of overall survival time when administered at clinically relevant dosing conditions. Our results indicate that treatment with oncolytic VSV-NDV, combined with adoptive T cell therapy, induces multi-mechanistic and synergistic tumor responses, which supports the further development of this promising translational approach.
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http://dx.doi.org/10.3390/cancers13051044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958625PMC
March 2021

Prediction of Outcome in Acute Pancreatitis by the qSOFA and the New ERAP Score.

Dig Dis Sci 2021 Mar 26. Epub 2021 Mar 26.

Klinik und Poliklinik für Innere Medizin II, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675, München, Germany.

Background: Early identification of patients with acute severe pancreatitis is important for prompt and adequate treatment. Existing scores for pancreatitis are often laborious or require serial patient evaluation, whereas the qSOFA score, that was established to predict outcome in patients with suspected infection, is simple to perform.

Aims And Methods: In this cohort study, we analyse the potential of the qSOFA score to predict outcome of patients with acute pancreatitis and refine the qSOFA score by rapid available laboratory parameters to the emergency room assessment of acute pancreatitis (ERAP) score. Validation was performed in a separate patient cohort.

Results: In total 203 patients with acute pancreatitis were recruited. The qSOFA score has the potential to predict ICU admission (AUC = 0.730, p = 0.002) and organ failure (AUC = 0.799, p = 0.013) in acute pancreatitis. Respiratory rate, mental status, blood urea nitrogen and C-reactive protein are the rapid available parameters with the highest individual impact in binary logistic regression analyses. Their combination to the ERAP score can predict severity of acute pancreatitis according to the revised Atlanta classification (AUC = 0.689 ± 0.041, p < 0.001), ICU admission (AUC = 0.789 ± 0.067, p < 0.001), multi-organ dysfunction syndrome (AUC = 0.963 ± 0.024, p < 0.001) and mortality (AUC = 0.952 ± 0.028, p = 0.001). The performance and prognostic validity for organ failure and mortality were validated in an independent patient cohort.

Conclusion: The qSOFA is a rapidly available prognostic score in acute pancreatitis with limited prognostic validity. A combination with the laboratory parameters BUN and CRP results in the new ERAP score with outstanding prognostic validity for multi-organ dysfunction syndrome and mortality.
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http://dx.doi.org/10.1007/s10620-021-06945-zDOI Listing
March 2021

PALLD mutation in a European family conveys a stromal predisposition for familial pancreatic cancer.

JCI Insight 2021 Mar 25. Epub 2021 Mar 25.

Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technischen Universität München, München, Germany.

Background And Aims: Pancreatic cancer is one of the deadliest cancers, still with low long term survival rates. Despite recent advances in treatment, it is extremely important to screen high-risk individuals in order to establish preventive and early detection measures and, in some cases, molecular driven therapeutic options. Familial pancreatic cancer (FPC) accounts for 4%-10% of pancreatic cancers. Several germline mutations are known to be related with an increased risk and might offer novel screening and therapy options. In this study, our goal was to discover the identity of a familial pancreatic cancer gene in two members of a family with FPC.

Methods: Whole exome sequencing and PCR confirmation was performed on the surgical specimen and peripheral blood of an index patient and her sister in a family with high incidence of pancreatic cancer, to identify somatic and germline mutations associated with familial pancreatic cancer. Compartment-specific gene expression data and immunohistochemistry was used to characterize PALLD expression.

Results: A germline mutation of the PALLD gene (NM_001166108.1:c.G154A:p.D52N) was detected in the index patient with pancreatic cancer. The identical PALLD mutation was identified in the tumor tissue of her sister. Whole genome sequencing showed similar somatic mutation patterns between the two sisters. Apart from the PALLD mutation, commonly mutated genes that characterize PDAC (KRAS and CDKN2A) were found in both tumor samples. However, the two patients harbored different somatic KRAS mutations (respectively G12D in the index patient and G12V in the index patient's sister). Analysis for PALLD mutation in the healthy siblings of the two sisters was negative, indicating that the identified PALLD mutation might have a disease specific impact. Of note, compartment-specific gene expression data and IHC suggested a predominant role in cancer associated fibroblasts (CAFs).

Conclusion: We identified a germline mutation of the palladin (PALLD) gene in two siblings in Europe, affected by familial pancreatic cancer, with a predominant function in the tumor stroma.
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http://dx.doi.org/10.1172/jci.insight.141532DOI Listing
March 2021

Defining and validating regenerative farm systems using a composite of ranked agricultural practices.

F1000Res 2021 15;10:115. Epub 2021 Feb 15.

Blue Dasher Farm, Ecdysis Foundation, Estelline, South Dakota, 57234, USA.

Ongoing efforts attempt to define farms as regenerative to aid marketers, policymakers, farmers, etc. The approach needs to balance precision with function, and must be transparent, simple, scalable, transferable, incorruptible, and replicable. We developed practice-based scoring systems to distinguish regenerative cropland and rangeland, and validate them based on whether these scores scaled with regenerative goals on actual farm operations. Study systems included cornfields of the Upper Midwest, almond orchards of California, and rangeland systems of the Northern Plains. Response variables included soil carbon and organic matter, soil micronutrients, water infiltration rates, soil microbial communities, plant community structure, invertebrate community structure, pest populations, yields, and profit. Regenerative outcomes were strongly correlated with our approach to farm scoring. Soil organic matter, fine particulate organic matter, total soil carbon, total soil nitrogen, phosphorous, calcium and sulfur all increased alongside regenerative matrix scores in one or both of the cropping systems. Water infiltration rates were significantly faster in more regenerative almond orchards. Soil bacterial biomass and Haney soil health test scores were higher as cropland incorporated more regenerative practices. Plant species diversity and biomass increased significantly with the number of regenerative practices employed on almonds and rangelands. Invertebrate species diversity and richness were positively associated with regenerative practices in corn, almonds, and rangelands, whereas pest populations and almond yields were unaffected by the number of regenerative practices. Corn yields were negatively associated with more regenerative practices, while almond yields were unaffected by the number of regenerative practices. Profit was significantly higher on more regenerative corn and almond operations. Our scoring system scaled positively with desired regenerative outcomes, and provides the basis for predicting ecosystem responses with minimal information about the farming operation. Natural clusters in the number of regenerative practices used can be used to distinguish regenerative and conventional operations.
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http://dx.doi.org/10.12688/f1000research.28450.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953916PMC
February 2021

Invasive pulmonary aspergillosis in critically ill patients with severe COVID-19 pneumonia: Results from the prospective AspCOVID-19 study.

PLoS One 2021 17;16(3):e0238825. Epub 2021 Mar 17.

Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.

Background: Superinfections, including invasive pulmonary aspergillosis (IPA), are well-known complications of critically ill patients with severe viral pneumonia. Aim of this study was to evaluate the incidence, risk factors and outcome of IPA in critically ill patients with severe COVID-19 pneumonia.

Methods: We prospectively screened 32 critically ill patients with severe COVID-19 pneumonia for a time period of 28 days using a standardized study protocol for oberservation of developement of COVID-19 associated invasive pulmonary aspergillosis (CAPA). We collected laboratory, microbiological, virological and clinical parameters at defined timepoints in combination with galactomannan-antigen-detection from nondirected bronchial lavage (NBL). We used logistic regression analyses to assess if COVID-19 was independently associated with IPA and compared it with matched controls.

Findings: CAPA was diagnosed at a median of 4 days after ICU admission in 11/32 (34%) of critically ill patients with severe COVID-19 pneumonia as compared to 8% in the control cohort. In the COVID-19 cohort, mean age, APACHE II score and ICU mortality were higher in patients with CAPA than in patients without CAPA (36% versus 9.5%; p<0.001). ICU stay (21 versus 17 days; p = 0.340) and days of mechanical ventilation (20 versus 15 days; p = 0.570) were not different between both groups. In regression analysis COVID-19 and APACHE II score were independently associated with IPA.

Interpretation: CAPA is highly prevalent and associated with a high mortality rate. COVID-19 is independently associated with invasive pulmonary aspergillosis. A standardized screening and diagnostic approach as presented in our study can help to identify affected patients at an early stage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238825PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968651PMC
March 2021

A prognostic score for non-small cell lung cancer resected after neoadjuvant therapy in comparison with the tumor-node-metastases classification and major pathological response.

Mod Pathol 2021 Mar 13. Epub 2021 Mar 13.

Institute of Pathology, University of Bern, Bern, Switzerland.

Studies validating the prognostic accuracy of the tumor-node-metastases (TNM) classification in patients with lung cancer treated by neoadjuvant therapy are scarce. Tumor regression, particularly major pathological response (MPR), is an acknowledged prognostic factor in this setting. We aimed to validate a novel combined prognostic score. This retrospective single-center study was conducted on 117 consecutive patients with non-small cell lung cancer resected after neoadjuvant treatment at a Swiss University Cancer Center between 2000 and 2016. All cases were clinicopathologically re-evaluated. We assessed the prognostic performance of a novel prognostic score (PRSC) combining T-category, lymph node status, and MPR, in comparison with the eighth edition of the TNM classification (TNM8), the size adapted TNM8 as proposed by the International Association for the Study of Lung Cancer (IASLC) and MPR alone. The isolated ypT-category and the combined TNM8 stages accurately differentiated overall survival (OS, stage p = 0.004) and disease-free survival (DFS, stage p = 0.018). Tumor regression had a prognostic impact. Optimal cut-offs for MPR emerged as 65% for adenocarcinoma and 10% for non-adenocarcinoma and were statistically significant for survival (OS p = 0.006, DFS p < 0.001). The PRSC differentiated between three prognostic groups (OS and DFS p < 0.001), and was superior compared to the stratification using MPR alone or the TNM8 systems, visualized by lower Akaike (AIC) and Bayesian information criterion (BIC) values. In the multivariate analyses, stage III tumors (HR 4.956, p = 0.003), tumors without MPR (HR 2.432, p = 0.015), and PRSC high-risk tumors (HR 5.692, p < 0.001) had significantly increased risks of occurring death. In conclusion, we support 65% as the optimal cut-off for MPR in adenocarcinomas. TNM8 and MPR were comparable regarding their prognostic significance. The novel prognostic score performed distinctly better regarding OS and DFS.
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http://dx.doi.org/10.1038/s41379-021-00777-yDOI Listing
March 2021

CRISPR-mediated kinome editing prioritizes a synergistic combination therapy for FGFR1-amplified lung cancer.

Cancer Res 2021 Mar 8. Epub 2021 Mar 8.

General Thoracic Surgery, University Hospital of Bern

Oncogenic activation of the fibroblast growth factor receptor (FGFR) pathway is frequent in lung and other cancers. However, due to drug resistance, pharmacological blockage of aberrant FGFR signaling has provided little clinical benefit in patients with FGFR-amplified tumors. The determining factors for the limited efficacy of FGFR-targeted therapy remain incompletely understood. In this study, we performed kinome-wide CRISPR/Cas9 loss-of-function screens in FGFR1-amplified lung cancer cells treated with an FGFR inhibitor. These screens identified PLK1 as a potent synthetic lethal target that mediates a resistance mechanism by overriding DNA damage and cell cycle arrest upon FGFR1 inhibition. Genetic and pharmacological antagonism of PLK1 in combination with FGFR inhibitor therapy synergized to enhance anti-proliferative effects and drove cancer cell death in vitro and in vivo through activation of the γH2AX-CHK-E2F1 axis. These findings suggest a previously unappreciated role for PLK1 in modulating FGFR1 inhibitor sensitivity and demonstrate a synergistic drug combination for treating FGFR1-amplified lung cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2276DOI Listing
March 2021

Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa.

Sci Rep 2021 Feb 24;11(1):4509. Epub 2021 Feb 24.

Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany.

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.
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http://dx.doi.org/10.1038/s41598-021-84011-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904766PMC
February 2021

Microbiota alteration at different stages in gastric lesion progression: a population-based study in Linqu, China.

Am J Cancer Res 2021 1;11(2):561-575. Epub 2021 Feb 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute Beijing, China.

In addition to Helicobacter pylori (H.pylori), gastric microbiota may be involved in carcinogenesis process. However, the longitudinal study to assess changes in the gastric microbiota associated with the development of gastric carcinogenesis is still limited. The aim of this study is to explore dynamic microbial alterations in gastric cancer (GC) development based on a 4-year endoscopic follow-up cohort in Linqu County, China. Microbial alterations were investigated by deep sequencing of the microbial 16S ribosomal RNA gene in 179 subjects with various gastric lesions, and validated in paired gastric biopsies prospectively collected before and after lesion progression and in non-progression controls. Significant differences were found in microbial diversity and community structure across various gastric lesions, with 62 candidate differential taxa between at least two lesion groups. Further validations identified Helicobacter, Bacillus, Capnocytophaga and Prevotella to be associated with lesion progression-to-dysplasia (DYS)/GC (all P < 0.05), especially for subjects progressing from intestinal metaplasia (IM) to DYS/GC. The combination of the four genera in a microbial dysbiosis index showed a significant difference after lesion progression-to-DYS/GC compared to controls (P = 0.027). The panel including the four genera identified subjects after progression-to-DYS/GC with an area under the receiver-operating curve (AUC) of 0.941. Predictive significance was found before lesion progression-to-DYS/GC with an AUC = 0.776 and an even better AUC (0.927) for subjects progressing from IM to DYS/GC. Microbiota may play different roles at different stages in gastric carcinogenesis. A panel of bacterial genera associated with gastric lesions may help to assess gastric microbial dysbiosis and show potential predictive values for lesion progression. Our findings provide new clues for the microbial mechanism of H.pylori-associated carcinogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868750PMC
February 2021

The interactive effects of heart rate variability and mindfulness on indicators of well-being in healthcare professionals' daily working life.

Int J Psychophysiol 2021 Feb 3. Epub 2021 Feb 3.

Department of Psychological Assessment and Intervention, Catholic University of Eichstätt-Ingolstadt, Eichstätt, Germany. Electronic address:

Objective: Heart rate variability (HRV) and mindfulness have been described as correlates of self-regulation and well-being. The goal of the present study was to investigate their interactions from a within-person perspective in the context of work.

Methods: Applying an ambulatory assessment approach, we studied 89 healthcare professionals across two to four work shifts. Self-reports of momentary job demands, mindfulness, and well-being (as indicated by emotional exhaustion, relaxation, and contentment) were provided three to four times a day via smartphone questionnaires. Electrocardiogram and activity sensors continuously recorded data from the beginning to the end of the shifts. Multilevel models based on 937 measurements were built for emotional exhaustion, relaxation, and contentment.

Results: After controlling for covariates, including bodily movement, shift, and job demands, short-term HRV was marginally significantly related to decreased emotional exhaustion and significantly related to increased relaxation. State mindfulness was significantly related to decreased emotional exhaustion, and increased relaxation and contentment. Furthermore, HRV and mindfulness significantly interacted such that emotional exhaustion was lowest and relaxation was highest when both HRV and mindfulness were high.

Conclusions: Together, the findings provide insights into the use of HRV and mindfulness as indexes of psychophysiological regulatory resources that seemingly intensify their respective beneficial effects on the daily well-being of employees.
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http://dx.doi.org/10.1016/j.ijpsycho.2021.01.012DOI Listing
February 2021

Second-generation lung-on-a-chip with an array of stretchable alveoli made with a biological membrane.

Commun Biol 2021 Feb 5;4(1):168. Epub 2021 Feb 5.

Organs-on-Chip Technologies Laboratory, ARTORG Center, University of Bern, Bern, Switzerland.

The air-blood barrier with its complex architecture and dynamic environment is difficult to mimic in vitro. Lung-on-a-chips enable mimicking the breathing movements using a thin, stretchable PDMS membrane. However, they fail to reproduce the characteristic alveoli network as well as the biochemical and physical properties of the alveolar basal membrane. Here, we present a lung-on-a-chip, based on a biological, stretchable and biodegradable membrane made of collagen and elastin, that emulates an array of tiny alveoli with in vivo-like dimensions. This membrane outperforms PDMS in many ways: it does not absorb rhodamine-B, is biodegradable, is created by a simple method, and can easily be tuned to modify its thickness, composition and stiffness. The air-blood barrier is reconstituted using primary lung alveolar epithelial cells from patients and primary lung endothelial cells. Typical alveolar epithelial cell markers are expressed, while the barrier properties are preserved for up to 3 weeks.
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http://dx.doi.org/10.1038/s42003-021-01695-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864995PMC
February 2021

Mucosal-Associated Invariant T (MAIT) Cells Are Highly Activated and Functionally Impaired in COVID-19 Patients.

Viruses 2021 02 3;13(2). Epub 2021 Feb 3.

Department of Internal Medicine II, University Hospital Rechts der Isar, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany.

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprises mild courses of disease as well as progression to severe disease, characterised by lung and other organ failure. The immune system is considered to play a crucial role for the pathogenesis of COVID-19, although especially the contribution of innate-like T cells remains poorly understood. Here, we analysed the phenotype and function of mucosal-associated invariant T (MAIT) cells, innate-like T cells with potent antimicrobial effector function, in patients with mild and severe COVID-19 by multicolour flow cytometry. Our data indicate that MAIT cells are highly activated in patients with COVID-19, irrespective of the course of disease, and express high levels of proinflammatory cytokines such as IL-17A and TNFα ex vivo. Of note, expression of the activation marker HLA-DR positively correlated with SAPS II score, a measure of disease severity. Upon MAIT cell-specific in vitro stimulation, MAIT cells however failed to upregulate expression of the cytokines IL-17A and TNFα, as well as cytolytic proteins, that is, granzyme B and perforin. Thus, our data point towards an altered cytokine expression profile alongside an impaired antibacterial and antiviral function of MAIT cells in COVID-19 and thereby contribute to the understanding of COVID-19 immunopathogenesis.
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http://dx.doi.org/10.3390/v13020241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913667PMC
February 2021

A pilot study on ecological momentary assessment in asylum-seeking children and adolescents resettled to Germany: Investigating compliance, post-migration factors, and the relation between daily mood, sleep patterns, and mental health.

PLoS One 2021 1;16(2):e0246069. Epub 2021 Feb 1.

Department of Psychology, Catholic University of Eichstätt-Ingolstadt, Eichstätt, Germany.

Background: Asylum-seeking children and adolescents (ASCs) resettled to western countries show elevated levels of psychological distress. While research on the mental health of ASCs is increasing, less is known about their day-to-day living experiences such as their daily mood, sleep patterns, and post-migration factors. Moreover, no examination in situ, using smartphone-assisted ecological momentary assessment (EMA), has been conducted up to now among ASCs. Furthermore, we do not know if screening measures succeed in reflecting the daily mood of ASCs experienced in everyday life.

Methods: We undertook a smartphone-assisted EMA study over a two-week period with 3 measurements a day. Participants were N = 40 ASCs from 10 different countries who had resettled to Germany. They completed standardized questionnaires screening for history of trauma and clinical symptoms (post-traumatic stress symptoms, depression, and anxiety) that were carried out in interview-like settings, and they participated in the subsequent EMA where they rated mood, sleep parameters, and post-migration factors on a daily basis. Multilevel models of clinical symptoms, daily mood, and sleep parameters were computed based on a total of 680 measurements.

Results: The multiply traumatized and highly distressed participants reported different levels of discrimination, and various social activities and contacts in the EMA. The overall compliance rate was shown to be 40.5%. Higher PTSS and anxiety scores were associated with lower levels of daily mood and poorer outcomes of some sleep parameters. Depression scores were not associated with any of the variables assessed in the EMA.

Conclusions: Smartphone-assisted EMA among ASCs resettled to Germany proved to be implementable despite a rather low compliance rate. Not only do ASCs show high symptom levels, they are also affected by these symptoms in their daily lives. The results emphasize the need for concise screenings and psychological treatment for this high-risk population. Limitations include the convenient nature of the sample and the lack of a comparison group.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246069PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850498PMC
February 2021

Toll-like receptor 3 expression in myeloid cells is essential for efficient regeneration after acute pancreatitis in mice.

Eur J Immunol 2021 Feb 1. Epub 2021 Feb 1.

School of Medicine, Medizinische Klinik und Poliklinik II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Stringent regulation of the inflammatory response is crucial for normal tissue regeneration. Here, we analyzed the role of Toll-like receptor 3 (TLR3) in pancreatic regeneration after acute pancreatitis (AP). AP was induced by caerulein treatment in mice with global TLR3 deficiency (TLR3 ) or in mice re-expressing TLR3 exclusively in the myeloid cell lineage (TLR3 ). Compared to WT mice, TLR3 mice had a markedly increased formation of acinar-to-ductal metaplasia (ADM) that persisted until day 7 after initiation of AP. Pancreatic tissue of WT mice was completely regenerated after 5 days with no detectable ADM structures. The enhancing effect of TLR3-deficiency on ADM formation was closely linked with an increased and prolonged accumulation of macrophages in pancreata of TLR3 mice. Importantly, the phenotype of TLR3 mice was rescued in TLR3 mice, demonstrating the causative role of myeloid cell selective TLR3 signaling. Moreover, in vitro stimulation of macrophages through TLR3 initiated cell death by a caspase-8-associated mechanism. Therefore, these findings provide evidence that TLR3 signaling in myeloid cells is sufficient to limit inflammation and ADM formation and to promote regeneration after AP. Notably, resolution of inflammation after AP was associated with macrophage sensitivity to TLR3-mediated cell death.
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http://dx.doi.org/10.1002/eji.202048771DOI Listing
February 2021

Endoscopic Diagnosis of Bouveret Syndrome.

Case Rep Gastroenterol 2020 Sep-Dec;14(3):683-686. Epub 2020 Dec 14.

Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.

Bouveret syndrome is a form of gallstone ileus and a rare complication of chole(cysto)lithiasis. It describes gastric outlet obstruction secondary to an impacted gallstone. Here, we report a case of an 82-year-old female patient with gastric outlet obstruction and penetration of gallstones into the duodenal bulb on endoscopic imaging. Based on these findings Bouveret syndrome was diagnosed and confirmed by computed tomography.
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http://dx.doi.org/10.1159/000510162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772864PMC
December 2020

CRISPR/Cas9 directed to the Ube3a antisense transcript improves Angelman syndrome phenotype in mice.

J Clin Invest 2021 Mar;131(5)

Gene editing holds the potential to correct mutations and cure devastating genetic disorders. The technology has not yet proven efficacious for therapeutic use in CNS diseases with ubiquitous neuronal defects. Angelman syndrome (AS), a severe neurodevelopmental disorder, is caused by a lack of maternal expression of the UBE3A gene. Because of genomic imprinting, only neurons are affected. One therapeutic approach focuses on the intact paternal UBE3A copy in patients with AS that is silenced by an antisense transcript (UBE3A-ATS). We show here that gene editing of Ube3a-ATS in the mouse brain resulted in the formation of base pair insertions/deletions (indels) in neurons and the subsequent unsilencing of the paternal Ube3a allele in neurons, which partially corrected the behavioral phenotype of a murine AS model. This study provides compelling evidence to further investigate editing of the homologous region of the human UBE3A-ATS because this may provide a lasting therapeutic effect for patients with AS.
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http://dx.doi.org/10.1172/JCI142574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919720PMC
March 2021

Endoscopic and percutaneous biliary interventions in patients with altered upper gastrointestinal anatomy-the Munich Multicenter Experience.

Surg Endosc 2021 Jan 4. Epub 2021 Jan 4.

Medizinische Klinik II, Krankenhaus Landshut-Achdorf, Akademisches Lehrkrankenhaus der TU München, Achdorferweg 3, 84036, Landshut, Germany.

Background: In patients with altered upper gastrointestinal anatomy, conventional endoscopic retrograde cholangiography is often not possible and different techniques, like enteroscopy-assisted or percutaneous approaches are required. Aim of this study was to analyze success and complication rates of these techniques in a large collective of patients in the daily clinical practice in a pre-endosonographic biliary drainage era.

Patients And Methods: Patients with altered upper gastrointestinal anatomy with biliary interventions between March 1st, 2006, and June 30th, 2014 in four tertiary endoscopic centers in Munich, Germany were retrospectively analyzed.

Results: At least one endoscopic-assisted biliary intervention was successful in 234/411 patients (56.9%)-in 192 patients in the first, in 34 patients in the second and in 8 patients in the third attempt. Success rates for Billroth-II/Whipple-/Roux-en-Y reconstruction were 70.5%/56.7%/49.5%. Complication rates for these reconstructions were 9.3%/6.5%/6.3%, the overall complication rate was 7.1%. Success rates were highest in patients with Billroth-II reconstruction where use of a duodenoscope was possible, complication rates were also highest in this scenario. Success rates were lowest in longer-limb anatomy like Roux-en-Y reconstruction. Percutaneous biliary drainages (PTBD) were inserted 268 times with substantially higher success (90.7%) as well as complication rates (11.6%) compared to the endoscopic approach. Compared to patients treated endoscopically, patients with PTBD had a lower performance status, more severe cholestasis and a significant higher rate of malignant underlying disease.

Conclusion: In patients with altered upper gastrointestinal anatomy, success rates of endoscopic-assisted biliary interventions are lower compared to PTBD. Still, due to the beneficial complication rates of the endoscopic approach, this technique should be preferred whenever possible and in selected patients who still need to be defined in detail, repeated endoscopic attempts are useful to help achieve the desired result.
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http://dx.doi.org/10.1007/s00464-020-08191-2DOI Listing
January 2021

Exosomal miRNAs as Potential Biomarkers to Monitor Phosphodiesterase 5 Inhibitor Induced Anti-Fibrotic Effects on CCl Treated Rats.

Int J Mol Sci 2020 Dec 31;22(1). Epub 2020 Dec 31.

Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr.65, 88397 Biberach, Germany.

MicroRNAs (miRNAs) are short, non-coding RNA species that are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of non-alcoholic fatty liver disease. Here, we investigated the phosphodiesterase 5 (PDE5) inhibitor induced effects on hepatic and plasma exosomal miRNA expression in CCl-treated rats. In the present study, hepatic miRNA profiling was conducted using the Nanostring nCounter technology and mRNA profiling using RNA sequencing from PDE5 treated rats in the model of CCl-induced liver fibrosis. To evaluate if the PDE5 inhibitor affected differentially expressed miRNAs in the liver can be detected in plasma exosomes, qRT-PCR specific assays were used. In livers from CCl-treated rats, the expression of 22 miRNAs was significantly increased (> 1.5-fold, adj. < 0.05), whereas the expression of 16 miRNAs was significantly decreased (> 1.5-fold, adj. < 0.05). The majority of the deregulated miRNA species are implicated in fibrotic and inflammatory processes. The PDE5 inhibitor suppressed the induction of pro-fibrotic miRNAs, such as miR-99b miR-100 and miR-199a-5p, and restored levels of anti-fibrotic miR-122 and miR-192 in the liver. In plasma exosomes, we observed elevated levels of miR-99b, miR-100 and miR-142-3p after treatment with the PDE5-inhibitor compared to CCl/Vehicle-treated. Our study demonstrated for the first time that during the development of hepatic fibrosis in the preclinical model of CCl-induced liver fibrosis, defined aspects of miRNA regulated liver pathogenesis are influenced by PDE5 treatment. In conclusion, miRNA profiling of plasma exosomes might be used as a biomarker for NASH progression and monitoring of treatment effects.
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http://dx.doi.org/10.3390/ijms22010382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795540PMC
December 2020

High lipasemia is frequent in Covid-19 associated acute respiratory distress syndrome.

Pancreatology 2021 Jan 29;21(1):306-311. Epub 2020 Nov 29.

Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675, München, Germany.

Background: Covid-19 is a rapidly spreading viral disease that can cause severe acute respiratory distress syndrome (ARDS). Besides the lungs it can also affect other organs like the heart or the liver. Whether there is a pancreatic manifestation as well is currently unclear.

Methods: and aims: We prospectively collected patient information of patients with Covid-19 associated ARDS in a registry (COvid Registry REChts der Isar intensive care Trial - CORRECT) and analyzed this patient cohort for signs of acute pancreatitis (e.g. lipase activity >3 times the upper limit).

Results: 12/38 (31.6%) patients with Covid-19 associated ARDS had a serum lipase activity >180 U/l. Median lipase activity was 422 U/l (186-1127). No patient showed typical findings of acute pancreatitis on imaging studies. On hemodynamic monitoring no patient had signs of intravascular fluid demand regarding MAP, GEDVI and therapy with vasopressors. To avoid worsening respiratory function no treatment with crystalloids was initiated. Lipasemia was not explained by gastroenteritis or renal insufficiency, occurred before as well as after viral clearance and 16.1 ± 6.0 days after the first symptoms. No patient developed severe acute pancreatitis during the follow up period of 35.8 ± 8.3 days.

Conclusion: High lipasemia without typical signs of acute pancreatitis is a frequent finding in severe Covid-19 associated ARDS. Considering the markedly high levels of serum lipase activity, we think impaired microcirculation in severely ill patients can explain this finding rather than extra-pancreatic co-morbidities (UTN: DRKS00021612).
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http://dx.doi.org/10.1016/j.pan.2020.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700722PMC
January 2021

Comparison of global end-diastolic volume index derived from jugular and femoral indicator injection: a prospective observational study in patients equipped with both a PiCCO-2 and an EV-1000-device.

Sci Rep 2020 11 27;10(1):20773. Epub 2020 Nov 27.

II. Medizinische Klinik Und Poliklinik, Klinikum Rechts Der Isar Der Technischen Universität München, Ismaninger Straße 22, 81675, Munich, Germany.

Transpulmonary thermodilution (TPTD)-derived global end-diastolic volume index (GEDVI) is a static marker of preload which better predicted volume responsiveness compared to filling pressures in several studies. GEDVI can be generated with at least two devices: PiCCO and EV-1000. Several studies showed that uncorrected indicator injection into a femoral central venous catheter (CVC) results in a significant overestimation of GEDVI by the PiCCO-device. Therefore, the most recent PiCCO-algorithm corrects for femoral indicator injection. However, there are no systematic data on the impact of femoral indicator injection for the EV-1000 device. Furthermore, the correction algorithm of the PiCCO is poorly validated. Therefore, we prospectively analyzed 14 datasets from 10 patients with TPTD-monitoring undergoing central venous catheter (CVC)- and arterial line exchange. PiCCO was replaced by EV-1000, femoral CVCs were replaced by jugular/subclavian CVCs and vice-versa. For PiCCO, jugular and femoral indicator injection derived GEDVI was comparable when the correct information about femoral catheter site was given (p = 0.251). By contrast, GEDVI derived from femoral indicator injection using the EV-1000 was obviously not corrected and was substantially higher than jugular GEDVI measured by the EV-1000 (846 ± 250 vs. 712 ± 227 ml/m; p = 0.001). Furthermore, measurements of GEDVI were not comparable between PiCCO and EV-1000 even in case of jugular indicator injection (p = 0.003). This is most probably due to different indexations of the raw value GEDV. EV-1000 could not be recommended to measure GEDVI in case of a femoral CVC. Furthermore, different indexations used by EV-1000 and PiCCO should be considered even in case of a jugular CVC when comparing GEDVI derived from PiCCO and EV-1000.
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http://dx.doi.org/10.1038/s41598-020-76286-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695713PMC
November 2020

Biomarker-guided targeted and immunotherapies in malignant pleural mesothelioma.

Ther Adv Med Oncol 2020 12;12:1758835920971421. Epub 2020 Nov 12.

Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 50, Bern, 3010, Switzerland.

Malignant pleural mesothelioma (MPM) is a lethal thoracic malignancy whose incidence is still increasing worldwide. MPM is characterized by frequent inactivation of tumor-suppressor genes (TSGs), e.g., the homozygous deletion of and various genetic alterations that inactivate , and . The leading cause for the poor prognosis of patients with MPM is the lack of effective treatment options, with conventional chemotherapy being the standard of care in the clinic, which has remained unchanged for almost 20 years. Precision oncology, a burgeoning effort to provide precise cancer treatment tailored to unique molecular changes in individual patients, has made tremendous progress in the last decade in several cancers, but not in MPM. Recent studies indicate a high degree of tumor heterogeneity in MPM and the importance to optimize histological and molecular classifications for improved treatment. In this review, we provide an up-to-date overview of recent advances in MPM by focusing on new stratifications of tumor subgroups, specific vulnerabilities associated with functional loss of TSGs and other biomarkers, and potential clinical implications. The molecularly based subdivisions not only deepen our understanding of MPM pathobiology, but more importantly, they may raise unprecedented new hopes for personalized treatment of MPM patients with biomarker-guided targeted and immunotherapies.
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http://dx.doi.org/10.1177/1758835920971421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672749PMC
November 2020

Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity.

Cancers (Basel) 2020 Nov 16;12(11). Epub 2020 Nov 16.

Division of General Thoracic Surgery, Inselspital, Bern University Hospital, CH3008 Bern, Switzerland.

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key component of the DNA-PK complex that has a well-characterized function in the non-homologous end-joining repair of DNA double-strand breaks. Since its identification, a large body of evidence has demonstrated that DNA-PKcs is frequently overexpressed in cancer, plays a critical role in tumor development and progression, and is associated with poor prognosis of cancer patients. Intriguingly, recent studies have suggested novel functions beyond the canonical role of DNA-PKcs, which has transformed the paradigm of DNA-PKcs in tumorigenesis and has reinvigorated the interest to target DNA-PKcs for cancer treatment. In this review, we update recent advances in DNA-PKcs, in particular the emerging roles in tumor metastasis, metabolic dysregulation, and immune escape. We further discuss the possible molecular basis that underpins the pleiotropism of DNA-PKcs in cancer. Finally, we outline the biomarkers that may predict the therapeutic response to DNA-PKcs inhibitor therapy. Understanding the functional repertoire of DNA-PKcs will provide mechanistic insights of DNA-PKcs in malignancy and, more importantly, may revolutionize the design and utility of DNA-PKcs-based precision cancer therapy.
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http://dx.doi.org/10.3390/cancers12113389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698146PMC
November 2020