Publications by authors named "Oliver Dietrich"

6 Publications

  • Page 1 of 1

Time-Resolved scRNA-Seq Tracks the Adaptation of a Sensitive MCL Cell Line to Ibrutinib Treatment.

Int J Mol Sci 2021 Feb 25;22(5). Epub 2021 Feb 25.

Institute of Pathology, University of Würzburg and Comprehensive Cancer Center (CCC) Mainfranken, 97080 Würzburg, Germany.

Since the approval of ibrutinib for relapsed/refractory mantle cell lymphoma (MCL), the treatment of this rare mature B-cell neoplasm has taken a great leap forward. Despite promising efficacy of the Bruton tyrosine kinase inhibitor, resistance arises inevitably and the underlying mechanisms remain to be elucidated. Here, we aimed to decipher the response of a sensitive MCL cell line treated with ibrutinib using time-resolved single-cell RNA sequencing. The analysis uncovered five subpopulations and their individual responses to the treatment. The effects on the B cell receptor pathway, cell cycle, surface antigen expression, and metabolism were revealed by the computational analysis and were validated by molecular biological methods. The observed upregulation of B cell receptor signaling, crosstalk with the microenvironment, upregulation of , and metabolic reprogramming towards dependence on oxidative phosphorylation favor resistance to ibrutinib treatment. Targeting these cellular responses provide new therapy options in MCL.
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http://dx.doi.org/10.3390/ijms22052276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956352PMC
February 2021

Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma.

Nat Med 2021 Feb 22. Epub 2021 Feb 22.

Department of Internal Medicine 2, University Hospital of Würzburg, Würzburg, Germany.

B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial ( NCT03361748 ) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy.
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http://dx.doi.org/10.1038/s41591-021-01245-5DOI Listing
February 2021

Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia.

Nat Cell Biol 2021 02 18;23(2):184-197. Epub 2021 Jan 18.

Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.

The transition zones of the squamous and columnar epithelia constitute hotspots for the emergence of cancer, often preceded by metaplasia, in which one epithelial type is replaced by another. It remains unclear how the epithelial spatial organization is maintained and how the transition zone niche is remodelled during metaplasia. Here we used single-cell RNA sequencing to characterize epithelial subpopulations and the underlying stromal compartment of endo- and ectocervix, encompassing the transition zone. Mouse lineage tracing, organoid culture and single-molecule RNA in situ hybridizations revealed that the two epithelia derive from separate cervix-resident lineage-specific stem cell populations regulated by opposing Wnt signals from the stroma. Using a mouse model of cervical metaplasia, we further show that the endocervical stroma undergoes remodelling and increases expression of the Wnt inhibitor Dickkopf-2 (DKK2), promoting the outgrowth of ectocervical stem cells. Our data indicate that homeostasis at the transition zone results from divergent stromal signals, driving the differential proliferation of resident epithelial lineages.
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http://dx.doi.org/10.1038/s41556-020-00619-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878191PMC
February 2021

Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment.

Cell 2020 09 5;182(6):1419-1440.e23. Epub 2020 Aug 5.

Department of Infectious Diseases and Respiratory Medicine, Charité, Universitätsmedizin Berlin, Berlin, Germany; German Center for Lung Research (DZL).

Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRCD11c inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DR monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
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http://dx.doi.org/10.1016/j.cell.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405822PMC
September 2020

Associations between motion activity, ketosis risk and estrus behavior in dairy cattle.

Prev Vet Med 2020 Feb 26;175:104857. Epub 2019 Nov 26.

Clinic of Ruminants with Herd Health and Ambulatory Services, Ludwig-Maximilians-Universität (LMU), Sonnenstr. 16, 85764, Oberschleißheim, Germany. Electronic address:

Ketosis (acetonaemia) is a metabolic disorder that occurs in cattle when energy demand exceeds energy intake and results in a negative energy balance. The course of the disease often starts with a subclinical phase, so early detection is crucial for decisive strategies. The aim of this study was to determine whether daily motion activity could be used as an indicator of subclinical ketosis in early lactation and to evaluatethe effect of subclinical ketosis on activity at estrus. The study was carried out on a 75-cow dairy farm over 6 months. Data were collected from 48 cows between day 0 and day 70 post-partum. Beta-Hydroxybutyrate (BHB) concentrations were evaluated in milk samples using rapid on-site ketosis tests. A test was considered positive at a concentration of >100 μmol/l. The animals were divided into two groups: group 'Healthy' (H) and group 'Ketosis' (K). Once the on-site test was positive, the cows were assigned to group K. Progesterone concentrations were evaluated in milk by photometric detection of the colour reaction of a competitive, heterologous enzyme immunoassay (EIA). Each drop from ≥0.3 ng/ml to <0.3 ng/ml with a subsequent increase to ≥0.3 ng/ml was considered estrus. Daily milk yield, concentrate intake and motion activity were recorded from a computerized dairy management system with the associated software (DairyPlan C21). Animals in group K had lower average daily activity levels than animals in group H. In this study, statistically significant reduced motion activity in animals in group K was observed on days 6-12 post-partum (P < 0.001, χ² test) compared with the herd mean daily motion activity. Furthermore, a significant association could be found between motion activity and group affiliation (logistic regression models). The sensitivity of the detection of cows at risk for ketosis was 81.8 %, and the specificity was 65.4 %, retrospectively determined by their activity behaviour. The mean motion activity on the day of estrus was significantly (P < 0.05) lower in animals in group K than in those in group H. This method may help to establish a future early warning system for the risk of ketosis in dairy cows. Thus, cows at risk may be identified for further targeted diagnostics and for selective treatment procedures. This study confirms the already reported lasting effect of subclinical ketosis on reproductive efficiency.
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http://dx.doi.org/10.1016/j.prevetmed.2019.104857DOI Listing
February 2020

Cereal processing at Early Neolithic Göbekli Tepe, southeastern Turkey.

PLoS One 2019 1;14(5):e0215214. Epub 2019 May 1.

Freie Universität Berlin, Institute of Geographical Sciences, Berlin, Germany.

We analyze the processing of cereals and its role at Early Neolithic Göbekli Tepe, southeastern Anatolia (10th / 9th millennium BC), a site that has aroused much debate in archaeological discourse. To date, only zooarchaeological evidence has been discussed in regard to the subsistence of its builders. Göbekli Tepe consists of monumental round to oval buildings, erected in an earlier phase, and smaller rectangular buildings, built around them in a partially contemporaneous and later phase. The monumental buildings are best known as they were in the focus of research. They are around 20 m in diameter and have stone pillars that are up to 5.5 m high and often richly decorated. The rectangular buildings are smaller and-in some cases-have up to 2 m high, mostly undecorated, pillars. Especially striking is the number of tools related to food processing, including grinding slabs/bowls, handstones, pestles, and mortars, which have not been studied before. We analyzed more than 7000 artifacts for the present contribution. The high frequency of artifacts is unusual for contemporary sites in the region. Using an integrated approach of formal, experimental, and macro- / microscopical use-wear analyses we show that Neolithic people at Göbekli Tepe have produced standardized and efficient grinding tools, most of which have been used for the processing of cereals. Additional phytolith analysis confirms the massive presence of cereals at the site, filling the gap left by the weakly preserved charred macro-rests. The organization of work and food supply has always been a central question of research into Göbekli Tepe, as the construction and maintenance of the monumental architecture would have necessitated a considerable work force. Contextual analyses of the distribution of the elements of the grinding kit on site highlight a clear link between plant food preparation and the rectangular buildings and indicate clear delimitations of working areas for food production on the terraces the structures lie on, surrounding the circular buildings. There is evidence for extensive plant food processing and archaeozoological data hint at large-scale hunting of gazelle between midsummer and autumn. As no large storage facilities have been identified, we argue for a production of food for immediate use and interpret these seasonal peaks in activity at the site as evidence for the organization of large work feasts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215214PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493732PMC
January 2020