Functional analysis of structural variants in single cells using Strand-seq

Somatic structural variants (SVs) are widespread in cancer, but their impact on disease evolution is understudied due to a lack of methods to directly characterize their functional consequences. We present a computational method, scNOVA, which uses Strand-seq to perform haplotype-aware integration of SV discovery and molecular phenotyping in single cells by using nucleosome occupancy to infer gene expression as a readout. Application to leukemias and cell lines identifies local effects of copy-balanced rearrangements on gene deregulation, and consequences of SVs on aberrant signaling pathways in subclones. We discovered distinct SV subclones with dysregulated Wnt signaling in a chronic lymphocytic leukemia patient. We further uncovered the consequences of subclonal chromothripsis in T cell acute lymphoblastic leukemia, which revealed c-Myb activation, enrichment of a primitive cell state and informed successful targeting of the subclone in cell culture, using a Notch inhibitor. By directly linking SVs to their functional effects, scNOVA enables systematic single-cell multiomic studies of structural variation in heterogeneous cell populations

Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies

Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN

The ASCAT soil moisture product: a review of its specifications, validation results, and emerging applications

Many physical, chemical and biological processes taking place at the land surface are strongly influenced by the amount of water stored within the upper soil layers. Therefore, many scientific disciplines require soil moisture observations for developing, evaluating and improving their models. One of these disciplines is meteorology where soil moisture is important due to its control on the exchange of heat and water between the soil and the lower atmosphere. Soil moisture observations may thus help to improve the forecasts of air temperature, air humidity and precipitation. However, until recently, soil moisture observations had only been available over a limited number of regional soil moisture networks. This has hampered scientific progress as regards the characterisation of land surface processes not just in meteorology but many other scientific disciplines as well. Fortunately, in recent years, satellite soil moisture data have increasingly become available. One of the freely available global soil moisture data sets is derived from the backscatter measurements acquired by the Advanced Scatterometer (ASCAT) that is a C-band active microwave remote sensing instrument flown on board of the Meteorological Operational (METOP) satellite series. ASCAT was designed to observe wind speed and direction over the oceans and was initially not foreseen for monitoring soil moisture over land. Yet, as argued in this review paper, the characteristics of the ASCAT instrument, most importantly its wavelength (5.7 cm), its high radiometric accuracy, and its multiple-viewing capabilities make it an attractive sensor for measuring soil moisture. Moreover, given the operational status of ASCAT, and its promising long-term prospects, many geoscientific applications might benefit from using ASCAT soil moisture data. Nonetheless, the ASCAT soil moisture product is relatively complex, requiring a good understanding of its properties before it can be successfully used in applications. To provide a comprehensive overview of the major characteristics and caveats of the ASCAT soil moisture product, this paper describes the ASCAT instrument and the soil moisture processor and near-real-time distribution service implemented by the European Organisation for the Exploitation of Meteorological Satellites (EUMETSAT). A review of the most recent validation studies shows that the quality of ASCAT soil moisture product is – with the exception of arid environments –comparable to, and over some regions (e.g. Europe) even better than currently available soil moisture data derived from passive microwave sensors. Further, a review of applications studies shows that the use of the ASCAT soil moisture product is particularly advanced in the fields of numerical weather prediction and hydrologic modelling. But also in other application areas such as yield monitoring, epidemiologic modelling, or societal risks assessment some first progress can be noted. Considering the generally positive evaluation results, it is expected that the ASCAT soil moisture product will increasingly be used by a growing number of rather diverse land applications.The Austrian Science Fund (FWF) through the Vienna Doctoral Programme on Water Resource Systems (http://www.waterresources.at/,DK-plusW1219-N22

Influence of Gender on Therapy and Outcome of Neuroendocrine Tumors of Gastroenteropancreatic Origin: A Single-Center Analysis

Introduction: Gender-specific treatment is gaining growing attention in various fields of medicine. In gastrointestinal cancer, influence of sex on outcome has been discussed, while this has not been the case in neuroendocrine tumors. Overall, the incidence of neuroendocrine neoplasms is rising, especially for appendiceal neuroendocrine neoplasms in women. Also, women seem to have a slight advantage in response to therapy, especially for liver metastases. Objectives: This single-center analysis aimed to investigate gender-specific differences in our cohort related to distribution, therapy, and outcome. Methods: Patients from the NET registry as well as the clinic database were evaluated retrospectively concerning overall survival and response to therapy with respect to gender. A subgroup analysis was carried out for patients with low grading and response to chemotherapy, as well as for patients with good and moderate grading receiving peptide receptor radionuclide therapy and for a group of patients with liver surgery. Results: No specific differences could be detected for overall survival or response to therapy between male and female patients. Mean survival was estimated with 242.2 months (+/- 10.39 SD) altogether and 221.7 months (+/- 13.02 SD) for male patients and 253.5 months (+/- 15.24 SD) for female patients from the NET registry from initial diagnosis. There was no significant difference between female and male patients (p = 0.136). For patients receiving chemotherapy, overall survival from initial diagnosis was calculated with 26 months (+/- 2.59) and did not show any significant differences between female and male patients 24.8 months (+/- 2.81 SD) vs. 27.8 months (+/- 3.86 SD, p = 0.87). Patients undergoing peptide receptor radionuclide therapy showed a median progression-free survival of 26.9 months (+/- 2.82 SD), with 16.9 (+/- 5.595 SD) and 26.9 months (+/- 3.019 SD) for male and female patients, respectively (p = 0.2). In the group of patients with liver surgery, female patients reached an estimated overall survival of 64.7 months (+/- 4.16 SD), male patients 65.1 months (+/- 2.79 SD, p = 0.562). Conclusion: Our cohort did not reveal significant differences in outcome and response to therapy with regards to gender

Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics

Cancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with it the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells.This project was financially supported by the Deutsche José Carreras Leukämie Stiftung grant DJCLS 20R/2017 (to L.V., S.H., L.M.S., and A.T.), the Emerson foundation grant 643577 (to L.V. and L.M.S.) and the German Bundesministerium für Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin “LeukoSyStem” (FKZ 01ZX1911D to L.V., S.H., and S.R). Contributions by S.R. were further supported by Emmy Noether Fellowship RA 3166/1-1 (DFG). Contributions by C.P. were supported by a Max-Eder Grant (German Cancer Aid 70111531). Contributions by D.N., J.C.J., W.K.H., and T.B. were supported by the Gutermuth Foundation, the H.W. & J. Hector fund, Baden-Württemberg, and the Dr. Rolf M. Schwiete Fund, Mannheim. D.N. is an endowed professor of the Deutsche José Carreras Leukämie Stiftung (DJCLS H 03/01