Environmental development and local human impact in the Jeetzel valley (N Germany) since 10 ka BP as detected by geoarchaeological analyses in a coupled aeolian and lacustrine sediment archive at Soven

While archaeological records indicate an intensive Mesolithic occupation of dune areas situated along river valleys, relatively little knowledge exists about environmental interactions in the form of land-use strategies and their possible local impacts. The combination of geoarchaeological, chronological, geochemical and palaeoecological research methods and their application both on a Mesoltihic site situated on top of a dune and the adjacent palaeochannel sediments allows for a detailed reconstruction of the local environmental development around the Soven site in the Jeetzel valley (Northern Germany) since ~10.5 ka cal BP. Based on the results, we identified four phases that may be related to local human impact twice during the Mesolithic, the Neolithic and the Iron Ages and are discussed on the backdrop of the regional settlement history. Although nearby Mesolithic occupation is evident on archaeological grounds, the identification of synchronous impacts on the vegetation in the local environmental records remains tentative even in respect of the broad methodical spectrum applied. Vice versa, human impact is strongly indicated by palaeoecological and geochemical proxies during the Neolithic period, but cannot be connected to archaeological records in the area so far. A younger phase of human impact – probably consisting of seasonal livestock farming in the wetlands – is ascribed to the Iron Age economy and comprises local soil erosion, raised concentrations of phosphates and urease, and the facilitation of grazing related taxa.researc

Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood–brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.</p

Synchronous vegetation response to the last glacial-interglacial transition in northwest Europe

The North Atlantic region experienced abrupt high-amplitude cooling at the onset of the Younger Dryas stadial. However, due to chronological uncertainties in the available terrestrial records it is unclear whether terrestrial ecosystem response to this event was instantaneous and spatially synchronous, or whether regional or time-transgressive lags existed. Here we use new palynological results from a robustly dated lake sediment sequence retrieved from lake Hämelsee (north Germany) to show that vegetation change started at 12,820 cal. yr BP, concurrent with the onset of changes in local climate. A comparison of the Hämelsee results to a compilation of precisely dated palynological records shows instant and, within decadal-scale dating uncertainty, synchronous response of the terrestrial plant community to Late-Glacial climate change across northwest Europe. The results indicate that the environmental impact of climate cooling was more severe than previously thought and illustrates the sensitivity of natural terrestrial ecosystems to external forcing. © 2022, The Author(s)

Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma

<p>Abstract</p> <p>Background</p> <p>The SRY-related HMG-box family of transcription factors member <it>SOX2 </it>has been mainly studied in embryonic stem cells as well as early foregut and neural development. More recently, SOX2 was shown to participate in reprogramming of adult somatic cells to a pluripotent stem cell state and implicated in tumorigenesis in various organs. In breast cancer, SOX2 expression was reported as a feature of basal-like tumors. In this study, we assessed SOX2 expression in 95 primary tumors of postmenopausal breast cancer patients.</p> <p>Methods</p> <p>Samples from 95 patients diagnosed and treated at the University of Tuebingen Institute of Pathology and Women's Hospital were analyzed by immunohistochemistry for SOX2 expression in the primary tumor samples and in corresponding lymph node metastasis, where present. Furthermore, SOX2 amplification status was assessed by FISH in representative samples. In addition, eighteen fresh frozen samples were analyzed for <it>SOX2</it>, <it>NANOG </it>and <it>OCT4 </it>gene expression by real-time PCR.</p> <p>Results</p> <p>SOX2 expression was detected in 28% of invasive breast carcinoma as well as in 44% of ductal carcinoma in situ (DCIS) lesions. A score of SOX2 expression (score 0 to 3) was defined in order to distinguish SOX2 negative (score 0) from SOX2 positive samples (score 1-3) and among latter the subgroup of SOX2 high expressors (score 3 > 50% positive cells). Overall, the incidence of SOX2 expression (score 1-3) was higher than previously reported in a cohort of lymph node negative patients (28% versus 16.7%). SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading. However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018). Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432).</p> <p>Conclusions</p> <p>In this report, we show that the embryonic stem cell factor SOX2 is expressed in a variety of early stage postmenopausal breast carcinomas and metastatic lymph nodes. Our data suggest that SOX2 plays an early role in breast carcinogenesis and high expression may promote metastatic potential. Further studies are needed to explore whether SOX2 can predict metastatic potential at an early tumor stage.</p

STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.Lukas Kenner and Jan Pencik are supported by FWF, P26011 and the Genome Research-Austria project “Inflammobiota” grants. Helmut Dolznig is supported by the Herzfelder Family Foundation and the Niederösterr. Forschungs-und Bildungsges.m.b.H (nfb). Richard Moriggl is supported by grant SFB-F2807 and SFB-F4707 from the Austrian Science Fund (FWF), Ali Moazzami is supported by Infrastructure for biosciences-Strategic fund, SciLifeLab and Formas, Zoran Culig is supported by FWF, P24428, Athena Chalaris and Stefan Rose-John are supported by the Deutsche Forschungsgemeinschaft (Grant SFB 877, Project A1and the Cluster of Excellence --“Inflammation at Interfaces”). Work of the Aberger lab was supported by the Austrian Science Fund FWF (Projects P25629 and W1213), the European FP7 Marie-Curie Initial Training Network HEALING and the priority program Biosciences and Health of the Paris-Lodron University of Salzburg. Valeria Poli is supported by the Italian Association for Cancer Research (AIRC, No IG13009). Richard Kennedy and Steven Walker are supported by the McClay Foundation and the Movember Centre of Excellence (PC-UK and Movember). Gerda Egger is supported by FWF, P27616. Tim Malcolm and Suzanne Turner are supported by Leukaemia and Lymphoma Research.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms873

Existence of reprogrammed lymphoma stem cells in a murine ALCL-like model.

Funder: DJCLS (R14/22) MSCA-ITN-2015-ETN AlkatrasFunder: DFG (CRC850)Funder: DFG (CRC850) BMBF (DeCaRe, FKZ 01ZX1409B)Funder: DJCLS (R14/22) MSCA-ITN-2015-ETN Alkatras DFG (FOR 2033 B1)Funder: DJCLS (R14/22) MSCA-ITN-2015-ETN Alkatras Grant from the Government of Baden-Württemberg (BSL)While cancer stem cells are well established in certain hematologic and solid malignancies, their existence in T cell lymphoma is unclear and the origin of disease is not fully understood. To examine the existence of lymphoma stem cells, we utilized a mouse model of anaplastic large cell lymphoma. Established NPM-ALK+ lymphomas contained heterogeneous cell populations ranging from mature T cells to undifferentiated hematopoietic stem cells. Interestingly, CD4-/CD8- double negative (DN) lymphoma cells aberrantly expressed the T cell receptor α/β chain. Serial transplantation of sorted CD4/CD8 and DN lymphoma subpopulations identified lymphoma stem cells within the DN3/DN4 T cell population, whereas all other subpopulations failed to establish serial lymphomas. Moreover, transplanted lymphoma DN3/DN4 T cells were able to differentiate and gave rise to mature lymphoma T cells. Gene expression analyses unmasked stem-cell-like transcriptional regulation of the identified lymphoma stem cell population. Furthermore, these lymphoma stem cells are characterized by low CD30 expression levels, which might contribute to limited long-term therapeutic success in patients treated with anti-CD30-targeted therapies. In summary, our results highlight the existence of a lymphoma stem cell population in a NPM-ALK-driven CD30+ mouse model, thereby giving the opportunity to test innovative treatment strategies developed to eradicate the origin of disease

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL

STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma

Funder: European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712 Czech Science Foundation (GA CR), junior project no. 19-23424Y MEYS CZ project CEITEC 2020 (LQ1601)Funder: MEYS CZ project CEITEC 2020 (LQ1601) NCMG research infrastructure (LM22018132 funded by MEYS CR)Funder: European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712.Funder: MH CZ-RVO 6526970

Biogeowissenschaftlich-paläoökologische Untersuchungen zur spätglazialen und holozänen Entwicklung von Landschaft und Flusssystem an der Jeetzel im mittleren Elbetal

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