Publications by authors named "Michael Hummel"

296 Publications

[Detection of BRAF V600E mutation in metastatic colorectal carcinoma : A QuIP round robin test].

Pathologe 2021 Nov 22. Epub 2021 Nov 22.

Institut für Pathologie, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Virchowweg 15, 10117, Berlin, Deutschland.

Round robin testing is an important instrument for quality assurance. Increasingly, this also applies to the results of molecular diagnostics in pathology, which directly influence therapy decisions in precision oncology. In metastatic colorectal carcinoma (mCRC), the focus has been on detecting KRAS and NRAS mutations, whose absence allows therapy with EGFR blocking antibodies. Recently, BRAF has been added as another predictive marker, since mCRC patients with BRAF V600E mutation benefit significantly from treatment with encorafenib (a BRAF inhibitor) in combination with cetuximab (anti-EGFR antibody) after systemic therapy. Due to the approval of this treatment in 2020, it is a pre-requisite that BRAF V600E mutation detection in diagnostic pathologies is reliably performed. Therefore, this round robin test with BRAF V600E testing either by immunohistochemistry or molecular methods was performed. The round robin test results demonstrate that molecular BRAF V600E detection is currently clearly superior to immunohistochemical detection.
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http://dx.doi.org/10.1007/s00292-021-01022-8DOI Listing
November 2021

Fast and quantitative compositional analysis of hybrid cellulose-based regenerated fibers using thermogravimetric analysis and chemometrics.

Cellulose (Lond) 2021 28;28(11):6797-6812. Epub 2021 May 28.

Department of Bioproducts and Biosystems, Aalto University, P. O. Box 16300, 00076 Espoo, Finland.

Cellulose can be dissolved with another biopolymer in a protic ionic liquid and spun into a bicomponent hybrid cellulose fiber using the Ioncell technology. Inside the hybrid fibers, the biopolymers are mixed at the nanoscale, and the second biopolymer provides the produced hybrid fiber new functional properties that can be fine-tuned by controlling its share in the fiber. In the present work, we present a fast and quantitative thermoanalytical method for the compositional analysis of man-made hybrid cellulose fibers by using thermogravimetric analysis (TGA) in combination with chemometrics. First, we incorporated 0-46 wt.% of lignin or chitosan in the hybrid fibers. Then, we analyzed their thermal decomposition behavior in a TGA device following a simple, one-hour thermal treatment protocol. With an analogy to spectroscopy, we show that the derivative thermogram can be used as a predictor in a multivariate regression model for determining the share of lignin or chitosan in the cellulose hybrid fibers. The method generated cross validation errors in the range 1.5-2.1 wt.% for lignin and chitosan. In addition, we discuss how the multivariate regression outperforms more common modeling methods such as those based on thermogram deconvolution or on linear superposition of reference thermograms. Moreover, we highlight the versatility of this thermoanalytical method-which could be applied to a wide range of composite materials, provided that their components can be thermally resolved-and illustrate it with an additional example on the measurement of polyester content in cellulose and polyester fiber blends. The method could predict the polyester content in the cellulose-polyester fiber blends with a cross validation error of 1.94 wt.% in the range of 0-100 wt.%. Finally, we give a list of recommendations on good experimental and modeling practices for the readers who want to extend the application of this thermoanalytical method to other composite materials.

Supplementary Information: The online version contains supplementary material available at 10.1007/s10570-021-03923-6.
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http://dx.doi.org/10.1007/s10570-021-03923-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550718PMC
May 2021

Effect of Enzymatic Depolymerization of Cellulose and Hemicelluloses on the Direct Dissolution of Prehydrolysis Kraft Dissolving Pulp.

Biomacromolecules 2021 11 21;22(11):4805-4813. Epub 2021 Oct 21.

Department of Bioproducts and Biosystems, Aalto University, P.O. Box 16300, FI-00076 Aalto, Finland.

Prehydrolysis kraft (PHK) pulps account for more than half of the global market of dissolving pulp. Characterized by high reactivity toward dissolution, their performances can still be improved by activation treatments. This study compares the dissolution kinetics in cupriethylenediamine of a hardwood and a softwood PHK pulps before and after their activation by high-solid-content mechano-enzymatic treatments. Three enzyme combinations were tested: endoglucanase (E), xylanase and mannanase (XM), and endoglucanase, xylanase, and mannanase (EXM). Xylanase and mannanase reduced the hemicellulose content of only hardwood (by max. 2.4%). Mixing and carbohydrate depolymerization decreased the dissolution time of hardwood and softwood pulps by a maximum of 63 and 30% with E, 37 and 16% with XM, and 44 and 30% with EXM, respectively. The shortening of the dissolution time was partially hindered by hornification, which increased with hemicellulose degradation. Interestingly, XM accelerated the dissolution while preserving a high weight-average molecular mass.
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http://dx.doi.org/10.1021/acs.biomac.1c01102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579402PMC
November 2021

Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL).

Cancers (Basel) 2021 Oct 7;13(19). Epub 2021 Oct 7.

Max-Delbrück-Center (MDC) for Molecular Medicine, 13125 Berlin, Germany.

In 50-60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK) ALCL. Key pathogenic events in ALK-negative (ALK) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK and ALK ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK ALCL or of CD95 death-receptor signaling in ALK ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity.
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http://dx.doi.org/10.3390/cancers13195012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507667PMC
October 2021

Cerebral Abnormalities in Spina Bifida: A Neuropathological Study.

Pediatr Dev Pathol 2021 Oct 6:10935266211040500. Epub 2021 Oct 6.

Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Introduction: Spina bifida (SB) is the most common neural tube defect in humans. Here, we analyzed systematically the neuropathological findings of the brain in SB cases.

Methods: 79 cases with SB aperta (SBA) and 6 cases with SB occulta (SBO) autopsied at the Charité Neuropathology from 1974 to 2000 were re-evaluated retrospectively. For this, case files and spinal cord as well as brain sections were studied.

Results: While no brain malformations were detected in SBO cases, 95% of SBA cases had brain malformations. Main brain anomalies identified were hydrocephalus (71%), Chiari II malformation (36%), heterotopia (34%), other cerebellar anomalies (36%), gyrification defects (33%), and ependymal denudation (29%). Hydrocephalus was observed as early as gestational week 17 and was highly associated to Chiari II and ependymal denudation. In 55% SBA was accompanied by further anomalies not primarily affecting the CNS.

Conclusion: We confirm using neuropathologic methods brain malformations in most SBA but none in SBO cases. In addition to our previous radiologic study, we now demonstrate the high prevalence of cerebellar malformations and cerebral heterotopias in SBA. The early detection of hydrocephalus and Chiari II malformation in fetuses raises the question whether these arise parallel rather than in strict temporal sequence.
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http://dx.doi.org/10.1177/10935266211040500DOI Listing
October 2021

Mucosal melanomas of different anatomic sites share a common global DNA methylation profile with cutaneous melanoma but show location-dependent patterns of genetic and epigenetic alterations.

J Pathol 2021 Sep 26. Epub 2021 Sep 26.

German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Cutaneous, ocular, and mucosal melanomas are histologically indistinguishable tumors that are driven by a different spectrum of genetic alterations. With current methods, identification of the site of origin of a melanoma metastasis is challenging. DNA methylation profiling has shown promise for the identification of the site of tumor origin in various settings. Here we explore the DNA methylation landscape of melanomas from different sites and analyze if different melanoma origins can be distinguished by their epigenetic profile. We performed DNA methylation analysis, next generation DNA panel sequencing, and copy number analysis of 82 non-cutaneous and 25 cutaneous melanoma samples. We further analyzed eight normal melanocyte cell culture preparations. DNA methylation analysis separated uveal melanomas from melanomas of other primary sites. Mucosal, conjunctival, and cutaneous melanomas shared a common global DNA methylation profile. Still, we observed location-dependent DNA methylation differences in cancer-related genes, such as low frequencies of RARB (7/63) and CDKN2A promoter methylation (6/63) in mucosal melanomas, or a high frequency of APC promoter methylation in conjunctival melanomas (6/9). Furthermore, all investigated melanomas of the paranasal sinus showed loss of PTEN expression (9/9), mainly caused by promoter methylation. This was less frequently seen in melanomas of other sites (24/98). Copy number analysis revealed recurrent amplifications in mucosal melanomas, including chromosomes 4q, 5p, 11q and 12q. Most melanomas of the oral cavity showed gains of chromosome 5p with TERT amplification (8/10), while 11q amplifications were enriched in melanomas of the nasal cavity (7/16). In summary, mucosal, conjunctival, and cutaneous melanomas show a surprisingly similar global DNA methylation profile and identification of the site of origin by DNA methylation testing is likely not feasible. Still, our study demonstrates tumor location-dependent differences of promoter methylation frequencies in specific cancer-related genes together with tumor site-specific enrichment for specific chromosomal changes and genetic mutations. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5808DOI Listing
September 2021

The journey to establishing an IT-infrastructure within the German Biobank Alliance.

PLoS One 2021 22;16(9):e0257632. Epub 2021 Sep 22.

German Biobank Node, Charité -Universitätsmedizin Berlin, Berlin, Germany.

Background: Biobanks ensure the long-term storage and accessibility of biospecimens and corresponding data sets. Thus, they form the foundation for many research projects which may contribute to improving medical care. With the establishment of the German Biobank Node and Alliance, expertise in biobanking is bundled and strengthened. An important component within this research infrastructure is the set-up of an information technology (IT) network for allowing feasibility requests across individual biobanks.

Objective: We aim to describe relevant aspects that have shaped the journey to interconnect biobanks, to enhance their visibility within the research-community, to harmonize data, and to enable feasibility searches to support access to available data and biosamples.

Methods: To achieve this task, we resorted to a wide variety of methods: we ran a requirement analysis, decided on the mode of operation for the federated team of IT-developers and on the development approach itself, took related national and international initiatives into account, and concluded with evaluations of the developed software artefacts and the operation of the entire chain of applications.

Results: We drew an IT framework including all heterogeneous data aspects derived from our requirement analysis and developed a comprehensive IT infrastructure. The successful implementation benefited from a smooth interaction of a federated IT team distributed across all participating sites that was even able to manage a major technology change mid-project. Authentication and project management services from associated partners could be integrated and the graphic user interface for an intuitive search tool for biospecimens was designed iteratively. The developed code is open source to ensure sustainability and the local implementation is concluded and functioning. The evaluation of the components was positive.

Conclusions: The entire project had given ample opportunity for challenges, predictable and unpredictable-from the mode of operation to changing some of the initial ideas. We learned our lessons concerning personnel, budget planning and technical as well as manual monitoring as well as some requirements arising only during the process of the project. Nevertheless, we can here report a success story of a network infrastructure, highly agile and much easier in local installation than initially anticipated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257632PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457464PMC
November 2021

BRAF testing in metastatic colorectal carcinoma and novel, chemotherapy-free therapeutic options.

Pathologe 2021 Nov 14;42(Suppl 1):98-109. Epub 2021 Jul 14.

Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany.

In the past 25 years, treatment of metastatic colorectal cancer (mCRC) has undergone profound changes. The approval of newer chemotherapeutics such as irinotecan and oxaliplatin was followed in 2005 by the first targeted therapies, for example, monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), as cetuximab and panitumumab, or the angiogenesis inhibitors bevacizumab, ramucirumab, and aflibercept. With the rapidly progressing molecular characterization of mCRC in the last 10 years and the classification of the disease in four consensus subtypes, further changes are emerging, which will promote, among other things, the introduction of protein-kinase inhibitors developed for specific molecular aberrations as well as immune checkpoint inhibitors into the treatment algorithm.Thorough molecular pathologic testing is indispensable today for guideline-compliant treatment of mCRC patients. In addition to RAS testing as a precondition for the therapy decision with regard to cetuximab and panitumumab, BRAF testing is of considerable relevance to allow decision making with regard to the newly approved chemotherapy-free combination of the BRAF inhibitor encorafenib and cetuximab in cases where a BRAF-V600E mutation is detected. Additional diagnostic tests should also include genome instability (microsatellite instability). Overall, more and more molecular alterations need to be investigated simultaneously, so that the use of focused next-generation sequencing is increasingly recommended.This overview describes the prognostic relevance of BRAF testing in the context of molecular pathologic diagnostics of mCRC, presents new treatment options for BRAF-mutated mCRC patients, and explains which modern DNA analytical and immunohistochemical methods are available to detect BRAF mutations in mCRC patients.
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http://dx.doi.org/10.1007/s00292-021-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571135PMC
November 2021

Next-Generation Sequencing-Based Clonality Assessment of Ig Gene Rearrangements: A Multicenter Validation Study by EuroClonality-NGS.

J Mol Diagn 2021 09 26;23(9):1105-1115. Epub 2021 Jun 26.

Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.

Ig gene (IG) clonality analysis has an important role in the distinction of benign and malignant B-cell lymphoid proliferations and is mostly performed with the conventional EuroClonality/BIOMED-2 multiplex PCR protocol and GeneScan fragment size analysis. Recently, the EuroClonality-NGS Working Group developed a method for next-generation sequencing (NGS)-based IG clonality analysis. Herein, we report the results of an international multicenter biological validation of this novel method compared with the gold standard EuroClonality/BIOMED-2 protocol, based on 209 specimens of reactive and neoplastic lymphoproliferations. NGS-based IG clonality analysis showed a high interlaboratory concordance (99%) and high concordance with conventional clonality analysis (98%) for the molecular conclusion. Detailed analysis of the individual IG heavy chain and kappa light chain targets showed that NGS-based clonality analysis was more often able to detect a clonal rearrangement or yield an interpretable result. NGS-based and conventional clonality analysis detected a clone in 96% and 95% of B-cell neoplasms, respectively, and all but one of the reactive cases were scored polyclonal. We conclude that NGS-based IG clonality analysis performs comparable to conventional clonality analysis. We provide critical parameters for interpretation and discuss a first step toward a quantitative scoring approach for NGS clonality results. Considering the advantages of NGS-based clonality analysis, including its high sensitivity and possibilities for accurate clonal comparison, this supports implementation in diagnostic practice.
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http://dx.doi.org/10.1016/j.jmoldx.2021.06.005DOI Listing
September 2021

Status quo of ALK testing in lung cancer: results of an EQA scheme based on in-situ hybridization, immunohistochemistry, and RNA/DNA sequencing.

Virchows Arch 2021 Aug 25;479(2):247-255. Epub 2021 Jun 25.

Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, 10117, Berlin, Germany.

With this external quality assessment (EQA) scheme, we aim to investigate the diagnostic performance of the currently available methods for the detection of ALK alterations in non-small cell lung cancer on a national scale, namely, in situ hybridization (ISH), immunohistochemistry (IHC), and RNA/DNA sequencing (NGS). The EQA scheme cohort consisted of ten specimens, including four ALK positive and six ALK negative samples, which were thoroughly pretested using IHC, ISH, and RNA/DNA NGS. Unstained tumor sections were provided to the 57 participants, and the results were retrieved via an online questionnaire. ISH was used by 29, IHC by 38, and RNA/DNA sequencing by 19 participants. Twenty-eight institutions (97%) passed the ring trial using ISH, 33 (87%) by using IHC, and 18 (95%) by using NGS. The highest sensitivity and interrater agreement (Fleiss ' kappa) was observed for RNA/DNA sequencing (99%, 0.975), followed by ISH (94%, 0.898) and IHC (92%, 0.888). However, the proportion of samples that were not evaluable due to bad tissue quality was also higher for RNA/DNA sequencing (4%) compared with ISH (0.7%) and IHC (0.5%). While all three methods produced reliable results between the different institutions, the highest sensitivity and concordance were observed for RNA/DNA sequencing. These findings encourage the broad implementation of this method in routine diagnostic, although the application might be limited by technical capacity, economical restrictions, and tissue quality of formalin-fixed samples.
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http://dx.doi.org/10.1007/s00428-021-03106-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364534PMC
August 2021

[Molecular tumor boards - insights and perspectives].

Pathologe 2021 Jul 25;42(4):357-362. Epub 2021 Jun 25.

Institut für Pathologie, Charité - Universitätsmedizin Berlin, Berlin, Deutschland.

The rapid development of molecular technologies and targeted therapies has fostered the implementation of specialized tumor conferences, known as molecular tumor boards (MTBs). MTBs become particularly important when treatment recommendations are needed based on molecular alterations beyond the approved targeted therapies. While an MTB's goals are based on individualized diagnostics and therapies of tumor patients using innovative technologies and biomarkers, the procedures of MTBs are still quite heterogeneous. This applies to the primary inclusion criteria for tumor patients, the composition of MTBs, the applied diagnostic tests and their assessment and reporting, the evaluation of their clinical value and implementation in a therapeutic strategy, and the associated quality assurance measurements as well as knowledge-gaining, economical, legal, and ethical aspects.This article provides an overview of the spectrum of MTBs, their challenges, and the potential for individualized cancer medicine.
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http://dx.doi.org/10.1007/s00292-021-00955-4DOI Listing
July 2021

Hypoglycemia in Older Adults: Time Trends and Treatment Differences in Patients Aged ≥75 Years With Type 2 Diabetes.

J Am Med Dir Assoc 2021 09 1;22(9):1898-1905.e1. Epub 2021 Jun 1.

Ulm University, Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm, Germany; German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany.

Objectives: Hypoglycemia is a potentially life-threatening drug event under antidiabetic treatment. The aim of the study was to examine time trends in severe hypoglycemia in older adults with type 2 diabetes mellitus (T2DM) and antidiabetic treatment.

Design: Multicenter prospective diabetes patient follow-up registry (DPV).

Setting And Participants: Patients aged ≥75 years with T2DM and documented treatment between 2005 and 2019.

Methods: Outcomes of interest were rates of severe hypoglycemia, diabetes therapy, body mass index, HbA1c, and estimated glomerular filtration rate. Time trends of outcomes were analyzed in the whole cohort and compared between age groups (75-<80, 80-<85, ≥85 years).

Results: A total of 136,931 patients from 188 diabetes centers were included. The adjusted HbA1c decreased from 7.3% (95% confidence interval 7.3-7.4) in 2005 to 7.2% (7.2-7.2) in 2019 (P < .001), with no significant difference between age groups (P = .47). Rates of severe hypoglycemia decreased from 6.7 (6.0-7.4) to 4.1 of 100 person-years (3.7-4.5) (P < .001) in the entire population. Patients aged ≥85 years had constantly lower HbA1c levels compared with younger groups (P < .001). Although severe hypoglycemia decreased the most in the ≥85 age group (P < .001), severe hypoglycemia remained consistently higher in this group compared with the 75 to <80 years group (P < .001).

Conclusions And Implications: During the analyzed time, the risk for severe hypoglycemia decreased. Although drugs with intrinsic risk for hypoglycemia were used less frequently, antidiabetic treatment in older adults should be further improved to continue reducing severe hypoglycemia in this age group, potentially accepting less strict metabolic control and age-specific target ranges.
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http://dx.doi.org/10.1016/j.jamda.2021.05.006DOI Listing
September 2021

Stakeholder engagement to ensure the sustainability of biobanks: a survey of potential users of biobank services.

Eur J Hum Genet 2021 May 24. Epub 2021 May 24.

German Biobank Node, Charité Universitätsmedizin Berlin, Berlin, Germany.

Biobanks are important infrastructures facilitating biomedical research. After a decade of rolling out such infrastructures, a shift in attention to the sustainability of biobanks could be observed in recent years. In this regard, an increase in the as yet relatively low utilisation rates of biobanks has been formulated as a goal. Higher utilisation rates can only be achieved if the perspectives of potential users of biobanks-particularly researchers not yet collaborating with biobanks-are adequately considered. To better understand their perspectives, a survey was conducted at ten different research institutions in Germany hosting a centralised biobank. The survey targeted potential users of biobank services, i.e. researchers working with biosamples. It addressed the general demand for biosamples, strategies for biosample acquisition/storage and reasons for/against collaborating with biobanks. In total, 354 researchers filled out the survey. Most interestingly, only a minority of researchers (12%) acquired their biosamples via biobanks. Of the respondents not collaborating with biobanks on sample acquisition, around half were not aware of the (services of the) respective local biobank. Those who actively decided against acquiring biosamples via a biobank provided different reasons. Most commonly, respondents stated that the biosamples required were not available, the costs were too high and information about the available biosamples was not readily accessible. Biobanks can draw many lessons from the results of the survey. Particularly, external communication and outreach should be improved. Additionally, biobanks might have to reassess whether their particular collection strategies are adequately aligned with local researchers' needs.
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http://dx.doi.org/10.1038/s41431-021-00905-xDOI Listing
May 2021

Validation of a Targeted Next-Generation Sequencing Panel for Tumor Mutation Burden Analysis: Results from the Onconetwork Immuno-Oncology Consortium.

J Mol Diagn 2021 07 6;23(7):882-893. Epub 2021 May 6.

Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy. Electronic address:

Tumor mutation burden (TMB) is evaluated as a biomarker of response to immunotherapy. We present the efforts of the Onconetwork Immuno-Oncology Consortium to validate a commercial targeted sequencing test for TMB calculation. A three-phase study was designed to validate the Oncomine Tumor Mutational Load (OTML) assay at nine European laboratories. Phase 1 evaluated reproducibility and accuracy on seven control samples. In phase 2, six formalin-fixed, paraffin-embedded samples tested with FoundationOne were reanalyzed with the OTML panel to evaluate concordance and reproducibility. Phase 3 involved analysis of 90 colorectal cancer samples with known microsatellite instability (MSI) status to evaluate TMB and MSI association. High reproducibility of TMB was demonstrated among the sites in the first and second phases. Strong correlation was also detected between mean and expected TMB in phase 1 (r = 0.998) and phase 2 (r = 0.96). Detection of actionable mutations was also confirmed. In colorectal cancer samples, the expected pattern of MSI-high/high-TMB and microsatellite stability/low-TMB was present, and gene signatures produced by the panel suggested the presence of a POLE mutation in two samples. The OTML panel demonstrated robustness and reproducibility for TMB evaluation. Results also suggest the possibility of using the panel for mutational signatures and variant detection. Collaborative efforts between academia and companies are crucial to accelerate the translation of new biomarkers into clinical research.
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http://dx.doi.org/10.1016/j.jmoldx.2021.04.008DOI Listing
July 2021

[BRAF-V600E testing in metastatic colorectal cancer and new, chemotherapy-free therapy options. German version].

Pathologe 2021 Nov 6;42(6):578-590. Epub 2021 May 6.

Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland.

In the past 25 years, treatment of metastatic colorectal cancer (mCRC) has undergone profound changes. The approval of newer chemotherapeutics such as irinotecan and oxaliplatin was followed in 2005 by the first targeted therapies, for example, monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), as cetuximab and panitumumab, or the angiogenesis inhibitors bevacizumab, ramucirumab, and aflibercept. With the rapidly progressing molecular characterization of mCRC in the last 10 years and the classification of the disease in four consensus subtypes, further changes are emerging, which will promote, among other things, the introduction of protein-kinase inhibitors developed for specific molecular aberrations as well as immune checkpoint inhibitors into the treatment algorithm.Thorough molecular pathologic testing is indispensable today for guideline-compliant treatment of mCRC patients. In addition to RAS testing as a precondition for the therapy decision with regard to cetuximab and panitumumab, BRAF testing is of considerable relevance to allow decision making with regard to the newly approved chemotherapy-free combination of the BRAF inhibitor encorafenib and cetuximab in cases where a BRAF-V600E mutation is detected. Additional diagnostic tests should also include genome instability (microsatellite instability). Overall, more and more molecular alterations need to be investigated simultaneously, so that the use of focused next-generation sequencing is increasingly recommended.This overview describes the prognostic relevance of BRAF testing in the context of molecular pathologic diagnostics of mCRC, presents new treatment options for BRAF-mutated mCRC patients, and explains which modern DNA analytical and immunohistochemical methods are available to detect BRAF mutations in mCRC patients.
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http://dx.doi.org/10.1007/s00292-021-00942-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536591PMC
November 2021

Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas.

Leukemia 2021 07 5;35(7):2002-2016. Epub 2021 May 5.

University of Duesseldorf, Medical Faculty, Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Düsseldorf, Germany.

B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood. By performing whole genome and transcriptome sequencing of 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct mutational signatures linked to SHM and CSR. We show that not only SHM, but presumably also CSR causes off-target mutations in non-IG genes. Kataegis clusters with high mutational density mainly affected early replicating regions and were enriched for SHM- and CSR-mediated off-target mutations. Moreover, they often co-occurred in loci physically interacting in the nucleus, suggesting that mutation hotspots promote increased mutation targeting of spatially co-localized loci (termed hypermutation by proxy). Only around 1% of somatic small variants were in protein coding sequences, but in about half of the driver genes, a contribution of B-cell specific mutational processes to their mutations was found. The B-cell-specific mutational processes contribute to both lymphoma initiation and intratumoral heterogeneity. Overall, we demonstrate that mutational processes involved in the development of gcBCL are more complex than previously appreciated, and that B cell-specific mutational processes contribute via diverse mechanisms to lymphomagenesis.
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http://dx.doi.org/10.1038/s41375-021-01251-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257491PMC
July 2021

Classification of Molecular Subtypes of High-Grade Serous Ovarian Cancer by MALDI-Imaging.

Cancers (Basel) 2021 Mar 25;13(7). Epub 2021 Mar 25.

Tumorbank Ovarian Cancer Network, ENGOT biobank, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.

Despite the correlation of clinical outcome and molecular subtypes of high-grade serous ovarian cancer (HGSOC), contemporary gene expression signatures have not been implemented in clinical practice to stratify patients for targeted therapy. Hence, we aimed to examine the potential of unsupervised matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) to stratify patients who might benefit from targeted therapeutic strategies. Molecular subtyping of paraffin-embedded tissue samples from 279 HGSOC patients was performed by NanoString analysis (ground truth labeling). Next, we applied MALDI-IMS paired with machine-learning algorithms to identify distinct mass profiles on the same paraffin-embedded tissue sections and distinguish HGSOC subtypes by proteomic signature. Finally, we devised a novel approach to annotate spectra of stromal origin. We elucidated a MALDI-derived proteomic signature (135 peptides) able to classify HGSOC subtypes. Random forest classifiers achieved an area under the curve (AUC) of 0.983. Furthermore, we demonstrated that the exclusion of stroma-associated spectra provides tangible improvements to classification quality (AUC = 0.988). Moreover, novel MALDI-based stroma annotation achieved near-perfect classifications (AUC = 0.999). Here, we present a concept integrating MALDI-IMS with machine-learning algorithms to classify patients according to distinct molecular subtypes of HGSOC. This has great potential to assign patients for personalized treatment.
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http://dx.doi.org/10.3390/cancers13071512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036744PMC
March 2021

KRAS/TP53 co-mutations identify long-term responders to first line palliative treatment with pembrolizumab monotherapy in PD-L1 high (≥50%) lung adenocarcinoma.

Transl Lung Cancer Res 2021 Feb;10(2):737-752

Klinik für Pneumologie - Evangelische Lungenklinik Berlin Buch, Berlin, Germany.

Background: Pembrolizumab is a standard of care as first line palliative therapy in PD-L1 overexpressing (≥50%) non-small cell lung cancer (NSCLC). This study aimed at the identification of KRAS and TP53-defined mutational subgroups in the PD-L1 high population to distinguish long-term responders from those with limited benefit.

Methods: In this retrospective, observational study, patients from 4 certified lung cancer centers in Berlin, Germany, having received pembrolizumab monotherapy as first line palliative treatment for lung adenocarcinoma (LuAD) from 2017 to 2018, with PD-L1 expression status and targeted NGS data available, were evaluated.

Results: A total of 119 patients were included. Rates for KRAS, TP53 and combined mutations were 52.1%, 47.1% and 21.9%, respectively, with no association given between KRAS and TP53 mutations (P=0.24). By trend, PD-L1 expression was higher in KRAS-positive patients (75% 65%, P=0.13). Objective response rate (ORR), median progression-free survival (PFS) and overall survival (OS) in the KRAS group (n=32, 51.6%) were 63.3%, 19.8 months (mo.) and not estimable (NE), respectively. Results in KRAS and wild type patients were similar and by far lower (42.7%, P=0.06; 6.2 mo., P<0.001; 23.4 mo., P=0.08). TP53 mutations alone had no impact on response and survival. However, KRAS/TP53 co-mutations (n=12) defined a subset of long-term responders (ORR 100.0%, PFS 33.3 mo., OS NE). In contrast, patients with KRAS/TP53 mutations showed a dismal prognosis (ORR 27.3%, P=0.002; PFS 3.9 mo., P=0.001, OS 9.7 mo., P=0.02).

Conclusions: A comprehensive assessment of KRAS subtypes and TP53 mutations allows a highly relevant prognostic differentiation of patients with metastatic, PD-L1 high LuAD treated upfront with pembrolizumab.
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http://dx.doi.org/10.21037/tlcr-20-958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947421PMC
February 2021

Towards a unification of treatments and interventions for tinnitus patients: The EU research and innovation action UNITI.

Prog Brain Res 2021 4;260:441-451. Epub 2021 Feb 4.

Tinnitus Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Tinnitus is the perception of a phantom sound and the patient's reaction to it. Although much progress has been made, tinnitus remains a scientific and clinical enigma of high prevalence and high economic burden, with an estimated prevalence of 10%-20% among the adult population. The EU is funding a new collaborative project entitled "Unification of Treatments and Interventions for Tinnitus Patients" (UNITI, grant no. 848261) under its Horizon 2020 framework. The main goal of the UNITI project is to set the ground for a predictive computational model based on existing and longitudinal data attempting to address the question of which treatment or combination of treatments is optimal for a specific patient group based on certain parameters. Clinical, epidemiological, genetic and audiological data, including signals reflecting ear-brain communication, as well as patients' medical history, will be analyzed making use of existing databases. Predictive factors for different patient groups will be extracted and their prognostic relevance validated through a Randomized Clinical Trial (RCT) in which different patient groups will undergo a combination of tinnitus therapies targeting both auditory and central nervous systems. From a scientific point of view, the UNITI project can be summarized into the following research goals: (1) Analysis of existing data: Results of existing clinical studies will be analyzed to identify subgroups of patients with specific treatment responses and to identify systematic differences between the patient groups at the participating clinical centers. (2) Genetic and blood biomarker analysis: High throughput Whole Exome Sequencing (WES) will be performed in well-characterized chronic tinnitus cases, together with Proximity Extension Assays (PEA) for the identification of blood biomarkers for tinnitus. (3) RCT: A total of 500 patients will be recruited at five clinical centers across Europe comparing single treatments against combinational treatments. The four main treatments are Cognitive Behavioral Therapy (CBT), hearing aids, sound stimulation, and structured counseling. The consortium will also make use of e/m-health applications for the treatment and assessment of tinnitus. (4) Decision Support System: An innovative Decision Support System will be implemented, integrating all available parameters (epidemiological, clinical, audiometry, genetics, socioeconomic and medical history) to suggest specific examinations and the optimal intervention strategy based on the collected data. (5) Financial estimation analysis: A cost-effectiveness analysis for the respective interventions will be calculated to investigate the economic effects of the interventions based on quality-adjusted life years. In this paper, we will present the UNITI project, the scientific questions that it aims to address, the research consortium, and the organizational structure.
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http://dx.doi.org/10.1016/bs.pbr.2020.12.005DOI Listing
November 2021

Green Conducting Cellulose Yarns for Machine-Sewn Electronic Textiles.

ACS Appl Mater Interfaces 2020 Dec 7;12(50):56403-56412. Epub 2020 Dec 7.

Department of Chemistry and Chemical Engineering, Chalmers University of Technology, 41296 Göteborg, Sweden.

The emergence of "green" electronics is a response to the pressing global situation where conventional electronics contribute to resource depletion and a global build-up of waste. For wearable applications, green electronic textile (e-textile) materials present an opportunity to unobtrusively incorporate sensing, energy harvesting, and other functionality into the clothes we wear. Here, we demonstrate electrically conducting wood-based yarns produced by a roll-to-roll coating process with an ink based on the biocompatible polymer:polyelectrolyte complex poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS). The developed e-textile yarns display a, for cellulose yarns, record-high bulk conductivity of 36 Scm, which could be further increased to 181 Scm by adding silver nanowires. The PEDOT:PSS-coated yarn could be machine washed at least five times without loss in conductivity. We demonstrate the electrochemical functionality of the yarn through incorporation into organic electrochemical transistors (OECTs). Moreover, by using a household sewing machine, we have manufactured an out-of-plane thermoelectric textile device, which can produce 0.2 μW at a temperature gradient of 37 K.
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http://dx.doi.org/10.1021/acsami.0c15399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747218PMC
December 2020

[Diagnosis and therapy of tumors with NTRK gene fusion].

Pathologe 2021 Feb;42(1):103-115

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

NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare tumors such as infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast, or salivary gland carcinoma. NTRK gene fusions or TRK fusion proteins are considered strong oncogenic drivers. If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. So far only larotrectinib is approved in the European Union. Both drugs have been shown to be effective and well tolerated in phase I and phase II studies. The low prevalence of TRK fusion-positive cancers poses challenges for diagnostic and clinical work-flows. On one hand, patients with NTRK gene fusions should be identified; on the other hand, epidemiological, histological, and resource-related aspects have to be taken into account. Based on these premises, we suggest a diagnostic algorithm for TRK fusion cancers and present current data on TRK inhibitors.
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http://dx.doi.org/10.1007/s00292-020-00864-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858552PMC
February 2021

Immunoprofiling in Neuroendocrine Neoplasms Unveil Immunosuppressive Microenvironment.

Cancers (Basel) 2020 Nov 19;12(11). Epub 2020 Nov 19.

Department of Hematology, Oncology and Tumor Immunology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 12203 Berlin, Germany.

Checkpoint inhibitors have shown promising results in a variety of tumors; however, in neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), low response rates were reported. We aimed herein to investigate the tumor immune microenvironment in NET/NEC to determine whether checkpoint pathways like programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) might play a role in immune escape and whether other escape mechanisms might need to be targeted to enable a functional antitumor response. Forty-eight NET and thirty NEC samples were analyzed by immunohistochemistry (IHC) and mRNA immunoprofiling including digital spatial profiling. Through IHC, both NET/NEC showed stromal, but less intratumoral CD3+ T cell infiltration, although this was significantly higher in NEC compared to NET. Expression of PD1, PD-L1, and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on immune cells was low or nearly absent. mRNA immunoprofiling revealed low expression of IFNγ inducible genes in NET and NEC without any spatial heterogeneity. However, we observed an increased mRNA expression of chemokines, which attract myeloid cells in NET and NEC, and a high abundance of genes related to immunosuppressive myeloid cells and genes with immunosuppressive functions like CD47 and CD74. In conclusion, NET and NEC lack signs of an activation of the adaptive immune system, but rather show abundance of several immunosuppressive genes that represent potential targets for immunomodulation.
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http://dx.doi.org/10.3390/cancers12113448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699546PMC
November 2020

Cellulose-lignin composite fibres as precursors for carbon fibres. Part 1 - Manufacturing and properties of precursor fibres.

Carbohydr Polym 2021 Jan 28;252:117133. Epub 2020 Sep 28.

Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems, P.O. Box 16300, 00076, Aalto, Finland. Electronic address:

Cellulose-lignin composite fibres were spun from ionic liquid (IL) solutions by dry-jet wet spinning. Birch pre-hydrolysed Kraft (PHK) pulp and organosolv beech (BL) or spruce lignin (SL) were dissolved in the IL 1,5-diazabicyclo[4.3.0]non-5-enium acetate ([DBNH]OAc) to prepare spinning dopes. Fibres with lignin concentrations of up to 50 % were spun successfully. The fibres were analysed focusing on important properties for the production of carbon fibres (CF). Due to the higher molar mass of the SL compared to the BL, SL showed higher stability in the spinning process, giving higher lignin content in the final fibres. The CF yield after carbonization increased with increasing lignin content. The higher carbon content of SL compared to BL, resulted in moderately higher CF yield of the SL fibres, compared to fibres with BL. Overall, the produced cellulose-lignin composite fibres show great potential as precursors for CF production.
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http://dx.doi.org/10.1016/j.carbpol.2020.117133DOI Listing
January 2021

TFE3 activation in a TSC1-altered malignant PEComa: challenging the dichotomy of the underlying pathogenic mechanisms.

J Pathol Clin Res 2021 01 12;7(1):3-9. Epub 2020 Nov 12.

Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Perivascular epithelioid cell tumors (PEComas) form a family of rare mesenchymal neoplasms that typically display myomelanocytic differentiation. Upregulation of mTOR signaling due the inactivation of TSC1/2 (Tuberous Sclerosis 1 and 2) is believed to be a key oncogenic driver in this disease. Recently, a subgroup of PEComas harboring TFE3 (Transcription Factor E3) rearrangements and presenting with a distinctive morphology has been identified. TSC1/2 and TFE3 aberrations are deemed to be mutually exclusive in PEComa, with two different pathogenic mechanisms assumed to lead to tumorigenesis. Here, we challenge this dichotomy by presenting a case of a clinically aggressive TCS1-mutated PEComa displaying a TFE3-altered phenotype. FISH analysis was suggestive of a TFE3 inversion; however, RNA and whole genome sequencing was ultimately unable to identify a fusion involving the gene. However, a copy number increase of the chromosomal region encompassing TFE3 was detected and transcriptome analysis confirmed upregulation of TFE3, which was also seen at the protein level. Therefore, we believe that the TSC1/2-mTOR pathway and TFE3 overexpression can simultaneously contribute to tumorigenesis in PEComa. Our comprehensive genetic analyses add to the understanding of the complex pathogenic mechanisms underlying PEComa and harbor insights for clinical treatment options.
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http://dx.doi.org/10.1002/cjp2.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737753PMC
January 2021

Cellulose-lignin composite fibers as precursors for carbon fibers: Part 2 - The impact of precursor properties on carbon fibers.

Carbohydr Polym 2020 Dec 17;250:116918. Epub 2020 Aug 17.

Institute for Frontier Materials, Deakin University, Geelong, Vic 3217, Australia. Electronic address:

Carbon fibers, despite being responsible lightweight structures that improve sustainability through fuel efficiency and occupational safety, remain largely derived from fossil fuels. Alternative precursors such as cellulose and lignin (bio-derived and low cost) are rapidly gaining attention as replacements for polyacrylonitrile (PAN, an oil-based and costly precursor). This study uses a cellulose-lignin composite fiber, to elucidate the influence of precursor fabrication parameters (draw ratio and lignin content) on the efficiency of stabilization and carbonization, from the perspective of the chemical, morphological and mechanical changes. The degradation of cellulose chains was the primary contributor to the decrease in mechanical properties during stabilization, but is slowed by the incorporation of lignin. The skin-core phenomenon, a typical effect in PAN-based carbon fibers production, was also observed. Finally, the carbonization of incompletely stabilized fibers is shown to produce hollow carbon fibers, which have potential application in batteries or membranes.
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http://dx.doi.org/10.1016/j.carbpol.2020.116918DOI Listing
December 2020

Integrative genomic analysis focused on cell cycle genes for MYC-driven aggressive mature B-cell lymphoma.

J Clin Exp Hematop 2020 ;60(3):87-96

Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany.

MYC is a transcriptional factor that regulates growth and proliferation through cell cycle pathways. MYC alterations, in particular MYC rearrangements, are important in assessing the prognosis of aggressive B-cell lymphoma. In this study, we focused on the impact of nine major cell cycle genes for MYC-driven aggressive mature B-cell lymphoma and analyzed the mutational status using targeted next generation sequencing. Our 40 cases of aggressive mature B-cell lymphomas included 5 Burkitt lymphomas, 17 high-grade B-cell lymphomas and 18 diffuse large B-cell lymphomas with MYC breaks in 100%, 88% and 11%, respectively. Our data allowed a molecular classification into four categories partially independent from the histopathological diagnosis but correlating with the Ki-67 labelling index: (I) harboring TP53 and CDKN2A mutations, being highly proliferative, (II) with MYC rearrangement associated with MYC and/or ID3 mutations, being highly proliferative, (III) with MYC rearrangement combined with additional molecular changes, being highly proliferative, and (IV) with a diverse pattern of molecular alterations, being less proliferative. Taken together, we found that mutations of TP53, CDKN2A, MYC and ID3 are associated with highly proliferative B-cell lymphomas that could profit from novel therapeutic strategies.
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http://dx.doi.org/10.3960/jslrt.20021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596913PMC
January 2021

Close Packing of Cellulose and Chitosan in Regenerated Cellulose Fibers Improves Carbon Yield and Structural Properties of Respective Carbon Fibers.

Biomacromolecules 2020 10 17;21(10):4326-4335. Epub 2020 Sep 17.

Department of Bioproducts and Biosystems, Aalto University, Vuorimiehentie 1, Espoo 02150, Finland.

A low carbon yield is a major limitation for the use of cellulose-based filaments as carbon fiber precursors. The present study aims to investigate the use of an abundant biopolymer chitosan as a natural charring agent particularly on enhancing the carbon yield of the cellulose-derived carbon fiber. The ionic liquid 1,5-diazabicyclo[4.3.0]non-5-enium acetate ([DBNH]OAc) was used for direct dissolution of cellulose and chitosan and to spin cellulose-chitosan composite fibers through a dry-jet wet spinning process (Ioncell). The homogenous distribution and tight packing of cellulose and chitosan revealed by X-ray scattering experiments enable a synergistic interaction between the two polymers during the pyrolysis reaction, resulting in a substantial increase of the carbon yield and preservation of mechanical properties of cellulose fiber compared to other cobiopolymers such as lignin and xylan.
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http://dx.doi.org/10.1021/acs.biomac.0c01117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608939PMC
October 2020

Synthetic Notch-Receptor-Mediated Transmission of a Transient Signal into Permanent Information via CRISPR/Cas9-Based Genome Editing.

Cells 2020 08 20;9(9). Epub 2020 Aug 20.

Translational Hepatology and Stem Cell Biology, Department of Gastroenterology, Hepatology and Endocrinology, REBIRTH-Center for Translational Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany.

Synthetic receptor biology and genome editing are emerging techniques, both of which are currently beginning to be used in preclinical and clinical applications. We were interested in whether a combination of these techniques approaches would allow for the generation of a novel type of reporter cell that would recognize transient cellular events through specifically designed synthetic receptors and would permanently store information about these events via associated gene editing. Reporting cells could be used in the future to detect alterations in the cellular microenvironment, including degenerative processes or malignant transformation into cancer cells. Here, we explored synthetic Notch (synNotch) receptors expressed in human embryonic kidney cells to investigate the efficacy of antigen recognition events in a time- and dose-dependent manner. First, we evaluated the most suitable conditions for synNotch expression based on dsRed-Express fluorophore expression. Then, we used a synNotch receptor coupled to transcriptional activators to induce the expression of a Cas9 nuclease targeted to a specific genomic DNA site. Our data demonstrate that recognition of various specific antigens via synNotch receptors robustly induced Cas9 expression and resulted in an indel formation frequency of 34.5%-45.5% at the targeted CXCR4 locus. These results provide proof of concept that reporter cells can be designed to recognize a given event and to store transient information permanently in their genomes.
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http://dx.doi.org/10.3390/cells9091929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563181PMC
August 2020

Exploring Large Ductility in Cellulose Nanopaper Combining High Toughness and Strength.

ACS Nano 2020 09 19;14(9):11150-11159. Epub 2020 Aug 19.

Department of Bioproducts and Biosystems, School of Chemical Engineering, Aalto University P.O. Box 16300, FI-00076 Espoo, Finland.

Cellulose nanopaper is a strong lightweight material made from renewable resources with a wide range of potential applications, from membranes to electronic displays. Most studies on nanopaper target high mechanical strength, which compromises ductility and toughness. Herein, we demonstrate the fabrication of highly ductile and tough cellulose nanopaper via mechanical fibrillation of hemicellulose-rich wood fibers and dispersion of the obtained cellulose nanofibrils (CNFs) in an ionic liquid (IL)-water mixture. This treatment allows hemicellulose swelling, which leads to dissociation of CNF bundles into highly disordered long flexible fibrils and the formation of a nanonetwork as supported by cryogenic transmission electron microscopy (cryo-TEM) imaging. Rheology of the suspensions shows a 300-fold increase in storage and loss moduli of CNF-IL-water suspensions, compared to their CNF-water counterparts. The nanopaper prepared by removing the IL-water shows a combination of large elongation (up to 35%), high strength (260 MPa), and toughness as high as 51 MJ/m, because of efficient interfibrillar slippage and energy dissipation in the highly disordered isotropic structure. This work provides a nanostructure-engineered strategy of making ductile and tough cellulose nanopaper.
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http://dx.doi.org/10.1021/acsnano.0c02302DOI Listing
September 2020

H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients.

Nat Commun 2020 07 20;11(1):3651. Epub 2020 Jul 20.

Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany.

Lesion-based targeting strategies underlie cancer precision medicine. However, biological principles - such as cellular senescence - remain difficult to implement in molecularly informed treatment decisions. Functional analyses in syngeneic mouse models and cross-species validation in patient datasets might uncover clinically relevant genetics of biological response programs. Here, we show that chemotherapy-exposed primary Eµ-myc transgenic lymphomas - with and without defined genetic lesions - recapitulate molecular signatures of patients with diffuse large B-cell lymphoma (DLBCL). Importantly, we interrogate the murine lymphoma capacity to senesce and its epigenetic control via the histone H3 lysine 9 (H3K9)-methyltransferase Suv(ar)39h1 and H3K9me3-active demethylases by loss- and gain-of-function genetics, and an unbiased clinical trial-like approach. A mouse-derived senescence-indicating gene signature, termed "SUVARness", as well as high-level H3K9me3 lymphoma expression, predict favorable DLBCL patient outcome. Our data support the use of functional genetics in transgenic mouse models to incorporate basic biology knowledge into cancer precision medicine in the clinic.
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http://dx.doi.org/10.1038/s41467-020-17467-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371731PMC
July 2020
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