Knowledge in the dark: scientific challenges and ways forward

A key dimension of our current era is Big Data, the rapid rise in produced data and information; a key frustration is that we are nonetheless living in an age of ignorance, as the real knowledge and understanding of people does not seem to be substantially increasing. This development has critical consequences, for example it limits the ability to find and apply effective solutions to pressing environmental and socioeconomic challenges. Here, we propose the concept of “knowledge in the dark”—or short: dark knowledge—and outline how it can help clarify key reasons for this development: (i) production of biased, erroneous, or fabricated data and information; (ii) inaccessibility and (iii) incomprehensibility of data and information; and (iv) loss of previous knowledge. Even in the academic realm, where financial interests are less pronounced than in the private sector, several factors lead to dark knowledge, that is they inhibit a more substantial increase in knowledge and understanding. We highlight four of these factors—loss of academic freedom, research biases, lack of reproducibility, and the Scientific tower of Babel—and offer ways to tackle them, for example establishing an international court of arbitration for research and developing advanced tools for research synthesis

Inhibition of IGF1-R overcomes IGFBP7-induced chemotherapy resistance in T-ALL

Background T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease with the need for treatment optimization. Previously, high expression of Insulin-like growth factor binding protein 7 (IGFBP7), a member of the IGF system, was identified as negative prognostic factor in adult T-ALL patients. Since aberrant IGFBP7 expression was observed in a variety of neoplasia and was relevant for prognosis in T-ALL, we investigated the functional role of IGFBP7 in Jurkat and Molt-4 cells as in vitro models for T-ALL. Methods Jurkat and Molt-4 cells were stably transfected with an IGFBP7 over-expression vector or the empty vector as control. Proliferation of the cells was assessed by WST-1 assays and cell cycle status was measured by flow-cytometry after BrDU/7-AAD staining. The effect of IGFBP7 over-expression on sensitivity to cytostatic drugs was determined in AnnexinV/7-AAD assays. IGF1-R protein expression was measured by Western Blot and flow-cytometric analysis. IGF1-R associated gene expression profiles were generated from microarray gene expression data of 86 T-ALL patients from the Microarrays Innovations in Leukemia (MILE) multicenter study. Results IGFBP7-transfected Jurkat cells proliferated less, leading to a longer survival in a nutrient–limited environment. Both IGFBP7-transfected Jurkat and Molt-4 cells showed an arrest in the G0/G1 cell cycle phase. Furthermore, Jurkat IGFBP7-transfected cells were resistant to vincristine and asparaginase treatment. Surface expression and whole protein measurement of IGF1-R protein expression showed a reduced abundance of the receptor after IGFBP7 transfection in Jurkat cells. Interestingly, combination of the IGF1-R inhibitor NPV-AEW541 restored sensitivity to vincristine in IGFBP7-transfected cells. Additionally, IGF1-R associated GEP revealed an up-regulation of important drivers of T-ALL pathogenesis and regulators of chemo-resistance and apoptosis such as NOTCH1, BCL-2, PRKCI, and TP53. Conclusion This study revealed a proliferation inhibiting effect of IGFBP7 by G0/G1 arrest and a drug resistance-inducing effect of IGFBP7 against vincristine and asparaginase in T-ALL. These results provide a model for the previously observed association between high IGFBP7 expression and chemotherapy failure in T-ALL patients. Since the resistance against vincristine was abolished by IGF1-R inhibition, IGFBP7 could serve as biomarker for patients who may benefit from therapies including IGF1-R inhibitors in combination with chemotherapy

Tabu, Problem oder Standard? Die Ethnisierung von race-Klassifikationen in der deutschen Medizin- und Gesundheitsforschung

Der Beitrag widmet sich dem Phänomen des medizinischen und medizinnahen Forschens mit der – so ein für ein Interview angefragter Mediziner – „delikaten“ Kategorie race unter besonderer Berücksichtigung deutscher Perspektiven. Zu diesem Zweck wird zunächst quantitativ dargestellt, wie häufig und abhängig von welchen Bedingungen race-Klassifikationen in medizinischen und gesundheitswissenschaftlichen Forschungsprojekten eingesetzt werden, wenn Wissenschaftler*innen deutscher Forschungseinrichtungen beteiligt sind. Datengrundlage bildet hier eine 546 Forschungsartikel umfassende Metastudie. Danach wendet sich der Beitrag der Frage zu, ob race-Klassifikationen diese Forscher*innen vor Probleme stellen. Berührt ihr Gebrauch ein Tabu oder gehört er für diese vielmehr zum Standard gegenwärtiger Medizinforschung und wird als unproblematisch angesehen? Ausgehend von einer qualitativen Studie, zu der neben den Publikationen auch 15 Autor*inneninterviews gehören, werden drei Formen der Ethnisierung von race vorgestellt, die das Ziel verfolgen den Gebrauch von race-Klassifikationen zu entproblematisieren

FLT3 mutations in Early T-Cell Precursor ALL characterize a stem cell like leukemia and imply the clinical use of tyrosine kinase inhibitors

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subgroup of acute T-lymphoblastic leukemia (T-ALL) with a high rate of FLT3-mutations in adults. To unravel the underlying pathomechanisms and the clinical course we assessed molecular alterations and clinical characteristics in a large cohort of ETP-ALL (n = 68) in comparison to non-ETP T-ALL adult patients. Interestingly, we found a high rate of FLT3-mutations in ETP-ALL samples (n = 24, 35%). Furthermore, FLT3 mutated ETP-ALL was characterized by a specific immunophenotype (CD2+/CD5-/CD13+/CD33-), a distinct gene expression pattern (aberrant expression of IGFBP7, WT1, GATA3) and mutational status (absence of NOTCH1 mutations and a low frequency, 21%, of clonal TCR rearrangements). The observed low GATA3 expression and high WT1 expression in combination with lack of NOTCH1 mutations and a low rate of TCR rearrangements point to a leukemic transformation at the pluripotent prothymocyte stage in FLT3 mutated ETP-ALL. The clinical outcome in ETP-ALL patients was poor, but encouraging in those patients with allogeneic stem cell transplantation (3-year OS: 74%). To further explore the efficacy of targeted therapies, we demonstrate that T-ALL cell lines transfected with FLT3 expression constructs were particularly sensitive to tyrosine kinase inhibitors. In conclusion, FLT3 mutated ETP-ALL defines a molecular distinct stem cell like leukemic subtype. These data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic stem cell transplantation for this high risk subgroup

The Adaptability of Full Cast Crown in Preclinical Practice

A study was made to evaluate the adaptability of full cast crowns in preclinical practice of the fifth year students at Matsumoto Dental College in 1984. Gap space between the inner surface of the full cast crown and the surface of the abutment tooth was investigated with silicon material. The results were as follows: 1) The adaptability of crowns was better at the mesial surface than at the distal surface, and better at the lingual surface than at the buccal surface. 2) The adaptability of crowns was better at the axial walls, especialy in the middle, than in the cervical margin. 3) At the occulusal surface, the adaptability of crowns was worst

The hierarchy-of-hypotheses approach: A synthesis method for enhancing theory development in ecology and evolution

13 páginas.- 4 figuras.- referencias.- Supplemental material is available at BIOSCI online. https://doi.org/10.1093/biosci/biaa130In the current era of Big Data, existing synthesis tools such as formal meta-analyses are critical means to handle the deluge of information. However, there is a need for complementary tools that help to (a) organize evidence, (b) organize theory, and (c) closely connect evidence to theory. We present the hierarchy-of-hypotheses (HoH) approach to address these issues. In an HoH, hypotheses are conceptually and visually structured in a hierarchically nested way where the lower branches can be directly connected to empirical results. Used for organizing evidence, this tool allows researchers to conceptually connect empirical results derived through diverse approaches and to reveal under which circumstances hypotheses are applicable. Used for organizing theory, it allows researchers to uncover mechanistic components of hypotheses and previously neglected conceptual connections. In the present article, we offer guidance on how to build an HoH, provide examples from population and evolutionary biology and propose terminological clarifications.The workshops were funded by Volkswagen Foundation (Az 92,807 and 94,246). TH, CAA, ME, PG, ADS, and JMJ received funding from German Federal Ministry of Education and Research within the Collaborative Project “Bridging in Biodiversity Science” (grant no. 01LC1501A). ME additionally received funding from the Foundation of German Business, JMJ from the Deutsche Forschungsgemeinschaft (grants no. JE 288/9–1 and JE 288/9–2), and IB from German Federal Ministry of Education and Research (grant no. FKZ 01GP1710). CJL was supported by a grant from The Natural Sciences and Engineering Research Council of Canada and in-kind synthesis support from the US National Center for Ecological Analysis and Synthesis. LGA was supported by the Spanish Ministry of Science, Innovation, and Universities through project no. CGL2014–56,739-R, and RRB received funding from the Brazilian National Council for Scientific and Technological Development (process no. 152,289/2018–6)Peer reviewe

Characterization of molecular markers BCL11b and IGFBP7 in acute T-lymphoblastic leukemia

Akute T-lymphoblastische Leukämien (T-ALL) sind genetisch heterogene Erkrankungen, deren Überlebensrate in den letzten Jahrzehnten durch Therapieoptimierung zwar verbessert werden konnte, aber dennoch heute bei erwachsenen Patient_innen bei nur 30 bis 50 % liegt. Es ist daher notwendig die Auswirkung von für T-ALLs charakteristischer genetischer Aberrationen zu entschlüsseln und basierend auf diesen Erkenntnissen neue Therapien zu entwickeln, die spezifisch gegen leukämische Blasten wirken. In dieser Arbeit konnten zwei Kandidatengene genauer charakterisiert werden, die auf unterschiedlichem Wege jeweils T-ALL-Pathogenese und Progression beeinflussen. B-Cell CLL/Lymphoma 11B (BCL11b) ist ein essenzieller T-Zell- Transkriptionsfaktor. In dieser Arbeit wurde bei insgesamt 264 Patient_innen der German Multicenter Acute Lymphoblastic Leukemia Study Group (GMALL)-Kohorte und gesunden Kontrollpersonen die BCL11b-mRNA-Expression durch quantitative Real-Time PCR bestimmt. Es zeigte sich eine Assoziation einer niedrigen BCL11b-Expression mit einem unreifen Blasten-Immunphänotyp und einer geringeren Gesamtüberlebenswahrscheinlichkeit nach 5 Jahren (Ü) (BCL11b- niedrig: n = 40, 35 % Ü; BCL11b-hoch: n = 129, 53 % Ü; P = 0,02). Besonders ausgeprägt war dieser Zusammenhang bei Patient_innen der als Standardrisiko bewerteten thymischen T-ALL-Subgruppe (BCL11b-niedrig: n = 18, 20 % Ü; BCL11b- hoch: n = 84, 62 % Ü; P < 0,001). Zusätzlich wurde durch Sanger-Sequenzierung eine hohe Mutationsrate des Exon 4 von BCL11b bei T-ALL-Patient_innen gefunden (14 %). Diese Ergebnisse charakterisieren BCL11b als wichtigen prognostischen Faktor der T-ALL, der besonders bei thymischen T-ALL-Patient_innen ein niedrigere Überlebenswahrscheinlichkeit anzeigt und Indikation für eine intensivierte Therapie geben könnte. Im zweiten Teil der Arbeit wurde mit Insulin-like growth factor binding protein 7 (IGFBP7) ein Mitglied des Insulin-like growth factors (IGF)-Systems untersucht. Vor dem Hintergrund der Assoziation einer hohen IGFBP7-Expression mit Chemotherapie-resistenz bei T -ALL-Patient_innen wurde in der vorliegenden Arbeit die Auswirkung von Knockdown und Überexpression von IGFBP7 in Leukämiezelllinien untersucht. Eine Überexpression des Gens führte dabei in der T-ALL-Zelllinie Jurkat zu einer geringeren Proliferation. In den T-ALL-Zelllinien Molt-4 und Jurkat war ein größerer Anteil an IGFBP7-transfizierten Zellen in G0/G1-Arrest als kontrolltransfizierte Zellen. Zusätzlich induzierte IGFBP7-Überexpression in Jurkat-Zellen Resistenz gegenüber den Zytostatika Vincristin und Asparaginase. Sowohl die Oberflächenexpression als auch die Gesamtproteinmenge des IGF-1-Rezeptors (IGF1-R) war in IGFBP7-transfizierten Jurkat-Zellen reduziert und Behandlung mit dem IGF1-R-Inhibitor AEW541 konnte die IGFBP7-induzierte Resistenz gegenüber Vincristin aufheben. Zusammengefasst zeigen diese Ergebnisse ein Modell zu IGFBP7-assoziiertem Therapieversagen in T-ALL- Patient_innen auf: Möglicherweise reduziert eine erhöhte Expression von IGFBP7 auf parakrinem oder autokrinen Weg IGF1-R-Signale. Dies resultiert in einem G0/G1-Arrest der Blasten, der mit einer Resistenz gegen bestimmte Zytostatika einhergeht. IGFBP7-Expression könnte daher als Biomarker fungieren, der auf mögliche Chemotherapieresistenzen hinweist, und eine Indikation für den Einsatz von IGF1-R-Inhibitoren darstellt.Acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease and although its survival rate has increased during the last decades, it still remains only at 30 to 50 % in adult patients. Therefore it is necessary to decipher the consequences genetic aberrations characteristic for T-ALL and, based on these findings, develop new therapies, which specifically target leukemic blasts. This work was able to characterize two candidate genes, who influence the pathogenesis and progression of T-ALL through different pathways, respectively. B-Cell CLL/Lymphoma 11B (BCL11b) is an essential T-cell transcription factor.. In this study BCL11b mRNA expression was determined in 264 T-ALL patients of the German Multicenter Acute Lymphoblastic Leukemia Study Group (GMALL) cohort and healthy controls by qRT-PCR. Low BCL11b expression in T-ALL patients was associated with an immature blast immunophenotype and a lower 5-year overall survival (OS) (BCL11b-low: n = 40, 35 % OS; BCL11b-high: n = 129, 53 % OS; P = 0.02). This association was especially strong in the subgroup of thymic T-ALL patients, normally rated as standard risk (BCL11b-low: n = 18, 20 % OS; BCL11b-high: n = 84, 62 % OS; P < 0.001). Additionally Sanger sequencing identified a high mutation rate (14%) of BCL11b exon 4 in T-ALL patients. These results characterize BCL11b as an important prognostic factor in T-ALL which low expression indicates, especially in thymic T-ALL patients, a poor prognosis and could imply the need for therapy intensification. In the second part of this work the functional role of Insulin-like growth factor binding protein 7 (IGFBP7), a member of the Insulin-like growth factors (IGF) system was investigated. In light of the association of high IGFBP7 expression with chemotherapy resistance in T-ALL patients this study investigated the effect of a knockdown or an overexpression of IGFBP7 in human leukemic cell lines. Overexpression of the gene in the T-ALL cell line Jurkat resulted in reduced proliferation. In the T-ALL cell lines Molt-4 and Jurkat a larger percentage of IGFBP7-transfected cells were in G0/G1 arrest than control-transfected cells. IGFBP7 overexpression additionally induced resistance against the cytostatic drugs vincristine and asparaginase. Both surface expression and total protein abundance of the IGF-1 receptor (IGF1-R) was reduced in IGFBP7-transfected Jurkat cells and treatment with small molecule IGF1-R inhibitor AEW451 was able to abrogate the IGFBP7-induced resistance against vincristine. In summary these results illustrate a model of IGFBP7-associated therapy failure in T-ALL patients: an increased expression of IGFBP7 possibly reduces IGF1-R signalling in a paracine or autocrine manner. This in turn results in an increase of G0/G1 arrest in the leukemic blasts, which leads to their resistance against certain cystostatic drugs inactive in this cell cycle phase. High IGFBP7 expression could represent a biomarker for chemotherapy resistance and indicate treatment with IGF1-R inhibitors

Do cancer stem cells exist? A pilot study combining a systematic review with the hierarchy-of-hypotheses approach.

The phenomenon of cancer cell heterogeneity has been explained by different hypotheses, each entailing different therapy strategies. The most recent is the cancer stem cell model, which says that tumourigenicity and self-renewal are restricted to rare stem cell-like cancer cells. Since its conception, conflicting evidence has been published. In this study, we tested the applicability of a new approach developed in the field of ecology, the hierarchy-of-hypotheses approach, for the Cancer Stem Cell hypothesis. This approach allows to structure a broad concept into more specific sub-hypotheses, which in turn can be connected to available empirical studies. To generate a dataset with empirical studies, we conducted a systematic literature review in the Web of Science limited to the first 1000 publications returned by the search. From this pool, 51 publications were identified that tested whether a cell sub-population had cancer stem cell properties. By classifying the studies according to: (1) assessed indicators, (2) experimental assays and (3) model cancer cells used, we built a hierarchical structure of sub-hypotheses. The empirical tests from the selected studies were subsequently assigned to this hierarchy of hypotheses, and the percentage of supporting, undecided and questioning evidence was calculated for each sub-hypothesis, as well as additional experimental characteristics. Our approach successfully allowed us to determine that within our dataset, the empirical support for the CSC hypothesis was only 49.0%. The support of different sub-hypotheses was highly variable. Most noticeable, the conception that putative cancer stem cells are a rare subset of cells could not be confirmed by most studies (13.5% support). The empirical support varied also between types of cancer, animal models and cell isolation method used. For the first time, this study showed the applicability of the hierarchy-of-hypotheses approach for synthesizing and evaluating empirical evidence for a broad hypothesis in the field of bio-medical research

Genetic Racial Profiling: Extended DNA Analyses and Entangled Processes of Discrimination

Over the last two decades, the analysis of DNA traces found at a crime scene have expanded the already established forensic DNA analysis for identification to include new techniques intended to predict a criminal suspect’s externally visible characteristics, such as eye, hair and skin colour (‘forensic DNA phenotyping’), or his or her ethnic, continental or regional origin (‘biogeographical ancestry’). In this paper, we conduct a dispositive analysis to investigate how extended DNA analysis in forensics catalyses inherent processes of racialization at three different levels: 1) in the categorizations that are integral to this technology, 2) in the images of the ‘dangerous other’ combined with inflated expectations regarding these technologies’ effectiveness that have framed discourses regarding the legalization of this technology, and 3) in the biases and stereotypes which often guide investigative practices using these technologies. We demonstrate that this is an example par excellence of how the interaction between different practice dimensions can exacerbate unintended discriminating, racialising and racist effects

Extended DNA analyses: Surveillance technology at the intersection of racism and sexism

Genetic data contains a multitude of highly personal information and is therefore deemed an especially sensitive data category by data protection laws. But technological advances and the increasing demands of security policymakers have led to the continuous expansion of governmental authority over DNA extraction, analysis and storage. The protection of women from sexual crimes is often put forward as grounds to legitimise these expansions. Sexism and racism intersect in the most recent debate on further policy change, building on existing public fears of the threat posed by unknown male migrants to white German women and presenting controversial DNA technology as a solution