Cadmium (Cd) is a toxic metal, targeting the lung, liver, kidney, and testes following acute intoxication, and causing nephrotoxicity, immunotoxicity, osteotoxicity and tumors after prolonged ...exposures. Reactive oxygen species (ROS) are often implicated in Cd toxicology. This minireview focused on direct evidence for the generation of free radicals in intact animals following acute Cd overload and discussed the association of ROS in chronic Cd toxicity and carcinogenesis. Cd-generated superoxide anion, hydrogen peroxide, and hydroxyl radicals
in vivo have been detected by the electron spin resonance spectra, which are often accompanied by activation of redox sensitive transcription factors (e.g., NF-κB, AP-1 and Nrf2) and alteration of ROS-related gene expression. It is generally agreed upon that oxidative stress plays important roles in acute Cd poisoning. However, following long-term Cd exposure at environmentally-relevant low levels, direct evidence for oxidative stress is often obscure. Alterations in ROS-related gene expression during chronic exposures are also less significant compared to acute Cd poisoning. This is probably due to induced adaptation mechanisms (e.g., metallothionein and glutathione) following chronic Cd exposures, which in turn diminish Cd-induced oxidative stress. In chronic Cd-transformed cells, less ROS signals are detected with fluorescence probes. Acquired apoptotic tolerance renders damaged cells to proliferate with inherent oxidative DNA lesions, potentially leading to tumorigenesis. Thus, ROS are generated following acute Cd overload and play important roles in tissue damage. Adaptation to chronic Cd exposure reduces ROS production, but acquired Cd tolerance with aberrant gene expression plays important roles in chronic Cd toxicity and carcinogenesis.
Computational materials design has made significant progress lately. However, one underexploited opportunity lies in the combination of physically based modelling and machine learning (ML). In the ...present work we exploit this combination for modelling of strain-induced martensitic phase transformation (SIMT) in austenitic steels. A fully predictive model for SIMT, responsible for the TRIP effect in many steels, is devised. An experimental dataset correlating SIMT with composition, temperature and strain is collected from the open literature firstly. Secondly, the Olson-Cohen model is applied to make physically based predictions on temperature and strain dependence of SIMT in order to expand the database to the final size of 16,500 entries relating the features and the target. Thirdly, ensemble ML methods are applied to model the data and the final model is validated on a holdout dataset, including also dual-phase alloys. The final model provides accurate predictions of SIMT in a temperature range from −196 to 100 °C and from 0 to 1 in strain. The model can readily be extended to consider further factors such as strain rate and stress state. Moreover, it can be used together with thermodynamic and kinetic calculations, or thermomechanical simulations, for the design of steels and components, respectively.
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•An integrated machine learning and physical modelling to predict strain-induced martensite in austenitic steels.•A fully predictive model of SIM features, responsible for the TRIP effect in many steels, is devised.•The model provides accurate predictions in comprehensive temperature and strain range in austenitic and dual phase steels.•The model can readily be extended to consider further factors such as strain rate and stress state.
This book gathers renowned researchers and policymakers from all continents who have accompanied Dirk Messner’s professional life in science and policy advice. Their articles and essays cover topics ...related to the ideational spheres and practice-oriented spaces which have consistently characterised Dirk Messner’s career. These include steps at the national, regional or global level to effectively accelerate the shift towards planetary sustainability; measures to forge or strengthen cross-sectoral, transboundary, multi-actor alliances for sustainable transformation; and key elements of universal ethics and shared norms which foster transnational cooperation for the global common good. With contributions by Manish Bapna, Lilian Busse, Ani Dasgupta, J. Carlos Domínguez, Ottmar Edenhofer, Jörg Faust, Thomas Fues, Hans Haake, Medelina K. Hendytio, Ariel Macaspac Hernandez, Anna-Katharina Hornidge, Adolf Kloke-Lesch, Claus Leggewie, Siddharth Mallavarapu, Simon Maxwell, Dirk Meyer, Nebojsa Nakicenovic, Sabine Nallinger, Andrew Norton, Franz Nuscheler, Jiahua Pan Jürgen Renn, Enrique Saravia, Sabine Schlacke, Uwe Schneidewind, Imme Scholz, Svenja Schulze, Zita Sebesvari, Wolfgang Seidel, Elizabeth Sidiropoulos, Achim Steiner, Franziska Wehinger and Heidemarie Wieczorek-Zeul.
Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or ...differentiate into immune cells that contribute to disease pathology in peripheral tissues
. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin
. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.
Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. Using a ...metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.
The YAP and TAZ paralogs are transcriptional co-activators recruited to target sites by TEAD proteins. Here, we show that YAP and TAZ are also recruited by JUNB (a member of the AP-1 family) and ...STAT3, key transcription factors that mediate an epigenetic switch linking inflammation to cellular transformation. YAP and TAZ directly interact with JUNB and STAT3 via a WW domain important for transformation, and they stimulate transcriptional activation by AP-1 proteins. JUNB, STAT3, and TEAD co-localize at virtually all YAP/TAZ target sites, yet many target sites only contain individual AP-1, TEAD, or STAT3 motifs. This observation and differences in relative crosslinking efficiencies of JUNB, TEAD, and STAT3 at YAP/TAZ target sites suggest that YAP/TAZ is recruited by different forms of an AP-1/STAT3/TEAD complex depending on the recruiting motif. The different classes of YAP/TAZ target sites are associated with largely non-overlapping genes with distinct functions. A small minority of target sites are YAP- or TAZ-specific, and they are associated with different sequence motifs and gene classes from shared YAP/TAZ target sites. Genes containing either the AP-1 or TEAD class of YAP/TAZ sites are associated with poor survival of breast cancer patients with the triple-negative form of the disease.
Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many ...oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.
Autophagy has been described to have tumor‐suppressive as well as tumor‐promoting functions. This review discusses how stage and context alters the role for autophagy in cancer, and argues for further research prior to targeting autophagy in cancer therapy.
Hepatocellular carcinoma (HCC) formation is a multi‐step pathological process that involves evolution of a heterogeneous immunosuppressive tumor microenvironment. However, the specific cell ...populations involved and their origins and contribution to HCC development remain largely unknown. Here, comprehensive single‐cell transcriptome sequencing was applied to profile rat models of toxin‐induced liver tumorigenesis and HCC patients. Specifically, we identified three populations of hepatic parenchymal cells emerging during HCC progression, termed metabolic hepatocytes (HCMeta), Epcam+ population with differentiation potential (EP+Diff) and immunosuppressive malignant transformation subset (MTImmu). These distinct subpopulations form an oncogenic trajectory depicting a dynamic landscape of hepatocarcinogenesis, with signature genes reflecting the transition from EP+Diff to MTImmu. Importantly, GPNMB+Gal‐3+ MTImmu cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 is required for the generation and malignant transformation of GPNMB+Gal‐3+ MTImmu cells. Enrichment of the GPNMB+Gal‐3+ MTImmu subset was found to be associated with poor prognosis and a higher rate of recurrence in patients. Collectively, we unraveled the single‐cell HCC progression atlas and uncovered GPNMB+Gal‐3+ parenchymal cells as a major subset contributing to the immunosuppressive microenvironment thus malignance in HCC.
Synopsis
Malignant transformation is the major driver of liver cancer, but the molecular and cellular bases for its induction remain poorly understood. Here, in‐depth profiling of hepatocellular carcinoma (HCC) initiation and progression defines new molecular markers involved and emerging malignant cell populations counteracting immune surveillance.
Longitudinal single‐cell RNA‐sequencing of toxin‐induced liver tumorigenesis in rats reveals a dynamic composition and transformation of hepatic parenchymal cells.
Complementary analyses of four HCC patients show conservation of HCC cell dynamics.
GPNMB+Gal‐3+ parenchymal cells arise from EPCAM+ cells during HCC progression and exhibit immunosuppressive and malignant properties in vivo.
The transcription factor SOX18 is required for the GPNMB+Gal‐3+ cell stemness and immunosuppressive capacity.
Enrichment of GPNMB+Gal‐3+ cells is associated with poor prognosis in HCC patients.
Longitudinal single‐cell profiling of liver cancer in rats and patients unveils an emerging aggressive parenchymal cell population counteracting immune surveillance.
Species evolve by mutations and epigenetic changes acting on individuals in a population; tumors evolve by similar mechanisms at a cellular level in a tissue. This article reviews growing evidence ...about tumor dormancy and suggests that (i) cellular malignancy is a natural byproduct of evolutionary mechanisms, such as gene mutations and epigenetic modifications, which is manifested in the form of tumor dormancy in healthy individuals as well as in cancer survivors; (ii) cancer metastasis could be an early dissemination event that could occur during malignant dormancy even before primary cancer is clinically detectable; and (iii) chronic inflammation is a key factor in awakening dormant malignant cells at the primary site, leading to primary cancer development, and at distant sites, leading to advanced stage diseases. On the basis of this evidence, it is reasonable to propose that we are all cancer survivors rather than cancer-free individuals because of harboring dormant malignant cells in our organs. A better understanding of local and metastatic tumor dormancy could lead to novel cancer therapeutics for the prevention of cancer.
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This research investigates how entrepreneurs of small and medium enterprises (SMEs) with inadequate capabilities and limited resources drove digital transformation in their companies, a phenomenon ...that remains under‐researched in the extant literature. We conduct qualitative research on digital transformation to cross‐border e‐commerce undergone by 7 SMEs on the Alibaba digital platform. We inductively derive a process model that aims to describe and explain how SME entrepreneurs, with support from the digital platform service provider, drive digital transformation through managerial cognition renewal, managerial social capital development, business team building, and organizational capability building. This model expands our understanding of both digital entrepreneurship and digital transformation. It also presents new insights into how digital platform service providers can help SMEs transform and compete.
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