Advances in Molecular Characterization and Targeted Therapy in Dermatofibrosarcoma Protuberans

The molecular pathogenesis of dermatofibrosarcoma protuberans (DFSP) involves distinctive rearrangement of chromosomes 17 and 22 leading to formation of the COL1A1-PDGFB fusion gene. The knowledge of molecular events underlying development of DFSP resulted in the implementation of targeted therapy with imatinib—a tyrosine kinase inhibitor (TKI), to the clinical practice. The striking efficacy of imatinib in advanced cases of DFSP has been demonstrated in a few clinical trials. Thus, imatinib is currently considered the gold standard in the treatment of inoperable and/or metastatic and/or recurrent cases of DFSP. Therapy with imatinib may potentially facilitate resection or decrease possible disfigurement related to radical surgical procedure. Following partial response on imatinib significant percentage of patients may be rendered free of the disease by surgery of the residual tumor

Reactivity of 2-formylphenylboronic acid toward secondary aromatic amines in amination–reduction reactions

The synthesis of 2-(arylaminomethyl)phenylboronic acid via an amination–reduction reaction has been investigated within a model system comprising 2-formylphenylboronic acid and N-ethylaniline. Adoption of the appropriate reaction conditions influences the reactivity of 2-formylphenylboronic acid, enabling efficient synthesis of so-far unobtainable 2-(arylaminomethyl)phenylboronic compounds. The first crystal structure of the aromatic amine derivative has been determined and described

Metabolomic and transcriptomic response to imatinib treatment of gastrointestinal stromal tumour in xenograft-bearing mice

Background Although imatinib is a well-established first-line drug for treating a vast majority of gastrointestinal stromal tumours (GIST), GISTs acquire secondary resistance during therapy. Multi-omics approaches provide an integrated perspective to empower the development of personalised therapies through a better understanding of functional biology underlying the disease and molecular-driven selection of the best-targeted individualised therapy. In this study, we applied integrative metabolomic and transcriptomic analyses to elucidate tumour biochemical processes affected by imatinib treatment. Materials and methods A GIST xenograft mouse model was used in the study, including 10 mice treated with imatinib and 10 non-treated controls. Metabolites in tumour extracts were analysed using gas chromatography coupled with mass spectrometry (GC-MS). RNA sequencing was also performed on the samples subset (n=6). Results Metabolomic analysis revealed 21 differentiating metabolites, whereas next-generation RNA sequencing data analysis resulted in 531 differentially expressed genes. Imatinib significantly changed the profile of metabolites associated mainly with purine and pyrimidine metabolism, butanoate metabolism, as well as alanine, aspartate, and glutamate metabolism. The related changes in transcriptomic profiles included genes involved in kinase activity and immune responses, as well as supported its impact on the purine biosynthesis pathway. Conclusions Our multi-omics study confirmed previously known pathways involved in imatinib anticancer activity as well as correlated imatinib-relevant downregulation of expression of purine biosynthesis pathway genes with the reduction of respectful metabolites. Furthermore, considering the importance of the purine biosynthesis pathway for cancer proliferation, we identified a potentially novel mechanism for the anti-tumour activity of imatinib. Based on the results, we hypothesise metabolic modulations aiming at the reduction in purine and pyrimidine pool may ensure higher imatinib efficacy or re-sensitise imatinib-resistant tumours.publishedVersio

Global Ban on Plastic and What Next? Are Consumers Ready to Replace Plastic with the Second-Generation Bioplastic? Results of the Snowball Sample Consumer Research in China, Western and Eastern Europe, North America and Brazil

ABSTRACT: Plastic can be used for many things and at the same time is the most versatile material in our modern world. However, the uncontrolled and unprecedented use of plastic comes to its end. The global ban on plastic brings significant changes in technology but even more so in civil perception-changes taking place before our eyes. The aim of this study was to find answers to the questions about the readiness of consumers for a global ban on plastic. Within the research, the differences in consumer acceptance in countries in Europe, South and North America and Asia and the expression of social readiness to change attitudes towards plastic food packaging were analyzed. This work sketches the legal framework related to limiting the use of one-use food packaging made of fossil raw materials at the level of the European Union, Poland and Portugal but also at the level of the two largest economies in the world, China and the United States, as well as lower-income countries, e.g., Ukraine and Brazil. The survey results were analyzed using descriptive and inferential statistics. The performed study demonstrates that, in in all the surveyed countries, appropriate legal acts related to the reduction of plastic in everyday life are already in place. Furthermore, this work demonstrates the full understanding of plastic banning in all surveyed countries. Consumers are aware that every effort should be made to prevent the world from drowning in plastic waste. Society is, in general, open to the use of bioplastics produced from the second-generation resource if second-generation bioplastics contribute to environmental and pollution reduction targets.info:eu-repo/semantics/publishedVersio

Global Ban on Plastic and What Next? Are Consumers Ready to Replace Plastic with the Second-Generation Bioplastic? Results of the Snowball Sample Consumer Research in China, Western and Eastern Europe, North America and Brazil

Plastic can be used for many things and at the same time is the most versatile material in our modern world. However, the uncontrolled and unprecedented use of plastic comes to its end. The global ban on plastic brings significant changes in technology but even more so in civil perception—changes taking place before our eyes. The aim of this study was to find answers to the questions about the readiness of consumers for a global ban on plastic. Within the research, the differences in consumer acceptance in countries in Europe, South and North America and Asia and the expression of social readiness to change attitudes towards plastic food packaging were analyzed. This work sketches the legal framework related to limiting the use of one-use food packaging made of fossil raw materials at the level of the European Union, Poland and Portugal but also at the level of the two largest economies in the world, China and the United States, as well as lower-income countries, e.g., Ukraine and Brazil. The survey results were analyzed using descriptive and inferential statistics. The performed study demonstrates that, in in all the surveyed countries, appropriate legal acts related to the reduction of plastic in everyday life are already in place. Furthermore, this work demonstrates the full understanding of plastic banning in all surveyed countries. Consumers are aware that every effort should be made to prevent the world from drowning in plastic waste. Society is, in general, open to the use of bioplastics produced from the second-generation resource if second-generation bioplastics contribute to environmental and pollution reduction targets

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials

Inhibition of ERβ Induces Resistance to Cisplatin by Enhancing Rad51–Mediated DNA Repair in Human Medulloblastoma Cell Lines

Cisplatin is one of the most widely used and effective anticancer drugs against solid tumors including cerebellar tumor of the childhood, Medulloblastoma. However, cancer cells often develop resistance to cisplatin, which limits therapeutic effectiveness of this otherwise effective genotoxic drug. In this study, we demonstrate that human medulloblastoma cell lines develop acute resistance to cisplatin in the presence of estrogen receptor (ER) antagonist, ICI182,780. This unexpected finding involves a switch from the G2/M to G1 checkpoint accompanied by decrease in ATM/Chk2 and increase in ATR/Chk1 phosphorylation. We have previously reported that ERβ, which is highly expressed in medulloblastomas, translocates insulin receptor substrate 1 (IRS-1) to the nucleus, and that nuclear IRS-1 binds to Rad51 and attenuates homologous recombination directed DNA repair (HRR). Here, we demonstrate that in the presence of ICI182,780, cisplatin-treated medulloblastoma cells show recruitment of Rad51 to the sites of damaged DNA and increase in HRR activity. This enhanced DNA repair during the S phase preserved also clonogenic potential of medulloblastoma cells treated with cisplatin. In conclusion, inhibition of ERβ considered as a supplemental anticancer therapy, has been found to interfere with cisplatin–induced cytotoxicity in human medulloblastoma cell lines