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Abstract: One of the new treatment options for unresectable locally advanced pancreatic cancer is electro-chemotherapy (ECT), a local ablative therapy that potentiates the entry of chemotherapeutic drugs into the cells, by the application of an electric field to the tumor. Its feasibility and safety were demonstrated in preclinical and clinical studies; however, there is a lack of preclinical studies assessing the actions of different drugs used in ECT, their mechanisms and interactions with other target drugs that are used in clinical practice. Materials and methods. The aim of the study was to determine the cytotoxicity of two chemotherapeutic drugs usually used in ECT (bleomycin and cisplatin) in the BxPC-3 human pancreatic carcinoma cell line and evaluate the interactions of ECT with the targeted drug sunitinib. First, the cytotoxicity of ECT using both chemotherapeutics was determined. In the next part, the interactions of ECT and sunitinib were evaluated through determination of combined cytotoxicity, sunitinib targets and kinetics of cell death.Results. The results demonstrate that ECT is effective in pancreatic cancer cell line, especially when bleomycin is used, with the onset of cell death in the first hours after the treatment, reaching a plateau at 20 hours after the treat-ment. Furthermore, we provide the rationale for combining ECT with bleomycin and the targeted drug sunitinib to potentiate cytotoxicity. The combined treatment of sunitinib and ECT was synergistic for bleomycin only at the high-est used concentration of bleomycin 0.14 μM, whereas with lower doses of bleomycin, this effect was not observed. The interaction of ECT and treatment with sunitinib was confirmed by course of the cell death, also indicating on synergism
Keywords: electrochemotherapy, pancreas, sunitinib, pancreatic cancer
Published in DiRROS: 24.07.2024; Views: 197; Downloads: 120
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Abstract: Background The Dickeya genus is part of the Pectobacteriaceae family that is included in the newly described enterobacterales order. It comprises a group of aggressive soft rot pathogens with wide geographic distribution and host range. Among them, the new Dickeya fangzhongdai species groups causative agents of maceration-associated diseases that impact a wide variety of crops and ornamentals. It affects mainly monocot plants, but D. fangzhongdai strains have also been isolated from pear trees and water sources. Here, we analysed which genetic novelty exists in this new species, what are the D. fangzhongdai-specific traits and what is the intra-specific diversity. Results The genomes of eight D. fangzhongdai strains isolated from diverse environments were compared to 31 genomes of strains belonging to other Dickeya species. The D. fangzhongdai core genome regroups approximately 3500 common genes, including most genes that encode virulence factors and regulators characterised in the D. dadantii 3937 model strain. Only 38 genes are present in D. fangzhongdai and absent in all other Dickeyas. One of them encodes a pectate lyase of the PL10 family of polysaccharide lyases that is found only in a few bacteria from the plant environment, soil or human gut. Other D. fangzhongdai-specific genes with a known or predicted function are involved in regulation or metabolism. The intra-species diversity analysis revealed that seven of the studied D. fangzhongdai strains were grouped into two distinct clades. Each clade possesses a pool of 100–150 genes that are shared by the clade members, but absent from the other D. fangzhongdai strains and several of these genes are clustered into genomic regions. At the strain level, diversity resides mainly in the arsenal of T5SS- and T6SS-related toxin-antitoxin systems and in secondary metabolite biogenesis pathways. Conclusion This study identified the genome-specific traits of the new D. fangzhongdai species and highlighted the intra-species diversity of this species. This diversity encompasses secondary metabolites biosynthetic pathways and toxins or the repertoire of genes of extrachromosomal origin. We however didn’t find any relationship between gene content and phenotypic differences or sharing of environmental habitats. Background Soft rot Pectobacteriaceae are Enterobacterales responsible for considerable economic losses in several important crops and ornamental plants [1,2,3]. Their virulence is mainly due to the production and secretion of a battery of plant cell wall degrading enzymes (PCWDEs) that cause maceration of the plant tissue; however, several other virulence factors have also been characterized [2, 4]. These bacteria often exhibit a very broad host range, and recent outbreaks in potato, for example, resulted from the action of a cohort of bacteria belonging to different Pectobacteriaceae species in a complex population dynamics history [5]. The Pectobacteriaceae family includes two genera comprising soft rot bacteria, Pectobacterium and Dickeya. The Dickeya genus was formed in 2005 by the reclassification of former Erwinia chrysanthemi into six species [6]. It has recently undergone multiple phylogenetic changes, including the addition of three new species, Dickeya solani [7], Dickeya aquatica [8] and, more recently, Dickeya fangzhongdai [9]. The description of this last new species was based on three isolates from pear trees in China with bleeding canker necrosis [9], but it was extended by a large number of strains isolated from monocot plants from Japan [10, 11]. D. fangzhongdai strains were associated with soft rot symptoms of many ornamental and economically important staple food plants [10, 12, 13], thereby highlighting the broad host range of the species. While there is little information regarding associated economic damages and the extent of its occurrence in different host plants outside of Asia, Alič et al. [14] recently identified D. fangzhongdai as the causative agent of soft rot of orchids in commercial production in Europe, starting with material from Asia [11]. Moreover, as previously reported, bacteriophages of different families, and active against D. fangzhongdai, were isolated from a wastewater treatment plant not associated to the orchid production site. This would suggest that D. fangzhongdai bacteria may be more widespread in nature than could currently be concluded on the basis of symptoms in plants. Its occurrence in water would suggest that it may potentially have a wider ecological niche than genomically close Dickeya spp., that is, Dickeya dadantii, Dickeya dianthicola, and D. solani. Previous experience with D. solani has shown that novel species or isolates can lead to clonal spread and high losses in affected host plants [15]. Together with repeated introductions of D. fangzhongdai, the co-occurrence of genetically and phenotypically diverse strains on the same plants (e.g., B16 and S1 on orchids, as reported by Alič et al. [11]) increases the probability of the development of recombined strains with novel pathogenic potential and may present a risk to agriculturally important plants. Their aggressiveness, high maceration potential on various plant tissues, and persistence in potato plants further exacerbate the risk for agriculture. Therefore, in this paper, we analysed the genomic characteristics of the D. fangzhongdai species, compared it to the other Dickeya species and determine the inter- and intra- species diversity. The study addressed the question whether the presence of the isolates in a specific environment is associated to a specific set of genes (water vs plant symptoms, monocots vs dicots, different geographical origin). We also analysed the virulence gene arsenal, in order to evaluate the virulence potential of this species. Methods Dickeya strain selection All D. fangzhongdai genomes publicly available in the NCBI database were included in this study. These genomes were compared to five D. solani, four D. dadantii, five D. dianthicola, five D. chrysanthemi, seven D. zeae, one D. aquatica, two D. paradisiaca and two unassigned Dickeya genomes extracted from the NCBI database. Information on the provenance and genomic data of the D. fangzhongdai strains used in this study are summarized in Table 1. The accession numbers and phylogenetic position of the other Dickeya strains used for the SiLix analyses are presented in Additional file 1: Figure S1.
Keywords: T5SS, T6SS, NRPS/PKS, zeamine, oocydin A, plant-bacteria interactions, plasmid, Dickeya fangzhongdai
Published in DiRROS: 23.07.2024; Views: 219; Downloads: 151
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Abstract: Understanding how organisms adapt to complex environments is a central goal of evolutionary biology and ecology. This issue is of special interest in the current era of rapidly changing climatic conditions. Here, we investigate clinal variation and plastic responses in life history, morphology and physiology in the butterfly Pieris napi along a pan‐European gradient by exposing butterflies raised in captivity to different temperatures. We found clinal variation in body size, growth rates and concomitant development time, wing aspect ratio, wing melanization and heat tolerance. Individuals from warmer environments were more heat‐tolerant and had less melanised wings and a shorter development, but still they were larger than individuals from cooler environments. These findings suggest selection for rapid growth in the warmth and for wing melanization in the cold, and thus fine‐tuned genetic adaptation to local climates. Irrespective of the origin of butterflies, the effects of higher developmental temperature were largely as expected, speeding up development; reducing body size, potential metabolic activity and wing melanization; while increasing heat tolerance. At least in part, these patterns likely reflect adaptive phenotypic plasticity. In summary, our study revealed pronounced plastic and genetic responses, which may indicate high adaptive capacities in our study organism. Whether this may help such species, though, to deal with current climate change needs further investigation, as clinal patterns have typically evolved over long periods.
Published in DiRROS: 23.07.2024; Views: 192; Downloads: 105
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Abstract: Pregnancy associated breast cancer is a rare disease. It presents a unique entity of breast cancer with aggressive phenotype. The main aim was to evaluate how the international guidelines were followed in daily practice. Patients and methods. Data concerning patients% and tumours% characteristics, management, delivery and ma-ternal outcome were recorded from institutional electronic database. In this paper a case series of pregnant breast cancer patients treated at single tertiary institution between 2007 and 2019 are presented and the key recommenda-tions on managing such patients are summarized.Results. Fourteen patients met the search criteria. The majority of tumours were high grade, triple negative or HER2 positive, two patients were de novo metastatic. Treatment plan was made for each patient by multidisciplinary team. Eight patients were treated with systemic chemotherapy with no excess toxicity or severe maternal/fetal adverse ef-fects. In all but two patients, delivery was on term and without major complications. Only one event, which was not in whole accordance with international guidelines, was identified. It was the use of blue dye in one patient.Conclusions. Women with pregnancy associated breast cancer should be managed like non-pregnant breast cancer patients and should expect a similar outcome, without causing harm to the unborn child. To achieve a good outcome in pregnancy associated breast cancer, a multidisciplinary approach is mandatory.
Keywords: breast cancer, pregnancy, clinical characteristics, therapeutic strategy
Published in DiRROS: 22.07.2024; Views: 203; Downloads: 64
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Keywords: assisted reproduction techniques, fertility preservation, infertility, pregnancy, sperm cryopreservation
Published in DiRROS: 22.07.2024; Views: 226; Downloads: 62
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