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Abstract: Head and neck squamous cell carcinoma (HNSCC) presents as locally advanced disease in a majority of patients and is prone to relapse despite aggressive treatment. Since immune checkpoint inhibitors (ICI) have shown clinically significant efficacy in patients with recurrent/metastatic HNSCC (R/M HNSCC), a plethora of trials are investigating their role in earlier stages of disease. At the same time, preclinical data showed the synergistic role of concurrently administered radiotherapy and ICIs (immunoradiotherapy) and explained several mechanisms behind it. Therefore, this approach is prospectively tested in a neoadjuvant, definitive, or adjuvant setting in non-R/M HNSCC patients. Due to the intricate relationship between host, immunotherapy, chemotherapy, and radiotherapy, each of these approaches has its advantages and disadvantages. In this narrative review we present the biological background of immunoradiotherapy, as well as a rationale for, and possible flaws of, each treatment approach, and provide readers with a critical summary of completed and ongoing trials. Conclusions. While immunotherapy with ICIs has already become a standard part of treatment in patients with R/M HNSCC, its efficacy in a non-R/M HNSCC setting is still the subject of extensive clinical testing. Irradiation can overcome some of the cancer%s immune evasive manoeuvres and can lead to a synergistic effect with ICIs, with possible additional benefits of concurrent platinum-based chemotherapy. However, the efficacy of this combination is not robust and details in trial design and treatment delivery seem to be of unprecedented importance.
Keywords: head and neck neoplasms, immunoradiotherapy, radiotherapy, immunotherapy
Published in DiRROS: 16.07.2024; Views: 292; Downloads: 81
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Abstract: Asbestos exposure is associated with the development of pleural plaques as well as malignant mesothelioma (MM). Asbestos fibres activate macrophages, leading to the release of inflammatory mediators including interleukin 1 beta (IL-1%). The expression of IL-1% may be influenced by genetic variability of IL1B gene or regulatory microRNAs (miRNAs). This study investigated the effect of polymorphisms in IL1B and MIR146A genes on the risk of developing pleural plaques and MM. Subjects and methods. In total, 394 patients with pleural plaques, 277 patients with MM, and 175 healthy control subjects were genotyped for IL1B and MIR146A polymorphisms. Logistic regression was used in statistical analysis. Results. We found no association between MIR146A and IL1B genotypes, and the risk of pleural plaques. MIR146A rs2910164 was significantly associated with a decreased risk of MM (OR = 0.31, 95% CI = 0.13%0.73, p = 0.008). Carriers of two polymorphic alleles had a lower risk of developing MM, even after adjustment for gender and age (OR = 0.34, 95% CI = 0.14%0.85, p = 0.020). Among patients with known asbestos exposure, carriers of at least one polymorphic IL1B rs1143623 allele also had a lower risk of MM in multivariable analysis (OR = 0.50, 95% CI = 0.28%0.92, p = 0.025). The interaction between IL1B rs1143623 and IL1B rs1071676 was significantly associated with an increased risk of MM (p = 0.050). Conclusions. Our findings suggest that genetic variability of inflammatory mediator IL-1% could contribute to the risk of developing MM, but not pleural plaques.
Keywords: asbestos, genetic variation, malignant mesothelioma, pleural plaques
Published in DiRROS: 16.07.2024; Views: 309; Downloads: 79
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Abstract: Coastal zones are exposed to various anthropogenic impacts, such as different types of wastewater pollution, e.g., treated wastewater discharges, leakage from sewage systems, and agricultural and urban runoff. These various inputs can introduce allochthonous organic matter and microbes, including pathogens, into the coastal marine environment. The presence of fecal bacterial indicators in the coastal environment is usually monitored using traditional culture-based methods that, however, fail to detect their uncultured representatives. We have conducted a year-around in situ survey of the pelagic microbiome of the dynamic coastal ecosystem, subjected to different anthropogenic pressures to depict the seasonal and spatial dynamics of traditional and alternative fecal bacterial indicators. To provide an insight into the environmental conditions under which bacterial indicators thrive, a suite of environmental factors and bacterial community dynamics were analyzed concurrently. Analyses of 16S rRNA amplicon sequences revealed that the coastal microbiome was primarily structured by seasonal changes regardless of the distance from the wastewater pollution sources. On the other hand, fecal bacterial indicators were not affected by seasons and accounted for up to 34% of the sequence proportion for a given sample. Even more so, traditional fecal indicator bacteria (Enterobacteriaceae) and alternative wastewater-associated bacteria (Lachnospiraceae, Ruminococcaceae, Arcobacteraceae, Pseudomonadaceae and Vibrionaceae) were part of the core coastal microbiome, i.e., present at all sampling stations. Microbial source tracking and Lagrangian particle tracking, which we employed to assess the potential pollution source, revealed the importance of riverine water as a vector for transmission of allochthonous microbes into the marine system. Further phylogenetic analysis showed that the Arcobacteraceae in our data set was affiliated with the pathogenic Arcobacter cryaerophilus, suggesting that a potential exposure risk for bacterial pathogens in anthropogenically impacted coastal zones remains. We emphasize that molecular analyses combined with statistical and oceanographic models may provide new insights for environmental health assessment and reveal the potential source and presence of microbial indicators, which are otherwise overlooked by a cultivation approach.
Published in DiRROS: 16.07.2024; Views: 317; Downloads: 187
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Abstract: In coastal seas, a variety of environmental variables characterise the average annual pattern of the physico-chemical environment and influence the temporal and spatial variations of phytoplankton communities. The aim of this study was to track the annual and interannual variability of phytoplankton biomass in different size classes in the Gulf of Trieste (Adriatic Sea) using phytoplankton pigments. The seasonal pattern of phytoplankton size classes showed a co-dominance of the nano and micro fractions during the spring peak and a predominance of the latter during the autumn peak. The highest picoplankton values occurred during the periods with the lowest total phytoplankton biomass, with chlorophytes dominating during the colder months and cyanobacteria during the summer. The highest number of significant correlations was found between phytoplankton taxa and size classes and temperature, nitrate and nitrite. The most obvious trend observed over the time series was an increase in picoplankton in all water layers, with the most significant trend in the bottom layer. Nano- and microplankton showed greater variation in biomass, with a decrease in nanoplankton biomass in 2011 and 2012 and negative trend in microplankton biomass in the bottom layer. These results suggest that changes in trophic relationships in the pelagic food web may also have implications for biogeochemical processes in the coastal sea.
Keywords: phytoplankton, biomass, phytoplankton size classes, phytoplankton pigments, HPLC, interannual variability, trends, Adriatic Sea
Published in DiRROS: 16.07.2024; Views: 321; Downloads: 223
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Abstract: Tyrosine kinase inhibitors (TKIs) are designed for targeted cancer therapy. The consumption of these drugs during the last 20 years has been constantly rising. In the zebrafish (Danio rerio) embryo toxicity test, we assessed the toxicity of six TKIs: imatinib mesylate, erlotinib, nilotinib, dasatinib, sorafenib and regorafenib. Imatinib mesylate and dasatinib induced lethal effects, while regorafenib, sorfenib and dasatinib caused a significant increase of sub-lethal effects, predominantly oedema, no blood circulation and formation of blood aggregates. The analyses of the changes in the expression of selected genes associated with the hormone system after the exposure to imatinib mesylate, dasatinib and regorafenib demonstrated that all three tested TKIs deregulated the expression of oestrogen receptor esr1, cytochrome P450 aromatase (cypa19b) and hydroxysteroid-dehydrogenase (hsd3b), regorafenib, and also thyroglobulin (tg). The expression of genes involved in the DNA damage response (gadd45 and mcm6) and apoptosis (bcl2) was deregulated only by exposure to regorafenib. The data indicate that common mechanisms, namely antiangiogenic activity and interference with steroidogenesis are involved in the TKI induced sub-lethal effects and potential hormone disrupting activity, respectively. The residues of TKIs may represent an environmental hazard; therefore, further ecotoxicological studies focusing also on the effects of their mixtures are warranted.
Keywords: aquatic toxicity, tyrosine kinase inhibitors, zebrafish embryo toxicity test, gene expression, environmental hazard
Published in DiRROS: 16.07.2024; Views: 310; Downloads: 197
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