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There is presented the possibility of using modern rapid prototyping methods in the form of reverse engineering on the example of lumbosacral spine of a human spine at the level of L3-L. Reverse engineering techniques were directly used in the generation and processing of point clouds from a real object. The point clouds were generated by using specialised Mimics software and basing on the results of computer tomography and magnetic resonance imaging using. In the next stage of processing, there was the export of the appropriately converted point clouds to STL format, compatible with CAD programs. The reverse engineering process took four steps: digitisation of the real object, using non-invasive imaging techniques (CT, MRI), processing the point clouds from the digitisation stage, construction of a surface model of the real object basing on the processed point clouds, realising of the real object’s copy by using rapid prototyping techniques. In the final stage, the model of the complex spinal’s part was tested to MES strength analysis.

Clinical trials are costly and time-intensive endeavors, with a high rate of drug candidate failures. Moreover, the standard approaches often evaluate drugs under a limited number of protocols. In oncology, where multiple treatment protocols can yield divergent outcomes, addressing this issue is crucial. Here, we present a computational framework that simulates clinical trials through a combination of mathematical and statistical models. This approach offers a means to explore diverse treatment protocols efficiently and identify optimal strategies for oncological drug administration. We developed a computational framework with a stochastic mathematical model as its core, capable of simulating virtual clinical trials closely recapitulating the clinical scenarios. Testing our framework on the landmark SOLO-1 clinical trial investigating Poly-ADP-Ribose Polymerase maintenance treatment in high-grade serous ovarian cancer, we demonstrate that managing toxicity through treatment interruptions or dose reductions does not compromise treatment's clinical benefits. Additionally, we provide evidence suggesting that further reduction of hematological toxicity could significantly improve the clinical outcomes. The value of this computational framework lies in its ability to expedite the exploration of new treatment protocols, delivering critical insights pivotal to shaping the landscape of upcoming clinical trials., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Research into the efficacy of photobiomodulation therapy (PBMT) in reducing inflammation has been ongoing for years, but standards for irradiation methodology still need to be developed. This study aimed to test whether PBMT stimulates in vitro human peripheral blood mononuclear cells (PBMCs) to synthesize pro-inflammatory cytokines, including chemokines. PBMCs were irradiated with laser radiation at two wavelengths simultaneously (λ = 808 nm in continuous emission and λ = 905 nm in pulsed emission). The laser radiation energy was dosed in one dose as a whole (5 J, 15 J, 20 J) or in a fractionated way (5 J + 15 J and 15 J + 5 J) with a frequency of 500, 1,500 and 2,000 Hz. The surface power densities were 177, 214 and 230 mW/cm 2 , respectively. A pro-inflammatory effect was observed at both the transcript and protein levels for IL-1β after PBMT at the energy doses 5 J and 20 J (ƒ=500 Hz) and only at the transcript level after application of PBMT at energy doses of 20 J (ƒ= 1,500; ƒ=2,000 Hz) and 5 + 15 J (ƒ=500 Hz). An increase in CCL2 and CCL3 mRNA expression was observed after PBMT at 5 + 15 J (ƒ=1,500 Hz) and 15 + 5 J (ƒ=2,000 Hz) and CCL3 concentration after application of an energy dose of 15 J (frequency of 500 Hz). Even though PBMT can induce mRNA synthesis and stimulate PBMCs to produce selected pro-inflammatory cytokines and chemokines, it is necessary to elucidate the impact of the simultaneous emission of two wavelengths on the inflammatory response mechanisms., (© 2024. The Author(s).)

Adipokines play essential roles in regulating a range of biological processes, but growing evidence indicates that they are also fundamental in immunological mechanisms and, primarily, inflammatory responses. Adipokines mediate their actions through specific receptors. However, although adipokine receptors are widely distributed in many cell and tissue types, limited data are available on their expression in mast cells (MCs) and, consequently, adipokine's significance in the modulation of MC activity within the tissues. In this study, we demonstrate that rat peritoneal MCs constitutively express the leptin receptor (i.e. LEPR), adiponectin receptors (i.e. ADIPOR1 and ADIPOR2) and the chemerin receptor (i.e. CMKLR1). We also found that LEPR, ADIPOR1, ADIPOR2 and CMKLR1 expression in MCs changes in response to stimulation by their specific ligands and some cytokines with potent proinflammatory properties. Furthermore, the involvement of intracellular signaling molecules in leptin-, adiponectin- and chemerin-induced MC response was analyzed. Overall, our findings suggest that adipokines leptin, adiponectin and chemerin can significantly affect the activity of MCs in various processes, especially during inflammation. These observations may contribute significantly to understanding the relationship between adipokines, immune mechanisms and diseases or conditions with an inflammatory component., (© 2024 the Australian and New Zealand Society for Immunology, Inc.)

Background: An accurate determination of the biological width and the relationship of the cemento-enamel junction with the border of the alveolar bone is crucial during a clinical crown-lengthening (CCL) procedure. The aim of this study was to present a technical note about the retraction techniques in cone beam computed tomography (CBCT) prior to CCL, highlighting the significant enhancement in procedural accuracy and predictability that these techniques offer. Methods: Clinical and radiological examinations should be performed before a CCL procedure. It is necessary to determine the length of the tooth crowns, the periodontal pockets' depth, and the phenotype of the gingiva. The ideal CBCT examination should be performed with soft tissue retraction. This can be achieved using retractors or cotton rolls. Results: Retraction of the lips, cheeks, and tongue allows one to assess the marginal gingiva, the cemento-enamel junction, and the alveolar bone. A detailed plan of the CCL procedure, which involves retraction, ensures both the aesthetic appeal and the achievement of a newly defined gingival zenith, enhancing the overall visual harmony. Conclusions: Compared with conventional radiographic imaging, the soft tissue retraction maneuver in CBCT prior to CCL surgery offers an effective approach to the evaluation and diagnosis of soft and hard tissue. This is because of the detailed planning of the aesthetic CCL procedure. Such an approach leads to superior aesthetic outcomes in dentistry, contributing to the advancement of aesthetic dentistry through a harmonious blend of art and science.

Background: Gestational diabetes mellitus (GDM) is the most common metabolic complication, which leads to short and long-term consequences in both mother and fetus exposed to hyperglycemia. The aetiology of this condition is proposed to be based on the dysfunction of the adipose tissue, which is characterised by the aberrant generation of adipokines. One of them is preadipocyte factor-1 (Pref-1), which could mediate controlling the adaptation of the maternal metabolism to pregnancy., Aims: The study aims to examine the level of Pref-1 in the cord blood of healthy pregnant women's neonates and fetuses born to mothers with GDM., Materials and Methods: Cord blood samples were collected from 30 newborns of mothers with GDM and 40 newborns of healthy pregnant women. Pref-1 concentrations were measured with an ELISA kit., Results: Fetal Pref-1 concentrations were significantly lower in newborns of mothers with GDM compared to the normal pregnancy group children (5.32 ± 0.29 vs. 7.38 ± 0.53; p < 0.001). Mothers with GDM had a significantly higher index of BMI before pregnancy, maternal gestational weight gain, and maternal fasting glucose. In-depth analysis through multiple variant linear regression revealed a significant association between fetal serum Pref-1 levels, exposure to GDM, and gestational age., Conclusion: These findings contribute valuable insights into maternal-fetal health and pave the way for more targeted and effective clinical interventions., (© 2024. The Author(s).)

Chronic odontogenic maxillary sinusitis (COMS), a prolonged inflammation of the maxillary sinus lasting over 12 weeks, is often a result of periapical lesions, marginal periodontitis, and complications like oro-antral communication (OAC) and fistula (OAF). OAC, commonly emerging post-teeth extraction in the lateral maxilla, lacks documented treatments using advanced platelet-rich fibrin (A-PRF). This study evaluates A-PRF's efficacy in treating COMS and immediately sealing extensive OAC. A case of a 28-year-old male with COMS linked to a periapical lesion and supernumerary molars is presented. Treatment involved extracting specific teeth while preserving adjacent ones and using A-PRF for immediate OAC closure. A-PRF, enriched with growth factors, was pivotal in healing, showcasing enhanced tissue regeneration, pain reduction, and faster recovery. The findings suggest A-PRF as an effective adjunct in treating extensive OAC and COMS, proposing its inclusion in standard treatment protocols. This study underscores A-PRF's potential in improving outcomes for patients with COMS and related complications.

Background: Flavokawain B is one of the naturally occurring chalcones in the kava plant (Piper methysticum). It exhibits anticancer, anti-inflammatory and antimalarial properties. Due to its therapeutic potential, flavokawain B holds promise for the treatment of many diseases. However, due to its poor bioavailability and low aqueous solubility, its application remains limited. The attachment of a sugar unit impacts the stability and solubility of flavonoids and often determines their bioavailability and bioactivity. Biotransformation is an environmentally friendly way to improve the properties of compounds, for example, to increase their hydrophilicity and thus affect their bioavailability. Recent studies proved that entomopathogenic filamentous fungi from the genera Isaria and Beauveria can perform O-methylglycosylation of hydroxyflavonoids or O-demethylation and hydroxylation of selected chalcones and flavones., Results: In the present study, we examined the ability of entomopathogenic filamentous fungal strains of Beauveria bassiana, Beauveria caledonica, Isaria farinosa, Isaria fumosorosea, and Isaria tenuipes to transform flavokawain B into its glycosylated derivatives. The main process occurring during the reaction is O-demethylation and/or hydroxylation followed by 4-O-methylglycosylation. The substrate used was characterized by low susceptibility to transformations compared to our previously described transformations of flavones and chalcones in the cultures of the tested strains. However, in the culture of the B. bassiana KCh J1.5 and BBT, Metarhizium robertsii MU4, and I. tenuipes MU35, the expected methylglycosides were obtained with high yields. Cheminformatic analyses indicated altered physicochemical and pharmacokinetic properties in the derivatives compared to flavokawain B. Pharmacological predictions suggested potential anticarcinogenic activity, caspase 3 stimulation, and antileishmanial effects., Conclusions: In summary, the study provided valuable insights into the enzymatic transformations of flavokawain B by entomopathogenic filamentous fungi, elucidating the structural modifications and predicting potential pharmacological activities of the obtained derivatives. The findings contribute to the understanding of the biocatalytic capabilities of these microbial cultures and the potential therapeutic applications of the modified flavokawain B derivatives., (© 2024. The Author(s).)

Drug resistance is a bottleneck in cancer treatment. Commonly, a molecular treatment for cancer leads to the emergence of drug resistance in the long term. Thus, some drugs, despite their initial excellent response, are withdrawn from the market. Lung cancer is one of the most mutated cancers, leading to dozens of targeted therapeutics available against it. Here, we have developed a mechanistic mathematical model describing sensitization to nine groups of targeted therapeutics and the emergence of intrinsic drug resistance. As we focus only on intrinsic drug resistance, we perform the computer simulations of the model only until clinical diagnosis. We have utilized, for model calibration, the whole-exome sequencing data combined with clinical information from over 1000 non-small-cell lung cancer patients. Next, the model has been applied to find an answer to the following questions: When does intrinsic drug resistance emerge? And how long does it take for early-stage lung cancer to grow to an advanced stage? The results show that drug resistance is inevitable at diagnosis but not always detectable and that the time interval between early and advanced-stage tumors depends on the selection advantage of cancer cells.

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and the median overall survival (OS) is approximately 2-3 years among patients with stage III disease. Furthermore, it is one of the deadliest types of cancer globally due to non-specific symptoms and the lack of a biomarker for early detection. The most important decision that clinicians need to make after a lung cancer diagnosis is the selection of a treatment schedule. This decision is based on, among others factors, the risk of developing metastasis., Methods: A cohort of 115 NSCLC patients treated using chemotherapy and radiotherapy (RT) with curative intent was retrospectively collated and included patients for whom positron emission tomography/computed tomography (PET/CT) images, acquired before RT, were available. The PET/CT images were used to compute radiomic features extracted from a region of interest (ROI), the primary tumor. Radiomic and clinical features were then classified to stratify the patients into short and long time to metastasis, and regression analysis was used to predict the risk of metastasis., Results: Classification based on binarized metastasis-free survival (MFS) was applied with moderate success. Indeed, an accuracy of 0.73 was obtained for the selection of features based on the Wilcoxon test and logistic regression model. However, the Cox regression model for metastasis risk prediction performed very well, with a concordance index (C-index) score equal to 0.84., Conclusions: It is possible to accurately predict the risk of metastasis in NSCLC patients based on radiomic features. The results demonstrate the potential use of features extracted from cancer imaging in predicting the risk of metastasis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-60/coif). The authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Quercetin is the most abundant flavonoid in food products, including berries, apples, cauliflower, tea, cabbage, nuts, onions, red wine and fruit juices. It exhibits various biological activities and is used for medical applications, such as treating allergic, inflammatory and metabolic disorders, ophthalmic and cardiovascular diseases, and arthritis. However, its low water solubility may limit quercetin's therapeutic potential. One method of increasing the solubility of active compounds is their coupling to polar molecules, such as sugars. The attachment of a glucose unit impacts the stability and solubility of flavonoids and often determines their bioavailability and bioactivity. Entomopathogenic fungi are biocatalysts well known for their ability to attach glucose and its 4- O -methyl derivative to bioactive compounds, including flavonoids. We investigated the ability of cultures of entomopathogenic fungi belonging to Beauveria , Isaria , Metapochonia , Lecanicillium and Metarhizium genera to biotransform quercetin. Three major glycosylation products were detected: ( 1 ), 7- O -β-D-(4″- O -methylglucopyranosyl)-quercetin, ( 2 ) 3- O -β-D-(4″- O -methylglucopyranosyl)-quercetin and ( 3 ) 3- O -β-D-(glucopyranosyl)-quercetin. The results show evident variability of the biotransformation process, both between strains of the tested biocatalysts from different species and between strains of the same species. Pharmacokinetic and pharmacodynamic properties of the obtained compounds were predicted with the use of cheminformatics tools. The study showed that the obtained compounds may have applications as effective modulators of intestinal flora and may be stronger hepato-, cardio- and vasoprotectants and free radical scavengers than quercetin., Competing Interests: The authors declare no conflicts of interest.

Depression has a multifactorial etiology comprising family history and unemployment. This review aims to summarize the evidence available for the antioxidant and anti-inflammatory effects of carotenoids in mood disorders. This review article's methodologies were based on a search of the PubMed database for all linked published papers. Epidemiological studies indicate that a diet rich in vegetables, fruits, nuts, fish, and olive oil may prevent the development of depression. Antioxidant supplementation has been found to combat various stress-induced psychiatric disorders, including depression and anxiety. A growing body of evidence indicates that carotenoids have both antioxidant and anti-inflammatory. Studies also suggest that poor dietary intake, particularly low intakes of fruit and vegetables and high intakes of fast food and other convenience foods, may increase the risk of developing depression. Thus, dietary interventions have the potential to help mitigate the risk of mental health decline in both the general population and those with mood disorders. Considering that carotenoids have both antioxidant and anti-inflammatory effects, it is expected that they might exert a promising antidepressant effect. Nevertheless, further studies (including interventional and mechanistic studies) assessing the effect of carotenoids on preventing and alleviating depression symptoms are needed.

Background: The majority of genes in the human genome is present in two copies but the expression levels of both alleles is not equal. Allelic imbalance is an aspect of gene expression relevant not only in the context of genetic variation, but also to understand the pathophysiology of genes implicated in genetic disorders, in particular, dominant genetic diseases where patients possess one normal and one mutant allele. Polyglutamine (polyQ) diseases are caused by the expansion of CAG trinucleotide tracts within specific genes. Spinocerebellar ataxia type 3 (SCA3) and Huntington's disease (HD) patients harbor one normal and one mutant allele that differ in the length of CAG tracts. However, assessing the expression level of individual alleles is challenging due to the presence of abundant CAG repeats in the human transcriptome, which make difficult the design of allele-specific methods, as well as of therapeutic strategies to selectively engage CAG sequences in mutant transcripts., Results: To precisely quantify expression in an allele-specific manner, we used SNP variants that are linked to either normal or CAG expanded alleles of the ataxin-3 (ATXN3) and huntingtin (HTT) genes in selected patient-derived cell lines. We applied a SNP-based quantitative droplet digital PCR (ddPCR) protocol for precise determination of the levels of transcripts in cellular and mouse models. For HD, we showed that the process of cell differentiation can affect the ratio between endogenous alleles of HTT mRNA. Additionally, we reported changes in the absolute number of the ATXN3 and HTT transcripts per cell during neuronal differentiation. We also implemented our assay to reliably monitor, in an allele-specific manner, the silencing efficiency of mRNA-targeting therapeutic approaches for HD. Finally, using the humanized Hu128/21 HD mouse model, we showed that the ratio of normal and mutant HTT transgene expression in brain slightly changes with the age of mice., Conclusions: Using allele-specific ddPCR assays, we observed differences in allele expression levels in the context of SCA3 and HD. Our allele-selective approach is a reliable and quantitative method to analyze low abundant transcripts and is performed with high accuracy and reproducibility. Therefore, the use of this approach can significantly improve understanding of allele-related mechanisms, e.g., related with mRNA processing that may be affected in polyQ diseases., (© 2023. The Author(s).)

Atherosclerosis, a common age-related disease, is characterized by intense immunological activity. Atherosclerotic plaque is composed of endothelial cells, vascular smooth muscle cells (VSMCs), lipids and immune cells infiltrating from the blood. During progression of the disease, VSMCs undergo senescence within the plaque and secrete SASP (senescence-associated secretory phenotype) factors that can actively modulate plaque microenvironment. We demonstrated that senescent VSMCs secrete increased number of extracellular vesicles (senEVs). Based on unbiased proteomic analysis of VMSC-derived EVs and of the soluble fraction of SASP (sSASP), more than 900 proteins were identified in each of SASP compartments. Comparison of the composition of VMSC-derived EVs with the SASP atlas revealed several proteins, including Serpin Family F Member 1 (SERPINF1) and Thrombospondin 1 (THBS1), as commonly upregulated components of EVs secreted by senescent VSMCs and fibroblasts. Among soluble SASP factors, only Growth Differentiation Factor 15 (GDF15) was universally increased in the secretome of senescent VSMCs, fibroblasts, and epithelial cells. Bioinformatics analysis of EV proteins distinguished functionally organized protein networks involved in immune cell function regulation. Accordingly, EVs released by senescent VSMCs induced secretion of IL-17, INFγ, and IL-10 by T cells and of TNFα produced by monocytes. Moreover senEVs influenced differentiation of monocytes favoring mix M1/M2 polarization with proinflammatory characteristics. Altogether, our studies provide a complex, unbiased analysis of VSMC SASP and prove that EVs derived from senescent VSMCs influence the cytokine milieu by modulating immune cell activity. Our results strengthen the role of senescent cells as an important inducer of inflammation in atherosclerosis., (© 2022. The Author(s).)

Modulating the gut microbiome and its influence on human health is the subject of intense research. The gut microbiota could be associated not only with gastroenterological diseases but also with psychiatric disorders. The importance of factors such as stress, mode of delivery, the role of probiotics, circadian clock system, diet, and occupational and environmental exposure in the relationship between the gut microbiota and brain function through bidirectional communication, described as "the microbiome-gut-brain axis", is especially underlined. In this review, we discuss the link between the intestinal microbiome and the brain and host response involving different pathways between the intestinal microbiota and the nervous system (e.g., neurotransmitters, endocrine system, immunological mechanisms, or bacterial metabolites). We review the microbiota alterations and their results in the development of psychiatric disorders, including major depressive disorder (MDD), schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD).

Mast cells (MCs) are the first immune cell type that can contact with the external environment, where they may rapidly sense the presence of pathogens. These cells are directly involved in innate defense through their ability to pathogen destruction by several mechanisms and the pattern recognition receptors (PRRs) they express. Several studies have focused on the aspects of MC responses to bacterial and viral pathogens or their specific components and the role of those cells in antibacterial or antiviral defense mechanisms. However, to date, the knowledge of the influence of various fungi-derived molecules on MC activity is primarily based on limited data. Thus, this study aims to compare the effect of the major fungi cell wall-associated antigens, i.e., two β-(1,3)-glucans: zymosan - β-(1,3)-glucan containing mannan and chitin, and curdlan - purified linear model β-(1,3)-glucan as well as mannan on peritoneal MC activity. In particular, the potency of various fungal cell wall components to induce MC migration, degranulation, and generation and/or release of de novo-synthesized mediators/cytokines/chemokines was analyzed. The most striking result to emerge from the data is that MC activation differs depending on the fungal stimuli. Our study outlines that components of the inner layer of the fungi cell wall - β-glucans, i.e., zymosan and curdlan, are more potent stimulators of MC activity compared to mannan. On this note, the data described here may provide a foundation for further studying the role of MC in antifungal immunity and be helpful for a better understanding of host-pathogenic fungi interactions., (Copyright © 2022. Published by Elsevier B.V.)

Progesterone biotransformation is worth studying because of the high industrial value of its derivatives. This study investigated the catalytic ability of the entomopathogenic filamentous fungus strain Isaria farinosa KCh KW1.1 to transform progesterone derivatives: 11α-hydroxyprogesterone, 17α-hydroxyprogesterone, 16α,17α-epoxyprogesterone and pregnenolone. In the culture of Isaria farinosa KCh KW1.1, 11α-hydroxyprogesterone was effectively transformed into only one product: 6β,11α-dihydroxyprogesterone. Transformation of 17α-hydroxyprogesterone gave three hydroxy derivatives: 6β,17α-dihydroxyprogesterone, 12β,17α-dihydroxyprogesterone and 6β,12β,17α-trihydroxyprogesterone. Two products: 6β-hydroxy-16α,17α-epoxyprogesterone and 6β,11α-dihydroxy-16α,17α-epoxyprogesterone, were obtained from the 16α,17α-epoxyprogesterone transformation. We isolated two compounds from the biotransformation medium with pregnenolone: 11α-hydroxy-7-oxopregnenolone and 5α,6α-epoxy-3β,11α-dihydroxypregnan-7,20-dione. In this study, we observed only mono- and dihydroxy derivatives of the tested substrates, and the number of obtained products for each biotransformation did not exceed three.

Introduction: Although schizophrenia is a severe mental illness, whose etiology is still largely unknown, its pathogenesis may be associated with dysregulation of the immune mechanisms. The present study compares the levels of interleukin (IL)-10, interleukin-8 (CXCL8), and fractalkine (CX3CL1) between schizophrenia patients and healthy controls. It also assesses the ability of peripheral peripheral blood mononuclear cells (PBMCs) to produce these cytokines spontaneously and following mitogen-stimulation., Materials and Methods: A prospective study was performed of 60 adult schizophrenia patients and 32 controls. CXCL8, IL-10, and fractalkine concentrations were measured in serum and supernatants from cultured PBMCs. Anthropometric (BMI, WHR) and body composition measurements were taken using bioimpedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA)., Results and Conclusion: The schizophrenia patients demonstrated significantly higher levels of serum CXCL8 (schizophrenia: 13.4 ± 15.7 pg/mL, control: 6.9 ± 4.2 pg/mL, p = 0.001) and lower level of serum fractalkine (schizophrenia: 22.8 ± 9.9 pg/mL, control: 45.4 ± 84.5 pg/mL, p = 0.041). Serum IL-10 levels did not significantly differ. No in vitro synthesis of fractalkine was observed. Neither unstimulated or PHA-stimulated CXCL8 secretion differed between the two groups ( p >0.05). The patients not taking mood stabilizers (MS-) demonstrated significantly higher CXCL8 levels than those on mood stabilizers (MS+) ( p = 0.03) and control ( p < 0.001). In addition, the MS- sub-group demonstrated significantly lower serum fraktalkine than controls ( p = 0.009). These effects could be described as pseudo-normalization of CXCL8 and fractalkine in schizophrenia patients taking mood stabilizers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arabska, Wysokiński, Brzezińska-Błaszczyk and Kozłowska.)

This research aimed to select yeast strains capable of the biotransformation of selected 2'-hydroxybromochalcones. Small-scale biotransformations were carried out using four substrates obtained by chemical synthesis (2'-hydroxy-2″-bromochalcone, 2'-hydroxy-3″-bromochalcone, 2'-hydroxy-4″-bromochalcone and 2'-hydroxy-5'-bromochalcone) and eight strains of non-conventional yeasts. Screening allowed for the determination of the substrate specificity of selected microorganisms and the selection of biocatalysts that carried out the hydrogenation of tested compounds in the most effective way. It was found that the position of the bromine atom has a crucial influence on the degree of substrate conversion by the tested yeast strains. As a result of the biotransformation of the 2'-hydroxybromochalcones, the corresponding 2'-hydroxybromodihydrochalcones were obtained. The products obtained belong to the group of compounds with high potential as precursors of sweet substances.

Hypoxia is an inherent factor in the inflammatory process and is important in the regulation of some immune cell functions, including the expression of mast cell pro- and anti-inflammatory mediators. Hypoxia also influences cell adhesion to the extracellular matrix (ECM). Hyaluronic acid is one of the major components of the ECM that is involved in inflammatory and tissue regeneration processes in which mast cells play a prominent role. This prompted us to investigate the effects of hypoxia on the expression of hyaluronic acid receptors in mast cells and mast cell adhesion to this ECM component. We found that human LAD2 mast cells spontaneously adhered to hyaluronic acid in a CD44-dependent manner and that reduced oxygen concentrations inhibited or even completely abolished this adhesion process. The mechanism of hypoxia downregulation of mast cell adhesion to hyaluronic acid did not involve a decrease in CD44 expression and hyaluronidase-mediated degradation of adhesion substrates but rather conformational changes in the avidity of CD44 to hyaluronic acid. Hypoxia-mediated regulation of mast cell adhesion to extracellular matrix components might be involved in the pathogenic accumulation of mast cells observed in the course of certain diseases including rheumatoid arthritis and cancer., (© 2021. The Author(s).)

Bacteria of the Neisseria genus are Gram-negative diplococci including both pathogenic and commensal species. We focused on pathogenic Neisseria gonorrhoeae and commensal Neisseria sicca . We have demonstrated that not only N. gonorrhoeae , but also N. sicca induce the secretion of pro-inflammatory cytokines IL-6, TNF-α, and chemokines CXCL8 and CCL20 by infected epithelial cells. However, N. sicca triggers a lesser effect than does N. gonorrhoeae . Furthermore, N. gonorrhoeae and N. sicca invoke distinct effects on the expression of genes (JUNB, FOSB, NFKB1, NFKBIA) encoding protein components of AP-1 and NF-κB transcription factors. We have also shown that the infection of epithelial cells by N. gonorrhoeae leads to significant overexpression of the long non-coding RNAs (lncRNAs), including MALAT1, ERICD, and RP11-510N19.5. This effect was not identified for N. sicca. In conclusion, data on the expression of lncRNAs and cytokine secretion in response to Neisseria spp. exposure indicate new directions for research on Neisseria -host interactions and can provide further insights into virulence of not only pathogenic, but also commensal Neisseria spp.

Invading pathogens are contained/eliminated by orchestrated actions of different humoral components of the innate immune response. One of them is endogenous molecules called alarmins, which contribute to diverse processes from danger sense until the infection extinction. Considering the participation of mast cells (MCs) in many aspects of the body's defense and, on the other hand, the importance of alarmins as molecules that signal damage/danger, in this study, we evaluated the effect of alarmins on MC phenotype and activity. We found that cathelicidin CRAMP and cytokine IL-33 significantly affect the appearance of Dectin-1, Dectin-2, RIG-I, and NOD1 receptors in mature MCs and modulate their inflammatory response. We established that chosen alarmins might stimulate MCs to release pro-inflammatory and immunoregulatory mediators and induce a migratory response. In conclusion, our data highlight that alarmins CRAMP and IL-33 might strongly influence MC features and activity, mainly by strengthening their role in the inflammatory mechanisms and controlling the activity of cells participating in antimicrobial processes., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Life course theory (LCT) diagnoses childhood and adolescent factors that determine an individual's involvement in crime in the future. Farrington lists eight key correlates identified by empirical analyses of criminal careers. In this paper, we seek to discuss the inconsistencies with LCT that we observed in our three empirical studies of the criminal careers of Polish offenders. During 12 years of qualitative research, we conducted direct observations and in-depth interviews in juvenile correction institutions (21) and prisons (8) across the country. We gained access to incarcerated (102) and released (30) juvenile offenders, as well as to incarcerated (68) and released (28) adult offenders. We also conducted in-depth interviews (92) with experts working with young and adult offenders. We similarly accessed some offenders' criminal records and psychological opinions. Our study revealed the strong presence of family and neighborhood influences on early criminality. Contrary to LCT assumptions, state-dependent institutions (military, work, family) were not strong enough determinants of delinquency. Polish offenders generally experience criminal onset later than LCT-oriented criminologists indicate. Based on our data, we also agree with the thesis that the onset of crime should be discussed as different age-related periods rather than just a general onset.

There is growing evidence that immune/inflammatory processes are related to the etiology of schizophrenia. Danger-/damage-associated molecular patterns (DAMPs), also called alarmins, are recognized as inflammatory mediators that play an important role in the development of many infection-induced or sterile inflammatory diseases. The importance of DAMPs particles in various mental disorders is still not clear. Therefore, this study aimed to evaluate serum levels of the most promising alarmins (IL-33, sST2, HMGB1, and S100B), as potent schizophrenia biomarkers. Sixty-eight adult patients with chronic schizophrenia and twenty-nine healthy volunteers were included in this prospective study. Enzyme-linked immunosorbent assay (ELISA) was used to assess the serum concentration of IL-33, sST2, HMGB1, and S100B. We documented that the serum levels of IL-33 (p = 0.006), sST2 (p = 0.02), HMGB1 (p = 0.01), and S100B (p = 0.04) are significantly higher in patients with schizophrenia than in healthy subjects. In male, but not in female, patients with schizophrenia, we found a significant difference in the serum IL-33, sST2, and HMGB1 concentrations as compared to the healthy men. In both male and female patients with schizophrenia, there was no significant difference in the serum concentrations of S100B in comparison to control subjects. In patients with schizophrenia, no significant correlations were noticed neither between any studied alarmins and PANSS scores nor between CDSS scores. Given that all investigated alarmins participate in the course of the neuroinflammatory process, they might be considered as biomarkers of neuroinflammatory process underlying schizophrenia. Based on our observations, it seems that the most useful biological indicator of schizophrenia would be IL-33., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Mast cells take part in host defense against microorganisms as they are numerous at the portal of infection, exert several essential mechanisms of pathogen destruction, and they express pattern recognition receptors. Accumulating evidence indicates that these cells are involved in the control and clearance of bacterial, viral, or parasitic infections, but much less is known about their contribution in defense against fungi. The study was aimed to establish whether mannan, which comprises an outermost layer and major structural constituent of the fungal cell wall, may directly stimulate tissue mast cells to the antifungal response. Our findings indicate that mannan activates mast cells isolated from the rat peritoneal cavity to initiate the proinflammatory response. We found that mannan stimulates mast cells to release histamine and to generate cysteinyl leukotrienes, cytokines (IFN-γ, GM-CSF, TNF), and chemokines (CCL2, CCL3). It also increased the mRNA expression of various cytokines/chemokines. We also documented that mannan strongly activates mast cells to generate reactive oxygen species and serves as a potent chemoattractant for these cells. Furthermore, we established that mannan-induced activity of mast cells is mediated via TLR4 with the involvement of the spleen tyrosine kinase molecule. Taking together, our results clearly support the idea that mast cells act as sentinel cells and crucially determine the course of the immune response during fungal infection. Additionally, presented data on IgE-coated mast cells suggest that exposure to fungal mannan could influence the severity of IgE-dependent diseases, including allergic ones., (©2020 Society for Leukocyte Biology.)

Purpose : To examine (a) the amount of health-related behavior, (b) the level of generalized optimism, (c) the belief about patients' abilities to cope with difficult situations and obstacles and (d) the subjective sense of social exclusion at baseline and at follow-up among patients with chronic mental health issues participating in a psychosocial rehabilitation program in a community mental health setting. Materials and Methods : This prospective study involved 52 participants aged 18-43 years and diagnosed with mental illness who participated in a 6-month psychosocial rehabilitation program, organized within a special community setting. Different questionnaires were used: the Health-Related Behavior Questionnaire, the Revised Life Orientation Test, the General Self-Efficacy Scale, the Personal Competence Scale and a self-made questionnaire concerning social exclusion problems. Results : Statistical analysis of the questionnaire results taken at the beginning and end of the six-month course, running from November 2015 to May 2016, revealed significant increases in health-related behavior ( p = 0.006) and general self-efficacy ( p = 0.01). Conclusions: Psychosocial rehabilitation programs offered by community mental health settings might serve as an easy, accessible strategy to deal with different interpersonal and intrapersonal problems and as a potential way to improve health behavior. Further research is required to evaluate other psychosocial rehabilitation programs in different community mental health settings in Lodz Voivodeship, Poland.

5,7-Dimethoxyflavone, a chrysin derivative, occurs in many plants and shows very low toxicity, even at high doses. On the basis of this phenomenon, we biotransformed a series of methoxy-derivatives of chrysin, apigenin, and tricetin obtained by chemical synthesis. We used entomopathogenic fungal strains with the confirmed ability of simultaneous hydroxylation/demethylation and glycosylation of flavonoid compounds. Both the amount and the place of attachment of the methoxy group influenced the biotransformation rate and the product's amount nascent. Based on product and semi-product structures, it can be concluded that they are the result of cascading transformations. Only in the case of 5,7,3',4',5'-pentamethoxyflavone, the strains were able to attach a sugar molecule in place of the methoxy substituent to give 3'- O -β-d-(4″- O -methylglucopyranosyl)-5,7,4',5'-tetramethoxyflavone. However, we observed the tested strains' ability to selectively demethylate/hydroxylate the carbon C-3' and C-4' of ring B of the substrates used. The structures of four hydroxyl-derivatives were determined: 4'-hydroxy-5,7-dimethoxyflavone, 3'-hydroxy-5,7-dimethoxyflavone, 3'-hydroxy-5,7,4',5'-tetramethoxyflavone, and 5,7-dimethoxy-3',4'-dihydroxyflavone (5,7-dimethoxy-luteolin).

Mast cells (MCs) play an essential role in host defense, primarily because of their location, their ability to pathogen destruction via several mechanisms, and the pattern recognition receptors they express. Even though most data is available regarding MC activation by various bacteria- or virus-derived molecules, those cells' activity in response to constituents associated with fungi is not recognized enough. Our research aimed to address whether Saccharomyces cerevisiae-derived zymosan, i.e., β-(1,3)-glucan containing mannan particles, impacts MC activity aspects. Overall, the obtained results indicate that zymosan has the potential to elicit a pro-inflammatory response of rat peritoneal MCs. For the first time ever, we provided evidence that zymosan induces fully mature MC migration, even in the absence of extracellular matrix (ECM) proteins. Moreover, the zymosan-induced migratory response of MCs is almost entirely a result of directional migration, i.e., chemotaxis. We found that zymosan stimulates MCs to degranulate and generate lipid mediators (cysLTs), cytokines (IFN-α, IFN-β, IFN-γ, GM-CSF, TNF), and chemokine (CCL2). Zymosan also upregulated mRNA transcripts for several cytokines/chemokines with pro-inflammatory/immunoregulatory activity. Moreover, we documented that zymosan activates MCs to produce reactive oxygen species (ROS). Lastly, we established that the zymosan-induced MC response is mediated through activation of the Dectin-1 receptor. In general, our results strongly support the notion that MCs contribute to innate antifungal immunity and bring us closer to elucidate their role in host-pathogenic fungi interactions. Besides, provided findings on IgE-sensitized MCs appear to indicate that exposure to fungal zymosan could affect the severity of IgE-dependent disorders, including allergic ones.

Background: Our study aimed to assess the level of IL-1β, CXCL8, and TNF-α in peri-implant sulcular fluid (PISF) collected from patients with no clinical symptoms of mucositis or peri-implantitis and compare them with cytokine concentration in gingival crevicular fluid (GCF) acquired from patients with healthy periodontium and those with varying severity of periodontitis., Methods: A total of 189 subjects were included in the study, and GCF/PISF samples were checked for IL-1β, CXCL8, and TNF-α levels using an ELISA test., Results: The IL-1β level in PISF in patients with implants was significantly lower than in GCF in patients with mild, moderate, or severe periodontitis. The CXCL8 level in PISF was considerably lower than in patients with moderate periodontitis. The TNF-α level in PISF in patients with implants was markedly higher compared to subjects with healthy periodontium or patients with mild periodontitis., Conclusion: Analysis of cytokine levels may help describe the pathogenesis and early diagnosis of peri-implantitis and prevision in high-risk patients.

Introduction: The aim of this study was to determine the mRNA expression profile of dopamine D 1 , D 2 , D 3 , D 4 and serotonin 5-HT 1A , 5-HT 2A , and 5-HT 3A receptors in peripheral blood mononuclear cells (PBMCs) in schizophrenia and the in vitro effect of antipsychotics on the expression of these receptors in PBMCs of healthy subjects. Materials and Methods: Twenty-seven patients with schizophrenia and 29 healthy controls were recruited for the study. All study subjects underwent thorough clinical assessment, including anthropometric and body composition measurements. The expression of mRNA for dopamine D 1-4 and serotonin 5-HT 1A-3A receptors was measured using quantitative RT-PCR in peripheral blood mononuclear cells. In vitro mRNA and protein expression of these receptors was measured using quantitative RT-PCR and Western Blotting in PBMCs cultured with quetiapine, haloperidol, aripiprazole, risperidone, olanzapine or clozapine at IC 50 , half of IC 50 , and one-quarter of IC 50 concentrations. Results: The key finding was that the schizophrenia group demonstrated significantly higher mRNA expression of D 1 , D 2 and D 4 receptors ( p < 0.001), and significantly lower mRNA expression of 5-HT 3A receptors ( p < 0.01). After adjusting for smoking, the mRNA expression of D 1 lost its significance, while that of D 3 , 5-HT 1A , 5-HT 2A became significant (all three were lower in the schizophrenia group). These receptors also demonstrated different ratios of mRNA expression in the schizophrenia group. The in vitro experiments showed that high concentrations of antipsychotics influenced the mRNA and protein expression of all studied receptors. Conclusion: Schizophrenia patients display a distinctive pattern of dopamine and serotonin receptor mRNA expression in blood mononuclear cells. This expression is little affected by antipsychotic treatment and it may therefore serve as a useful diagnostic biomarker for schizophrenia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wysokiński, Kozłowska, Szczepocka, Łucka, Agier, Brzezińska-Błaszczyk and Sobierajska.)

Bearing in mind that mast cell contribution to viral clearance is still not fully understood, in this study, we evaluated the effect of Toll-like receptor (TLR)7 viral single-stranded ribonucleic acid (ssRNA) mimic ligand, namely resiquimod (R)848, on mast cell phenotype and activity. We demonstrated that rat peritoneal mast cells exhibit surface and intracellular expression of ssRNA-specific TLR7 molecule, and that mimic ligand switches the self-expression of this receptor. We also detected other proteins associated with the cellular antiviral response: interferon-alpha receptor 1 (IFNAR1), interferon-gamma receptor 1 (IFNGR1), and major histocompatibility complex I (MHC I). Moreover, we showed that R848 caused the decrease of all molecule's expression after prolonged incubation. Interestingly, we found that R848 induced the increase of high-affinity IgE receptor (FcεRI) expression. Finally, we documented that TLR7 ligand-stimulated mast cells synthesize/release interferon (IFN)-α and -β, tumor necrosis factor (TNF), and chemokines CCL3, CXCL8, as well as pro-inflammatory lipid mediators. Our findings confirm that mast cells may respond to TLR7 ligand by altering their phenotype and synthesizing mediators and could serve as active participants in the antiviral immune response., (Copyright © 2020 Elsevier Inc. All rights reserved.)

It has been suggested that immune-inflammatory processes might be involved in the etiopathogenesis of schizophrenia. Since growing evidence indicates that adipokines strongly modulate the course of immune response and inflammatory processes, it is currently suggested the contribution of those factors in the etiology of schizophrenia as well. The aim of this study was to determine the serum levels of 4 adipokines-apelin, resistin, chemerin, and omentin-in patients with schizophrenia as compared with healthy subjects. Fifty-seven adult patients with schizophrenia and 31 healthy volunteers were included in this prospective study. ELISA was used to measure the serum concentration of resistin, apelin, omentin-1, and chemerin. No difference in the mean concentration of resistin (p=0.20) and chemerin (p=0.30) between patients with schizophrenia and the healthy group was observed. Apelin concentration was significantly (p=0.004) lower in patients with schizophrenia as compared with controls. A significant difference in apelin level between men with schizophrenia and control group (p=0.04) was reported. Apelin concentration was significantly correlated with waist-to-hip ratio, whereas chemerin concentration was significantly correlated with the Positive and Negative Syndrome Scale G score. There exists evidence that apelin might be involved in the pathogenesis of schizophrenia., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction and Objectives: According to immunological theory of schizophrenia, dysfunctions of the immune system are linked with the pathology of schizophrenia. Among cytokines, tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) seem to be correlated with psychopathology of schizophrenia. Both IL-6 and TNF-α are produced in the fat tissue by adipocytes. Thus, cytokine levels in obese patients are increased compared with healthy subjects. These metabolic underlying mechanisms may be an important confounding factor in the studies on cytokines levels in schizophrenia. The aim of this study was to evaluate how metabolic alterations affect peripheral IL-6 and TNF-α levels in schizophrenia patients., Materials and Methods: This was a case-control study, 30 schizophrenia patients were recruited in the study group and 30 healthy subjects were matched by sex and age. Serum levels of TNF-α and Il-6 were measured using ELISA test, together with detailed anthropometric, laboratory and body composition parameters (determined using bioelectric impedance analysis)., Results and Conclusions: Serum TNF-α concentration in the schizophrenia group was 6.05 ± 1.61 ng/mL and 5.94 ± 1.26 ng/mL in the control group. The difference between these two groups was not significant (p = .79). Serum IL-6 concentration in the schizophrenia group was 1.54 ± 1.46 ng/mL and in the control group 1.39 ± 1.39 ng/mL. Again, the difference was not significant (p = .51). We have analysed the relationship between anthropometric and metabolic variables and serum IL-6 and TNF-α concentrations. In conclusion, TNF-α was more sensitive to metabolic alterations compared with IL-6. This observation may be beneficial for further research on immune system in schizophrenia, indicating that studies of IL-6 and TNF-α should be controlled at least for major metabolic parameters (BMI, WHR)., Competing Interests: Declaration of Competing Interest None to declare, (Copyright © 2020 Elsevier B.V. All rights reserved.)

We developed a computational platform including machine learning and a mechanistic mathematical model to find the optimal protocol for administration of platinum-doublet chemotherapy in a palliative setting. The platform has been applied to advanced metastatic non-small cell lung cancer (NSCLC). The 42 NSCLC patients treated with palliative intent at Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, were collected from a retrospective cohort of patients diagnosed in 2004-2014. Patients were followed-up, for three years. Clinical data collected include complete information about the clinical course of the patients including treatment schedule, response according to RECIST classification, and survival. The core of the platform is the mathematical model, in the form of a system of ordinary differential equations, describing dynamics of platinum-sensitive and platinum-resistant cancer cells and interactions reflecting competition for space and resources. The model is simulated stochastically by sampling the parameter values from a joint probability distribution function. The machine learning model is applied to calibrate the mathematical model and to fit it to the overall survival curve. The model simulations faithfully reproduce the clinical cohort at three levels long-term response (OS), the initial response (according to RECIST criteria), and the relationship between the number of chemotherapy cycles and time between two consecutive chemotherapy cycles. In addition, we investigated the relationship between initial and long-term response. We showed that those two variables do not correlate which means that we cannot predict patient survival solely based on the initial response. We also tested several chemotherapy schedules to find the best one for patients treated with palliative intent. We found that the optimal treatment schedule depends, among others, on the strength of competition among various subclones in a tumor. The computational platform developed allows optimizing chemotherapy protocols, within admissible limits of toxicity, for palliative treatment of metastatic NSCLC. The simplicity of the method allows its application to chemotherapy optimization in different cancers., Competing Interests: The authors have declared that no competing interests exist.

Adipokines are predominantly known to play a vital role in the control of food intake, energy homeostasis and regulation of glucose and lipid metabolism. However, evidence supporting the concept of their extensive involvement in immune system defence mechanisms and inflammatory processes continues to grow. Some of the adipokines, that is, leptin and resistin, have been recognized to exhibit mainly pro-inflammatory properties, whereas others such as visfatin, chemerin, apelin and vaspin have been found to exert regulatory effects. In contrast, adiponectin or omentin are known for their anti-inflammatory activities. Hence, adipokines influence the activity of various cells engaged in innate immune response and inflammatory processes mainly by affecting adhesion molecule expression, chemotaxis, apoptosis and phagocytosis, as well as mediators production and release. However, much less is known about the role of adipokines in processes involving lymphoid lineage cells. This review summarizes the current knowledge regarding the importance of different adipokines in the lymphopoiesis, recirculation, differentiation and polarization of lymphoid lineage cells. It also provides insight into the influence of selected adipokines on the activity of those cells in tissues., (© 2020 World Obesity Federation.)

Chalcones are interesting candidates for anti-cancer drugs due to the ease of their synthesis and their extensive biological activity. The study presents antitumor activity of newly synthesized chalcone analogues with a methoxy group on a panel of canine lymphoma and leukemia cell lines. The antiproliferative effect of the 2'-hydroxychalcone and its methoxylated derivatives was evaluated in MTT assay after 48 h of treatment in different concentrations. The proapoptotic activity was studied by cytometric analysis of cells stained with Annexin V/FITC and propidium iodide and by measure caspases 3/7 and 8 activation. The DNA damage was evaluated by Western blot analysis of phosphorylated histone H2AX. The new compounds had selective antiproliferative activity against the studied cell lines, the most effective were the 2'-hydroxy-2″,5″-dimethoxychalcone and 2'-hydroxy-4',6'-dimethoxychalcone. 2'-Hydroxychalcone and the two most active derivatives induced apoptosis and caspases participation, but some percentage of necrotic cells was also observed. Comparing phosphatidylserine externalization after treatment with the different compounds it was noted that the addition of two methoxy groups increased the proapoptotic potential. The most active compounds triggered DNA damage even in the cell lines resistant to chalcone-induced apoptosis. The results confirmed that the analogues could have anticancer potential in the treatment of canine lymphoma or leukemia.

There is evidence that major components of the fungi cell wall not only define fungal properties and survival but also are responsible for their biological activities. Some data indicate that structural components of the fungal cell wall exert stimulatory/modulatory effects on immunocompetent cells acting as pathogen-associated molecular patterns (PAMPs). Fungal components can influence the activity of certain immune cell populations by affecting cell maturation and proliferation, promoting phagocytosis, cytotoxic activity, and cell migration, as well as production of various mediators. However, there is little information available concerning the impact of fungal-derived components on peripheral blood mononuclear cell (PBMC) activation. The aim of this study was to determine whether certain fungi-associated molecules, i.e., β-(1,3)-glucans (zymosan and curdlan) and mannan activate in vitro human PBMCs to synthesize cytokines, including chemokines. We documented that PBMCs, in response to stimulation with zymosan, curdlan, and mannan, express cytokines IFN-γ and GM-CSF, and chemokine CCL3, both at protein and transcript levels, as well as cytokine IL-1β and chemokine CXCL8, at mRNA level. Our observations support the idea that fungal-derived components can activate immune cells, including PBMCs, by stimulation of cytokine/chemokine production. A thorough understanding of this interaction is of prime importance since it influence both pathophysiological and immune processes as well as anti-fungal defense mechanisms., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

The synthesis and biotransformation of five flavones containing methoxy substituents in the B ring: 2'-, 3'-, 4'-methoxyflavones, 2',5'-dimethoxyflavone and 3',4',5'-trimethoxyflavone are described. Strains of entomopathogenic filamentous fungi were used as biocatalysts. Five strains of the species Beauveria bassiana (KCh J1.5, J2.1, J3.2, J1, BBT), two of the species Beauveria caledonica (KCh J3.3, J3.4), one of Isaria fumosorosea (KCh J2) and one of Isaria farinosa (KCh KW 1.1) were investigated. Both the number and the place of attachment of the methoxy groups in the flavonoid structure influenced the biotransformation rate and the amount of nascent products. Based on the structures of products and semi-products, it can be concluded that their formation is the result of a cascading process. As a result of enzymes produced in the cells of the tested strains, the test compounds undergo progressive demethylation and/or hydroxylation and 4- O -methylglucosylation. Thirteen novel flavonoid 4- O -methylglucosides and five hydroxy flavones were isolated and identified.

Sepsis survivors suffer from increased vulnerability to infections, and lymphopenia presumably contributes to this problem. The mechanisms of the recovery of memory CD4+ T cells after sepsis remain elusive. We used the cecal ligation and puncture mouse model of sepsis to study the restoration of the memory CD4+ T cells during recovery from sepsis. Then, adoptive transfer of antigen-specific naive CD4+ T cells followed by immunization and BrdU labeling were performed to trace the proliferation and migration of memory CD4+ T cells. We revealed that the bone marrow (BM) is the primary site of CD4+ memory T cell homing and proliferation after sepsis-induced lymphopenia. Of interest, BM CD4+ T cells had a higher basal proliferation rate in comparison with splenic T cells. These cells also show features of resident memory T cells yet have the capacity to migrate outside the BM niche and engraft secondary lymphoid organs. The BM niche also sustains viability and functionality of CD4+ T cells. We also identified IL-7 as the major inducer of proliferation of the BM memory CD4+ T cells and showed that recombinant IL-7 improves the recovery of these cells. Taken together, we provide data on the mechanism and location of memory CD4+ T cell proliferation during recovery from septic lymphopenia, which are of relevance in studying immunostimulatory therapies in sepsis.

Background: Steroid compounds with a 6,19-oxirane bridge possess interesting biological activities including anticonvulsant and analgesic properties, bacteriostatic activity against Gram-positive bacteria and selective anti-glucocorticoid action, while lacking mineralocorticoid and progestagen activity., Results: The study aimed to obtain new derivatives of 3β-acetyloxy-5α-chloro-6,19-oxidoandrostan-17-one by microbial transformation. Twelve filamentous fungal strains were used as catalysts, including entomopathogenic strains with specific activity in the transformation of steroid compounds. All selected strains were characterised by high biotransformation capacity for steroid compounds. However, high substrate conversions were obtained in the cultures of 8 strains: Beauveria bassiana KCh BBT, Beauveria caledonica KCh J3.4, Penicillium commune KCh W7, Penicillium chrysogenum KCh S4, Mucor hiemalis KCh W2, Fusarium acuminatum KCh S1, Trichoderma atroviride KCh TRW and Isaria farinosa KCh KW1.1. Based on gas chromatography (GC) and nuclear magnetic resonance (NMR) analyses, it was found that almost all strains hydrolysed the ester bond of the acetyl group. The strain M. hiemalis KCh W2 reduced the carbonyl group additionally. From the P. commune KCh W7 and P. chrysogenum KCh S4 strain cultures a product of D-ring Baeyer-Villiger oxidation was isolated, whereas from the culture of B. bassiana KCh BBT a product of hydroxylation at the 11α position and oxidation of the D ring was obtained. Three 11α-hydroxy derivatives were obtained in the culture of I. farinosa KCh KW1.1: 3β,11α-dihydroxy-5α-chloro-6,19-oxidoandrostan-17-one, 3β,11α,19-trihydroxy-5α-chloro-6,19-oxidoandrostan-17-one and 3β,11α-dihydroxy-5α-chloro-6,19-oxidoandrostan-17,19-dione. They are a result of consecutive reactions of hydrolysis of the acetyl group at C-3, 11α- hydroxylation, then hydroxylation at C-19 and its further oxidation to lactone., Conclusions: As a result of the biotransformations, seven steroid derivatives, not previously described in the literature, were obtained: 3β-hydroxy-5α-chloro-6,19-oxidoandrostan-17-one, 3β,17α-dihydroxy-5α-chloro-6,19-oxidoandrostane, 3β-hydroxy-5α-chloro-17α-oxa-D-homo-6,19-oxidoandrostan-17-one, 3β,11α-dihydroxy-5α-chloro-17α-oxa-D-homo-6,19-oxidoandrostan-17-one and the three above-mentioned 11α-hydroxy derivatives. This study will allow a better understanding and characterisation of the catalytic abilities of individual microorganisms, which is crucial for more accurate planning of experiments and achieving more predictable results.

A major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials. Using a virtual clinical trial simulations approach, we present a mathematical framework to estimate the added value of combinatorial treatments in ovarian cancer. This approach was applied to identify effective targeted therapies that can be combined with the platinum-taxane regimen and overcome platinum resistance in high-grade serous ovarian cancer. We modeled and evaluated the effectiveness of three drugs that target the main platinum resistance mechanisms, which have shown promising efficacy in vitro, in vivo, and early clinical trials. Our results show that drugs resensitizing chemoresistant cells are superior to those aimed at triggering apoptosis or increasing the bioavailability of platinum. Our results further show that the benefit of using biomarker stratification in clinical trials is dependent on the efficacy of the drug and tumor composition. The mathematical framework presented herein is suitable for systematically testing various drug combinations and clinical trial designs in solid cancers.