Theoretical Study of Metal-Ligand Interactions in Lead Complexes with Radiopharmaceutical Interest.

The 203Pb and 212Pb lead radioisotopes are attracting growing interest as they can aid in the development of personalized, targeted radionuclide treatment for advanced and currently untreatable cancers. In the present study, the bonding interactions of Pb2+ with twelve macrocyclic ligands, having an octa and nona coordination, were assessed using Density Functional Theory (DFT) calculations. The molecular structures in an aqueous solution were computed utilizing the polarized continuum model. The preference for the twisted square antiprismatic (TSAP) structure was confirmed for ten out of the eleven cyclen-based complexes. The characteristics of the bonding were assessed using a Natural Energy Decomposition Analysis (NEDA). The analysis revealed a strong electrostatic character of the bonding in the complexes, with minor variations in electrical terms. The charge transfer (CT) had a comparable energetic contribution only in the case of neutral ligands, while in general, it showed notable variations regarding the various donor groups. Our data confirmed the general superiority of the carboxylate O and aromatic N donors. The combination of the selected efficient pendant arms pointed out the superiority of the acetate pendant arms and the lack of significant cooperation between the different pendant arms in the probed ligands. Altogether, the combination led only to a marginal enhancement in the total CTs in the complexes.

Acute pulmonary embolism pretest probability estimation by d-dimer test, our modified, new ECG score and clinical prediction rules.

Objectives: We investigated whether a sufficiently sensitive D-dimer test could exclude acute pulmonary embolism (acPE) as a stand-alone diagnostic test and compared our previously published, modified ECG score with the Wells and Geneva scores in the estimation of acPE pretest probability. Methods: We retrospectively evaluated 345 patients who underwent chest CT angiography (CTA) for the suspicion of acPE. The pretest probability of acPE was assessed in 120 D-dimer negative [DD (-)] and 225 D-dimer positive [DD (+)] patients. Results: Chest CTA verified acPE in 57/345 (16.5 %) patients and in 1/120 (0.8 %) DD (-) patient. In DD (-) patients the test accuracy (TA) and specificity (SP) of the ECG score (98 %, 99 %) were better than those of the Wells score (92.5 %, 92.4 %) (p = 0.063 and p < 0.05 respectively) and the Geneva score (76.7 %, 76.5 %) (p < 0.001 for both), the Wells score TA and SP were greater than those of the Geneva score (p < 0.001 for both). In DD (+) patients the SPs, TAs and positive predictive values (PPV) of the ECG score (94 %, 78.6 %, 69 %) and the Wells score (91.8 %, 75.1 %, 48 %) were greater than those of the Geneva score (71.3 %, 64.9 %, 38.2 %) (p < 0.001 for both SP and TA respectively, and p < 0.001 for PPV of the ECG score vs. the Geneva score and p < 0.05 for PPV of the Wells score vs. Geneva score), their sensitivities (SE) (36.4 %, 23.6 %) were less than that of the Geneva score (47.5 %) (p < 0.05 and p < 0.001 respectively). The ECG score's TA in a trend, its SE and PPV were significantly (p < 0.01 and p < 0.001) better than those of the Wells score. Conclusion: In contrast to the current guidelines, a stand-alone high sensitivity DD (-) test, without prediction rules, could reliably exclude acPE. Our ECG score slightly outperformed the Wells score, the ECG score and Wells score far outperformed the Geneva score in the estimation of acPE pretest probability. An acPE diagnosis with the ECG score, in addition to the supportive diagnosis with the clinical prediction rules, may further increase the chance of true DD positivity.

Cardioprotective microRNAs (protectomiRs) in a pig model of acute myocardial infarction and cardioprotection by ischaemic conditioning: MiR-450a.

BACKGROUND AND PURPOSE: Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect. EXPERIMENTAL APPROACH: ProtectomiR candidates were selected after systematic analysis of miRNA expression changes in cardiac tissue samples from a closed-chest AMI model in pigs subjected to sham operation, AMI and ischaemic preconditioning, postconditioning or remote preconditioning, respectively. Cross-species orthologue protectomiR candidates were validated in simulated ischaemia-reperfusion injury (sI/R) model of isolated rat ocardiomyocytes and in human AC16 cells as well. For miR-450a, we performed target prediction and analysed the potential mechanisms of action by GO enrichment and KEGG pathway analysis. KEY RESULTS: Out of the 220 detected miRNAs, four were up-regulated and 10 were down-regulated due to all three conditionings versus AMI. MiR-450a and miR-451 mimics at 25 nM were protective in rat cardiomyocytes, and miR-450a showed protection in human cardiomyocytes as well. MiR-450a has 3987 predicted mRNA targets in pigs, 4279 in rats and 8328 in humans. Of these, 607 genes are expressed in all three species. A total of 421 common enriched GO terms were identified in all three species, whereas KEGG pathway analysis revealed 13 common pathways. CONCLUSION AND IMPLICATIONS: This is the first demonstration that miR-450a is associated with cardioprotection by ischaemic conditioning in a clinically relevant porcine model and shows cardiocytoprotective effect in human cardiomyocytes, making it a promising drug candidate. The mechanism of action of miR-450a involves multiple cardioprotective pathways.

Size and fluorescence calibrated imaging flow cytometry: From arbitrary to standard units.

Imaging flow cytometry (IFCM) is a technique that can detect, size, and phenotype extracellular vesicles (EVs) at high throughput (thousands/minute) in complex biofluids without prior EV isolation. However, the generated signals are expressed in arbitrary units, which hinders data interpretation and comparison of measurement results between instruments and institutes. While fluorescence calibration can be readily achieved, calibration of side scatter (SSC) signals presents an ongoing challenge for IFCM. Here, we present an approach to relate the SSC signals to particle size for IFCM, and perform a comparability study between three different IFCMs using a plasma EV test sample (PEVTES). SSC signals for different sizes of polystyrene (PS) and hollow organosilica beads (HOBs) were acquired with a 405 nm 120 mW laser without a notch filter before detection. Mie theory was applied to relate scatter signals to particle size. Fluorescence calibration was accomplished with 2 µm phycoerythrin (PE) and allophycocyanin (APC) MESF beads. Size and fluorescence calibration was performed for three IFCMs in two laboratories. CD235a-PE and CD61-APC stained PEVTES were used as EV-containing samples. EV concentrations were compared between instruments within a size range of 100-1000 nm and a fluorescence intensity range of 3-10,000 MESF. 81 nm PS beads could be readily discerned from background based on their SSC signals. Fitting of the obtained PS bead SSC signals with Mie theory resulted in a coefficient of determination >0.99 between theory and data for all three IFCMs. 216 nm HOBs were detected with all instruments, and confirmed the sensitivity to detect EVs by SSC. The lower limit of detection regarding EV-size for this study was determined to be ~100 nm for all instruments. Size and fluorescence calibration of IFCM data increased cross-instrument data comparability with the coefficient of variation decreasing from 33% to 21%. Here we demonstrate - for the first time - scatter calibration of an IFCM using the 405 nm laser. The quality of the scatter-to-diameter relation and scatter sensitivity of the IFCMs are similar to the most sensitive commercially available flow cytometers. This development will support the reliability of EV research with IFCM by providing robust standardization and reproducibility, which are pre-requisites for understanding the biological significance of EVs.

Comparison of mouse models of heart failure with reduced ejection fraction.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of death worldwide; thus, therapeutic improvements are needed. In vivo preclinical models are essential to identify molecular drug targets for future therapies. Transverse aortic constriction (TAC) is a well-established model of HFrEF; however, highly experienced personnel are needed for the surgery, and several weeks of follow-up are necessary to develop HFrEF. To this end, we aimed (i) to develop an easy-to-perform mouse model of HFrEF by treating Balb/c mice with angiotensin-II (Ang-II) for 2 weeks by minipump and (ii) to compare its cardiac phenotype and transcriptome to the well-established TAC model of HFrEF in C57BL/6J mice. METHODS: Mortality and gross pathological data, cardiac structural and functional characteristics assessed by echocardiography and immunohistochemistry and differential gene expression obtained by RNA-sequencing and gene-ontology analyses were used to characterize and compare the two models. To achieve statistical comparability between the two models, changes in treatment groups related to the corresponding control were compared (ΔTAC vs. ΔAng-II). RESULTS: Compared with the well-established TAC model, chronic Ang-II treatment of Balb/c mice shares similarities in cardiac systolic functional decline (left ventricular ejection fraction: -57.25 ± 7.17% vs. -43.68 ± 5.31% in ΔTAC vs. ΔAng-II; P = 0.1794) but shows a lesser degree of left ventricular dilation (left ventricular end-systolic volume: 190.81 ± 44.13 vs. 57.37 ± 10.18 mL in ΔTAC vs. ΔAng-II; P = 0.0252) and hypertrophy (cell surface area: 58.44 ± 6.1 vs. 10.24 ± 2.87 µm2 in ΔTAC vs. ΔAng-II; P < 0.001); nevertheless, transcriptomic changes in the two HFrEF models show strong correlation (Spearman's r = 0.727; P < 0.001). In return, Ang-II treatment in Balb/c mice needs significantly less procedural time [38 min, interquartile range (IQR): 31-46 min in TAC vs. 6 min, IQR: 6-7 min in Ang-II; P < 0.001] and surgical expertise, is less of an object for peri-procedural mortality (15.8% in TAC vs. 0% in Ang-II; P = 0.105) and needs significantly shorter follow-up for developing HFrEF. CONCLUSIONS: Here, we demonstrate for the first time that chronic Ang-II treatment of Balb/c mice is also a relevant, reliable but significantly easier-to-perform preclinical model to identify novel pathomechanisms and targets in future HFrEF research.

Fitting of Coupled Potential Energy Surfaces via Discovery of Companion Matrices by Machine Intelligence.

Fitting coupled potential energy surfaces is a critical step in simulating electronically nonadiabatic chemical reactions and energy transfer processes. Analytic representation of coupled potential energy surfaces enables one to perform detailed dynamics calculations. Traditionally, fitting is performed in a diabatic representation to avoid fitting the cuspidal ridges of coupled adiabatic potential energy surfaces at conical intersection seams. In this work, we provide an alternative approach by carrying out fitting in the adiabatic representation using a modified version of the Frobenius companion matrices, whose usage was first proposed by Opalka and Domcke. Their work involved minimizing the errors in fits of the characteristic polynomial coefficients (CPCs) and diagonalizing the resulting companion matrix, whose eigenvalues are adiabatic potential energies. We show, however, that this may lead to complex eigenvalues and spurious discontinuities. To alleviate this problem, we provide a new procedure for the automatic discovery of CPCs and the diagonalization of a companion matrix by using a special neural network architecture. The method effectively allows analytic representation of global coupled adiabatic potential energy surfaces and their gradients with only adiabatic energy input and without experience-based selection of a diabatization scheme. We demonstrate that the new procedure, called the companion matrix neural network (CMNN), is successful by showing applications to LiH, H3, phenol, and thiophenol.

Semiochemical-baited traps as a new method supplementing light traps for faunistic and ecological studies of Macroheterocera (Lepidoptera).

Attractivity and selectivity of two types of traps with synthetic, long-lasting, bisexual generic attractants were compared to conventional light traps to promote their wider use, as an easy-to-use standardised method for entomology. The targeted herbivorous Macroheterocera species playing important role in ecosystems as food source for higher trophic levels (e.g. predatory arthropods, birds and mammals), while other hand they can cause significant economic loss in agriculture. Data on their population dynamic and composition of their assemblages are necessary for both nature conservation and efficient pest management. Light- and semiochemical-baited traps with semisynthetic- (SBL = the acronym stands for semisynthetic bisexual lure) and synthetic lures (FLO = the acronym stands for floral lure of synthetic floral compounds) were used in species rich area of West Ukraine, and in all 10,926 lepidopterans trapped were identified. The attractivity of the light trap was highest with 252 species caught, while traps with semiochemicals captured 132 species including 28 exclusively caught only by them. The qualitative selectivity of light vs. semiochemical-baited traps differed considering both taxa and habitat preferences in such a way that they completed each-other. Differences in quantitative selectivity were also proved even in case of pest species. The parameters of methods varied depending on the phenological phases of the studied assemblages. Considering the revealed attractivity and selectivity, the parallel use of the two methods can offer improved reliable data for conservation biology and pest management.

Endocannabinoid and neuroplasticity-related changes as susceptibility factors in a rat model of posttraumatic stress disorder.

Traumatic experiences result in the development of posttraumatic stress disorder (PTSD) in 10-25% of exposed individuals. While human clinical studies suggest that susceptibility is potentially linked to endocannabinoid (eCB) signaling, neurobiological PTSD susceptibility factors are poorly understood. Employing a rat model of contextual conditioned fear, we characterized distinct resilient and susceptible subpopulations based on lasting generalized fear, a core symptom of PTSD. In these groups, we assessed i.) eCB levels by mass spectrometry and ii.) expression variations of eCB system- and iii.) neuroplasticity-related genes by real-time quantitative PCR in the circuitry relevant in trauma-induced changes. Furthermore, employing unsupervised and semi-supervised machine learning based statistical analytical models, we assessed iv.) gene expression patterns with the most robust predictive power regarding PTSD susceptibility. According to our findings, in our model, generalized fear responses occurred with sufficient variability to characterize distinct resilient and susceptible subpopulations. Resilient subjects showed elevated prelimbic and lower ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG) compared to resilient and non-shocked control subjects. Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, susceptibility was associated with i.) prefrontal, hippocampal and amygdalar neuronal hypoactivity, ii.) marked decrease in the expression of genes of transcription factors modulating neuroplasticity and iii.) an altered expression pattern of eCB-related genes, including enzymes involved in eCB metabolism. Unsupervised and semi-supervised statistical approaches highlighted that hippocampal gene expression patterns possess strong predictive power regarding susceptibility. Taken together, the marked eCB and neuroplasticity changes in susceptible individuals associated with abnormal activity patterns in the fear circuitry possibly contribute to context coding deficits, resulting in generalized fear.

Molecular fingerprints of cardiovascular toxicities of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by unleashing the power of the immune system against malignant cells. However, their use is associated with a spectrum of adverse effects, including cardiovascular complications, which can pose significant clinical challenges. Several mechanisms contribute to cardiovascular toxicity associated with ICIs. First, the dysregulation of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand (PD-L1), and molecular mimicry with cardiac autoantigens, leads to immune-related adverse events, including myocarditis and vasculitis. These events result from the aberrant activation of T cells against self-antigens within the myocardium or vascular endothelium. Second, the disruption of immune homeostasis by ICIs can lead to autoimmune-mediated inflammation of cardiac tissues, manifesting as cardiac dysfunction and heart failure, arrhythmias, or pericarditis. Furthermore, the upregulation of inflammatory cytokines, particularly tumor necrosis factor-alpha, interferon-γ, interleukin-1ß, interleukin-6, and interleukin-17 contributes to cardiac and endothelial dysfunction, plaque destabilization, and thrombosis, exacerbating cardiovascular risk on the long term. Understanding the intricate mechanisms of cardiovascular side effects induced by ICIs is crucial for optimizing patient care and to ensure the safe and effective integration of immunotherapy into a broader range of cancer treatment protocols. The clinical implications of these mechanisms underscore the importance of vigilant monitoring and early detection of cardiovascular toxicity in patients receiving ICIs. Future use of these key pathological mediators as biomarkers may aid in prompt diagnosis of cardiotoxicity and will allow timely interventions.

Novel insights into the modulation of the voltage-gated potassium channel KV1.3 activation gating by membrane ceramides.

Membrane lipids extensively modulate the activation gating of voltage-gated potassium channels (KV), however, much less is known about the mechanisms of ceramide and glucosylceramide actions including which structural element is the main intramolecular target and whether there is any contribution of indirect, membrane biophysics-related mechanisms to their actions. We used two-electrode voltage-clamp fluorometry capable of recording currents and fluorescence signals to simultaneously monitor movements of the pore domain (PD) and the voltage sensor domain (VSD) of the KV1.3 ion channel after attaching an MTS-TAMRA fluorophore to a cysteine introduced into the extracellular S3-S4 loop of the VSD. We observed rightward shifts in the conductance-voltage (G-V) relationship, slower current activation kinetics, and reduced current amplitudes in response to loading the membrane with C16-ceramide (Cer) or C16-glucosylceramide (GlcCer). When analyzing VSD movements, only Cer induced a rightward shift in the fluorescence signal-voltage (F-V) relationship and slowed fluorescence activation kinetics, whereas GlcCer exerted no such effects. These results point at a distinctive mechanism of action with Cer primarily targeting the VSD, while GlcCer only the PD of KV1.3. Using environment-sensitive probes and fluorescence-based approaches, we show that Cer and GlcCer similarly increase molecular order in the inner, hydrophobic regions of bilayers, however, Cer induces a robust molecular reorganization at the membrane-water interface. We propose that this unique ordering effect in the outermost membrane layer in which the main VSD rearrangement involving an outward sliding of the top of S4 occurs can explain the VSD targeting mechanism of Cer, which is unavailable for GlcCer.

Sodium-glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.

Identification of a Novel Structural Class of HV1 Inhibitors by Structure-Based Virtual Screening.

The human voltage-gated proton channel, hHV1, is highly expressed in various cell types including macrophages, B lymphocytes, microglia, sperm cells and also in various cancer cells. Overexpression of HV1 has been shown to promote tumor formation by highly metastatic cancer cells, and has been associated with neuroinflammatory diseases, immune response disorders and infertility, suggesting a potential use of hHV1 inhibitors in numerous therapeutic areas. To identify compounds targeting this channel, we performed a structure-based virtual screening on an open structure of the human HV1 channel. Twenty selected virtual screening hits were tested on Chinese hamster ovary (CHO) cells transiently expressing hHV1, with compound 13 showing strong block of the proton current with an IC50 value of 8.5 µM. Biological evaluation of twenty-three additional analogs of 13 led to the discovery of six other compounds that blocked the proton current by more than 50% at 50 µM concentration. This allowed for an investigation of structure-activity relationships. The antiproliferative activity of the selected promising hHV1 inhibitors was investigated in the cell lines MDA-MB-231 and THP-1, where compound 13 inhibited growth with an IC50 value of 9.0 and 8.1 µM, respectively. The identification of a new structural class of HV1 inhibitors contributes to our understanding of the structural requirements for inhibition of this ion channel and opens up the possibility of investigating the role of HV1 inhibitors in various pathological conditions and in cancer therapy.

Perinatal asphyxia leads to acute kidney damage and increased renal susceptibility in adulthood.

Perinatal asphyxia (PA) poses a significant threat to multiple organs, particularly the kidneys. Diagnosing PA-associated kidney injury remains challenging, and treatment options are inadequate. Furthermore, there is a lack of long-term follow-up data regarding the renal implications of PA. In this study, 7-day-old male Wistar rats were exposed to PA using a gas mixture (4% O2; 20% CO2 in N2 for 15 min) to investigate molecular pathways linked to renal tubular damage, hypoxia, angiogenesis, heat shock response, inflammation, and fibrosis in the kidney. In a second experiment, adult rats with a history of PA were subjected to moderate renal ischemia-reperfusion (IR) injury to test the hypothesis that PA exacerbates renal susceptibility. Our results revealed an increased gene expression of renal injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), hypoxic and heat shock factors (hypoxia-inducible factor-1α, heat shock factor-1, and heat shock protein-27), proinflammatory cytokines (interleukin-1ß, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1), and fibrotic markers (transforming growth factor-ß, connective tissue growth factor, and fibronectin) promptly after PA. Moreover, a machine learning model was identified through random forest analysis, demonstrating an impressive classification accuracy (95.5%) for PA. Post-PA rats showed exacerbated functional decline and tubular injury and more intense hypoxic, heat shock, proinflammatory, and profibrotic response after renal IR injury compared with controls. In conclusion, PA leads to subclinical kidney injury, which may increase the susceptibility to subsequent renal damage later in life. In addition, the parameters identified through random forest analysis provide a robust foundation for future biomarker research in the context of PA.NEW & NOTEWORTHY This article demonstrates that perinatal asphyxia leads to subclinical kidney injury that permanently increases renal susceptibility to subsequent ischemic injury. We identified major molecular pathways involved in perinatal asphyxia-induced renal complications, highlighting potential targets of therapeutic approaches. In addition, random forest analysis revealed a model that classifies perinatal asphyxia with 95.5% accuracy that may provide a strong foundation for further biomarker research. These findings underscore the importance of multiorgan follow-up for perinatal asphyxia-affected patients.

Comparing novel small-angle x-ray scattering approaches for absolute size and number concentration measurements of spherical SiO2particles to established methods.

Biomedical analytical applications, as well as the industrial production of high-quality nano- and sub-micrometre particles, require accurate methods to quantify the absolute number concentration of particles. In this context, small-angle x-ray scattering (SAXS) is a powerful tool to determine the particle size and concentration traceable to the Système international d'unités (SI). Therefore, absolute measurements of the scattering cross-section must be performed, which require precise knowledge of all experimental parameters, such as the electron density of solvent and particles, whereas the latter is often unknown. Within the present study, novel SAXS-based approaches to determine the size distribution, density and number concentrations of sub-micron spherical silica particles with narrow size distributions and mean diameters between 160 nm and 430 nm are presented. For the first-time traceable density and number concentration measurements of silica particles are presented and current challenges in SAXS measurements such as beam-smearing, poorly known electron densities and moderately polydisperse samples are addressed. In addition, and for comparison purpose, atomic force microscopy has been used for traceable measurements of the size distribution and single particle inductively coupled plasma mass spectrometry with the dynamic mass flow approach for the accurate quantification of the number concentrations of silica particles. The possibilities and limitations of the current approaches are critically discussed in this study.

Interfacial Behavior of Biodegradable Poly(lactic-co-glycolic acid)-Pluronic F127 Nanoparticles and Its Impact on Pickering Emulsion Stability.

Biodegradable nanoparticle-based emulsions exhibit immense potential in various applications, particularly in the pharmaceutical, cosmetic, and food industries. This study delves into the intricate interfacial behavior of Pluronic F127 modified poly(lactic-co-glycolic acid) (PLGA-F127) nanoparticles, a crucial determinant of their ability to stabilize Pickering emulsions. Employing a combination of Langmuir balance, surface tension, and diffusion coefficient measurements, we investigate the interfacial dynamics of PLGA-F127 nanoparticles under varying temperature and ionic strength conditions. Theoretical calculations are employed to elucidate the underlying mechanisms governing these phenomena. Our findings reveal a profound influence of temperature-dependent Pluronic layer behavior and electrostatic and steric interactions on the interfacial dynamics. Nonlinear changes in surface tension are observed, reflecting the interplay of these factors. Particle aggregation is found to be prevalent at elevated temperatures and ionic strengths, compromising the stability and emulsification efficiency of the formed emulsions. This work provides insights into the rational design of stable and efficient biodegradable nanoparticle-based Pickering emulsions, broadening their potential applications in various fields.

Treatment options for immune-related adverse events associated with immune checkpoint inhibitors.

The immunotherapy revolution with the use of immune checkpoint inhibitors (ICIs) started with the clinical use of the first ICI, ipilimumab, in 2011. Since then, the field of ICI therapy has rapidly expanded - with the FDA approval of 10 different ICI drugs so far and their incorporation into the therapeutic regimens of a range of malignancies. While ICIs have shown high anti-cancer efficacy, they also have characteristic side effects, termed immune-related adverse events (irAEs). These side effects hinder the therapeutic potential of ICIs and, therefore, finding ways to prevent and treat them is of paramount importance. The current protocols to manage irAEs follow an empirical route of steroid administration and, in more severe cases, ICI withdrawal. However, this approach is not optimal in many cases, as there are often steroid-refractory irAEs, and there is a potential for corticosteroid use to promote tumour progression. This review surveys the current alternative approaches to the treatments for irAEs, with the goal of summarizing and highlighting the best attempts to treat irAEs, without compromising anti-tumour immunity and allowing for rechallenge with ICIs after resolution of the irAEs.

The Proteoglycans Biglycan and Decorin Protect Cardiac Cells against Irradiation-Induced Cell Death by Inhibiting Apoptosis.

Radiation-induced heart disease (RIHD), a common side effect of chest irradiation, is a primary cause of mortality among patients surviving thoracic cancer. Thus, the development of novel, clinically applicable cardioprotective agents which can alleviate the harmful effects of irradiation on the heart is of great importance in the field of experimental oncocardiology. Biglycan and decorin are structurally related small leucine-rich proteoglycans which have been reported to exert cardioprotective properties in certain cardiovascular pathologies. Therefore, in the present study we aimed to examine if biglycan or decorin can reduce radiation-induced damage of cardiomyocytes. A single dose of 10 Gray irradiation was applied to induce radiation-induced cell damage in H9c2 cardiomyoblasts, followed by treatment with either biglycan or decorin at various concentrations. Measurement of cell viability revealed that both proteoglycans improved the survival of cardiac cells post-irradiation. The cardiocytoprotective effect of both biglycan and decorin involved the alleviation of radiation-induced proapoptotic mechanisms by retaining the progression of apoptotic membrane blebbing and lowering the number of apoptotic cell nuclei and DNA double-strand breaks. Our findings provide evidence that these natural proteoglycans may exert protection against radiation-induced damage of cardiac cells.

Extracellular vesicles promote migration despite BRAF inhibitor treatment in malignant melanoma cells.

Extracellular vesicles (EVs) constitute a vital component of intercellular communication, exerting significant influence on metastasis formation and drug resistance mechanisms. Malignant melanoma (MM) is one of the deadliest forms of skin cancers, because of its high metastatic potential and often acquired resistance to oncotherapies. The prevalence of BRAF mutations in MM underscores the importance of BRAF-targeted therapies, such as vemurafenib and dabrafenib, alone or in combination with the MEK inhibitor, trametinib. This study aimed to elucidate the involvement of EVs in MM progression and ascertain whether EV-mediated metastasis promotion persists during single agent BRAF (vemurafenib, dabrafenib), or MEK (trametinib) and combined BRAF/MEK (dabrafenib/trametinib) inhibition.Using five pairs of syngeneic melanoma cell lines, we assessed the impact of EVs - isolated from their respective supernatants - on melanoma cell proliferation and migration. Cell viability and spheroid growth assays were employed to evaluate proliferation, while migration was analyzed through mean squared displacement (MSD) and total traveled distance (TTD) measurements derived from video microscopy and single-cell tracking.Our results indicate that while EV treatments had remarkable promoting effect on cell migration, they exerted only a modest effect on cell proliferation and spheroid growth. Notably, EVs demonstrated the ability to mitigate the inhibitory effects of BRAF inhibitors, albeit they were ineffective against a MEK inhibitor and the combination of BRAF/MEK inhibitors. In summary, our findings contribute to the understanding of the intricate role played by EVs in tumor progression, metastasis, and drug resistance in MM.