Redox balance and immunity of piglets pre- and post-E. coli challenge after treatment with hemp or fish oil, and vitamin E.

This study investigated the influence of polyunsaturated fatty acid composition and vitamin E supplementation on oxidative status and immune responses in weanling piglets pre- and post-E. coli challenge. Suckling piglets (n = 24) were randomly selected from two litters for an oral supplementation (1 mL/day) with fish oil or hemp oil and vitamin E supplementation (60 mg natural vitamin E/mL oil) from day 10 to 28 of age. At day 29 and 30 of age, each piglet was orally inoculated with 6.7 × 108 and 3.96 × 108 CFU of F4 and F18 E. coli, respectively. Blood was sampled from all piglets on day 28 before E. coli challenge and on day 35 of age to investigate immunological and oxidative stress markers in plasma. One week after weaning and exposure to E. coli, a general reduction in the α-tocopherol concentration and activity of GPX1 was obtained. Vitamin E supplementation lowered the extent of lipid peroxidation and improved the antioxidative status and immune responses after E. coli challenge. Hemp oil had the greatest effect on antioxidant enzyme activity. Provision of hemp oil and vitamin E to suckling piglets may reduce the incidence of post-weaning diarrhea.

Effect of reduced-calcium and high-calcium cheddar cheese consumption on the excretion of faecal fat: a 2-week cross-over dietary intervention study.

PURPOSE: Studies show that dairy fat consumed in the form of cheese reduce LDL-cholesterol concentration (LDL-c) compared to butter and mechanistic suggestions include the calcium content of cheese leading to enhanced faecal fat excretion. The aim of this study was to test the effect of varying the calcium content within a cheese, on faecal fat excretion as a primary outcome, and blood lipid markers, fasting glucose and calcium excretion as secondary outcomes. METHODS: 7 healthy males (BMI 18-25) participated in this randomized, cross-over control intervention, of 3 × 2 week periods. Diets contained 240 g/day cheese; a High Calcium Cheese (HCC) diet, a Reduced Calcium Cheese (RCC) diet, and a control arm: Reduced Calcium Cheese + CaCO3 Supplement (RCC + Supp) diet. Diets differed in calcium content and form but were otherwise controlled for energy and key macronutrients. Blood and 5-day faecal samples were collected. RESULTS: There was no significant difference in faecal fat excretion (g/day) between the diets (P = 0.066). Percent fat of faecel excretion was higher after RCC + Supp (P = 0.016). None of the individual fatty acids were different. Fasting LDL-c was significantly lower following the HCC diet vs. the other arms (P = 0.002). Faecal Ca was different across all diets (P = 0.001), lowest after RCC, and greatest after RCC + Supp. No differences were observed for fasting blood parameters or changes in anthropometry. CONCLUSION: Varying the calcium content within a cheese matrix significantly affected fasting LDL-c values. Results did not support higher faecal fat excretion as an underlying mechanism, but the high attrition rate was a limitation. Trial registerer Trial Registered at ISRCTN.org, registration number ISRCTN11663659 on 12.07.2022. Retrospectively registered.

Natural Vitamin E Supplementation during Pregnancy in Rats Increases RRR-α-Tocopherol Stereoisomer Proportion and Enhances Fetal Antioxidant Capacity, Compared to Synthetic Vitamin E Administration.

INTRODUCTION: Low dietary intake of vitamin E is a global public health issue. RRR-α-tocopherol (RRR-αT) is the only naturally occurring vitamin E stereoisomer, but the equimolecular mixture of all eight stereoisomers, synthetic vitamin E (S-αT), is commonly consumed. The objective of this study was to evaluate bioavailability and antioxidant activity of RRR-αT versus S-αT, in both mother and fetus, after maternal supplementation during pregnancy. METHODS: Female rats (7 weeks of age) received a modified AIN-93G diet supplemented with 75 IU/kg of RRR-αT (NVE, n = 20) or S-αT (SVE, n = 17). At delivery, the levels of αT, stereoisomer distribution, and antioxidant capacity were analyzed in maternal and fetal plasma. RESULTS: NVE administration significantly increased the proportion of RRR-αT stereoisomer in maternal and fetal plasma. The percentage of RRR-αT increased from 32.76% to 88.33% in maternal plasma, and 35.25% to 97.94% in fetal plasma, in the NVE group compared to SVE. Fetal plasma from the NVE group was found to have higher total antioxidant capacity compared to SVE. Lastly, fetal plasma RRR-αT stereoisomer percentage was positively associated with expression levels of scavenger receptor class B type 1 (SR-B1) in the placenta. CONCLUSIONS: Both natural and synthetic sources of vitamin E showed similar bioavailability. Still, NVE supplementation increased the proportion of RRR-αT and promoted higher antioxidant activity in fetal plasma at birth. Placental SR-B1 might be involved in the stereoselective transfer of RRR-αT stereoisomer across the placenta and may improve αT bioactivity in the fetus.

STEEP mediates STING ER exit and activation of signaling.

STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.

Robust and highly sensitive micro liquid chromatography-tandem mass spectrometry method for analyses of polar pesticides (glyphosate, aminomethylphosfonic acid, N-acetyl glyphosate and N-acetyl aminomethylphosfonic acid) in multiple biological matrices.

Glyphosate is the most used herbicide in agriculture. To monitor glyphosate exposure, analytical methods have to fulfill requirements with regard to sensitivity, reproducibility, ease of handling/high-throughput and applicability to multiple biological matrices. Furthermore, the methods have to include the degradation product of glyphosate, aminomethylphosfonic acid (AMPA) and preferably metabolites of glyphosate and AMPA, N-acetyl AMPA and N-acetyl glyphosate. Majority of the published methods for glyphosate and AMPA require derivatization to be able to achieve high sensitivity. In this work, we present highly sensitive microLC-MS/MS method for simultaneous quantification of glyphosate, AMPA, N-acetyl AMPA and N-acetyl glyphosate in multiple biological matrices without derivatization. The combination of simple sample clean-up procedures for simultaneous handling of 96 sample and short chromatographic run of only 3.4 min, meets the requirements for high-throughput methods. Simple mobile phase of water containing formic and medronic acids and isocratic run provided robust chromatographic separation on hypercarb column. The use of micro-flow system decreased the background noise, increasing the sensitivity. Achieved Low Limits of Quantification (LOQs) for liquid samples (plasma/serum/urine) were 0.00005 mg L-1 and 0.0001 mg kg-1 for solid samples (grain and soybean based feed/stomach/gizzard/intestinal content), which is more than 100 time more sensitive compared to QuPPe-Method. The method was validated in representative matrices with minimum of five fortification levels, six measurements per spiked concentration and three batches. All the samples were spiked with corresponding internal standards for all four analytes before sample clean-up procedures, ensuring high accuracy and precision. Recoveries for plasma/serum ranged between 86-108%, urine 93-120%, feed 91-115% and stomach/gizzard/intestinal content 92-110% with precision below 20%. The method's applicability was tested on 2000 samples measured during one year period.

A Review on the Role of Chromium Supplementation in Ruminant Nutrition-Effects on Productive Performance, Blood Metabolites, Antioxidant Status, and Immunocompetence.

With the increase in the global herd, the use of metabolic modifiers has become an important area for many researchers looking for a supraphysiological diet to improve production parameters. For improving the performance of high yielding cows, the optimal balance of all nutrients including microminerals is important. Chromium (Cr) is one of the important micronutrients which plays an important role in metabolism of ruminants. Experimental studies have found that Cr could change performance, immune responses, glucose and fatty acid metabolism, and antioxidant status in dairy cows. In some studies, Cr supplementation improved dry matter intake, milk production, and milk composition of dairy cows in the early, mid, or late stage of lactation. Also, in some studies, performance of growing animal, immune response, and some blood parameters responded positively to Cr supplementation. In conclusion, the effects of Cr supplementation on performance of ruminants are inconsistent; however, its long-term effects on health, productivity, immune system, and antioxidant activity of ruminants still need to be investigated.

White clover fractions as protein source for monogastrics: dry matter digestibility and protein digestibility-corrected amino acid scores.

BACKGROUND: The present study aimed to evaluate the use of white clover as an alternative protein source for monogastrics. White clover plant and leaves were processed using a screw-press resulting in a solid pulp and a juice from which protein was acid-precipitated. The chemical composition of all fractions was determined and digestibility of dry matter (DM) and protein was assessed in an experiment with growing rats. RESULTS: Protein concentrates were produced with crude protein (CP) contents of 451 g kg-1 and 530 g kg-1 DM for white clover plant and leaves, respectively, and a pulp with CP contents of 313 and 374 g kg-1 DM from plant and leaves, respectively. The amino acid composition ranged from 4.72 to 6.49 g per 16 g of nitrogen (N) for lysine, 1.82-2.6 g per 16 g N for methionine and cysteine, and 3.66-5.24 g per 16 g N for threonine. True faecal digestibility of protein varied from 0.81 to 0.88, whereas DM digestibility was in the range 0.72-0.80. Methionine and cysteine were found to be limiting in all fractions, regardless of the reference group used. CONCLUSION: A high digestibility of white clover protein was found irrespective of the physical fractionation. Together with a well-balanced amino acid composition, this makes white clover a promising protein source for monogastrics. © 2017 Society of Chemical Industry.

StUbEx PLUS-A Modified Stable Tagged Ubiquitin Exchange System for Peptide Level Purification and In-Depth Mapping of Ubiquitination Sites.

Modulation of protein activities by reversible post-translational modifications (PTMs) is a major molecular mechanism involved in the control of virtually all cellular processes. One of these PTMs is ubiquitination, which regulates key processes including protein degradation, cell cycle, DNA damage repair, and signal transduction. Because of its importance for numerous cellular functions, ubiquitination has become an intense topic of research in recent years, and proteomics tools have greatly facilitated the identification of many ubiquitination targets. Taking advantage of the StUbEx strategy for exchanging the endogenous ubiquitin with an epitope-tagged version, we created a modified system, StUbEx PLUS, which allows precise mapping of ubiquitination sites by mass spectrometry. Application of StUbEx PLUS to U2OS cells treated with proteasomal inhibitors resulted in the identification of 41 589 sites on 7762 proteins, which thereby revealed the ubiquitous nature of this PTM and demonstrated the utility of the approach for comprehensive ubiquitination studies at site-specific resolution.

Effects of vitamin D and its metabolites on cell viability and Staphylococcus aureus invasion into bovine mammary epithelial cells.

Vitamin D has been found have various biological effects that may be potent in preventing bovine mastitis. Two forms of vitamin D, vitamin D2 (D2) and vitamin D3 (D3), can be hydroxylated to functional metabolites in cattle. The objectives of the present study were to investigate the potential of vitamin D compounds for controlling bovine mastitis using in vitro cell models, and to compare the differences between D2 and D3 compounds. Results showed that D2 compounds have comparable effects to their D3 analogues on inhibiting MAC-T cell viability in vitro. S. aureus growth was inhibited by high concentrations of D2, D3, 25(OH)D2 and 25(OH)D3. 25(OH)D2 and 25(OH)D3 induced CYP24A1 expression but reduced VDR mRNA expression, whereas the expression of CYP27B1, occludin, and E-cadherin did not change. Additionally, the induction of CYP24A1 expression by 25(OH)D3 was higher than that of 25(OH)D2, which may contribute to their differences in inhibiting cell viability. S. aureus invaded into MAC-T cells and universally inhibited gene expressions. Pre-treat MAC-T cells with 25(OH)D2 reduced S. aureus adhesion while pre-treatment with 25(OH)D3 inhibited S. aureus invasion, but neither of the compounds attenuated the S. aureus-induced gene expression reduction. In conclusion, the present study shows that D2 compounds have comparable effects on inhibiting cell viability and S. aureus invasion to their D3 analogues in vitro, suggesting that D2 and its metabolites have potential in controlling bovine mastitis.

HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression.

Herpes simplex virus (HSV) 1 stimulates type I IFN expression through the cGAS-STING-TBK1 signaling axis. Macrophages have recently been proposed to be an essential source of IFN during viral infection. However, it is not known how HSV-1 inhibits IFN expression in this cell type. Here, we show that HSV-1 inhibits type I IFN induction through the cGAS-STING-TBK1 pathway in human macrophages, in a manner dependent on the conserved herpesvirus protein ICP27. This viral protein was expressed de novo in macrophages with early nuclear localization followed by later translocation to the cytoplasm where ICP27 prevented activation of IRF3. ICP27 interacted with TBK1 and STING in a manner that was dependent on TBK1 activity and the RGG motif in ICP27. Thus, HSV-1 inhibits expression of type I IFN in human macrophages through ICP27-dependent targeting of the TBK1-activated STING signalsome.

StUbEx: Stable tagged ubiquitin exchange system for the global investigation of cellular ubiquitination.

Post-translational modification of proteins with the small polypeptide ubiquitin plays a pivotal role in many cellular processes, altering protein lifespan, location, and function and regulating protein-protein interactions. Ubiquitination exerts its diverse functions through complex mechanisms by formation of different polymeric chains and subsequent recognition of the ubiquitin signal by specific protein interaction domains. Despite some recent advances in the analytical tools for the analysis of ubiquitination by mass spectrometry, there is still a need for additional strategies suitable for investigation of cellular ubiquitination at the proteome level. Here, we present a stable tagged ubiquitin exchange (StUbEx) cellular system in which endogenous ubiquitin is replaced with an epitope-tagged version, thereby allowing specific and efficient affinity purification of ubiquitinated proteins for global analyses of protein ubiquitination. Importantly, the overall level of ubiquitin in the cell remains virtually unchanged, thus avoiding ubiquitination artifacts associated with overexpression. The efficiency and reproducibility of the method were assessed through unbiased analysis of epidermal growth factor (EGF) signaling by quantitative mass spectrometry, covering over 3400 potential ubiquitinated proteins. The StUbEx system is applicable to virtually any cell line and can be readily adapted to any of the ubiquitin-like post-translational modifications.

Listeria monocytogenes induces IFNß expression through an IFI16-, cGAS- and STING-dependent pathway.

Listeria monocytogenes is a gram-positive facultative intracellular bacterium, which replicates in the cytoplasm of myeloid cells. Interferon ß (IFNß) has been reported to play an important role in the mechanisms underlying Listeria disease. Although studies in murine cells have proposed the bacteria-derived cyclic-di-AMP to be the key bacterial immunostimulatory molecule, the mechanism for IFNß expression during L. monocytogenes infection in human myeloid cells remains unknown. Here we report that in human macrophages, Listeria DNA rather than cyclic-di-AMP is stimulating the IFN response via a pathway dependent on the DNA sensors IFI16 and cGAS as well as the signalling adaptor molecule STING. Thus, Listeria DNA is a major trigger of IFNß expression in human myeloid cells and is sensed to activate a pathway dependent on IFI16, cGAS and STING.

Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator.

BACKGROUND: Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays. METHODS: Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR. RESULTS: We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C. CONCLUSIONS: A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.

Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis.

PURPOSE: Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain. PATIENTS AND METHODS: We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. RESULTS: Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5'VNTR2R/3R and 3'UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10(-6)). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. CONCLUSION: A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value-better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.

Synthesis of structurally well-defined and liquid-phase-processable graphene nanoribbons.

The properties of graphene nanoribbons (GNRs) make them good candidates for next-generation electronic materials. Whereas 'top-down' methods, such as the lithographical patterning of graphene and the unzipping of carbon nanotubes, give mixtures of different GNRs, structurally well-defined GNRs can be made using a 'bottom-up' organic synthesis approach through solution-mediated or surface-assisted cyclodehydrogenation reactions. Specifically, non-planar polyphenylene precursors were first 'built up' from small molecules, and then 'graphitized' and 'planarized' to yield GNRs. However, fabrication of processable and longitudinally well-extended GNRs has remained a major challenge. Here we report a bottom-up solution synthesis of long (>200 nm) liquid-phase-processable GNRs with a well-defined structure and a large optical bandgap of 1.88 eV. Self-assembled monolayers of GNRs can be observed by scanning probe microscopy, and non-contact time-resolved terahertz conductivity measurements reveal excellent charge-carrier mobility within individual GNRs. Such structurally well-defined GNRs may prove useful for fundamental studies of graphene nanostructures, as well as the development of GNR-based nanoelectronics.

IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication.

Replication of lentiviruses generates different DNA forms, including RNA:DNA hybrids, ssDNA, and dsDNA. Nucleic acids stimulate innate immune responses, and pattern recognition receptors detecting dsDNA have been identified. However, sensors for ssDNA have not been reported, and the ability of RNA:DNA hybrids to stimulate innate immune responses is controversial. Using ssDNAs derived from HIV-1 proviral DNA, we report that this DNA form potently induces the expression of IFNs in primary human macrophages. This response was stimulated by stem regions in the DNA structure and was dependent on IFN-inducible protein 16 (IFI16), which bound immunostimulatory DNA directly and activated the stimulator of IFN genes -TANK-binding kinase 1 - IFN regulatory factors 3/7 (STING-TBK1-IRF3/7) pathway. Importantly, IFI16 colocalized and associated with lentiviral DNA in the cytoplasm in macrophages, and IFI16 knockdown in this cell type augmented lentiviral transduction and also HIV-1 replication. Thus, IFI16 is a sensor for DNA forms produced during the lentiviral replication cycle and regulates HIV-1 replication in macrophages.

Adenovirus-based vaccine against Listeria monocytogenes: extending the concept of invariant chain linkage.

The use of replication-deficient adenoviruses as vehicles for transfer of foreign genes offers many advantages in a vaccine setting, eliciting strong cellular immune responses involving both CD8(+) and CD4(+) T cells. Further improving the immunogenicity, tethering of the inserted target Ag to MHC class II-associated invariant chain (Ii) greatly enhances both the presentation of most target Ags, as well as overall protection against viral infection, such as lymphocytic choriomeningitis virus (LCMV). The present study extends this vaccination concept to include protection against intracellular bacteria, using Listeria monocytogenes as a model organism. Protection in C57BL/6 mice against recombinant L. monocytogenes expressing an immunodominant epitope of the LCMV glycoprotein (GP33) was greatly accelerated, augmented, and prolonged following vaccination with an adenoviral vaccine encoding GP linked to Ii compared with vaccination with the unlinked vaccine. Studies using knockout mice demonstrated that CD8(+) T cells were largely responsible for this protection, which is mediated through perforin-dependent lysis of infected cells and IFN-γ production. Taking the concept a step further, vaccination of C57BL/6 (L. monocytogenes-resistant) and BALB/c (L. monocytogenes-susceptible) mice with adenoviral vectors encoding natural L. monocytogenes-derived soluble Ags (listeriolysin O and p60) revealed that tethering of these Ags to Ii markedly improved the vaccine-induced CD8(+) T cell response to two of three epitopes studied. More importantly, Ii linkage accelerated and augmented vaccine-induced protection in both mouse strains and prolonged protection, in particular that induced by the weak Ag, p60, in L. monocytogenes-susceptible BALB/c mice.

Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING.

The innate immune system senses infection by detecting either evolutionarily conserved molecules essential for the survival of microbes or the abnormal location of molecules. Here we demonstrate the existence of a previously unknown innate detection mechanism induced by fusion between viral envelopes and target cells. Virus-cell fusion specifically stimulated a type I interferon response with expression of interferon-stimulated genes, in vivo recruitment of leukocytes and potentiation of signaling via Toll-like receptor 7 (TLR7) and TLR9. The fusion-dependent response was dependent on the stimulator of interferon genes STING but was independent of DNA, RNA and viral capsid. We suggest that membrane fusion is sensed as a danger signal with potential implications for defense against enveloped viruses and various conditions of giant-cell formation.

Data-driven assessment of the association of polymorphisms in 5-Fluorouracil metabolism genes with outcome in adjuvant treatment of colorectal cancer.

A major challenge in the assessment of medicines, treatment options, etc., is to establish a framework for the comparison of risks and benefits of many different types and magnitudes, a framework that at the same time allows a clear distinction between the roles played by the statistical analyses of data and by judgements based on personal experience and expertise. The purpose of this study was to demonstrate how clinical data can be weighted, scored and presented by the use of an eight-step data-driven benefit-risk assessment method, where two genetic profiles are compared. Our aim was to present a comprehensive approach that is simple to apply, allows direct comparison of different types of risks and benefits, quantifies the clinical relevance of data and is tailored for the comparison of different options. We analysed a cohort of 302 patients with colorectal cancer treated with 5-Fluorouracil (5-FU). Endpoints were cure rate, survival rate, time-to-death (TTD), time-to-relapse (TTR) and main adverse drug reactions. Multifactor dimensionality reduction (MDR) was used to identify genetic interaction profiles associated with outcome. We have been able to demonstrate that a specific MDR-derived combination (the MDR-1 group) of dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms is associated with increased and clinically significant difference for cure and survival rates, TTD and probably also for TTR, which are seen as the most important endpoints. An inferior profile was observed for severe myocardial ischaemia. A probably inferior profile was seen for severe arthralgia/myalgia and severe infections. A clear superior profile was seen for severe mucositis/stomatitis. The proposed approach offers comprehensive, data-driven assessment that can facilitate decision processes, for example, in a clinical setting. It employs descriptive statistical methods to highlight the clinically relevant differences between options.