Stress combined with loss of the Candida albicans SUMO protease Ulp2 triggers selection of aneuploidy via a two-step process.

A delicate balance between genome stability and instability ensures genome integrity while generating genetic diversity, a critical step for evolution. Indeed, while excessive genome instability is harmful, moderated genome instability can drive adaptation to novel environments by maximising genetic variation. Candida albicans, a human fungal pathogen that colonises different parts of the human body, adapts rapidly and frequently to different hostile host microenvironments. In this organism, the ability to generate large-scale genomic variation is a key adaptative mechanism triggering dangerous infections even in the presence of antifungal drugs. Understanding how fitter novel karyotypes are selected is key to determining how C. albicans and other microbial pathogens establish infections. Here, we identified the SUMO protease Ulp2 as a regulator of C. albicans genome integrity through genetic screening. Deletion of ULP2 leads to increased genome instability, enhanced genome variation and reduced fitness in the absence of additional stress. The combined stress caused by the lack of ULP2 and antifungal drug treatment leads to the selection of adaptive segmental aneuploidies that partially rescue the fitness defects of ulp2Δ/Δ cells. Short and long-read genomic sequencing demonstrates that these novel genotypes are selected via a two-step process leading to the formation of novel chromosomal fragments with breakpoints at microhomology regions and DNA repeats.

Decreased skeletal muscle intramyocellular lipid droplet-mitochondrial contact contributes to myosteatosis in cancer cachexia.

Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. Although its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular lipid droplet (LD) content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis lung carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n = 20) were implanted with LLC cells (106) in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red O/lipid staining [tibialis anterior (TA)], and protein (gastrocnemius). LLC mice had a greater number (232%; P = 0.006) and size (130%; P = 0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; P = 0.0109) and "very high" oil-red O positive (178%; P = 0.0002) fibers compared with controls and this was inversely correlated with fiber size (R2 = 0.5294; P < 0.0001). Morphological analyses of LDs show increased elongation and complexity [aspect ratio: intermyofibrillar (IMF) = 9%, P = 0.046) with decreases in circularity [circularity: subsarcolemmal (SS) = 6%, P = 0.042] or roundness (roundness: whole = 10%, P = 0.033; IMF = 8%, P = 0.038) as well as decreased LD-mitochondria touch (-15%; P = 0.006), contact length (-38%; P = 0.036), and relative contact (86%; P = 0.004). Furthermore, dysregulation in lipid metabolism (adiponectin, CPT1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (P < 0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia.NEW & NOTEWORTHY We sought to advance our understanding of skeletal muscle lipid metabolism and dynamics in cancer cachexia. Cachexia increased the number and size of intramyocellular lipid droplets (LDs). Furthermore, decreases in LD-mitochondrial touch, contact length, and relative contact along with increased LD shape complexity with decreases in circularity and roundness. Dysregulation in lipid metabolism and LD-associated proteins was also documented. Collectively, we show that myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in cancer cachexia.

Microstructural Characterization of Dry Powder Inhaler Formulations Using Orthogonal Analytical Techniques.

PURPOSE: For locally-acting dry powder inhalers (DPIs), developing novel analytical tools that are able to evaluate the state of aggregation may provide a better understanding of the impact of material properties and processing parameters on the in vivo performance. This study explored the utility of the Morphologically-Directed Raman Spectroscopy (MDRS) and dissolution as orthogonal techniques to assess microstructural equivalence of the aerosolized dose of DPIs collected with an aerosol collection device. METHODS: Commercial DPIs containing different strengths of Fluticasone Propionate (FP) and Salmeterol Xinafoate (SX) as monotherapy and combination products were sourced from different regions. These inhalers were compared with aerodynamic particle size distribution (APSD), dissolution, and MDRS studies. RESULTS: APSD testing alone might not be able to explain differences reported elsewhere in in vivo studies of commercial FP/SX drug products with different Advair® strengths and/or batches. Dissolution studies demonstrated different dissolution rates between Seretide™ 100/50 and Advair® 100/50, whereas Flixotide™ 100 and Flovent® 100 had similar dissolution rates between each other. These differences in dissolution profiles were supported by MDRS results: the dissolution rate is increased if the fraction of FP associated with high soluble components is increased. Principle component analysis was used to identify the agglomerate classes that better discriminate different products. CONCLUSIONS: MDRS and dissolution studies of the aerosolized dose of DPIs were successfully used as orthogonal techniques. This study highlights the importance of further assessing in vitro tools that are able to provide a bridge between material attributes or process parameters and in vivo performance.

Sensitivity of Pharmacokinetics to Differences in the Particle Size Distribution for Formulations of Locally Acting Mometasone Furoate Suspension-Based Nasal Sprays.

To assess bioequivalence of locally acting suspension-based nasal sprays, the U.S. FDA currently recommends a weight-of-evidence approach. In addition to in vitro and human pharmacokinetic (PK) studies, this includes a comparative clinical endpoint study to ensure equivalent bioavailability of the active pharmaceutical ingredient (API) at the site of action. The present study aimed to assess, within an in vitro/in vivo correlation paradigm, whether PK studies and dissolution kinetics are sensitive to differences in drug particle size for a locally acting suspension-based nasal spray product. Two investigational suspension-based nasal formulations of mometasone furoate (MF-I and MF-II; delivered dose: 180 µg) differed in API particle size and were compared in a single-center, double-blind, single-dose, randomized, two-way crossover PK study in 44 healthy subjects with oral charcoal block. Morphology-directed Raman spectroscopy yielded volume median diameters of 3.17 µm for MF-I and 5.50 µm for MF-II, and dissolution studies showed that MF-II had a slower dissolution profile than MF-I. The formulation with larger API particles (MF-II) showed a 45% smaller Cmax and 45% smaller AUC0-inf compared to those of MF-I. Systemic bioavailability of MF-I (2.20%) and MF-II (1.18%) correlated well with the dissolution kinetics, with the faster dissolving formulation yielding the higher bioavailability. This agreement between pharmacokinetics and dissolution kinetics cross-validated both methods and supported their use in assessing potential differences in slowly dissolving suspension-based nasal spray products.

Utilisation and valorisation of distillery whisky waste streams via biomass electrolysis: electrosynthesis of hydrogen.

Fuel-flexible hydrogen generation methods, such as electrochemical conversion of biomass, offer a route for sustainable production of hydrogen whilst valorising feedstocks that are often overlooked as waste products. This work explores the potential of a novel, two-stage electrolysis process to convert biomass-containing solid (draff/spent barley) and liquid (pot ale and spent lees) whisky co-products, from the Isle of Raasay Distillery, into hydrogen, using a phosphomolybdic acid (H3[PMo12O40] or PMA) catalyst. Characterisation results for whisky distillery co-products will be presented, including thermogravimetric, differential scanning calorimetric, CHN elemental, total organic carbon and chemical oxygen demand analysis data. The results indicated that the characteristics of these co-products align well with those reported across the Scotch whisky distillation sector. Subsequently, the concept of thermal digestion of each co-product type, using the Keggin-type polyoxometalate PMA catalyst to abstract protons and electrons from biomass, will be outlined. UV-visible spectrophotometry was employed to assess the extent of reduction of the catalyst, after digestion of each co-product, and indicated that draff and pot ale offer the largest scope for hydrogen production, whilst digestion and electrolysis of spent lees is not viable due to the low biomass content of this distillation co-product. Finally, details of electrolysis of the PMA-biomass solutions using a proton-exchange membrane electrolysis cell (PEMEC) will be provided, including electrochemical data that help to elucidate the performance-limiting processes of the PEMEC operating on digested biomass-PMA anolytes.

Stopping versus continuing long-term mepolizumab treatment in severe eosinophilic asthma (COMET study).

BACKGROUND: The long-term efficacy and safety of mepolizumab for treatment of severe eosinophilic asthma are well established. Here, we examine the clinical impact of stopping mepolizumab after long-term use. METHODS: COMET (NCT02555371) was a randomised, double-blind, placebo-controlled, parallel-group, multicentre study. Patients who had completed COLUMBA (NCT01691859) or COSMEX (NCT02135692) and received continuous mepolizumab treatment for ≥3 years were randomised 1:1 to stop (switch to placebo) or continue subcutaneous mepolizumab 100 mg every 4 weeks for 52 weeks. Primary end-point: time to first clinically significant exacerbation; secondary end-points: time to first exacerbation requiring hospitalisation/emergency department visit, time to decrease in asthma control (≥0.5-point increase in Asthma Control Questionnaire-5 score from COMET baseline) and blood eosinophil count ratio to COMET baseline. Safety was assessed. RESULTS: Patients stopping (n=151) versus continuing (n=144) mepolizumab had significantly shorter times to first clinically significant exacerbation (hazard ratio 1.61, 95% CI 1.17-2.22; p=0.004) and decrease in asthma control (hazard ratio 1.52, 95% CI 1.13-2.02; p=0.005), and higher blood eosinophil counts at week 52 (270 versus 40 cells·µL-1; ratio (stopping versus continuing) 6.19, 95% CI 4.89-7.83; p<0.001). Differences in efficacy outcomes between groups were observed when assessed from week 12 (16 weeks after last mepolizumab dose). Exacerbations requiring hospitalisation/emergency department visit were rare. Adverse events in patients continuing mepolizumab were consistent with previous studies. For patients who stopped mepolizumab, the safety profile was consistent with other eosinophilic asthma populations. CONCLUSION: Patients who stopped mepolizumab had an increase in exacerbations and reduced asthma control versus those who continued.

Development of methodology for assessing steroid-tapering in clinical trials for biologics in asthma.

BACKGROUND: Long-term use of oral corticosteroids (OCS) is associated with a risk of adverse events and comorbidities. As such, a goal in assessing the efficacy of biologics in severe asthma is often to monitor reduction in OCS usage. Importantly, however, OCS dose reductions must be conducted without loss of disease control. MAIN BODY: Herein, we describe the development of OCS-sparing study methodologies for biologic therapies in patients with asthma. In particular, we focus on four randomized, placebo-controlled, parallel-group studies of varying sizes (key single-center study [n = 20], SIRIUS [n = 135], ZONDA [n = 220], VENTURE [n = 210]) and one open-label study (PONENTE [n = 598]), which assessed the effect of asthma biologics (mepolizumab, benralizumab or dupilumab) on OCS use using predefined OCS-tapering schedules. In particular, we discuss the evolution of study design elements in these studies, including patient eligibility criteria, the use of tailored OCS dose reduction schedules, monitoring of outcomes, the use of biomarkers and use of repetitive assessments of adrenal function during OCS tapering. CONCLUSION: Taken together, these developments have improved OCS-sparing asthma studies in recent years and the lessons learned may help with optimization of further OCS-sparing studies, and potentially clinical practice in the future.

The role of urinary N-acetyl-ß-D-glucosaminidase in early detection of acute kidney injury among pediatric patients with neoplastic disorders in a retrospective study.

BACKGROUND: The 1-year cumulative incidence of AKI reportedly is high (52%) in pediatric neoplastic disorders. About half of these events occur within 2 weeks. However, subclinical AKI episodes may remain unrecognized by the conventional creatinine-based approaches. We investigated the diagnostic value of urinary N-acetyl-ß-D-glucosaminidase (uNAG) as an early marker of acute kidney injury (AKI). METHODS: In our retrospective study, 33 children with neoplastic disorders were inculded who had serial uNAG tests (at least 5 samples/patient) with a total of 367 uNAG measurements. Renal function was determined by cystatin-C and creatinine based GFR, and relative increase of uNAG index (uNAGRI). We focused on detecting both clinical and subclinical AKI episodes (according to Biomarker-Guided Risk Assessment using pRIFLE criteria and /or elevated uNAG levels) and the incidence of chronic kidney damage. RESULTS: Sixty episodes in 26 patients, with positivity at least in one parameter of kidney panel, were identified during the observation period. We detected 18/60 clinical and 12/60 subclinical renal episodes. In 27/60 episodes only uNAG values was elevated with no therapeutic consequence at presentation. Two patients were detected with decreased initial creatinine levels with 3 "silent" AKI. In 13 patients, modest elevation of uNAG persisted suggesting mild, reversible tubular damage, while chronic tubuloglomerular injury occurred in 5 patients. Based on ROC analysis for the occurence of AKI, uNAGRI significantly indicated the presence of AKI, the sensitivity and specificity are higher than the changes of GFRCreat. Serial uNAG measurements are recommended for  the reduction of the great amount of false positive uNAG results, often due to overhydratation. CONCLUSION: Use of Biomarker-guided Risk Assessment for AKI identified 1.5 × more clinical and subclinical AKI episodes than with creatinine alone in our pediatric cancer patients. Based on the ROC curve for the occurence of AKI, uNAGRI has relatively high sensitivity and specificity comparable to changes of GFRCysC. The advantage of serial uNAG measurements is to decrease the number of false positive results. TRIAL REGISTRATION: The consent to participate is not applicable because it was not reqired for ethical approval and it is a retrospectiv study.

Benefit of switching to mepolizumab from omalizumab in severe eosinophilic asthma based on patient characteristics.

BACKGROUND: The OSMO study assessed the efficacy of switching to mepolizumab in patients with severe eosinophilic asthma that was uncontrolled whilst receiving omalizumab. The objective of this analysis was to assess the proportion of patients achieving pre-defined improvements in up to four efficacy outcomes and the relationship between patient baseline characteristics and treatment response. METHODS: This was a post hoc analysis of OSMO study data (GSK ID:204471; ClinicalTrials.gov No. NCT02654145). Patients with severe eosinophilic asthma uncontrolled by high-dose inhaled corticosteroids, other controller(s) and omalizumab subcutaneously (≥ 4 months) were switched to mepolizumab 100 mg administered subcutaneously. Endpoints included the proportion of responders-i.e. patients achieving a pre-defined clinical improvement in ≥ 1 of the following outcomes: (1) Asthma Control Questionnaire (ACQ)-5 score (≥ 0.5-points), (2) St George's Respiratory Questionnaire (SGRQ) total score (≥ 4-points), (3) pre-bronchodilator forced expiratory volume in 1s (FEV1; ≥ 100 mL), all at Week 32, and (4) annualised rate of clinically significant exacerbations (≥ 50% reduction). RESULTS: Of the 145 patients included, 94%, 83%, 63% and 31% were responders for ≥ 1, ≥ 2, ≥ 3 and 4 outcomes, respectively; 75% and 78% were ACQ-5 and SGRQ score responders, and 50% and 69% were FEV1 and exacerbation responders. Subgroup analyses demonstrated improvements irrespective of baseline blood eosinophil count, prior omalizumab treatment regimen/duration, comorbidities, prior exacerbation history, maintenance oral corticosteroid use, ACQ-5 and SGRQ scores, and body weight/body mass index. CONCLUSIONS: After switching to mepolizumab, almost all patients with uncontrolled severe eosinophilic asthma on omalizumab achieved a beneficial response in ≥ 1 clinical outcome. Improvements were observed regardless of baseline characteristics. Trial registration This manuscript is a post hoc analysis of data from the OSMO study. ClinicalTrials.gov, NCT02654145. Registered January 13, 2016.

Initial Clinical Experience With Novel Directional Low-Dose Rate Brachytherapy for Retroperitoneal Sarcoma.

BACKGROUND: A novel Palladium-103 low-dose rate (LDR) brachytherapy device was developed to provide dose-escalation to the tumor bed after resection while shielding adjacent tissues. This multicenter report describes the initial experience with this device in patients with retroperitoneal sarcoma (RPS). MATERIALS AND METHODS: Patients with recurrent RPS, prior radiotherapy, and/or concern for positive margins were considered. An LDR brachytherapy dose of 20-60 Gy was administered, corresponding to biologically effective dose values of 15-53 Gy and equivalent dose values of 12-43 Gy. RESULTS: Six patients underwent implantation at four institutions. Of these, five had recurrent disease in the retroperitoneum or pelvic sidewall, one had untreated locally advanced leiomyosarcoma, two had prior external beam radiation therapy at the time of initial diagnosis, and four received neoadjuvant external beam radiation therapy plus brachytherapy. The device was easily implanted and conformed to the treatment area. Median follow-up was 16 mo; radiation was delivered to the at-risk margin with minimal irradiation of adjacent structures. No local recurrences at the site of implantation, device migration, or radiation-related toxicities were observed. CONCLUSIONS: The novel LDR directional brachytherapy device successfully delivered a targeted dose escalation to treat RPS high-risk margins. Lack of radiation-related toxicity demonstrates its safety.

Genotypic and phenotypic diversity among Lactobacillus plantarum and Lactobacillus pentosus isolated from industrial scale cucumber fermentations.

The Lactobacillus plantarum and Lactobacillus pentosus genotypes existing in industrial-scale cucumber fermentations were defined using rep-PCR-(GTG)5. The ability of each genotype to ferment cucumbers under various conditions was evaluated. Rep-PCR-(GTG)5 was the technique capable of illustrating the most intraspecies discrimination compared to the sequencing of housekeeping genes (recA, dnaK, pheS and rpoA), MLST and RAPD with primers LP1, OPL5, M14 and COC. Ten genotypic clusters were defined for the 199 L. pentosus tested and three for the 17 L. plantarum clones. The ability of the 216 clones genotyped and 37 additional cucumber fermentation isolates, of the same species, to rapidly decrease the pH of cucumber juice medium under various combinations of sodium chloride (0 or 6%), initial pH (4.0 or 5.2) and temperatures (15 or 30 °C) was determined using a fractional factorial screening design. A reduced fermentation ability was observed for the L. plantarum strains as compared to L. pentosus, except for clone 3.2.8, which had a ropy phenotype and aligned to genotypic cluster A. L. pentosus strains belonging to three genotypic clusters (B, D and J) were more efficient in cucumber juice fermentation as compared to most L. plantarum strains. This research identified three genetically diverse L. pentosus strains and one L. plantarum as candidates for starter cultures for commercial cucumber fermentations.

Assessing efficacy in important subgroups in confirmatory trials: An example using Bayesian dynamic borrowing.

Assessment of efficacy in important subgroups - such as those defined by sex, age, race and region - in confirmatory trials is typically performed using separate analysis of the specific subgroup. This ignores relevant information from the complementary subgroup. Bayesian dynamic borrowing uses an informative prior based on analysis of the complementary subgroup and a weak prior distribution centred on a mean of zero to construct a robust mixture prior. This combination of priors allows for dynamic borrowing of prior information; the analysis learns how much of the complementary subgroup prior information to borrow based on the consistency between the subgroup of interest and the complementary subgroup. A tipping point analysis can be carried out to identify how much prior weight needs to be placed on the complementary subgroup component of the robust mixture prior to establish efficacy in the subgroup of interest. An attractive feature of the tipping point analysis is that it enables the evidence from the source subgroup, the evidence from the target subgroup, and the combined evidence to be displayed alongside each other. This method is illustrated with an example trial in severe asthma where efficacy in the adolescent subgroup was assessed using a mixture prior combining an informative prior from the adult data in the same trial with a non-informative prior.

Long-term safety and pharmacodynamics of mepolizumab in children with severe asthma with an eosinophilic phenotype.

BACKGROUND: Mepolizumab is approved for patients with severe asthma with an eosinophilic phenotype aged 12 or more (United States) or 6 or more (European Union) years, but its long-term use in children aged 6 to 11 years has not yet been assessed. OBJECTIVE: We sought to assess the long-term safety, efficacy, and pharmacodynamics of mepolizumab in children aged 6 to 11 years with severe asthma with an eosinophilic phenotype. METHODS: In this open-label, uncontrolled, repeat-dose extension study (NCT02377427), children aged 6 to 11 years with severe asthma with an eosinophilic phenotype (blood eosinophil counts ≥150 cells/µL at screening or ≥300 cells/µL in the previous year) received a body weight-dependent dose of subcutaneous mepolizumab of 40 mg (<40 kg) or 100 mg (≥40 kg) over 52 weeks. End points included the incidence of adverse events (AEs) and immunogenicity (primary), absolute blood eosinophil counts (cells per microliter; secondary), and annualized exacerbation rates and asthma control questionnaire/childhood asthma control test scores (exploratory). RESULTS: Over 52 weeks, 30 children received mepolizumab; 27 (90%) and 7 (23%) experienced on-treatment AEs and serious AEs, respectively. No serious AEs were treatment related. There were no fatal AEs. No specific patterns of AEs were evident, and no anti-drug antibody or neutralizing antibody responses were reported. Compared with baseline values, mepolizumab treatment reduced blood eosinophil counts and asthma exacerbations and improved asthma control across all treatment groups. CONCLUSION: Long-term safety, pharmacodynamic, and efficacy data from this study support a positive benefit-risk profile for mepolizumab in children with severe asthma with an eosinophilic phenotype and were similar to data in studies in adults and adolescents.

Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma.

BACKGROUND: Mepolizumab has demonstrated favorable safety and efficacy profiles in placebo-controlled trials of 12 months' duration or less; however, long-term data are lacking. OBJECTIVE: We sought to evaluate the long-term safety and efficacy of mepolizumab in patients with severe eosinophilic asthma (SEA). METHODS: COLUMBA (Open-label Long Term Extension Safety Study of Mepolizumab in Asthmatic Subjects, NCT01691859) was an open-label extension study in patients with SEA previously enrolled in DREAM (Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma, NCT01000506). Patients received 100 mg of subcutaneous mepolizumab every 4 weeks plus standard of care until a protocol-defined stopping criterion was met. Safety end points included frequency of adverse events (AEs), serious AEs, and AEs of special interest. Efficacy end points included annualized exacerbation rates, changes from baseline in Asthma Control Questionnaire 5 scores, and blood eosinophil counts. Immunogenicity was also assessed. RESULTS: Overall, 347 patients were enrolled for an average of 3.5 years (maximum, 4.5 years; total exposure, 1201 patient-years). On-treatment AEs were reported in 94% of patients (exposure-adjusted rate, 3688 events/1000 patient-years). The most frequently reported on-treatment AEs were respiratory tract infection, headache, bronchitis, and asthma worsening. Seventy-nine (23%) patients experienced 1 or more on-treatment serious AEs; there were 6 deaths, none of which were assessed as related to mepolizumab. For patients with 156 weeks or greater enrollment, the exacerbation rate was 0.74 events/y (weeks 0-156), a 56% reduction from the off-treatment period between DREAM and COLUMBA. For all patients, at the first postbaseline assessment, the mean Asthma Control Questionnaire 5 score was reduced by 0.47 points, and blood eosinophil counts were reduced by 78%, with similar improvements maintained throughout the study. The immunogenicity profile (8% anti-drug antibodies) was consistent with previous studies. CONCLUSION: These data support the long-term safety and efficacy of mepolizumab in patients with SEA.

Oral corticosteroid dose changes and impact on peripheral blood eosinophil counts in patients with severe eosinophilic asthma: a post hoc analysis.

BACKGROUND: An inverse relationship between oral corticosteroid (OCS) dose and peripheral blood eosinophil (PBE) count is widely recognized in patients with severe eosinophilic asthma; however, there are limited data available to quantify this relationship. This post hoc analysis of the SIRIUS study (NCT01691508) examined the impact of weekly incremental OCS dose reductions on PBE counts during the 3-8-week optimization phase of the study. METHODS: SIRIUS was a randomized, double-blind study involving patients with severe asthma (≥12 years old), which included an initial OCS dose optimization phase prior to randomization. Regression analysis assuming a linear relationship between change in OCS dose and change in log (PBE count) during the optimization phase was used to estimate the changes in PBE count following specific decreases in OCS dose. RESULTS: All 135 patients from the SIRIUS intent-to-treat population were included in this analysis. During the optimization period, 44% (60/135) of patients reduced their OCS dose, with an increase in geometric mean PBE count of 110 cells/µL (200 to 310 cells/µL; geometric mean ratio from beginning to end of the optimization phase: 1.52) recorded in these patients. The model estimated that reduction of daily OCS dose by 5 mg/day led to a 41% increase in PBE count (mean ratio to beginning of optimization phase: 1.41 [95% confidence interval (CI); 1.22, 1.63]). CONCLUSION: These data confirmed and quantified the inverse association between OCS dose and PBE count. These insights will help to inform clinicians when tapering OCS doses in patients with severe eosinophilic asthma.

The clinical benefit of mepolizumab replacing omalizumab in uncontrolled severe eosinophilic asthma.

BACKGROUND: Mepolizumab and omalizumab are treatments for distinct but overlapping severe asthma phenotypes. OBJECTIVE: To assess if patients eligible for both biologics but not optimally controlled with omalizumab experience improved asthma control when switched directly to mepolizumab. METHODS: OSMO was a multicenter, open-label, single-arm, 32-week trial in patients with ≥2 asthma exacerbations in the year prior to enrollment, despite receiving high-dose inhaled corticosteroids and other controller(s), plus omalizumab (≥4 months). At baseline, patients with blood eosinophil counts ≥150 cells/µL (or ≥300 cells/µL in the prior year) and an Asthma Control Questionnaire (ACQ)-5 score ≥1.5 discontinued omalizumab and immediately commenced mepolizumab 100 mg subcutaneously every 4 weeks. Endpoints included change from baseline in ACQ-5 score (primary), St George's Respiratory Questionnaire (SGRQ) score and the proportions of ACQ-5 and SGRQ responders, all at Week 32, and the annualized exacerbation rate over the study period. RESULTS: At Week 32 (intent-to-treat population [n = 145]), the least squares (LS) mean changes (standard error [SE]) in ACQ-5 and SGRQ total scores were -1.45 (0.107) and -19.0 (1.64) points; with 77% and 79% of patients achieving the minimum clinically important differences (ACQ-5: ≥0.5 points; SGRQ: ≥4 points), respectively. The annualized rate of clinically significant exacerbations was 1.18 events/year, a 64% reduction from 3.26 events/year during the previous year. Safety and immunogenicity profiles were consistent with previous trials. CONCLUSION: After directly switching from omalizumab to mepolizumab, patients with uncontrolled severe eosinophilic asthma experienced clinically significant improvements in asthma control, health status, and exacerbation rate, with no tolerability issues reported.

An endogenous aryl hydrocarbon receptor ligand, ITE, induces regulatory T cells and ameliorates experimental colitis.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that affects millions of people with high morbidity and health care costs. The precise etiology of IBD is unknown, but clear evidence suggests that intestinal inflammation is caused by an excessive immune response to mucosal antigens. Recent studies have shown that activation of the aryl hydrocarbon receptor (AhR) induces regulatory T cells (Tregs) and suppresses autoimmune diseases. In the current study, we investigated if a nontoxic ligand of AhR, 2-(1' H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can attenuate dextran sodium sulfate-induced colitis. Our studies demonstrated that in mice that received ITE treatment in vivo, colitis pathogenesis, including a decrease in body weight, was significantly reversed along with the systemic and intestinal inflammatory cytokines. ITE increased the expression of Tregs in spleen, mesenteric lymph nodes (MLNs), and colon lamina propria lymphocytes (cLPL) of mice with colitis when compared with controls. This induction of Tregs was reversed by AhR antagonist treatment in vitro. ITE treatment also increased dendritic cells (CD11c+) and decreased macrophages (F4/80+) from the spleen, MLNs, and cLPL in mice with colitis. ITE also reversed the systemic and intestinal frequency of CD4+ T cells during colitis and suppressed inflammatory cytokines including IFN-γ, TNF-α, IL-17, IL-6, and IL-1 as well as induced IL-10 levels. These findings suggest that ITE attenuates colitis through induction of Tregs and reduction in inflammatory CD4+ T cells and cytokines. Therefore, our work demonstrates that the nontoxic endogenous AhR ligand ITE may serve as a therapeutic modality to treat IBD. NEW & NOTEWORTHY We report the novel finding that activation of the aryl hydrocarbon receptor with the nontoxic ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induces regulatory T cells (Tregs) and suppresses inflammatory bowel disease (IBD). Our data suggest that ITE diminishes colitis pathology through induction of Tregs; reduces inflammatory cytokines, inflammation score, and macrophage frequency; and induces DCs resulting in amelioration of colitis. Therefore, nontoxic endogenous ITE promotes the induction of Tregs and may be useful for the treatment of IBD.