A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's.

OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated. CONCLUSION: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.

Synthesis of Mixed Phosphonate Esters and Amino Acid-Based Phosphonamidates, and Their Screening as Herbicides.

While organophosphorus chemistry is gaining attention in a variety of fields, the synthesis of the phosphorus derivatives of amino acids remains a challenging task. Previously reported methods require the deprotonation of the nucleophile, complex reagents or hydrolysis of the phosphonate ester. In this paper, we demonstrate how to avoid these issues by employing phosphonylaminium salts for the synthesis of novel mixed n-alkylphosphonate diesters or amino acid-derived n-alkylphosphonamidates. We successfully applied this methodology for the synthesis of novel N-acyl homoserine lactone analogues with varying alkyl chains and ester groups in the phosphorus moiety. Finally, we developed a rapid, quantitative and high-throughput bioassay to screen a selection of these compounds for their herbicidal activity. Together, these results will aid future research in phosphorus chemistry, agrochemistry and the synthesis of bioactive targets.

Standardized nailfold capillaroscopy in children with rheumatic diseases: a worldwide study.

OBJECTIVES: To standardly assess and describe nailfold videocapillaroscopy (NVC) assessment in children and adolescents with juvenile rheumatic and musculoskeletal diseases (jRMD) vs healthy controls (HCs). MATERIAL AND METHODS: In consecutive jRMD children and matched HCs from 13 centres worldwide, 16 NVC images per patient were acquired locally and read centrally per international consensus standard evaluation of the EULAR Study Group on Microcirculation in Rheumatic Diseases. A total of 95 patients with JIA, 22 with JDM, 20 with childhood-onset SLE (cSLE), 13 with juvenile SSc (jSSc), 21 with localized scleroderma (lSc), 18 with MCTD and 20 with primary RP (PRP) were included. NVC differences between juvenile subgroups and HCs were calculated through multivariable regression analysis. RESULTS: A total of 6474 images were assessed from 413 subjects (mean age 12.1 years, 70.9% female). The quantitative NVC characteristics were significantly lower or higher in the following subgroups compared with HCs: for density: lower in jSSc, JDM, MCTD, cSLE and lSc; for dilations: higher in jSSc, MCTD and JDM; for abnormal shapes: higher in JDM and MCTD; for haemorrhages: higher in jSSc, MCTD, JDM and cSLE. The qualitative NVC assessment of JIA, lSc and PRP did not differ from HCs, whereas the cSLE and jSSc, MCTD, JDM and cSLE subgroups showed more non-specific and scleroderma patterns, respectively. CONCLUSIONS: This analysis resulted from a pioneering registry of NVC in jRMD. The NVC assessment in jRMD differed significantly from HCs. Future prospective follow-up will further elucidate the role of NVC in jRMD.

The biological interactions between kynurenine and AhR in melanocytes: in vitro studies.

Kynurenine (KYN), a tryptophan metabolite, is endogenously produced by the skin cells and is present in human sweat. The aim of this study was to determine the molecular mechanism of the antiproliferative activity of KYN on human epidermal melanocytes. KYN significantly inhibited the metabolic activity of HEMa cells by decreasing cyclin D1 and cyclin-dependent kinase 4 (CDK4) levels via the aryl hydrocarbon receptor (AhR) pathway. The results suggested that KYN might be involved in the regulation of physiological and pathological processes mediated by melanocytes.

Meeting Patient Expectations: Assessing Medical Service and Quality of Care Using the SERVQUAL Model in Dermatology Patients at a Single Center in Poland.

BACKGROUND This study applied the SERVQUAL model, a widely recognized tool for assessing the quality of services, to understand the gap between patient expectations and perceptions of care quality among 413 dermatology patients at a single medical center in Poland. MATERIAL AND METHODS The study cohort included 413 patients: 195 inpatients and 218 outpatients. The SERVQUAL model's 5 dimensions - reliability, assurance, tangibility, empathy, and responsiveness, each including multiple specific items - served as our assessment criteria. Patient responses to these items measured the perceived and expected quality of service. The service quality index (SQ), calculated as the difference between perception and expectation ratings, was the study's primary outcome measure. A negative SQ score was interpreted as patient dissatisfaction. RESULTS The study results showed a negative SQ score, which signified a discrepancy between high patient expectations and the actual perceived quality of service. The largest gap was seen in the tangibility dimension. Differences emerged based on treatment setting, with inpatient and outpatient settings showing varying expectations and perceptions. Patient sex and residential location also influenced the tangibility dimension. Employed patients and patients with diminished quality of life had heightened expectations in certain dimensions, while patients below 36 years of age expressed higher expectations in responsiveness, assurance, and empathy. CONCLUSIONS The findings emphasize the critical role of care quality in shaping patients' satisfaction and perception, particularly in dermatology. Using the SERVQUAL model, this study identified the tangibility dimension as an area needing improvement. This insight serves as a stepping stone toward enhancing patient satisfaction by addressing these unmet expectations.

PPARs and the Kynurenine Pathway in Melanoma-Potential Biological Interactions.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in various physiological and pathological processes within the skin. PPARs regulate several processes in one of the most aggressive skin cancers, melanoma, including proliferation, cell cycle, metabolic homeostasis, cell death, and metastasis. In this review, we focused not only on the biological activity of PPAR isoforms in melanoma initiation, progression, and metastasis but also on potential biological interactions between the PPAR signaling and the kynurenine pathways. The kynurenine pathway is a major pathway of tryptophan metabolism leading to nicotinamide adenine dinucleotide (NAD+) production. Importantly, various tryptophan metabolites exert biological activity toward cancer cells, including melanoma. Previous studies confirmed the functional relationship between PPAR and the kynurenine pathway in skeletal muscles. Despite the fact this interaction has not been reported in melanoma to date, some bioinformatics data and biological activity of PPAR ligands and tryptophan metabolites may suggest a potential involvement of these metabolic and signaling pathways in melanoma initiation, progression, and metastasis. Importantly, the possible relationship between the PPAR signaling pathway and the kynurenine pathway may relate not only to the direct biological effect on melanoma cells but also to the tumor microenvironment and the immune system.

Synthesis and Structural Studies of New Selenium Derivatives Based on Covalent Functionalization of MWCNTs.

Modifying the surface of nanomaterials, such as carbon nanotubes, by introducing heteroatoms or larger functional groups into the structure causes a change in chemical properties-manifested in the increase in reactivity as well as a change in conductivity. This paper presents the new selenium derivatives obtained by a covalent functionalization of brominated multi-walled carbon nanotubes (MWCNTs). The synthesis was carried out in mild conditions (3 days at room temperature), and was additionally assisted with ultrasound. After a two-stage purification, the obtained products were identified and characterized by the following methods: scanning and transmission electron microscopy imaging (SEM and TEM), energy dispersive X-ray microanalysis (EDX), X-ray photoelectron spectroscopy (XPS), Raman and nuclear magnetic resonance (NMR), and X-ray diffraction (XRD). In the selenium derivatives of carbon nanotubes, the content of selenium and phosphorus reached 14 and 4.2 wt%, respectively.

Selected miRNA and Psoriasis-Cardiovascular Disease (CVD)-Overweight/Obesity Network-A Pilot Study.

Psoriasis is nowadays recognized as a multifactorial systemic disease with complex and not fully understood pathogenesis. In psoriatic patients, the increased cardiovascular disease (CVD) risk and frequent comorbidities like obesity are observed. The aim of this study was to investigate differences in miRNA (miR-22-3p, miR-133a-3p, miR-146a-5p, miR-369-3p, and Let-7b-5p) involved in CVD risk among psoriatic patients with overweight/obesity and with normal weight. The study comprised 28 male psoriatic patients and 16 male healthy controls. miRNA isolated from peripheral blood mononuclear cells was reverse-transcribed and RT-qPCR was performed. We have found decreased levels of miR-22, miR-133a, miR-146a, and miR-369 among the psoriatic patients. There was a statistically significant difference in miR-22 and miR-146a levels between psoriatic patients with overweight/obesity and with normal weight. There were positive correlations between miR-22 and miR-146a levels and psoriatic arthritis (PsA) in psoriatic patients with normal weight and between the miR-133a level and PsA in the overweight/obese patients. The decreased levels of selected miRNA are consistent with the levels observed in CVD indicating their impact on the CVD risk in psoriatic patients. miR-22 and miR-146 may be recognized as one of the contributing factors in the obesity-CVD-psoriasis network.

Multiple Cytokine Analysis of Th1/Th2/Th9/Th17/Th22/Treg Cytokine Pathway for Individual Immune Profile Assessment in Patients with Psoriasis.

BACKGROUND Psoriasis is an autoimmune and autoinflammatory disorder that has a significant impact on patient quality of life. The aim of the study was to assess the immune profiles of patients with psoriasis with multiple cytokine analysis. MATERIAL AND METHODS Fifty-two male psoriatic patients and 24 healthy male volunteers were recruited. Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-gamma), interleukin (IL)-1 beta, IL-2, Il-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-18, IL-21, IL-22, IL-23, IL-27, and tumor necrosis factor (TNF)-alpha were measured in patients' serum with a Th1/Th2/Th9/Th17/Th22/Treg Cytokine 18-Plex Human ProcartaPlex Panel, based on Luminex xMAP technology. RESULTS The median fluorescence intensities of serum GM-CSF, IL-2, IL-5, IL-10, IL-13, IL-17A, IL-21, and IL-22 were not intensive enough to calculate the cytokine concentration. We observed elevated levels of IL-6 (P=0.001) and IL-9 (P=0.003) in patients, compared with the control group. The levels of IL-1beta (P=0.008) and IL-27 (P=0.006) were decreased. In patients with psoriatic arthritis, we noticed a decreased level of IL-9 compared with that in patients without arthritis (P=0.034). The levels of IL-12 (P<0.05) and IL-18 (P<0.05) correlated positively with the Psoriasis Area and Severity Index. We found negative correlations of IL-9 (P<0.05), IL-12 (P<0.05), and IL-23 (P<0.05) with the age of psoriatic patients; IL-12 (P<0.05) and IL-23 (P<0.05) with psoriasis duration; and IL-6 (P<0.05) and IL-9 (P<0.05) with the Nail Psoriasis Severity Index. CONCLUSIONS Multiple cytokine analysis seems to be an important form of individual immune profile assessment before treatment selection.

Chronic Inflammation as the Underlying Mechanism of the Development of Lung Diseases in Psoriasis: A Systematic Review.

Psoriasis is a systemic inflammatory disease caused by dysfunctional interactions between the innate and adaptive immune responses. The systemic inflammation in psoriasis may be associated with the development of comorbidities, including lung diseases. In this review, we aimed to provide a summary of the evidence regarding the prevalence of lung diseases in patients with psoriasis and the potential underlying mechanisms. Twenty-three articles published between March 2010 and June 2021 were selected from 195 initially identified records. The findings are discussed in terms of the prevalence of asthma, chronic obstructive pulmonary disease, interstitial lung disease, obstructive sleep apnea, pulmonary hypertension, and sarcoidosis in psoriasis. A higher prevalence of lung diseases in psoriasis has been confirmed in asthma, chronic obstructive pulmonary disease, obstructive sleep apnea, and pulmonary hypertension. These conditions are important as they are previously unrecognized causes of morbidity and mortality in psoriasis. The development of lung diseases in patients with psoriasis can be explained by several mechanisms, including common risk factors, shared immune and molecular characteristics associated with chronic inflammation, as well as other mechanisms. Understanding the prevalence of lung diseases in psoriasis and their underlying mechanisms can help implement appropriate preventative and therapeutic strategies to address respiratory diseases in patients with psoriasis.

New Insights into Psoriasis.

Psoriasis is a chronic inflammatory skin disease with many comorbidities resulting from not only local but also systemic inflammation [...].

Anticancer Activity of Amantadine and Evaluation of Its Interactions with Selected Cytostatics in Relation to Human Melanoma Cells.

Patients with Parkinson's disease are prone to a higher incidence of melanoma. Amantadine (an anti-Parkinson drug) possesses the antiproliferative potential that can be favorable when combined with other chemotherapeutics. Cisplatin (CDDP) and mitoxantrone (MTO) are drugs used in melanoma chemotherapy, but they have many side effects. (1) Clinical observations revealed a high incidence of malignant melanoma in patients with Parkinson's disease. Amantadine as an anti-Parkinson drug alleviates symptoms of Parkinson's disease and theoretically, it should have anti-melanoma properties. (2) To characterize the interaction profile for combinations of amantadine with CDDP and MTO in four human melanoma cell lines (A375, SK-MEL 28, FM55P and FM55M2), type I isobolographic analysis was used in the MTT test. (3) Amantadine produces the anti-proliferative effects in various melanoma cell lines. Flow cytometry analysis indicated that amantadine induced apoptosis and G1/S phase cell cycle arrest. Western blotting analysis showed that amantadine markedly decreased cyclin-D1 protein levels and increased p21 levels. Additionally, amantadine significantly increased the Bax/Bcl-2 ratio. The combined application of amantadine with CDDP at the fixed-ratio of 1:1 exerted an additive interaction in the four studied cell lines in the MTT test. In contrast, the combination of amantadine with MTO (ratio of 1:1) produced synergistic interaction in the FM55M2 cell line in the MTT (* p < 0.05). The combination of amantadine with MTO was also additive in the remaining tested cell lines (A375, FM55P and SK-MEL28) in the MTT test. (4) Amantadine combined with MTO exerted the most desirable synergistic interaction, as assessed isobolographically. Additionally, the exposure of melanoma cell lines to amantadine in combination with CDDP or MTO augmented the induction of apoptosis mediated by amantadine alone.

The Analysis of a Genome-Wide Association Study (GWAS) of Overweight and Obesity in Psoriasis.

There is evidence that the concomitance of psoriasis and obesity may originate from the interplay between multiple genetic pathways and involve gene−gene interactions. The aim of this study was to compare the genetic background related to obesity among psoriatic patients versus healthy controls by means of a Genome-Wide Association Study (GWAS). A total of 972 psoriatic patients and a total of 5878 healthy donors were enrolled in this study. DNA samples were genotyped for over 500,000 single nucleotide polymorphisms (SNPs) using Infinium CoreExome BeadChips (Illumina, San Diego, CA, USA). Statistical analysis identified eleven signals (p < 1 × 10−5) associated with BMI across the study groups and revealed a varying effect size in each sub-cohort. Seven of the alternative alleles (rs1558902 in the FTO gene, rs696574 in the CALCRL gene, as well as rs10968110, rs4551082, rs4609724, rs9320269, and rs2338833,) are associated with increased BMI among all psoriatic patients and four (rs1556519 in the ITLN2 gene, rs12972098 in the AC003006.7 gene, rs12676670 in the PAG1 gene, and rs1321529) are associated with lower BMI. The results of our study may lead to further insights into the understanding of the pathogenesis of obesity among psoriatic patients.

Gut microbiome in systemic sclerosis: a potential therapeutic target.

Introduction: Systemic sclerosis (SSc) is a chronic, connective tissue disease characterized by inflammation, fibrosis and microcirculation disturbances. Gastrointestinal involvement and impaired gut motility observed in SSc promotes the small intestinal bacterial overgrowth (SIBO) defined as the increase in the number of bacteria to over 105 CFU/ml or as the presence of atypical flora. Aim: To investigate the prevalence and characteristics of SIBO and to assess the efficacy of rifaximin in SIBO treatment in SSc patients. Material and methods: 40 SSc patients and 39 healthy individuals were enrolled in the study. All subjects completed UCLA SCTC GIT 2.0 questionnaire and query for gastrointestinal symptoms. The presence of SIBO was assessed by the lactulose hydrogen breath test (LHBT). Patients with SIBO received 1200 mg rifaximin daily for 10 days. The same diagnostic procedure was performed after completed treatment in order to evaluate SIBO eradication. Results: The prevalence of SIBO was higher in SSc patients compared with the control group (47.5% vs. 12.8%; p = 0.0008). SIBO eradication after rifaximin treatment was successful in 73.3% of SSc patients. Conclusions: These data suggest that SIBO occurs more frequently in SSc patients than in controls. Eradication therapy with rifaximin is associated with satisfactory results and a high safety profile.

Assessment of Selected Matrix Metalloproteinases (MMPs) and Correlation with Cytokines in Psoriatic Patients.

Metalloproteinases (MMPs) and cytokines have a great impact on the pathogenesis of psoriasis. Cytokines, as key mediators of inflammation and autoimmune processes, play a crucial role in the regulation of MMP expression in different cell types. Parallel, MMPs have an influence on cytokine production. This interaction was not well recognized in psoriatic patients. Our study is aimed at assessing the selected serum MMP levels and their correlations with cytokine levels in the serum of psoriatic patients. We observed a significantly elevated level of pro-MMP-1 and MMP-9 in psoriatic patients' serum in comparison to the control group. We did not observe any statistically significant differences of MMP-3 and pro-MMP-10 between the psoriatic patients and the control group. We did not observe any statistically significant differences in all the studied MMP levels between the patients with and without psoriatic arthritis (PsA). MMP-3 level correlated positively with proinflammatory cytokines, i.e., IL-12p/70, IL-17A, and TNF-α as well as MMP-3 and pro MMP-1 correlated positively with IL-4 in the psoriatic patients. In the control group, a positive correlation between pro-MMP-1 and TNF-α was found. These results confirm MMPs and Th1 and Th17 cytokine interaction in the inflammatory regulation in psoriasis.

Novel Application of Light-Emitting Diode Therapy in the Treatment of Eyebrow Loss in Frontal Fibrosing Alopecia.

BACKGROUND: Eyebrow loss in the course of frontal fibrosing alopecia (FFA) is becoming a growing issue among older females. It has a considerable negative impact on patients' quality of life. Since there is no standardized treatment, photobiomodulation with light-emitting diodes (LEDs) could be an option. Here we assess, for the first time, the efficacy of LED therapy in the treatment of eyebrow loss in females with FFA. METHODS: 16 female patients with FFA aged 60-74 years were enrolled in the study. LED therapy was performed once a week for a 10-week session. The LEDs' effectiveness was assessed at the baseline, after 10 irradiations, and 6 months after the end of treatment during a follow-up visit. RESULTS: The therapy was well tolerated. After 10 irradiations, the total eyebrow hair count increased significantly, as did the number of thick hairs and mid-thick hairs (p = 0.002, p = 0.002, and p = 0.044, respectively). During the follow-up visit, the total number of eyebrow hairs remained significantly higher than before treatment (p = 0.002). CONCLUSION: The study revealed that LED therapy seems to be a novel and promising therapeutic option for eyebrow loss in patients with FFA. It is safe and well tolerated and leads to clinically and cosmetically acceptable improvement.

Chiral Polythiophenes: Part I: Syntheses of Monomeric Precursors.

The purpose of this mini-review is to comprehensively present the synthetic approaches used for the preparation of non-racemic mono- and multi-substituted thiophenes, which, in turn, can be applied as precursors for the synthesis of chiral polythiophenes isolated as a single chemical entity or having supramolecular thin-layer architectures.

PD1/PD-L1 pathway in psoriasis and psoriatic arthritis: a review.

Programmed-death 1 (PD-1) is a co-receptor that inhibits the inflammatory response, and thus helps in maintenance of peripheral immunotolerance. Impairment in the PD-1/PD-L1 pathway is believed to play an important role in many immune-mediated diseases, including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and autoimmune hepatitis, and, as emphasized recently, in psoriasis and psoriatic arthritis. Biologic drugs targeting immune checkpoint regulators may be associated with new-onset psoriasis or exacerbations of pre-existing dermatosis. In this review we discuss the role of PD-1/PD-L1 pathway in psoriasis basing on data published to date.

Absolute Configuration and Conformation of (-)-R-t-Butylphenylphosphinoamidate: Chiroptical Spectroscopy and X-ray Analysis.

The absolute configuration and conformations of (-)-tert-butylphenylphosphinoamidate were determined using three different chiroptical spectroscopic methods, namely vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and optical rotatory dispersion (ORD). In each of the spectroscopic methods used, experimental data for the (-)-enantiomer of tert-butylphenylphosphinoamidate were measured in the solution phase. Using the concentration-dependent experimental infrared spectra, the existence of dimers in the solution was investigated, and the monomer-dimer equilibrium constant was determined. Concomitant quantum mechanical predictions of the VCD, ECD, and ORD for monomeric tert-butylphenylphosphinoamidate were carried out using density functional theory (DFT) calculations using the B3LYP functional and the 6-31G(d), 6-311G(2d,2p) and aug-cc-pVDZ basis sets. Similar predictions for dimeric tert-butylphenylphosphinoamidate were also obtained using the B3LYP/6-31G(d) method. A comparison of theoretically predicted data with the corresponding experimental data led to the elucidation of the absolute configuration as (-)-(R)-tert-butylphenylphosphinoamidate with one predominant conformation in the solution. This conclusion was independently supported by X-ray analysis of the complex with (+)-R-2,2'-dihydroxy-1,1'-binaphthol ((+)-R- BINOL).

IL-17A in the Psoriatic Patients' Serum and Plaque Scales as Potential Marker of the Diseases Severity and Obesity.

The aim of the study was to evaluate concentrations of IL-17 in the serum and plaque scales of psoriatic patients. We analyzed their association with the clinical activity of the disease and with body mass index (BMI). Demographic data, medical history, serum, and scale from psoriatic plaques for assessment of IL-17 were collected from all the participants. The disease severity was assessed with PASI (Psoriasis Area and Severity Index), BSA (Body Surface Area), PGA (Physician Global Assessment), NAPSI (Nail Psoriasis Severity Index), and DLQI (Dermatology Quality of Life Index) scores. Obesity was diagnosed by calculating body mass index. Serum and scale concentration of IL-17 was determined with Human IL-17A High Sensitivity ELISA kit and Human IL-17 ELISA kit. In the psoriatic patients, BMI was statistically significantly higher than in the control group. Most of the patients presented BMI higher than normal. Our study confirms that overweight is a problem among psoriatic patients. A significant positive correlation between the IL-17 serum and scale concentrations and psoriasis severity indicates that IL-17 can be used as the marker of disease severity. More data from human studies can be crucial for understanding that relationship between IL-17, psoriasis, and obesity.