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BACKGROUND: G-EPOSS is a prospective, non-interventional, German multicentre study of patients with moderate-to-severe plaque psoriasis receiving guselkumab, a therapeutic monoclonal antibody targeting interleukin-23, in a real-world setting. OBJECTIVES: The objective of the study was to evaluate the effectiveness and safety of guselkumab, including its impact on skin, health-related quality of life (HRQoL), sexuality, and perceived stigmatization. METHODS: Patients (≥18 years old) received guselkumab per routine clinical practice. The primary endpoint was the proportion of patients achieving absolute Psoriasis Area and Severity Index (PASI) ≤ 3 at Week (W)28. Secondary endpoint assessments over 28 weeks included the Nail Psoriasis Severity Index (NAPSI), anogenital Physician's Global Assessment (aPGA), and Dermatology Life Quality Index (DLQI). Sexuality and perceived stigmatization were assessed by patients using the Relationship and Sexuality Scale (RSS) and Perceived Stigmatization Questionnaire (PSQ), respectively. RESULTS: Overall, 293 patients were included in the evaluable set population. Mean age and disease duration were 45.6 and 17.6 years, respectively. At baseline, mean PASI, aPGA and DLQI scores were 15.3, 2.7 and 11.3, respectively. In total, 25.9% of patients had received a prior biologic. Overall, 83.0% of patients achieved PASI ≤ 3, and 56.2%/35.1% achieved PASI ≤ 1/PASI = 0, respectively, at W28. Among those with NAPSI ≥ 1 and aPGA ≥ 1 at baseline, NAPSI = 0 and aPGA = 0 were achieved by 39.2% and 61.1% of patients, respectively, and 61.4% of patients achieved DLQI 0-1 at W28. Improvements were observed over 28 weeks across individual items of the DLQI, RSS and PSQ, indicating improved HRQoL and sex life, and decreased perceived stigmatization. Based on DLQI Question (Q)9, 53.6% of patients experienced sexual difficulties at baseline, which decreased to 12.1% at W28. DLQI Q9 responses were consistent with RSS item responses, highlighting DLQI Q9 as a sentinel for sexual impairment. CONCLUSIONS: Guselkumab improved overall skin symptoms and HRQoL in patients with psoriasis and decreased sexual impairment and perceived stigmatization. No new safety signals were observed. STUDY CODE: CNTO1959PSO4008.
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The platelet endothelial cell adhesion molecule 1 (PECAM-1) plays an important role in many inflammatory processes, including the development of atherosclerosis. Polymorphism rs668 of the PECAM-1 gene (373C/G) is functional, and it was reported to be associated with increased serum levels of PECAM-1. We investigated the association between the rs668 polymorphism of PECAM-1 and subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). Five hundred and ninety-five T2DM subjects and 200 control subjects were enrolled. The carotid intima-media thickness (CIMT) and plaque characteristics (presence and structure) were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Geno-typing of the PECAM-1 gene polymorphism (rs668) was performed using KASPar assays. The control examinations were performed 3.8 ± 0.5 years after the initial examination. Higher CIMT was found in patients with T2DM in comparison with subjects without T2DM. Statistically sig-nificantly faster progression of the atherosclerotic markers was shown in subjects with T2DM in comparison with the control group. When adjusted to other risk factors, the rs668 GG genotype was associated with an increased risk of carotid plaques in subjects with T2DM. We concluded that our study demonstrated a minor effect of the rs668 PECAM-1 on markers of carotid atherosclerosis in subjects with T2DM.
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Diabetic nephropathy (DN) is the leading cause of endstage renal disease (ESRD) in developed countries. Several environmental and genetic factors predict the development and progression of DN. The renin-angiotensin system was demonstrated to be involved in the development of DN. We evaluated the association between rs4340 of the angiotensin-converting enzyme (ACE) gene and DN in Caucasians with type 2 diabetes mellitus (T2DM) in 276 Slovenian patients with T2DM who had DN, and 375 patients without clinical signs of DN. Genetic analysis was performed with either standard polymerase chain reaction (PCR) (for rs4340). Results were analyzed using the χ2 test and multivariate logistic regression analyses. We found no association between rs4340 and DN. Cystatin C was significantly higher in the DN+ group (p <0.001) than in the DN group. Cystatin C was a better marker for the estimation of renal function than estimated glomerular filtration rate (eGFR) according to the modification diet in renal disease (MDRD) equation mL/ min. We concluded that there was no association between the rs4340 of the ACE gene and DN in Caucasian patients who have T2DM.
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The current study was designed to reveal possible associations between the angiotensin-converting-enzyme (ACE) gene polymorphisms (rs4646994 and rs4341) with markers of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM) in a 4-year-long follow-up study. Five hundred and ninety-five T2DM subjects and 200 control subjects were enrolled. Genotyping of ACE polymorphisms was performed using KASPar assays, and ultrasound examinations were performed twice (at the enrollment and at follow-up). With regard to the progression of atherosclerosis in subjects with T2DM, statistically significant differences were demonstrated in the change of the sum of carotid plaques thickness for the rs4646994 polymorphism. We did not demonstrate an association between the tested polymorphisms (rs4646994 and rs4341) and either carotid intima media thickness (CIMT) or CIMT progression in a 3.8-year period. In our study, we demonstrated that subjects with T2DM with the DD genotype of the rs4646994 [ACE insertion/deletion (I/D)] polymorphism had faster progression of atherosclerosis in comparison to subjects with other genotypes.
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We have characterized the monocarboxylate permease family of Saccharomyces cerevisiae comprising five proteins. We could not find any evidence that the monocarboxylate transporter-homologous (Mch) proteins of S. cerevisiae are involved in the uptake or secretion of monocarboxylates such as lactate, pyruvate or acetate across the plasma membrane. A yeast mutant strain deleted for all five MCH genes exhibited no growth defects on monocarboxylic acids as the sole carbon and energy sources. Moreover, the uptake and secretion rates of monocarboxylic acids were indistinguishable from the wild-type strain. Additional deletion of the JEN1 lactate transporter gene completely blocked uptake of lactate and pyruvate. However, uptake of acetate was not even affected after the additional deletion of the gene YHL008c, which had been proposed to code for an acetate transporter. The mch1-5 mutant strain showed strongly reduced biomass yields in aerobic glucose-limited chemostat cultures, pointing to the involvement of Mch transporters in mitochondrial metabolism. Indeed, intracellular localization studies indicated that at least some of the Mch proteins reside in intracellular membranes. However, pyruvate uptake into isolated mitochondria was not affected in the mch1-5 mutant strain. It is concluded that the yeast monocarboxylate transporter-homologous proteins perform other functions than do their mammalian counterparts.
