Clinical Presentation and Prognostic Features in Patients with Immunotherapy-Induced Vitiligo-like Depigmentation: A Monocentric Prospective Observational Study

Vitiligo-like depigmentation (VLD) is an immune-related adverse event (irAE) of checkpoint-inhibitor (CPI) treatment, which has previously been associated with a favourable outcome. The aim of this study was to explore clinical, biological and prognostic features of melanoma patients with VLD under CPI-treatment and to explore whether they exhibit a characteristic immune response profile in peripheral blood. Melanoma patients developing VLD under CPI were included in a prospective observational single-center cohort study. We collected and analysed clinical parameters, photographs and serum from 28 VLD patients. They received pembrolizumab (36%), nivolumab (11%), ipilimumab/nivolumab (32%) or clinical trial medications (21%). We performed a high-throughput proteomics assay (Olink), in which we identified a distinct proteomic signature in VLD patients in comparison to non-VLD CPI patients. Our clinical assessments revealed that VLD lesions had a predominantly symmetrical distribution pattern, with mostly smaller “freckle-like” macules and a preferential distribution in UV-exposed areas. Patients with previous targeted therapy showed a significantly longer time lapse between CPI initiation and VLD onset compared to non-pre-treated patients (12.5 vs. 6.25 months). Therapy responders exhibited a distinct proteomic profile when compared with non-responders in VLD such as upregulation of EDAR and downregulation of LAG3. ITGA11 was elevated in the VLD-group when compared to non-VLD-CPI-treated melanoma patients. Our findings demonstrate that on a proteomic level, VLD is characterized by a distinct immune signature when compared to CPI-treated patients without VLD and that therapy responsiveness is reflected by a characteristic immune profile. The pathomechanisms underlying these findings and how they could relate to the antitumoral response in melanoma remain to be elucidated

The epithelial barrier: The gateway to allergic, autoimmune, and metabolic diseases and chronic neuropsychiatric conditions

Since the 1960 s, our health has been compromised by exposure to over 350,000 newly introduced toxic substances, contributing to the current pandemic in allergic, autoimmune and metabolic diseases. The "Epithelial Barrier Theory" postulates that these diseases are exacerbated by persistent periepithelial inflammation (epithelitis) triggered by exposure to a wide range of epithelial barrier-damaging substances as well as genetic susceptibility. The epithelial barrier serves as the body's primary physical, chemical, and immunological barrier against external stimuli. A leaky epithelial barrier facilitates the translocation of the microbiome from the surface of the afflicted tissues to interepithelial and even deeper subepithelial locations. In turn, opportunistic bacterial colonization, microbiota dysbiosis, local inflammation and impaired tissue regeneration and remodelling follow. Migration of inflammatory cells to susceptible tissues contributes to damage and inflammation, initiating and aggravating many chronic inflammatory diseases. The objective of this review is to highlight and evaluate recent studies on epithelial physiology and its role in the pathogenesis of chronic diseases in light of the epithelial barrier theory

Biological therapy and tissue engineering approaches for the treatment of osteoarthritis

In this thesis, we aimed to find an effective therapy to treat or impede osteoarthritis (OA) and to regenerate damaged articular cartilage. To achieve this goal, inhibition of pro-inflammatory cytokines that are excessively abundant in OA joints is necessary. Furthermore, for regeneration of damaged cartilage, it is essential to increase the chondrocytes anabolism. Pharmacological therapy and tissue engineering approaches are the two most promising strategies towards cartilage regeneration. Currently, there is no effective pharmacotherapy featuring both anti-inflammatory and anabolic effects to restore the degenerated cartilage in OA or other degenerative joint diseases. Therefore, we used an inflammatory model of human OA chondrocytes microtissues, in which after screening of 34 herbal compounds with potential anti-inflammatory and anabolic effects, VA, Epi C, PS, PCA, 4-HBA and 5-HMF were selected for further studies. We selectively identified the mechanism of action of Vanillic acid (VA) and Epimedin C (Epi C). Our results indicated that VA had significant anti-inflammatory effects through inhibition of IKK complex in NF-κB signaling and Epi C showed a significant anabolic effect by increasing the expression of collagenous and non-collagenous matrix proteins. Additionally, we developed a tunable and injectable hydrogel for drug delivery and cartilage tissue engineering by crosslinking different concentrations of HA-Tyramine (HA) with aqueous Silk-fibroin (SF) solutions. HA20/SF80 composite hydrogel showed the longest and the most sustained release profile for VA and Epi C over time, which is necessary for the long treatment duration for OA joints. Also, we showed superior ECM production in HA20/SF80 chondrocyte-laden constructs. Therefore to achieve a successful therapy for OA, the combination of all mentioned approaches in pre-clinical studies is envisioned

The Power of Social Studies Curriculum: Inclusion and Awareness of English Language Learners (ELLs)

Nurturing citizenship in all students, especially English Language Learners (ELL) is the main goal of Social Studies and English as a Second Language ESL curriculum. In order for ELLs to construct a new identity and be successful in merging into the new language, culture, and academic lives, there must be an emphasis on immersing them both in their social and educational lives. Engaging in meaningful conversations would improve their creativity, cognitive thinking, and problem-solving skills. The question that this dissertation explores is ‘How is a small sample of social science teachers modifying their instruction to support the social science learning of their ELLs in nurturing responsible Canadian citizens, and what outcomes do they observe from these students? This qualitative research has drawn on some case-study characteristics for recruiting participants from a school that operates separate Social Studies courses for ELLs. Both participants in this study have more than five years experience in teaching Social Studies content to ELLs and are active participants in extracurricular that involves ELLs as well. The chapters of this work focus on the importance of Social Studies curriculum, instructional strategies, challenges, and further program recommendations in addressing the topic of nurturing responsible citizenship in ELLs. According to literature gathered and research participants, it is crucial to address Social Studies content with ELLs, since it is essential to offer them a different perspective and knowledge on the world and the social matters around them. The results also indicate, student success in all subjects is achieved when teachers’ standards are high for all students and the learning is facilitated through students’ differentiated needs. The Power of Social Studies Education is dependant of teachers’ engagement in the content and facilitation of instructions for all learners, including the ELLs, which is the main source of nurturing responsible citizenship in our future youths

Regulation of Inflammatory Response in Human Osteoarthritic Chondrocytes by Novel Herbal Small Molecules

In this study, 34 Traditional Chinese Medicine (TCM) compounds were screened for potential anabolic and anti-inflammatory properties on human osteoarthritic (OA) chondrocytes. The anabolic effects were assessed by measuring the glycosaminoglycan (GAG) relative to the DNA content using a 3D pellet culture model. The most chondrogenic compounds were tested in an inflammatory model consisting of 3 days of treatment with cytokines (IL-1β/TNF-α) with or without supplementation of TCM compounds. The anti-inflammatory effects were assessed transcriptionally, biochemically and histologically. From the 34 compounds, Vanilic acid (VA), Epimedin A (Epi A) and C (Epi C), 2′′-O-rhamnosylicariside II (2-O-rhs II), Icariin, Psoralidin (PS), Protocatechuicaldehyde (PCA), 4-Hydroxybenzoic acid (4-HBA) and 5-Hydroxymethylfurfural (5-HMF) showed the most profound anabolic effects. After induction of inflammation, pro-inflammatory and catabolic genes were upregulated, and GAG/DNA was decreased. VA, Epi C, PS, PCA, 4-HBA and 5-HMF exhibited anti-catabolic and anti-inflammatory effects and prevented the up-regulation of pro-inflammatory markers including metalloproteinases and cyclooxygenase 2. After two weeks of treatment with TCM compounds, the GAG/DNA ratio was restored compared with the negative control group. Immunohistochemistry and Safranin-O staining confirmed superior amounts of cartilaginous matrix in treated pellets. In conclusion, VA, Epi C, PS, PCA, 4-HBA and 5-HMF showed promising anabolic and anti-inflammatory effects

International practices in the dietary management of fructose 1-6 biphosphatase deficiency

Contains fulltext : 191323.pdf (publisher's version ) (Open Access

Incidence of obesity and its predictors in children and adolescents in 10 years of follow up: Tehran lipid and glucose study (TLGS)

Abstract Background Childhood obesity is one of the most challenging public health issues of twenty-first century. While we know that there is an increase in prevalence of childhood and adolescence obesity, incidence studies must be carried out. The main objective of this study was to determine childhood obesity incidence and its potential predictors in Tehranian urban population. Methods This study was conducted within the framework of the Tehran Lipid and Glucose Study (TLGS), addressing incidence and risk factors of obesity throughout several phases from 1999–2001 to 2009–2011 among Tehranian urban population. Total study subjects were 1033 non-obese children, aged between 7 to 11 years, with a median 8.7 years of follow-up. Body mass Index (BMI) was used to define obesity and overweight based on World Health Organization (WHO) criteria, and definition of metabolic syndrome (MetS) for children was based on the Cook survey. Cumulative incidence of obesity and obesity incidence rates were calculated for each gender. Cox proportional hazard models was used to estimate potential risk factors of obesity. Results Our Participants had a mean age of 9.2 ± 1.4 years, mean BMI of 16.1 ± 2.2 kg/m2 and mean waist circumference (WC) of 57.2 ± 6.7 at baseline. Total cumulative incidence of obesity was calculated to be 17%, CI =14.1–20.4 for whole population (19.6%, CI =15.4–24.8 for boys and 14.5%,CI = 10.9–19.1 for girls). Participants which were in the age group of 7–9 years at baseline experienced higher rate of cumulative obesity incidence compared to those who were in the age group of 10–11 years at baseline (22% vs 10.8%). In addressing risk factors, 5 parameters were significantly associated with obesity incidence: being overweight at baseline (HR = 14.93 95%CI: 9.82–22.70), having higher WC (HR = 5.05 95%CI: 3.01–8.48), suffering from childhood MetS (HR: 2.77 95%CI: 1.57–4.89) and having a obese father (HR: 2.69 95%CI: 1.61–4.50) or mother (HR: 3.04 95%CI: 1.96–4.72). Conclusion Incidence of obesity is significantly high in Tehranian children, especially the age group 7–9 years. Best predictors of childhood obesity incidence are childhood overweight, WC above 90th percentile, childhood MetS and parental obesity

Animal models of osteochondral defect for testing biomaterials

202006 bcmaVersion of RecordPublishe

Anti-Inflammatory and Chondroprotective Effects of Vanillic Acid and Epimedin C in Human Osteoarthritic Chondrocytes

In osteoarthritis (OA), inhibition of excessively expressed pro-inflammatory cytokines in the OA joint and increasing the anabolism for cartilage regeneration are necessary. In this ex-vivo study, we used an inflammatory model of human OA chondrocytes microtissues, consisting of treatment with cytokines (interleukin 1β (IL-1β)/tumor necrosis factor α (TNF-α)) with or without supplementation of six herbal compounds with previously identified chondroprotective effect. The compounds were assessed for their capacity to modulate the key catabolic and anabolic factors using several molecular analyses. We selectively investigated the mechanism of action of the two most potent compounds Vanillic acid (VA) and Epimedin C (Epi C). After identification of the anti-inflammatory and anabolic properties of VA and Epi C, the Ingenuity Pathway Analysis showed that in both treatment groups, osteoarthritic signaling pathways were inhibited. In the treatment group with VA, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was inhibited by attenuation of the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα) phosphorylation. Epi C showed a significant anabolic effect by increasing the expression of collagenous and non-collagenous matrix proteins. In conclusion, VA, through inhibition of phosphorylation in NF-κB signaling pathway and Epi C, by increasing the expression of extracellular matrix components, showed significant anti-inflammatory and anabolic properties and might be potentially used in combination to treat or prevent joint OA