Increased Cell Turnover Research Articles

50717 Hydrolyzed Collagen and Cacay Oil Increase Collagen, Elastin, and Cell Turnover: In-Vivo and Ex-Vivo Efficacy of a Novel Retinol-Alternative Body Cream

50717 Hydrolyzed Collagen and Cacay Oil Increase Collagen, Elastin, and Cell Turnover: In-Vivo and Ex-Vivo Efficacy of a Novel Retinol-Alternative Body Cream

Inflammation, Oxidative Stress, and Endothelial Dysfunction in the Pathogenesis of Vascular Damage: Unraveling Novel Cardiovascular Risk Factors in Fabry Disease.

Anderson-Fabry disease (AFD), a genetic disorder caused by mutations in the α-galactosidase-A (GLA) gene, disrupts lysosomal function, leading to vascular complications. The accumulation of globotriaosylceramide (Gb3) in arterial walls triggers upregulation of adhesion molecules, decreases endothelial nitric oxide synthesis, and induces reactive oxygen species production. This cascade results in fibrotic thickening, endothelial dysfunction, hypercontractility, vasospasm, and a pro-thrombotic phenotype. AFD patients display increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating heightened cardiovascular risk. Nailfold capillaroscopy (NFC) shows promise in diagnosing and monitoring microcirculatory disorders in AFD, though it remains underexplored. Morphological evidence of AFD as a storage disorder can be demonstrated through electron microscopy and immunodetection of Gb3. Secondary pathophysiological disturbances at cellular, tissue, and organ levels contribute to the clinical manifestations, with prominent lysosomal inclusions observed in vascular, cardiac, renal, and neuronal cells. Chronic accumulation of Gb3 represents a state of ongoing toxicity, leading to increased cell turnover, particularly in vascular endothelial cells. AFD-related vascular pathology includes increased renin-angiotensin system activation, endothelial dysfunction, and smooth muscle cell proliferation, resulting in IMT increase. Furthermore, microvascular alterations, such as atypical capillaries observed through NFC, suggest early microvascular involvement. This review aims to unravel the complex interplay between inflammation, oxidative stress, and endothelial dysfunction in AFD, highlighting the potential connections between metabolic disturbances, oxidative stress, inflammation, and fibrosis in vascular and cardiac complications. By exploring novel cardiovascular risk factors and potential diagnostic tools, we can advance our understanding of these mechanisms, which extend beyond sphingolipid accumulation to include other significant contributors to disease pathogenesis. This comprehensive approach can pave the way for innovative therapeutic strategies and improved patient outcomes.

126 A nutritional solution based on calcidiol (25-OH-D3, HyD) and triterpenoid affects muscle protein synthesis pathways in grower-finisher pigs

Abstract To boost profitability in pig production, it is important to achieve increased lean growth rates and maximize efficiency, especially in grower-finisher pigs where feed intakes are high. Molecular research, especially the study of gene expression, is a proven tool for understanding the precise mechanisms behind muscle tissue growth, including a recent focus on pathways such as the mammalian target of rapamycin (mTOR). In the current work, gene expression analyses were used to study the mode of action of the combination of calcidiol (25-OH-D3, HyD) and triterpenoid, which has shown significant growth and efficiency improvements in grower-finisher pigs (McCormack et al., 2024). Three experimental diets were evaluated for 7 wk; Positive control: 0.7% total Ca, 0.36% total P, vit D3 at 1500IU/kg feed (PC), negative control: PC diet + 30% reduced Ca and 10% reduced P (NC), and NC diet with 1,500IU D3 in calcidiol form (25-OH-D3, HyD) and triterpenoid (NC+). At 19 wk of age, 16 animals per treatment were sacrificed and tissue samples were taken from the longissimus muscle and preserved in RNA later solution. The RNA was extracted, quality control checked, and mRNA sequenced using the Illumina platform with 150 base pair paired-end sequencing and 30M read depth. The sequenced data were aligned to the Sus scrofa reference genome (Sscrofa11.1) using Kallisto. Data were normalized and analyzed for differentially expressed genes (DEGs) between treatments using DeSeq2. Genes were assigned to biological pathways using Biofractal’s customisation of the Reactome pathway database. For statistical analysis, RNA integrity number and treatment were included in the model. In the PC compared with the NC, there were 71 DEGs using a false discovery rate (FDR) of < 0.10. Altered pathways included the inhibition of cellular stress pathways and increased cell turnover in the muscle of PC compared with NC pigs. In the NC+ compared with the NC, there were 155 DEGs (FDR < 0.10). The most significantly upregulated gene in the NC+ treatment was adenylate cyclase (FDR < 0.001), an upstream regulator of several pathways related to energy metabolism and muscle protein synthesis. This mechanism was confirmed in the pathway analysis, which found that the NC+ treatment activated PKA-mediated phosphorylation of CREB, a pathway that inhibits muscle atrophy. Furthermore, the NC+ treatment activated several pathways related to muscle growth, including the mammalian target of rapamycin complex 1 (mTORC1). In this study the addition of calcidiol (25-OH-D3, HyD) and triterpenoid to the diet was found to specifically affect molecular pathways in the muscle of grower-finisher pigs involved in both the inhibition of muscle breakdown as well as activating muscle growth.

Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis.

Immune checkpoint inhibitor (ICI) therapy has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). Little is understood about the pathogenic mechanisms driving irColitis, which does not readily occur in model organisms, such as mice. To define molecular drivers of irColitis, we used single-cell multi-omics to profile approximately 300,000 cells from the colon mucosa and blood of 13 patients with cancer who developed irColitis (nine on anti-PD-1 or anti-CTLA-4 monotherapy and four on dual ICI therapy; most patients had skin or lung cancer), eight controls on ICI therapy and eight healthy controls. Patients with irColitis showed expanded mucosal Tregs, ITGAEHi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs and recirculating ITGB2Hi CD8 T cells. Cytotoxic GNLYHi CD4 T cells, recirculating ITGB2Hi CD8 T cells and endothelial cells expressing hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 therapy compared to anti-PD-1 therapy. Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption. Together, these data suggest roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and identify potential therapeutic targets for irColitis.

Tumor-immune metaphenotypes orchestrate an evolutionary bottleneck that promotes metabolic transformation.

Metabolism plays a complex role in the evolution of cancerous tumors, including inducing a multifaceted effect on the immune system to aid immune escape. Immune escape is, by definition, a collective phenomenon by requiring the presence of two cell types interacting in close proximity: tumor and immune. The microenvironmental context of these interactions is influenced by the dynamic process of blood vessel growth and remodelling, creating heterogeneous patches of well-vascularized tumor or acidic niches. Here, we present a multiscale mathematical model that captures the phenotypic, vascular, microenvironmental, and spatial heterogeneity which shapes acid-mediated invasion and immune escape over a biologically-realistic time scale. The model explores several immune escape mechanisms such as i) acid inactivation of immune cells, ii) competition for glucose, and iii) inhibitory immune checkpoint receptor expression (PD-L1). We also explore the efficacy of anti-PD-L1 and sodium bicarbonate buffer agents for treatment. To aid in understanding immune escape as a collective cellular phenomenon, we define immune escape in the context of six collective phenotypes (termed "meta-phenotypes"): Self-Acidify, Mooch Acid, PD-L1 Attack, Mooch PD-L1, Proliferate Fast, and Starve Glucose. Fomenting a stronger immune response leads to initial benefits (additional cytotoxicity), but this advantage is offset by increased cell turnover that leads to accelerated evolution and the emergence of aggressive phenotypes. This creates a bimodal therapy landscape: either the immune system should be maximized for complete cure, or kept in check to avoid rapid evolution of invasive cells. These constraints are dependent on heterogeneity in vascular context, microenvironmental acidification, and the strength of immune response. This model helps to untangle the key constraints on evolutionary costs and benefits of three key phenotypic axes on tumor invasion and treatment: acid-resistance, glycolysis, and PD-L1 expression. The benefits of concomitant anti-PD-L1 and buffer treatments is a promising treatment strategy to limit the adverse effects of immune escape.

An Inflammatory Biomarker Signature Reproducibly Predicts CAR-T Treatment Failure in Patients with Aggressive Lymphoma across the Zuma Trials Cohorts

Background: Disease progression and relapse remain significant challenges to chimeric antigen receptor (CAR)-T cell therapy in relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Using an unsupervised machine learning approach applied to pre-infusion labs and cytokines assessing organ function and inflammation, we previously identified unique signatures (inflammatory vs. non-inflammatory clusters). The inflammatory cluster was enriched for patients with elevated inflammatory markers, increased cell turnover, or end-organ sequelae of inflammation (e.g., hepatitis, bone marrow suppression) and was strongly associated with CAR-T treatment failure in the clinical setting (Raj S et al. ASH 2022). Methods: Here, we validated the model, named InflaMix, and evaluated its utility in a large cohort of patients with LBCL (n=352) treated with axicabtagene ciloleucel (axi-cel) as part of the ZUMA-1 (NCT02348216; n=182, 52%) and ZUMA-7 (NCT03391466; n=170, 48%) registrational studies. InflaMix was applied using 14 pre-infusion, day 0 laboratory and cytokine (hemoglobin, platelets, white blood cells, CRP, ferritin, IL-6, IL-10, TNF∝, d-dimer, aspartate transaminase, alkaline phosphatase, total bilirubin, LDH, albumin) measurements. Results: InflaMix assigned 46 % and 30% of patients to the inflammatory cluster in the ZUMA-1 and ZUMA-7 cohorts, respectively. Patients in the inflammatory clusters were more likely to have had more prior lines of therapy and higher baseline LDH than those in the non-inflammatory clusters ( p < 0.001). Assignment to the inflammatory cluster vs. non-inflammatory cluster was significantly associated with an increased risk of not achieving complete response (CR) by day 100 across both ZUMA-1 (odds ratio [OR] 1.68 [95% confidence interval (CI) 1.31 to 2.64) and ZUMA-7 (OR 1.57 [95% CI 1.25 to 2.53]) cohorts ( Figure A). Importantly, the inflammatory cluster was also significantly associated with inferior overall survival compared with the non-inflammatory cluster ( Figure B) in ZUMA-1 and ZUMA-7 (hazard ratio [HR] 1.65 [95% CI 1.38 to 2.14] and HR1.75 [95% CI 1.39 to 2.59], respectively), as well as decreased progression-free survival in ZUMA-1. All analyses were adjusted for age, pre-lymphodepletion LDH as a surrogate for baseline disease burden, and history of primary refractory disease, and adjustment for prophylactic steroid treatment in the ZUMA-1 cohort; prophylactic steroids were administered immediately before and after infusion in sub-cohort 6 of ZUMA-1. Conclusion: InflaMix identifies a unique inflammatory biomarker signature that can be derived using a simple blood draw prior to CAR-T infusion. We show that the signature reproducibly stratifies patients with LBCL by risk for CAR-T treatment failure and inferior survival is valid in patients treated with axi-cel as second-line treatment or later. Potential clinical applications of InflaMix include prognostication and informed design of clinical trials to target high-risk populations.

PO-03-238 CARDIAC ARRHYTHMIA IN THE PATIENT ON RITUXIMAB. A PHARMACOVIGILANCE STUDY FROM 2010-2022 FAERS DATABASE

Rituximab is a commonly used monoclonal antibody in most hematological diseases. Cardiac arrhythmia is one of the most common causes of morbidity and mortality in a hematological patient, given the increased cell turnover and electrolyte imbalance, especially after the treatment. Therefore, we explore potential arrhythmic complications related to the most commonly used drug. Given the high risk of cardiac complications in the age group between 65 and 85, we sought to study Rituximab’s arrhythmic complications and outcomes in this patient population. We conducted a retrospective analysis of all reported cases of arrhythmic complication in patients using Rituximab, utilizing data reported to the FDA and registered in the FDA Adverse Event Reporting System (FAERS) database over the past 12 years. We included patients between the 65 to 85 age group; these cases were identified and classified using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. A total of 28,595 patients aged 65 to 85 were reported to use Rituximab from 2010 to 2022. Among 2797 patients with cardiac complications, 31% (n=883) developed cardiac arrhythmias. 70% (n=619) of the reported cases were hospitalized, and 24% (n=149) died. Most deaths were in males, 60% (n=88) Fig.2. Commonly reported arrhythmia is shown in Fig1. The most frequently reported arrhythmia was atrial fibrillation at 72% (n=635), with a mortality rate of 16%. Furthermore, even incidence of ventricular arrhythmia was low at 6% (n=50), the mortality rate was high at 36%. Despite the relatively lower number (3%) of the total reported cases, the development of arrhythmia in patients using Rituximab was associated with increased hospitalization and mortality. Physicians should be aware of cardiological and rhythmic disorders for a commonly used medication like Rituximab. This might help with the early reorganization of the arrhythmia and finally improve the overall outcomes.

Progesterone and Estrogen Receptors in Meningiomas – A Clinicopathological Analysis

Background – Meningiomas are common tumors of the Central Nervous System. Recurrence in meningiomas has been proven to be associated with factors like extent of resection and grade of tumor. Decrease in progesterone receptor expression has been linked to increased rate of recurrence. We undertook this study to know about progesterone and estrogen receptor expression in meningiomas and its association with different clinicopathological variables as data is lacking in the Indian population.
 Materials and Methods – Meningiomas operated in a tertiary referral centre of North Kerala, India in 2 years were taken into the study. The tumors were graded and immunohistochemistry was performed using antibodies to Estrogen and progesterone receptors (ER&PR) and Ki-67. The expression of PR and ER was correlated with clinicopathologic variables. The patients were followed up for 2 years.
 Results – Grade I and grade II tumors constituted 85.3% and 14.7% respectively of the total number of meningioma cases. There were no grade III tumors in the series. The average PR positivity in grade I tumors (60.77%) was higher than in grade II tumors (46.88%). There was no gender related difference in PR staining. ER positivity was found only in a few cases.
 Conclusion – PR deterioration was associated with increased cell turnover. Meningiomas occurring in this study population are similar in clinicopathological parameters to those tumors occurring in other parts of the country but different in some aspects like grade from tumors occurring in other parts of the world. Strict follow up of a larger cohort of patients for a longer time period will be required to draw conclusions about prognosis in this population.

Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory Tcells.

The cytokine interleukin-23 (IL-23) is involved in the pathogenesis of inflammatory and autoimmune conditions including inflammatory bowel disease (IBD). IL23R is enriched in intestinal Tregs, yet whether IL-23 modulates intestinal Tregs remains unknown. Here, investigating IL-23R signaling in Tregs specifically, we show that colonic Tregs highly express Il23r compared with Tregs from other compartments and their frequency is reduced upon IL-23 administration and impairs Treg suppressive function. Similarly, colonic Treg frequency is increased in mice lacking Il23r specifically in Tregs and exhibits a competitive advantage over IL-23R-sufficient Tregs during inflammation. Finally, IL-23 antagonizes liver X receptor pathway, cellular cholesterol transporter Abca1, and increases Treg apoptosis. Our results show that IL-23R signaling regulates intestinal Tregs by increasing cell turnover, antagonizing suppression, and decreasing cholesterol efflux. These results suggest that IL-23 negatively regulates Tregs in the intestine with potential implications for promoting chronic inflammation in patients with IBD.

Rac1 controls cell turnover and reversibility of the involution process in postpartum mammary glands.

Cell turnover in adult tissues is essential for maintaining tissue homeostasis over a life span and for inducing the morphological changes associated with the reproductive cycle. However, the underlying mechanisms that coordinate the balance of cell death and proliferation remain unsolved. Using the mammary gland, we have discovered that Rac1 acts as a nexus to control cell turnover. Postlactational tissue regression is characterised by the death of milk secreting alveoli, but the process is reversible within the first 48 h if feeding recommences. In mice lacking epithelial Rac1, alveolar regression was delayed. This defect did not result from failed cell death but rather increased cell turnover. Fitter progenitor cells inappropriately divided, regenerating the alveoli, but cell death also concomitantly accelerated. We discovered that progenitor cell hyperproliferation was linked to nonautonomous effects of Rac1 deletion on the macrophageal niche with heightened inflammation. Moreover, loss of Rac1 impaired cell death with autophagy but switched the cell death route to apoptosis. Finally, mammary gland reversibility failed in the absence of Rac1 as the alveoli failed to recommence lactation upon resuckling.

Asymmetric mucosal structure, mesenteric versus antimesenteric, in mouse, rat, and human small intestines.

The morphology of the small intestinal mucosa is reflected by the degree of stimuli. Previous studies have come to different conclusion about whether the mucosa is equally symmetrical. The aim of the study is to investigate whether there are structural differences in the mesenteric versus antimesenteric mucosa in mice, rats, and humans. Jejunal biopsies from mice and rats were saved. Samples from human small intestine were obtained from patients undergoing Roux-en-Y gastric bypass surgery. Fixed samples were used to morphologically evaluate villus height and enlargement factor due to villi. The number of goblet cells, mast cells, enteroendocrine cells, and Paneth cells were histologically analyzed in the villus structure. Cell turnover was analyzed by Ki-67 staining. There was a significant increased villi height and villus enlargement factor antimesenterically in mice, rats, and human small intestines. The distribution of goblet cells, mast cells, and Paneth cells were equal while the number of enteroendocrine cells was increased antimesenteric in the human samples. The crypt mitotic activity was almost 20% higher in the antimesenteric part of jejunum. In summary we found longer villi, greater surface enlargement, and increased number of enteroendocrine cells as well as increased cell turnover antimesenterically. These differences may be of importance in understanding normal gastrointestinal physiology in health and disease.

Tyre particle exposure affects the health of two key estuarine invertebrates

Tyre wear particles may be the largest source of microplastic to the natural environment, yet information on their biological impacts is inadequate. Two key estuarine invertebrates; the clam Scrobicularia plana and the ragworm Hediste diversicolor were exposed to 10% tyre particles in sediment for three days. Both species consumed the particles, although S. plana consumed 25x more than H. diversicolor (967 compared with 35 particles.g−1 wet weight, respectively). We then investigated the impact of 21 days exposure to different concentrations of tyre particles in estuarine sediments (0.2, 1, and 5% dry weight sediment) on aspects of the health of S. plana and H. diversicolor. Reductions in feeding and burial rates were observed for S. plana but not H. diversicolor, whilst both species showed a decrease in protein content in response to the greatest tyre particle concentration (5%), linked to an 18% decrease in energy reserves for H. diversicolor. Five percent tyre particle exposure led to an increase in total glutathione in the tissues of H. diversicolor, whilst lipid peroxidation decreased in the digestive glands of S. plana, possibly due to an increase in cell turnover. This study found that S. plana's health was impacted at lower concentrations than H. diversicolor, likely due to its consumption of large quantities of sediment. At the high exposure concentration (5%), the health of both invertebrates was impacted. This study did not separate the effects caused by the microplastic particles versus the effects of the chemical additives leaching from these particles, but our results do indicate that future studies should investigate effects in isolation and in combination, to determine the main drivers of toxicity.

Effects of a phthalate metabolite mixture on both normal and tumoral human prostate cells.

Phthalates represent a group of substances used in industry that have antiandrogenic activity and are found in different concentrations in human urine and plasma. More than 8 million tons of phthalates are used each year, predominantly as plasticizers in polyvinyl chloride (PVC) products. Phthalates are widely used in everyday consumer products and improperly discarded into the environment. Furthermore, in vivo studies carried out in our laboratory showed that a mixture of phthalates, equivalent to the mixture used in this study, deregulated the expression of genes and miRNAs associated with prostatic carcinogenic pathways. Thus, this study was designed to establish an in vitro model to assess pathways related to cell survival, proliferation, apoptosis, and biosynthesis of miRNAs, using both normal and tumoral prostatic epithelial cells exposed to an environmentally relevant mixture of phthalate metabolites. Tumor (LNCaP) and normal (PNT-2) prostatic epithelial cell lines were exposed for 24 and 72 h to vehicle control or the phthalate mixture. The selected metabolite mixture (1000 μmol/L) consisted of 36.7% monoethyl phthalate (MEP), 19.4% mono(2-ethylhexyl) phthalate (MEHP), 15.3% monobutyl phthalate (MBP), 10.2% monoisobutyl phthalate (MiBP), 10.2% monoisononyl phthalate (MiNP), and 8.2% monobenzyl phthalate (MBzP). Gene expression was performed by qRT-PCR and cell migratory potential was measured using cell migration assays. Our results showed that the mixture of phthalates increased cell turnover, oxidative stress, biosynthesis, and expression of miRNAs in LNCaP cells; thus, increasing their cellular expansive and migratory potential and modulating tumor behavior, making them possibly more aggressive. However, these effects were less pronounced in benign cells, demonstrating that, in the short term, benign cells are able to develop effective mechanisms or more resistance against the insult.

Late Presentation of Xeroderma Pigmentosa With Squamous Cell Carcinoma in Septic Shock: Report of a Rare Case

Xeroderma pigmentosum (XP) is a rare autosomal recessive pathology affecting nucleotide excision repair against ultraviolet radiation. This leads to an increased predisposition to developing ophthalmological, neurological, and cutaneous conditions with an increased cell turnover. This case reports a late presentation of XP presenting with metastatic squamous cell carcinoma (SCC) and septic shock in an eight-year-old Indian male. Emergency management with IV fluid boluses and broad-spectrum antibiotics showed no improvement in vitals. Urgent surgical debridement and tumor debulking failed to improve laboratory values. Postoperative leukocytosis with fever spikes warranted the need to transfer the patient to a super-specialty oncology unit. Such an adverse presentation is commonly seen in XP-related invasive squamous cell carcinoma. Preventive management requires early identification and a multidisciplinary approach involving dermatologists, ophthalmologists, and surgeons. Late presentations revolve around control of the disease process by sharp debridement and chemotherapy with regular surveillance as the lesions tend to reoccur even after excision and chemotherapy.

Metabolic changes in the cingulate gyrus, precuneus, and white matter in anorexia nervosa using multivoxel MR spectroscopy.

Background and PurposeThis study aimed to highlight anorexia nervosa‐related metabolic changes in different brain regions with different gray and white matter contents.MethodsIn a prospective study, 25 anorexic patients with mean body mass index (BMI) of 14.79 kg/m2 (range 10.04–20.58) were compared with 15 healthy controls with mean BMI of 21.08 kg/m2 (range 18.36–27.34). Two‐dimensional magnetic resonance spectroscopic imaging was acquired in the axial plane above the corpus callosum, including frontal, precentral, postcentral, cingular, and parietal regions, as well as the precuneus, each voxel containing gray and white matter.ResultsIn the anorexic group, a significant increase of choline/creatine was observed in all brain regions except the precuneus: frontal (p = 0.009), cingulate (p = 0.001), precentral (p = 0.001), postcentral (p = 0.001), and parietal (p = 0.002); and in white and gray matter (p< 0.001). Macromolecules09/creatine was decreased in the following regions: frontal (p = 0.003), cingulate (p< 0.001), precentral (p = 0.004), and precuneus (p = 0.007), and in white and gray matter (p< 0.05). We observed significantly lower values of N‐acetyl aspartate/creatine in the frontal (p < 0.001) and precentral (p< 0.001) regions and in voxels containing more than 50% white matter (p = 0.001); and significantly lower values of myo‐inositol/creatine in the precentral (p = 0.006), postcentral (p< 0.001), and precuneus (p = 0.006) regions.ConclusionsWe observed an increase in choline/creatine in anorexics, possibly reflecting increased cell turnover; a decrease in macromolecules, which was particularly low in the cingulate and precuneus the former being known to be altered in eating disorders; and a decrease in N‐acetyl aspartate/creatine considered as a marker of neuronal density and function.

26279 In vitro efficacy of a topical formulation containing peptides and vitamin C developed for skin ageing

Introduction: Peptide-C (PC) contains a biocomplex of peptides, 10% of vitamin C, hyaluronic acid and Vichy volcanic mineralizing water. Due to its low pH, it does not require any preservatives and allows for an optimized bioavailability of vitamin C in a minimalist formulation. Clinical studies demonstrated its efficacy in increasing cell turnover and in decreasing the number of facial wrinkles, while improving skin radiance.

Monocyte M1/M2 profile is altered in paediatric burn patients with hypertrophic scarring

Hypertrophic scars (HTS) remain a common outcome of burn injury, particularly in children. They can arise from variations in the wound healing stages, such as an excessive inflammatory response or inefficient remodelling. Of the cells contributing to these healing stages, macrophages and fibrocytes are crucial. Specifically, the inflammatory phase is dominated by M1 macrophages, the proliferation/remodelling stages by M2 macrophages, and scar tissue contains numerous fibrocytes. As the progenitors to these cells, monocytes, can also exhibit M1- and M2-skewing, we proposed that their profile, or circulating fibrocyte counts, could be used to predict poor healing outcomes. To investigate this, we obtained blood samples from paediatric controls and burns patients, which were then divided into HTS and NoHTS groups upon scar assessment at 12 months. The samples were assessed by whole blood flow cytometry to quantify fibrocytes and monocyte subset proportions and to determine monocyte levels of M1 (CD86, CD120b, CD319) and M2 (CD93, CD163, CD200R) markers. Both burns groups had higher proportions of classical monocytes compared to controls, indicating increased cell turnover and/or entry of other subsets into the wound. In burns patients who took more than 21 days to heal, the HTS group had lower M2 (CD200R) expression with the ratio of M1/M2 (CD86/CD200R) being significantly higher. These results suggest an elevated early inflammatory monocyte response contributes to development of HTS. Correlations of marker expression with remaining healing time revealed a significant positive correlation with M1 (CD120b) and M1/M2 (CD120b/CD200R), suggesting a potential role for CD120b as an indicator of healing delay. Fibrocytes did not significantly differ between the groups. In conclusion, increased monocyte inflammation likely contributes to slower healing and development of scarring, but further studies are needed to determine the predictive power of monocyte inflammatory profile.

Increased Mortality Associated with Hypermagnesemia in Severe COVID-19 Illness.

Although electrolyte abnormalities are common among patients with COVID-19, very little has been reported on magnesium homeostasis in these patients. Here we report the incidence of hypermagnesemia, and its association with outcomes among patients admitted with COVID-19. We retrospectively identified all patients with a positive test result for SARS-CoV-2 who were admitted to a large quaternary care center in New York City in spring 2020. Details of the patients' demographics and hospital course were obtained retrospectively from medical records. Patients were defined as having hypermagnesemia if their median magnesium over the course of their hospitalization was >2.4 mg/dl. A total of 1685 patients hospitalized with COVID-19 had their magnesium levels checked during their hospitalization, and were included in the final study cohort, among whom 355 (21%) had hypermagnesemia. Patients who were hypermagnesemic had a higher incidence of shock requiring pressors (35% vs 27%, P<0.01), respiratory failure requiring mechanical ventilation (28% vs 21%, P=0.01), AKI (65% vs 50%, P<0.001), and AKI severe enough to require renal replacement therapy (18% vs 5%, P<0.001). In an adjusted multivariable model, hypermagnesemia was observed more commonly with increasing age, male sex, AKI requiring RRT, hyperkalemia, and higher CPK. Survival probability at 30 days was 34% for the patients with hypermagnesemia, compared with 65% for patients without hypermagnesemia. An adjusted multivariable time to event analysis identified an increased risk of mortality with older age, need for vasopressors, higher C-reactive protein levels, and hypermagnesemia (HR, 2.03; 95% CI, 1.63 to 2.54, P<0.001). In conclusion, we identified an association between hypermagnesemia among patients hospitalized with COVID-19 and increased mortality. Although the exact mechanism of this relationship remains unclear, hypermagnesemia potentially represents increased cell turnover and higher severity of illness, which is frequently associated with more severe forms of AKI.

Topical treatment of pigmentation disorders with cosmetic and pharmaceutical agents

Esthetically unattractive hyperpigmentation can occur post-inflammatory or as aresult of genetic or hormonal influences, UV exposure or medication. Important parameters for the quality of topical treatments are evidence-based invivo and invitro efficacy as well as scientifically verified wanted and unwanted effects. This paper will present cosmetic and pharmaceutical topical ingredients against hyperpigmentation that have been proven in scientific studies. Asearch of PubMed database was performed in October 2020 using the various ingredient names, "melasma" and "hyperpigmentation." Two reviewers independently screened titles, leading to the selection of 30papers. Hydroquinone, atyrosinase inhibitor, has been used for over 40years to treat hyperpigmentation. It is the most commonly studied agent for lightening pigment. Despite the limited evidence-based research on novel treatment approaches, several ingredients did show efficacy as depigmenting agents, including tyrosinase inhibitors, substances that increase cell turnover, and plant derivatives. Hydroquinone is still the gold standard for the treatment of hyperpigmentation, along with the triple therapy of hydrochinon, tretinoin, and steroids in different modifications. In summary, hyperpigmentation is best treated using acombination therapy of different approaches that includes consequent UV protection.

O15 Recognition of subclinical macrophage activation syndrome in an adolescent systemic juvenile idiopathic arthritis patient receiving tocilizumab: a case report

O15 Recognition of subclinical macrophage activation syndrome in an adolescent systemic juvenile idiopathic arthritis patient receiving tocilizumab: a case report