The study of cellular cytotoxicity of argireline® - an anti-aging peptide

Argireline® is well know, innovative anti-aging product used in the cosmetic market. This short chain peptide is used as active ingredient in dermal ointment and creams. Argireline® prevents formation of skin lines and wrinkles in a very similar way to the botulinum toxin (Botox), inhibiting neurotransmitter release at the neuromuscular junction. Argireline® does not require under skin muscle injections and it is believed to be relatively safe. However, despite the fact that some toxicity data has been provided by the product manufacturer, there is an evident lack of reliable information about cytotoxicity of argireline® in the literature. The aim of the presented study was to estimate the antiproliferation effect of argireline® solution in several concentrations. The influence of argireline® on cellular proliferation was examined against: human embryonic kidney HEK-293 cell line, human neuroblastoma IMR-32 cell line, and human primary skin fibroblasts. Tests were performed using formazan-based cell proliferation assay: EZ4U, which allows to measure the efficiency of mitochondrial oxidative activity in living cells. The argireline® inhibitory concentration, IC50 values were calculated and the results were compared to the IC50 value of the reference compound: doxorubicin. In conclusion, the considered method resulted in dose-dependent argireline® anti-proliferation effects. However, the significant cytotoxicity of argireline® solution was observed under 18 to 10 000 fold higher concentrations (depending on cells that were examined) in comparison to doxorubicin

The research landscape of tuberous sclerosis complex–associated neuropsychiatric disorders (TAND)—a comprehensive scoping review

Background Tuberous sclerosis complex (TSC)–associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed, under-treated and under-researched. We performed a comprehensive scoping review of all TAND research to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND research. Methods The study was conducted in accordance with stages outlined within the Arksey and O’Malley scoping review framework. Ten research questions relating to study characteristics, research design and research content of TAND levels and clusters were examined. Results Of the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal studies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in 2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults (16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA (89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low–middle income countries (LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non-pharmacological, and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the autism spectrum disorder–like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the least (53/200; 27%). Conclusions Despite the recent increase in TAND research, studies that represent participants across the lifespan, LMIC research sites and non-pharmacological interventions were identified as future priorities. The quality of cohort studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In human studies, the academic level in particular warrants further investigation. Remote technologies could help to address many of the TAND knowledge gaps identified

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Protein, peptide anti-wrinkle active ingredients

Argirelina jest heksapeptydem o sekwencji Ac-Glu-Glu-Met-Glu-Arg-Arg-NH2 zbudowanym z sześciu aminokwasów: kwasu glutaminowego, metioniny i argininy. Peptyd naśladuje działaniem toksynę botulinową. Wykazuje skuteczne działanie w zmniejszaniu głębokości zmarszczek mimicznych, dlatego też znalazł zastosowanie w kosmetologii. Badanie argireliny pod kątem toksyczności można przeprowadzić za pomocą testu cytotoksyczności MTS, oraz testu proliferacji komórek. Testy wykorzystują zdolność żywych komórek do redukcji bezbarwnej soli tetrazolowej do barwnego formazanu. Przeprowadzone badania eksperymentalne w teście MTS wykazały najwyższą cytotoksyczność roztworu argireliny na komórki embrionalne nerki HEK293 w stężeniu: 111 uM (a także w stężeniu: 167 uM, 250 uM i 375 uM). W zakresie stężeń od 15 uM do 74 uM zaobserwowano częściową cytotoksyczność. Brak cytotoksycznego działania stwierdzono w stężeniu argireliny: 10 uM. W teście proliferacji całkowite zahamowanie namnażania komórek zaobserwowano już w stężeniu: 111 uM ( a także w stężeniach: od 167 uM do 375 uM roztworu argireliny. Częściowe zahamowanie proliferacji zaobserwowano w zakresie stężeń: od 15 uM do 74 uM. Brak zahamowania namnażania komórek zaobserwowano w stężeniu: 10 uM.Argireline is a hexapeptide having the sequence Ac-Glu-Glu-Met-Glu-Arg-Arg-NH2 composed of six amino acids: glutamic acid, methionine and arginine. Peptide follows the action of botulinum toxin. The peptide demonstrated to have efficacy in reducing the depth of wrinkles, and therefore is used in cosmetology. Toxicity test of argireline was carried out in cytotoxicity MTS assay. Cell proliferation test was performed also for argireline The both tests used the ability of living cells to reduce the colorless tetrazolium salt to colored formazan. The study showed the highest cytotoxicity experiments on embryonic kidney HEK293 cells at a concentration of: 111 uM (as well as in 167 uM, 250 uM and 375 uM) argireline. In the concentration range of: 15 uM to 74 uM partial cytotoxicity was observed. No cytotoxic effects were found in concentration: 10 uM. In the proliferation assay, total inhibition of cell proliferation was observed at a concentration: 111 uM (and in concentrations from 167 uM to 375 uM). Partial inhibition of proliferation was observed in the concentration range from 15 uM to 74 uM. No inhibition of cell proliferation was observed at a concentration: 10 uM

International consensus recommendations for the identification and treatment of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND)

Abstract Background Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific. Methods The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community. Results At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to “screen” for TAND at least annually, to “act” using appropriate next steps for evaluation and treatment, and to “repeat” the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families. Conclusions The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a “TAND toolkit” of “what to seek” and “what to do” when difficulties are identified in TAND clusters

Empowering families through technology : a mobile-health project to reduce the TAND Identification and Treatment Gap (TANDem)

INTRODUCTION: Tuberous Sclerosis Complex (TSC) is a multi-system genetic disorder with various TSC-Associated Neuropsychiatric Disorders (TAND) that significantly impact the mental health and wellbeing of individuals with TSC and their caregivers. TAND represents the number one concern to families worldwide, yet is highly under-identified and under-treated. The clinician-administered TAND-Checklist (Lifetime version, TAND-L) has improved identification of TAND in clinical settings. However, many individuals with TSC and their caregivers still have difficulty accessing suitable support for diagnosis and evidence-informed interventions. The TANDem study is a community-based participatory research project with a broad range of TSC stakeholders aimed at reducing the TAND identification and treatment gap. OBJECTIVES: Participatory research identified three priority next steps: 1) development and validation of a self-report, quantified version of the TAND Checklist (TAND-SQ) and building the TAND-SQ into a smartphone application, 2) generation of consensus clinical recommendations for the identification and treatment of TAND, to be incorporated as a TAND toolkit on the app, and 3) establishment of a global TAND consortium through networking, capacity-building and public engagement activities. METHODS: TANDem is a four-year project, and includes 24 consortium members from 10 countries representing all World Health Organization regions. Collaborators represent five stakeholder groups (family representatives, technology experts, clinical experts, non-profit organisations and researchers). Here we outline the project study protocol in detail, describing the scientific rationale, the project aims and objectives, the methods involved in participant recruitment, multi-site and multi-phase data collection, data analysis, ethical considerations including informed consent, data protection, privacy and confidentiality considerations related to the European Union General Data Protection Regulation and the USA Health Insurance Portability and Accountability Act. The expected outcomes and potential impact on the TSC community, implementation and dissemination of results, as well as future scale-up and scale-out plans are also discussed. CONCLUSIONS: The TANDem project has the potential to transform the global TSC community by empowering families living with TSC through an easily accessible digital solution to allow them to document their own TAND needs linked to an evidence-informed toolkit to enhance personalised healthcare, and by providing healthcare professionals with consensus clinical recommendations to prevent, identify and manage TAND manifestations