tbuckley/cabot-search huggingface dataset:
Comparing Data from Three Satellites on Artificial Light at Night (ALAN): Focusing on Blue Light’s Influence on Colorectal Cancer in a Case–Control Study in Spain
Authors: Barbara N. Harding, Anna Palomar-Cros, Antonia Valentín, Ana Espinosa, Alejandro Sánchez de Miguel, Gemma Castaño-Vinyals, Marina Pollán, Beatriz Perez, Victor Moreno, Manolis Kogevinas
Journal: Environmental Health Perspectives (2024)
Fellows’ Corner
Authors: Robert M. Wilechansky
Journal: Hepatology (2024)

1Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA 2Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA Abbreviations: CTI, continuous terlipressin infusion; HGS, hand-grip strength; LT, liver transplant; MELD, Model for End-Stage Liver Disease; NGF, nasogastric feeding; RCT, randomized controlled trial; TXA, tranexamic acid. Correspondence Robert M. Wilechansky, Massachusetts General Hospital, 15 Parkman St., Wang 5, Boston, MA 02114, USA. Email: [email protected]
Elevating Platinum to Volumetric Capacitance: High Surface Area Electrodes through reactive Pt sputtering
Authors: Maciej Gryszel, Marie Jakešová, Xuan Thang Vu, Sven Ingebrandt, Eric Daniel Głowacki
Journal: Advanced Healthcare Materials (2024)

Platinum is the most widespread electrode material used for implantable biomedical and neuroelectronic devices, motivating exploring ways to improve its performance and understand its fundamental properties. Using reactive magnetron sputtering, PtO
Prolonged use of nomegestrol acetate and risk of intracranial meningioma: a population-based cohort study
Authors: Pierre Nguyen, Noémie Roland, Anke Neumann, Léa Hoisnard, Thibault Passeri, Lise Duranteau, Joël Coste, Sébastien Froelich, Mahmoud Zureik, Alain Weill
Journal: The Lancet Regional Health - Europe (2024)

Nomegestrol acetate (NOMAC) is a synthetic potent progestogen. This study aimed to assess the risk of intracranial meningioma associated with the prolonged use of NOMAC.
Specialist physiotherapy for functional motor disorder in England and Scotland (Physio4FMD): a pragmatic, multicentre, phase 3 randomised controlled trial
Authors: Glenn Nielsen, Jon Stone, Teresa C Lee, Laura H Goldstein, Louise Marston, Rachael Maree Hunter, Alan Carson, Kate Holt, Jon Marsden, Marie Le Novere, Irwin Nazareth, Hayley Noble, Markus Reuber, Ann-Marie Strudwick, Beatriz Santana Suarez, Mark J Edwards
Journal: The Lancet Neurology (2024)
Breaking down causes, consequences, and mediating effects of telomere length variation on human health
Authors: Samuel Moix, Marie C Sadler, Zoltán Kutalik, Chiara Auwerx
Journal: Genome biology (2024)

Abstract Background Telomeres form repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Yet, factors modulating telomere attrition and the health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants of European ancestry. Results Using linear regression and bidirectional univariable and multivariable Mendelian randomization (MR), we elucidate the relationships between leukocyte telomere length (LTL) and 142 complex traits, including diseases, biomarkers, and lifestyle factors. We confirm that telomeres shorten with age and show a stronger decline in males than in females, with these factors contributing to the majority of the 5.4% of LTL variance explained by the phenome. MR reveals 23 traits modulating LTL. Smoking cessation and high educational attainment associate with longer LTL, while weekly alcohol intake, body mass index, urate levels, and female reproductive events, such as childbirth, associate with shorter LTL. We also identify 24 traits affected by LTL, with risk for cardiovascular, pulmonary, and some autoimmune diseases being increased by short LTL, while longer LTL increased risk for other autoimmune conditions and cancers. Through multivariable MR, we show that LTL may partially mediate the impact of educational attainment, body mass index, and female age at childbirth on proxied lifespan. Conclusions Our study sheds light on the modulators, consequences, and the mediatory role of telomeres, portraying an intricate relationship between LTL, diseases, lifestyle, and socio-economic factors.
Emerging targets in lipid metabolism for cancer therapy
Authors: Alexander R. Terry, Nissim Hay
Journal: Trends in Pharmacological Sciences (2024)

Cancer cells perturb lipid metabolic pathways for a variety of pro-tumorigenic functions, and deregulated cellular metabolism is a hallmark of cancer cells. Although alterations in lipid metabolism in cancer cells have been appreciated for over 20 years, there are no FDA-approved cancer treatments that target lipid-related pathways. Recent advances pertaining to cancer cell fatty acid synthesis (FAS), desaturation, and uptake, microenvironmental and dietary lipids, and lipid metabolism of tumor-infiltrating immune cells have illuminated promising clinical applications for targeting lipid metabolism. This review highlights emerging pathways and targets for tumor lipid metabolism that may soon impact clinical treatment.
Dynamic microphysiological system chip platform for high-throughput, customizable, and multi-dimensional drug screening
Authors: Yuxuan Zhu, Deming Jiang, Yong Qiu, Xin Liu, Yuhan Bian, Shichao Tian, Xiandi Wang, K. Jimmy Hsia, Hao Wan, Liujing Zhuang, Ping Wang
Journal: Bioactive Materials (2024)

Spheroids and organoids have attracted significant attention as innovative models for disease modeling and drug screening. By employing diverse types of spheroids or organoids, it is feasible to establish microphysiological systems that enhance the precision of disease modeling and offer more dependable and comprehensive drug screening. High-throughput microphysiological systems that support optional, parallel testing of multiple drugs have promising applications in personalized medical treatment and drug research. However, establishing such a system is highly challenging and requires a multidisciplinary approach. This study introduces a dynamic Microphysiological System Chip Platform (MSCP) with multiple functional microstructures that encompass the mentioned advantages. We developed a high-throughput lung cancer spheroids model and an intestine-liver-heart-lung cancer microphysiological system for conducting parallel testing on four anti-lung cancer drugs, demonstrating the feasibility of the MSCP. This microphysiological system combines microscale and macroscale biomimetics to enable a comprehensive assessment of drug efficacy and side effects. Moreover, the microphysiological system enables evaluation of the real pharmacological effect of drug molecules reaching the target lesion after absorption by normal organs through fluid-based physiological communication. The MSCP could serves as a valuable platform for microphysiological system research, making significant contributions to disease modeling, drug development, and personalized medical treatment.
P37 Drug repurposing for treatment of recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma
Authors: John Pritchard, Jasbani Dayal, Christina Schoenherr, Michela Raponi, Jayanthi Anand, Lynn McGarry, Ryan Corbyn, Leo Carlin, Karen Blyth, Gareth Inman
Journal: British Journal of Dermatology (2024)

Abstract Background Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disorder that leads to severe wounding and blistering of the skin. Patients with RDEB develop aggressive cutaneous squamous cell carcinoma (cSCC) with a mortality rate of approximately 90% by age 55 years. The current primary treatment is wide excision of tumours, often leading to amputations. Identifying new therapeutic avenues for RDEB cSCC remains a priority. Here, we approach this in two ways. Firstly, we identified a SMAD4-dependent sphingosine pathway response to endogenous transforming growth factor (TGF)-β, essential for RDEB cSCC proliferation which could be targeted as a potential therapeutic strategy. Secondly, we utilized a US Food and Drug Administration (FDA) screen of &amp;gt; 3000 drugs to identify potential druggable pathways that could be used to treat RDEB cSCC. Methods RDEB cSCC cell lines were used to test Siponimod, a sphingosine-1 receptor modulator, on proliferation, clonogenicity and invasion in vitro. Siponimod was used in vivo to test tumour growth effect of targeting the sphingosine pathway. We carried out an FDA-approved drug screen on four RDEB cSCC cell lines using the Opera Phenix high-throughput microscope to identify targets. Results Treatment of RDEB cSCC cell lines with Siponimod showed compromised proliferation compared with untreated cells in addition to significant reduction in colony formation. There was a significant decrease in the invasive capability of RDEB SCC cells. Treatment of normal human keratinocytes showed no effect on proliferation. Our FDA-approved screen identified multiple drugs that target MEK, mechanistic target of rapamycin complex, histone deacetylase, signal transducer and activator of transcription, and topoisomerase I/II in the top 50 hits. The most common target was DNA damage/repair pathways, but cytoskeletal signalling, transmembrane transporters and proteases were identified as other potential avenues for treatment of RDEB cSCC. Conclusions There is an unmet need for therapeutic options in RDEB cSCC. Here, we have demonstrated the potential of repurposing previously licensed drugs to identify treatment avenues for RDEB cSCC.
P36 Environmental triggers of psoriasis and relationship to disease severity: insights from the mySkin study
Authors: Madeline Kroah-Hartman, Niamh Dooley, Maaike Mineur, William Tan, Jade Pizzato, Freya Jackson-Duffy, Kingsley Powell, Georgia Sewell, Camille Lancelot, Lucy Moorhead, Helen McAteer, Bola Coker, John Weinman, Jonathan Barker, Sarah Chapman, Sam Norton, Cathrine Smith, Satveer Mahil
Journal: British Journal of Dermatology (2024)

Abstract Introduction and aims Psoriasis is a common debilitating inflammatory skin condition with an established genetic basis. Despite a wealth of genetic research on psoriasis susceptibility, epidemiological studies characterizing environmental triggers of disease onset are limited. Our aim is to identify self-reported triggers of psoriasis onset, and investigate the relationship between triggers and subsequent disease severity. Methods Self-reported data from people with a clinician-confirmed diagnosis of psoriasis were collected through the online mySkin survey. mySkin was launched UK-wide in June 2023 and all surveys completed by 6 December 2023 were analysed. Measures of disease severity at the time of survey completion included Patient Global Assessment and Dermatology Life Quality Index. The association between triggers of psoriasis onset and disease severity was analysed using one-way Anova tests. Results Of 529 participants, 93.4% were of White ethnicity, 64.8% were female and their average age was 51.1 years. Overall, 49.9% reported a family history of psoriasis and 55% (n = 289) of participants reported at least 1 trigger of psoriasis onset. Of those who reported a trigger, the most commonly reported trigger was stress (n = 167, 57.8%), followed by infection (n = 85, 29.4%) and low mood (n = 23, 7.9%). For participants who selected multiple triggers, there was considerable coselection of stress, low mood, climate (pollution, weather) and lifestyle (weight gain, alcohol, smoking) factors. A greater proportion of participants with a family history of psoriasis reported climate and hormonal (pregnancy, childbirth, menopause) triggers of psoriasis onset, compared with those without a family history (73% vs. 26% and 69% vs. 31%, respectively). There was no significant association between triggers of psoriasis onset and disease severity (P = 0.76). Conclusions These self-reported data highlight the importance of stress in psoriasis onset. The co-occurrence of different triggers, including in those with vs. without a family history of psoriasis, underscores the complex aetiology of psoriasis. Further characterization of gene–environment interactions is warranted.
P31 Modelling epidermal melanocytes behaviour during plaque psoriasis resolution
Authors: Sarah Lussoso, Brian Kirby, Desmond Tobin
Journal: British Journal of Dermatology (2024)

Abstract Introduction and aims Melanocytes in the human epidermis exist in the stratum basale at a ratio of 1 melanocyte to approximately 10 keratinocytes. They do not divide, even upon ultraviolet radiation stimulation, and do not appear to apoptose. In psoriasis, this melanocyte/keratinocyte ratio is retained, despite the enormous keratinocyte hyperplasia, inferring a commensurate expansion in melanocyte number. Therefore, here we investigate whether melanocyte number is altered following the reduction of keratinocytes upon treatment of psoriasis plaques with biologic therapy. Methods Matching lesional and nonlesional epidermis sets of patients (n = 4) at day 0 and after 4 and 12 weeks of treatment were compared with healthy controls. To assess the presence of apoptotic melanocytes, the terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay was performed. Immunohistochemistry with microphthalmia-associated transcription factor (melanocyte marker) and Ki-67 (proliferation marker) was used to assess melanocyte proliferation. Finally, melanocyte number per mm of basal layer and melanocyte/keratinocyte ratio were estimated by image analysis using ImageJ. Results Proliferating melanocytes were detected in nonlesional and lesional samples and in resolving plaques after 4 and 12 weeks of treatment but not in healthy epidermis. Melanocyte number per mm of basal layer was significantly higher in nonlesional than lesional sections compared with healthy controls (P &amp;lt; 0.01) suggesting that melanocyte expansion already occurs prior to lesion establishment, revealing early melanocyte deregulation. After 4 and 12 weeks of treatment the number of melanocytes in lesional and nonlesional sections was still significantly higher than controls (P &amp;lt; 0.05) and had not returned to normal despite the dramatic reduction in keratinocytes. The TUNEL assay did not detect evidence of melanocyte apoptosis. Conclusions This study shows that rare melanocyte proliferation occurs in nonlesional psoriasis skin and in resolving lesional skin. Given our inability to detect apoptotic melanocytes, it remains unclear how melanocyte numbers return to normal after plaque resolution These unique findings support a role for melanocytes in psoriasis pathogenesis and encourage further investigation.
O07 Lower doses of retinol facilitate cell proliferation and epidermal thickening in photoaged skin
Authors: Bezaleel Mambwe, Eleanor Bradley, Mike Bell, Abigail Langton
Journal: British Journal of Dermatology (2024)

Abstract Introduction and aims Chronic exposure to solar ultraviolet radiation leads to cutaneous hypertrophic photoageing which clinically manifests as wrinkles, skin laxity and hyperpigmentation. This photoaged phenotype is underscored by a remodelled cutaneous microenvironment including epidermal thinning and rete ridge flattening. We have previously shown that cosmeceutical formulations of 0.3% and 1% retinol can effectively induce epidermal thickening and keratinocyte proliferation. However, these concentrations require careful usage to limit potential irritancy issues, highlighting a need to explore the benefits of lower dose retinol for daily skincare. Therefore, we compare the efficacy of lower doses of retinol in facilitating epidermal thickness and proliferation in photoaged skin, as this currently remains unknown. Methods Using the in vivo Manchester Patch Test Assay, test substances (vehicle and retinol at concentrations of 0.025%, 0.05%, 0.1% and 1%) were applied under occlusion to extensor forearms of healthy but photoaged volunteers (three men, three women; age range 66–86 years) for 12 days. Resultant skin biopsies were processed for histological assessment of epidermal thickness and keratinocyte proliferation. Results Epidermal thickness was significantly increased with 0.025% (P &amp;lt; 0.05), 0.05%, 0.1% and 1% (all P &amp;lt; 0.01) retinol treatment, compared with baseline or vehicle. Immunofluorescence staining of the proliferation marker Ki67 identified elevated keratinocyte proliferation following retinol treatment (P &amp;lt; 0.05 for 0.025%, 0.05% and 1%) compared with baseline. Although Ki67 expression in the 0.1% retinol treatment was elevated, significance was not achieved compared with baseline. However, compared with the vehicle, all retinol concentrations significantly increased Ki67 expression (P &amp;lt; 0.05). Clinically, 50% of volunteers showed an erythemal irritancy response to 1% retinol only. Conclusions We established that lower doses of retinol are capable of inducing keratinocyte proliferation and epidermal thickening without irritancy issues. Therefore, long-term effective treatment of photoaged skin with low-dose retinol products may be the preferred choice for individuals where retinol sensitivity has previously been an issue.
O03 Genetic impacts on the skin methylome
Authors: Christopher Shore, Sergio Villicaña Muñoz, Panos Deloukas, David Gunn, Veronique Bataille, Jordana Bell
Journal: British Journal of Dermatology (2024)

Abstract Introduction and aims DNA methylation at CpG dinucleotides is a dynamic epigenetic mechanism that has been linked to numerous skin phenotypes and diseases. Previous studies in blood show that a substantial proportion of the human DNA methylome exhibits evidence for genetic influence, and that 15–17% of narrow-sense methylation heritability is explained by genetic variants, or methylation quantitative trait loci (meQTLs). However, no genome-wide meQTL studies have previously been performed in skin. The primary purpose of this work was to identify the genetic basis of DNA methylation levels in whole skin. Methods Utilizing a twin-based heritability model, we estimated DNA methylation heritability using 414 bulk skin tissue samples from healthy older female twins from the TwinsUK cohort, profiled using the Illumina Infinium HumanMethylation450 BeadChip (Illumina, San Diego, CA, USA). We then integrated genomic data for 394 of these twins to perform genome-wide meQTL analyses. Finally, we integrated these meQTL Results with skin eQTL Results from an overlapping sample (N = 664). Results Over 8.2% of measured CpG sites showed evidence for strong heritability (h2 &amp;gt; 0.4), with a mean additive heritability estimate of 11.07% across all tested sites. We identified 76 442 CpG sites (18.8% of measured CpG sites) associated with a meQTL in cis (&amp;lt; 1 MB variant-CpG distance) and 1438 (0.35%) in trans. Both CpG sites under meQTL effects, and genetic variants underlying these meQTL effects in skin, are enriched in regions previously identified from genome-wide and epigenome-wide association studies for skin-related phenotypes, including psoriasis, melanoma and vitiligo. Additionally, some meQTLs influence gene expression via mediation of expression quantitative trait loci effects in skin, including in genes linked to melanoma and psoriasis. Conclusions Our study is the first genome-wide DNA methylation heritability and meQTL analysis of whole skin, giving insights into the regulatory landscape of epigenomic variation in skin.
P24 Folliculin silencing in human hair follicles <i>ex vivo</i> upregulates intrafollicular mechanistic target of rapamycin complex 1 activity: a new model for studying Birt–Hogg–Dubé syndrome
Authors: William Fostier, Kinga Linowiecka, Jérémy Chéret, Ralf Paus, Neil Rajan
Journal: British Journal of Dermatology (2024)

Abstract Introduction and aims Birt–Hogg–Dubé (BHD) syndrome is a rare multisystem disorder caused by germline pathogenic variants in the FLCN gene. BHD skin tumours predominantly affect facial skin, confer a significant psychosocial burden, and there is a lack of nonsurgical therapies. Here we report a novel ex vivo human model to study the impact of FLCN loss in human hair follicles (HFs), the putative origin of BHD skin tumours. Methods Organ-cultured human anagen HFs and scalp skin were treated with small interfering RNA targeting FLCN (n = 2 donors) for 6 days ex vivo, followed by quantitative real-time polymerase chain reaction (qRT-PCR), and quantitative immunohistomorphometry (qIHM). Results Successful FLCN knockdown was confirmed at both the mRNA (34% reduction compared with nontargeting control levels measured by qRT-PCR) and protein level (12% reduction in FLCN expression measured by qIHM). In FLCN-silenced HFs (n = 14, two donors), our preliminary Results demonstrated an increase in p-S6 expression, a direct downstream kinase of mechanistic target of rapamycin complex (mTORC)1 signalling. This was spatially restricted to the hair bulb and proximal outer root sheath keratinocytes, and was significantly greater than quantified in nontargeting control HFs (P &amp;lt; 0.05). Conclusions FLCN silencing in ex vivo cultured, healthy human HFs and scalp skin provides a novel, instructive and accessible preclinical research model. We aim to delineate whether FLCN interacts with the key endogenous inhibitor of mTORC1 activity, TSC2, in future work, to gain insight into the role of FLCN in the pathobiology of BHD and the maintenance of healthy human HFs.
O21 Raman spectroscopy for detection of squamous cell carcinoma in recessive dystrophic epidermolysis bullosa skin
Authors: Marija Dimitrievska, Ciro Chiappini, John McGrath, Mads S Bergholt
Journal: British Journal of Dermatology (2024)

Abstract Introduction and aims Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin disorder caused by biallelic pathogenic variants in COL7A1, which encodes type VII collagen (C7). Lack of C7 leads to blistering, chronic wounds, scarring and early onset of life-shortening squamous cell carcinomas (SCCs). Currently, the suspicion of SCC is mostly determined by clinical observation of visible changes in chronic wounds, and often requires multiple biopsies for histological diagnosis. This project aims to improve clinical care by developing a new noninvasive means of detecting SCC. To achieve this, we used Raman spectroscopy, a nondestructive analytical technique to study the changes occurring in RDEB skin when SCC is present, with the goal of creating a bedside test that can aid clinicians in the early diagnosis of SCC. Methods Raman spectroscopic imaging was performed on 7-µm frozen skin sections from RDEB (n = 3), RDEB SCC (n = 3) and normal skin (n = 3) to identify signalling changes between nonlesional and lesional states. An in-depth molecular composition analysis of the samples was performed using multivariate analysis with the goal of highlighting changes in abundance of specific molecules when SCC is present. Results For both nonmalignant and RDEB SCC skin sites we found specific Raman peaks associated with protein (1004 cm−1, 1650 cm−1) or lipids (1450 cm−1). RDEB SCC indicated a relative increase in DNA and protein. High-quality Raman spectroscopic images could be acquired that showed clear correlation with histological appearances. Current work is under way to determine which specific biological compounds contribute to the Raman spectra observed. Conclusions Raman spectroscopic imaging can provide comprehensive and noninvasive molecular tissue mapping with resolution comparable to histological sections, enabling molecular-based detection of SCC. Future work will focus on characterization of the SCC molecular profile, in addition to determining whether fibre optic Raman spectroscopy can be used to guide the biopsy/resection of RDEB lesions.