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Curly textured hair presents unique diagnostic and therapeutic challenges because of its distinct properties. In the September issue of the Journal, we explore recent advancements in understanding and treating various hair disorders, focusing on the specific challenges and treatments for curly hair. We discuss whether glucagon-like peptide-1 agonists contribute to or alleviate hair loss and highlight a promising, innovative therapy using adipose stem cell-derived exosomes to promote hair growth. Additionally, we examine therapeutic options for managing filler-induced alopecia and treating folliculitis decalvans.
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Melanoma , Proteínas Proto-Oncogénicas B-raf , Humanos , Melanoma/genética , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Proteínas Proto-Oncogénicas B-raf/genética , Mutación , Mitocondrias/genética , Masculino , Femenino , Persona de Mediana Edad , Metástasis de la Neoplasia/genéticaRESUMEN
Introduction: While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Methods: Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Results: Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Discussion: Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.
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Artificial intelligence (AI) is revolutionizing dermatology by enhancing diagnostic accuracy and offering personalized treatment recommendations based on individual patient characteristics and medical history. This month's editorial discusses the transformative role of AI in dermatology, emphasizing its potential to enhance diagnostic accuracy, personalize treatment, and improve healthcare delivery efficiency. It highlights three manuscripts addressing AI's applications in dermatopathology, climate change-related skin disorders, and health care for undocumented immigrants. Ethical concerns, such as AI transparency and overdiagnosis, are also noted. Additionally, new treatments for atopic dermatitis (AD) are examined. We specifically recommend two recent reports on the efficacy of dupilumab in pediatric AD and refractory hand eczema (HE), demonstrating advancements in dermatological therapy for treatment-resistant conditions.
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The skin-brain axis has been suggested to play a role in several pathophysiological conditions, including opioid addiction, Parkinson's disease and many others. Recent evidence suggests that pathways regulating skin pigmentation may directly and indirectly regulate behaviour. Conversely, CNS-driven neural and hormonal responses have been demonstrated to regulate pigmentation, e.g., under stress. Additionally, due to the shared neuroectodermal origins of the melanocytes and neurons in the CNS, certain CNS diseases may be linked to pigmentation-related changes due to common regulators, e.g., MC1R variations. Furthermore, the HPA analogue of the skin connects skin pigmentation to the endocrine system, thereby allowing the skin to index possible hormonal abnormalities visibly. In this review, insight is provided into skin pigment production and neuromelanin synthesis in the brain and recent findings are summarised on how signalling pathways in the skin, with a particular focus on pigmentation, are interconnected with the central nervous system. Thus, this review may supply a better understanding of the mechanism of several skin-brain associations in health and disease.
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Encéfalo , Pigmentación de la Piel , Piel , Rayos Ultravioleta , Humanos , Pigmentación de la Piel/efectos de la radiación , Encéfalo/metabolismo , Animales , Piel/metabolismo , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Melaninas/metabolismo , Melaninas/biosíntesis , Transducción de Señal , ConductaRESUMEN
Vitamin D receptor (VDR) has been implicated in fatty liver pathogenesis, but its role in the regulation of organismal energy usage remains unclear. Here, we illuminate the evolutionary function of VDR by demonstrating that zebrafish Vdr coordinates hepatic and organismal energy homeostasis through antagonistic regulation of nutrient storage and tissue growth. Hepatocyte-specific Vdr impairment increases hepatic lipid storage, partially through acsl4a induction, while simultaneously diminishing fatty acid oxidation and liver growth. Importantly, Vdr impairment exacerbates the starvation-induced hepatic storage of systemic fatty acids, indicating that loss of Vdr signaling elicits hepatocellular energy deficiency. Strikingly, hepatocyte Vdr impairment diminishes diet-induced systemic growth while increasing hepatic and visceral fat in adult fish, revealing that hepatic Vdr signaling is required for complete adaptation to food availability. These data establish hepatocyte Vdr as a regulator of organismal energy expenditure and define an evolutionary function for VDR as a transcriptional effector of environmental nutrient supply.
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Metabolismo Energético , Hepatocitos , Receptores de Calcitriol , Pez Cebra , Animales , Pez Cebra/metabolismo , Receptores de Calcitriol/metabolismo , Hepatocitos/metabolismo , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Hígado/metabolismo , Nutrientes/metabolismo , Transducción de Señal , Metabolismo de los Lípidos , Homeostasis , Ácidos Grasos/metabolismoRESUMEN
While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making.
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Pancreatic cancer (PC) poses a substantial global health challenge, ranking as the fourth leading cause of cancer-related deaths due to its high mortality rate. Late-stage diagnoses are common due to the absence of specific symptoms. Pancreatic ductal adenocarcinoma (PDAC) accounts for the majority of PC cases. Recent research has suggested a potential link between elevated serum levels of bile acids (BAs) and tumorigenesis of PDAC. This study aims to understand how taurochenodeoxycholic acid (TCDCA), a secondary BA, influences PDAC using RNA sequencing techniques on the Capan-1 cell line. We identified 2,950 differentially expressed genes (DEGs) following TCDCA treatment, with 1,597 upregulated and 1,353 downregulated genes. These DEGs were associated with critical PDAC pathways, including coagulation, angiogenesis, cell migration, and signaling regulation. Furthermore, we reviewed relevant literature highlighting genes like DKK-1, KRT80, UPLA, and SerpinB2, known for their roles in PDAC tumorigenesis and metastasis. Our study sheds light on the complex relationship between BAs and PDAC, offering insights into potential diagnostic markers and therapeutic targets. Further research is needed to unravel these findings' precise mechanisms and clinical implications, potentially improving PDAC diagnosis and treatment.
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Carcinoma Ductal Pancreático , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas , Ácido Tauroquenodesoxicólico , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ácido Tauroquenodesoxicólico/farmacología , Carcinoma Ductal Pancreático/genética , Análisis de Secuencia de ARN , Movimiento Celular/efectos de los fármacosRESUMEN
Introduction: Adipose tissue-derived mesenchymal stem cells are promising contributors to regenerative medicine, exhibiting the ability to regenerate tissues and modulate the immune system, which is particularly beneficial for addressing chronic inflammatory ulcers and wounds. Despite their inherent capabilities, research suggests that pretreatment amplifies therapeutic effectiveness. Methods: Our experimental design exposed adipose-derived mesenchymal stem cells to six inflammatory factors for 24 h. We subsequently evaluated gene expression and proteome profile alterations and observed the wound closure rate post-treatment. Results: Specific pretreatments, such as IL-1ß, notably demonstrated an accelerated wound-healing process. Analysis of gene and protein expression profiles revealed alterations in pathways associated with tissue regeneration. Discussion: This suggests that licensed cells exhibit potentially higher therapeutic efficiency than untreated cells, shedding light on optimizing regenerative strategies using adipose tissue-derived stem cells.
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The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here we mine large scale MM proteogenomic data integrating it with MM cell line dependency screen, and drug sensitivity data to identify druggable targets and forecast treatment efficacy and resistance. Leveraging protein profiles from established MM subtypes and molecular structures of 82 cancer treatment drugs, we identified nine candidate hub proteins, mTOR, FYN, PIK3CB, EGFR, MAPK3, MAP4K1, MAP2K1, SRC and AKT1, across five distinct MM subtypes. These proteins serve as potential drug targets applicable to one or multiple MM subtypes. By analyzing transcriptomic data from 48 publicly accessible melanoma cell lines sourced from Achilles and CRISPR dependency screens, we forecasted 162 potentially targetable genes. We also identified genetic resistance in 260 genes across at least one melanoma subtype. In addition, we employed publicly available compound sensitivity data (Cancer Therapeutics Response Portal, CTRPv2) on the cell lines to assess the correlation of compound effectiveness within each subtype. We have identified 20 compounds exhibiting potential drug impact in at least one melanoma subtype. Remarkably, employing this unbiased approach, we have uncovered compounds targeting ferroptosis, that demonstrate a striking 30x fold difference in sensitivity among different subtypes. This implies that the proteogenomic classification of melanoma has the potential to predict sensitivity to ferroptosis compounds. Our results suggest innovative and novel therapeutic strategies by stratifying melanoma samples through proteomic profiling, offering a spectrum of novel therapeutic interventions and prospects for combination therapy. Highlights: (1) Proteogenomic subtype classification can define the landscape of genetic dependencies in melanoma (2) Nine proteins from molecular subtypes were identified as potential drug targets for specified MM patients (3) 20 compounds identified that show potential effectiveness in at least one melanoma subtype (4) Proteogenomics can predict specific ferroptosis inducers, HDAC, and RTK Inhibitor sensitivity in melanoma subtypes.
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Alopecia Areata , Azetidinas , Purinas , Pirazoles , Sulfonamidas , Humanos , Alopecia Areata/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Azetidinas/uso terapéutico , Purinas/uso terapéutico , Pirazoles/uso terapéutico , Enfermedades de la Uña/tratamiento farmacológico , Enfermedades de la Uña/etiología , Femenino , Resultado del Tratamiento , Inhibidores de las Cinasas Janus/uso terapéutico , Masculino , AdultoRESUMEN
We hypothesise that regression may have an impact on the effectiveness of adjuvant IFN therapy, based on its role in the host immune response. Our purpose is to investigate regression and ulceration as prognostic factors in case of interferon-alpha (IFN)-treated melanoma patients. We followed 357 IFN-treated melanoma patients retrospectively, investigating progression-free survival (PFS) and overall survival (OS) depending on the presence of ulceration and regression. A Kaplan-Meier analysis was performed, and we used a Cox regression analysis to relate risk factors. The survival function of the Cox regression was used to measure the effect of regression and ulceration on PFS and OS depending on the Breslow thickness (T1-T4) of the primary tumour. Regression was significantly positively related to PFS ( P â =â 0.0018, HRâ =â 0.352) and OS ( P â =â 0.0112, HRâ =â 0.380), while ulceration showed a negative effect (PFS: P â =â 0.0001, HRâ =â 2.629; OS: P â =â 0.0003, HRâ =â 2.388). They influence survival independently. The most favourable outcome was measured in the regressed/non-ulcerated group, whereas the worse was in the non-regressed/ulcerated one. Of risk factors, Breslow thickness is the most significant predictor. The efficacy of regression is regardless of Breslow thickness, though the more favourable the impact of regression was in the thicker primary lesions. Our results indicate that regression is associated with a more favourable outcome for IFN-treated melanoma patients, whereas ulceration shows an inverse relation. Further studies are needed to analyse the survival benefit of regression in relation to innovative immune checkpoint inhibitors.
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Antineoplásicos , Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/patología , Neoplasias Cutáneas/patología , Estudios Retrospectivos , Antineoplásicos/uso terapéutico , Interferón-alfa/efectos adversos , PronósticoRESUMEN
Micro-environmental factors, including stromal and immune cells, cytokines, and circulating hormones are well recognized to determine cancer progression. Melanoma cell growth was recently shown to be suppressed by cholecystokinin/gastrin (CCK) receptor antagonists, and our preliminary data suggested that melanoma patients with Helicobacter gastritis (which is associated with elevated serum gastrin) might have an increased risk of cancer progression. Therefore, in the present study, we examined how gastrin may act on melanoma cells. In 89 melanoma patients, we found a statistically significant association between circulating gastrin concentrations and melanoma thickness and metastasis, which are known risk factors of melanoma progression and prognosis. Immunocytochemistry using a validated antibody confirmed weak to moderate CCK2R expression in both primary malignant melanoma cells and the melanoma cell lines SK-MEL-2 and G361. Furthermore, among the 219 tumors in the Skin Cutaneous Melanoma TCGA Pan-Cancer dataset showing gastrin receptor (CCKBR) expression, significantly higher CCKBR mRNA levels were linked to stage III-IV than stage I-II melanomas. In both cell lines, gastrin increased intracellular calcium levels and stimulated cell migration and invasion through mechanisms inhibited by a CCK2 receptor antagonist. Proteomic studies identified increased MMP-2 and reduced TIMP-3 levels in response to gastrin that were likely to contribute to the increased migration of both cell lines. However, the effects of gastrin on tumor cell invasion were relatively weak in the presence of the extracellular matrix. Nevertheless, dermal fibroblasts/myofibroblasts, known also to express CCK2R, increased gastrin-induced cancer cell invasion. Our data suggest that in a subset of melanoma patients, an elevated serum gastrin concentration is a risk factor for melanoma tumor progression, and that gastrin may act on both melanoma and adjacent stromal cells through CCK2 receptors to promote mechanisms of tumor migration and invasion.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/metabolismo , Gastrinas/farmacología , Gastrinas/metabolismo , Proteómica , Receptores de Colecistoquinina , Receptor de Colecistoquinina B/genética , Receptor de Colecistoquinina B/metabolismoRESUMEN
Keratinocytes are one of the primary cells affected by psoriasis inflammation. Our study aimed to delve deeper into their morphology, transcriptome, and epigenome changes in response to psoriasis-like inflammation. We created a novel cytokine mixture to mimic mild and severe psoriasis-like inflammatory conditions in cultured keratinocytes. Upon induction of inflammation, we observed that the keratinocytes exhibited a mesenchymal-like phenotype, further confirmed by increased VIM mRNA expression and results obtained from confocal microscopy. We performed RNA sequencing to achieve a more global view, revealing 858 and 6987 DEGs in mildly and severely inflamed keratinocytes, respectively. Surprisingly, we found that the transcriptome of mildly inflamed keratinocytes more closely mimicked that of the psoriatic epidermis transcriptome than the severely inflamed keratinocytes. Genes involved in the IL-17 pathway were a major contributor to the similarities of the transcriptomes between mildly inflamed KCs and psoriatic epidermis. Mild and severe inflammation led to the gene regulation of epigenetic modifiers such as HATs, HDACs, DNMTs, and TETs. Immunofluorescence staining revealed distinct 5-hmC patterns in inflamed versus control keratinocytes, and consistently low 5-mC intensity in both groups. However, the global DNA methylation assay detected a tendency of decreased 5-mC levels in inflamed keratinocytes versus controls. This study emphasizes how inflammation severity affects the transcriptomic similarity of keratinocytes to psoriatic epidermis and proves dynamic epigenetic regulation and adaptive morphological changes in inflamed keratinocytes.
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Psoriasis , Transcriptoma , Humanos , Transcriptoma/genética , Epigénesis Genética , Queratinocitos/metabolismo , Epidermis/metabolismo , Psoriasis/genética , Psoriasis/metabolismo , Inflamación/genética , Inflamación/metabolismoRESUMEN
The skin is a tightly regulated, balanced interface that maintains our integrity through a complex barrier comprising physical or mechanical, chemical, microbiological, and immunological components. The skin's microbiota affect various properties, one of which is the establishment and maintenance of the physical barrier. This is achieved by influencing multiple processes, including keratinocyte differentiation, stratum corneum formation, and regulation of intercellular contacts. In this review, we summarize the potential contribution of Cutibacterium acnes to these events and outline the contribution of bacterially induced barrier defects to the pathogenesis of acne vulgaris. With the combined effects of a Westernized lifestyle, microbial dysbiosis, epithelial barrier defects, and inflammation, the development of acne is very similar to that of several other multifactorial diseases of barrier organs (e.g., inflammatory bowel disease, celiac disease, asthma, atopic dermatitis, and chronic rhinosinusitis). Therefore, the management of acne requires a complex approach, which should be taken into account when designing novel treatments that address not only the inflammatory and microbial components but also the maintenance and strengthening of the cutaneous physical barrier.
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Acné Vulgar , Dermatitis Atópica , Microbiota , Humanos , Piel/patología , Acné Vulgar/microbiología , Epidermis/patología , Dermatitis Atópica/patologíaRESUMEN
Microphthalmia-associated transcription factor (MITF) plays pivotal roles in melanocyte development, function, and melanoma pathogenesis. MITF amplification occurs in melanoma and has been associated with resistance to targeted therapies. Here, we show that MITF regulates a global antioxidant program that increases survival of melanoma cell lines by protecting the cells from reactive oxygen species (ROS)-induced damage. In addition, this redox program is correlated with MITF expression in human melanoma cell lines and patient-derived melanoma samples. Using a zebrafish melanoma model, we show that MITF decreases ROS-mediated DNA damage in vivo . Some of the MITF target genes involved, such as IDH1 and NNT , are regulated through direct MITF binding to canonical enhancer box (E-BOX) sequences proximal to their promoters. Utilizing functional experiments, we demonstrate the role of MITF and its target genes in reducing cytosolic and mitochondrial ROS. Collectively, our data identify MITF as a significant driver of the cellular antioxidant state. One Sentence Summary: MITF promote melanoma survival via increasing ROS tolerance.
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Background: Lymphedema (LE) is a chronic condition, which refers to tissue swelling due to excess interstitial fluid accumulation or impaired lymphatic conduit. Theoretically, lymphedema-related fluid retention could affect left ventricular (LV) mechanics, which could be detailed by recent three-dimensional speckle-tracking echocardiography. Therefore, it was purposed to examine LV strains in LE patients before and one hour after the use of medical compression stockings and to compare findings to those of matched normal subjects. Methods: The study comprised 26 cases with lymphedema, however, 4 cases had to be excluded due to inferior quality of images. Their results were compared to 27 age- and gender-matched healthy controls. Results: Global LV circumferential and area strains and mean segmental LV circumferential strain were increased in lymphedema patients before the use of medical compression stockings as compared to controls. One hour after the use of medical compression stockings, no global and mean segmental LV strain showed significant impairment or improvement, but tendentious reduction was seen in LV circumferential strain. With LV segmental analysis, midventricular LV radial, circumferential and area strains proved to be significantly increased, while basal LV longitudinal strain and midventricular LV three-dimensional strain were decreased as compared to controls. No changes in regional LV strains could be detected after one-hour medical compression stockings use as compared to data collected at rest. Conclusions: Increased global LV circumferential strain is seen in lymphedema. With using medical compression stockings, LV deformation parameters change towards the normal range emphasizing their importance on cardiac function.