RESUMO
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genodermatosis caused by mutations in the gene coding for type VII collagen (COL7A1). More than 800 different pathogenic mutations in COL7A1 have been described to date; however, the ancestral origins of many of these mutations have not been precisely identified. In this study, 32 RDEB patient samples from the Southwestern United States, Mexico, Chile, and Colombia carrying common mutations in the COL7A1 gene were investigated to determine the origins of these mutations and the extent to which shared ancestry contributes to disease prevalence. The results demonstrate both shared European and American origins of RDEB mutations in distinct populations in the Americas and suggest the influence of Sephardic ancestry in at least some RDEB mutations of European origins. Knowledge of ancestry and relatedness among RDEB patient populations will be crucial for the development of future clinical trials and the advancement of novel therapeutics.
Assuntos
Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/genética , Hispânico ou Latino/genética , Judeus/genética , Chile/epidemiologia , Colômbia/epidemiologia , Epidermólise Bolhosa Distrófica/epidemiologia , Feminino , Genes Recessivos/genética , Humanos , Masculino , México/epidemiologia , Fenótipo , Estados Unidos/epidemiologiaRESUMO
Alopecia areata (AA) is a common autoimmune skin disease resulting in the loss of hair on the scalp and elsewhere on the body that affects over 146 million people worldwide at some point in their lives. Founded in 1981, the National AA Foundation (NAAF) is a nonprofit organization that supports research to find a cure or acceptable treatment for AA, supports those with the disease, and educates the public about AA. NAAF conducts research summits every two years to review progress and create new directions in its funded and promoted research. This report from the seventh AA Research Summit, Forging the Future, held December 4-5, 2018 in New York City provides highlights of the research presented and future research priorities identified during targeted discussion sessions.
Assuntos
Alopecia em Áreas/terapia , Hidradenite Supurativa/terapia , Avaliação de Resultados em Cuidados de Saúde , Psoríase/terapia , Artrite Psoriásica/terapia , Ensaios Clínicos como Assunto , Congressos como Assunto , Determinação de Ponto Final , Humanos , Satisfação do PacienteRESUMO
During its 25th anniversary year, the National Alopecia Areata Foundation (NAAF) undertook a project to completely re-evaluate their research program and to help focus and direct future directions of alopecia areata (AA) research to better meet the goals of individuals with and the scientists working to discover mechanisms of disease and better treatments for AA. This project was embodied in five research summits in 2008, 2009, 2010, 2012, and 2014 as part of the NAAF's main strategic initiative, the Alopecia Areata Treatment Development Program, to accelerate progress toward a viable treatment. The sixth summit, "Building and Crossing the Translational Bridge," was held in 2016 and highlighted strong clinical data on the efficacy of topical and oral JAK inhibitors in mouse models and human AA. The advances discussed in this most recent summit provide real hope for a reliable and relatively safe treatment for AA. This work validates the last 10 years of research translating basic research of AA into new treatments based on the firm foundation of modern immunologic and genetic research.
Assuntos
Alopecia em Áreas/terapia , Pesquisa Biomédica , HumanosRESUMO
BACKGROUND: Digital dermoscopic image analysis of pigmented skin lesions (PSLs) has become increasingly popular, despite its unclear clinical utility. Unbiased, high-powered studies investigating the efficacy of commercially available systems are limited. OBJECTIVE: To investigate the diagnostic performance of the FotoFinder Mole-Analyzer in assessing PSLs for cutaneous melanoma. METHODS: In this 15-year retrospective study, the histopathologies of 1076 biopsied PSLs among a total of 2500 imaged PSLs were collected. The biopsied PSLs were categorized as benign or malignant (cutaneous melanoma) based on histopathology. Analyzer scores (0-1.00) for these PSLs were obtained and grouped according to histopathology. RESULTS: At an optimized cutoff score of 0.50, a sensitivity of 56% and a specificity of 74% were achieved. The area under the receiver operating characteristics curve was 0.698, indicating poor accuracy as a diagnostic tool. LIMITATIONS: This study had a retrospective design and involved only a single institution. CONCLUSION: Our study reveals a low sensitivity of the scoring function of this digital dermoscopic image analyzer for detecting cutaneous melanomas. Physicians must apply keen clinical judgment when using such devices in the screening of suspicious PSLs.
Assuntos
Dermoscopia/instrumentação , Diagnóstico por Computador/métodos , Melanoma/patologia , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biópsia por Agulha , Estudos de Coortes , Dermoscopia/métodos , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Melanoma/diagnóstico , Pessoa de Meia-Idade , Nevo Pigmentado/diagnóstico , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias Cutâneas/diagnóstico , Análise e Desempenho de Tarefas , Melanoma Maligno CutâneoRESUMO
Vitiligo is the most frequent human pigmentary disorder, characterized by progressive autoimmune destruction of mature epidermal melanocytes. Of the current treatments offering partial and temporary relief, ultraviolet (UV) light is the most effective, coordinating an intricate network of keratinocyte and melanocyte factors that control numerous cellular and molecular signaling pathways. This UV-activated process is a classic example of regenerative medicine, inducing functional melanocyte stem cell populations in the hair follicle to divide, migrate, and differentiate into mature melanocytes that regenerate the epidermis through a complex process involving melanocytes and other cell lineages in the skin. Using an in-depth correlative analysis of multiple experimental and clinical data sets, we generated a modern molecular research platform that can be used as a working model for further research of vitiligo repigmentation. Our analysis emphasizes the active participation of defined molecular pathways that regulate the balance between stemness and differentiation states of melanocytes and keratinocytes: p53 and its downstream effectors controlling melanogenesis; Wnt/ß-catenin with proliferative, migratory, and differentiation roles in different pigmentation systems; integrins, cadherins, tetraspanins, and metalloproteinases, with promigratory effects on melanocytes; TGF-ß and its effector PAX3, which control differentiation. Our long-term goal is to design pharmacological compounds that can specifically activate melanocyte precursors in the hair follicle in order to obtain faster, better, and durable repigmentation.
Assuntos
Melanócitos/patologia , Medicina Regenerativa/métodos , Células-Tronco/patologia , Vitiligo/terapia , Animais , Humanos , Melanócitos/efeitos dos fármacos , Medicina Regenerativa/tendências , Células-Tronco/efeitos dos fármacos , Vitiligo/tratamento farmacológico , Vitiligo/patologiaRESUMO
To characterize the gene expression profile of regenerated melanocytes in the narrow band UVB (NBUVB)-treated vitiligo epidermis and their precursors in the hair follicle, we present here a strategy of RNA isolation from in situ melanocytes using human frozen skin. We developed a rapid immunostaining protocol using the NKI-beteb antibody, which labels differentiated and precursor melanocytes, followed by fluorescent laser capture microdissection. This technique enabled the direct isolation, from melanocyte and adjacent keratinocyte populations, of satisfactory quality RNA that was successfully amplified and analysed by qRT-PCR. The melanocyte-specific gene transcripts TYR, DCT, TYRP1 and PMEL were significantly upregulated in our NBUVB-treated melanocyte samples as compared with the keratinocyte samples, while keratinocyte-specific genes (KRT5 and KRT14) were expressed significantly higher in the keratinocyte samples as compared with the melanocyte samples. Furthermore, in both NBUVB-treated vitiligo skin and normal skin, when bulge melanocytes were compared with epidermal melanocytes, we found significantly lower expression of melanocyte-specific genes and significantly higher expression of three melanocytic stem cell genes (SOX9, WIF1 and SFRP1), while ALCAM and ALDH1A1 transcripts did not show significant variation. We found significantly higher expression of melanocyte-specific genes in the epidermis of NBUVB-treated vitiligo, as compared to the normal skin. When comparing bulge melanocyte samples from untreated vitiligo, NBUVB-treated vitiligo and normal skin, we did not find significant differences in the expression of melanocyte-specific genes or melanocytic stem cell genes. These techniques offer valuable opportunities to study melanocytes and their precursors in vitiligo and other pigmentation disorders.
Assuntos
Microdissecção e Captura a Laser , Melanócitos/metabolismo , RNA/isolamento & purificação , Vitiligo/metabolismo , Estudos de Casos e Controles , Humanos , RNA/metabolismo , Vitiligo/radioterapiaRESUMO
During its 25th anniversary year, the National Alopecia Areata Foundation undertook a project to completely re-evaluate their research program and to help focus and direct future directions of alopecia areata research to better meet the goals of people with alopecia areata (AA) and the scientists working to discover mechanisms of disease and better treatments for AA. This project was embodied in four research summits in 2008, 2009, 2010, and 2012, as part of the Foundation's main strategic initiative, the Alopecia Areata Treatment Development Program to accelerate progress toward a viable alopecia areata treatment. The first summit was an evaluation of the progress of AA research in a global sense, with an emphasis on how to use the research programs to bring better treatments to patients. The second summit focused on immunology and how to better understand the autoimmune nature of AA. The third summit focused on developing a clinical research network that could most effectively bring new treatments to patients. The fourth summit consolidated the considerable evidence of the mechanisms of AA, and how these mechanisms could be targeted by modern therapies, many of which were being used effectively in other autoimmune diseases. These four summits laid the foundation for the fifth summit in the series: From Targets to Treatments: Bridging Autoimmune Research to Advance Understanding of Alopecia Areata.
Assuntos
Alopecia em Áreas , Pesquisa Biomédica , Congressos como Assunto , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/epidemiologia , Alopecia em Áreas/genética , Alopecia em Áreas/imunologia , Animais , Pesquisa Biomédica/organização & administração , Modelos Animais de Doenças , Fundações , HumanosRESUMO
Alopecia areata is a common autoimmune skin disease resulting in the loss of hair on the scalp and elsewhere on the body that affects over 146 million people worldwide at some point in their lives. Founded in 1981, the National Alopecia Areata Foundation (NAAF) is a nonprofit organization that supports research to find a cure or acceptable treatment for alopecia areata, supports those with the disease, and educates the public about alopecia areata. NAAF conducts research summits every 2 years that are central to achieving the goals of a major strategic initiative, the Alopecia Areata Treatment Development Program, which are: to accelerate progress toward a safe, effective, affordable treatment or a cure for alopecia areata. These summits have played a key role in transforming the understanding of alopecia areata from largely inflammatory and dermatological perspectives to a focus on the genetic and immunological factors that are now recognized as driving and active determinants of the disease process.
Assuntos
Alopecia em Áreas , Doenças Autoimunes , Pesquisa Biomédica/economia , Organização do Financiamento , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/epidemiologia , Alopecia em Áreas/genética , Alopecia em Áreas/imunologia , Animais , Doenças Autoimunes/imunologia , Modelos Animais de Doenças , HumanosRESUMO
Immune checkpoint inhibitors (ICIs) are now the first-line treatment for patients with advanced melanoma. Despite promising clinical results, many patients fail to respond to these therapies. BH3 mimetics, a novel class of small molecule inhibitors that bind and inhibit anti-apoptotic members of the BCL2 family proteins such as BCL2 or MCL1, have been very successful in treating hematologic malignancies. However, there are limited studies on the immunomodulatory role of the BH3 mimetics. Several factors contribute to ICI resistance including myeloid-derived suppressor cells (MDSCs) that exert immunosuppressive effects through direct and indirect inhibition of antitumor immunity. Thus, targeting MDSCs to enhance antitumor immunity has the potential to enhance the efficacy of ICIs. In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell-dependent manner in mice. Specifically, S64315 enhances antitumor immunity by reducing MDSC frequency and by promoting the activity of CD8+T cells. Additionally, human MDSCs are 10 times more sensitive to S64315 than cutaneous melanoma lines. Further, we found that a higher expression of MCL1 is associated with poor survival for patients treated with anti-PD-1. Finally, combining S64315 and anti-PD-1 significantly slowed tumor growth compared to either agent alone. Together, this proof-of-concept study demonstrates the potential of combining an MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma.
Assuntos
Antineoplásicos , Melanoma , Células Supressoras Mieloides , Neoplasias Cutâneas , Humanos , Animais , Camundongos , Inibidores de Checkpoint Imunológico/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Melanoma/tratamento farmacológico , Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Células Supressoras Mieloides/metabolismoRESUMO
We have discovered that human vitiligo patients treated with narrow-band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery-stage RNA-Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non-responding) and compared them with repigmented (responding) lesions from the same patient. Non-responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non-responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/ß-catenin repigmentation pathway. Vitiligo-responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro-melanogenic effect of α-MSH. Understanding the pathways that govern lack of NBUVB-induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo.
Assuntos
Epiderme , Melanócitos , Pigmentação da Pele , Vitiligo , Vitiligo/patologia , Vitiligo/radioterapia , Vitiligo/metabolismo , Humanos , Epiderme/patologia , Epiderme/metabolismo , Epiderme/efeitos da radiação , Pigmentação da Pele/efeitos da radiação , Melanócitos/patologia , Melanócitos/metabolismo , Melanócitos/efeitos da radiação , Terapia Ultravioleta/métodos , Queratinócitos/metabolismo , Queratinócitos/patologia , Queratinócitos/efeitos da radiação , Raios Ultravioleta , Feminino , Masculino , Via de Sinalização Wnt , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genéticaRESUMO
A better understanding of human melanocyte (MC) and MC stem cell biology is essential for treating MC-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate SASH1 function in the MC lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical examinations, human cell assays, yeast 2-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. In vitro, we identified SASH1 as a regulator in MC stem cell maintenance and discovered that TNKS2 is crucial for SASH1's role. In addition, the S519N variant is located in one of multiple tankyrase-binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder links both gain and loss of pigmentation in the same individual, hinting to accelerated aging in human MC stem cells. The findings offer insights into the roles of SASH1 and TNKS2 in MC stem cell maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with MC-related disorders should include an assessment and history of hair pigmentation loss.
RESUMO
Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmune disorders and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined. Here, we report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS. We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. We then report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints. Analysis of the first 10 participants to complete the 16-week study shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS. ClinicalTrials.gov identifier: NCT04246372.
RESUMO
Melanoma is a very aggressive skin cancer with increasing incidence worldwide. MicroRNAs are small, noncoding RNAs that regulate gene expression of targeted gene(s). The hallmark of cancer model outlined by Hanahan and Weinberg offers a meaningful framework to consider the roles of microRNAs in melanoma development and progression. In this systematic review of the literature, we associate what is known about deregulation of microRNAs and their targeted genes in melanoma development with the hallmarks and characteristics of cancer. The diagnostic and therapeutic potential of microRNAs for future melanoma management will also be discussed.
Assuntos
Melanoma/genética , MicroRNAs/genética , Neoplasias Cutâneas/genética , Animais , Apoptose , Biomarcadores Tumorais/sangue , Proliferação de Células , Senescência Celular , Genes Supressores de Tumor , Instabilidade Genômica , Humanos , Inflamação/metabolismo , Melanoma/metabolismo , Melanoma/patologia , MicroRNAs/metabolismo , Terapia de Alvo Molecular , Invasividade Neoplásica , Metástase Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Although the concept of cancer stem cells (CSCs) is well-accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In this study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased cell viability in vitro, and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer.
Assuntos
Aldeído Desidrogenase/genética , Transformação Celular Neoplásica/genética , Melanoma/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Cutâneas/genética , Aldeído Desidrogenase/antagonistas & inibidores , Família Aldeído Desidrogenase 1 , Aldeído Oxirredutases , Animais , Apoptose/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Melanoma/enzimologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , RNA Interferente Pequeno/genética , Elementos de Resposta , Retinal Desidrogenase , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Temozolomida , Tretinoína/química , Tretinoína/farmacologiaRESUMO
Alopecia areata (AA) is a nonscarring and recurrent disease characterized by hair loss that may significantly affect patient health-related quality of life (HRQoL). Given the lack of reliable and accurate reporting of HRQoL status in patients with AA, we analyzed data from 532 AA patients from the National Alopecia Areata Registry whose registry record included HRQoL assessments using three validated instruments: Skindex-16, brief version of the Fear of Negative Evaluation Scale, and Dermatology Life Quality Index. The mean HRQoL scores were compared with previously reported HRQoL levels from healthy controls and patients with other skin diseases. Two-step cluster analysis of Skindex-16 scales divided patients into two groups: 481 (57%) with good HRQoL and 361 (43%) with poor HRQoL. Multivariate logistic regression modeling revealed a set of risk factors for poor HRQoL: age <50 years (odds ratio (OR) 3.99, 95% confidence interval (CI) 1.66-9.58), female gender (OR 2.74, 95% CI 1.73-4.34), hair loss 25-99% (OR 2.47, 95% CI 1.12-5.45), family stress (OR 1.8, 95% CI 1.13-2.86), and job change (OR 2.01, 95% CI 1.02-3.94). The current analysis provides an overview of the HRQoL status of AA patients and may guide patient care in the future.
Assuntos
Alopecia em Áreas/psicologia , Nível de Saúde , Qualidade de Vida , Sistema de Registros , Estresse Psicológico/psicologia , Adulto , Fatores Etários , Emprego/psicologia , Família/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
Both aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1 S519N variant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1 S519N was defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for SASH1's promotion of stem-like function. Further, the SASH1 S519N variant is in a bona fide Tankyrase-binding motif, and SASH1 S519N alters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Incidência , Sistema de Registros , Programa de SEER , Estados UnidosRESUMO
Sulfate adsorption capacity of B-horizons of base-poor, predominantly stagnopodzol, soils from the Plynlimon catchments, mid-Wales was determined by combination of laboratory adsorption and desorption isotherms. Results show that sulfate adsorption capacity of a range of stagnopodzol (Histic-stagno-podzol (Leptic), WRB), brown podzolic soil (Histic-umbrisol (Leptic), WRB) and stagnohumic gley (Histic-stagno-gleysol, WRB) B-horizons was positively related to the amounts of extractable (pyrophosphate and oxalate) Fe + Al, with the stagnopodzol and brown podzolic soil Bs horizon having the largest adsorption capacity and stagnohumic gley Bg horizon the smallest adsorption capacity. Results show that dissolved organic carbon (DOC) has a negative but limited effect on sulfate adsorption in these soils. Results obtained from a set of historical soil samples revealed that the grassland brown podzolic soil Bs horizon and afforested stagnopodzol Bs horizon were highly saturated with sulfate in the 1980s, at 63% and 89% respectively, whereas data from some recently sampled soil from two sites revisited in 2010-11 indicates that percentage sulfate adsorption saturation has since fallen substantially, to 41% and 50% respectively. Between 1984 and 2009 the annual rainfall-weighted mean excess SO(4)-S concentration in bulk precipitation declined linearly from 0.37 mg S l(-1) to 0.17 mg S l(-1). Over the same period, flow weighted annual mean stream water SO(4)-S concentrations decreased approximately linearly from 1.47 mg S l(-1) to 0.97 mg S l(-1) in the plantation afforested Hafren catchment compared to a drop from 1.25 to 0.69 mg S l(-1) in the adjacent moorland catchment of the Afon Gwy. In flux terms, the mean decrease in annual stream water SO(4)-S flux has been approximately 0.4 kg S ha(-1) yr(-1), whilst the recovery in stream water quality in the Afon Cyff grassland catchment has been partly offset by loss of SO(4)-S by desorption from the soil sulfur pool of approximately 0.2 kg S ha(-1) yr(-1).
Assuntos
Poluição do Ar/estatística & dados numéricos , Poluentes do Solo/análise , Sulfatos/análise , Enxofre/análise , Adsorção , Atmosfera , Meio Ambiente , Monitoramento Ambiental , Rios/química , Solo/química , País de Gales , Poluentes Químicos da Água/análiseRESUMO
Uveal melanoma (UM) is a subtype of melanoma. Although they share a melanocytic origin with cutaneous melanoma (CM), patients with UM have few treatment options. BCL2 homologous 3 mimetics are small-molecule drugs that mimic proapoptotic BCL2 family members. We compared BCL2 family member expression between UM and CM using immunoblot and The Cancer Genome Atlas transcriptomic analysis. UM has a unique signature of low BFL1 and high PUMA proteins compared with CM and 30 other cancer types, making them an attractive candidate for BCL2 homologous 3 protein mimetics. We tested the efficacy of a BCL2 inhibitor and MCL1 inhibitor (MCL1i) in UM, with viability assays, live-cell imaging, sphere assays, and mouse xenograft models. UM had a higher sensitivity to MCL1i than CM. Overexpression of BFL1 or knockdown of PUMA made the UM more resistant to MCL1i. In contrast, MAPK/extracellular signalâregulated kinase inhibitor treatment in CM made them more sensitive to MCL1i. However, MCL1i-alone treatment was not very effective to reduce the UM initiating cells; to overcome this, we employed a combination of MCL1i with BCL2 inhibitor that synergistically inhibited UM initiating cell's capacity to expand. Overall, we identify a distinct expression profile of BCL2 family members for UM that makes them susceptible to BCL2 homologous 3 mimetics.