Miracle-dz/UniFAR-FTUs huggingface dataset:
Evidence suggesting that di‐n‐butyl phthalate has antiandrogenic effects in fish

Phthalate ester plasticizers are antiandrogenic in mammals. High doses of certain phthalates consistently interfere with the normal development of male offspring exposed in utero, causing disrupted sperm production, abnormal development of the genitalia, and in some cases infertility. In the environment, phthalates are considered ubiquitous and are commonly measured in aquatic ecosystems at low nanograms to micrograms per liter concentrations. Given the similarity between mammalian and teleost endocrine systems, phthalate esters may be able to cause antiandrogenic endocrine disruption in fish in the wild. In the present study, adult male three‐spined sticklebacks (Gasterosteus aculetaus; n = 8) were exposed to di‐n‐butyl phthalate (DBP; 0, 15, and 35 µg DBP/L) for 22 d and analyzed for changes in nesting behavior, plasma androgen concentrations, spiggin concentrations, and steroidogenic gene expression. Plasma testosterone concentrations were significantly higher in males from the 35 µg DBP/L group compared with the solvent control, whereas plasma 11‐ketotestosterone concentrations were not significantly affected. Expression of steroid acute regulatory protein and 3β‐hydroxysteroid dehydrogenase remained unchanged. Spiggin concentrations were significantly lower in the males exposed to 35 µg DBP/L. Nest building appeared to be slower in some males exposed to DBP, but this was not statistically significant. These results suggest that DBP has antiandrogenic effects in fish. However, further research is required to firmly establish the consequences of chronic DBP exposure in fish. Environ. Toxicol. Chem. 2011; 30:1338–1345. © 2011 SETAC
Selenium concentrations and enzyme activities of glutathione metabolism in wild long‐tailed ducks and common eiders

The relationships of selenium (Se) concentrations in whole blood with plasma activities of total glutathione peroxidase, Se‐dependent glutathione peroxidase, and glutathione reductase were studied in long‐tailed ducks (Clangula hyemalis) and common eiders (Somateria mollissima) sampled along the Beaufort Sea coast of Alaska, USA. Blood Se concentrations were >8 µg/g wet weight in both species. Linear regression revealed that the activities of total and Se‐dependent glutathione peroxidase were significantly related to Se concentrations only in long‐tailed ducks, raising the possibility that these birds were experiencing early oxidative stress. Environ. Toxicol. Chem. 2011; 30:1479–1481. © 2011 SETAC
A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib

Background: Mastocytosis is a myeloproliferative neoplasm characterized by the excessive proliferation of mast cells. Mast cell leukaemia (MCL), the aggressive form of this disease, requires cytoreductive therapy, such as cladribine, interferon‐alpha‐2b and, most recently, tyrosine kinase inhibitors – dasatinib or imatinib.
Quantification of perchloroethylene residues in dry‐cleaned fabrics

We have used a novel gas chromatography/mass spectrometry (GC/MS)‐based approach to quantify perchloroethylene (PCE) residues in dry‐cleaned fabrics. Residual PCE was extracted from fabric samples with methanol and concentration was calculated by the gas chromatographic peak area, standardized using PCE calibration data. Extracts examined were from samples of 100% wool, polyester, cotton, or silk, which were dry cleaned from one to six times in seven different Northern Virginia dry‐cleaning establishments. Additional experiments were conducted to investigate the kinetics of PCE release in the extraction solvent and to the open air. We found that polyester, cotton, and wool retained ≥ µM levels of PCE, that these levels increased in successive dry‐cleaning cycles, and that PCE is slowly volatilized from these fabrics under ambient room air conditions. We found that silk does not retain appreciable PCE. Measured differences across dry‐cleaning establishments and fabric type suggest more vigorous monitoring of PCE residues may be warranted. Environ. Toxicol. Chem. 2011;30:2481–2487. © 2011 SETAC
Garp as a therapeutic target for modulation of T regulatory cell function

ABSTRACT Introduction: Foxp3+ T regulatory cells (Tregs) play critical roles in immune homeostasis primarily by suppressing many aspects of the immune response. Tregs uniquely express GARP on their cell surface and GARP functions as a delivery system for latent TGF-β. As Treg-derived TGF-β may mediate the suppressive functions of Tregs, GARP may represent a target to inhibit Treg suppression in cancer or augment suppression in autoimmunity. Areas covered: This article will focus on 1) the role of Treg-derived TGF-β in the suppressive activity of Treg, 2) the cellular and molecular regulation of expression of GARP on mouse and human Tregs, 3) the role of integrins in the activation of latent-TGF-β/GARP complex, 4) an overview of our present understanding of the function of the latent-TGF-β/GARP complex. Expert opinion: Two approaches are outlined for targeting the L-TGF-β1/GARP complex for therapeutic purposes. Tregs play a major role in suppressive effector T cell responses to tumors and TGF-β1 may be a major contributor to this process. One approach is to specifically block the production of active TGF-β1 from Tregs as an adjunct to tumor immunotherapy. The second approach in autoimmunity is to selectively enhance the production of TGF-β by Tregs at sites of chronic inflammation.
Fibroblast activation protein-α in fibrogenic disorders and cancer: more than a prolyl-specific peptidase?

ABSTRACT Introduction: Fibroblast activation protein-α (FAP-α) belongs to the family of prolyl-specific serine proteases. FAP-α displays both exopeptidase and endopeptidase/gelatinase/collagenase activities. FAP-α protein and/or activity have been associated with fibrosis, inflammation and cancer, but the protein is undetectable in most normal tissues. FAP-α is selectively expressed at sites of tissue remodeling and repair and enhances tumor progression, suggesting that this protease may be a therapeutic target to treat human disorders associated with fibrotic dysregulation. Areas covered: In this review, we summarize the mechanisms driving tissue fibrosis and describe some of the enzymes involved in fibrosis, concentrating on FAP-α. We describe its enzymatic properties, discuss the tools developed to control its activity and the problem of selectivity toward the other proteases of the family and outline its potential biological substrates. We also consider non-enzymatic functions of this protein and suggest that repression of FAP-α expression may represent therapeutic options. Expert opinion: Questions remain regarding the biological functions of FAP-α, either dependent or independent of its enzyme activity. However, as progress is underway to develop FAP-α-specific inhibitors and therapeutic antibodies, its role in diseases associated with fibrosis is starting to emerge, ultimately leading to novel therapeutic options for inflammatory and oncologic diseases.
Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

ABSTRACT Introduction: Ocular hypertension in open-angle glaucoma is caused by a reduced rate of removal of aqueous humour (AH) from the eye, with the majority of AH draining from the anterior chamber through the conventional outflow pathway, comprising the trabecular meshwork (TM) and Schlemm’s Canal. Resistance to outflow is generated, in part, by the extracellular matrix (ECM) of the outflow tissues. Current pressure-lowering topical medications largely suppress AH production, or enhance its clearance through the unconventional pathway. However, therapies targeting the ECM of the conventional pathway in order to decrease intraocular pressure have become a recent focus of attention. Areas covered: We discuss the role of ECM of the TM in outflow homeostasis and its relevance as a target for glaucoma therapy, including progress in development of topical eye formulations, together with gene therapy approaches based on inducible, virally-mediated expression of matrix metalloproteinases to enhance aqueous outflow. Expert opinion: There remains a need for improved glaucoma medications that more specifically act upon sites causative to glaucoma pathogenesis. Emerging strategies targeting the ECM of the conventional outflow pathway, or associated components of the cytoskeleton of TM cells, involving new pharmacological formulations or genetically-based therapies, are promising avenues of future glaucoma treatment.
NOD2 and bacterial recognition as therapeutic targets for Crohn’s disease

ABSTRACT Introduction: Crohn’s disease (CD) is a chronic, disabling disease of the gastrointestinal tract that mostly affects young adults. Despite extensive research, the pathogenesis of CD is still not completely understood. It is thought that an abnormal mucosal immune response is elicited towards the luminal microbiota in genetically predisposed persons. Genome-wide association studies and meta-analysis have greatly improved our insight into the genetic background of CD. One of the most studied CD-associated genes is nucleotide-binding oligomerization domain 2 (NOD2). Areas covered: We summarize the current knowledge about NOD2, its use in clinical practice, the functional implications of NOD2 mutations and the therapeutic options for targeting NOD2 in CD. Expert opinion: Almost 2 decades after the identification of NOD2 variants in CD, it has become clear that wild type NOD2 is involved in preserving intestinal barrier integrity and immune homeostasis, properly functioning autophagy and balancing the gut microbiota composition. Given the high prevalence and effect size of NOD2 risk alleles in patients with CD and their interplay with important molecular pathways involved in the disease, NOD2 should seriously be considered as a therapeutic target for CD. Several therapeutic approaches exist and these should be further explored to treat NOD2-related deficiencies in CD.
ABCG2 as a therapeutic target candidate for gout

ABSTRACT Introduction: Hyperuricemia (chronically elevated serum uric acid) is the main pathology underlying the development of gout, the most common inflammatory arthropathy. Management of these conditions therefore relies on controlling serum uric acid levels. ATP-binding cassette transporter, sub-family G, member 2 (ABCG2/BCRP) is a well-studied urate transporter expressed on apical membranes in several tissues, including the intestine, liver, and kidney. Here, we discuss the potential of future gout therapies targeting ABCG2. Areas covered: ABCG2 regulates serum uric acid via physiologically important roles in both renal and extra-renal urate excretion. ABCG2 dysfunction, which promotes onset of hyperuricemia, often results in decreased urate excretion through the extra-renal (principally intestinal), rather than the renal pathway. This review covers recent attempts to establish the basis of ABCG2 function according to genetic diathesis, its molecular structure, and the effects of medication. Furthermore, the possibility of treating gout and hyperuricemia by upregulating intestinal ABCG2 expression is examined. Expert opinion: ABCG2 holds great promise as a therapeutic target for these conditions, particularly considering its involvement in extra-renal urate excretion. Manipulation of ABCG2, including controlling the level and location of its expression, has the potential to prevent gout by promoting uric acid excretion as effectively as general uricosuric drugs. Abbreviations: ATP-binding cassette (ABC), transmembrane domain (TMD), nucleotide binding domain (NBD), single nucleotide polymorphism (SNP), single nucleotide polymorphisms (SNPs).
Recent advances in targeting protein arginine methyltransferase enzymes in cancer therapy

ABSTRACT Introduction: Exploration in the field of epigenetics has revealed the diverse roles of the protein arginine methyltransferase (PRMT) family of proteins in multiple disease states. These findings have led to the development of specific inhibitors and discovery of several new classes of drugs with potential to treat both benign and malignant conditions. Areas covered: We provide an overview on the role of PRMT enzymes in healthy and malignant cells, highlighting the role of arginine methylation in specific pathways relevant to cancer pathogenesis. Additionally, we describe structure and catalytic activity of PRMT and discuss the mechanisms of action of novel small molecule inhibitors of specific members of the arginine methyltransferase family. Expert opinion: As the field of PRMT biology advances, it’s becoming clear that this class of enzymes is highly relevant to maintaining normal physiologic processes as well and disease pathogenesis. We discuss the potential impact of PRMT inhibitors as a broad class of drugs, including the pleiotropic effects, off target effects the need for more detailed PRMT-centric interactomes, and finally, the potential for targeting this class of enzymes in clinical development of experimental therapeutics for cancer.
An update on molecular aspects of the non‐syndromic ichthyoses

Abstract: Ichthyosis includes a number of subtypes from congenital severe forms, such as harlequin ichthyosis (HI), to mild non‐congenital forms, such as ichthyosis vulgaris. Recently, research into the pathomechanisms of ichthyoses has dramatically advanced and led to the identification of several causative genes and molecules underlying the genetic defects. In most types of ichthyosis, pathogenic mechanisms are associated with defects in skin barrier function. Three major components of the stratum corneum barrier are (i) intercellular lipid layers, (ii) cornified cell envelope and (iii) keratin‐filaggrin degradation products. The causative molecules underlying ichthyosis subtypes include ABCA12, lipoxygenase‐3, 12R‐lipoxygenase, CYP4F2 homolog, ichthyin and steroid sulphatase and all these are thought to be related to the intercellular lipid layers. Transglutaminase 1 has a function in cornified cell envelope formation. Keratins 1, 10 and 2 are involved in the keratin network of suprabasal keratinocytes and filaggrin are essential for formation of keratohyalin granules. In fact, loss of ABCA12 function leads to a defective lipid barrier in the stratum corneum, resulting in the HI phenotype and ABCA12 is a known keratinocyte lipid transporter associated with lipid transport in lamellar granules. Filaggrin gene mutations in ichthyosis vulgaris cause keratohyalin granule deficiency. Information concerning genetic defects and ichthyotic disease pathomechanisms are beneficial to develop effective therapy and provide information for genetic counselling including prenatal diagnosis for families affected by ichthyotic disease.
Tackling non-muscle invasive bladder cancer in the clinic

ABSTRACT Introduction: Non-muscle invasive bladder cancer (NMIBC) is a common disease process with a high propensity for recurrence and risk of progression to muscle-invasive or systemic disease. Optimal management of NMIBC depends on appropriate resection and staging, risk-based use of intravesical therapy and tailored surveillance. Current challenges include compliance with guideline recommendations and cancers which are refractory to standard therapies. Areas covered: This review summarizes the conventional management of NMIBC – which relies on strict cystoscopic surveillance and intravesical therapies with chemotherapy and/or immunotherapy in the form of bacillus Calmette-Guerin (BCG). As many patients will be resistant to conventional treatment, investigational therapies and novel prognostic models will also be discussed. Expert commentary: For decades, the management of NMIBC has been predicated on intravesical therapies, most often through the instillation of BCG which has proven clinical efficacy over transurethral resection alone. Despite this, many patients will recur or progress after BCG therapy. While radical cystectomy remains the standard for such patients, suitable alternatives are being actively investigated. An increased interest in immunotherapy for malignancy has reinvigorated this field and on-going advances in disease prognostication are likely to improve upon the existing treatment paradigms for NMIBC.
Anti-GD2 immunotherapy for neuroblastoma

ABSTRACT Introduction: Current therapeutic approaches for high-risk neuroblastoma (HR-NB) include high-dose chemotherapy, surgery and radiotherapy; interventions that are associated with long and short-term toxicities. Effective immunotherapy holds particular promise for improving survival and quality of life by reducing exposure to cytotoxic agents. GD2, a surface glycolipid is the most common target for immunotherapy. Areas covered: We review the status of anti-GD2 immunotherapies currently in clinical use for neuroblastomas and novel GD2-targeted strategies in preclinical development. Expert commentary: Anti-GD2 monoclonal antibodies are associated with improved survival in patients in their first remission and are increasingly being used for chemorefractory and relapsed neuroblastoma. As protein engineering technology has become more accessible, newer antibody constructs are being tested. GD2 is also being targeted by natural killer cells and T-cells. Active immunity can be elicited by anti-GD2 vaccines. The rational combination of currently available and soon-to-emerge immunotherapeutic approaches, and their integration into conventional multimodality therapies will require further investigation to optimize their use for HR-NB.
Surgical management of spinal metastases

ABSTRACT Introduction: Metastatic spinal disease is a source of significant morbidity in patients with cancer. Recent advancements in adjuvant oncologic therapy has led to increased survival for many patients who harbor neoplastic disease. As a result of this, the chance of developing metastatic spinal disease over the course of a cancer patient’s lifespan has increased. Symptomatic metastatic spinal disease can cause significant morbidity including severe pain, neurologic deficit, and loss of ambulation. Current treatment of these patients typically involves the use of multiple modalities, including surgery, radiation, and chemotherapy. Areas covered: An extensive literature review was performed to support the author’s opinion on the matter of surgical management of spinal metastatic disease. Pubmed was utilized as a primary search engine. Expert commentary: Despite advances in chemotherapy and radiation therapy, surgery remains a mainstay in many of these patients, particularly with those with either significant metastatic spinal epidural compression or spinal instability. This review discusses the surgical management of metastatic spinal disease including a framework for decision making and technical considerations when deciding to operate on these patients.
p63 directly induces expression of Alox12, a regulator of epidermal barrier formation

Abstract: Epidermal development and differentiation are tightly controlled processes that culminate in the formation of the epidermal barrier. A critical regulator of different stages of epidermal development and differentiation is the transcription factor p63. More specifically, we previously demonstrated elsewhere that p63 is required for both the commitment to stratification and the commitment to terminal differentiation. We now demonstrate that ΔNp63α, the predominantly expressed p63 isoform in postnatal epidermis, also plays a role in the final stages of epidermal differentiation, namely the formation of the epidermal barrier. We found that ΔNp63α contributes to epidermal barrier formation by directly inducing expression of ALOX12, a lipoxygenase which contributes to epidermal barrier function. Our data demonstrate that ΔNp63α directly interacts with the promoter of Alox12 in the developing epidermis. Furthermore, we found that the induction of Alox12 expression by ΔNp63α depends on intact p63 binding sites in the Alox12 promoter. Finally, we found that ΔNp63α can induce Alox12 expression only in differentiating keratinocytes, consistent with the role of ALOX12 in epidermal barrier formation.
Biological markers of prognosis, response to therapy and outcome in ovarian carcinoma

ABSTRACT Introduction: Ovarian cancer (OvCa) is among the most common types of cancer and is the leading cause of death from gynecological malignancies in western countries. Cancer biomarkers have a potential for improving the management of OvCa patients at every point from screening and detection, diagnosis, prognosis, follow up, response to therapy and outcome. Areas covered: The literature search has indicated a number of candidate biomarkers have recently emerged that could facilitate the molecular definition of OvCa, providing information about prognosis and predicting response to therapy. These potentially promising biomarkers include immune cells and their products, tumor-derived exosomes, nucleic acids and epigenetic biomarkers. Expert commentary: Although most of the biomarkers available today require prospective validation, the development of noninvasive liquid biopsy-based monitoring promises to improve their utility for evaluations of prognosis, response to therapy and outcome in OvCa.
The potential use of cell-free-circulating-tumor DNA as a biomarker for prostate cancer

ABSTRACT Introduction: We are yet to identify an accurate, precise and non-invasive biomarker for the detection of prostate cancer. It would undoubtedly be useful to have a reliable and cost-effective biomarker to inform clinical practice, in order to make a non-invasive diagnosis and to predict risk of progression to aggressive prostate cancer. Since the detection of cell-free-circulating-tumor DNA in the body fluids of prostate cancer patients, a number of studies have been conducted to assess diagnostic and/or prognostic information. Areas covered: In this literature review we evaluate the utility of cell-free-circulating-tumor-DNA for the development of a diagnostic and/or prognostic tool for prostate cancer. In addition, we identify potential areas for future research. Results from both quantitative and qualitative studies are presented. Expert commentary: Evidence for the suitability of a panel of DNA methylation markers for the non-invasive diagnosis of prostate cancer is strong. This panel would likely include the assessment of methylation status in gene promoter regions within the EDNR, GSTP1 and MDR genes. TIMP3 and APC show potential as diagnostic markers and should be further researched. Similarly, quantitation of cell-free-circulating-tumor-DNA in blood and urine requires further investigation.
Exploring the role of stem cells in cutaneous wound healing

Abstract: The skin offers a perfect model system for studying the wound healing cascade, which involves a finely tuned interplay between several cell types, pathways and processes. The dysregulation of these factors may lead to wound healing disorders resulting in chronic wounds, as well as abnormal scars such as hypertrophic and keloid scars. As the contribution of stem cells towards tissue regeneration and wound healing is increasingly appreciated, a rising number of stem cell therapies for cutaneous wounds are currently under development, encouraged by emerging preliminary findings in both animal models and human studies. However, we still lack an in‐depth understanding of the underlying mechanisms through which stem cells contribute to cutaneous wound healing. The aim of this review is, therefore, to present a critical synthesis of our current understanding of the role of stem cells in normal cutaneous wound healing. In addition to summarizing wound healing principles and related key molecular and cellular players, we discuss the potential participation of different cutaneous stem cell populations in wound healing, and list corresponding stem cells markers. In summary, this review delineates current strategies, future applications, and limitations of stem cell‐based or stem cell‐targeted therapy in the management of acute and chronic skin wounds.