Transcriptomics analysis reveals molecular alterations underpinning spaceflight dermatology.

BACKGROUND: Spaceflight poses a unique set of challenges to humans and the hostile spaceflight environment can induce a wide range of increased health risks, including dermatological issues. The biology driving the frequency of skin issues in astronauts is currently not well understood. METHODS: To address this issue, we used a systems biology approach utilizing NASA's Open Science Data Repository (OSDR) on space flown murine transcriptomic datasets focused on the skin, biochemical profiles of 50 NASA astronauts and human transcriptomic datasets generated from blood and hair samples of JAXA astronauts, as well as blood samples obtained from the NASA Twins Study, and skin and blood samples from the first civilian commercial mission, Inspiration4. RESULTS: Key biological changes related to skin health, DNA damage & repair, and mitochondrial dysregulation are identified as potential drivers for skin health risks during spaceflight. Additionally, a machine learning model is utilized to determine gene pairings associated with spaceflight response in the skin. While we identified spaceflight-induced dysregulation, such as alterations in genes associated with skin barrier function and collagen formation, our results also highlight the remarkable ability for organisms to re-adapt back to Earth via post-flight re-tuning of gene expression. CONCLUSION: Our findings can guide future research on developing countermeasures for mitigating spaceflight-associated skin damage.

Spaceflight is a hostile environment which can lead to health problems in astronauts, including in the skin. It is not currently well understood why these skin problems occur. Here, we analyzed data from the skin of space flown mice and astronauts to try and identify possible explanations for these skin problems. It appears that changes in the activation of genes related to damage to DNA, skin barrier health, and mitochondria (the energy-producing parts of cells) may play a role in these skin problems. Further research will be needed to confirm exactly how these changes influence skin health, which could lead to solutions for preventing and managing such issues in astronauts.

More than a Feeling: Dermatological Changes Impacted by Spaceflight.

Spaceflight poses a unique set of challenges to humans and the hostile Spaceflight environment can induce a wide range of increased health risks, including dermatological issues. The biology driving the frequency of skin issues in astronauts is currently not well understood. To address this issue, we used a systems biology approach utilizing NASA's Open Science Data Repository (OSDR) on spaceflown murine transcriptomic datasets focused on the skin, biomedical profiles from fifty NASA astronauts, and confirmation via transcriptomic data from JAXA astronauts, the NASA Twins Study, and the first civilian commercial mission, Inspiration4. Key biological changes related to skin health, DNA damage & repair, and mitochondrial dysregulation were determined to be involved with skin health risks during Spaceflight. Additionally, a machine learning model was utilized to determine key genes driving Spaceflight response in the skin. These results can be used for determining potential countermeasures to mitigate Spaceflight damage to the skin.

Management of skin cancer in recipients of solid organ transplants.

Recent improvements in post-transplant care have led to an increased life expectancy for recipients of organ transplants. These patients require lifelong immunosuppression, which is associated with an increased incidence of malignant disease. Skin cancers are the most common malignancies seen in recipients of organ transplants and are associated with significant morbidity and mortality. This review describes factors pertaining to the development and prognosis of skin cancers in recipients of organ transplants, as well as outlining prevention and management strategies in this cohort.

Diagnosis by numbers: defining skin disease pathogenesis through collated gene signatures.

Disease gene expression profiles can be utilized as biomarkers for diagnostic, prognostic, and targeted therapeutic purposes, although individual data sets may be of limited generic value. To develop broader clinical relevance from disease gene signatures, Inkeles et al. demonstrate how mining publically available microarray data from a range of skin disorders can elucidate disease pathways, generate a multi-disease classifier, and identify potential therapeutic targets. This integrative molecular classification and functional analysis offers a new approach to understanding disease pathogenesis, with significant implications for diagnostics and the development of personalized medicine.

Epithelial inflammation resulting from an inherited loss-of-function mutation in EGFR.

Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases, but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283 G>A; p.Gly428Asp) in a male infant with lifelong inflammation affecting the skin, bowel, and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules--similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient's skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died at the age of 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on other tissues.

Inherited blistering skin diseases: underlying molecular mechanisms and emerging therapies.

A key function of human skin is the formation of a structural barrier against the external environment. In part, this is achieved through the formation of a cornified cell envelope derived from a stratified squamous epithelium attached to an epithelial basement membrane. Resilient in health, the structural integrity of skin can become impaired or break down in a collection of inherited skin diseases, referred to as the blistering genodermatoses. These disorders arise from inherited gene mutations in a variety of structural and signalling proteins and manifest clinically as blisters or erosions following minor skin trauma. In some patients, blistering can be severe resulting in significant morbidity. Furthermore, a number of these conditions are associated with debilitating extra-cutaneous manifestations including gastro-intestinal, cardiac, and ocular complications. In recent years, an improved understanding of the molecular basis of the blistering genodermatoses has led to better disease classification and genetic counselling. For patients, this has also advanced translational research with the advent of new clinical trials of gene, protein, cell, drug, and small molecule therapies. Although curing inherited blistering skin diseases still remains elusive, significant improvements in patients' quality of life are already being achieved.

Next generation diagnostics of heritable connective tissue disorders.

Finding pathogenic mutations in monogenic diseases represents one of the significant milestones of late 20th century molecular genetics. Mutation data can improve genetic counseling, assist disease modeling and provide a basis for translational research and therapeutics. The logistics of detecting disease mutations, however, has not always been easy or straightforward. Traditional approaches using genetic linkage or candidate gene analysis have often been laborious and expensive, but the advent of next generation sequencing technologies is changing the very nature of modern-day gene discovery and mutation detection. The application of whole-exome and whole-genome sequencing has demonstrated how these new approaches can improve diagnostic sensitivity as well as disclose completely novel and unsuspected disease-gene associations. Use of next generation sequencing in inherited diseases that display genetic heterogeneity is already a cost-effective methodology for mutation detection. Further reductions in sequencing costs and machine run time, as well as improved bioinformatics, are likely to lead to the incorporation of next generation sequencing into routine diagnostics within clinical genetics. In the short term, the impact of next generation sequencing on the genetically diverse and clinically protean heritable connective tissue disorders is likely to mean more comprehensive documentation of individual mutations. Longer term, dissection of bioinformatics data may lead to further insight into individual prognosis and an era of new personal therapeutics.

Impact of next generation sequencing on diagnostics in a genetic skin disease clinic.

Individuals with inherited skin diseases often pose one of the most difficult diagnostic challenges in dermatology. The hunt for the underlying molecular pathology may involve candidate gene screening or linkage analysis, which is usually determined by the initial history, the physical findings and laboratory tests. Recent technical advances in DNA sequencing, however, are shifting the diagnostic paradigm. Notably, next-generation sequencing allows a more comprehensive approach to diagnosing inherited diseases, with potential savings of both time and money. In the setting of a paediatric dermatology genetics clinic in Kuwait, we therefore performed whole-exome sequencing on seven individuals without a priori detailed knowledge of the patients' disorders: from these sequencing data, we diagnosed X-linked hypohidrotic ectodermal dysplasia (two cases), acrodermatitis enteropathica, recessive erythropoietic protoporphyria (two siblings) and localized recessive dystrophic epidermolysis bullosa (two siblings). All these groups of disorders are clinically and genetically heterogeneous, but the sequencing data proved inherently useful in improving patient care and avoiding unnecessary investigations. Our observations highlight the value of whole-exome sequencing, in combination with robust bioinformatics analysis, in determining the precise molecular pathology and clinical diagnosis in patients with genetic skin disorders, notably at an early stage in the clinical evaluation of these often complex disorders and thereby support a new paradigm for future diagnostics.

The great deception: tranexamic acid and extensive pulmonary emboli.

Pulmonary embolism (PE) is a common and life-threatening condition. The British Thoracic Society PE guidelines state that PE is reliably excluded in patients with low-intermediate clinical probability and a negative D-dimer. We are reporting the case of a 47-year-old lady, taking tranexamic acid for menorrhagia, who presented with shortness of breath and was diagnosed with extensive bilateral PE. She had a low clinical risk of PE as determined by her Wells score, and a subsequent negative D-dimer. This patient's D-dimer value of 15 ng/ml (HemosIL DD HS assay) was the lowest associated with any CT pulmonary angiogram (n=1645) recorded at our trust over a 2-year period. This lady was successfully treated with a heparin infusion and warfarin. No further thromboembolic events had occurred by 18-month follow-up. To our knowledge, this is the first case report to describe tranexamic acid causing an extremely low false-negative D-dimer masking PE.

External iliac vein stenosis owing to prolonged cycling.

Prolonged cycling has previously been associated with external iliac artery stenosis, termed "cyclists' iliac syndrome." However, no association between external iliac vein stenoses and cycling has been previously described. We describe a unique case of a 70-year-old cyclist presenting with an iliofemoral deep venous thrombosis owing to an external iliac vein stenosis. This is the first case of a potential association between cycling and iliac vein stenosis. Further study and follow-up will be required to assess whether angioplasty and stenting is the optimal method of therapy for iliac vein stenoses owing to cycling.

Gerodermia osteodysplastica/wrinkly skin syndrome: report of three patients and brief review of the literature.

Gerodermia osteodysplastica and wrinkly skin syndrome are rare autosomal recessive disorders. Due to the many phenotypic similarities in these two conditions, it has been proposed that they represent the same disorder. Both conditions are well delineated in the genetic literature, but despite skin involvement being a striking feature, they are rarely reported in dermatology journals. In this report, we describe three Arab children from two consanguineous families who exhibit overlapping features of gerodermia osteodysplastica and wrinkly skin syndrome. All the patients had dysmorphic facial features, wrinkled skin more marked on the hands and feet, hyperextensible joints, intrauterine growth retardation, developmental delay, congenital dislocation of hips, and osteoporosis. Our observations also support the contention that gerodermia osteodysplastica and wrinkly skin syndrome have the same clinical spectrum; however, this needs to be confirmed at the molecular level.