Exchange Rate Dynamics: Where is the Saddle Path?

overshooting, cointegration, Johansen test, simulation, convergence behavior

Standardization of a new photodiagnosis method based on LEDs for patients with solar urticaria sensitive to visible light

Standard methods for photodiagnosis of solar urticaria are based in exposure of patient skin to different polychromatic UV and visible sources where minimal urticarial doses for different spectral bands (UVB and UVA) are established. Classical photodiagnosis devices are based in solar simulation and use of UVB and UVA enhanced fluorescent lamps. In case of visible US photodiagnosis, US patient skin is exposed for 15 min to a slight projector, provided with halogen lamp, at a distance of 15 cms and presence of erythema and/or wheals is determined as positive reaction. Slights projector is from several years almost out of market due to use of new projection digital technologies and new visible light emerging technologies are good candidates for their substitution as photodiagnosis tool. The objective of the present work is to analyze photodiagnosis of visible light solar urticaria with using a LED device in comparison to normal slight projector exposure protocol. A total of twenty patients, from 7 different photodiagnosis units have participated in the study. Patients, with SU positive to visible light (with or without to UV radiation) following the standard photodiagnosis protocols were included in the study. Slight projector used in all photodiagnosis units were of similar characteristics and irradiance at 15 cm distance, as well as total dose of visible light after 15 min were calculated for each halogen lamp device. LED exposure was performed in parallel in a closed zone of the back of the patients. For LED photodiagnosis a prototype from University of Málaga (Spain) has been developed consisting in a black box provided with 4 holes of 12 mm diameter in which each hole white warm of a LED of 1 W is emitted. Thus, each LEDs dose is controlled independently and the device allows establishing, as well as for UVB and UVA normal protocols a MUD also under visible light. In that case, maximal visible light dose is reached in less than 5 min compared to 15 min under exposure to slight projector. All patients were positive to LED warm visible light with presence of erythema and / or wheals in parallel to the exposure to the slight projector. A MUD to visible light has been established with significant variations between patients which reveals different grade to visible light sensibilization. In conclusion, a new technology of illumination based in LEDs can be used in photodiagnosis of SU.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Standardization of a new photodiagnosis method based on LEDs for patients with solar urticaria

Standard methods for photodiagnosis of solar urticaria are based in exposure of patient skin to different polychromatic UV and visible sources where minimal urticarial doses for different spectral bands (UVB and UVA) are established. Classical photodiagnosis devices are based in solar simulation and use of UVB and UVA enhanced fluorescent lamps. In case of visible US photodiagnosis, US patient skin is exposed for 15 min to a slight projector, provided with halogen lamp, at a distance of 15 cms and presence of erythema and/or wheals is determined as positive reaction. Slights projector is from several years almost out of market due to use of new projection digital technologies and new visible light emerging technologies are good candidates for their substitution as photodiagnosis tool. The objective of the present work is to analyze photodiagnosis of visible light solar urticaria with using a LED device in comparison to normal slight projector exposure protocol. A total of 30patients, from 8 different photodiagnosis units have participated in the study. Patients, with SU positive to visible light (with or without to UV radiation) following the standard photodiagnosis protocols were included in the study. Slight projector used in all photodiagnosis units were of similar characteristics and irradiance at 15 cm distance, as well as total dose of visible light after 15 min were calculated for each halogen lamp device. LED exposure was performed in parallel in a closed zone of the back of the patients. For LED photodiagnosis a prototype from University of Málaga (Spain) has been developed consisting in a black box provided with 4 holes of 12 mm diameter in which each hole white warm of a LEDof 1 W is emitted. Thus, each LEDs dose is controlled independently and the device allows establishing, as well as for UVB and UVA normal protocols a MUD also under visible light. In that case, maximal visible light dose is reached in less than 5 min compared to 15 min under exposure to slight projector. All patients were positive to LED warm visible light with presence of erythema and / or wheals in parallel to the exposure to the slight projector. A MUD to visible light has been established with significant variations between patients which reveals different grade to visible light sensibilization. In conclusion, a new technology of illumination based in LEDs can be used in photodiagnosis of SU.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Complex signatures of selection for the melanogenic loci TYR, TYRP1 and DCT in humans

<p>Abstract</p> <p>Background</p> <p>The observed correlation between ultraviolet light incidence and skin color, together with the geographical apportionment of skin reflectance among human populations, suggests an adaptive value for the pigmentation of the human skin. We have used Affymetrix U133a v2.0 gene expression microarrays to investigate the expression profiles of a total of 9 melanocyte cell lines (5 from lightly pigmented donors and 4 from darkly pigmented donors) plus their respective unirradiated controls. In order to reveal signatures of selection in loci with a bearing on skin pigmentation in humans, we have resequenced between 4 to 5 kb of the proximal regulatory regions of three of the most differently expressed genes, in the expectation that variation at regulatory regions might account for intraespecific morphological diversity, as suggested elsewhere.</p> <p>Results</p> <p>Contrary to our expectations, expression profiles did not cluster the cells into unirradiated versus irradiated melanocytes, or into lightly pigmented versus darkly pigmented melanocytes. Instead, expression profiles correlated with the presence of Bovine Pituitary Extract (known to contain α-MSH) in the media. This allowed us to differentiate between melanocytes that are synthesizing melanin and those that are not. <it>TYR, TYRP1 </it>and <it>DCT </it>were among the five most differently expressed genes between these two groups. Population genetic analyses of sequence haplotypes of the proximal regulatory flanking-regions included Tajima's D, HEW and DHEW neutrality tests analysis. These were complemented with EHH tests (among others) in which the significance was obtained by a novel approach using extensive simulations under the coalescent model with recombination. We observe strong evidence for positive selection for <it>TYRP1 </it>alleles in Africans and for <it>DCT </it>and <it>TYRP1 </it>in Asians. However, the overall picture reflects a complex pattern of selection, which might include overdominance for <it>DCT </it>in Europeans.</p> <p>Conclusion</p> <p>Diversity patterns clearly evidence adaptive selection in pigmentation genes in Africans and Asians. In Europeans, the evidence is more complex, and both directional and balancing selection may be involved in light skin. As a result, different non-African populations may have acquired light skin by alternative ways, and so light skin, and perhaps dark skin too, may be the result of convergent evolution.</p

Melanoma and nevi subtype histopathological characterization with optical coherence tomography

Background: Melanoma incidence has continued to rise in the latest decades, and the forecast is not optimistic. Non-invasive diagnostic imaging techniques such as optical coherence tomography (OCT) are largely studied; however, there is still no agreement on its use for the diagnosis of melanoma. For dermatologists, the differentiation of non-invasive (junctional nevus, compound nevus, intradermal nevus, and melanoma in-situ) versus invasive (superficial spreading melanoma and nodular melanoma) lesions is the key issue in their daily routine. Methods: This work performs a comparative analysis of OCT images using haematoxylin-eosin (HE) and anatomopathological features identified by a pathologist. Then, optical and textural properties are extracted from OCT images with the aim to identify subtle features that could potentially maximize the usefulness of the imaging technique in the identification of the lesion?s potential invasiveness. Results: Preliminary features reveal differences discriminating melanoma in-situ from superficial spreading melanoma and also between melanoma and nevus subtypes that pose a promising baseline for further research. Conclusions: Answering the final goal of diagnosing non-invasive versus invasive lesions with OCT does not seem feasible in the short term, but the obtained results demonstrate a step forward to achieve this.This work has been funded by the Department of Economic Development, Sustainability and the Environment of the Basque Government (Spain) ELKARTEK projects ONKOTOOLS with grant numbers KK-2020/00069, the Spanish Ministry of Science and Education CERVERA project AI4ES with grant numbers CER-20211030, and by the ECSEL JU European project ASTONISH with the grant number 692470, UC Industrial Doctorate DI14

The Interplay between Natural Selection and Susceptibility to Melanoma on Allele 374F of SLC45A2 Gene in a South European Population

We aimed to study the selective pressures interacting on SLC45A2 to investigate the interplay between selection and susceptibility to disease. Thus, we enrolled 500 volunteers from a geographically limited population (Basques from the North of Spain) and by resequencing the whole coding region and intron 5 of the 34 most and the 34 least pigmented individuals according to the reflectance distribution, we observed that the polymorphism Leu374Phe (L374F, rs16891982) was statistically associated with skin color variability within this sample. In particular, allele 374F was significantly more frequent among the individuals with lighter skin. Further genotyping an independent set of 558 individuals of a geographically wider population with known ancestry in the Spanish population also revealed that the frequency of L374F was significantly correlated with the incident UV radiation intensity. Selection tests suggest that allele 374F is being positively selected in South Europeans, thus indicating that depigmentation is an adaptive process. Interestingly, by genotyping 119 melanoma samples, we show that this variant is also associated with an increased susceptibility to melanoma in our populations. The ultimate driving force for this adaptation is unknown, but it is compatible with the vitamin D hypothesis. This shows that molecular evolution analysis can be used as a useful technology to predict phenotypic and biomedical consequences in humans

Involvement of ANXA5 and ILKAP in Susceptibility to Malignant Melanoma

Single nucleotide-polymorphisms (SNPs) are a source of diversity among human population, which may be responsible for the different individual susceptibility to diseases and/or response to drugs, among other phenotypic traits. Several low penetrance susceptibility genes associated with malignant melanoma (MM) have been described, including genes related to pigmentation, DNA damage repair and oxidative stress pathways. In the present work, we conducted a candidate gene association study based on proteins and genes whose expression we had detected altered in melanoma cell lines as compared to normal melanocytes. The result was the selection of 88 loci and 384 SNPs, of which 314 fulfilled our quality criteria for a case-control association study. The SNP rs6854854 in ANXA5 was statistically significant after conservative Bonferroni correction when 464 melanoma patients and 400 controls were analyzed in a discovery Phase I. However, this finding could not be replicated in the validation phase, perhaps because the minor allele frequency of SNP rs6854854 varies depending on the geographical region considered. Additionally, a second SNP (rs6431588) located on ILKAP was found to be associated with melanoma after considering a combined set of 1,883 MM cases and 1,358 disease-free controls. The OR was 1.29 (95% CI 1.12–1.48; p-value = 4×10−4). Both SNPs, rs6854854 in ANXA5 and rs6431588 in ILKAP, show population structure, which, assuming that the Spanish population is not significantly structured, suggests a role of these loci on a specific genetic adaptation to different environmental conditions. Furthermore, the biological relevance of these genes in MM is supported by in vitro experiments, which show a decrease in the transcription levels of ANXA5 and ILKAP in melanoma cells compared to normal melanocyte

Association of TYR SNP rs1042602 with Melanoma Risk and Prognosis

Cutaneous melanoma is the most aggressive of skin tumors. In order to discover new biomarkers that could help us improve prognostic prediction in melanoma patients, we have searched for germline DNA variants associated with melanoma progression. Thus, after exome sequencing of a set of melanoma patients and healthy control individuals, we identified rs1042602, an SNP within TYR, as a good candidate. After genotyping rs1042602 in 1025 patients and 773 healthy donors, we found that the rs1042602-A allele was significantly associated with susceptibility to melanoma (CATT test: p = 0.0035). Interestingly, we also observed significant differences between patients with good and bad prognosis (5 years of follow-up) (n = 664) (CATT test for all samples p = 0.0384 and for men alone p = 0.0054). Disease-free-survival (DFS) analyses also showed that patients with the A allele had shorter DFS periods. In men, the association remained significant even in a multivariate Cox Proportional-hazards model, which was adjusted for age at diagnosis, Breslow thickness, ulceration and melanoma subtype (HR 0.4; 95% confidence interval (CI) 0.20–0.83; p = 0.0139). Based on our results, we propose that rs1042602-A is a risk allele for melanoma, which also seems to be responsible for a poorer prognosis of the disease, particularly in men

Serum markers improve current prediction of metastasis development in early-stage melanoma patients: a machine learning-based study

Metastasis development represents an important threat for melanoma patients, even when diagnosed at early stages and upon removal of the primary tumor. In this scenario, determination of prognostic biomarkers would be of great interest. Serum contains information about the general status of the organism and therefore represents a valuable source for biomarkers. Thus, we aimed to define serological biomarkers that could be used along with clinical and histopathological features of the disease to predict metastatic events on the early-stage population of patients. We previously demonstrated that in stage II melanoma patients, serum levels of dermcidin (DCD) were associated with metastatic progression. Based on the relevance of the immune response on the cancer progression and the recent association of DCD with local and systemic immune response against cancer cells, serum DCD was analyzed in a new cohort of patients along with interleukin 4 (IL-4), IL-6, IL-10, IL-17A, interferon gamma (IFN-gamma), transforming growth factor-beta (TGF- beta), and granulocyte-macrophage colony-stimulating factor (GM-CSF). We initially recruited 448 melanoma patients, 323 of whom were diagnosed as stages I-II according to AJCC. Levels of selected cytokines were determined by ELISA and Luminex, and obtained data were analyzed employing machine learning and Kaplan-Meier techniques to define an algorithm capable of accurately classifying early-stage melanoma patients with a high and low risk of developing metastasis. The results show that in early-stage melanoma patients, serum levels of the cytokines IL-4, GM-CSF, and DCD together with the Breslow thickness are those that best predict melanoma metastasis. Moreover, resulting algorithm represents a new tool to discriminate subjects with good prognosis from those with high risk for a future metastasis.We are grateful to the Basque Biobank for providing the serum samples. We are also most grateful to Drs Arantza Arrieta and Natalia Maruri (Cruces University Hospital) for their technical support with the serum marker detection. This work was supported by grants from the Basque Government (KK2016-036 and KK2017-041 to MDB), UPV/EHU (GIU17/066 to MDB), H2020-ESCEL JTI (15/01 to MDB), and MINECO (PCIN-2015-241 to MDB

Simultaneous purifying selection on the ancestral MC1R allele and positive selection on the melanoma-risk allele V60L in South Europeans

In humans, the geographical apportionment of the coding diversity of the pigmentary locus melanocortin-1 receptor (MC1R) is, unusually, higher in Eurasians than in Africans. This atypical observation has been interpreted as the result of purifying selection due to functional constraint on MC1R in high UV-B radiation environments. By analyzing 3,142 human MC1R alleles from different regions of Spain in the context of additional haplotypic information from the 1000 Genomes (1000G) Project data, we show that purifying selection is also strong in southern Europe, but not so in northern Europe. Furthermore, we show that purifying and positive selection act simultaneously on MC1R. Thus, at least in Spain, regions at opposite ends of the incident UV-B radiation distribution show significantly different frequencies for the melanoma-risk allele V60L (a mutation also associated to red hair and fair skin and even blonde hair), with higher frequency of V60L at those regions of lower incident UV-B radiation. Besides, using the 1000G south European data, we show that the V60L haplogroup is also characterized by an extended haplotype homozygosity (EHH) pattern indicative of positive selection. We, thus, provide evidence for an adaptive value of human skin depigmentation in Europe and illustrate how an adaptive process can simultaneously help to maintain a disease-risk allele. In addition, our data support the hypothesis proposed by Jablonski and Chaplin (Human skin pigmentation as an adaptation to UVB radiation. Proc Natl Acad Sci U S A. 2010;107:8962-8968), which posits that habitation of middle latitudes involved the evolution of partially depigmented phenotypes that are still capable of suitable tanning.This works was supported by the former Spanish Ministerio de Ciencia e Innovación, project CGL2008-04066/BOS to S.A.; by the Dpt. Educacion, Universidades e Investigación of the Basque Government, project IT542-10; by program UFI11/09 by the University of the Basque Country, by "Programa de Investigacion Cientifica de la Universidad de La Laguna" (boc-a- 2010-255-7177), and by grants from the Health Institute “Carlos III” (FIS PI08/1383, FIS PI11/00623) to C.F. and co-financed by the European Regional Development Funds, “A way of making Europe” from the European Union. M.P.Y. was supported by a postdoctoral fellowship from Fundación Ramón Areces. We thank the Spanish Banco Nacional de AND (BNADN) (http://www.bancoadn.org/) for providing us with DNA samples from all over Spain. We also thank the Spanish Agencia Estatal de Meteorología (AEMET) (http://www.aemet.es/) for kindly providing us with the UV-B radiation data