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Extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER)-associated proteins that facilitate the tethering of the ER to the plasma membrane (PM), participating in lipid transfer between the membranes and supporting the Orai1-STIM1 interaction at ER-PM junctions. Orai1 and STIM1 are the core proteins of store-operated Ca 2+ entry (SOCE), a major mechanism for Ca 2+ influx that regulates a variety of cellular functions. Aberrant modulation of SOCE in cells from different types of cancer has been reported to underlie the development of several tumoral features. Here we show that estrogen receptor-positive (ER+) breast cancer MCF7 and T47D cells and triple-negative breast cancer (TNBC) MDA-MB-231 cells overexpress E-Syt1 and E-Syt2 at the protein level; the latter is also overexpressed in the TNBC BT20 cell line. E-Syt1 and E-Syt2 knockdown was without effect on SOCE in non-tumoral MCF10A breast epithelial cells and ER+ T47D breast cancer cells; however, SOCE was significantly attenuated in ER+ MCF7 cells and TNBC MDA-MB-231 and BT20 cells upon transfection with siRNA E-Syt1 or E-Syt2. Consistent with this, E-Syt1 and E-Syt2 knockdown significantly reduced cell migration and viability in ER+ MCF7 cells and the TNBC cells investigated. To summarize, E-Syt1 and E-Syt2 play a relevant functional role in breast cancer cells.

Background: Multiple, large or giant congenital melanocytic nevi (CMN) are uncommon and affected patients can show progressive growth and thickening, associate neurocutaneous melanocytosis or develop melanoma. Current treatment modalities are mostly complex surgeries that frequently do not solve the disease and its risks completely. Thus, investigation on new treatment options for CMN and its complications must continue. MAPK pathway inhibitors are being investigated, also targeting PI3K-AKT. Omipalisib (PI3K inhibitor, with no indications approved yet) has been studied for CMN in vitro and in mice with promising results. However, alpelisib, a PI3K inhibitor approved with an adequate safety profile for patients with severe manifestations of PROS (PIK3CA-Related Overgrowth Spectrum), had not yet been tested for CMN., Objective: To evaluate the effect of alpelisib in nevocytes of congenital melanocytic nevi., Methods: Nevomelanocytic tissue samples of 10 patients were collected prospectively and, following a previously reported preclinical ex vivo model, explants were placed in organotypic culture for 5 days, with or without alpelisib. Consecutively, tissue sections were stained and using scanned images with Qupath and ImageJ softwares, representative regions from the dermis were analysed (using Wilcoxon test and Spearman's correlation)., Results: When comparing alpelisib-treated explants with respect to control explants, we found a decrease in cell density (p = 0.0273), in density of SOX10 + -cells (p = 0.0391) and also in the % of S-100 + area (p = 0.0078), in alpelisib samples. The three markers showed a positive correlation (p < 0.05)., Conclusions: This study provides first-time evidence that alpelisib induces nevocyte reduction in CMN from patient-derived explants, probably inducted by autophagy. Alpelisib is an approved drug with an adequate safety profile used in another mosaicism affecting PI3K (PROS). Further studies are needed to evaluate its efficacy in treating CMN and potentially, their complications, either with local or systemic administration, alone or in combination., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Immunosuppressed (IS) patients, particularly solid organ transplant recipients and those on immunosuppressive therapy, face a higher incidence and recurrence of nonmelanoma skin cancers (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Mohs micrographic surgery (MMS) is the preferred treatment for high-risk NMSC due to its high cure rate and margin examination capabilities. However, IS patients may experience more complications, such as surgical site infections, and a greater risk of recurrence, making their outcomes a subject of interest., Objectives: This study aimed to compare IS and immunocompetent (IC) patients undergoing MMS for NMSC in terms of baseline characteristics, intra- and post-surgical complications, and postoperative recurrence rates., Methods: The study utilized data from the REGESMOHS registry, a 7-year prospective cohort study in Spain. It included 5226 patients, categorizing them into IC (5069) and IS (157) groups. IS patients included solid organ transplant recipients, those on immunosuppressive treatments, individuals with haematological tumours and HIV-positive patients. Patient data, tumour characteristics, surgical details and outcomes were collected and analysed., Results: IS patients demonstrated a higher proportion of SCC, multiple synchronous tumours and tumours invading deeper structures. Complex closures, unfinished MMS and more surgical sections were observed in the IS group. Although intra-operative morbidity was higher among IS patients, this difference became non-significant when adjusted for other variables such as year of surgery, antiplatelet/anticoagulant treatment or type of closure. Importantly, IS patients had a substantially higher recurrence rate (IRR 2.79) compared to IC patients., Conclusions: This study suggests that IS patients may be at a higher risk of development of AE such as bleeding or tumour necrosis and are at a higher risk of tumour recurrence. Close follow-up and consideration of the specific characteristics of NMSC in IS patients are crucial. Further research with extended follow-up is needed to better understand the long-term outcomes for this patient group., (© 2024 European Academy of Dermatology and Venereology.)

Background: We have conducted cooperative campaigns focusing on albino patients in a rural area of Malawi. What have we learned?, Methods: Three surgical campaigns were performed in Nkhotakota district (2019-2023). Albino clinical and tumor characteristics were collected., Results: Between 22 and 75 albinos were evaluated in each campaign (mean age < 28 years old). Most patients did not use sunscreen in a way that provided optimal photoprotection. Regarding tumors, the proportion of basal and squamous cell carcinomas ranged from 1:1 to almost 2:1. Of 156 albino patients, 34 attended more than once. However, of the 19 patients with 30 tumors operated on in 2021, only seven were assessed the following year (12 were lost to follow-up). At least 14 albinos with locally advanced tumors were evaluated., Conclusions: Distributing photoprotective clothing could be more efficient or perhaps an earlier measure of sunscreen in rural Africa as it does not require permanent repositioning. Very-high-risk patients (previous interventions with positive margins or high-risk tumors, intense actinic damage, and new tumors constantly appearing, especially those presenting SCCs) require close follow-up and treatment and represent our main target. Secondary prevention with Malawian collaboration and the use of teledermatology is essential for patient tracking, as they are able to offer curative treatments.

Neonatal platelets present a reduced response to the platelet agonist, thrombin (Thr), thus resulting in a deficient Thr-induced aggregation. These alterations are more pronounced in premature newborns. Here, our aim was to uncover the causes underneath the impaired Ca 2+ homeostasis described in neonatal platelets. Both Ca 2+ mobilization and Ca 2+ influx in response to Thr are decreased in neonatal platelets compared to maternal and control woman platelets. In neonatal platelets, we observed impaired Ca 2+ mobilization in response to the PAR-1 agonist (SFLLRN) or by blocking SERCA3 function with tert-butylhydroquinone. Regarding SOCE, the STIM1 regulatory protein, SARAF, was found overexpressed in neonatal platelets, promoting an increase in STIM1/SARAF interaction even under resting conditions. Additionally, higher interaction between SARAF and PDCD61/ALG2 was also observed, reducing SARAF ubiquitination and prolonging its half-life. These results were reproduced by overexpressing SARAF in MEG01 and DAMI cells. Finally, we also observed that pannexin 1 permeability is enhanced in response to Thr in control woman and maternal platelets, but not in neonatal platelets, hence, leading to the deregulation of the Ca 2+ entry found in neonatal platelets. Summarizing, we show that in neonatal platelets both Ca 2+ accumulation in the intracellular stores and Thr-evoked Ca 2+ entry through either capacitative channels or non-selective channels are altered in neonatal platelets, contributing to deregulated Ca 2+ homeostasis in neonatal platelets and leading to the altered aggregation observed in these subjects., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

(1) Background : The preferred reconstructive option for closing small- or medium-sized defects of the distal half of the nose is the use of local flaps. The dorsal nasal (Rieger) flap is suitable for closing medium-sized defects at this location, especially when they are medially located, and are wider rather than tall. We describe a rotation-transposition dorsal nasal flap reconstruction for large nasal defects. The novelty of this design includes the addition of a small transposition lobe to the rotation flap, enabling the acquisition of tissue from either the lateral sidewall or the nasolabial sulcus, facilitating closure with guitar-string sutures. (2) Methods : We conducted a retrospective chart review of all the patients with large defects (>20 mm) of the nose who underwent nasal dorsum rotation-transposition flap repair between January 2019 and November 2022 at a single academic center. (3) Results : Fourteen patients (eight males, six females; ages 47-83, mean age 60 years) with defects (range: 20.00-35.00 mm) on the dorsum and nasal tip were recruited. Follow-up duration ranged from 12 months to 3 years, with all cases showing good or excellent oncologic and cosmetic results. (4) Conclusions : The rotation-transposition dorsal nasal flap was demonstrated to be a reproducible one-stage technique for large defects of the dorsum and nasal tip, with minimal risk of aesthetic or functional complications. Guitar-string sutures allowed the reduction of the defect size, facilitating a smaller flap design.

Competing Interests: Conflicts of interest None disclosed.

Reconstruction of the auricular concha poses a challenge due to its difficult access and limited tissue flexibility; however, there are no recommendations in the literature on which reconstructive technique should be favored for this anatomical site. This systematic review intends to describe and compare the reconstructive techniques used in conchal bowl reconstruction following cutaneous oncologic surgery of this region, with regard to their complications and aesthetic results. In doing so, we aim to identify the best suited reconstructive procedure(s) for the conchal bowl. The six databases searched (PubMed, Scopus, Web of Science, Ovid, SciELO, and CENTRAL) yielded twelve eligible studies that explored the revolving door flap, split-thickness skin grafts (STSG), full-thickness skin grafts (FTSG), second intention healing, the preauricular translocation flap, subcutaneous pedicle grafts, and other local flaps. Qualitative synthesis of the results concluded that the revolving door flap could be the reconstructive procedure of choice for the auricular concha, following skin cancer excision. It has a low risk of necrosis, infection, and postoperative hemorrhage, as well as excellent aesthetic outcomes. STSG may be used as an alternative. Nonetheless, due to the low sample size and the high risk of bias in some studies, further investigations must be conducted on this subject.

Hypoxia is considered to be a stressful physiological condition, which may occur during labor and the later stages of pregnancy as a result of, among other reasons, an aged placenta. Therefore, when gestation or labor is prolonged, low oxygen supply to the tissues may last for minutes, and newborns may present breathing problems and may require resuscitation maneuvers. As a result, poor oxygen supply to tissues and to circulating cells may last for longer periods of time, leading to life-threatening conditions. In contrast to the well-known platelet activation that occurs after reperfusion of the tissues due to an ischemia/reperfusion episode, platelet alterations in response to reduced oxygen exposition following labor have been less frequently investigated. Newborns overcome temporal hypoxic conditions by changing their organ functions or by adaptation of the intracellular molecular pathways. In the present review, we aim to analyze the main platelet modifications that appear at the protein level during hypoxia in order to highlight new platelet markers linked to complications arising from temporal hypoxic conditions during labor. Thus, we demonstrate that hypoxia modifies the expression and activity of hypoxic-response proteins (HRPs), including hypoxia-induced factor (HIF-1), endoplasmic reticulum oxidase 1 (Ero1), and carbonic anhydrase (CIX). Finally, we provide updates on research related to the regulation of platelet function due to HRP activation, as well as the role of HRPs in intracellular Ca 2+ homeostasis.

Background: Repairing lower extremity defects presents challenges due to the scarcity of available local tissue. Skin grafting is a widely employed technique for addressing non-healing ulcers, improving the quality of life of patients and minimizing discomfort. However, using traditional donor sites, such as the thigh, can hinder mobility and result in noticeable scarring and pigmentation changes., Objectives: This study aims to assess the effectiveness of a novel approach utilizing autologous ultra-thin split-thickness skin grafts (STSGs) harvested from the scalp using a disposable, commercially available razor blade named DermaBlade., Methods: Fifteen patients (median age: 72 years, eight males and seven females) with diverse lower limb lesions, including carcinomas and ulcers of varying etiologies, were prospectively enrolled. Donor sites included the sideburn extending to the hairy temporal skin (nine cases) and hairy occipital skin (six cases). Ultra-thin skin strips (<0.2 mm thick) were obtained from the scalp through the use of the disposable flexible blade DermaBlade. The strips were positioned over the receptor area with no sutures in most cases and secured using dressings. A substantial majority of patients (90%) achieved successful graft take with no complications. Swift re-epithelialization occurred within a median of 12 days for the donor site and 24 days for the receptor site. No hair transfer or alopecic scars were noted., Conclusions: In contrast to traditional grafting methods, DermaBlade-assisted scalp grafting yields highly viable STSGs that adhere to wound beds without the need for sutures. Notable advantages of this technique encompass rapid wound healing, minimal complications, and superior cosmetic outcomes. Furthermore, it avoids scarring and alopecia, making it a promising approach for addressing lower extremity defects.

The conservation of threatened local livestock genetic resources involves characterising them to implement conservation strategies. The Utrerana is a Mediterranean-type chicken breed, included in the Official Catalogue of Livestock Breeds of Spain and in the Domestic Animal Diversity Information System (DAD-IS) of the Food and Agriculture Organization (FAO), native to south Spain created in 1926 by a farmer from Utrera (Seville province). It was selected for laying performance and with four plumage varieties (White, Black, Black-barred and Partridge), reaching average yields of 180 eggs per hen per year. It was widely used in commercial farming in the second quarter of the 20th century, being subsequently displaced in the second half of the 20th century by the spreading of the improved foreign breeds and lines. The Utrerana breed was reared from then on for its aesthetic values and in backyard systems, being endangered with a vulnerable local risk status (1822 birds in 2022 with an increasing trend) and having worsened its laying performance as selection for productivity ceased. The breed has received little attention from the research community. Therefore, this work aims to review the literature on the origin, selection, genetic and productive characterisation and status of the populations of the breed, as well as the conservation strategies. The Utrerana chicken is a polymorphic breed showing high genetic diversity, sexual dimorphism and morpho-functional differences among varieties. Currently, Utrerana hens start laying at 6 months of age, and a hen lays 94-121 high quality eggs (59-64 g) per year, showing seasonality. It is a slow-growing breed with mature weights of 2.4-2.6 kg for roosters and 1.9-2.0 g for hens. The Utrerana chicken breed is rustic and adapted to alternative farming systems. This review has identified research gaps to be filled, such as characterising the carcass and meat quality of the Utrerana chicken, and evidences the need to make efforts to promote the breed and expand its populations.

The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca 2+ entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca 2+ sensors in the endoplasmic reticulum (ER) and, upon Ca 2+ store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca 2+ signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders. Therefore, understanding the mechanisms underlying Ca 2+ signaling pathways is crucial for developing therapeutic strategies targeting these diseases. This review focuses on several rare conditions associated with STIM1 mutations that lead to either gain- or loss-of-function, characterized by myopathy, hematological and immunological disorders, among others, and due to abnormal activation of CRACs. In addition, we summarize the current evidence concerning STIM2 allele duplication and deletion associated with language, intellectual, and developmental delay, recurrent pulmonary infections, microcephaly, facial dimorphism, limb anomalies, hypogonadism, and congenital heart defects.

The forehead and temporal region are frequent areas of skin cancer development. After tumor removal, reconstruction must be performed, maintaining the frontal-temporal line of the scalp and symmetry of the eyebrows in an attempt to hide the scars within these marks or natural folds and wrinkles. Second wound healing and skin grafts generally do not produce an acceptable cosmetic result. When direct closure is not possible, the technique of choice is skin flaps. In the midfrontal line continuation of the glabella, there is a remnant of skin to be used as a donor area for local flaps; similarly, it occurs in the preauricular cheek, which can move toward the temple. In addition to the classic advancement and rotation flaps, the frontalis myocutaneous transposition flap is an excellent technique for closing defects which are wider than higher on the forehead. Its design is very versatile and can be performed between the two pupil lines at different heights depending on the location of the defect. On the other hand, the preauricular skin advancement flap with an infralobular Burow's triangle is also an excellent option for reconstructing tumors in the temporal area.

The long-term storage of eggs before incubation is a common practice in some alternative poultry systems but needs to be performed under conditions that preserve egg viability. The effects of the long-term storage of game farmed quail ( Coturnix coturnix ) eggs on weight loss during the storage and incubation periods, chick weight at hatch, hatchability, and incubation length were investigated. The eggs were arranged in six treatments submitted to 0-, 7-, 14-, 21-, 28-, and 35-day storage periods at 15.8 °C and 80% relative humidity. The storage length reduced the hatchability of eggs ( p < 0.05) when the storage was extended to 35 days, decreasing by more than half compared to eggs stored up to 28 days. Egg weight loss during storage progressively increased with the storage length ( p < 0.05). Chick weight at hatching was reduced in eggs stored for more than 14 days ( p < 0.05), and relative chick weight decreased significantly in eggs stored for 35 days ( p < 0.05). Incubation length progressively increased with the storage length ( p < 0.05), achieving less hatching synchrony in eggs stored for a longer time ( p < 0.05). In conclusion, game quail eggs store well with little deterioration up to 28 days at 15.8 °C and 80% relative humidity, allowing for extended storage when shipping long-shelf-life eggs or assembling batches large enough to fully set an incubator in farms with small breeding flocks.

Background: Satellitosis or in-transit metastasis (S-ITM) has clinical outcomes comparable to node-positivity in cutaneous squamous cell carcinoma (cSCC). There is a need to stratify the risk groups., Objective: To determine which prognostic factors of S-ITM confer an increased risk of relapse and cSCC-specific-death., Methods: A retrospective, multicenter cohort study. Patients with cSCC developing S-ITM were included. Multivariate competing risk analysis evaluated which factors were associated with relapse and specific death., Results: Of a total of 111 patients with cSCC and S-ITM, 86 patients were included for analysis. An S-ITM size of ≥20 mm, >5 S-ITM lesions, and a primary tumor deep invasion was associated with an increased cumulative incidence of relapse (subhazard ratio [SHR]: 2.89 [95% CI, 1.44-5.83; P = .003], 2.32 [95% CI, 1.13-4.77; P = .021], and 2.863 [95% CI, 1.25-6.55; P = .013]), respectively. Several >5 S-ITM lesions were also associated with an increased probability of specific death (SHR: 3.48 [95% CI, 1.18-10.2; P = .023])., Limitations: Retrospective study and heterogeneity of treatments., Conclusion: The size and the number of S-ITM lesions confer an increased risk of relapse and the number of S-ITM an increased risk of specific-death in patients with cSCC presenting with S-ITM. These results provide new prognostic information and can be considered in the staging guidelines., Competing Interests: Conflicts of interest The authors have no conflicts of interest to declare., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

(1) Introduction: The association between melanoma (MM) and the occurrence of second primary neoplasms (SPNs) has been extensively studied, with reported incidence rates ranging from 1.5% to 20%. This study aims to evaluate the occurrence of SPNs in patients with a history of primary MM and to describe the factors that make the risk higher in our population. (2) Material and Methods: We conducted a prospective cohort study and calculated the incidence rates and relative risks (RR) for the development of different SPNs in 529 MM survivors from 1 January 2005 to 1 August 2021. Survival and mortality rates were obtained, and the Cox proportional hazards model was used to determine the demographic and MM-related factors that influence the overall risk. (3) Results: Among the 529 patients included, 89 were diagnosed with SPNs (29 prior to MM diagnosis, 11 synchronous, and 49 after MM), resulting in 62 skin tumors and 37 solid organ tumors. The estimated probability of developing SPNs after MM diagnosis was 4.1% at 1 year, 11% at 5 years, and 19% at 10 years. Older age, primary MM location on the face or neck, and histologic subtype of lentigo maligna mm were significantly associated with a higher risk of SPNs. (4) Conclusions: In our population, the risk of developing SPNs was higher in patients with primary MM located on the face and neck and with the histological subtype of lentigo maligna-MM. Age also independently influences the risk. Understanding these hazard factors can aid in the development of MM guidelines with specific follow-up recommendations for individuals with the highest risk.

Background: Altered intracellular Ca 2+ homeostasis in neonatal platelets has been previously reported. This study aims to examine the changes in the Ca 2+ entry through the store-operated calcium entry (SOCE) mechanism in neonatal platelets., Methods: Human platelets from either control women, mothers, and neonates were isolated and, following, were fixed after being treated as required. Platelet samples were analyzed by Western blotting, qRT-PCR, and MALDITOF/TOF. Ca 2+ homeostasis was also determined. Culture cells were used as surrogated of platelets to overexpress the proteins of interest to reproduce the alterations observed in platelets., Results: Altered TG (thapsigargin)-evoked SOCE, alternative molecular weight form of STIM1 (stromal interaction molecule 1; s-STIM1 [short STIM1 isoform (478 aa)], around 60 kDa) and overexpression of SARAF (SOCE-associated regulatory factor) were found in neonatal platelets as compared to maternal and control women platelets. s-STIM1 may result due to CAPN1 (calpain1)-dependent processing, as confirmed in platelets and MEG01 cells by using calpeptin and overexpressing CAPN1, respectively. In HEK293 (STIM1 and STIM2 [stromal interaction molecule 2] double knockout) cells transfected either with c-STIM1 (canonical STIM1 [685 aa]), s-STIM1 (478), STIM1B (540), and CAPN1 overexpression plasmids, we found s-STIM1 and c-STIM1, except in cells overexpressing s-STIM1 (478) that lacked CAPN1 target residues. These results and the in silico analysis, lead us to conclude that STIM1 is cleaved at Q496 by CAPN1. Ca 2+ imaging analysis and coimmunoprecipitation assay using MEG01 and HEK293 cells overexpressing SARAF together with s-STIM1 (478) reported a reduced slow Ca 2+ -dependent inactivation, so reproducing the Ca 2+ -homeostasis pattern observed in neonatal platelets., Conclusions: CAPN1 may cleave STIM1 in neonatal platelets, hence, impairing SARAF coupling after SOCE activation. s-STIM1 may avoid slow Ca 2+ -dependent inactivation and, subsequently, results in an enhanced TG-evoked SOCE as observed in neonatal platelets.

Introduction: There is still a need to develop a simple algorithm to identify patients likely to need complex Mohs micrographic surgery (MMS) and optimize MMS schedule. The main objectives of this study are to identify factors associated with a complex MMS and develop a predictor model of the number of stages needed in surgery and the need for a complex closure., Materials and Methods: A nationwide prospective cohort study (REGESMOHS, the Spanish Mohs surgery registry) was conducted including all patients with a histological diagnosis of basal cell carcinoma (BCC). Factors related to three or more stages and a complex closure (that needing a flap and/or a graft) were explored and predictive models were constructed and validated to construct the REGESMOSH scale., Results: A total of 5226 patients that underwent MMS were included in the REGESMOHS registry, with 4402 (84%) having a histological diagnosis of BCC. A total of 3689 (88.9%) surgeries only needed one or two stages and 460 (11.1%) required three or more stages. A model to predict the need for three or more stages included tumour dimension, immunosuppression, recurrence, location in risk areas, histological aggressiveness and previous surgery. Regarding the closure type, 1616 (38.8%) surgeries were closed using a non-complex closure technique and 2552 (61.2%) needed a complex closure. A model to predict the need for a complex closure included histological aggressiveness, evolution time, patient age, maximum tumour dimension and location., Conclusion: We present a model to predict MMS needing ≥3 stages and a complex closure based on epidemiological and clinical data validated in a large population (with real practice variability) including different centres that could be easily implemented in clinical practice. This model could be used to optimize surgery schedule and properly inform patients about the surgery duration., (© 2023 European Academy of Dermatology and Venereology.)

Quail ( Coturnix genus) game farms were characterised in Spain using variables related to their age, geographical distribution, farmed species, structure, size, and commercialisation, using a survey conducted on 21 farms in 2018. It was found that 38.1% of the sample represented complete-cycle farms, and 61.9%, which have no breeding flocks, undertook only the finishing phase of quail raising. The average size of the breeding flock, with regard to complete-cycle farms, was 1096 males and 3735 females, with a female/male ratio of 3.6, and 75% of these farms carried out self-replacement of breeding quails. The most farmed species was European quail ( Coturnix coturnix ), followed by Japanese quail ( Coturnix japonica ), and hybrids of both species. In addition to quail, all farms produced other gamebird species such as pheasant ( Phasianus colchicus ) and red-legged partridge ( Alectoris rufa ). The rearing phase, which began when the chicks were one-day-old, lasted 35.3 days on average (range: 25-49 days), with an average stocking density of 47.2 birds/m 2 in the brooder house. The finishing phase, which was carried out in flying pens at a stocking density of 9.5 birds/m 2 , ended when the quails' average age was 60.5 days. All farms sold quails for release in hunting reserves (EUR 1.54 per bird) and for dog training (EUR 1.65 per bird) for almost 10 months of the year; only 62% sold quails for shooting after being thrown with an adapted clay-pigeon shooting machine (EUR 1.49 per bird). Transporting quails to their destination (95.2% of the farms) and releasing the birds in the client's hunting preserve (52.4% of the farms) were services offered by the farms, among others. The main advertising and promotional strategies undertaken by the quail game farms to gain a share of the market included maintaining a business website (85.7% of the farms) and attending game and agricultural fairs (47.6% of the farms). In conclusion, this alternative poultry sector has been consolidated in Spain, five decades since the establishment of the first game farms, and it satisfies a relevant part of the demand for quail hunting.

Background: Fifteen to forty percent of patients with localized cutaneous melanoma (CM) (stages I-II) will experience disease relapse. The 31-gene expression profile (31-GEP) uses gene expression data from the primary tumor in conjunction with clinicopathologic features to refine patient prognosis. The study's objective was to evaluate 31-GEP risk stratification for disease-free survival (DFS) in a previously published cohort with longer follow-up., Methods: Patients with stage IB-II CM ( n = 86) were prospectively tested with the 31-GEP. Follow-up time increased from 2.2 to 3.9 years. Patient outcomes were compared using Kaplan-Meier and Cox regression analysis., Results: A Class 2B result was a significant predictor of 3-year DFS (hazard ratio (HR) 8.4, p = 0.008) in univariate analysis. The 31-GEP significantly stratified patients by risk of relapse ( p = 0.005). A Class 2B result was associated with a lower 3-year DFS (75.0%) than a Class 1A result (100%). The 31-GEP had a high sensitivity (77.8%) and negative predictive value (95.0%)., Conclusions: The 31-GEP is a significant predictor of disease relapse in patients with stage IB-II melanoma and accurately stratified patients by risk of relapse.

Background: Large prospective studies on the safety of Mohs micrographic (MMS) surgery are scarce, and most focus on a single type of surgical adverse event. Mid-term scar alterations and functional loss have not been described., Objectives: To describe the risk of MMS complications and the risk factors for them., Methods: A nationwide prospective cohort collected all adverse events on consecutive patients in 22 specialised centres. We used multilevel mixed-effects logistic regression to find out factors associated with adverse events., Results: 5,017 patients were included, with 14,421 patient-years of follow-up. 7.0% had some perioperative morbidity and 6.5% had mid-term and scar-related complications. The overall risk of complications was mainly associated with use of antiaggregant/anticoagulant and larger tumours, affecting deeper structures, not reaching a tumour-free border, and requiring complex repair. Age and outpatient setting were not linked to the incidence of adverse events. Risk factors for haemorrhage (0.9%) were therapy with antiaggregant/anticoagulants, tumour size, duration of surgery, and unfinished surgery. Wound necrosis (1.9%) and dehiscence (1.0%) were associated with larger defects and complex closures. Immunosuppression was only associated with an increased risk of necrosis. Surgeries reaching deeper structures, larger tumours and previous surgical treatments were associated with wound infection (0.9%). Aesthetic scar alterations (5.4%) were more common in younger patients, with larger tumours, in H-area, and in flap and complex closures. Risk factors for functional scar alterations (1.7%) were the need for general anaesthesia, larger tumours that had received previous surgery, and flaps or complex closures., Conclusions: MMS shows a low risk of complications. Most of the risk factors for complications were related to tumour size and depth, and the resulting need for complex surgery. Antiaggregant/anticoagulant intake was associated with a small increase in the risk of haemorrhage, that probably does not justify withdrawal. Age and outpatient setting were not linked to the risk of adverse events., (© 2021 S. Karger AG, Basel.)

Background: Regucalcin, or senescence marker protein-30 (SMP30), is a Ca 2+ -binding protein with multiple functions reported in the literature. Physical exercise has been shown to improve aging markers; nevertheless, SMP30 in humans has not been extensively researched. Older adults experience a decline in functional capacity and body composition. The purpose of this study was to examine the effects of a multicomponent training (MCT) program on SMP30 and its regulation of walking ability and body composition in functionally limited, frail, and pre-frail older adults., Methods: A total of 34 older adults (aged 80.3 ± 6.1 years) were divided into an intervention group (IG = 20) and control group (CG = 14). The IG performed a supervised MCT (strength, endurance, balance, coordination, and flexibility) program for 6 months, 3 days per week, whereas the CG continued their normal lives without any specific physical training. SMP30 was analyzed in plasma after 3 and 6 months of MCT, while some physical fitness variables (Timed Up and Go (TUG) and 6-min walk test (6MWT)) and body composition (fat mass and lean mass) were measured at baseline, as well as after 3 months and 6 months of MCT., Results: No significant changes were observed in SPM30 between the IG (877.5 a.u. to 940.5 a.u., respectively) and CG (790.4 a.u. to 763.8 a.u., respectively). Moreover, no SMP30 differences were found between groups after 3 and 6 months of MCT. The IG improved significantly in the 6MWT after 3 months (472.2 ± 84.2 m) compared to baseline (411.2 ± 75.2 m). The IG also significantly enhanced their TUG performance after 3 months (7.6 ± 1.6 s) and 6 months (7.3 ± 1.8 s) of training compared to baseline (9.3 ± 3.2 s) (all, p < 0.001). There were no significant differences in body composition between the IG and CG through the 6 months of MCT., Conclusions: The present study suggests that MCT did not change SMP30 levels from 3 to 6 months, where there were changes in neither walking ability nor body composition; however, MCT was effective in improving 6MWT and TUG performance from baseline to 3 months.

Breast cancer is a heterogeneous disease from the histological and molecular expression point of view, and this heterogeneity determines cancer aggressiveness. Store-operated Ca 2+ entry (SOCE), a major mechanism for Ca 2+ entry in non-excitable cells, is significantly remodeled in cancer cells and plays an important role in the development and support of different cancer hallmarks. The store-operated CRAC (Ca 2+ release-activated Ca 2+ ) channels are predominantly comprised of Orai1 but the participation of Orai2 and Orai3 subunits has been reported to modulate the magnitude of Ca 2+ responses. Here we provide evidence for a heterogeneous expression of Orai2 among different breast cancer cell lines. In the HER2 and triple negative breast cancer cell lines SKBR3 and BT20, respectively, where the expression of Orai2 was greater, Orai2 modulates the magnitude of SOCE and sustain Ca 2+ oscillations in response to carbachol. Interestingly, in these cells Orai2 modulates the activation of NFAT1 and NFAT4 in response to high and low agonist concentrations. Finally, we have found that, in cells with high Orai2 expression, Orai2 knockdown leads to cell cycle arrest at the G0-G1 phase and decreases apoptosis resistance upon cisplatin treatment. Altogether, these findings indicate that, in breast cancer cells with a high Orai2 expression, Orai2 plays a relevant functional role in agonist-evoked Ca 2+ signals, cell proliferation and apoptosis resistance.

Randomized studies to assess the efficacy of Mohs micrographic surgery in basal cell and squamous cell carcinomas are limited by methodological and ethical issues and a lack of long follow-up periods. This study presents the "real-life" results of a nationwide 7-years cohort on basal cell carcinoma and squamous cell carcinoma treated with Mohs micrographic surgery. A prospective cohort was conducted in 22 Spanish centres (from July 2013 to February 2020) and a multivariate analysis, including characteristics of patients, tumours, surgeries and follow-up, was performed. A total of 4,402 patients followed up for 12,111 patient-years for basal cell carcinoma, and 371 patients with 915 patient-years of follow-up for squamous cell carcinoma were recruited. Risk factors for recurrence included age, non-primary tumours and more stages or unfinished surgeries for both tumours, and immunosuppression for squamous cell carcinoma. Incidence rates of recurrence were 1.3 per 100 person-years for basal cell carcinoma (95% confidence interval 1.1-1.5) and 4.5 for squamous cell carcinoma (95% confidence interval 3.3-6.1), being constant over time (0-5 years). In conclusion, follow-up strategies should be equally intense for at least the first 5 years, with special attention paid to squamous cell carcinoma (especially in immunosuppressed patients), elderly patients, non-primary tumours, and those procedures requiring more stages, or unfinished surgeries.

Purpose: The aim of this study was to evaluate the outcomes, complications and psychosocial impact of surgical treatment of giant congenital melanocytic nevus (GCMN)., Methods: Patients with surgically treated GCMN who attended our clinic between May 2014 and May 2018 were included. Patient demographics and data on the characteristics of the nevus, surgical treatment, and the psychosocial impact (including C-DLQI/DLQI questionnaires) were collected., Results: One hundred thirty-six patients were included (median age 9 years). Mean age at first surgery was 34 (+/- 61.45) months; 5.53 (+/- 3.69) surgical interventions were necessary to completely excise the nevus. The expanded skin flap was the preferred surgical technique in most locations. Complications were common but not severe. Of the patients studied, 70.4% reported that the surgery had a minor impact on their quality of life (QoL). Patients and caregivers stated that surgical treatment should begin as soon as possible, even in cases where early treatment did not have an impact on their QoL nor on their satisfaction with the surgery (p < 0.05). The lower the patient age at first surgery, the higher the surgeon's satisfaction (p < 0.01)., Conclusions: Surgical treatment is a safe option for management of GCMN, and has a low impact on QoL. Patients, caregivers, and surgeons agree that the treatment should begin as soon as possible. This is the largest single-center study evaluating surgical treatment in GCMN patients and its psychosocial impact, and the first to take into account the patient, caregivers and dermatologists opinion of surgical results., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rabbits often experience stress when they perceive certain stimuli, such as handling. The physiological response of animals to stress and temperament is associated with feeding efficiency, with those with the least capacity to react to stress showing the highest performance. The aim of this study was to evaluate the impact of stress due to heat (temperature-humidity index; THI) or handling, assessed using infrared thermography, on the performance parameters of rabbits of a Spanish Common breed. Thirty-nine rabbits were analyzed during a 38-d fattening period at two times of the year: a cold period and a warm period. The rabbits' stress due to handling was assessed by the temperature difference taken in the inner ear, before and after being handled. The animals were more productive in the cold season. Temperature-humidity index significantly influenced average daily gain (ADG) and daily feed intake (DFI). Rabbits with higher levels of stress showed higher ADG, DFI and feed conversion ratio (FCR) values. The greater the stress due to handling, the less efficient the animals were. FCR increased with higher THI. It was concluded that changes in animal welfare caused by the rabbits' reactivity to both climatic and individual factors affect animal productivity.

Characterization of patients, surgery procedures and the risk factors for dermatofibrosarcoma protuberans (DFSP) recurrences is poorly defined. In this study, we aimed to describe the demographics, tumor characteristics and interventions of DFSP treated with Mohs micrographic surgery (MSS) to determine the rate and risk factors for recurrence. Data were collected from REGESMOHS, a nationwide prospective cohort study of patients treated with MMS in Spain. From July 2013 to February 2020, 163 patients with DFSP who underwent MMS were included. DFSP was mostly located on trunk and extremities. Recurrent tumors had deeper tumor invasion and required higher number of MMS stages. Paraffin MMS was the most frequently used technique. Overall recurrence rate was 0.97 cases/100 person-years (95% IC = 0.36-2.57). No differences were found in epidemiological, tumor, surgery characteristics or surgical technique (frozen or paraffin MMS [p = 0.6641]) in terms of recurrence. Median follow-up time was 28.6 months with 414 patient-years of follow-up. In conclusion, we found an overall low recurrence rate of DFSP treated with MMS. None of the studied risk factors, including MMS techniques, was associated with higher risk for recurrence., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers 1-5 . However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.

Progesterone receptor membrane component 1 (PGRMC1) has been shown to regulate some cancer hallmarks. Progesterone (P 4 ) evokes intracellular calcium (Ca 2+ ) changes in the triple-negative breast cancer cell lines (MDA-MB-231, MDA-MB-468, and BT-20) and in other breast cancer cell lines like the luminal MCF7 cells. PGRMC1 expression is elevated in MDA-MB-231 and MCF7 cells as compared to non-tumoral MCF10A cell line, and PGRMC1 silencing enhances P 4 -evoked Ca 2+ mobilization. Here, we found a new P 4 -dependent Ca 2+ mobilization pathway in MDA-MB-231 cells and other triple-negative breast cancer cells, as well as in MCF7 cells that involved Stromal interaction molecule 2 (STIM2), Calcium release-activated calcium channel protein 1 (Orai1), and Transient Receptor Potential Channel 1 (TRPC1). Stromal interaction molecule 1 (STIM1) was not involved in this novel Ca 2+ pathway, as evidenced by using siRNA STIM1. PGRMC1 silencing reduced the negative effect of P 4 on cell proliferation and cell death in MDA-MB-231 cells. In line with the latter observation, Nuclear Factor of Activated T-Cells 1 (NFAT1) nuclear accumulation due to P 4 incubation for 48 h was enhanced in cells transfected with the small hairpin siRNA against PGRMC1 (shPGRMC1). These results provide evidence for a novel P 4 -evoked Ca 2+ entry pathway that is downregulated by PGRMC1.

The effect of consuming breads made with wheat flour and Amaranth ( Amaranthus dubius Mart. ex Thell.) wholemeal flour on Sprague Dawley rats with hyperlipidaemia and hyperglycaemia induced through feeding was studied. Four diets were provided: control (CD: Ratarina ® ), commercial bread (CBD), bread with 100 g·kg -1 (ABD10) and 200 g·kg -1 (ABD20) amaranth flour. Zoometric and blood chemistry parameters were measured before and after consuming the diets. A completely random factorial design of 2 × 4 × 2 was used. The factors were blood lipids and glucose level (normal, N and elevated, E), diet (CD, CBD, ABD10 and ABD20) and sex (female, F and male, M). The rats consuming ABD10 and ABD20 diets presented the lowest glucose values, although with no differences ( p > 0.05) between the groups of elevated blood lipids and glucose rats (E). Triglyceride concentrations decreased in ABD10 and ABD20 treatments in comparison with CD, elevated blood lipids and glucose (E) rats, while ABD10 rats showed lower total cholesterol level than normal (N) rats. The high-density lipoprotein cholesterol values increased in the ABD10 and ABD20 groups ( p < 0.05), while it did lower for very low-density lipoprotein cholesterol and cardiac risk index ( p < 0.05). In ABD10 and ABD20 treatments, the abdominal circumference decreased in both sexes ( p < 0.05) between weeks 23 and 31. In conclusion, consumption of bread with amaranth improved lipid profiles of rats and could help to prevent metabolic and cardiovascular diseases.

Arachidonic acid (AA) is a phospholipase A2 metabolite that has been reported to mediate a plethora of cellular mechanisms involved in healthy and pathological states such as platelet aggregation, lymphocyte activation, and tissue inflammation. AA has been described to activate Ca 2+ entry through the arachidonate-regulated Ca 2+ -selective channels (ARC channels). Here, the analysis of the changes in the intracellular Ca 2+ homeostasis revealed that, despite MDA-MB-231 cells expressing the ARC channel components Orai1, Orai3, and STIM1, AA does not evoke Ca 2+ entry in these cells. We observed that AA evokes Ca 2+ entry in MDA-MB-231 cells transiently expressing ARC channels. Nevertheless, MDA-MB-231 cell treatment with AA reduces cell proliferation and migration while inducing cell death through apoptosis. The latter mostly likely occurs via mitochondria membrane depolarization and the activation of caspases-3, -8, and -9. Altogether, our results indicate that AA exerts anti-tumoral effects on MDA-MB-231 cells, without having any effect on non-tumoral breast epithelial cells, by a mechanism that is independent on the activation of Ca 2+ influx via ARC channels.

Background: The use of Mohs micrographic surgery (MMS) for rare cutaneous tumors is poorly defined. We aim to describe the demographics, tumor presentation and topography, surgery characteristics and complications of MMS for rare cutaneous tumors in a national registry., Methods: Prospective cohort study of patients treated with MMS in Spain between July 2013 and June 2018. The inclusion criteria were patients with cutaneous tumors with final diagnosis different from basal cell carcinoma, squamous cell carcinoma, dermatofibrosarcoma protuberans, or any kind of melanoma., Results: Five thousand and ninety patients were recorded in the registry, from which only 73 tumors (1.4%) fulfilled the inclusion criteria: atypical fibroxanthoma (18), microcystic adnexal carcinoma (10), extramammary Paget's disease (7), Merkel cell carcinoma (5), dermatofibroma (4), trichilemmal carcinoma (4), desmoplastic trichoepithelioma (4), sebaceous carcinoma (3), leiomyosarcoma (2), porocarcinoma (2), angiosarcoma (2), trichoblastoma (1), superficial acral fibromyxoma (1), and others (10). No intra-surgery morbidity was registered. Postsurgery complications appeared in six patients (9%) and were considered mild. Median follow-up time was 0.9 years during which three Merkel cell carcinomas, one angiosarcoma, one microcystic adnexal carcinoma, and four others recurred (12.3%)., Conclusion: This national registry shows that rare cutaneous tumors represent a negligible part of the total MMS performed in our country with a low complication rate., (© 2019 The International Society of Dermatology.)

In order to study the effect of different amounts of concentrate feed and the effectiveness of natural antioxidants on the fatty acid stability of intramuscular fat during the first days postmortem, 75 young bulls of the Retinta breed were divided in three groups: 30 were grazed, 30 were fed on medium concentrate diets, and 15 were fed on high-concentrate diets. Young bulls were slaughtered at commercial weight, around a 500 kg final body weight. Samples from Longissimus lumborum muscle were assigned to two ageing periods (0 and 7 d) and were vacuum packaged in vacuum bags ( O 2 permeability: 9.3  mL   O 2 / m 2 per 24  h at 0  ∘ C ) using an EGARVAC ® sealer. Beef from grass-fed bulls showed a higher polyunsaturated fatty acid content than concentrate-fed bulls. During the first 7 d postmortem, no changes in the fatty acids profile were observed, because α -tocopherol content was optimal to prevent lipid oxidation. The higher level of natural antioxidants in grass than in grain resulted in the stability of the fatty acid profile. This study shows that the anti-oxidative potential of natural antioxidants in meat plays an important role during the first 7 d postmortem., Competing Interests: The authors declare that they have no conflict of interest., (Copyright: © 2020 Alberto Horcada et al.)

(1) Background: The structure of the Sigma 2 receptor/TMEM97 (σ2RTMEM97) has recently been reported. (2, 3) Methods and results: We used genetic and biochemical approaches to identify the molecular mechanism downstream of σ2R/TMEM97. The novel σ2R/TMEM97 fluorescent ligand, NO1, reduced the proliferation and survival of the triple negative breast cancer cell lines (TNBC: MDA-MB-231 and MDA-MB-468 cell lines), due to NO1-induced apoptosis. Greater bioaccumulation and faster uptake of NO1 in MDA-MB-231 cells compared to MCF10A or MCF7 cell lines were also shown. Accordingly, elevated σ2R/TMEM97 expression was confirmed by Western blotting. In contrast to NO1, other σ2R/TMEM97 ligands, such as SM21 and PB28, enhanced MDA-MB-231 cell proliferation and migration. Store-operated calcium entry (SOCE) is crucial for different cancer hallmarks. Here, we show that NO1, but not other σ2R/TMEM97 ligands, reduced SOCE in MDA-MB-231 cells. Similarly, TMEM97 silencing in MDA-MB-231 cells also impaired SOCE. NO1 administration downregulated STIM1-Orai1 interaction, probably by impairing the positive regulatory effect of σ2R/TMEM97 on STIM1, as we were unable to detect interaction with Orai1. (4) Conclusion: σ2R/TMEM97 is a key protein for the survival of triple negative breast cancer cells by promoting SOCE; therefore, NO1 may become a good pharmacological tool to avoid their proliferation., Competing Interests: Authors declare not conflict of interest.

Store-Operated Ca 2+ Entry (SOCE) is an important Ca 2+ influx pathway expressed by several excitable and non-excitable cell types. SOCE is recognized as relevant signaling pathway not only for physiological process, but also for its involvement in different pathologies. In fact, independent studies demonstrated the implication of essential protein regulating SOCE, such as STIM, Orai and TRPCs, in different pathogenesis and cell disorders, including cardiovascular disease, muscular dystrophies and angiogenesis. Compelling evidence showed that dysregulation in the function and/or expression of isoforms of STIM, Orai or TRPC play pivotal roles in cardiac hypertrophy and heart failure, vascular remodeling and hypertension, skeletal myopathies, and angiogenesis. In this chapter, we summarized the current knowledge concerning the mechanisms underlying abnormal SOCE and its involvement in some diseases, as well as, we discussed the significance of STIM, Orai and TRPC isoforms as possible therapeutic targets for the treatment of angiogenesis, cardiovascular and skeletal muscle diseases.