Tumor microenvironment in non-melanoma skin cancer resistance to photodynamic therapy.

Non-melanoma skin cancer has recently seen an increase in prevalence, and it is estimated that this grow will continue in the coming years. In this sense, the importance of therapy effectiveness has increased, especially photodynamic therapy. Photodynamic therapy has attracted much attention as a minimally invasive, selective and repeatable approach for skin cancer treatment and prevention. Although its high efficiency, this strategy has also faced problems related to tumor resistance, where the tumor microenvironment has gained a well-deserved role in recent years. Tumor microenvironment denotes a wide variety of elements, such as cancer-associated fibroblasts, immune cells, endothelial cells or the extracellular matrix, where their interaction and the secretion of a wide diversity of cytokines. Therefore, the need of designing new strategies targeting elements of the tumor microenvironment to overcome the observed resistance has become evident. To this end, in this review we focus on the role of cancer-associated fibroblasts and tumor-associated macrophages in the resistance to photodynamic therapy. We are also exploring new approaches consisting in the combination of new and old drugs targeting these cells with photodynamic therapy to enhance treatment outcomes of non-melanoma skin cancer.

Lossless Medical Image Compression by Using Difference Transform.

This paper introduces a new method of compressing digital images by using the Difference Transform applied in medical imaging. The Difference Transform algorithm performs the decorrelation process of image data, and in this way improves the encoding process, achieving a file with a smaller size than the original. The proposed method proves to be competitive and in many cases better than the standards used for medical images such as TIFF or PNG. In addition, the Difference Transform can replace other transforms like Cosine or Wavelet.

Territorial Strategy of Medical Units for Addressing the First Wave of the COVID-19 Pandemic in the Metropolitan Area of Mexico City: Analysis of Mobility, Accessibility and Marginalization.

BACKGROUND: The COVID-19 pandemic has caused an exponential increase in the demand for medical care worldwide. In Mexico, the COVID Medical Units (CMUs) conversion strategy was implemented. OBJECTIVE: To evaluate the CMU coverage strategy in the Mexico City Metropolitan Area (MCMA) by territory. MATERIALS: The CMU directory was used, as were COVID-19 infection and mobility statistics and Mexican 2020 census information at the urban geographic area scale. The degree of urban marginalization by geographic area was also considered. METHOD: Using descriptive statistics and the calculation of a CMU accessibility index, population aggregates were counted based on coverage radii. In addition, two regression models are proposed to explain (1) the territorial and temporal trend of COVID-19 infections in the MCMA and (2) the mobility of the COVID-infected population visiting medical units. RESULTS: The findings of the evaluation of the CMU strategy were (1) in the MCMA, COVID-19 followed a pattern of contagion from the urban center to the periphery; (2) given the growth in the number of cases and the overload of medical units, the population traveled greater distances to seek medical care; (3) after the CMU strategy was evaluated at the territory level, it was found that 9 out of 10 inhabitants had a CMU located approximately 7 km away; and (4) at the metropolitan level, the lowest level of accessibility to the CMU was recorded for the population with the highest levels of marginalization, i.e., those residing in the urban periphery.

Characteristics and Risk Factors Associated With Mortality in a Multicenter Spanish Cohort of Patients With COVID-19 Pneumonia.

INTRODUCTION: Spain is one of the countries with the highest number of COVID-19 patients. Unfortunately, few data for regions are available. OBJECTIVES: This study aimed to describe the characteristics and independent risk factors associated with COVID-19 mortality in Castilla-La Mancha, Spain. METHODS: Cohort and multicenter study in all 14 public hospitals of the Castilla-La Mancha Health Service. Baseline characteristics, preexisting comorbidities, symptoms, clinical features and treatments were included. Multivariable logistic regression was used to evaluate factors associated with death and Kaplan-Meier test to examine survival probability. Statistical significance was considered with p < 0.05 (95% CI). SPSS (version 24.0 for Windows) and R 4.0.2 (R Statistics) software were used. RESULTS: The cohort comprised 12,126 patients sequentially attended between February 11 and May 11, 2020. The mean age of patients was 66.4 years; 5667 (46.7%) were women. Six protective factors against exitus were defined: female sex, anosmia, cough, chloroquine and azithromycin. The risk factors were: age over 50, obesity, cardiac pathology, fever, dyspnea, lung infiltrates, lymphopenia, D-dimer above 1000 ng/mL, and mechanical ventilation requirement. Survival analysis showed higher survival rate in women (75.7%) than men (72.1%). Cumulative survival was 87.5% for non-hospitalized patients, 70.2% for patients admitted to hospital and 61.2% in ICU patients. Additionally, survival probability decreased with increasing age range. CONCLUSION: Determination of protective or death-promoting factors could be useful to stratify patients by severity criteria and to improve COVID-19 care management.

INTRODUCCIÓN: España es uno de los países con mayor número de pacientes con COVID-19. Desafortunadamente, se dispone de pocos datos por regiones. OBJETIVOS: Describir las características y los factores de riesgo independientes asociados a mortalidad por COVID-19 en Castilla-La Mancha, España. MÉTODOS: Estudio de cohorte, multicéntrico de los 14 hospitales públicos de Castilla-La Mancha. Se evaluaron las características clínicas, comorbilidades preexistentes, síntomas y tratamientos. Se utilizó una regresión logística multivariable para evaluar los factores asociados a muerte y Kaplan-Meier para medir supervivencia. Se consideró significación estadística con p < 0,05 (IC 95%). Se utilizaron los programas SPSS (versión 24.0 para Windows) y R 4.0.2 (R Statistics). RESULTADOS: Se estudiaron 12.126 pacientes atendidos secuencialmente entre el 11 de febrero y el 11 de mayo de 2020. La edad media fue de 66,4 años; 5.667 (46,7%) fueron mujeres. Se definieron seis factores protectores contra el exitus: sexo femenino, anosmia, tos, cloroquina y azitromicina. Los factores de riesgo fueron: edad superior a 50, obesidad, patología cardíaca, fiebre, disnea, infiltrados pulmonares, linfopenia, dímero-D > 1.000 ng/mL y necesidad de ventilación mecánica. Se observó mayor tasa de supervivencia en mujeres (75,7%) que en hombres (72,1%). La supervivencia acumulada fue del 87,5% para pacientes no hospitalizados, 70,2% para admitidos en planta hospitalaria y 61,2% en la Unidad de Cuidados Intensivos (UCI). Además, la probabilidad de supervivencia disminuyó con el aumento del rango de edad. CONCLUSIÓN: La determinación de los factores protectores o favorecedores de muerte podría ser útil para estratificar pacientes por criterios de gravedad y mejorar la atención frente a la COVID-19.

Characterization of Permeability Barrier Dysfunction in a Murine Model of Cutaneous Field Cancerization Following Chronic UV-B Irradiation: Implications for the Pathogenesis of Skin Cancer.

Chronic ultraviolet B (UV-B) irradiation is known to be one of the most important hazards acting on the skin and poses a risk of developing photoaging, skin with cutaneous field cancerization (CFC), actinic keratosis (AKs), and squamous cell carcinomas (SCCs). Most of the UV-B light is absorbed in the epidermis, affecting the outermost cell layers, the stratum corneum, and the stratum granulosum, which protects against this radiation and tries to maintain the permeability barrier. In the present work, we show an impairment in the transepidermal water loss, stratum corneum hydration, and surface pH after chronic UV-B light exposure in an immunologically intact mouse model (SKH1 aged mice) of skin with CFC. Macroscopic lesions of AKs and SCCs may develop synchronically or over time on the same cutaneous surface due to both the presence of subclinical AKs and in situ SCC, but also the accumulation of different mutations in keratinocytes. Focusing on skin with CFC, yet without the pathological criteria of AKs or SCC, the presence of p53 immunopositive patches (PIPs) within the epidermis is associated with these UV-B-induced mutations. Reactive epidermis to chronic UV-B exposure correlated with a marked hyperkeratotic hyperplasia, hypergranulosis, and induction of keratinocyte hyperproliferation, while expressing an upregulation of filaggrin, loricrin, and involucrin immunostaining. However, incidental AKs and in situ SCC might show neither hypergranulosis nor upregulation of differentiation markers in the upper epidermis. Despite the overexpression of filaggrin, loricrin, involucrin, lipid enzymes, and ATP-binding cassette subfamily A member 12 (ABCA12) after chronic UV-B irradiation, the permeability barrier, stratum corneum hydration, and surface pH were severely compromised in the skin with CFC. We interpret these results as an attempt to restore the permeability barrier homeostasis by the reactive epidermis, which fails due to ultrastructural losses in stratum corneum integrity, higher pH on skin surface, abundant mast cells in the dermis, and the common presence of incidental AKs and in situ SCC. As far as we know, this is the first time that the permeability barrier has been studied in the skin with CFC in a murine model of SCC induced after chronic UV-B irradiation at high doses. The impairment in the permeability barrier and the consequent keratinocyte hyperproliferation in the skin of CFC might play a role in the physiopathology of AKs and SCCs.

Topical Applications of Thiosulfinate-Enriched Allium sativum Extract Accelerates Acute Cutaneous Wound Healing in Murine Model.

OBJECTIVE: To determine whether topical applications of thiosulfinate-enriched Allium sativum extract (TASE) can accelerate acute cutaneous wound healing (WH) in a murine model. METHODS: Keratinocyte viability and in vitro wound closure were assessed in keratinocyte cultures. Effects of topical TASE (0.5 µg/mL of allicin in 97% ethanol) on acute cutaneous WH were determined in a murine model of acute cutaneous wound. Twelve mice were alternately assigned to the vehicle- and TASE-treated groups (n=6 per group). Expression levels of mRNA for keratinocyte differentiation marker-related proteins (filaggrin, loricrin and involucrin) and lipid synthetic enzymes (elongation of very long chain fatty acids protein 4 (ELOVL4), fatty acid synthase (FA2H), 3-hydroxy- 3-methyl-glutaryl-coenzyme A reductase (HMGCoA), and serine palmitoyltransferase (SPT)) were assessed using real-time quantitative polymerase chain reaction on day 3 and 8 after wounding, while transepidermal water loss (TEWL) rates were measured in wounded areas. RESULTS: TASE accelerated WH both in vivo (40% vs. 22% reduction in wound area, P<0.01) and in vitro (90% vs. 65% reduction in wound area, P<0.01). Moreover, topical applications of TASE upregulated the expression levels of epidermal mRNA for ELOVL4, HMGCoA, SPT, filaggrin, loricrin and involucrin (P<0.05 vs. vehicle-treated controls) on day 3 after wounding. Likewise, TASE significantly lowered TEWL rates in comparison with vehicle alone on day 8 (33.06±2.09 g/(m2·h) vs. 24.60±2.04 g/(m2·h), P<0.01). CONCLUSIONS: Topical applications of TASE stimulated keratinocyte proliferation and formation of epidermal permeability barrier function, leading to acceleration of acute cutaneous WH. Topical products containing TASE could be used to manage acute cutaneous WH.

Anti-Inflammatory and Skin Barrier Repair Effects of Topical Application of Some Plant Oils.

Plant oils have been utilized for a variety of purposes throughout history, with their integration into foods, cosmetics, and pharmaceutical products. They are now being increasingly recognized for their effects on both skin diseases and the restoration of cutaneous homeostasis. This article briefly reviews the available data on biological influences of topical skin applications of some plant oils (olive oil, olive pomace oil, sunflower seed oil, coconut oil, safflower seed oil, argan oil, soybean oil, peanut oil, sesame oil, avocado oil, borage oil, jojoba oil, oat oil, pomegranate seed oil, almond oil, bitter apricot oil, rose hip oil, German chamomile oil, and shea butter). Thus, it focuses on the therapeutic benefits of these plant oils according to their anti-inflammatory and antioxidant effects on the skin, promotion of wound healing and repair of skin barrier.

Association between Stress and the HPA Axis in the Atopic Dermatitis.

The hypothalamic-pituitary-adrenal (HPA) axis is one of the body's neuroendocrine networks that responds to psychological stress (PS). In the skin, there exists a peripheral HPA axis similar to the central axis. Glucocorticoids (GCs) are key effector molecules of the HPA axis and are essential for cutaneous homeostasis. Atopic dermatitis (AD) is a condition typically characterized by a chronic relapsing course that often results in PS. HPA dysfunction is present in AD patients by the decreased response of GCs elevation to stress as compared to those unaffected by AD. Nevertheless, in skin, acute PS activates several metabolic responses that are of immediate benefit to the host. During the acute phase of PS, increased endogenous GCs have been shown to provide benefit rather than by aggravating cutaneous inflammatory dermatoses. However, a chronic T helper cell type 2 (Th2) predominant cytokine profile acts as a negative feedback loop to blunt the HPA axis response in AD. In this article, we reviewed the role of CRF, pro-opiomelanocortin (POMC)-derived peptides, GCs of the HPA, and 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) in AD, with a discussion of the pathogenetic mechanisms of inflammation and skin barrier functions, including antimicrobial defense, and their association with PS.

Paradoxical benefits of psychological stress in inflammatory dermatoses models are glucocorticoid mediated.

Acute psychological stress (PS) mobilizes metabolic responses that are of immediate benefit to the host, but the current medical paradigm holds that PS exacerbates systemic and cutaneous inflammatory disorders. Although the adverse consequences of PS are usually attributed to neuroimmune mechanisms, PS also stimulates an increase in endogenous glucocorticoids (GCs) that compromises permeability barrier homeostasis, stratum corneum cohesion, wound healing, and epidermal innate immunity in normal skin. Yet, if such PS-induced increases in GC were uniformly harmful, natural selection should have eliminated this component of the stress response. Hence, we hypothesized here instead that stress-induced elevations in endogenous GC could benefit, rather than aggravate, cutaneous function and reduce inflammation in three immunologically diverse mouse models of inflammatory diseases. Indeed, superimposed exogenous (motion-restricted) stress reduced, rather than aggravated inflammation and improved epidermal function in all three models, even normalizing serum IgE levels in the atopic dermatitis model. Elevations in endogenous GC accounted for these apparent benefits, because coadministration of mifepristone prevented stress-induced disease amelioration. Thus, exogenous stress can benefit rather than aggravate cutaneous inflammatory dermatoses through the anti-inflammatory activity of increased endogenous GC.

Topical apigenin improves epidermal permeability barrier homoeostasis in normal murine skin by divergent mechanisms.

The beneficial effects of certain herbal medicines on cutaneous function have been appreciated for centuries. Among these agents, chrysanthemum extract, apigenin, has been used for skin care, particularly in China, for millennia. However, the underlying mechanisms by which apigenin benefits the skin are not known. In this study, we first determined whether topical apigenin positively influences permeability barrier homoeostasis, and then the basis thereof. Hairless mice were treated topically with either 0.1% apigenin or vehicle alone twice daily for 9 days. At the end of the treatments, permeability barrier function was assessed with either an electrolytic water analyzer or a Tewameter. Our results show that topical apigenin significantly enhanced permeability barrier homoeostasis after tape stripping, although basal permeability barrier function remained unchanged. Improved barrier function correlated with enhanced filaggrin expression and lamellar body production, which was paralleled by elevated mRNA levels for the epidermal ABCA12. The mRNA levels for key lipid synthetic enzymes also were upregulated by apigenin. Finally, both cathelicidin-related peptide and mouse beta-defensin 3 immunostaining were increased by apigenin. We conclude that topical apigenin improves epidermal permeability barrier function by stimulating epidermal differentiation, lipid synthesis and secretion, as well as cutaneous antimicrobial peptide production. Apigenin could be useful for the prevention and treatment of skin disorders characterized by permeability barrier dysfunction, associated with reduced filaggrin levels and impaired antimicrobial defenses, such as atopic dermatitis.

Topical antihistamines display potent anti-inflammatory activity linked in part to enhanced permeability barrier function.

Systemic antagonists of the histamine type 1 and 2 receptors (H1/2r) are widely used as anti-pruritics and central sedatives, but demonstrate only modest anti-inflammatory activity. Because many inflammatory dermatoses result from defects in cutaneous barrier function, and because keratinocytes express both Hr1 and Hr2, we hypothesized that H1/2r antagonists might be more effective if they were used topically to treat inflammatory dermatoses. Topical H1/2r antagonists additively enhanced permeability barrier homeostasis in normal mouse skin by the following mechanisms: (i) stimulation of epidermal differentiation, leading to thickened cornified envelopes; and (ii) enhanced epidermal lipid synthesis and secretion. As barrier homeostasis was enhanced to a comparable extent in mast cell-deficient mice, with no further improvement following application of topical H1/2r antagonists, H1/2r antagonists likely oppose mast cell-derived histamines. In four immunologically diverse, murine disease models, characterized by either inflammation alone (acute irritant contact dermatitis, acute allergic contact dermatitis) or by prominent barrier abnormalities (subacute allergic contact dermatitis, atopic dermatitis), topical H1/2r agonists aggravated, whereas H1/2r antagonists improved, inflammation and/or barrier function. The apparent ability of topical H1r/2r antagonists to target epidermal H1/2r could translate into increased efficacy in the treatment of inflammatory dermatoses, likely due to decreased inflammation and enhanced barrier function. These results could shift current paradigms of antihistamine utilization from a predominantly systemic to a topical approach.

A humanized mouse model of HPV-associated pathology driven by E7 expression.

Human papillomavirus (HPV) is the causative agent of human cervical cancer and has been associated with oropharyngeal squamous cell carcinoma development. Although prophylactic vaccines have been developed, there is a need to develop new targeted therapies for individuals affected with malignant infected lesions in these locations, which must be tested in appropriate models. Cutaneous beta HPV types appear to be involved in skin carcinogenesis. Virus oncogenicity is partly achieved by inactivation of retinoblastoma protein family members by the viral E7 gene. Here we show that the E7 protein of cutaneous beta HPV5 binds pRb and promotes its degradation. In addition, we described an in vivo model of HPV-associated disease in which artificial human skin prepared using primary keratinocytes engineered to express the E7 protein is engrafted onto nude mice. Expression of E7 in the transplants was stably maintained for up to 6 months, inducing the appearance of lesions that, in the case of HPV16 E7, histologically resembled human anogenital lesions caused by oncogenic HPVs. Moreover, it was confirmed through biomarker expression analysis via immunodetection and/or quantitative PCR from mRNA and miRNA that the 16E7-modified engrafted skin shares molecular features with human HPV-associated pretumoral and tumoral lesions. Finally, our findings indicate a decrease of the in vitro capacity of HPV5 E7 to reduce pRb levels in vivo, possibly explaining the phenotypical differences when compared with 16E7-grafts. Our model seems to be a valuable platform for basic research into HPV oncogenesis and preclinical testing of HPV-associated antitumor therapies.

Cellular changes that accompany shedding of human corneocytes.

Corneocyte desquamation has been ascribed to the following: 1) proteolytic degradation of corneodesmosomes (CDs); 2) disorganization of extracellular lamellar bilayers; and/or 3) "swell-shrinkage-slough" from hydration/dehydration. To address the cellular basis for normal exfoliation, we compared changes in lamellar bilayer architecture and CD structure in D-Squame strips from the first versus fifth stripping ("outer" vs. "mid"-stratum corneum (SC), respectively) from nine normal adult forearms. Strippings were either processed for standard electron microscopy (EM) or for ruthenium-, or osmium-tetroxide vapor fixation, followed by immediate epoxy embedment, an artifact-free protocol, which, to our knowledge, is previously unreported. CDs are largely intact in the mid-SC, but replaced by electron-dense (hydrophilic) clefts (lacunae) that expand laterally, splitting lamellar arrays in the outer SC. Some undegraded desmoglein 1/desmocollin 1 redistribute uniformly into corneocyte envelopes (CEs) in the outer SC (shown by proteomics, Z-stack confocal imaging, and immunoEM). CEs then thicken, likely facilitating exfoliation by increasing corneocyte rigidity. In vapor-fixed images, hydration only altered the volume of the extracellular compartment, expanding lacunae, further separating membrane arrays. During dehydration, air replaced water, maintaining the expanded extracellular compartment. Hydration also provoked degradation of membranes by activating contiguous acidic ceramidase activity. Together, these studies identify several parallel mechanisms that orchestrate exfoliation from the surface of normal human skin.

Venous malformation of the eyelid treated with pulsed-dye-1064-nm neodymium yttrium aluminum garnet sequential laser: an effective and safe treatment.

Venous malformations of the skin and subcutaneous tissue are compressible, blue-purple tumors that are present at birth. According to the location and symptoms caused, venous malformations can be treated with surgery, sclerotherapy, or a combination of both. Laser therapy can also be used, especially when surgery is contraindicated. We report the case of a 24-year-old man who presented with a venous malformation on the upper and lower left eyelids, which provoked a mechanical ptosis. Treatment with sequential pulsed-dye neodymium yttrium aluminum garnet (PDL-Nd:YAG) laser was performed. After 2 treatments, a marked reduction of volume and blanching of the venous malformation was observed, with satisfactory cosmetic results. The sequential PDL-Nd:YAG laser seems to be an effective and safe therapy for the treatment of cutaneous venous malformations. It penetrates deeper than pulsed-dye laser alone, and because it allows the use of lower fluencies than Nd:YAG laser alone, it reduces the risk of adverse effects.

A new route toward 7-Oxo-13-hydroxy-8,11,13-podocarpatrienes from labdane diterpenes.

Trinorlabdane 1,5-diketones (7, 10a,b, 13a,b), which are easily prepared from labdane diterpenes, are directly converted into the corresponding 7-oxo-13-hydroxy-8,11,13-podocarpatrienes, immediate precursors of bioactive compounds, under basic treatment. Utilizing this strategy, the first enantiospecific synthesis of 13-hydroxy-8,11,13-podocarpatriene (20), a constituent of Taiwania cryptomerioides, was achieved starting from (-)-sclareol (5) after a seven-step sequence in 55% overall yield.