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The authors report a case of bullous pemphigoid (BP) that occurred during pembrolizumab therapy in a 67-year-old male patient with advanced melanoma. Following regression of BP blisters, they reintroduced anti-PD-1 treatment. Due to the flare-up of BP, immunotherapy was discontinued again and corticosteroid was restarted. As the BP lesions regressed, interestingly, new skin metastases developed, exactly where the blisters were. One year after discontinuation of anti-PD-1 treatment, considering the significant tumor progression, pembrolizumab was restarted. This induced tumor remission, while the added low-dose corticosteroid was able to prevent the recurrence of BP. The patient carries the BP-predisposingImmune checkpoint inhibitors prolong the survival of patients with metastatic melanoma. Bullous pemphigoid (BP) is a rare, cutaneous, immune-related adverse event. The authors report a case of BP that occurred during pembrolizumab therapy in a 67-year-old male patient with advanced melanoma who responded to anti-PD-1 treatment with a partial response. Following the resolution of BP symptoms, pembrolizumab treatment was restarted after discontinuation of systemic corticosteroid therapy. Due to the flare-up of BP, anti-PD-1 treatment was discontinued and steroid therapy was restarted; however, skin metastases soon developed, exactly where the BP blisters were. Pembrolizumab rechallenge was successful in inducing the complete regression of skin metastases, while the added low-dose corticosteroid was able to prevent the recurrence of BP.

Background: Intestinal symptoms are common in patients with hidradenitis suppurativa (HS). HS patients may experience a broad spectrum of chronic inflammatory intestinal disorders (CIID), not exclusive to inflammatory bowel diseases, which are diagnosed by colonoscopy and intestinal biopsies. The frequency of CIID in patients with HS has not been investigated. Objective: The objectives of this study were to determine the occurrence of CIID in HS and characterise this clinical population. Furthermore, the feasibility of using fecal calprotectin (FC) test or anti-Saccharomyces cerevisiae antibody (ASCA) levels to assess the colonic inflammation of CIID in HS patients was investigated. Methods: All newly diagnosed and untreated HS patients (n=74) were referred to a gastroenterologist for FC followed by colonoscopy after informed consent. C-reactive protein (CRP), white blood cell count, nucleotide-binding-oligomerisation-domain-containing-protein-2 (NOD2) polymorphism, and ASCA levels were measured. Patients were divided into HS-only and HS with CIID (HS+CIID) groups, based on the absence or presence of CIID. Laboratory and clinical parameters (age, gender, HS onset, clinical stage, family history, body mass index (BMI), smoking) were compared between the groups. Results: Thirteen patients complained gastrointestinal symptoms prior to any examination, including 11 in the HS+CIID group. The CIID frequency in HS was 28.4% (n=21/74), based on colonoscopy and histology. Significantly more patients had severe disease state in the HS+CIID group compared with the HS-only group, and BMI was significantly lower in the HS+CIID group (28.20±5.58 vs. 32.74±6.45, p=0.006). FC positivity occurred significantly more in HS+CIID patients compared with HS-only patients (90.48% vs. 3.77%, p

Melanomas account for only approximately 4% of diagnosed skin cancers in the United States but are responsible for the majority of deaths caused by skin cancer. Both genetic factors and ultraviolet (UV) radiation exposure play a role in the development of melanoma. Although melanomas have a strong propensity to metastasize when diagnosed late, melanomas that are diagnosed and treated early pose a low mortality risk. In particular, the identification of patients with increased metastatic risk, who may benefit from early adjuvant therapies, is crucial, especially given the advent of new melanoma treatments. However, the accuracy of classic clinical and histological variables, including the Breslow thickness, presence of ulceration, and lymph node status, might not be sufficient to identify such individuals. Thus, there is a need for the development of additional prognostic melanoma biomarkers that can improve early attempts to stratify melanoma patients and reliably identify high-risk subgroups with the aim of providing effective personalized therapies.In our current work, we discuss and assess emerging primary melanoma tumor biomarkers and prognostic circulating biomarkers.Several promising biomarkers show prognostic value (eg, exosomal MIA (ie, melanoma inhibitory activity), serum S100B, AMLo signatures, and mRNA signatures); however, the scarcity of reliable data precludes the use of these biomarkers in current clinical applications.Further research is needed on several promising biomarkers for melanoma. Large-scale studies are warranted to facilitate the clinical translation of prognostic biomarker applications for melanoma in personalized medicine.

BACKGROUND The incidence of cutaneous melanoma has risen faster than almost any other type of cancer in the last 50 years. Ultraviolet (UV) radiation and genetic susceptibility are the most important risk factors. OBJECTIVE We aimed to determine the epidemiologic indicators of melanoma in Hungary, a country with an estimated population of 9.8 million and an area of 93 030 km2. METHODS Anonymized patient records from the National Health Insurance Fund Management covering the entire population were used to determine the incidence and prevalence of melanoma in the counties of Hungary from 2013 to 2017. Altogether 20 030 melanoma cases were identified for inclusion in this study. RESULTS The prevalence of melanoma increased over the investigated period and was significantly higher among women than men. The incidence of melanoma stagnated during this period and the incidence rate was the highest among the elderly. Interestingly, the incidence was higher in males in the elderly population, while the incidence was higher in females in the younger (

Összefoglaló. Két fiatal nőbetegnél a valproátról lamotriginre történő gyógyszerátállítás során a 3–4. héten influenzaszerű prodromalis tüneteket követően toxikus epidermalis necrolysis (TEN), más néven Lyell-szindróma alakult ki. Mindkét beteg 5 napja kezdődött bőr- és nyálkahártyatünetekkel, kiterjedt hámleválást okozó hámnekrózissal került felvételre a Debreceni Egyetem Bőrgyógyászati Klinikájának Égési Intenzív Osztályára. Multidiszciplináris szupportív terápia mellett nagy dózisú szteroid- és immunglobulin-terápiát alkalmaztunk. A 37 éves nőbetegnél 3 hét után a kórkép fatális kimenetellel végződött. A 19 éves nőbeteg tünetei 4 hét intenzív terápia után szövődményekkel gyógyultak. A TEN ritka, gyógyszer által okozott, életet veszélyeztető, késői hiperszenzitivitási reakció. Patogenezisében a gyógyszermolekula, a humán leukocytaantigén (HLA) I. osztályú molekula és a T-sejt-receptor kóros interakciója szerepel. Kezelésében a legfontosabb a kiváltó gyógyszer elhagyása, valamint az azonnal kezdett komplett szupportív terápia alkalmazása. A specifikus kezelést illetően nincsenek egységes szakmai irányelvek. A veszélyes gyógyszerek titrált bevezetése csökkentheti a kialakuló hiperszenzitivitás súlyosságát, ezenfelül a beteg szoros követése és az adverz tünetek korai felismerése javíthatja a TEN kimenetelét. Orv Hetil. 2020; 161(46): 1959–1965. Summary. After switching from valproate to lamotrigine, on the 3rd–4th weeks, two young female patients developed flu-like prodromal symptoms, followed by the development of toxic epidermal necrolysis (TEN), also known as Lyell syndrome. Both patients were admitted to the Burn Intensive Care Unit of the Department of Dermatology, University of Debrecen with skin and mucosa symptoms; extensive epithelial death and detachment started 5 days earlier. In addition to multidisciplinary supportive treatment, high-dose corticosteroid and immunoglobulin therapy were administered. In the case of the 37-year-old female patient, the disease resulted in a fatal outcome. The 19-year-old patient healed with some sequelae. TEN is a rare, life-threatening delayed-type hypersensitivity reaction caused by drugs. Its pathogenesis involves an interaction between small-molecule drug, human leukocyte antigen class I molecule and T-cell receptor. The most important treatment is immediate withdrawal of potentially causative drugs and prompt application of supportive therapy. There is no standard guidance on specific treatment. Slow dose escalation of dangerous drugs can be beneficial in avoiding severe reactions, furthermore, close patient follow-up and early detection of the possible adverse reactions contribute to a more favourable outcome of TEN. Orv Hetil. 2020; 161(46): 1959–1965.

BackgroundRecent real-world studies have reported significant improvements in the survival of malignant melanoma in the past few years, mainly as a result of modern therapies. However, long-term survival data from Central Eastern European countries such as Hungary are currently lacking.MethodsThis nationwide, retrospective study examined melanoma survival in Hungary between 2011–2019 using the databases of the National Health Insurance Fund (NHIF) and Central Statistical Office (CSO) of Hungary. Crude overall survival and age-standardized 5-year net survival as well as the association between age, sex, and survival were calculated.ResultsBetween 2011 and 2019, 22,948 newly diagnosed malignant melanoma cases were recorded in the NHIF database (47.89% male, mean age: 60.75 years (SD: ±16.39)). 5-year overall survival was 75.40% (women: 80.78%; men: 69.52%). Patients diagnosed between 2017–2019 had a 20% lower risk of mortality compared to patients diagnosed between 2011–2012 (HR 0.80, 95% CI 0.73–0.89; pConclusionHungary has similar melanoma survival rates to Western European countries. Based on net survival, the risk of dying of melanoma within 5 years was cut by more than half (55%) during the study period, which coincides with the successful implementation of awareness campaigns and the wide availability of modern therapies.

Here we developed a powerful tool for comprehensive data collection and mapping of molecular and elemental signatures in the Melanoma-bearing Libechov Minipig (MeLiM) model. The combination of different mass spectrometric methods allowed for detail investigation of specific melanoma markers and elements and their spatial distribution in tissue sections. MALDI-MSI combined with HPLC-MS/MS analyses resulted in identification of seven specific proteins, S100A12, CD163, MMP-2, galectin-1, tenascin, resistin and PCNA that were presented in the melanoma signatures. Furthermore, the ICP-MS method allowed for spatial detection of zinc, calcium, copper, and iron elements linked with the allocation of the specific binding proteins.

Looking insight pathological processes, metallothioneins (MTs) are considered to be potential biomarkers for monitoring of a development of various types of diseases, such as cancer. The early identification of the MTs in biological tissues could be important tool for the estimation of appropriate clinical therapy. Therefore, here we investigated the application of matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) together with immunohistochemical analyses (IHC) using MT-1/2 antibody for MT detection in formalin-fixed paraffin-embedded (FFPE) biopsy specimens of human skin. Principal component analyses revealed differences in the peptide/protein profiles separating healthy skin from the carcinoma specimens. Statistically significant ion peaks at m/z 6038, 6300, 6676, and 7026 were more frequently detected in squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. Using IHC, we found that MT-1/2 was significantly higher in SCC and melanoma compared to healthy skin. Surprisingly, significantly low levels of MT-1/2 were found in BCC. On one side, the results indicate important role of MTs in melanoma occurrence and progression, as on the second side, there are hidden processes associated with MTs based on differences of the occurrence of the MS peaks, which could be associated with cycling of MTs isoforms.

The high incidence of skin cancers in the Caucasian population is primarily due to the accumulation of DNA damage in epidermal cells induced by chronic ultraviolet B (UVB) exposure. UVB-induced DNA photolesions, including cyclobutane–pyrimidine dimers (CPDs), promote mutations in skin cancer driver genes. In humans, CPDs are repaired by nucleotide excision repair (NER). Several commonly used and investigational medications negatively influence NER in experimental systems. Despite these molecules’ ability to decrease NER activity in vitro, the role of these drugs in enhancing skin cancer risk is unclear. In this study, we investigated four molecules (veliparib, resveratrol, spironolactone, and arsenic trioxide) with well-known NER-inhibitory potential in vitro, using UVB-irradiated CHO epithelial and HaCaT immortalized keratinocyte cell lines. Relative CPD levels, hypoxanthine phosphoribosyltransferase gene mutation frequency, cell viability, cell cycle progression, and protein expression were assessed. All four molecules significantly elevated CPD levels in the genome 24 h after UVB irradiation. However, veliparib, spironolactone, and arsenic trioxide reduced the mutagenic potential of UVB, while resveratrol did not alter UVB-induced mutation formation. UVB-induced apoptosis was enhanced by spironolactone and arsenic-trioxide treatment, while veliparib caused significantly prolonged cell cycle arrest and increased autophagy. Spironolactone also enhanced the phosphorylation level of mammalian target of rapamycin (mTOR), while arsenic trioxide modified UVB-driven mitochondrial fission. Resveratrol induced only mild changes in the cellular UVB response. Our results show that chemically inhibited NER does not result in increased mutagenic effects. Furthermore, the UVB-induced mutagenic potential can be paradoxically mitigated by NER-inhibitor molecules. We identified molecular changes in the cellular UVB response after NER-inhibitor treatment, which may compensate for the mitigated DNA repair. Our findings show that metabolic cellular response pathways are essential to consider in evaluating the skin cancer risk–modifying effects of pharmacological compounds.

Összefoglaló. Két fiatal nőbetegnél a valproátról lamotriginre történő gyógyszerátállítás során a 3-4. héten influenzaszerű prodromalis tüneteket követően toxikus epidermalis necrolysis (TEN), más néven Lyell-szindróma alakult ki. Mindkét beteg 5 napja kezdődött bőr- és nyálkahártyatünetekkel, kiterjedt hámleválást okozó hámnekrózissal került felvételre a Debreceni Egyetem Bőrgyógyászati Klinikájának Égési Intenzív Osztályára. Multidiszciplináris szupportív terápia mellett nagy dózisú szteroid- és immunglobulin-terápiát alkalmaztunk. A 37 éves nőbetegnél 3 hét után a kórkép fatális kimenetellel végződött. A 19 éves nőbeteg tünetei 4 hét intenzív terápia után szövődményekkel gyógyultak. A TEN ritka, gyógyszer által okozott, életet veszélyeztető, késői hiperszenzitivitási reakció. Patogenezisében a gyógyszermolekula, a humán leukocytaantigén (HLA) I. osztályú molekula és a T-sejt-receptor kóros interakciója szerepel. Kezelésében a legfontosabb a kiváltó gyógyszer elhagyása, valamint az azonnal kezdett komplett szupportív terápia alkalmazása. A specifikus kezelést illetően nincsenek egységes szakmai irányelvek. A veszélyes gyógyszerek titrált bevezetése csökkentheti a kialakuló hiperszenzitivitás súlyosságát, ezenfelül a beteg szoros követése és az adverz tünetek korai felismerése javíthatja a TEN kimenetelét. Orv Hetil. 2020; 161(46): 1959-1965. Summary. After switching from valproate to lamotrigine, on the 3rd-4th weeks, two young female patients developed flu-like prodromal symptoms, followed by the development of toxic epidermal necrolysis (TEN), also known as Lyell syndrome. Both patients were admitted to the Burn Intensive Care Unit of the Department of Dermatology, University of Debrecen with skin and mucosa symptoms; extensive epithelial death and detachment started 5 days earlier. In addition to multidisciplinary supportive treatment, high-dose corticosteroid and immunoglobulin therapy were administered. In the case of the 37-year-old female patient, the disease resulted in a fatal outcome. The 19-year-old patient healed with some sequelae. TEN is a rare, life-threatening delayed-type hypersensitivity reaction caused by drugs. Its pathogenesis involves an interaction between small-molecule drug, human leukocyte antigen class I molecule and T-cell receptor. The most important treatment is immediate withdrawal of potentially causative drugs and prompt application of supportive therapy. There is no standard guidance on specific treatment. Slow dose escalation of dangerous drugs can be beneficial in avoiding severe reactions, furthermore, close patient follow-up and early detection of the possible adverse reactions contribute to a more favourable outcome of TEN. Orv Hetil. 2020; 161(46): 1959-1965.

Vitamin D status is influenced by well-known determinants, but factors associated with low 25-hydroxyvitamin D levels in the cutaneous melanoma population are not well defined. The aim of this study was to confirm the well-known determinants and to assess new determinants for 25-hydroxyvitamin D levels in a cutaneous melanoma population. In a prospectively included cohort of 387 patients with cutaneous melanoma the association of 25-hydroxyvitamin D levels with sex, age, body mass index, time of blood withdrawal, Fitzpatrick phototype, vitamin D supplementation, score for intensity of lifetime sun exposure, smoking, education level, hair and skin colour, eye colour, total number of benign naevi, freckles and parameters of chronic sun damage was investigated. In addition, 25-hydroxyvitamin D levels were correlated with pathological parameters of the primary tumour and melanoma stage (8th edition of the American Joint Committee on Cancer (AJCC). Univariate and multivariate logistic regressions were performed using R software. The following factors had a significant effect on vitamin D status: body mass index, seasonal time of blood sampling, vitamin D supplementation, and a subtype of skin, and hair colour. ispartof: ACTA DERMATO-VENEREOLOGICA vol:102 ispartof: location:Sweden status: published

Background The role of sun exposure in the development of melanoma and nonmelanoma skin cancers is known; however, there are limited data on the contribution of pretransplantation total sun burden (TSB) to the increased skin cancer risk in organ transplant recipients (OTRs). The importance of patient education about sun-safe behaviors is understood, but educations are often unsuccessful in OTRs. Methods A questionnaire-based cross-sectional study was performed with kidney transplant patients at a single academic center to assess the pre- and post-transplant sun exposure, sun protection habits, and skin cancers. Results Two hundred and twenty-one patients participated in the study. 13.1% developed at least one skin cancer. High total sun burden before transplantation was reported by 58.4%, and 65.2% reported education about increased skin cancer risk at the time of transplantation. However, that education did not lead to less sun exposure or better sun protection methods after transplantation. Overall, OTR related but not sun protection-guided lifestyle changes affecting OTRs after transplantation led to reduction in sun exposure. Conclusion Our findings highlight the need for more tailored, population-specific education programmes, even for patients who expect to receive a transplant in the future, and suggest the importance of pretransplantation TSB in determining the post-transplant skin cancer risk.

Introduction: Ultraviolet light induced DNA damage, combined with immunosuppression and inflammation are involved in the pathogenesis of actinic keratosis. Photodynamic therapy not only destroys dysplastic cells via tissue destruction and vascular shutdown, but also induces an acute local inflammatory response and activates both the innate and adaptive immune system. In our current work we aimed to compare immunohistochemistry features of inflammatory infiltrate of actinic keratoses after 5-aminolevulinic acid photodynamic therapy with or without Er:YAG laser resurfacing. Methods: Eleven patients with multiple actinic keratosis on the scalp, face, hands or forearms were treated by conventional and Er:YAG laser assisted 5-aminolevulinic acid PDT in split-site manner. Biopsies of AKs were taken before, 48 h and 3 months after the treatment. CD3, CD4, CD8, CD1a, Ki67 and p53 expressions were analyzed by immunohistochemical methods. Results: The number of p53 and Ki67 positive cells decreased significantly 3 months after treatment, but the abnormal cells were not eliminated totally. The number of CD1a+ Langerhans cells significantly decreased 48 h after both treatments, while CD8+ T cell count was significantly lower 3 months after Er:YAG laser assisted photodynamic therapy. However, the number of CD3+ and CD4+ T cells were not changed significantly 48 h and 3 months later. Conclusions: One session of 5-aminolevulinic acid photodynamic therapy even with Er:YAG laser pretreatment could not terminate actinic damage totally. Photodynamic therapy induced immunological changes. However further investigations are needed to answer how the composition of actinic keratosis’ immune infiltrate influence the effect of photodynamic therapy.

Cardiotoxicity is a serious complication of anticancer therapy by anthracycline antibiotics. Except for intercalation into DNA/RNA structure, inhibition of DNA-topoisomerase and histone eviction from chromatin, the main mechanism of their action is iron-mediated formation of various forms of free radicals, which leads to irreversible damage to cancer cells. The most serious adverse effect of anthracyclines is, thus, cardiomyopathy leading to congestive heart failure, which is caused by the same mechanisms. Here, we briefly summarize the basic types of free radicals formed by anthracyclines and the main processes how to scavenge them. From these, the main attention is paid to metallothioneins. These low-molecular cysteine-rich proteins are introduced and their functions and properties are reviewed. Further, their role in detoxification of metals and drugs is discussed. Based on these beneficial roles, their use as a new therapeutic agent against oxidative stress and for cardioprotection is critically evaluated with respect to their ability to increase chemoresistance against some types of commonly used cytostatics.

The authors present the case of a 59-year-old male patient, whose first kidney transplantation was in 1983 and the second in 2000. The first squamous cell carcinoma appeared on the skin 2 years after the first transplantation. Since 2003, at least two precancerous lesions or non-melanoma skin tumors have been removed surgically yearly. These cancers appeared predominantly on the sun-exposed skin, and were multiple. As these tumors could behave aggressively and prone to recurrence, complex treatment was applied, which included a switch in immunosuppressive drugs and the application of field therapies. The authors give an overview of these treatment options in relation to the case presentation, emphasizing that not only early detection and active treatment of the precancerous lesions and skin cancers are essential, but education of proper sun-protection methods and dermatology care are also important in order to avoid the development of these tumors. Orv. Hetil., 2016, 157(24), 971–976.

The use of photodynamic therapy is extensive, due to its antitumoral, antibacterial and photorejuvenation effects. It destroys tumor via direct cell destruction and indirectly via vascular shutdown, induction of acute local inflammatory response and activation of the immune system. Both innate and adaptive immune cells are involved in the immunological effects of photodynamic therapy. In addition to UV-induced DNA damage, inflammation and immunosuppression are also essential elements in the pathogenesis of actinic keratosis. Both immunosuppression induced by UV and defective immune response to dysplastic keratinocytes may be the target of photodynamic therapy to eliminate actinic keratosis. These elements are discussed in the present review, highlighting the possible mechanism of photodynamic therapy to effectively treat actinic keratosis.

Inflammatory cytokines can impair the skin barrier, but the question as to whether barrier alterations affect keratinocyte immune responses remains unanswered. The aim of this study was to investigate whether immune-mediated skin inflammation differs between severe atopic dermatitis patients with or without filaggrin mutation. The levels of filaggrin, inflammatory T helper 2 polarizing cytokines (thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL-33)) and chemokine (C-C motif) ligand 27 (CCL27), histological severity markers, T and dendritic cell counts in biopsies from lesional skin of severe atopic dermatitis patients with and without filaggrin mutation and healthy skin were quantified by immunohistochemistry. The results were confirmed by quantitative PCR analyses. No significant differences were found between the 2 patient groups. Expression of atopic dermatitis-specific cytokines showed significant correlation with histological severity. These findings suggest that the immune-mediated skin inflammation (represented by keratinocyte-derived factors, T cell and dendritic cell counts) is similar in the 2 patient groups with severe atopic dermatitis, and that immune activation is connected to the severity of the disease rather than to the origin of barrier alterations.

SummaryBackground The most important risk factors for malignant melanoma are skin type I or II, large number of atypical naevi and a history of sunburn in childhood and adolescence. Methods A cross-sectional study was performed to assess skin type, number of pigmented lesions and sun protection behaviour in 1157 12- to 19-year-old Hungarian students at 20 primary and secondary schools in Debrecen, Hungary. After receiving dermatological training, 18 school doctors examined the students' skin. A questionnaire was completed by the students with the assistance of their parents about sun protection, sunburns and the use of sunbed. Data from 612 questionnaires were evaluated. Results Based on the doctors' evaluation, most of the pupils were classified as having skin type II and majority of them had 5–20 naevi, particularly on the trunk. Based on the student's response, 5.2% purposely sunbathed daily, 10.1% did not use any form of sun protection, 32.2% wore sun-protective clothing and 65.7% applied sunscreen generally. 6.9% used sunbed, and 74.0% previously experienced serious sunburn at least once. Indoor tanning statistically correlated with the number of melanocytic naevi. Conclusion A high prevalence of sunburn was reported by the students and some of them did not apply any sun protection methods but used sunbed at a critical age for developing melanoma at a later time. These data highlight the importance of educating children and parents about appropriate sun protection.

Keratinocytes provide the first line of defense of the human body against carcinogenic ultraviolet (UV) radiation. Acute and chronic UVB-mediated cellular responses were widely studied. However, little is known about the role of mitochondrial regulation in UVB-induced DNA damage. Here, we show that poly (ADP-ribose) polymerase 1 (PARP1) and ataxia-telangiectasia-mutated (ATM) kinase, two tumor suppressors, are important regulators in mitochondrial alterations induced by UVB. Our study demonstrates that PARP inhibition by ABT-888 upon UVB treatment exacerbated cyclobutane pyrimidine dimers (CPD) accumulation, cell cycle block and cell death and reduced cell proliferation in premalignant skin keratinocytes. Furthermore, in human keratinocytes UVB enhanced oxidative phosphorylation (OXPHOS) and autophagy which were further induced upon PARP inhibition. Immunoblot analysis showed that these cellular responses to PARP inhibition upon UVB irradiation strongly alter the phosphorylation level of ATM, adenosine monophosphate-activated kinase (AMPK), p53, protein kinase B (AKT), and mammalian target of rapamycin (mTOR) proteins. Furthermore, chemical inhibition of ATM led to significant reduction in AMPK, p53, AKT, and mTOR activation suggesting the central role of ATM in the UVB-mediated mitochondrial changes. Our results suggest a possible link between UVB-induced DNA damage and metabolic adaptations of mitochondria and reveal the OXPHOS-regulating role of autophagy which is dependent on key metabolic and DNA damage regulators downstream of PARP1 and ATM.

In a recent work, we have proposed a novel way to approximate point sets with grids using the LLL algorithm, which operates in polynomial time. Now, we show how this approach can be applied to pattern recognition purposes with interpreting the rate of approximation as a new feature for regularity measurement. Our practical problem is the characterization of pigment networks in skin lesions. For this task we also introduce a novel image processing method for the extraction of the pigment network. Then, we show how our grid approximation framework can be applied with specializing it for the recognition of hexagonal patterns. The classification performance of our approach for the pigment network characterization problem is measured on a database annotated by a clinical expert. Throughout the paper we address several practical issues that may help to apply our general framework to other practical tasks, as well.

The authors present the case of a 59-year-old male patient, whose first kidney transplantation was in 1983 and the second in 2000. The first squamous cell carcinoma appeared on the skin 2 years after the first transplantation. Since 2003, at least two precancerous lesions or non-melanoma skin tumors have been removed surgically yearly. These cancers appeared predominantly on the sun-exposed skin, and were multiple. As these tumors could behave aggressively and prone to recurrence, complex treatment was applied, which included a switch in immunosuppressive drugs and the application of field therapies. The authors give an overview of these treatment options in relation to the case presentation, emphasizing that not only early detection and active treatment of the precancerous lesions and skin cancers are essential, but education of proper sun-protection methods and dermatology care are also important in order to avoid the development of these tumors.

Background The formation of metastases and the efficacy of systemic therapies in cutaneous malignant melanoma (CMM) depend on the characteristics of the tumour cells and the host immune response. Aberrant expression of metallothionein (MT) has been observed in several types of cancers with poor prognoses. Objective To perform an immunohistochemical study on primary CMM comparing the MT expression of tumours without metastases (n = 23) to that of samples with haematogenous metastases (n = 23) and to examine the correlation between MT staining and immunological markers relevant in CMM progression. Methods The immunohistochemical labelling of different tumour sections was analysed using tissue microarrays for the evaluation of the suitability of this method in future studies. Results Our results suggest that MT overexpression is significantly more frequent in primary CMM with haematogenous metastases (P = 0.018) and that the overexpression is independent of the Breslow tumour thickness (R = 0.102, P = 0.501). Interestingly, MT overexpression of the tumour cells was correlated with the presence of tumour-infiltrating CD68+ macrophages (P = 0.003), a known predictive factor for melanoma progression, thereby suggesting a role for MT in the development of a defective host immune response. Furthermore, the presence of CD163+ macrophages infiltrating the tumours correlated with metastasis formation (P

Recently, sunlight-induced damage of healthy human skin, including skin malignancies and a large scale of photodermatoses representing a diverse group of diseases, have increased in childhood as a result of unfavorable environmental changes. This article yields an overview of the diagnosis, the clinical features and the treatment of these conditions and disorders and also reveals perspectives. Some diseases are more frequent in the pediatric population than in adulthood, whereas others heal spontaneously during adolescence and vice versa. The majority of cases are idiopathic photodermatoses, mainly polymorphic light eruption. Photosensitivity may be an early symptom of genetic disorders, such as porphyria, or very rare genophotodermatoses. Photosensitivity, secondary to topical or systemic external agents as well as photoexacerbated dermatoses, is not so frequent in childhood. Effective photoprotection is crucial.

In vitro-synthesized mRNA containing nucleoside modifications has great therapeutical potential to transiently express proteins with physiological importance. One such protein is photolyase which rapidly removes UV-induced DNA damages, but this enzyme is absent in humans. Here, we apply a novel mRNA-based platform to achieve functional nonhuman photolyase production in cultured human keratinocytes. Transfection of nucleoside-modified mRNA encoding photolyase leads to accelerated repair of DNA photolesions in human keratinocytes.

Metallothioneins (MTs), low molecular mass cysteine-rich proteins, which are able to bind up to 20 monovalent and up to 7 divalent heavy metal ions are widely studied due to their functions in detoxification of metals, scavenging free radicals and cells protection against the oxidative stress. It was found that the loss of the protective effects of MT leads to an escalation of pathogenic processes and carcinogenesis. The most extensive area is MTs expression for oncological applications, where the information about gene patterns is helpful for the identification biological function, resistance to drugs and creating the correct chemotherapy. In other medical applications the effect of oxidative stress to cell lines exposed to heavy metals and hydrogen peroxide is studied as well as influence of drugs and cytokines on MTs expression and MTs expression in the adipose tissue. The precise detection of low metallothionein concentrations and its isoforms is necessary to understand the connection between quantity and isoforms of MTs to size, localization and type of cancer. This information is necessary for well-timed therapy and increase the chance to survival. Microarray chips appear as good possibility for finding all information about expression of MTs genes and isoforms not only in cancer, but also in other diseases, especially diabetes, obesity, cardiovascular diseases, ageing, osteoporosis, psychiatric disorders and as the effects of toxic drugs and pollutants, which is discussed in this review.

Zinc is an essential microelement; its importance to the skin is highlighted by the severe skin symptoms in hereditary or acquired zinc deficiency, by the improvement of several skin conditions using systemic or topical zinc preparations and by the induced intracellular zinc release upon UVB exposure, which is the main harmful environmental factor to the skin. Understanding the molecular background of the role of zinc in skin may help gain insight into the pathology of skin disorders and provide evidence for the therapeutic usefulness of zinc supplementation. Herein, we studied the effects of zinc chloride (ZnCl2) exposure on the function of HaCaT keratinocytes, and the results showed that a non-toxic elevation in the concentration of extracellular zinc (100 μM) facilitated cell proliferation and induced significant alterations in the mRNA expression of NOTCH1, IL8, and cyclooxygenase-2. In addition, increased heme oxygenase-1 (HMOX1) expression and non-toxic generation of superoxide were detected in the first 4 h. Regarding the effects on the UVB-induced toxicity, although the level of cyclobutane pyrimidine dimers in the keratinocytes pre-treated with zinc for 24 h was reduced 3 h after UVB irradiation, significantly enhanced superoxide generation was observed 10 h after UVB exposure in the zinc pre-exposed cells. The overall survival was unaffected; however, there was a decrease in the percentage of early apoptotic cells and an increase in the percentage of late apoptotic plus necrotic cells. These results suggest that the exposure of human keratinocytes to non-toxic concentrations of ZnCl2 impacts gene expression, cell proliferation and the responses to environmental stress in the skin. It would be important to further examine the role of zinc in skin and further clarify whether this issue can affect our thinking regarding the pathogenesis of skin diseases.

High-density lipoprotein (HDL)-associated antioxidant paraoxonase (PON) may reduce low-density lipoprotein (LDL) oxidation and prevent atherosclerosis. The aim of this present study was to investigate the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor atorvastatin on hydrogen-peroxide-induced DNA damage by comet assay and the correlation between oxidative DNA damage and antioxidant PON activity. Thirteen type-II/a hyperlipidemic patients were enrolled in the study. We examined the effect of 10 mg/day atorvastatin treatment on lipid levels and the degree of DNA damage in lymphocytes separated from hyperlipidemic patients, nitric oxide (NO), thiobarbituric acid-reactive substances (TBARS), PON levels and activity. After 6 months, atorvastatin treatment significantly decreased serum cholesterol and LDL-cholesterol levels. The triglyceride level did not change, and there was no significant change in the HDL cholesterol level. The visual score characteristic to the degree of DNA damage in comet assay was significantly decreased, as well as the TBARS level, while the level of NO was non-significantly increased. PON activity and the PON/HDL ratio were significantly increased after atorvastatin treatment. There was a negative correlation between DNA damage and PON activity, as well as between DNA damage and the PON/HDL ratio before and after atorvastatin treatment. These findings show that atorvastatin treatment favorably affected the lipid profile, increasing the activity of HDL-associated PON and decreasing the cytotoxic effect of oxidative stress.

Aim: It is not clear whether the mutations in hemochromatosis (HFE) gene and hepatitis C virus (HCV) infection act independently in the pathogenesis of porphyria cutanea tarda (PCT). The prevalence of both risk factors varies greatly in different parts of the world. PCT patients from Hungary were evaluated to assess both factors. Methods: The prevalence of C282Y and H63D mutations in the HFE gene was determined in 50 PCT patients and compared with the reported control frequencies. Furthermore, the presence of HCV infection was determined and related to the patients' HFE gene status. Results: The C282Y mutation was found in 8/50 cases (three homozygotes and five heterozygotes), with an 11% allele frequency (vs. 3.8% control) (P

Major biological effects of UVB are attributed to cyclobutane pyrimidine dimers (CPDs), the most common photolesions formed on DNA. To investigate the contribution of CPDs to UVB-induced changes of gene expression, a model system was established by transfecting keratinocytes with pseudouridine-modified mRNA (psi-mRNA) encoding CPD-photolyase. Microarray analyses of this model system demonstrated that more than 50% of the gene expression altered by UVB was mediated by CPD photolesions. Functional classification of the gene targets revealed strong effects of CPDs on the regulation of the cell cycle and transcriptional machineries. To confirm the microarray data, cell cycle-regulatory genes, CCNE1 and CDKN2B that were induced exclusively by CPDs were selected for further investigation. Following UVB irradiation, expression of these genes increased significantly at both mRNA and protein levels, but not in cells transfected with CPD-photolyase psi-mRNA and exposed to photoreactivating light. Treatment of cells with inhibitors of c-Jun N-terminal kinase (JNK) blocked the UVB-dependent upregulation of both genes suggesting a role for JNK in relaying the signal of UVB-induced CPDs into transcriptional responses. Thus, photolyase mRNA-based experimental platform demonstrates CPD-dependent and-independent events of UVB-induced cellular responses, and, as such, has the potential to identify novel molecular targets for treatment of UVB-mediated skin diseases.

Background The precise role of total body 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) in the clinical management of patients with cutaneous malignant melanoma (CMM) is not well established. Objective The purpose of this study was to investigate the diagnostic accuracy of PET/CT in early- and late-stage patients with high-risk CMM. Methods We retrospectively analysed various imaging, histopathological and clinical data from 97 patients also examined by PET/CT during a 5-year period (2007–2011). Three groups were assessed: stage I/II, resected stage III and unresectable stage III/stage IV. Results The median follow-up time of living patients was 43.48 ± 19.67 (15–142) months. We observed a high diagnostic accuracy in all stages (91.3%, 92.5% and 96.2% respectively). PET/CT appeared to be reliable diagnostic tool even for the detection of small lymph node metastases. PET/CT was informative in 14 of 19 cases wherein another imaging examination provided inconclusive results regarding lesion dignity. However, PET/CT was less suitable for properly evaluating the dignity of a lung lesion. A true positive scan was twice as likely in clinically negative patients with resected stage III disease than in patients with stage I/II disease (35.9% and 14.5%, P = 0.007). Conclusions These results confirm that PET/CT is an important diagnostic tool in the management of patients with high-risk CMM, but it cannot replace the standard of care examinations. More accurate clinicopathological and timing criteria must be defined to best utilize the advantages of this imaging method.

In the Author Byline, the name of the fifth author was misspelled. It should be: Hector Hernandez-Vargas. The correct Citation is: Rakosy Z, Ecsedi S, Toth R, Vizkeleti L, Hernandez-Vargas H, et al. (2013) Integrative Genomics Identifies Gene Signature Associated with Melanoma Ulceration. PLoS ONE 8(1): e54958. doi:10.1371/journal.pone.0054958 In Table 1, in the second column and the '20-50' row, the correct value is 7.