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Abstract Introduction Topical 5-fluorouracil (5-FU)-containing treatments are effective for actinic keratosis (AK); however, they frequently lead to transient local skin reactions (LSRs), which often result in treatment non-adherence. Methods The aim of this international, phase IV clinical trial was to investigate whether addition of an emollient to topical 4% 5-FU would reduce the frequency and severity of LSRs over 4 weeks of treatment (intervention group) compared with 4% 5-FU alone (control group) in patients with AK. The primary objective was to assess the severity of LSRs (i.e. erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration) at week 4 of treatment (or before, in case of a major local reaction). Key secondary objectives were LSR total scores at weeks 2 and 8, the scores of individual LSR items at each visit, and the proportions of patients with 100% and ≥ 75% AK lesion clearance at week 8. Results In total, 141 patients were included in the efficacy analysis (71 in the intervention group and 70 in the control group). There were no statistically or clinically significant differences between the treatment groups in terms of LSR total score at week 4 (overall and by subgroups defined by the number of lesions and patient age at baseline), scores of individual LSR items at any time point, and AK lesion clearance rates at week 8. LSR scores with topical 4% 5-FU alone were lower than expected. Skin reactions were the most common treatment-emergent adverse events in both groups, leading to treatment discontinuation in nine patients (12.3%) in the intervention group and seven (9.9%) in the control group. No new safety signals were observed with the addition of an emollient to 4% 5-FU. Conclusions Daily emollient applications during the 4-week treatment course did not impact the safety and efficacy profile of 4% 5-FU.

Advanced cutaneous squamous cell carcinoma (cSCC) can be a life-threatening disease for which effective and safe treatment in advanced stages is very limited. GP-2250 has been recently proven to have—in vitro and in vivo—antineoplastic effects on cancer cells. This study aims to investigate the potential anti-neoplastic effects of GP-2250 on the cSCC cell lines SCC13 and A431 through dose finding assessments, MTT cytotoxicity assays, cell migration assays, BrdU proliferation assays and FCM analysis. Our preliminary results have shown for the first time evidence for anti-neoplastic effects of GP-2250 on cSCC cells, enhancing cytotoxicity, attenuating cancer cell proliferation, inducing apoptosis and reducing tumour cell migration. Further investigations evaluating the modes of action of GP-2250 on cSCC cell lines are warranted in order to justify the use in vivo studies.

Actinic keratosis is a lesion that develops in sun-exposed areas of the skin and is considered to be a precancerous condition or an early in situ squamous cell carcinoma. Treatment of actinic keratosis is important for reducing skin cancer risk, with treatment choice based on patient-, lesion- and treatment-related considerations. Of the topical treatments used for field-directed therapy, those containing 5-fluorouracil are among the most effective and widely prescribed. The most recently developed topical 5-fluorouracil preparation (Tolak®; Pierre Fabre, France) contains 4% 5-fluorouracil in an aqueous cream. This narrative review discusses data on 4% 5-fluorouracil cream to treat actinic keratosis, and provides the authors’ expert opinion on issues associated with it use. The effect of the cream has been evaluated in phase 2 and 3 trials of adult patients with actinic keratosis on the face, ears or scalp. These trials included patients with severe baseline disease, defined by high lesion counts and large-size treatment fields, which possibly affected the proportion of patients who were able to achieve complete clearance. Other efficacy parameters (e.g. percentage change in lesion count, ≥ 75% clearance of lesions or clinically significant changes in validated severity scales) should also be assessed to fully evaluate 4% 5-fluorouracil treatment efficacy in these patients. Nevertheless, 4% 5-fluorouracil is associated with high efficacy, a low level of recurrence and a satisfactory safety profile.

ABSTRACT: Actinic keratoses are keratotic lesions occurring on skin areas extensively damaged by sunlight. Using data from a previously published Phase III randomized, controlled clinical trial in patients with at least 5 actinic keratoses, we explored the potential link between the number of visible actinic keratosis lesions before any treatment and the total number of lesions of the field cancerization as revealed by 5-fluorouracil cream. Our analysis suggests that the baseline number of visible actinic keratoses is a poor indicator of the real number of lesions in the field of cancerization, reinforcing the need to explain the field cancerization concept to patients. (Curr Ther Res Clin Exp. 2022; 82:XXX–XXX) © 2022 Elsevier HS Journals, Inc.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting in inverse body regions. In a systematic review, the role of hormones in HS will be presented to better understand the pathomechanisms of HS. The review is based on the PRISMA criteria. Systematic research was carried out using keywords. Subsequently, the data were analyzed based on the clinical response and other relevant information. The main focus of our systematic review was on HS manifestation, exacerbation, sex hormones, antiandrogen therapy, thyroid function, polycystic ovary syndrome, insulin resistance, and adipokines. In HS, there appears to be a dysregulated adipokine release that is shifted towards pro-inflammatory adipokines. Insulin resistance is significantly more common in HS than in healthy patients regardless of BMI, age, and gender. Insulin resistance in HS patients leads to further cardiovascular disease. The mechanism of insulin resistance and role of adipokines should be investigated in future studies to better provide the pathomechanisms of HS. The role of androgens seems to be important in a certain subgroup of female patients. Anti-androgenic therapy can be useful and helpful in some patients. However, further studies are needed to better understand the hormonal relationship in HS.

The term sinecatechins designates an extract containing a high percentage of catechins obtained from green tea, which is commercially registered as Veregen or Polyphenon E (PE) and may be considered for treatment of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK). As shown here, treatment of four cSCC cell lines with 200 µg/mL of PE resulted in strong, dose-dependent decrease in cell proliferation (20–30%) as well as strongly decreased cell viability (4–21% of controls, 48 h). Effects correlated with loss of mitochondrial membrane potential, whereas early apoptosis was less pronounced. At the protein level, some activation of caspase-3 and enhanced expression of the CDK inhibitor p21 were found. Loss of MMP and induced cell death were, however, largely independent of caspases and of the proapoptotic Bcl-2 proteins Bax and Bak, suggesting that sinecatechins induce also non-apoptotic, alternative cell death pathways, in addition to apoptosis. Reactive oxygen species (ROS) were downregulated in response to PE at 4 h, followed by an increase at 24 h. The contributory role of initially reduced ROS was supported by the antioxidant N-acetyl cysteine, which in combination with PE further enhanced the negative effects on cell viability. Thus, sinecatechins inhibited cell proliferation and viability of cSCC cells, which could suggest the use of PE for AK treatment. The mechanisms appear as linked to an imbalance of ROS levels.

Incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis has increased worldwide, and non-steroidal anti-inflammatory drugs as celecoxib are considered for treatment. We show here strong anti-proliferative effects of celecoxib in four cSCC cell lines, while apoptosis and cell viability largely remained unaffected. Impeded apoptosis was overcome in combinations with agonistic CD95 antibody or TNF-related apoptosis-inducing ligand (TRAIL), resulting in up to 60% apoptosis and almost complete loss of cell viability. Proapoptotic caspase cascades were activated, and apoptosis was suppressed by caspase inhibition. TRAIL receptor (DR5) and proapoptotic Bcl-2 proteins (Puma and Bad) were upregulated, while anti-apoptotic factors (survivin, XIAP, cFLIP, Mcl-1, and Bcl-w) were downregulated. Strongly elevated levels of reactive oxygen species (ROS) turned out as particularly characteristic for celecoxib, appearing already after 2 h. ROS production alone was not sufficient for apoptosis induction but may play a critical role in sensitizing cancer cells for apoptosis and therapy. Thus, the full therapeutic potential of celecoxib may be better used in combinations with death ligands. Furthermore, the immune response against cSCC/AK may be improved by celecoxib, and combinations with checkpoint inhibitors, recently approved for the treatment of cSCC, may be considered.

Background: Quality of life in patients represents an important area of assessment. However, attention to health professionals should be equally important. The literature on the quality of life (QOL) of emergency physicians is scarce. This pilot study investigated QOL in emergency physicians in Germany. Materials and Methods: We conducted a cross-sectional study from January to June in 2015. We approached the German Association of Emergency Medicine Physicians and two of the largest recruitment agencies for emergency physicians in Germany and invited their members to participate. We used the WHO Q-BREF to obtain QOL scores in four domains that included physical, mental, social, and environmental health. Results: The 478 German emergency physicians included in the study held board certifications in general medicine (n = 40; 8.4%), anesthesiology (n = 243; 50.8%), surgery (n = 63; 13.2%), internal medicine (n = 81; 17.0%), or others (n = 51; 10.7%). The women surveyed tended to report a better QOL but worse general health than the men. Regarding specific domains, women scored worse in physical health, particularly energy during everyday work (relative risk ratio [RRR]: 1.98 [1.21–3.24]). Both men and women scored worse in psychological health than general health, particularly young women. Women were also more likely to view their safety (RRR: 1.87 [1.07–3.28]) and living place (RRR: 2.51 [1.10–5.73]) as being poor than their male counterparts. Conclusion: QOL in German prehospital emergency care physicians is satisfactory for the included participants; however, there were some negative effects in the psychological health domain. This is particularly obvious in young female emergency physicians.

Despite a growing knowledge about the biological diversity of papillomaviruses (PV), only little is known about non-human PV in general and about PV mice models in particular. We cloned and sequenced the complete genomes of two novel PV types from the Norway rat (Rattus norvegicus; RnPV2) and the wood mouse (Apodemus sylvaticus; AsPV1) as well as a novel variant of the recently described MmuPV1 (originally designated as MusPV) from a house mouse (Mus musculus; MmuPV1 variant). In addition, we conducted phylogenetic analyses using a systematically representative set of 79 PV types, including the novel sequences. As inferred from concatenated amino acid sequences of six proteins, MmuPV1 variant and AsPV1 nested within the Beta+Xi-PV super taxon as members of the Pi-PV. RnPV2 is a member of the Iota-PV that has a distant phylogenetic position from Pi-PV. The phylogenetic results support a complex scenario of PV diversification driven by different evolutionary forces including co-divergence with hosts and adaptive radiations to new environments. PV types particularly isolated from mice and rats are the basis for new animal models, which are valuable to study PV induced tumors and new treatment options.

The BH3 domain of Bcl-2 proteins was regarded as indispensable for apoptosis induction and for mutual regulation of family members. We recently described Bcl-x(AK), a proapoptotic splice product of the bcl-x gene, which lacks BH3 but encloses BH2, BH4 and a transmembrane domain. It remained however unclear, how Bcl-x(AK) may trigger apoptosis.For efficient overexpression, Bcl-x(AK) was subcloned in an adenoviral vector under Tet-OFF control. The construct resulted in significant apoptosis induction in melanoma and nonmelanoma cell lines with up to 50% apoptotic cells as well as decreased cell proliferation and survival. Disruption of mitochondrial membrane potential, and cytochrome c release clearly indicated activation of the mitochondrial apoptosis pathways. Both Bax and Bak were activated as shown by clustering and conformation analysis. Mitochondrial translocation of Bcl-x(AK) appeared as an essential and initial step. Bcl-x(AK) was critically dependent on either Bax or Bak, and apoptosis was abrogated in Bax/Bak double knockout conditions as well by overexpression of Bcl-2 or Bcl-x(L). A direct interaction with Bcl-2, Bax, Bad, Noxa or Puma was however not seen by immunoprecipitation. Thus besides BH3-mediated interactions, there exists an additional way for mutual regulation of Bcl-2 proteins, which is independent of the BH3. This pathway appears to play a supplementary role also for other proapoptotic family members, and its unraveling may help to overcome therapy resistance in cancer.

Ultraviolet irradiation (UV) is the major risk factor for the development of skin cancer. Moreover, increasing evidence suggests cutaneotropic human papillomaviruses (HPV) from the beta genus to play a causal role as a co-factor in the development of cutaneous squamous cell carcinoma. Homeodomain-interacting protein kinase 2 (HIPK2) operates as a potential suppressor in skin tumorigenesis and is stabilized by UV-damage. HIPK2 is an important regulator of apoptosis, which forms a complex with the tumor suppressor p53, mediating p53 phosphorylation at Ser 46 and thus promoting pro-apoptotic gene expression. In our study, we demonstrate that cutaneous HPV23 E6 protein directly targets HIPK2 function. Accordingly, HPV23 E6 interacts with HIPK2 both in vitro and in vivo. Furthermore, upon massive UVB-damage HPV23 E6 co-localizes with endogenous HIPK2 at nuclear bodies. Functionally, we demonstrate that HPV23 E6 inhibits HIPK2-mediated p53 Ser 46 phosphorylation through enforcing dissociation of the HIPK2/p53 complex. In addition, HPV23 E6 co-accumulates with endogenous HIPK2 upon UV damage suggesting a mechanism by which HPV23 E6 keeps HIPK2 in check after UV damage. Thus, cutaneous HPV23 E6 prevents HIPK2-mediated p53 Ser 46 phosphorylation, which may favour survival of UV-damaged keratinocytes and skin carcinogenesis by apoptosis evasion.

Abstract  The diversity of papillomaviruses (PVes) infecting stratified squamous epithelia of warm-blooded animals, such as birds and mammals, is only fragmentarily documented. The PV types are sequenced from 9 of 18 placental taxa at the order level to date. Current phylogenetic analyses of PV sequences frequently do not consider evolutionary polarity and statistical evaluation of internal nodes, that are required for robust evolutionary conclusions. In this study, we isolated and characterized three putatively novel animal PV types from hair follicles comprising the first known insectivoran PV and two cervid PVes. With the help of the primer pair FAP59/FAP64, we amplified L1 gene fragments consisting of approximately 470 base pairs. Phylogenetic analyses were performed with a representative set of 73 PV sequences that included the three novel PVes using Maximum Likelihood, Bayesian inference, Maximum Parsimony, and distance-based methods on amino acid alignments. The three novel PVes appear to be components of the βγπξ-PV supertaxon, within which the insectivoran PV has an isolated phylogenetic position. The two cervid PVes constitute a distinct group that is only distantly related to the core cervid PVes of the δ-PVes. The molecular data supports a complex evolutionary scenario for PVes which is driven by multiple mechanisms comprising host-linked evolution, adaptive radiation establishing different ecological niches, and multiple infections across species borders. [ABSTRACT FROM AUTHOR]

Epidermal wound healing is a complex and dynamic regenerative process necessary to reestablish skin integrity. Fluorescence confocal laser scanning microscopy (FLSM) is a noninvasive imaging technique that has previously been used for evaluation of inflammatory and neoplastic skin disorders in vivo and at high resolution. We employed FLSM to investigate the evolution of epidermal wound healing noninvasively over time and in vivo. Two suction blisters were induced on the volar forearms of the study participants, followed by removal of the epidermis. To study the impact of wound ointment on the process of reepithelization, test sites were divided into two groups, of which one test site was left untreated as a negative control. FLSM was used for serial/consecutive evaluations up to 8 days. FLSM was able to visualize the development of thin keratinocyte layers developing near the wound edge and around hair follicles until the entire epidermis has been reestablished. Wounds treated with the wound ointment were found to heal significantly faster than untreated wounds. This technique allows monitoring of the kinetics of wound healing noninvasively and over time, while offering new insights into the potential effects of topically applied drugs on the process of tissue repair. [ABSTRACT FROM AUTHOR]

Excisional biopsies and routine histology remains the gold standard for the histomorphologic evaluation of normal and diseased skin. However, there is increasing interest in the development of noninvasive optical technologies for evaluation, diagnosis, and monitoring of skin disease in vivo. Fluorescent confocal microscopy is an innovative optical technology that has previously been used for morphologic evaluation of live human tissue. We evaluate the clinical applicability of a fluorescent confocal laser scanning microscope (FLSM) for a systematic evaluation of normal and diseased skin in vivo and in correlation with routine histology. A total of 40 patients were recruited to participate in the study. Skin sites of 10 participants with no prior history of skin disease served as controls and to evaluate topographic variations of normal skin in vivo. Thirty patients with a suspected diagnosis of nonmelanoma skin cancer were evaluated, whereby FLSM features of actinic keratoses (AK) and basal cell carcinoma (BCC) were recorded in an observational analysis. Selected BCCs were monitored for their skin response to topical therapy using Imiquimod as an immune-response modifier. A commercially available fluorescence microscope (OptiScan Ltd., Melbourne, Australia) was used to carry out all FLSM evaluations. Common FLSM features to AK and BCC included nuclear pleomorphism at the level of the granular and spinous layer and increased vascularity in the superficial dermal compartment. Even though the presence of superficial disruption and mere atypia of epidermal keratinocytes was more indicative of AK, the nesting of atypical basal cells, increased blood vessel tortuosity, and nuclear polarization were more typical for BCC. All diagnoses were confirmed by histology. FLSM allowed a monitoring of the local immune response following therapy with Imiquimod and demonstrated a continuous normalization of diseased skin on repeated evaluations over time. This study illustrates potential applications of FLSM in clinical dermatology for the evaluation of dynamic skin conditions and monitoring of cutaneous response to noninvasive therapies. The findings are of preliminary nature and warrant further investigations in the future. [ABSTRACT FROM AUTHOR]