REVIEW | doi:10.20944/preprints202211.0160.v1
Subject: Life Sciences, Molecular Biology Keywords: chondroitin sulfate proteoglycan; cutaneous squamous cell carcinoma; head and neck squamous cell carcinoma; cancer biomarker; gene expression.
Online: 9 November 2022 (01:08:57 CET)
Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the extracellular matrix (ECM) to promote tumour cell invasion, migration as well as inflammation and angiogenesis. While CSPG4 has been widely studied in certain malignancies, such as melanoma, evidence is emerging from global gene expression studies, which suggests a role for CSPG4 in squamous cell carcinoma (SCC). While relatively treatable, lack of widely agreed upon diagnostic markers for SCCs is problematic, especially for clinicians managing certain patients, including those who are aged or infirm, as well as those with underlying conditions such as epidermolysis bullosa (EB), for which a delayed diagnosis is likely lethal. In this review, we have discussed the structure of CSPG4, and quantitatively analysed CSPG4 expression in the tissues and pathologies where it has been identified. The aim of this review has been to collate the information available from functional studies and recent transcriptome analysis to determine the usefulness of CSPG4 expression as a diagnostic marker and therapeutic target in management of malignant SCC.
BRIEF REPORT | doi:10.20944/preprints202004.0150.v1
Subject: Medicine & Pharmacology, Dermatology Keywords: actinic keratosis; cutaneous squamous cell carcinoma; cytoplams; skin cancer; heat shock protein
Online: 9 April 2020 (12:21:19 CEST)
Background: Cutaneous squamous skin cell carcinoma (SCC) is the second most frequent type of non- melanoma skin cancer and the second cause of death by skin cancer in caucasian population. However, at present it is difficult to predict patients with worst SCC prognosis. Objective: To identify proteins whose expression level could predict SCC infiltration in SCC arising from actinic keratosis (AC). Methods: A total of 20 biopsies of 20 different patients were studied, 10 were from SCC-AK samples and 10 from normal skin. Early infiltrated SCC-AK were selected on histological examination and to determine the expression of proteins fresh skin samples were processed by 2DE-electrophoresis Results: The expression levels of three proteins namely alpha-hemoglobin, heat shock protein (Hsp)-27 and 70 were significantly increased in SCC-AK samples with respect to normal control skin. However, only the expression level of Hsp70 protein positively correlated with the level of SCC-AK dermis infiltration. Immnunohistological examination suggested that the increased expression of Hsp70 proteins seems to mainly occur in the keratinocytes cytoplasm. The increased cytoplasmic Hsp70 expression in SCC-AK was confirmed by Western-blot experiments. Conclusion: Cytoplasmic expression of Hsp70 could be potential biomarker of early infiltration of SCC arising from an AK. Keywords: actinic keratosis, cutaneous squamous cell carcinoma; cytoplasm, skin cancer; heat shock protein.
REVIEW | doi:10.20944/preprints201912.0393.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: cutaneous lymphoma in elderly; skin tumors; T-cell lymphomas; sport activity training
Online: 30 December 2019 (05:43:39 CET)
PcALCL mainly concerns elderly patients. It is a large CD30+ T-cell neoplasm composed of large cells with anaplastic, pleomorphic or immunoblastic morphology, with exclusively cutaneous onset and localization. The clinical course of pcALCL is predominantly indolent. Most elderly patients with lymphoma tend to have a sedentary lifestyle, which has a negative effect on their quality of life (QoL) and on their survival. Several studies indicate that exercise has a positive impact on QoL because it reduces peak oxygen consumption, improves physical capacity, increases self-esteem, reduces accumulated stress and promotes relaxation. Therefore, particularly in indolent lymphomas, it is necessary to indicate a program of physical activity to be practiced systematically. The complete surgical excision and local radiotherapy are the first line gold standard in pcALCL with solitary lesion.
ARTICLE | doi:10.20944/preprints202204.0136.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: cutaneous melanoma; altitude; coast-plain-hill gradient
Online: 14 April 2022 (14:54:11 CEST)
The incidence of cutaneous melanoma has been increasing in the last decades among fair-skinned population. Despite etiology is complex and multifactorial, the exposure to ultraviolet radiation (UVR) is the most consistent modifiable risk factor associated with melanoma. Several factors influence the amount of UVR reaching Eart’s surface. The aim of our study is to explore the association between melanoma and altitude in an area characterized by a mixed geographic morphology, such as in the Veneto region. For this purpose, 2752 melanoma patients, who referred to our attention between 1998 and 2014, were included in this study. For each patient we extracted demographic, histological and clinical-survival data. Head/neck and acral melanoma were more common in patients from the hills and the mountains, while the prevalence of limb and trunk melanoma was higher in patients living in plain and coastal areas. With increase of altitude, the Breslow thickness, ulceration and mitotic rate get worse but no significant difference was observed in overall and disease free-survival. Geographical area of origin of melanoma patients and the “coast-plain-hill gradient” could help to estimate the influence of different sun exposure and to explain the importance of vitamin D level in skin-cancer control.
ARTICLE | doi:10.20944/preprints202111.0309.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: psoriasis; cutaneous nervous system; axon development; myelination
Online: 17 November 2021 (12:54:23 CET)
An increasing amount of evidence indicates the critical role of the cutaneous nervous system in the initiation and maintenance of psoriatic skin lesions by neurogenic inflammation. However, molecular mechanisms affecting cutaneous neurons are largely uncharacterized. Therefore, we reanalyzed a psoriatic RNA sequencing dataset from published transcriptome experiments of nearly 300 individuals. Using the Ingenuity Pathway Analysis software, we associated several hundreds of differentially expressed transcripts (DETs) to nervous system development and functions. Since neuronal projections were previously reported to be affected in psoriasis, we performed an in-depth analysis of neurite formation-related processed. Our in silico analysis suggests that SEMA-PLXN and ROBO-DCC-UNC5 regulating axonal growth and repulsion are differentially affected in non-lesional and lesional skin samples. We identified opposing expressional alterations in secreted ligands for axonal guidance signaling (RTN4/NOGOA, NTNs, SEMAs, SLITs) and non-conventional axon guidance regulating ligands, including WNT5A and their receptors, modulating axon formation. These differences in neuritogenesis may explain the abnormal cutaneous nerve filament formation described in psoriatic skin. The processes also influence T cell activation and infiltration, thus highlighting an additional angle of the crosstalk between the cutaneous nervous system and the immune responses in psoriasis pathogenesis, in addition to the known neurogenic pro-inflammatory mediators.
ARTICLE | doi:10.20944/preprints202207.0162.v1
Subject: Life Sciences, Genetics Keywords: Circular RNA; Cutaneous Melanoma; Immunotherapy; metastasis; LncRNA; ecRNA
Online: 11 July 2022 (14:14:53 CEST)
Cutaneous Melanoma (CM) is the most lethal form of skin cancer if it becomes metastatic, where treatment options and survival chances decrease dramatically. Immunotherapy treatments based on the immunologic checkpoint inhibitors (PD-1 and CTLA4) constituted a main breakthrough in the treatment of metastatic CM, particularly in the long-term benefit. However, several molecular pathways are responsible for the failure of this strategy in about 50-70% of CM patients. Some Long Non-coding RNAs (lncRNAs), and circular RNAs (circRNA) are implicated in triggering pro- and antitumorigenic responses to various cancer treatments. The relationship between lncRNA, circRNA and Immune Checkpoint Blockade (ICB) immunotherapy is not extensively explored in cutaneous metastatic melanoma (CMM). The aim of this study is to evaluate the potential role of both circRNA and lncRNA as a predictive immunotherapy biomarker in CMM. RNA-seq from 12 FFPE samples from the metastatic biopsy of metastatic melanoma patients treated with Nivolumab were analyzed. Our findings indicate that specific lncRNA and circRNA are involved in regulatory networks of the immune response against metastatic melanoma under treatment with nivolumab. Moreover, we have established a risk score that allows the prediction of Overall survival (OS) and Progression-free survival (PFS) of CMM patients with high accuracy. This proof of principle work provides a possible insight on the function of ceRNA, contributing to decipher the complex molecular mechanism of ICB cancer treatment response.
REVIEW | doi:10.20944/preprints202205.0128.v1
Subject: Medicine & Pharmacology, Other Keywords: systemic lupus erythematosus; anifrolumab; interferon; cutaneous lupus erythematosus
Online: 10 May 2022 (07:45:29 CEST)
Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease, and organ manifestations, such as lupus nephritis (LN) or skin disease, may be refractory to standard treatment. Therefore, new agents are required to allow for a more personalized therapeutic approach. Recently, several new therapies have been approved internationally, including voclosporine for LN and anifrolumab for moderately to severely active SLE. Here, we report a case of SLE with a predominant and refractory cutaneous manifestation despite treatment with glucocorticoids, hydroxychloroquine, mycophenolate mofetil, and belimumab. Belimumab was switched to anifrolumab, and the patient responded quickly after two infusions (eight weeks) with a reduction of the Cutaneous Lupus Assessment and Severity Index (CLASI) from 17 to 7. In addition, we review the available clinical trial data for anifrolumab with a focus on cutaneous outcomes. Based on phase II and III clinical trials investigating the intravenous administration, a consistent CLASI improvement was observed at 12 weeks. Interestingly, in a phase II trial of subcutaneous anifrolumab application, CLASI response was not different from placebo at 12 weeks but numerically different at 24 and 52 weeks, respectively. Thus, anifrolumab emerges as an attractive new therapeutic option suggesting a possible domain-based approach.
ARTICLE | doi:10.20944/preprints202112.0236.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: cat; cutaneous lymphocytosis; dog; immunohistochemistry; lymphoma; PARR; skin
Online: 14 December 2021 (13:01:19 CET)
Cutaneous lymphocytosis (CL) is an uncommon and controversial lymphoproliferative disorder described in dogs and cats. CL is generally characterized by a heterogeneous clinical presentation and histological features that may overlap with epitheliotropic lymphoma. Therefore, its neoplastic or reactive nature is still debated. Here, we describe clinicopathological, immunohistochemical and clonality features of a retrospective case series of 19 cats and 10 dogs with lesions histologically compatible with CL. In both species, alopecia, erythema and scales were the most frequent clinical signs. Histologically, a dermal infiltrate of small to medium-sized lymphocytes, occasionally extending to the subcutis, was always identified. Conversely, when present, epitheliotropism was generally mild. In cats, the infiltrate was consistently CD3+; in dogs, a mixture of CD3+ and CD20+ lymphocytes was observed only in 4 cases. The infiltrate was polyclonal in all cats, while BCR and TCR clonal rearrangements were identified in dogs. Overall, cats had a long-term survival (median overall survival=1080 days) regardless of the treatment received, while dogs showed a shorter and variable clinical course, with no evident associations with clinicopathological features. In conclusion, our results support a reactive nature of the disease in cats, associated with prolonged survival; despite a similar histological picture, canine CL was associated with a more heterogeneous lymphocytic infiltrate, clonality results, and response to treatment.
Subject: Medicine & Pharmacology, Allergology Keywords: Psoriasis; cutaneous psoriasis; systemic psoriasis; classification criteria; therapy
Online: 26 September 2020 (15:03:59 CEST)
Psoriasis is a chronic, multisystem, inflammatory disease. The typical clinical cutaneous manifestation of psoriasis is scaly erythema or plaque, limited or widely distributed. However, psoriasis is far beyond the skin involvement and provides many challenges, including associated comorbidities. In this review, we classify psoriasis as cutaneous and systemic psoriasis, according to the clinical diversity and associated comorbid diseases, and recommend classification criteria for psoriasis. The key objective of this novel classification is to raise awareness of the complexity of this multifaceted disease and help to better understand and manage this complex disease comprehensively.
ARTICLE | doi:10.20944/preprints202010.0624.v1
Subject: Medicine & Pharmacology, Allergology Keywords: medical record systems; cutaneous malignant melanoma; survival analysis; immunotherapy
Online: 29 October 2020 (16:02:44 CET)
Background: Cutaneous malignant melanoma (CMM) is one of the most aggressive types of skin cancer. Currently, innovative approaches such as target therapies and immunotherapies have been introduced in clinical practice for the treatment of metastatic CMM. Data of clinical trials and real life studies that evaluate the outcomes of these therapeutic associations are necessary to establish their clinical utility. The aim of this study is to investigate the types of oncological treatments employed in the real-life clinical management of patients with advanced CMM in several Italian centers which are part of the Clinical National Melanoma Registry (CNMR), and the oncological outcomes obtained. Methods: CNMR collects data of patients with a histologically confirmed diagnosis of primary CMM treated in one of the 38 Italian institutions (hospitals, research institutes, etc.) participating in the network. Melanoma-specific survival and Overall survival were calculated. Kaplan-Meier curves and medians of OS and 95% CI are presented overall and by immunotherapy and target treatments. The Log-rank test compared curves by treatments. Multivariate Cox regression models were used to estimate the hazard ratios adjusting for confounders and other prognostic factors. Results: The median follow-up time was 36 months (range 1.2-185.1). 787 CMM were included in the analysis with completed information about therapies.Global immunotherapy showed a significant improved survival compared with all other therapies (p=0.001). 75% was the highest reduction of death reached by nivolumab/pembrolizumab immunotherapy (anti-PD1 HR=0.25 95% CI 0.14-0.42), globally immunotherapy was significantly associated with improved survival, either for anti-CTL A4 monotherapy or combined with anti-PD1 (HR=0.47;95% CI 0.33-0.66 and HR=0.26; 95% CI 0.15-0.46, respectively). Conclusions: The nivolumab/pembrolizumab and the combination of ipilimumab can be considered the best therapy to improve survival in a real-world-population. The CNMR can complement clinical registries with the intent of improving cancer management and standardizing cancer treatment.
ARTICLE | doi:10.20944/preprints201902.0177.v1
Subject: Life Sciences, Virology Keywords: Bovine cutaneous papilloma, Iraq, Immunohistochemical (IHC), hyperkeratosis, p53 marker.
Online: 19 February 2019 (11:04:23 CET)
Background: Papillomaviruses (PVs) are double-stranded DNA viruses and are more common in skin of ruminants in Iraq. A P53 (tumor suppressor protein) reveals an essential role in cell cycle control. This study aimed to describe the clinical, histopathological and immunohistochemical aspects of naturally occurring cutaneous ruminant’s papillomatosis. Methods: Samples were collected from totally, 10 animals (3 cattle, 3 goats and 4 sheep) with multiple papillomatosis lesions. Results: Clinically, exophytic multiple, cauliflower-like growths (warts) of varying sizes (0.5-11 cm) were found in different areas of the animal’s bodies. Histopathological features were various degrees of koilocytosis, ortho and parakeratotic, hyperkeratosis, hypergranulosis in granular layer and acanthosis. Immunohistochemical (IHC) investigations revealed some nuclei in the granular and basal layers of the epidermis with intense positivity for papillomavirus antigen. All tumor samples were positive for p53 expression that appeared as a strong cytoplasmic and perinuclear staining mainly in the basal and parabasal layers. Conclusion: this study described the papillomavirus lesions in bovine, ovine and caprine, that located in different anatomical areas with minor variations in histopathological features. The tumor samples showed positive results for PV antigen and P53 expression that considered as the useful markers in the diagnosis of cutaneous papilloma.
ARTICLE | doi:10.20944/preprints202009.0239.v1
Subject: Medicine & Pharmacology, Dermatology Keywords: Cutaneous Melanoma; Immunotherapy; Lymphocytes; Monocytes; Macrophages; RNAseq; tumor immune microenvironment
Online: 11 September 2020 (04:02:03 CEST)
Background: Cutaneous Melanoma (SKCM) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of SKCM (n=328) was utilized. The immune microenvironment was characterized using CIBERSORTX to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Samples were separated into those obtained from the primary tumor site and regional skin or soft tissue (locoregional), or distant metastasis and regional lymph node (metastatic). Analysis of overall survival (OS) was performed using Kaplan-Meier estimates and Cox-regression multivariable analyses. Results: Four immune clusters were identified, largely defined by lymphocyte:monocyte (L:M) ratio, monocyte-enrichment, and M0-macrophage-enrichment (L:MLow, MonocyteHigh, M0High; L:MLow, MonocyteMid, M0Low; L:MMid, MonocyteLow, M0Low; L:MHigh, MonocyteLow, M0Low). The L:MLow, MonocyteHigh, M0High cluster demonstrated significantly worse OS than clusters 2-4 in the locoregional group (HR 2.804, 95% CI 1.262–6.234, p=0.0114). Membership in the L:MLow, MonocyteHigh, M0High cluster was an independently poor prognostic factor for survival (HR 3.03, 95% CI 1.12–8.20, p=0.029). The L:MLow, MonocyteHigh, M0High cluster correlated with higher rates of metastasis and decreased predicted response to immune checkpoint blockade compared to the other clusters as determined by the Tumor Immune Dysfunction and Exclusion tool (TIDE). Conclusion: Distinct tumor immune clusters with a M0-macrophage-enriched, L:M ratio low phenotype in the primary melanoma tumor site independently characterize an aggressive phenotype that may differentially respond to treatment.
REVIEW | doi:10.20944/preprints202104.0703.v1
Subject: Biology, Anatomy & Morphology Keywords: Cell mogration; Cutaneous wound healing; Wound healing assay; lab-on-a-chip; Skin; Microvasculature; Microfluidics
Online: 27 April 2021 (10:17:44 CEST)
Cutaneous wound healing is a complex multi-stage process involving direct and indirect cell communication events with the aim of efficiently restoring the barrier function of the skin. One key aspect in cutaneous wound healing is associated with cell movement and migration into the physically, chemically and biologically injured area resulting in wound closure. Understanding the conditions under which cell migration is impaired and elucidating the cellular and molecular mechanisms that improve healing dynamics is therefore crucial in devising novel therapeutic strategies to elevate patient suffering, reduce scaring and eliminate chronic wounds. Following the global trend towards automation, miniaturization and integration of cell-based assays into microphysiological systems, conventional wound healing assays such as the scratch assay or cell exclusion assay have recently been translated and improved using microfluidics and lab-on-a-chip technologies. These miniaturized cell analysis systems allow precise spatial and temporal control over a range of dynamic microenvironmental factors including shear stress, biochemical and oxygen gradients to create more reliable in vitro models that resemble the in vivo microenvironment of a wound more closely on a molecular, cellular, and tissue level. The current review provides (a) an overview on the main molecular and cellular processes that take place during wound healing, (b) a brief introduction into conventional in vitro wound healing assays, and (c) a perspective on future cutaneous and vascular wound healing research using microfluidic technology.
ARTICLE | doi:10.20944/preprints201806.0020.v1
Subject: Medicine & Pharmacology, Dermatology Keywords: Annona muricata; apoptosis; basal cell carcinoma; cutaneous squamous cell carcinoma; graviola; Hedgehog signaling pathway; natural products chemistry; non-melanoma skin cancer
Online: 1 June 2018 (13:00:02 CEST)
Non-melanoma skin cancers (NMSCs) are the leading cause of skin cancer-related morbidity and mortality. Effective strategies are needed to control NMSC occurrence and progression. Non-toxic, plant-derived extracts have been shown to exert multiple anti-cancer effects. Graviola (Annona muricata), a tropical fruit-bearing plant, has been used in traditional medicine against multiple human diseases including cancer. The current study investigated the effects of graviola leaf and stem extract (GLSE) and its solvent-extracted fractions on two human NMSC cell lines, UW-BCC1 and A431. GLSE was found to: i) dose-dependently suppress UW-BCC1 and A431 cell growth, motility, wound closure, and clonogenicity; ii) induce G0/G1 cell cycle arrest by downregulating cyclin/cdk factors while upregulating cdk inhibitors, and (iv) induce apoptosis as evidenced by cleavage of caspases-3, -8 and PARP. Further, GLSE suppressed levels of activated hedgehog (Hh) pathway components Smo, Gli 1/2, and Shh while inducing SuFu. GLSE also decreased the expression of pro-apoptotic protein Bax while decreasing the expression of the anti-apoptotic protein Bcl-2. We determined that these activities were concentrated in an acetogenin/alkaloid-rich dichloromethane subfraction of GLSE. Our data identify graviola extracts and their constituents as promising sources for new chemopreventive and therapeutic agent(s) to be further developed for the control of NMSCs
REVIEW | doi:10.20944/preprints201805.0158.v1
Subject: Medicine & Pharmacology, Dermatology Keywords: celiac disease; dermatitis herpetiformis; alopecia areata; cutaneous vasculitis; urticaria; atopic dermatitis; psoriasis; recurrent aphtous ulceration; chronic ulcerative stomatitis; gluten-free diet
Online: 10 May 2018 (08:04:40 CEST)
Celiac disease (CD) is an immune-mediated gluten-induced enteropathy that affects predisposed individuals of all ages. Many patients with CD do not report gastrointestinal symptoms making it difficult to reach an early diagnosis. On the other hand, CD is related to a wide spectrum of extra-intestinal manifestations, being dermatitis herpetiformis (DH) the best characterized. These associated conditions may be the clue for reaching the diagnosis of CD. Over the last years, there have been multiple reports of the association between CD and several cutaneous manifestations that may improve with a gluten-free diet (GFD). The presence of some of these skin diseases, even in absence of gastrointestinal symptoms, should give rise to an appropriate screening for CD. The aim of this paper is to describe the different cutaneous manifestations that have been associated to CD and the possible mechanisms involved.
ARTICLE | doi:10.20944/preprints201806.0299.v1
Subject: Life Sciences, Virology Keywords: Crimean-Congo hemorrhagic fever virus; Crimean-Congo hemorrhagic fever; Hyalomma marginatum; human cutaneous immune response; Langerhans cells; dermal dendritic cells; tick-borne virus; tick-virus-host interface
Online: 19 June 2018 (11:50:54 CEST)
Crimean-Congo hemorrhagic fever virus is one the most important and wide spread tick-borne viruses. Very little is known about the transmission from the tick and the early aspects of pathogenesis. Here, we generate human cutaneous antigen presenting cells: dermal dendritic cells and Langerhans cells, from umbilical cord progenitor cells. In order to mimic the environment created during tick feeding, tick salivary gland extract was generated from semi-engorged Hyalomma marginatum ticks. Our findings indicate that human dermal dendritic cells and Langerhans cells are susceptible and permissive to Crimean-Congo hemorrhagic fever virus infection, however, to different degrees. Infection leads to cell activation and cytokine/chemokine secretion, although these responses vary between the different cell types. Hyalomma marginatum salivary gland extract had minimal effect on cell responses, with some synergy with viral infection with respect to cytokine secretion. However, salivary gland extract appeared to inhibit antigen presenting cell (APC) migration. Based on the findings here we hypothesize that human dermal dendritic cells and Langerhans cells serve as early target cells. Rather affecting Crimean-Congo hemorrhagic fever virus replication, tick saliva likely immunomodulates and inhibits migration of these APC from the feeding site.