Diagnostic, prognostic, and immunological roles of CDSN in ovarian cancer.

Globally, ovarian cancer (OC) ranks as a principal cause of cancer-related mortality in females. Immunotherapy has revolutionized the treatment of OC, but the efficacy of immunotherapy is often limited by different immune microenvironments. The objective of this research was to pinpoint and validate candidate genes with potential value as diagnostic and prognostic biomarkers and therapeutic targets in OC. Data on genes associated with gene mutation, prognostic survival, and immune infiltration in OC were procured from the Cancer Genome Atlas (TCGA). Gene differential analysis, mutation site analysis, prognosis and survival analysis, and functional and signaling pathway enrichment analysis were conducted to identify and evaluate key genes. The genes were further investigated using immune infiltration analysis, receiver operating characteristic curves, and immunohistochemistry. The impact of CDSN on OC cell proliferation was investigated utilizing CCK-8, colony formation, and apoptosis detection assays. We identified a set of genes (CDSN, WARS, and CD38) that were highly expressed in OC and significantly associated with mutations and prognosis. Immune infiltration analysis and immunohistochemistry results indicated a correlation with immune infiltration in the tumor microenvironment, particularly in antigen-presenting cells. Receiver operating characteristic curve analysis demonstrated the diagnostic potential of these three genes in OC, with all three genes showing the area under the curve (AUC) above 0.8. In vitro studies suggested that knocked down CDSN expression resulted in a marked lower in the proliferative capacity of OC cells. The candidate gene CDSN identified through bioinformatics analysis and in vitro experiments is associated with mutation and immune infiltration, showing promise as a diagnostic and prognostic biomarker, as well as a therapeutic objective in OC.

Overcoming Limitations in Water-Ethanol Sprayed Superstrate Solar Cells by Compositional Engineering of Cu2CdSn(S,Se)4.

The increasing demand for solar energy requires materials from earth-abundant elements to ensure cost-effective production. One such light harvester Cu2CdSn(S,Se)4 fulfills this property. We report the development of functional solar cells based on Cu2CdSn(S,Se)4, which has been previously unreported. Furthermore, we deposited the thin films of Cu2CdSn(S,Se)4 by spray pyrolysis using environmentally benign solvents, in a superstrate architecture, reducing the potential cost of upscaling, the environmental hazards, and enabling its use in semitransparent or tandem solar cells. We analyze the Cu2CdSn(S,Se)4 and its optoelectronic characteristics with different sulfur and selenium ratios in the composition. We noted that Se is homogeneously distributed in the absorber and electron transport layer, forming a Cd(S,Se) phase that impacts the optoelectronic properties. The introduction of Se, up to 30%, is found to have a positive impact on the solar cell performance, largely improving the fill factor and absorption in the infrared region, while the voltage deficit is reduced. The device with a Cu2CdSn(S2.8Se1.2) composition had a 3.5% solar-to-electric conversion efficiency, which is on par with the reported values for chalcogenides and the first report using Cu2CdSn(S,Se)4. We identified the critical factors that limit the efficiency, revealing pathways to further reduce the losses and improve the performance. This work provides the first proof of concept of a novel material, paving the way for developing cost-efficient solar cells based on earth-abundant materials.

Carbon dots conjugated to SN38 for improved colorectal anticancer therapy.

Irinotecan (CTP-11) is one of the standard therapies for colorectal cancer (CRC). CTP-11 is enzymatically converted to the hydrophobic 7-ethyl-10-hydroxycamptothecin (SN38), a one hundred-fold more active metabolite. Conjugation of hydrophobic anticancer drugs to nanomaterials is a strategy to improve their solubility, efficacy, and selectivity. Carbon dots (CDs) have garnered interest for their small sizes (<10 â€‹nm), low toxicity, high water solubility, and bright fluorescence. This paper describes the use of CDs to improve drug vehiculation, stability, and chemotherapeutic efficiency of SN38 through a direct intracellular uptake in CRC. The covalent conjugation of SN38 to CDs via a carbamate bond provides a CD-SN38 hybrid material for slow, sustained, and pH-responsive drug release. CD-SN38 successfully penetrates the CRC cells with a release in the nucleus affecting first the cell cycle and then the cytoskeleton. Moreover, CD-SN38 leads to a deregulation of the extracellular matrix (ECM), one of the major components of the cancer niche considered a possible target therapy for reducing the cancer progression. This work shows the combined therapeutic and imaging potential of CD-based hybrid materials for the treatment of CRC. Future efforts for targeted therapy of chronic diseases characterized by altered ECM deposition, such as chronic kidney disease and chronic allograft nephropathy in kidney transplant patients are envisaged.

PSORS1 Locus Genotyping Profile in Psoriasis: A Pilot Case-Control Study.

(1) Background: The psoriasis susceptibility 1 (PSORS1) locus, located within the major histocompatibility complex, is one of the main genetic determinants for psoriasis, the genotyping profile for three single-nucleotide polymorphisms (SNPs) comprising the PSORS1 locus: rs1062470 within PSORS1C1/CDSN genes, rs887466 within PSORS1C3 gene, rs10484554 within LOC105375015 gene, were investigated and correlated with psoriasis risk and severity. (2) Methods: This pilot case-controlled study involved 100 psoriatic patients and 100 healthy individuals. We investigated three SNPs and assessed the relative gene expression profile for the PSORS1C1 gene. We then correlated the results with both disease risk and severity. (3) Results: The most significantly associated SNP in PSORS1 locus with psoriasis was rs10484554 with its C/T genotype 5.63 times more likely to develop psoriasis under codominant comparison. Furthermore, C/T and T/T genotypes were 5 times more likely to develop psoriasis. The T allele was 3 times more likely to develop psoriasis under allelic comparison. The relative gene expression of PSORS1C1 for psoriatic patients showed to be under-expressed compared to normal controls. (4) Conclusions: Our study revealed the association of the three studied SNPs with psoriasis risk and severity in an Egyptian cohort, indicating that rs10484554 could be the major key player in the PSORS1 locus.

Loricrin and NRF2 Coordinate Cornification.

Cornification involves cytoskeletal cross-linkages in corneocytes (the brick) and the secretion of lipids/adhesion structures to the interstitial space (the mortar). Because the assembly of lipid envelopes precedes corneocyte maturation, loricrin is supposed to be dispensable for the protection against desiccation. Although the phenotypes of Lor knockout (LKO) mice are obscure, the antioxidative response on the KEAP1/NRF2 signaling pathway compensates for the structural defect in utero. In this study, we asked how the compensatory response is evoked after the defects are repaired. To this end, the postnatal phenotypes of LKO mice were analyzed with particular attention to the permeability barrier function primarily maintained by the mortar. Ultrastructural analysis revealed substantially thinner cornified cell envelopes and increased numbers of lamellar granules in LKO mice. Superficial epidermal damages triggered the adaptive repairing responses that evoke the NRF2-dependent upregulation of genes associated with lamellar granule secretion in LKO mice. We also found that corneodesmosomes are less degraded in LKO mice. The observation suggests that loricrin and NRF2 are important effectors of cornification, in which proteins need to be secreted, cross-linked, and degraded in a coordinated manner.

Kallikreins: Essential epidermal messengers for regulation of the skin microenvironment during homeostasis, repair and disease.

As the outermost layer of the skin, the epidermis is playing a major role in organism homeostasis providing the first barrier against external aggressions. Although considered as an extracellular matrix (ECM)-poor subtissue, the epidermal microenvironment is a key regulator of skin homeostasis and functionality. Among the proteins essential for upholding the epidermal microenvironment are the members of the kallikrein (KLK) family composed of 15 secreted serine proteases. Most of the members of these epithelial-specific proteins are present in skin and regulate skin desquamation and inflammation. However, although epidermal products, the consequences of KLK activities are not confined to the epidermis but widespread in the skin. In this review starting with the location and proteolytic activation cascade of KLKs, we present KLKs involvement in skin homeostasis, regeneration and pathology. KLKs have a large variety of substrates including ECM proteins, and evidence suggests that they are involved in the different steps of skin wound healing as discussed here. KLKs are also used as prognosis/diagnosis markers for many cancer types and we are focusing later on KLKs in cutaneous cancers, although their pathogenicity remains to be fully elucidated. Dysregulation of the KLK cascade is directly responsible for skin diseases with heavy inflammatory aspects, highlighting their involvement in skin immune homeostasis. Future studies will be needed to support the therapeutic potential of adjusting KLK activities for treatment of inflammatory skin diseases and wound healing pathologies.

Efficient novel amphiphilic double shells layer coupled with nanoscale zero-valent composite for the degradation of trichloroethylene.

An efficient novel amphiphilic material composed of core-double shells nanocomposite (CDSN) with nanoscale zero-valent iron (NZVI) as the core and PS100-b-PAA16 as inner shell and chitosan as outmost shell has been synthesized successfully. Its application to remove the trichloroethylene (TCE) in stimulated TCE solution with 7.3 ±â€¯0.3 mg/L dissolved oxygen was investigated. The results showed that CDSN after exposure to air for a month could still remove 92.6% of TCE as compared to 61.5% removal rate of NZVI in 360 min (the gram ratio of material: TCE equals to 10:1), exhibiting the great oxidation resistance performance. Specifically, dynamic research of the total removal divided into adsorption by shell layer and degradation by reducibility of NZVI at a predetermined interval was engaged to understand the complete mass transfer process of TCE. The results revealed that CDSN adsorbed 1.5 to 2 folds time TCE as compared to NZVI in the same initial pH = 8.5 aqueous solution. Importantly, CDSN could sustain fixed reactivity to remove about 94.8% of TCE from the start to end. NZVI exhibited greater removal capacity in first 180 min, but later it lost the reducibility and finial removal rate was 89%. The selective adsorption to protonated CDSN was strengthened to increase the removal of TCE at pH 3.5 while NZVI had a worse removal in pH 3.5 performance than pH 8.5.

Evaluation of skin- or sweat-characteristic mRNAs for inferring the human origin of touched contact traces.

The source of small amounts of touch DNA, which is transferred from the skin to an object when it is handled or touched, could be an issue in the forensic analysis of criminal cases. Here, we performed an extended evaluation of skin- or sweat-characteristic mRNAs to investigate their usability to infer whether an object has been handled or touched by someone. First, we compared the expression levels of candidate genes between skin swabs and other body fluids by quantitative RT-PCR analysis. Among the analyzed genes, corneodesmosin (CDSN), late cornified envelope 1C (LCE1C), filaggrin (FLG), desmocollin 1, and dermcidin were selected for further analysis on the basis of their specificities and sensitivities. Then, we tried to detect these genes from mock casework samples. As a result, CDSN, LCE1C, and FLG could be good markers because of their detectability. Finally, we determined the correlation between the expression of these genes and DNA yield of skin swabs to assess their adaptability as a screening test for touch DNA samples. However, the detectability of these genes was not correlated with the DNA yield of skin swab samples. In conclusion, gene expression analysis of the skin- or sweat-characteristic mRNAs CDSN, LCE1C, and FLG could be useful for inferring the skin origin of touched contact traces, but the use of the expression levels of these mRNAs for the prediction of DNA yield is problematic. To develop a screening test for touch DNA samples, other markers that have a well-correlated sensitivity with DNA analysis should be investigated.

HLA-C*06:02-independent, gender-related association of PSORS1C3 and PSORS1C1/CDSN single-nucleotide polymorphisms with risk and severity of psoriasis.

Psoriasis vulgaris (PsV) is a common, chronic skin disease with a complex genetic and environmental etiology. We investigated, in 461 psoriatic patients and 454 healthy controls, the associations with psoriasis of four single-nucleotide polymorphisms (SNPs) from the psoriasis susceptibility 1 (PSORS1) interval: rs1062470 (PSORS1C1/CDSN), rs887466 (PSORS1C3), rs2894207 and rs10484554 (LOC105375015). The minor alleles of three SNPs (rs1062470A, rs2894207C and rs10484554T) strongly increased the disease risk (OR = 2.17, p < 0.0001; OR = 2.33, p < 0.0001 and OR = 2.68, p < 0.0001, respectively), whereas the minor A allele of rs887466 exerted a protective effect (OR = 0.73, p = 0.001). The strength of association for SNPs was the highest in patients with very early onset psoriasis (≤ 20 years), while in late onset psoriasis (> 40 years) the association was the weakest. The haplotype rs1062470A/rs887466G/rs2894207C/rs10484554T highly significantly increased the disease risk (OR = 3.58, p = 8.0e-027), while the haplotypes rs1062470G/rs887466A/rs2894207T/rs10484554C and rs1062470G/rs887466G/rs2894207T/rs10484554C were strongly protective (OR = 0.65, p = 0.002 and OR = 0.55, p = 2.4e-009, respectively). Additionally, we showed a HLA-C*06:02-independent gender-related effect of the rs887466A allele which was protective against psoriasis in males (OR = 0.61, p = 9.2e-005), but not in females (p = 0.66). We also demonstrated a correlation of PASI score value with rs1062470 genotype, and again only in male patients (p = 0.006) and HLA-C*06:02-independent. Our results show, for the first time, the male-only associations of the PSORS1C3 gene with psoriasis risk and of the PSORS1C1/CDSN gene with severity of disease. However, the age dependent associations need to be validated in larger sample sizes as well as in other populations.

A Case of Inflammatory Generalized Type of Peeling Skin Syndrome Possibly Caused by a Homozygous Missense Mutation of CDSN.

A 54-year-old Japanese woman had repetitive superficial skin peeling and ensuing erythematous changes in the sites since infancy. Her parents had a consanguineous marriage, and she was the only individual affected in her family tree. The erythematous changes seemed to worsen in the summer. Histologically, hyperkeratosis and splitting of the epidermis within the stratum corneum was noted, and electron microscopy revealed shedding of corneal cells in the horny layer and normal-looking corneodesmosomes. Gene analysis revealed a homozygous missense mutation at c.1358G>A in CDSN. Electron microscopic examination of the length and number of corneodesmosomes revealed statistically significant shortness and sparsity in the affected individual (mean ± SD 386.2 ± 149.5 nm) compared with that of an age- and site-matched control (406.6 ± 182.3 nm). We speculate that this size shrinkage of corneodesmosomes might be the result of a missense mutation of CDSN and that this could be one of the factors contributing to the pathological process of skin peeling.

Homozygous deletion of six genes including corneodesmosin on chromosome 6p21.3 is associated with generalized peeling skin disease.

BACKGROUND: Peeling skin syndrome (PSS) is a rare autosomal recessive form of ichthyosis showing skin exfoliation. PSS is divided into acral and generalized PSS, and the latter is further classified into non-inflammatory type (PSS type A) and inflammatory type (PSS type B). PSS type B is now called peeling skin disease (PSD). Different loss-of-function mutations in the corneodesmosin (CDSN) gene have been reported to cause PSD. OBJECTIVE: The aim of this study was to determine genetic basis of disease in a 14-year-old Japanese patient with PSD. METHODS AND RESULTS: Immunohistochemical study showed lack of corneodesmosin (CDSN) in the skin, and standard PCR for genomic DNA failed to amplify CDSN product, suggesting CDSN defect. Multiplex ligation-dependent probe amplification and genomic quantitative real-time PCR analyses detected large homozygous deletion of 59,184bp extending from 40.6kb upstream to 13.2kb downstream of CDSN, which included 6 genes (TCF19, CCHCR1, PSORS1C2, PSORS1C1, CDSN and C6orf15). The continuous gene lost did not result in additional clinical features. Inverted repeats with 85% similarity flanking the deletion breakpoint were considered to mediate the deletion by non-homologous end joining or fork stalling and template switching/microhomology-mediated break-induced replication. Parents were clinically unaffected and were heterozygote carriers of the same deletion, which was absent in 284 ethnically matched control alleles. We also developed simple PCR method, which is useful for detection of this deletion. CONCLUSION: Although 5 other genes were also deleted, homozygous deletion of CDSN was considered to be responsible for this PSD.

Alu-mediated large deletion of the CDSN gene as a cause of peeling skin disease.

Peeling skin disease (PSD) is an autosomal recessive skin disorder caused by mutations in CDSN and is characterized by superficial peeling of the upper epidermis. Corneodesmosin (CDSN) is a major component of corneodesmosomes that plays an important role in maintaining epidermis integrity. Herein, we report a patient with PSD caused by a novel homozygous large deletion in the 6p21.3 region encompassing the CDSN gene, which abrogates CDSN expression. Several genes including C6orf15, PSORS1C1, PSORS1C2, CCHCR1, and TCF19 were also deleted, however, the patient showed only clinical features typical of PSD. The deletion size was 59.1 kb. Analysis of the sequence surrounding the breakpoint showed that both telomeric and centromeric breakpoints existed within Alu-S sequences that were oriented in opposite directions. These results suggest an Alu-mediated recombination event as the mechanism underlying the deletion in our patient.

A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis.

BACKGROUND: Flaky tail (ma/ma Flg(ft/ft)) mice have a frameshift mutation in the filaggrin (Flg(ft)) gene and are widely used as a model of human atopic dermatitis associated with FLG mutations. These mice possess another recessive hair mutation, matted (ma), and develop spontaneous dermatitis under specific pathogen-free conditions, whereas genetically engineered Flg(-/-) mice do not. OBJECTIVE: We identified and characterized the gene responsible for the matted hair and dermatitis phenotype in flaky tail mice. METHODS: We narrowed down the responsible region by backcrossing ma/ma mice with wild-type mice and identified the mutation using next-generation DNA sequencing. We attempted to rescue the matted phenotype by introducing the wild-type matted transgene. We characterized the responsible gene product by using whole-mount immunostaining of epidermal sheets. RESULTS: We demonstrated that ma, but not Flg(ft), was responsible for the dermatitis phenotype and corresponded to a Tmem79 gene nonsense mutation (c.840C>G, p.Y280*), which encoded a 5-transmembrane protein. Exogenous Tmem79 expression rescued the matted hair and dermatitis phenotype of Tmem79(ma/ma) mice. Tmem79 was mainly expressed in the trans-Golgi network in stratum granulosum cells in the epidermis in both mice and humans. The Tmem79(ma/ma) mutation impaired the lamellar granule secretory system, which resulted in altered stratum corneum formation and a subsequent spontaneous dermatitis phenotype. CONCLUSIONS: The Tmem79(ma/ma) mutation is responsible for the spontaneous dermatitis phenotype in matted mice, probably as a result of impaired lamellar granule secretory system and altered stratum corneum barrier function.

PSORS1C1 may be involved in rheumatoid arthritis.

PSORS1C1/CDSN is a susceptibility gene for psoriasis. Both psoriasis and rheumatoid arthritis (RA) are autoimmune diseases. This study investigated whether PSORS1C1/CDSN was involved in RA. The TagSNPs rs3130983, rs3778638 and rs4959053 in the PSORS1C1/CDSN locus were shown to predict susceptibility to RA in two independent RA cohorts using a TaqMan genotyping assay and Sequenom MassARRAY. The expression of PSORS1C1/CDSN was determined with western blotting and ELISA. Cultured synovial fibroblasts from RA patients (RASF) were treated with anti-PSORS1C1 siRNA. The TaqMan genotyping assay demonstrated significant differences in the rs3130983 and rs4959053 allele frequencies (p = 0.002001 and 1.74E-07, respectively) and genotype frequencies (0.010503 and 1.07E-06, respectively) between the RA patients and controls. Sequenom MassARRAY results indicated that SNP rs3778638 allele frequency and genotype frequency were significantly associated with RA (p = 7.35E-05 and 0.000357, respectively). Western blotting revealed a significant increase in expression of PSORS1C1 in RA synovial tissues, and ELISA detected high levels of PSORS1C1 and CDSN in the blood of RA patients. PSORS1C1-siRNA treatment significantly decreased the PSORS1C1 expression, IL-17 level, Il-1ß level and cell proliferation in RASF. These results suggest that PSORS1C1 might play an important role in the development of RA.