Exploring a specialized programmed-cell death patterns to predict the prognosis and sensitivity of immunotherapy in cutaneous melanoma via machine learning.

The mortality and therapeutic failure in cutaneous melanoma (CM) are mainly caused by wide metastasis and chemotherapy resistance. Meanwhile, immunotherapy is considered a crucial therapy strategy for CM patients. However, the efficiency of currently available methods and biomarkers in predicting the response of immunotherapy and prognosis of CM is limited. Programmed cell death (PCD) plays a significant role in the occurrence, development, and therapy of various malignant tumors. In this research, we integrated fourteen types of PCD, multi-omics data from TCGA-SKCM and other cohorts in GEO, and clinical CM patients to develop our analysis. Based on significant PCD patterns, two PCD-related CM clusters with different prognosis, tumor microenvironment (TME), and response to immunotherapy were identified. Subsequently, seven PCD-related features, especially CD28, CYP1B1, JAK3, LAMP3, SFN, STAT4, and TRAF1, were utilized to establish the prognostic signature, namely cell death index (CDI). CDI accurately predicted the response to immunotherapy in both CM and other cancers. A nomogram with potential superior predictive ability was constructed, and potential drugs targeting CM patients with specific CDI have also been identified. Given all the above, a novel CDI gene signature was indicated to predict the prognosis and exploit precision therapeutic strategies of CM patients, providing unique opportunities for clinical intelligence and new management methods for the therapy of CM.

PRF1 as a prognostic gene for lymphatic metastasis in skin melanoma.

BACKGROUND: Melanoma is a highly aggressive tumor, predominantly found in the skin, recognized as skin cutaneous melanoma (SKCM). Lymph node metastasis is commonly used as the route of metastasis in SKCM, necessitating the discovery of prognostic genes associated with this process for improved prognosis. METHODS: The prognostic significance of lymph node metastasis in SKCM was assessed through Kaplan-Meier analysis in SEER and TCGA-SKCM datasets. Prognostic genes were identified and a prognostic risk model was constructed Enrichment analysis and immune cell infiltration analysis were also carried out.Moreover, a validation in vitro and in vivo were conducted by CCK8,flow cytometry, transwell and animal study. RESULTS: The Kaplan-Meier survival curve revealed that patients with lymph node metastasis had a worse prognosis compared to those without. FCGR3B and PRF1 were screened by TCGA analysis.Additionally, significant differences in nine immune cell types were observed between the two risk groups. Notably, a strong positive association with CD8 T cells and a negative relationship with M2 macrophages were exhibited by PRF1. The validation of our nomogram were conducted in vitro and in vivo, and the results showed the correlations between CD8+ T cell and PRF1. CONCLUSION: In summary, two prognostic genes (FCGR3B and PRF1) were identified, and a prognostic risk model was developed for SKCM. These findings provide a novel approach for the diagnosis and treatment of SKCM.

Persistent poverty and incidence-based melanoma mortality in Texas.

PURPOSE: Previous studies have shown that individuals living in areas with persistent poverty (PP) experience worse cancer outcomes compared to those living in areas with transient or no persistent poverty (nPP). The association between PP and melanoma outcomes remains unexplored. We hypothesized that melanoma patients living in PP counties (defined as counties with ≥ 20% of residents living at or below the federal poverty level for the past two decennial censuses) would exhibit higher rates of incidence-based melanoma mortality (IMM). METHODS: We used Texas Cancer Registry data to identify the patients diagnosed with invasive melanoma or melanoma in situ (stages 0 through 4) between 2000 and 2018 (n = 82,458). Each patient's PP status was determined by their county of residence at the time of diagnosis. RESULTS: After adjusting for demographic variables, logistic regression analyses revealed that melanoma patients in PP counties had statistically significant higher IMM compared to those in nPP counties (17.4% versus 11.3%) with an adjusted odds ratio of 1.35 (95% CI 1.25-1.47). CONCLUSION: These findings highlight the relationship between persistent poverty and incidence-based melanoma mortality rates, revealing that melanoma patients residing in counties with persistent poverty have higher melanoma-specific mortality compared to those residing in counties with transient or no poverty. This study further emphasizes the importance of considering area-specific socioeconomic characteristics when implementing place-based interventions to facilitate early melanoma diagnosis and improve melanoma treatment outcomes.

Randomized Trial of Postoperative Radiation Therapy After Wide Excision of Neurotropic Melanoma of the Head and Neck (RTN2 Trial 01.09).

BACKGROUND: Cutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision. METHODS: Participants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity. RESULTS: The trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009-2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03-2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study. CONCLUSION: Due to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports.

Validation of the Melanoma Institute of Australia's Sentinel Lymph Node Biopsy Risk Prediction Tool for Cutaneous Melanoma.

BACKGROUND: For patients with cutaneous melanoma, sentinel lymph node biopsy (SLNB) is used to stage regional lymph nodes pathologically and inform prognosis, treatment, and surveillance. To reduce unnecessary surgeries, predictive tools aim to identify those at lowest risk for node-positive disease. The Melanoma Institute of Australia (MIA)'s Prediction Tool for Sentinel Node Metastasis Risk estimates risk of a positive SLNB using patient age and primary melanoma Breslow depth, histologic subtype, ulceration, mitotic rate, and lymphovascular invasion. METHODS: A single-institution validation was performed of the MIA Calculator with 982 cutaneous melanoma patients that included all relevant clinicopathologic factors and SLNB pathology outcomes. The study evaluated discrimination via receiver operating characteristic (ROC) curves, calibration via calibration plots, and clinical utility via decision curve analysis of the MIA model in various subgroups. The data were fit to MIA model parameters via a generalized linear model to assess the odds ratio of parameters in our dataset. RESULTS: The Calculator demonstrated limited discrimination based on ROC curves (C-statistic, 0.709) and consistently underestimated risk of SLN positivity. It did not provide a net benefit over SLNB performed on all patients or reduce unnecessary procedures in the risk domain of 0% to 16%. Compared with the original development and validation cohorts, the current study cohort had thinner tumors and a larger proportion of acral melanomas. CONCLUSIONS: The Calculator generally underestimated SLN positivity risk, including assessment in patients who would be counseled to forego SLNB based on a predicted risk lower than 5%. Recognition of the tool's current limitations emphasizes the need to refine it further for use in medical decision-making.

Leveraging single-cell sequencing analysis and bulk-RNA sequencing analysis to forecast necroptosis in cutaneous melanoma prognosis.

Cutaneous melanoma, a malignancy of melanocytes, presents a significant challenge due to its aggressive nature and rising global incidence. Despite advancements in treatment, the variability in patient responses underscores the need for further research into novel therapeutic targets, including the role of programmed cell death pathways such as necroptosis. The melanoma datasets used for analysis, GSE215120, GSE19234, GSE22153 and GSE65904, were downloaded from the GEO database. The melanoma data from TCGA were downloaded from the UCSC website. Using single-cell sequencing, we assess the heterogeneity of necroptosis in cutaneous melanoma, identifying distinct cell clusters and necroptosis-related gene expression patterns. A combination of 101 machine learning algorithms was employed to construct a necroptosis-related signature (NRS) based on key genes associated with necroptosis. The prognostic value of NRS was evaluated in four cohorts (one TCGA and three GEO cohorts), and the tumour microenvironment (TME) was analysed to understand the relationship between necroptosis, tumour mutation burden (TMB) and immune infiltration. Finally, we focused on the role of key target TSPAN10 in the prognosis, pathogenesis, immunotherapy relevance and drug sensitivity of cutaneous melanoma. Our study revealed significant heterogeneity in necroptosis among melanoma cells, with a higher prevalence in epithelial cells, myeloid cells and fibroblasts. The NRS, developed through rigorous machine learning techniques, demonstrated robust prognostic capabilities, distinguishing high-risk patients with poorer outcomes in all cohorts. Analysis of the TME showed that high NRS scores correlated with lower TMB and reduced immune cell infiltration, indicating a potential mechanism through which necroptosis influences melanoma progression. Finally, TSPAN10 has been identified as a key target for cutaneous melanoma and is highly associated with poor prognosis. The findings highlight the complex role of necroptosis in cutaneous melanoma and introduce the NRS as a novel prognostic tool with potential to guide therapeutic decisions.

Association of lipid-lowering drug targets with risk of cutaneous melanoma: a mendelian randomization study.

BACKGROUND: Melanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies. METHOD: This study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs. RESULTS: Our findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08-1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10-2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses. CONCLUSION: The study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease.

RNF144A-AS1 stabilizes TAF15 and promotes malignant biological behaviors of skin cutaneous melanoma.

LncRNAs have been demonstrated to regulate biological processes in malignant tumors. In our previous study, we identified the immune-related LncRNA RNF144A-AS1 as a potential regulator in SKCM. However, its precise function and regulatory mechanism remain unclear. In this study, we observed upregulation of RNF144A-AS1 in SKCM and found that knockdown of RNF144A-AS1 suppressed proliferation, migration, invasion, and epithelial-mesenchymal transition abilities of melanoma cells. Mechanistically, as a high-risk prognostic factor, RNF144A-AS1 regulated biological processes of SKCM by interacting with TAF15 through an RNA-binding protein-dependent (RBP-dependent) manner. Furthermore, we confirmed that TAF15 activated downstream transcriptional regulation of YAP1 to modulate malignant behaviors in melanoma cells. In vivo experiments revealed that knockdown of RNF144A-AS1 inhibited tumorigenic capacity of melanoma cells and exhibited promising therapeutic effects. Collectively, these findings highlight the significance of the RNF144A-AS1/TAF15/YAP1 axis in promoting malignant behaviors in SKCM and provide novel insights into potential prognostic biomarkers and therapeutic targets for this disease.

Analysis of the expression of cytokines and chemokines, platelet-leukocyte aggregates, sCD40L and sCD62P in cutaneous melanoma.

BACKGROUND: Cutaneous melanoma (CM) is a malignancy with a variable incidence worldwide and a poor advanced-stage prognosis. Melanoma growth is closely associated with the immune system. METHODS: A cross-sectional study was performed on CM patients admitted at the Hospital de Cancer de Pernambuco (HCP) between 2015 and 2018. Fifty-one CM patients were included, and 30 healthy individuals. The study aimed to evaluate the association of platelet activation mechanisms and inflammatory response in patients with cutaneous melanoma. RESULTS: Elevated serum IL10 and low serum TNF levels in CM patients compared to controls (p < 0.05). High IL6 levels in patients with negative lymph nodes LN (-) compared to positive lymph nodes group (LN +, p = 0.0005). Low RANTES levels in patients compared to controls (p < 0.05). Elevated levels of platelet-lymphocyte (PLA), platelet-monocytes (PMA), and platelet-neutrophils (PNA) aggregates were observed in patients compared to controls (p < 0.05). CM patients with stage II had lower PMA levels than stages I and III (p < 0.05). High PMA levels were observed in patients with LN (+) compared to the LN (-) group (p < 0.0001). Patients with SSM had high levels of sCD40L and sCD62P compared to controls (p < 0.05)). High sCD40L levels in stage II compared to the stage III group, and sCD62P in stages I and II compared to the stage III group (p < 0.05). High sCD62P levels in patients with LN (-) compared to the group LN (+) (p < 0.05). CONCLUSION: It was observed the immunosuppressive profile in CM may favor tumor progression. High levels of platelet-leukocyte aggregates, sCD40L, and sCD62P may be associated with the worst prognosis.

Loss in life expectancy in patients with stage II-III cutaneous melanoma in Sweden: A population-based cohort study.

BACKGROUND: Survival in cutaneous melanoma (CM) is heterogeneous. Loss in life expectancy (LLE) measures impact of CM on remaining lifespan compared to general population. OBJECTIVES: Investigating LLE in operated stage II-III CM patients. METHODS: Data from 8061 patients (aged 40-80 years) with stage II-III CM in Sweden, diagnosed between 2005 and 2018, were analyzed (Swedish Melanoma Registry). A flexible parametric survival model estimated life expectancy and LLE. RESULTS: Based on 2018 diagnoses, stage II and III CM patients lost 2209 and 1902 life years, respectively. LLE was higher in stage III: 5.2 versus 10.9 years (stage II vs III 60-year-old females). Younger patients had higher LLE: 10.7 versus 3.9 years (stage II CM in 40 vs 70-year-old males). In stage II, females had lower LLE than males; 50-year-old females and males stage II CM had LLE equal to 7.3 and 8.3 years, respectively. LLE increased with higher substages, stage IIB resembling IIIB and IIC resembling IIIC-D. LIMITATIONS: Extrapolation was used to estimate LLE. Varying stage group sizes require caution. CONCLUSIONS: Our results are both clinically relevant and easy-to-interpret measures of the impact of CM on survival, but the results also summarize the prognosis over the lifetime of a CM patient.

Management of Localized Melanoma in the Anti-PD-1 Era.

PURPOSE OF REVIEW: The management of cutaneous melanoma has rapidly progressed over the past decade following the introduction of effective systemic therapies. Given the large number of recent clinical trials which have dramatically altered the management of these patients, an updated review of the current evidence regarding the management of localized melanoma is needed. RECENT FINDINGS: The role of effective systemic therapies in earlier stages (I-III) melanoma, both in adjuvant and neoadjuvant settings is rapidly changing the role of surgery in the management cutaneous melanoma, particularly regarding surgical safety margins for wide local excision (WLE), the role of sentinel lymph node biopsy (SLNB) and the extent of lymph node dissections. The randomized phase 2 SWOG1801 trial has demonstrated superiority of neoadjuvant-adjuvant anti-PD1 therapy in improving event-free survival by 23% at 2-years over adjuvant anti-PD-1 therapy only. Furthermore, the PRADO trial has suggested a more tailored approach both the extent of surgery as well as adjuvant therapy can safely and effectively be done, depending on the response to initial neoadjuvant immunotherapy. These results await validation and it is expected that in 2024 the phase 3 Nadina trial (NCT04949113) will definitively establish neo-adjuvant combination immunotherapy as the novel standard. This will further redefine the management of localized melanoma. The use of effective systemic therapies will continue to evolve in the next decade and, together with new emerging diagnostic and surveillance techniques, will likely reduce the extent of routine surgery for stage I-III melanoma.

Can angiotropism and lymphovascular invasion refine the current cutaneous melanoma staging system?

BACKGROUND: Several prognostic factors for primary cutaneous melanoma (PCM) have been identified, and these predict metastasis and survival, to a certain extent. We sought to determine the frequency of angiotropism (AT) and lymphovascular invasion (LVI) in PCM and the relationship between AT, LVI, and other clinicopathological parameters and patient's prognosis. METHODS: This study included 538 cases of PCM diagnosed between 2003 and 2016. It comprised 246 females and 292 males whose clinicopathological variables were evaluated with respect to LVI and AT using univariate and multivariate analyses. Overall survival (OS) was assessed by Kaplan-Meier (KM) analysis and Cox regression multivariate analysis. RESULTS: AT occurred more frequently than LVI. Ulceration, mitotic rate, and Breslow thickness were found to be highly associated with both LVI and AT (p < 0.01). All LVI+ cases had AT, with a significant positive correlation (p < 0.01). Both AT and LVI predicted lymph node (LN) metastasis (odds ratio [OR] = 1.47, 1.12, respectively). Multivariate analysis showed LN metastasis, Breslow thickness, LVI, and AT as predictors of OS. LVI and AT independently predicted adverse OS by Cox regression analysis (hazard ratio [HR] = 1.66, 1.49, respectively) and with KM survival analysis. CONCLUSION: AT is a marker for angiotropic extravascular migratory tumor spread (angiotropic EVMM), and LVI is a marker for intra-lymphovascular tumor spread. Both predict poor prognosis. Given its ease of detection, AT could be adopted as a histologpathological feature in the routine assessment of primary cutaneous malignant melanoma cases.

A Retrospective Study of Diameter and Breslow Thickness in Invasive Melanomas.

INTRODUCTION: A diameter larger than 6 mm is included in the criteria used in public health messages to detect a cutaneous melanoma. We aimed to investigate the independent association of Breslow thickness with the melanoma diameter. METHODS: A retrospective study was performed in patients with invasive melanomas of the nodular melanoma (NM) or superficial spreading melanoma (SSM) subtype. The quartiles of the diameter (lower, median, upper) were studied in non-parametric quantile regression model. RESULTS: In total, 537 cases of invasive melanomas were included and 60% had Breslow thickness ≤1.0 mm. There were 429 SSM (79.9%) and 108 NM (20.1%). Although NMs were significantly thicker (median Breslow thickness: 2.7 mm vs. 0.7 mm, respectively, p < 0.0001), they were not associated with larger diameter compared to SSMs (p = 0.71). After adjustment for age and sex, melanoma location and subtype, having Breslow thickness ≤1.0 mm was not significantly associated with the lower quartile, median and upper quartile of the diameter (p values: 0.063, 0.083, and 0.791, respectively). CONCLUSION: In our study including melanomas of the NM or SSM subtype, Breslow thickness was not associated with the diameter, adding evidence to support the limitations of using diameter larger than 6 mm for the detection of invasive melanomas and indicating the potential of smaller melanomas to be thicker tumors.

Identification of potential therapeutic targets for skin cutaneous melanoma on the basic of transcriptomics.

BACKGROUND: Advanced skin cutaneous melanoma (SKCM) is responsible for the majority of skin cancer-related deaths. Apart from the rare BRAF V600F mutation, which can be targeted with specific drugs, there are currently no other novel effective therapeutic targets. METHODS: We used SMR analysis with cis-expressed quantitative trait locus (cis-eQTL) as the exposure variable and SKCM as the outcome variable to identify potential therapeutic targets for SKCM. Colocalization assays and HEIDI tests are used to test whether SKCM risk and gene expression are driven by common SNPs. Replication analysis further validated the findings, and we also constructed protein-protein interaction networks to explore the relationship between the identified genes and known SKCM targets. Drug prediction and molecular docking further validated the medicinal value of drug targets. Transcriptome differential analysis further validated that there were differences between normal tissues and SKCM for the selected targets. RESULTS: We identified 13 genes significantly associated with the risk of SKCM, including five protective genes and eight harmful genes. The HEIDI test and co-localization analysis further indicates a causal association between genes (SOX4, MAFF) and SKCM, categorized as Class 1 evidence targets. The remaining 11 genes, except for HELZ2 show a moderately causal association with SKCM, categorized as Class 2 evidence targets. Target druggability predictions from DGIdb suggest that SOX4, MAFF, ACSF3, CDK10, SPG7, and TCF25 are likely to be future drug targets. CONCLUSION: The study provides genetic evidence for targeting available drug genes for the treatment of SKCM.

Inhibiting IL11RA to mitigate hepatic metastasis in skin cutaneous melanoma: Comprehensive insights from in vitro and in vivo investigations.

OBJECTIVE: This study aimed to investigate the role of Interleukin-11 receptor alpha (IL11RA) in skin cutaneous melanoma (SKCM) metastasis to the liver. METHODS: Human SKCM cell lines (A375, A375-MA2, SK-MEL-28, RPMI-7951) and primary dermal fibroblasts (HDFa) were utilized to assess IL11RA expression. IL11RA siRNA was transfected into RPMI-7951 and A375-MA2 cells for Wound healing and Transwell invasion assays. Il11ra knockout (KO) mice and wild-type (WT) mice were injected with B16-F10 cells into the spleen to evaluate hepatic melanoma metastasis. Correlation between IL11RA and MMP family genes was explored using online databases, including LinkedOmics, TIMER (Tumor Immune Estimation Resource), and GEPIA (Gene Expression Profiling Interactive Analysis). RT-qPCR and Western blotting were performed for expression analysis of Mmp2 and Mmp9 in liver tissues of mice. The impact of IL11RA on the STAT3 pathway was investigated in vitro and in vivo. RESULTS: Elevated expression of IL11RA was observed in SKCM cell lines compared to normal cells. IL11RA downregulation significantly inhibited migratory and invasive capabilities of A375-MA2 and RPMI-7951 in vitro. Il11ra gene knockout in mice demonstrated a substantial reduction in hepatic melanoma metastasis. Correlation analyses revealed associations between IL11RA and MMP2/MMP8. Il11ra gene knockout significantly decreased Mmp2 expression while increasing Mmp8 in liver tissues. IL11RA correlated positively with STAT3, and its inhibition led to a suppressed STAT3 pathway in SKCM cells and mouse liver tissue. CONCLUSION: IL11RA plays a crucial role in SKCM metastasis, affecting migratory and invasive abilities. Targeting IL11RA may offer a promising avenue for therapeutic interventions in cutaneous melanoma progression.

Identification of novel disulfidptosis-related lncRNA signatures to predict the prognosis and immune microenvironment of skin cutaneous melanoma patients.

BACKGROUND: Skin cutaneous melanoma (SKCM) is an aggressive form of malignant melanoma with poor prognosis and high mortality rates. Disulfidptosis is a newly discovered cell death regulatory mechanism caused by the abnormal accumulation of disulfides. This unique pathway is guiding significant new research to understand cancer progression for targeted treatment. However, the correlation between disulfidptosis with long non-coding RNAs (lncRNAs) in SKCM remains unknown at present. METHODS: The Cancer Genome Atlas database furnished lncRNA expression data and clinical information for SKCM patients. Pearson correlation and Cox regression analyses identified disulfidptosis-related lncRNAs associated with SKCM prognosis. ROC curves and a nomogram validated the model. TME, immune infiltration, GSEA analysis, immune checkpoint gene expression profiling, and drug sensitivity were assessed in high and low-risk groups. Consistent clustering categorized SKCM patients for personalized clinical treatment guidance. RESULTS: A total of twelve disulfidptosis-related lncRNAs were identified for the development of prognosis prediction models. The area under the curve (AUC) values of the ROC curve and the nomogram provided reliable discrimination to evaluate the prognostic potential for SKCM patients. The TME played a crucial role in tumorigenesis, progression and prognosis, and the risk scores were closely related to immune cell infiltration. Meanwhile, the combination of chemotherapy, targeted therapy, and immunotherapy was recommended for low-risk patients based on drug sensitivity and immune efficacy analyses. CONCLUSION: We identified a risk model of twelve disulfidptosis-related lncRNAs that could be used to predict the prognosis of SKCM patients and help guide immunotherapy and chemotherapy for personalized treatment plans.

Prognostic Value of CXCR6 and the Correlation with Immune Infiltration in the Microenvironment of Skin Cutaneous Melanoma.

Increasing evidence has demonstrated that CXCRs are associated with the tumor infiltration of immune cells and regulate the tumor immune response. However, the prognostic value of CXCRs expression in patients with skin cutaneous melanoma (SKCM) remains unclear. In this study, we aimed to investigate the expression characteristics of CXCRs in SKCM tissues, analyze their prognostic value and the correlation with immune cell infiltration. Multiple public databases were used for exploration, including GEPIA2, GSCA, ULCAN, Metascape, STRING, TIMER2.0, HPA, and Cistrome DB database. And a confirmation experiment was conducted on melanoma mice with flow cytometry. Compared with normal tissues, lower expression of CXCR2/7/8 and higher expression of CXCR3/4 were found in SKCM tissues. CXCR3/4/6 were abnormally expressed in each pathological stage. Moreover, CXCRs were closely related to immune-related biological functions, and mainly interacted with CXCLs. The high expression of CXCR3/5/6 indicated better overall survival of patients. Among them, CXCR6 had the most significant prognostic value, and was most related to tumor infiltration of CD8+T cells, which was verified in melanoma mice. Finally, ETS1 and STAT5B were predicted as the transcription factor of CXCR6. Our findings play an important role in the study of prognostic markers in patients with SKCM.

Cutaneous Melanoma and 486 Human Blood Metabolites: A Mendelian Randomization Study.

BACKGROUND: Cutaneous melanoma (CM) has long been recognized as a lethal form of cancer. Despite persistent research endeavors, the precise underlying pathological mechanisms remain largely unclear, and the optimal treatment for this patient population remains undetermined. OBJECTIVES: This study aims to examine the causal associations between CM and 486 metabolites. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted to ascertain the causal relationship between blood metabolites and CM. The causality analysis involved the inverse variance weighted (IVW) method, followed by the MR-Egger and weighted median (WM) methods. To increase the robustness of our findings, several sensitivity analyses, including the MR-Egger intercept, Cochran's Q test, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were performed. The robustness of our results was further validated in independent outcome samples followed by a meta-analysis. Additionally, a metabolic pathway analysis was carried out. RESULTS: The two-sample MR analysis yielded a total of 27 metabolites as potential causal metabolites. After incorporating the outcomes of the sensitivity analyses, seven causal metabolites remained. Palmitoylcarnitine (OR 0.9903 95% CI 0.9848-0.9958, p = 0.0005) emerged as the sole metabolite with a significant causality after Bonferroni correction. Furthermore, the reverse MR analysis provided no evidence of reverse causality from CM to the identified metabolites. CONCLUSIONS: This study suggested a causal relationship between seven human blood metabolites and the development of CM, thereby offering novel insights into the underlying mechanisms involved. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

TNFRSF1B Gene Variants in Clinicopathological Aspects and Prognosis of Patients with Cutaneous Melanoma.

Regulatory T lymphocytes play a critical role in immune regulation and are involved in the aberrant cell elimination by facilitating tumor necrosis factor connection to the TNFR2 receptor, encoded by the TNFRSF1B polymorphic gene. We aimed to examine the effects of single nucleotide variants TNFRSF1B c.587T>G, c.*188A>G, c.*215C>T, and c.*922C>T on the clinicopathological characteristics and survival of cutaneous melanoma (CM) patients. Patients were genotyped using RT-PCR. TNFRSF1B levels were measured using qPCR. Luciferase reporter assay evaluated the interaction of miR-96 and miR-1271 with the 3'-UTR of TNFRSF1B. The c.587TT genotype was more common in patients younger than 54 years old than in older patients. Patients with c.*922CT or TT, c.587TG or GG + c.*922CT or TT genotypes, as well as those with the haplotype TATT, presented a higher risk of tumor progression and death due to the disease effects. Individuals with the c.*922TT genotype had a higher TNFRSF1B expression than those with the CC genotype. miR-1271 had less efficient binding with the 3'-UTR of the T allele when compared with the C allele of the SNV c.*922C>T. Our findings, for the first time, demonstrate that TNFRSF1B c.587T>G and c.*922C>T variants can serve as independent prognostic factors in CM patients.

A Proteomics Approach Identifies RREB1 as a Crucial Molecular Target of Imidazo-Pyrazole Treatment in SKMEL-28 Melanoma Cells.

Cutaneous melanoma is the most dangerous and deadly form of human skin malignancy. Despite its rarity, it accounts for a staggering 80% of deaths attributed to cutaneous cancers overall. Moreover, its final stages often exhibit resistance to drug treatments, resulting in unfavorable outcomes. Hence, ensuring access to novel and improved chemotherapeutic agents is imperative for patients grappling with this severe ailment. Pyrazole and its fused systems derived thereof are heteroaromatic moieties widely employed in medicinal chemistry to develop effective drugs for various therapeutic areas, including inflammation, pain, oxidation, pathogens, depression, and fever. In a previous study, we described the biochemical properties of a newly synthesized group of imidazo-pyrazole compounds. In this paper, to improve our knowledge of the pharmacological properties of these molecules, we conduct a differential proteomic analysis on a human melanoma cell line treated with one of these imidazo-pyrazole derivatives. Our results detail the changes to the SKMEL-28 cell line proteome induced by 24, 48, and 72 h of 3e imidazo-pyrazole treatment. Notably, we highlight the down-regulation of the Ras-responsive element binding protein 1 (RREB1), a member of the zinc finger transcription factors family involved in the tumorigenesis of melanoma. RREB1 is a downstream element of the MAPK pathway, and its activation is mediated by ERK1/2 through phosphorylation.