Soil Cd bioavailability response characteristics to microbes in paddy fields with co-incorporation of milk vetch, rice straw and amendments.

Excessive heavy metals in soils can threaten food security and soil health. New practical technology is urgently needed to remediate cadmium (Cd) contaminated paddies in many parts of the world. Chinese milk vetch (M), rice straw (R), and soil amendments can reduce Cd activity in soil; however, the mechanism underlying this reduction is not well understood. This study explored the impact of co-incorporation of milk vetch, rice straw, and either lime (L), sesbania biochar (B), or sepiolite on soil Cd bioavailability through field experiments. The results indicated that the rice grain Cd concentrations in soil treated with milk vetch + rice straw + fertilizer (MRF, 16.6 %), milk vetch + rice straw + fertilizer + sesbania biochar (MRFB, 50.1 %), and milk vetch + rice straw + fertilizer + lime (MRFL, 48.3 %) were significantly lower than those in soil treated with fertilizer (F). The acid-soluble Cd concentrations influenced rice grain Cd uptake and were 33.9 % and 47.5 % lower for the MRFB and MRFL treatments, respectively, than for F alone. A decrease in acid-soluble Cd (AciCd) was accompanied by a decrease in Eh and increases in pH, Fe2+, cation exchange capacity, and dissolved organic carbon. The MRFB treatment promoted iron plaque (IP) formation on the rice root surface. The relative abundances of Desulfobacterota and Verrucomicrobiota were higher for the MRFB treatment than for the other treatments. A partial least squares path model confirmed that Aci-Cd and low-crystalline IP (IP-Feh) influenced the rice grain Cd concentration.

Smart diabetic foot ulcer scoring system.

Current assessment methods for diabetic foot ulcers (DFUs) lack objectivity and consistency, posing a significant risk to diabetes patients, including the potential for amputations, highlighting the urgent need for improved diagnostic tools and care standards in the field. To address this issue, the objective of this study was to develop and evaluate the Smart Diabetic Foot Ulcer Scoring System, ScoreDFUNet, which incorporates artificial intelligence (AI) and image analysis techniques, aiming to enhance the precision and consistency of diabetic foot ulcer assessment. ScoreDFUNet demonstrates precise categorization of DFU images into "ulcer," "infection," "normal," and "gangrene" areas, achieving a noteworthy accuracy rate of 95.34% on the test set, with elevated levels of precision, recall, and F1 scores. Comparative evaluations with dermatologists affirm that our algorithm consistently surpasses the performance of junior and mid-level dermatologists, closely matching the assessments of senior dermatologists, and rigorous analyses including Bland-Altman plots and significance testing validate the robustness and reliability of our algorithm. This innovative AI system presents a valuable tool for healthcare professionals and can significantly improve the care standards in the field of diabetic foot ulcer assessment.

Curcumin-Based Ionic Liquid Hydrogel for Topical Transdermal Delivery of Curcumin To Improve Its Therapeutic Effect on the Psoriasis Mouse Model.

Psoriasis is a systemic, recurrent, chronic autoimmune skin disease. However, psoriasis drugs have poor skin permeability and high toxicity, resulting in low bioavailability and affecting their clinical application. In this study, we propose a curcumin-based ionic liquid hydrogel loaded with ilomastat (Cur-Car-IL@Ilo hydrogel), which can effectively maintain the sustained release of drugs and improve the skin permeability of drugs. We used a model of imiquimod-induced psoriasis and demonstrated that local application of Cur-Car-IL@Ilo hydrogel can improve skin lesions in mice with significantly reduced expression levels of inflammatory factors, matrix metalloproteinase 8, and collagen-I. The expressions of iron death-related proteins SLC7A11 and ASL4 were significantly decreased after treatment with Cur-Car-IL@Ilo hydrogel. Flora analysis showed that the content of anaerotruncus, proteus, and UCG-009 bacteria in the gut of psoriatic mice increased. The levels of paludicola, parabacteroides, prevotellaceae_UCG-001, escherichia-shigella, and aerococcus decreased, and the levels of some of the above bacteria tended to be normal after treatment. Therefore, the curcumin-based ionic liquid hydrogel can be used as a multifunctional, nonirritating, noninvasive, and highly effective percutaneous treatment of psoriasis.

Automated detection of otosclerosis with interpretable deep learning using temporal bone computed tomography images.

Objective: This study aimed to develop an automated detection schema for otosclerosis with interpretable deep learning using temporal bone computed tomography images. Methods: With approval from the institutional review board, we retrospectively analyzed high-resolution computed tomography scans of the temporal bone of 182 participants with otosclerosis (67 male subjects and 115 female subjects; average age, 36.42 years) and 157 participants without otosclerosis (52 male subjects and 102 female subjects; average age, 30.61 years) using deep learning. Transfer learning with the pretrained VGG19, Mask RCNN, and EfficientNet models was used. In addition, 3 clinical experts compared the system's performance by reading the same computed tomography images for a subset of 35 unseen subjects. An area under the receiver operating characteristic curve and a saliency map were used to further evaluate the diagnostic performance. Results: In prospective unseen test data, the diagnostic performance of the automatically interpretable otosclerosis detection system at the optimal threshold was 0.97 and 0.98 for sensitivity and specificity, respectively. In comparison with the clinical acumen of otolaryngologists at P < 0.05, the proposed system was not significantly different. Moreover, the area under the receiver operating characteristic curve for the proposed system was 0.99, indicating satisfactory diagnostic accuracy. Conclusion: Our research develops and evaluates a deep learning system that detects otosclerosis at a level comparable with clinical otolaryngologists. Our system is an effective schema for the differential diagnosis of otosclerosis in computed tomography examinations.

Unveiling the distinctive ossification patterns of diffuse idiopathic skeletal hyperostosis and ankylosing spondylitis using computed tomography three-dimensional reconstruction.

OBJECTIVE: To quantitatively analyze the morphological characteristics of osteophytes in DISH and syndesmophytes in AS, and summarize different ossification patterns to help identify the two diseases. Associated factors for new bone formation would be investigated. METHODS: Fifty patients with DISH and 50 age-, sex-, CT examination site- matched patients with AS were enrolled. Radiographic and clinical data were reviewed. Osteophytes (syndesmophytes) in front of each vertebral body and the corresponding intervertebral disc space were defined as vertebral osteophytes unit (VOU). The volume, angle and location (contralateral, ipsilateral, bilateral) of osteophytes in each VOU were measured and compared between DISH and AS groups. RESULTS: In each VOU, the volume and angle of osteophytes in DISH were significantly larger. The best osteophytes volume and angle cutoff value in predicting DISH was 0.59 cm3 and 40.15°. Contralateral, bilateral, ipsilateral osteophytes were recorded in 59.32%, 36.38%, 4.3% of assessed VOUs in patients with DISH and 64.78%, 29.31%, 5.91% in AS (p<0.001), respectively. As to ipsilateral osteophytes, the volume was inversely correlated with the center of the vertebral body to the center of the descending aorta (DISH: r = -0.45, p= 0.01; AS: r = -0.83, p<0.001). Advanced age, disease duration, smoking and overweight contribute to the progression of osteophytes and syndesmophytes. CONCLUSION: Morphological features of osteophytes are helpful to distinguish DISH with AS. Aortic pulsations inhibit or hinder new bone formation in both DISH and AS. Maintaining normal BMI could postpone osteophytes formation.

Comprehensive Treatment of a Rare Case of Complete Primary Pachydermoperiostosis with Large Facial Keloid Scars: A Case Report and Literature Review.

Introduction: Pachydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy, is a rare autosomal dominant disease with primary clinical features of pachydermia (thickening of skin) and periostosis (new bone formation). Keloid scar formation is also rather obscure, and some scientists have claimed that keloid scars contain an excessive amount of fibroblasts compared with normal skin as well as a dense mass of irregularly deposited connective tissues. Case Presentation: A 25-year-old man exhibited extensive skin folding on his face, a gyrus-like scalp, depressed nasolabial folds, and keloids. Symptoms began at 18 years of age, progressing insidiously. Additionally, he experienced clubbing of fingers and toes, joint pain, muscle soreness, and hyperhidrosis. Radiographic examinations revealed thickened bone and cystic regions. Diagnosed with complete primary PDP and facial keloid scars, he underwent skin dermabrasion, biopsies, and a comprehensive treatment involving, botulinum toxin injections, 5-fluorouracil, and a carbon dioxide lattice laser. Conclusion: PDP presents challenges due to its unclear etiology but stabilizes over time in most cases. Comprehensive treatment strategies, including dermabrasion and a combination of intralesional therapies, are effective in managing keloids in PDP patients. This case contributes to the understanding of managing rare diseases and underscores the importance of personalized approaches to improve therapeutic outcomes in patients with complete primary PDP and concurrent keloids.

Hydrogel Loaded with Components for Therapeutic Applications in Hypertrophic Scars and Keloids.

Hypertrophic scars and keloids are common fibroproliferative diseases following injury. Patients with pathologic scars suffer from impaired quality of life and psychological health due to appearance disfiguration, itch, pain, and movement disorders. Recently, the advancement of hydrogels in biomedical fields has brought a variety of novel materials, methods and therapeutic targets for treating hypertrophic scars and keloids, which exhibit broad prospects. This review has summarized current research on hydrogels and loaded components used in preventing and treating hypertrophic scars and keloids. These hydrogels attenuate keloid and hypertrophic scar formation and progression by loading organic chemicals, drugs, or bioactive molecules (such as growth factors, genes, proteins/peptides, and stem cells/exosomes). Among them, smart hydrogels (a very promising method for loading many types of bioactive components) are currently favoured by researchers. In addition, combining hydrogels and current therapy (such as laser or radiation therapy, etc.) could improve the treatment of hypertrophic scars and keloids. Then, the difficulties and limitations of the current research and possible suggestions for improvement are listed. Moreover, we also propose novel strategies for facilitating the construction of target multifunctional hydrogels in the future.

Approaching expert-level accuracy for differentiating ACL tear types on MRI with deep learning.

Treatment for anterior cruciate ligament (ACL) tears depends on the condition of the ligament. We aimed to identify different tear statuses from preoperative MRI using deep learning-based radiomics with sex and age. We reviewed 862 patients with preoperative MRI scans reflecting ACL status from Hunan Provincial People's Hospital. Based on sagittal proton density-weighted images, a fully automated approach was developed that consisted of a deep learning model for segmenting ACL tissue (ACL-DNet) and a deep learning-based recognizer for ligament status classification (ACL-SNet). The efficacy of the proposed approach was evaluated by using the sensitivity, specificity and area under the receiver operating characteristic curve (AUC) and compared with that of a group of three orthopedists in the holdout test set. The ACL-DNet model yielded a Dice coefficient of 98% ± 6% on the MRI datasets. Our proposed classification model yielded a sensitivity of 97% and a specificity of 97%. In comparison, the sensitivity of alternative models ranged from 84 to 90%, while the specificity was between 86 and 92%. The AUC of the ACL-SNet model was 99%, demonstrating high overall diagnostic accuracy. The diagnostic performance of the clinical experts as reflected in the AUC was 96%, 92% and 88%, respectively. The fully automated model shows potential as a highly reliable and reproducible tool that allows orthopedists to noninvasively identify the ACL status and may aid in optimizing different techniques, such as ACL remnant preservation, for ACL reconstruction.

[Corrigendum] Downregulation of CD147 induces malignant melanoma cell apoptosis via the regulation of IGFBP2 expression.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that the ß­actin bands shown for the western blots portrayed in Fig. 4A and E on p. 2403 appeared to be strikingly similar, albeit that the bands were inverted with respect to their orientation and the dimensions of the bands differed slightly. After re­examining their original data, the authors have realized that these data in Fig. 4 had inadvertently been assembled incorrectly. The revised version of Fig. 4, showing the correct data for all the experiments in Fig. 4E, is shown on on the next page. The authors are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum, and all the authors agree to its publication. Furthermore, the authors apologize to the readership for any inconvenience caused. [International Journal of Oncology 53: 2397­2408, 2018; DOI: 10.3892/ijo.2018.4579].

Enhancing Transdermal Delivery of Curcumin-Based Ionic Liquid Liposomes for Application in Psoriasis.

To improve the permeation of curcumin, we prepared curcumin-based ionic liquid (Cur-Bet-IL) (IL formed using curcumin succinic anhydride and betaine) from curcumin by combining theoretical calculation and experimental research and then prepared curcumin-based ionic liquid liposome (Cur-Bet-IL-Lip). The Cur-Bet-IL-Lip has good stability (stored for 10 days without significant changes) and biocompatibility, which encompasses not only the properties of curcumin but also the characteristics of ionic liquids and liposomes. Cur-Bet-IL-Lip can penetrate the stratum corneum and deliver curcumin to the epidermis and dermis of the skin, and the cumulative permeability of curcumin after 24 h was 49%. Compared to Cur-Bet-IL, Cur-Bet-IL-Lip has a good uptake ability on human immortalized keratinocyte (HaCaT) cells (1.87-fold), which can reduce the expression of TNF-α (1.59-fold), IL-1ß (1.19-fold), IL-17A (1.53-fold), IL-17F (1.18-fold), and IL-22 (1.49-fold) in HaCaT cells and then increase the expression of collagen-I (1.14-fold). Therefore, Cur-Bet-IL-Lip has guiding significance in improving the solubility and permeation of insoluble drugs, which also provides a potential value for the clinical application of curcumin.

Do disease-modifying antirheumatic drugs and non-steroidal anti-inflammatory drugs increase the burden on ankylosing spondylitis patients with mild-moderate COVID-19? evidence from a retrospective cohort study.

Objectives: The impact of non-steroidal anti-inflammatory drugs (NSAIDs), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and tumor necrosis factor inhibitors (TNFi) on the outcomes of mild-moderate COVID-19 in patients with ankylosing spondylitis (AS) remains unclear. This study aimed to evaluate the effects of NSAIDs, csDMARDs, and TNFi on AS patients with mild-moderate COVID-19. Methods: This cohort study utilized patient-reported PCR/antigen tests to determine the occurrence of COVID-19 and assessed clinical manifestations to determine its severity. The study focused on two primary outcomes: an increased number of COVID-19 symptoms and a prolonged disease course (longer than 10 or 28 days). Modified Poisson regression was performed to analyze the association between exposures and outcomes. Results: A total of 521 patients were included in the analysis. The median age was 34.8 (inter-quartile range: 27.2-46.7), with 420 (80.6%) being men. Among the patients, 52 (10.0%) had comorbidities and 443 (85%) had been vaccinated. After adjusting for confounding factors, there was no significant association between csDMARDs or TNFi and the presence of more than 5 symptoms in mild-moderate COVID-19 (adjusted relative risk (RRa) 1.08, 95% CI: 0.84-1.40 or 1.09, 0.92-1.29 for csDMARDs or TNFi, respectively), whereas the prevalence of experiencing more than 5 symptoms increased in patients with NSAID monotherapy (RRa 1.22, 95% CI: 1.01-1.46). Similarly, there was no significant association with having more than 10 symptoms (RRa 0.65, 95% CI: 0.26-1.64; 0.95, 0.36-2.54; and 1.01, 0.53-1.91 for NSAIDs, csDMARDs, and TNFi, respectively). Patients who had pre-existing use of NSAIDs, csDMARDs and TNFi had similar odds of experiencing a disease course longer than 10 days (RRa 1.17, 95% CI: 0.82-1.66; 1.18, 0.78-1.77; and 1.22, 0.92-1.63 for NSAIDs, csDMARDs, and TNFi, respectively) and longer than 28 days (RRa 0.94, 95% CI: 0.31-2.81; 0.97, 0.25-3.74 and 1.05, 0.44-2.49, respectively) compared to those not using medication. Conclusion: AS patients treated with csDMARDs or TNFi did not show inferior outcomes in terms of symptom burden or recovery compared to those not using medication in mild-moderate COVID-19. The observed inverse association between pre-existing NSAIDs use and COVID-19 symptom burden in AS deserves further investigation.

Therapeutic role of exosomes and conditioned medium in keloid and hypertrophic scar and possible mechanisms.

Exosomes, ranging from 40 to 160 nm in diameter, are extracellular lipid bilayer microvesicles that regulate the body's physiological and pathological processes and are secreted by cells that contain proteins, nucleic acids, amino acids and other metabolites. Previous studies suggested that mesenchymal stem cell (MSC)-derived exosomes could either suppress or support keloid and hypertrophic scar progression. Although previous research has identified the potential value of MSC-exosomes in keloid and hypertrophic scar, a comprehensive analysis of different sources of MSC-exosome in keloid and hypertrophic scar is still lacking. This review mainly discusses different insights regarding the roles of MSC-exosomes in keloid and hypertrophic scar treatment and summarizes possible underlying mechanisms.

In Situ Tyrosinase Monitoring by Wearable Microneedle Patch toward Clinical Melanoma Screening.

Despite the potential indicating role of tyrosinase (TYR) in cutaneous melanoma, how to capture the real changes of TYR in suspicious skin remains a major challenge. Unlike the traditional human serum test, this study reports a sensing platform that incorporates a wearable microneedle (MN) patch and trimetallic Au@Ag-Pt nanoparticles (NPs) for surface-enhanced Raman scattering (SERS) and colorimetric dual-mode detecting TYR in human skin in situ toward potential melanoma screening. In the presence of TYR, catechol immobilized on MN is preferentially oxidized to benzoquinone, which competitively impedes the interaction of MN and Au@Ag-Pt NPs, triggering the SERS-colorimetric signal reciprocal switch. Using a B16F10 mouse melanoma model, our platform is capable of noninvasively piercing the skin surface and detecting TYR levels before and during anti-PD-1 antibody treatment, which would be highly informative for prognostic judgment and illness monitoring of melanoma. Through in situ sensing for capturing the metabolic changes of TYR in advance, this platform was successfully applied to discriminate the melanoma subjects from skin moles and normal ones (p < 0.001), as well as screen potential melanoma from lactate dehydrogenase (LDH)-negative patients. Melanoma growth and prognosis can still be monitored through recording the continuous change of TYR levels. More importantly, the well-defined flexible and stretchable characteristics of the MN patch allow robustly adhering to the skin without inducing chemical or physical irritation. We believe this platform integrating MN-based in situ sensing, TYR responsiveness, and SERS/colorimetric dual-readout strategy will have high clinical importance in early diagnosis and monitoring of cutaneous melanoma.

Prevalence of developmental dysplasia of the hip (DDH) in infants: a systematic review and meta-analysis.

OBJECTIVE: To estimate the prevalence of developmental dysplasia of the hip (DDH) in infants with a systematic review and meta-analysis. METHOD: A literature search was conducted in April 2023, using databases such as Cochrane Library, PubMed, MEDLINE, CNKI, and SinoMed, without language restrictions. Eligible studies included cross-sectional studies reporting the prevalence of DDH among infants aged 0-12 months. Two independent reviewers manually selected and coded the studies, with any disagreements resolved by a third reviewer. Meta-analysis was performed using a random-effects model to calculate the prevalence of DDH. Regression analysis examined the trend of DDH prevalence, and stratification analysis explored heterogeneity between studies. RESULTS: A total of 65 studies involving 3 451 682 infants were included in the meta-analysis. None of the studies were classified as high quality, four were medium-to-high quality, 50 were low-to-medium quality, and eight were low quality. The pooled prevalence of DDH was 1.40% (95% CI: 0.86 to 2.28, I2=100%), and prevalence of dysplasia, subluxation, and dislocation was 1.45% (95% CI: 0.93 to 2.24, I2=97%), 0.37% (95% CI: 0.22 to 0.60, I2=94%), and 0.21% (95% CI: 0.13 to 0.34, I2=92%), respectively. Notably, the overall prevalence has a slight upward trend in the last three decades (ß=0.24, p=0.35), but the dysplasia was downward trend (ß=-0.48, p<0.01). Girls have higher risk of DDH than boys (1.46% vs 0.66%; Q=5.83, df=1, p=0.02). There were no significant differences based on gender, country, setting, or screening technique. CONCLUSION: The prevalence of DDH among infants is approximately one in a 100, with girls being at higher risk. Though the prevalence of dysplasia has decreased, there is a slight upward trend in overall DDH. Therefore, routine screening for DDH in infants is recommended to prevent more serious developmental problems.

Erratum: Author correction to 'Real-time SERS monitoring anticancer drug release along with SERS/MR imaging for pH-sensitive chemo-phototherapy' [Acta Pharm Sin B 13 (2023) 1303-1317].

[This corrects the article DOI: 10.1016/j.apsb.2022.08.024.].

Association of Calpain10 polymorphisms with polycystic ovarian syndrome susceptibility: a systematic review and meta-analysis with trial sequential analysis.

Insulin resistance plays an important role in the pathogenesis of polycystic ovarian syndrome (PCOS). Calpain10 (CAPN10) gene was the first identified susceptibility gene for type 2 diabetes mellitus and closely related to insulin sensitivity. A lot of research attention has been attracted on the relationship between CAPN10 polymorphisms and PCOS risk, but they didn't reach a consistent conclusion. We therefore performed this systematic review and meta-analysis to assess the association of CAPN10 common variants with PCOS susceptibility. A total of 21 studies were eligible for inclusion. Meta-analyses were done for 5 variants that had at least two data sources: UCSNP-19, -43, -44, -56 and -63. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under five genetic models. Subgroup analyses by ethnicity, PCOS diagnostic criteria, and source of controls were conducted. Moreover, false-positive report probability (FPRP) test and trial sequential analysis (TSA) were performed to assess the significant associations. The results showed a possible negative association between UCSNP-19 and PCOS risk (ins/ins vs. del/del + del/ins: OR = 0.84, 95% CI: 0.72-0.98). In subgroup analyses, FPRP test indicated that noteworthy associations were observed in mixed ethnicities for UCSNP-43 (A vs. G: OR = 1.81, 95% CI: 1.17-2.79; AA + AG vs. GG: OR = 2.14, 95% CI: 1.20-3.80) and in Asians for UCSNP-44 (CC vs. TT: OR = 2.07, 95% CI: 1.21-3.51; CC vs. CT + TT: OR = 2.19, 95% CI: 1.31-3.69), but TSA plots showed that the accumulated sample sizes of these associations were insufficient to draw firm conclusions. In summary, our study suggested that UCSNP-19, UCSNP-43, and UCSNP-44 in CAPN10 gene may be involved in PCOS susceptibility. These findings warrant further studies.

Urchin-Shaped Au-Ag@Pt Sensor Integrated Lateral Flow Immunoassay for Multimodal Detection and Specific Discrimination of Clinical Multiple Bacterial Infections.

A new lateral flow immunoassay strip (LFIA) combining sensitive detection and identification of multiple bacteria remains a huge challenge. In this study, we first developed multifunctional urchin-shaped Au-Ag@Pt nanoparticles (UAA@P NPs) with a unique combination of colorimetric-SERS-photothermal-catalytic (CM/SERS/PT/CL) properties and integrated them with LFIA for multiplexed detection and specific discrimination of pathogenic bacteria in blood samples. Unlike the conventional LFIA that relied on antibody (Ab), this novel LFIA introduced 4-mercaptophenylboronic acid (4-MPBA) as an ideal Ab replacer that was functionalized on UAA@P NPs (UAA@P/M NPs) with outstanding binding and enrichment capacities toward bacteria. Taking Staphylococcus aureus (S. aureus) as model bacteria, the limit of detection (LOD) was 3 CFU/mL for SERS-LFIA, 27 CFU/mL for PT-LFIA, and 18 CFU/mL for CL-LFIA, three of which were over 330-fold, 37-fold, and 55-fold more sensitive than ordinary visual CM-LFIA, respectively. Besides, this SERS-LFIA is capable of identifying three types of bacterial spiked blood samples (E. coli, S. aureus, and P. aeruginosa) effectively according to specific bacterial Raman "fingerprints" by partial least-squares-discriminant analysis (PLS-DA). More importantly, this LFIA was successfully applied to blood samples with satisfactory recoveries from 90.3% to 108.8% and capable of identifying the infected patients (N = 4) from healthy subjects (N = 2) with great accuracy. Overall, the multimodal LFIA incorporates bacteria discrimination and quantitative detection, offering an avenue for early warning and diagnosis of bacterial infection.

Analysis on tumor immune microenvironment and construction of a prognosis model for immune-related skin cutaneous melanoma. / å ç–«ç›¸å ³çš„çš®è‚¤é»‘è‰²ç´ ç˜¤é¢„åŽæ¨¡åž‹æž„å»ºåŠè‚¿ç˜¤å ç–«å¾®çŽ¯å¢ƒåˆ†æž.

OBJECTIVES: Malignant melanoma is a highly malignant and heterogeneous skin cancer. Although immunotherapy has improved survival rates, the inhibitory effect of tumor microenvironment has weakened its efficacy. To improve survival and treatment strategies, we need to develop immune-related prognostic models. Based on the analysis of the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Sequence Read Archive (SRA) database, this study aims to establish an immune-related prognosis prediction model, and to evaluate the tumor immune microenvironment by risk score to guide immunotherapy. METHODS: Skin cutaneous melanoma (SKCM) transcriptome sequencing data and corresponding clinical information were obtained from the TCGA database, differentially expressed genes were analyzed, and prognostic models were developed using univariate Cox regression, the LASSO method, and stepwise regression. Differentially expressed genes in prognostic models confirmed by real-time reverse transcription PCR (real-time RT-PCR) and Western blotting. Survival analysis was performed by using the Kaplan-Meier method, and the effect of the model was evaluated by time-dependent receiver operating characteristic curve as well as multivariate Cox regression, and the prognostic model was validated by 2 GEO melanoma datasets. Furthermore, correlations between risk score and immune cell infiltration, Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) score, immune checkpoint mRNA expression levels, tumor immune cycle, or tumor immune micro-environmental pathways were analyzed. Finally, we performed association analysis for risk score and the efficacy of immunotherapy. RESULTS: We identified 4 genes that were differentially expressed in TCGA-SKCM datasets, which were mainly associated with the tumor immune microenvironment. A prognostic model was also established based on 4 genes. Among 4 genes, the mRNA and protein levels of killer cell lectin like receptor D1 (KLRD1), leukemia inhibitory factor (LIF), and cellular retinoic acid binding protein 2 (CRABP2) genes in melanoma tissues differed significantly from those in normal skin (all P<0.01). The prognostic model was a good predictor of prognosis for patients with SKCM. The patients with high-risk scores had significantly shorter overall survival than those with low-risk scores, and consistent results were achieved in the training cohort and multiple validation cohorts (P<0.001). The risk score was strongly associated with immune cell infiltration, ESTIMATE score, immune checkpoint mRNA expression levels, tumor immune cycle, and tumor immune microenvironmental pathways (P<0.001). The correlation analysis showed that patients with the high-risk scores were in an inhibitory immune microenvironment based on the prognostic model (P<0.01). CONCLUSIONS: The immune-related SKCM prognostic model constructed in this study can effectively predict the prognosis of SKCM patients. Considering its close correlation to the tumor immune microenvironment, the model has some reference value for clinical immunotherapy of SKCM.

Evaluation of drug sensitivity, immunological characteristics, and prognosis in melanoma patients using an endoplasmic reticulum stress-associated signature based on bioinformatics and pan-cancer analysis.

We aimed to develop endoplasmic reticulum (ER) stress-related risk signature to predict the prognosis of melanoma and elucidate the immune characteristics and benefit of immunotherapy in ER-related risk score-defined subgroups of melanoma based on a machine learning algorithm. Based on The Cancer Genome Atlas (TCGA) melanoma dataset (n = 471) and GTEx database (n = 813), 365 differentially expressed ER-associated genes were selected using the univariate Cox model and LASSO penalty Cox model. Ten genes impacting OS were identified to construct an ER-related signature by using the multivariate Cox regression method and validated with the Gene Expression Omnibus (GEO) dataset. Thereafter, the immune features, CNV, methylation, drug sensitivity, and the clinical benefit of anticancer immune checkpoint inhibitor (ICI) therapy in risk score subgroups, were analyzed. We further validated the gene signature using pan-cancer analysis by comparing it to other tumor types. The ER-related risk score was constructed based on the ARNTL, AGO1, TXN, SORL1, CHD7, EGFR, KIT, HLA-DRB1 KCNA2, and EDNRB genes. The high ER stress-related risk score group patients had a poorer overall survival (OS) than the low-risk score group patients, consistent with the results in the GEO cohort. The combined results suggested that a high ER stress-related risk score was associated with cell adhesion, gamma phagocytosis, cation transport, cell surface cell adhesion, KRAS signalling, CD4 T cells, M1 macrophages, naive B cells, natural killer (NK) cells, and eosinophils and less benefitted from ICI therapy. Based on the expression patterns of ER stress-related genes, we created an appropriate predictive model, which can also help distinguish the immune characteristics, CNV, methylation, and the clinical benefit of ICI therapy. KEY MESSAGES: Melanoma is the cutaneous tumor with a high degree of malignancy, the highest fatality rate, and extremely poor prognosis. Model usefulness should be considered when using models that contained more features. We constructed the Endoplasmic Reticulum stress-associated signature using TCGA and GEO database based on machine learning algorithm. ER stress-associated signature has excellent ability for predicting prognosis for melanoma.