Circular RNA circFCHO2(hsa_circ_0002490) promotes the proliferation of melanoma by directly binding to DND1.

Circular RNAs (circRNAs) have been documented to play crucial roles in the biology of various cancers. However, their investigation in melanoma is still at an early stage, particularly as a broader mechanism beyond acting as miRNA sponges needs to be explored. We report here that circFCHO2(hsa_circ_0002490), a circRNA encompassing exons 19 and 20 of the FCHO2 gene, exhibited a consistent overexpression in melanoma tissues. Furthermore, elevated circFCHO2 levels demonstrated a positive correlation with the malignant phenotype and poor prognosis among the 158 melanoma patients studied. Besides, we observed that heightened levels of circFCHO2 promoted melanoma cell proliferation, migration, and invasion in vitro, along with contributing to tumor growth in vivo. Furthermore, we found differences in the secondary structure of circFCHO2 compared to most other circular RNA structures. It has fewer miRNA binding sites, while it has more RNA binding protein binding sites. We therefore speculate that circFCHO2 may have a function of interacting with RNA binding proteins. Mechanistically, it was confirmed by fluorescence in situ hybridization (FISH), RNA-pull down, RNA immunoprecipitation (RIP), and western blotting assays that circFCHO2 interacts with dead end protein homolog 1 (DND1) and reverses the inhibition of the PI3K/AKT signaling pathway by binding to DND1. Our findings reveal that circFCHO2 drives melanoma progression by regulating the PI3K/AKT signaling pathway through direct binding to DND1 and may serve as a potential diagnostic biomarker and therapeutic target for the treatment of melanoma.

miRSNP rs188493331: A key player in genetic control of microRNA-induced pathway activation in hypertrophic scars and keloids.

BACKGROUND: Our study aims to delineate the miRSNP-microRNA-gene-pathway interactions in the context of hypertrophic scars (HS) and keloids. MATERIALS AND METHODS: We performed a computational biology study involving differential expression analysis to identify genes and their mRNAs in HS and keloid tissues compared to normal skin, identifying key hub genes and enriching their functional roles, comprehensively analyzing microRNA-target genes and related signaling pathways through bioinformatics, identifying MiRSNPs, and constructing a pathway-based network to illustrate miRSNP-miRNA-gene-signaling pathway interactions. RESULTS: Our results revealed a total of 429 hub genes, with a strong enrichment in signaling pathways related to proteoglycans in cancer, focal adhesion, TGF-ß, PI3K/Akt, and EGFR tyrosine kinase inhibitor resistance. Particularly noteworthy was the substantial crosstalk between the focal adhesion and PI3K/Akt signaling pathways, making them more susceptible to regulation by microRNAs. We also identified specific miRNAs, including miRNA-1279, miRNA-429, and miRNA-302e, which harbored multiple SNP loci, with miRSNPs rs188493331 and rs78979933 exerting control over a significant number of miRNA target genes. Furthermore, we observed that miRSNP rs188493331 shared a location with microRNA302e, microRNA202a-3p, and microRNA20b-5p, and these three microRNAs collectively targeted the gene LAMA3, which is integral to the focal adhesion signaling pathway. CONCLUSIONS: The study successfully unveils the complex interactions between miRSNPs, miRNAs, genes, and signaling pathways, shedding light on the genetic factors contributing to HS and keloid formation.

One-stop [18F]FDG and [68Ga]Ga-DOTA-FAPI-04 total-body PET/CT examination with dual-low activity: a feasibility study.

PURPOSE: Positron emission tomography/computed tomography (PET/CT) based on fibroblast activation protein inhibitors (FAPI) has shown complementary values to 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG) in cancer imaging. This study aimed to investigate the feasibility of a one-stop FDG-FAPI dual-tracer imaging protocol with dual-low activity for oncological imaging. METHODS: Nineteen patients with malignancies underwent one-stop [18F]FDG (0.37 MBq/kg) PET (PETFDG) and dual-tracer PET 30-40 and 50-60 min (hereafter, PETD30-40 and PETD50-60, respectively) after additional injection of [68Ga]Ga-DOTA-FAPI-04 (0.925 MBq/kg), with a single diagnostic CT to generate the PET/CT. The lesion detection rate and tumor-to-normal ratios (TNRs) of tracer uptake were compared between PETFDG/CT and PETD50-60/CT and between PETD50-60/CT and PETD30-40/CT. In addition, a visual scoring system was established to compare the lesion detectability. RESULTS: The dual-tracer PETD50-60 and PETD30-40/CT showed similar performance in detecting primary tumors but presented significantly higher lesion TNRs than PETFDG. Significantly, more metastases with higher TNRs were identified on PETD50-60 than PETFDG (491 vs. 261, P < 0.001). The dual-tracer PETD50-60 received significantly higher visual scores than single PETFDG (111 vs. 10) in demonstrating both primary tumors (12 vs. 2) and metastases (99 vs. 8). However, these differences were not significant between PETD50-60 and PETD30-40. These resulted in tumor upstaging in 44.4% patients taking PET/CT for initial assessment, and more recurrences (68 vs. 7) were identified in patients taking PET/CT for restaging, both on PETD50-60 and PETD30-40, compared to PETFDG. The reduced effective dosimetry per patient (26.2 ± 2.57 mSv) was equal to that of a single standard whole-body PET/CT. CONCLUSION: The one-stop dual-tracer dual-low-activity PET imaging protocol combines the strengths of [18F]FDG and [68Ga]Ga-DOTA-FAPI-04 with shorter duration and lesser radiation and is thus clinically applicable.

Diagnostic performance of total-body 18F-FDG PET/CT with fast 2-min acquisition for liver tumours: comparison with conventional PET/CT.

PURPOSE: To comparatively evaluate the diagnostic performances of total-body 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) with fast 2-min acquisition and conventional PET/CT in liver cancer patients. METHODS: This study included 156 patients with liver tumours. Seventy-eight patients underwent total-body PET/CT. PET raw data were reconstructed using acquisition durations of 2 min (G2) and 15 min (G15). Another 78 patients with liver lesions (control patients) underwent conventional uMI780 PET/CT (G780). All patients were evaluated based on TNM staging. The maximum tumour standardized uptake value (tumour SUVmax), mean normal liver SUV (SUVmean), and tumour SUVmax-to-liver SUVmean ratio (TLR) were determined for all patients. G15 data were used as the reference in the lesion detectability analysis. The diagnostic performances of PET/CT in terms of visual parameters and of PET in terms of semi-quantitative parameters such as SUVmax and TLR were evaluated. Receiver operating characteristics (ROC) curve analysis of SUVmax and TLR at G2 was performed. Pathologic findings of surgical specimens served as the gold standard for all patients. RESULTS: The lesions found in G15 were also noted in G2; three lymph nodes were missed in G2. However, no significant difference was found in the TNM stage among G2, G15, and G780. For benign and malignant lesions, the liver SUVmean in G2 and G15 was higher than that in G780 (all P < 0.05). The tumour SUVmax and TLR in G2 were equivalent to those in G15 and G780 regardless of whether the lesions were benign or malignant. ROC curve analysis (SUVmax cutoff: 4.34, TLR cutoff: 1.34) demonstrated that G2 also had good sensitivity in detecting liver cancer. CONCLUSION: The diagnostic performance of total-body PET/CT in G2 was comparable to that in G15 among liver cancer patients. Further, the diagnostic efficiency of total-body PET/CT imaging with fast 2-min acquisition and conventional PET/CT was similar.

Ultrafast 30-s total-body PET/CT scan: a preliminary study.

PURPOSE: The aim of this study is to explore the diagnostic value of the images obtained in ultrafast 30-s acquisition time by the total-body PET/CT (18F-FDG injection dose of about 3.7 MBq/kg), and to evaluate whether they can meet the requirements of clinical diagnosis or not. METHODS: This retrospective study explored the clinical value of ultrafast 30-s 18F-FDG total-body PET/CT in 88 oncology patients, using the post-surgical pathological diagnosis as the reference standard. The data were acquired over 300 s and reconstructed using all 300-s data (G300) and only the initial 30 s (G30). Two readers independently assessed all images qualitatively and quantitatively. The diagnostic performance was compared between G300 and G30. RESULTS: The G300 average qualitative score was higher than G30 (P < 0.001). G300 and G30 also differed quantitatively in the liver and mediastinum SUVmax, SD, and SNR (all P < 0.001), but had similar sensitivities (89.09% vs. 86.36%, P = 0.250). The G300 group had higher accuracy (79.73%) and a larger area under the curve (0.709) than G30 (77.70% and 0.695, respectively; all P > 0.05). CONCLUSION: The 30-s total-body PET/CT could meet clinical diagnostic requirements for malignant tumors in patients intolerant to prolonged horizontal positioning.

Investigating ultra-low-dose total-body [18F]-FDG PET/CT in colorectal cancer: initial experience.

PURPOSE: This study was to evaluate the effects of an ultra-low dose of [18F]-FDG on the image quality of total-body PET/CT and its lesion detectability in colorectal cancer (CRC). METHODS: Sixty-two CRC patients who underwent total-body PET/CT (uEXPLORER, United Imaging Healthcare, Shanghai, China) with an ultra-low dose (0.37 MBq/kg) of [18F]-FDG were enrolled in this retrospective study. The PET images were reconstructed with the entire 15-min dataset first and then split into 13-, 8-, 5-, 4-, 3-, 2-, and 1-min duration groups to simulate fast scanning images. For simplicity, the images reconstructed with the data from 15 to 1 min were referred to as G15, G13, and so on until G1. Subjective image quality was assessed with 5-point Likert scales. The objective image quality parameters included the SUVmax, SUVmean, and signal-to-noise ratio (SNR) of the liver and blood pool and the SUVmax and tumor-to-background ratio (TBR) of the lesions. G15 served as the control to evaluate lesion detectability. RESULTS: A total of 62 patients (43 men, 19 women; age 41-88, mean ± SD 64.0 ± 10.9 years) with 64 CRC primary tumor lesions and 10 low-grade intraepithelial neoplasia (LGIN) lesions were enrolled in this study. The subjective scores were highest for G15 (4.5 ± 0.5) and then decreased from G13 (4.3 ± 0.4) to G8 (3.7 ± 0.5). The liver SNR increased with the extension of acquisition time from G8 (17.2 ± 2.8) to G13 (20.6 ± 3.4) and G15 (21.9 ± 3.4). The liver SNR of G8 was not significantly different from that of G13 (p = 0.15) and was significantly different from that of G15 (p = 0.001). All 64 CRC lesions could be identified in all image groups, even on G1. One of ten LGINs was missed on G1, G2, and G3, and one LGIN was missed on G1, G2, G3, and G4. G15 served as the control, and 100% (48/48) lymph nodes could be found on G13 and G8 compared to 93.8% (45/48) lymph nodes on G5 and G4, 85.4% (41/48) lymph nodes on G3, 81.3% (39/48) lymph nodes on G2, and 77.1% (37/48) lymph nodes on G1. For liver metastases, there were no missed liver lesions on G13 and G8 and 3, 4, 6, 7, and 9 missed liver lesions on G5, G4, G3, G2, and G1, respectively. For other areas of metastasis, including the lung, peritoneum, and ovaries, there were no missed lesions in any group. CONCLUSIONS: Total-body PET/CT with an ultra-low dose of [18F]-FDG can maintain satisfactory image quality and lesion detectability in CRC.

Ultra-low-activity total-body dynamic PET imaging allows equal performance to full-activity PET imaging for investigating kinetic metrics of 18F-FDG in healthy volunteers.

PURPOSE: To investigate the feasibility of ultra-low-activity total-body positron emission tomography (PET) dynamic imaging for quantifying kinetic metrics of 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) in normal organs and to verify its clinical relevance with full-activity imaging. METHODS: Dynamic total-body PET imaging was performed in 20 healthy volunteers, with eight using full activity (3.7 MBq/kg) of 18F-FDG and 12 using 10× activity reduction (0.37 MBq/kg). Image contrast, in terms of liver-to-muscle ratio (LMR), liver-to-blood ratio (LBR), and blood-to-muscle ratio (BMR) of radioactivity concentrations were assessed. A two-tissue compartment model was fitted to the time-to-activity curves in organs based on regions of interest (ROIs) delineation using PMOD, and constant rates (k1, k2, and k3) were generated. Kinetic constants, corresponding coefficients of variance (CoVs), image contrast, radiation dose, prompt counts, and data size were compared between full- and low-activity groups. RESULTS: All constant rates, corresponding CoVs, and image contrast in different organs were comparable with none significant differences between full- and ultra-low-activity groups. PET images in the ultra-low-activity group generated significantly lower effective radiation dose (median, 0.419 vs. 4.886 mSv, P < 0.001), reduced prompt counts (median, 2.79 vs. 55.68 billion, P < 0.001), and smaller data size (median, 71.11 vs. 723.18 GB, P < 0.001). CONCLUSION: Total-body dynamic PET imaging using 10× reduction of injected activity could achieve relevant kinetic metrics of 18F-FDG and comparable image contrast with full-activity imaging. Activity reduction results in significant decrease of radiation dose and data size, rendering it more acceptable and easier for data reconstruction, transmission, and storage for clinical practice.

Circular RNA circ_0020710 drives tumor progression and immune evasion by regulating the miR-370-3p/CXCL12 axis in melanoma.

BACKGROUND: Circular RNAs (circRNAs) have been reported to have critical regulatory roles in tumor biology. However, their contribution to melanoma remains largely unknown. METHODS: CircRNAs derived from oncogene CD151 were detected and verified by analyzing a large number of melanoma samples through quantitative real-time polymerase chain reaction (qRT-PCR). Melanoma cells were stably transfected with lentiviruses using circ_0020710 interference or overexpression plasmid, and then CCK-8, colony formation, wound healing, transwell invasion assays, and mouse xenograft models were employed to assess the potential role of circ_0020710. RNA immunoprecipitation, luciferase reporter assay and fluorescence in situ hybridization were used to evaluate the underlying mechanism of circ_0020710. RESULTS: Our findings indicated that circ_0020710 was generally overexpressed in melanoma tissues, and high level of circ_0020710 was positively correlated with malignant phenotype and poor prognosis of melanoma patients. Elevated circ_0020710 promoted melanoma cell proliferation, migration and invasion in vitro as well as tumor growth in vivo. Mechanistically, we found that high level of circ_0020710 could upregulate the CXCL12 expression via sponging miR-370-3p. CXCL12 downregulation could reverse the malignant behavior of melanoma cells conferred by circ_0020710 over expression. Moreover, we also found that elevated circ_0020710 was correlated with cytotoxic lymphocyte exhaustion, and a combination of AMD3100 (the CXCL12/CXCR4 axis inhibitor) and anti-PD-1 significantly attenuated tumor growth. CONCLUSIONS: Elevated circ_0020710 drives tumor progression via the miR-370-3p/CXCL12 axis, and circ_0020710 is a potential target for melanoma treatment.

Telocytes inhibited inflammatory factor expression and enhanced cell migration in LPS-induced skin wound healing models in vitro and in vivo.

BACKGROUND: Cell proliferation and death are key components of wound healing and tissue repair. Telocytes (TCs) represent a newly discovered cell type that can protect tissue from acute injury via cell-cell communication with adjacent cells. The aim of this study was to use a mouse model of skin wound healing and lipopolysaccharide (LPS)-induced cell injury to evaluate the effects of TCs on skin wound healing in vivo and in vitro. MATERIAL/METHODS: Immunohistochemical staining was performed to evaluate the alteration of TCs in tissues from normal and chronic wound patients. Then, a male C57BL/6 mouse wound model of the back was established. The mice were divided randomly into three groups, and wound healing was estimated according to the wound healing rate and histology. An LPS-induced co-culture model of a mouse lung telocyte cell line (TCs) with human keratinocyte (HaCaT), human dermal microvascular endothelial cell (HDMEC) or murine fibroblast (L929) cell lines was established to analyse the effects of TCs on constitutive cell types of the skin. Cell proliferation, migration and apoptosis were examined, and reactive oxygen species (ROS) and inflammatory factors in HaCaT cells, HDMECs, and L929 cells were detected to study the mechanisms involved in TC protection in skin wounds. RESULTS: TCs were significantly increased in tissues from chronic wound patients compared with healthy controls. Wound healing was significantly improved in wound mouse models treated with exogenous TCs compared with LPS-induced models. TCs reversed the LPS-induced inhibition of HaCaT cells and HDMECs and reduced the LPS-induced apoptosis of HaCaT cells and the death ratios of HDMECs and L929 cells. TCs reversed LPS-induced ROS in HDMECs and L929 cells and decreased inflammatory factor mRNA levels in HaCaT cells, HDMECs and L929 cells. CONCLUSIONS: TCs reduce wound healing delay, and inflammatory responses caused by LPS might be mediated by inflammatory inhibition, thus restricting apoptosis and promoting migration of the main component cell types in the skin.

Hsa-let-7b Suppresses Cell Proliferation by Targeting UHRF1 in Melanoma.

UHRF1 promotes melanoma progression by inducing cell proliferation, and is correlated with poor prognosis of melanoma patients. However, the regulation mechanism has not been fully elaborated. Here, we detected hsa-let-7b expression and its role in melanoma. Through Targetscan and miRanda predication, 30 overlapped miRNAs were found; further survival analysis revealed that hsa-let-7b was the only miRNA that affected the overall survival. Overexpressed hsa-let-7b could significantly inhibit the proliferation ability of A375 and A2058 cells, and this phenomenon was reversed after co-transfection with pLenti-UHRF1. In conclusion, hsa-let-7b regulates melanoma cells proliferation in vitro by targeting UHRF1.

HDAC6 interacts with PTPN1 to enhance melanoma cells progression.

Histone deacetylase 6 (HDAC6) plays an important role in oncogenic transformation and cancer metastasis. Our previous study has demonstrated that HDAC6 was highly expressed in melanoma cells, and contributed to the proliferation and metastasis of melanoma cells. However, the underlying mechanism of HDAC6 in melanoma metastasis and progression remains largely unclear. In this study, we reported that HDAC6 directly interacted with Tyrosine-protein phosphatase non-receptor type 1 (PTPN1) by performing co-immunoprecipitation (Co-IP) combined with liquid chromatography tandem mass spectrometry (LC-MS/MS). HDAC6 increased the protein level of PTPN1 independent of histone modifying activity. In addition, PTPN1 promoted proliferation, colony formation and migration while decreased apoptosis of melanoma cells through activating extracellular signal-regulated kinase 1/2 (ERK1/2). Furthermore, we found that matrix metallopeptidase 9 (MMP9) was increased by HDAC6/PTPN1/ERK1/2 axis, which might serve as a mechanism for melanoma invasion and metastasis. In conclusion, HDAC6 might enhance aggressive melanoma cells progression via interacting with PTPN1, which was independent of its histone modifying activity.

Perioperative Glucocorticoid Treatment of Soft Tissue Reconstruction in Patients on Long-term Steroid Therapy: The Experience of 6 Cases Using Reversed Posterior Interosseous Flap for Hand Neoplasm Surgery.

INTRODUCTION: Long-term steroid therapy is associated with increased postoperative morbidity. Whether to use a stress dose of glucocorticoids (GCs) in surgical patients remains controversial. In the present study, we reported our experience in perioperative GC treatment of 6 patients on long-term steroid therapy for autoimmune diseases undergoing hand reconstruction using reversed interosseous flap. METHODS: The reversed interosseous flap reconstructions were performed after local extended resection of hand neoplasms. The patients were all diagnosed with autoimmune diseases and were undergoing long-term steroid therapy. Stress dose of GCs was not given in any case, and all the patients either remained on their baseline maintenance dose or decreased the dose until the morning of the operation day. Hypotension, water-electrolyte imbalance, hypoglycemia, and other symptoms of adrenal insufficiency were carefully assessed. Appearances of flap complications were recorded. RESULTS: None of the patients developed hypotension or other symptomatic adrenal insufficiency. Flap infection, venous congestion, or complete or partial loss of flap was not observed in any patient. Effusion underneath the flap was developed in only 1 case and was solved by proper drainage. CONCLUSIONS: It is safe, reliable, and versatile to use reversed interosseous flap to repair hand defects in patients on long-term steroid therapy. A stress dose of GCs might not be necessary in this procedure and other equally moderate soft tissue reconstructive surgeries.

Both HDAC5 and HDAC6 are required for the proliferation and metastasis of melanoma cells.

BACKGROUND: Histone deacetylase (HDAC) inhibitors are widely used in clinical investigation as novel drug targets. For example, panobinostat and vorinostat have been used to treat patients with melanoma. However, HDAC inhibitors are small-molecule compounds without a specific target, and their mechanism of action is unclear. Therefore, it is necessary to investigate which HDACs are required for the proliferation and metastasis of melanoma cells. METHODS: We used overexpression and knocking down lentivirus to clarify the influence of HDAC5 and HDAC6 in melanoma development. Also, we introduced stable HDAC5 or HDAC6 knockdown cells into null mice and found that the knockdown cells were unable to form solid tumors. Finally, we tested HDAC5 and HDAC6 expression and sub-location in clinical melanoma tissues and tumor adjacent tissues. RESULTS: In this study, and found that HDAC5 and HDAC6 were highly expressed in melanoma cells but exhibited low expression levels in normal skin cells. Furthermore, we knocked down HDAC5 or HDAC6 in A375 cells and demonstrated that both HDAC5 and HDAC6 contributed to the proliferation and metastasis of melanoma cells. CONCLUSIONS: This study demonstrated both HDAC5 and HDAC6 were required for melanoma cell proliferation and metastasis through different signaling pathways.

Heavy path mining of protein-protein associations in the malaria parasite.

Annotating and understanding the function of proteins and other elements in a genome can be difficult in the absence of a well-studied and evolutionarily close relative. The causative agent of malaria, one of the oldest and most deadly global infectious diseases, is a good example of this problem. The burden of malaria is huge and there is a pressing need for new, more effective antimalarial strategies. However, techniques such as homology-dependent annotation transfer are severely impaired in this parasite because there are no well-understood close relatives. To circumvent this approach we developed a network-based method that uses a heavy path network-mining algorithm. We uncovered the protein-protein associations that are implicated in important cellular processes including genome integrity, DNA repair, transcriptional regulation, invasion, and pathogenesis, thus demonstrating the utility of this method. The URL of the source code for super-sequence mining method is http://www.cs.utsa.edu/~korkmaz/research/heavy-path-mining/.

A retrospective study on a hospital-based cleft care center in Shanghai.

OBJECTIVE: The objective of this investigation was to describe the characteristics of the current cleft treatment situation in a hospital-based cleft center in Shanghai and provide references to clinical diagnosis, treatment, and nursing. METHODS: A total of 1584 patients from the Center for Cleft Lip and Palate, Department of Oral and Cranio-Maxillofacial Science, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine during June 2006 to February 2008 were analyzed retrospectively. Data regarding sex, native place, type of cleft, cleft side, accompanied malformations, family history, and age at surgery were analyzed in detail. Length of stay after surgery, the primary operation fee, and some other hospitalized information were also investigated. RESULTS: From 1584 patients(1590 operations; 6 patients had 6 operations), there were 939 male and 645 female patients (M:F = 1.46:1). The number of Shanghai local patients is 249 (15.72%), whereas the other 1335 patients were from out of Shanghai. Approximately 15% of the patients had certain family history. The age at operating varied from 2 months to 36 years; the mean value was 6.95 years. The postoperation hospital stay varied from 1 day to 15 days; the mean value was 5.54 days. The primary operation fee was 235 to 673 USD depending on the different surgical procedures. The number of cleft types or other malformation, which had not been treated in the statistics varied from zero to 3; the mean value was 0.4375. The cleft morphology was classified as follows: cleft lip, 591 cases (37.31%); cleft palate, 651 cases (41.10%); alveolar cleft, 144 cases (9.10%); facial traverse cleft, 27 cases (1.70%); velopharyngeal insufficiency, 105 cases (6.63%); velocardiofacial syndrome, 57 cases (3.60%); and Pierre Robin sequence, 15 cases (0.95%). In all the classifications, left was more than right (L:R = 2.10:1). CONCLUSION: As a busy hospital-based cleft care center, most of the patients are from out of Shanghai. The current multidisciplinary protocol for cleft care in such specialist cleft center is cost-effective. There may be a tendency that the patients with cleft palate are more than the patients with cleft lips in recent years, which may due to the popularization of prenatal examination in China.

Predicting immunotherapy response in melanoma using a novel tumor immunological phenotype-related gene index.

Introduction: Melanoma is a highly aggressive and recurrent form of skin cancer, posing challenges in prognosis and therapy prediction. Methods: In this study, we developed a novel TIPRGPI consisting of 20 genes using Univariate Cox regression and the LASSO algorithm. The high and low-risk groups based on TIPRGPI exhibited distinct mutation profiles, hallmark pathways, and immune cell infiltration in the tumor microenvironment. Results: Notably, significant differences in tumor immunogenicity and TIDE were observed between the risk groups, suggesting a better response to immune checkpoint blockade therapy in the low-TIPRGPI group. Additionally, molecular docking predicted 10 potential drugs that bind to the core target, PTPRC, of the TIPRGPI signature. Discussion: Our findings highlight the reliability of TIPRGPI as a prognostic signature and its potential application in risk classification, immunotherapy response prediction, and drug candidate identification for melanoma treatment. The "TIP genes" guided strategy presented in this study may have implications beyond melanoma and could be applied to other cancer types.

Melanoma Derived Exosomes Amplify Radiotherapy Induced Abscopal Effect via IRF7/I-IFN Axis in Macrophages.

Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor-bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single-cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor-derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I-IFN) secretion and M1 polarization via the miR-872-3p/IRF7 axis. Secreted I-IFN activated the JAK/STAT signaling pathway in CD8+ T cells, and promoted IFN-γ and GZMB secretion. Together, the study shows that tumor-derived exosomes promote I-IFN secretion via the circPIK3R3/miR-872-3p/IRF7 axis in macrophages and enhance the anti-tumor immune response of CD8+ T cells.

An advanced comprehensive muti-cell-type-specific model for predicting anti-PD-1 therapeutic effect in melanoma.

Rationale: Immune checkpoint inhibitors targeting the programmed cell death (PD)-1/PD-L1 pathway have promise in patients with advanced melanoma. However, drug resistance usually results in limited patient benefits. Recent single-cell RNA sequencing studies have elucidated that MM patients display distinctive transcriptional features of tumor cells, immune cells and interstitial cells, including loss of antigen presentation function of tumor cells, exhaustion of CD8+T and extracellular matrix secreted by fibroblasts to prevents immune infiltration, which leads to a poor response to immune checkpoint inhibitors (ICIs). However, cell subgroups beneficial to anti-tumor immunity and the model developed by them remain to be further identified. Methods: In this clinical study of neoadjuvant therapy with anti-PD-1 in advanced melanoma, tumor tissues were collected before and after treatment for single-nucleus sequencing, and the results were verified using multicolor immunofluorescence staining and public datasets. Results: This study describes four cell subgroups which are closely associated with the effectiveness of anti-PD-1 treatment. It also describes a cell-cell communication network, in which the interaction of the four cell subgroups contributes to anti-tumor immunity. Furthermore, we discuss a newly developed predictive model based on these four subgroups that holds significant potential for assessing the efficacy of anti-PD-1 treatment. Conclusions: These findings elucidate the primary mechanism of anti-PD-1 resistance and offer guidance for clinical drug administration for melanoma.

A novel subnetwork alignment approach predicts new components of the cell cycle regulatory apparatus in Plasmodium falciparum.

BACKGROUND: According to the World Health organization, half the world's population is at risk of contracting malaria. They estimated that in 2010 there were 219 million cases of malaria, resulting in 660,000 deaths and an enormous economic burden on the countries where malaria is endemic. The adoption of various high-throughput genomics-based techniques by malaria researchers has meant that new avenues to the study of this disease are being explored and new targets for controlling the disease are being developed. Here, we apply a novel neighborhood subnetwork alignment approach to identify the interacting elements that help regulate the cell cycle of the malaria parasite Plasmodium falciparum. RESULTS: Our novel subnetwork alignment approach was used to compare networks in Escherichia coli and P. falciparum. Some 574 P. falciparum proteins were revealed as functional orthologs of known cell cycle proteins in E. coli. Over one third of these predicted functional orthologs were annotated as "conserved Plasmodium proteins" or "putative uncharacterized proteins" of unknown function. The predicted functionalities included cyclins, kinases, surface antigens, transcriptional regulators and various functions related to DNA replication, repair and cell division. CONCLUSIONS: The results of our analysis demonstrate the power of our subnetwork alignment approach to assign functionality to previously unannotated proteins. Here, the focus was on proteins involved in cell cycle regulation. These proteins are involved in the control of diverse aspects of the parasite lifecycle and of important aspects of pathogenesis.