Low-molecular-weight fucoidan inhibits the proliferation of melanoma via Bcl-2 phosphorylation and PTEN/AKT pathway

Fucoidan,a sulfate polysaccharide obtained from brown seaweed,has various bioactive properties,including anti-inflammatory,anti-cancer,anti-viral,anti-oxidant,anti-coagulant,anti-thrombotic,anti-angiogenic,and anti-Helicobacter pylori properties.However,the effects of low-molecular-weight fucoidan(LMW-F)on melanoma cell lines and three dimensional(3D)cell culture models are not well understood.This study aimed to investigate the effects of LMW-F on A375 human melanoma cells and cryopreserved biospecimens derived from patients with advanced melanoma.Ultrasonic wave was used to fragment fucoidan derived from Fucus vesiculosus into smaller LMW-F.MTT and live/dead assays showed that LMW-F inhibited cell proliferation in both A375 cells and patientderived melanoma explants in a 3D-printed collagen scaffold.The PTEN/AKT pathway was found to be involved in the anti-melanoma effects of fucoidan.Western blot analysis revealed that LMW-F reduced the phosphorylation of Bcl-2 at Thr 56,which was associated with the prevention of anti-apoptotic activity of cancer cells.Our findings suggested that LMW-F could enhance anti-melanoma chemotherapy and improve the outcomes of patients with melanoma resistance.

Biological characteristics and clinical management of uveal and conjunctival melanoma

Uveal and conjunctival melanomas are relatively rare tumors;nonetheless,they pose a significant risk of mortality for a large number of affected individuals.The pathogenesis of melanoma at different sites is very similar,however,the prognosis for patients with ocular melanoma remains unfavourable,primarily due to its distinctive genetic profile and tumor microenvironment.Regardless of considerable advances in understanding the genetic characteristics and biological behaviour,the treatment of uveal and conjunctival melanoma remains a formidable challenge.To enhance the prospect of success,collaborative efforts involving medical professionals and researchers in thefields of ocular biology and oncology are essential.Current data show a lack of well-designed randomized clinical trials and limited benefits in current forms of treatment for these tumors.Despite advancements in the development of effective melanoma therapeutic strategies,all current treatments for uveal melanoma(UM)and conjunctival melanoma(CoM)remain unsatisfactory,resulting in a poor long-term prognosis.Ongoing trials offer hope for positive outcomes in advanced and metastatic tumors.A more comprehensive understanding of the genetic and molecular abnormalities involved in the development and progression of ocular melanomas opens the way for the development of personalized therapy,with various potential therapeutic targets currently under consideration.Increased comprehension of the molecular pathogenesis of UM and CoM and their specificities may aid in the development of new and more effective systemic therapeutic agents,with the hope of improving the prognosis for patients with metastatic disease.

CRABP2 regulates infiltration of cancer-associated fibroblasts and immune response in melanoma

Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is limited research on the relationship between CRABP2 and immunotherapy response.This study found that negative correlations of CRABP2 and immune checkpoint markers(PD-1,PD-L1,and CTLA-4)were observed in breast invasive carcinoma(BRCA),skin cutaneous melanoma(SKCM),stomach adenocarcinoma(STAD)and testicular germ cell tumors(TGCT).In particular,in SKCM patients who were treated with PD-1 inhibitors,high levels of CRABP2 predicted poor prognosis.Additionally,CRABP2 expression was elevated in cancer-associated fibroblasts(CAFs)at the single-cell level.The expression of CRABP2 was positively correlated with markers of CAFs,such as MFAP5,PDPN,ITGA11,PDGFRα/βand THY1 in SKCM.To validate the tumor-promoting effect of CRABP2 in vivo,SKCM xenograft mice models with CRABP2 overexpression have been constructed.These models showed an increase in tumor weight and volume.Enrichment analysis indicated that CRABP2 may be involved in immunerelated pathways of SKCM,such as extracellular matrix(ECM)receptor interaction and epithelial-mesenchymal transition(EMT).The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs.In conclusion,this study provides new insights into the role of CRABP2 in immunotherapy response.The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients.Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.

BET inhibitors potentiate melanoma ferroptosis and immunotherapy through AKR1C2 inhibition

Dear Editor,Ferroptosis,an iron-dependent form of cell death driven by overwhelming lipid peroxidation,represents a vulnerability in cancers,and therapeutic strategies to further potentiate ferroptosis hold great potential for melanoma treatment.

Absent in melanoma 2 attenuates proliferation and migration and promotes apoptosis of human colorectal cancer cells by activating P38MAPK signaling pathway

Colorectal cancer(CRC)stands among the top prevalent cancers worldwide and holds a prominent position as a major contributor to cancer-related mortality globally.Absent in melanoma 2(AIM2),a constituent of the interferoninducible hematopoietic interferon-inducible nuclear antigens with 200 amino acid repeats protein family,contributes to both cancer progression and inflammasome activation.Despite this understanding,the precise biological functions and molecular mechanisms governed by AIM2 in CRC remain elusive.Consequently,this study endeavors to assess AIM2’s expression levels,explore its potential antitumor effects,elucidate associated cancer-related processes,and decipher the underlying signaling pathways in CRC.Our findings showed a reduced AIM2 expression in most CRC cell lines.Elevation of AIM2 levels suppressed CRC cell proliferation and migration,altered cell cycle by inhibiting G1/S transition,and induced cell apoptosis.Further research uncovered the participation of P38 mitogen-activated protein kinase(P38MAPK)in AIM2-mediated modulation of CRC cell apoptosis and proliferation.Altogether,our achievements distinctly underscored AIM2’s antitumor role in CRC.AIM2 overexpression inhibited proliferation and migration and induced apoptosis of CRC cells via activating P38MAPK signaling pathway,indicating AIM2 as a prospective and novel therapeutic target for CRC.

Circ_0053943 complexed with IGF2BP3 drives uveal melanoma progression via regulating N6-methyladenosine modification of Epidermal growth factor receptor

Numerous studies have characterized the critical role of circular RNAs(circRNAs)as regulatory factors in the progression of multiple cancers.However,the biological functions of circRNAs and their underlying molecular mechanisms in the progression of uveal melanoma(UM)remain enigmatic.In this study,we identified a novel circRNA,circ_0053943,through re-analysis of UM microarray data and quantitative RT-PCR.Circ_0053943 was found to be upregulated in UM and to promote the proliferation and metastatic ability of UM cells in both in vitro and in vivo settings.Mechanistically,circ_0053943 was observed to bind to the KH1 and KH2 domains of insulin-like growth factor 2 mRNA-binding protein 3(IGF2BP3),thereby enhancing the function of IGF2BP3 by stabilizing its target mRNA.RNA sequencing assays identified epidermal growth factor receptor(EGFR)as a target gene of circ_0053943 and IGF2BP3 at the transcriptional level.Rescue assays demonstrated that circ_0053943 exerts its biological function by stabilizing EGFR mRNA and regulating the downstream mitogen-activated protein kinase/extracellular signal-regulated kinase(MAPK/ERK)signaling pathway.Collectively,circ_0053943 may promote UM progression by stabilizing EGFR mRNA and activating the MAPK/ERK signaling pathway through the formation of a circ_0053943/IGF2BP3/EGFR RNA-protein ternary complex,thus providing a potential biomarker and therapeutic target for UM.

Intracranial hypertension as the primary symptom of malignant melanoma:A case report

BACKGROUND The etiological diagnosis of intracranial hypertension is quite complicated but important in clinical practice.Some common causes are craniocerebral injury,intracranial space-occupying lesion,subarachnoid hemorrhage,and hydrocephalus.When a patient presents with intracranial hypertension,the common causes are to be considered first so that other causes would be dismissed.With the morbidity lower than 9%,neuromelanin is very rare.Common symp-toms include nerve damage symptoms,epilepsy,psychiatric symptoms,and cognitive disorders.CASE SUMMARY We present a patient with melanoma which manifested with isolated intracranial hypertension without any other neurological signs.A 22-year-old male had repeated nausea and vomiting for 2 mo with Babinski sign(+)on both sides,nuchal rigidity,and subarachnoid hemorrhage.He had been diagnosed with melanoma and was given surgery and whole-brain radiation.Ultimately,the patient died 2 mo later.CONCLUSION Malignant melanoma should be taken into consideration in the differential diagnosis of intracranial hypertension.

Primary thoracolumbar intraspinal malignant melanoma:A case report

BACKGROUND Primary intraspinal malignant melanoma is a very rare tumor that most often occurs in the cervical,thoracic,or thoracolumbar segment.CASE SUMMARY A rare case of primary thoracolumbar malignant melanoma is described.A 45-year-old female patient complained of low back pain with numbness and fatigue in both lower limbs.MR revealed an intradural space-occupying lesion at the thoracic 12 to lumbar 1 level.The tumor was partially excised,and a malignant melanoma was confirmed by histopathology.CONCLUSION Primary intraspinal malignant melanoma has rarely been reported,and surgical resection and related characteristics and diagnoses have been discussed.

Endoscopic ultrasound features of rectal melanoma:A case report and review of literature

BACKGROUND Rectal mucosal melanoma is a rare and highly aggressive disease.Common symptoms include anal pain,an anal mass,or bleeding.As such,the disease is usually detected on rectal examination of patients with other suspected anorectal diseases.However,due to its rarity and nonspecific symptoms,melanoma of the rectal mucosa is easily misdiagnosed.CASE SUMMARY This report describes the case of a 58-year-old female patient who presented with a history of blood in her stool for the prior one or two months,without any identifiable cause.During colonoscopy,a bulge of approximately 2.2 cm×2.0 cm was identified.Subsequently,the patient underwent endoscopic ultrasound(EUS)to characterize the depth of invasion of the lesions.EUS suggested a hypoechoic mucosal mass with involvement of the submucosal layer and heterogeneity of the internal echoes.Following surgical intervention,the excised tissue samples were examined and confirmed to be rectal malignant melanoma.The patient recovered well with no evidence of recurrence during follow-up.CONCLUSION This case shows that colonoscopy with EUS and pathological examination can accurately diagnose rare cases of rectal mucosal melanoma.

Malignant melanoma:An important differential diagnosis for clear cell sarcoma of the gastrointestinal tract

A case report by Liu et al describes the characteristics of metastatic clear cell sarcoma(CCS)of the pancreas and provides valuable therapeutic insights for this rare malignancy.This case is interesting because of its rarity,suggesting that the pancreas may be a potential target organ for CCS,either primary or metastatic.At the same time,the authors also emphasize the importance of regular postoperative follow-up for timely detection of recurrent lesions,as CCS is characterized by a high degree of malignancy and a high rate of recurrent metastases.Considering that CCS of the gastrointestinal tract is easily confused with malignant melanoma(MM)of the gastrointestinal tract,here we compare the clinical features,histopathological and immunohistochemical characteristics,diagnosis,treatment,and prognosis of CCS and MM of the gastrointestinal tract,hoping to provide a reference for clinical work.

Uveal melanoma:Recent advances in immunotherapy

Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection,up to 50%of UM patients develop metastases that usually involve the liver and are fatal within 1 year.To date,chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM,which is still characterized by poor prognosis.No standard therapeutic approaches for its prevention or treatment have been established.The application of immunotherapy agents,such as immune checkpoint inhibitors that are effective in cutaneous melanoma,has shown limited effects in the treatment of ocular disease.This is due to UM’s distinct genetics,natural history,and complex interaction with the immune system.Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations,UMs are usually triggered by a mutation in GNAQ or GNA11.As a result,more effective immunotherapeutic approaches,such as cancer vaccines,adoptive cell transfer,and other new molecules are currently being studied.In this review,we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.

Amelanotic primary cervical malignant melanoma:A case report and review of literature

BACKGROUND Primary malignant melanoma of the cervix(PMMC)is an extremely rare disease that originates from primary cervical malignant melanoma and frequently re-presents a challenge in disease diagnosis due to unclarified clinical and histo-logical presentations,particularly those without melanin.CASE SUMMARY Here,we report a case of amelanotic PMMC,with a history of breast cancer and thyroid carcinoma.The patient was finally diagnosed by immunohistochemical staining and staged as IB2 based on the International Federation of Gynecology and Obstetrics with reference to National Comprehensive Cancer Network guide-lines and was treated with radical hysterectomy,bilateral salpingo-oophorectomy and pelvic lymphadenectomy.She then received combination therapy consisting of immunotherapy with tislelizumab and radiofrequency hyperthermia.She has remained free of disease for more than 1 year.CONCLUSION The differential diagnosis process reenforced the notion that immunohisto-chemical staining is the most reliable approach for amelanotic PMMC diagnosis.Due to the lack of established therapeutic guidelines,empirical information from limited available studies does not provide the rationale for treatment-decision making.By integrating'omics'technologies and patient-derived xenografts or mini-patient-derived xenograft models this will help to identify selective thera-peutic window(s)and screen the appropriate therapeutics for targeted therapies,immune checkpoint blockade or combination therapy strategies effectively and precisely that will ultimately improve patient survival.

Acalypha australis L.extract inhibits B16 melanoma cell metastasis through PI3K/AKT signaling pathway

Background:Melanoma is a deadly skin tumor resulting from the malignant transformation of melanocytes.It is highly malignant and invasive,with the highest mortality rate among skin cancers.Acalypha australis L.(AAL),a plant with dual medicinal and culinary purposes,is commonly regarded as an edible wild vegetable in southern China.Additionally,AAL has a long history of medicinal use in China,often employed for its hemostatic,anti-diarrheal,and anti-inflammatory properties.Modern pharmacology has demonstrated that AAL possesses functions such as weight loss,antimicrobial activity,antiviral effects,and treatment for ulcerative colitis.However,there is currently no research available regarding its effectiveness and mechanisms of action on melanoma.Methods:In this investigation,we used methyl thiazolyl tetrazolium assay to detect cell viability,transwell assay to detect cell migration and invasion ability,and Western blot assay to detect relevant signaling pathways.Results:The present study reveals that 2 mg/mL AAL effectively suppresses the metastasis of B16 cells,while simultaneously triggering the expression of key apoptosis-related proteins,including Bcl-2,Bax,and cleaved caspased 3.Subsequent investigations demonstrate that AAL exerts this inhibitory effect via the PI3K/AKT signal transduction pathway,as evidenced by the observed deficits in Ras,AKT,p-AKT,and PI3K expression levels.Conclusion:These findings indicated that AAL could be a valuable therapeutic option for reducing the metastatic potential of B16 melanoma cells.

Primary Malignant Melanoma of the Larynx:Case Report and Literature Review

Primary malignant melanoma of the larynx is extremely rare.This paper reports a case of a patient with primary malignant melanoma of the larynx.Preoperative laryngoscopy revealed a cauliflower-like mass in the supraglottic region,and a CT scan of the pharynx suggested laryngeal cancer with cervical lymph node metastasis.The patient underwent a total laryngectomy with lymph node dissection,and postoperative pathology confirmed a malignant melanoma in the supraglottic region of the larynx.

Fecal transplantation in patient with metastatic melanoma refractory to immunotherapy:A case report

BACKGROUND Immunotherapy has revolutionized the treatment of metastatic melanoma,but a significant proportion of patients still experience treatment resistance.Fecal microbiota transplantation(FMT)has emerged as a potential strategy to overcome immunotherapy resistance by modulating the gut microbiome.CASE SUMMARY We present a case report of a 57-year-old male with metastatic melanoma refractory to immunotherapy who received FMT in combination with antiprogrammed death-ligand 1(PD-L1)immunotherapy(pembrolizumab).After failing multiple lines of treatment,the patient underwent a single FMT procedure by colonoscopy using fecal material from a female metastatic melanoma donor who successfully responded to immunotherapy.Following FMT,the patient demonstrated a response with decreased subcutaneous disease and subsequently underwent surgery to remove the residual disease.Despite a subsequent recurrence in the small bowel that was resected,the patient remained on pembrolizumab without evidence of melanoma recurrence at the time of writing.CONCLUSION The favorable clinical and long-lasting effect we saw in our patient without significant toxicity suggests that this procedure should be considered in similar patients with immunotherapy refractory melanomas.

Epigenetic drug library screening reveals targeting DOT1L abrogates NAD^(+)synthesis by reprogramming H3K79 methylation in uveal melanoma

Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide(NAD^(+))synthesis.Therapeutically,DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.

In vitro polymerization of the dopamine-borate melanin precursor:A proof-of-concept regarding^(10)boron neutron-capture therapy for melanoma

The^(10)boron neutron-capture therapy(BNCT)is an emerging antitumoral method that shows increasing biomedical interest.BNCT is based on the selective accumulation of the^(10)boron isotope within the tumor,which is then irradiated with low-energy thermal neutrons,generating nuclear fission that produces 7lithium,4helium,andγrays.Simple catechol-borate esters have been rather overlooked as precursors of melanin biosynthesis,and therefore,a proof-of-concept approach for using dopamine-borate(DABO)as a suitable boron-containing candidate for potential BNCT is presented here.DABO can spontaneously oxidize and autopolymerize in vitro,giving a soluble,eumelaninlike brown-black poly-DABO product.Melanotic melanoma cell cultures treated with 1 mM DABO for 24 and 48 h were viable and showed no signs of damage or cell death.The stability and possible trans-esterification of DABO is shortly discussed.Chemical calculations and quantitative structure-activity relationships(QSAR)analysis of DABO and the BNCT agent BPA indicated that they should be cell permeant and accumulate within lysosomes and melanosomes.Molecular modeling allows visualization of both the DABO precursor and the structure of a borate derivative of the proposed catechol-porphycene model for eumelanin,showing interesting features from molecular orbital calculations.The main difference between DABO and other agents,such as BPA,is that it is not a boronic acid nor a boron cluster.This simple catechol-borate ester(protected from oxidation and blackening)could be administrated to living cells and organisms,in which biosynthesis of boron-melanin in melanoma melanocytes can lead to improved BNCT.

Regional chemotherapy for uveal melanoma liver metastases

Chemotherapy remains an important approach for the treatment of liver metastases from uveal melanoma(UM).Compared with systemic chemotherapy,regional chemotherapy has similar efficacy and fewer systemic adverse effects.Regional chemotherapy for UM liver metastases includes hepatic ar ter y infusion(HAI),transarterial chemoembolization(TACE),and isolated hepatic perfusion(IHP).In this review,we aim to examine the efficacy of regional chemotherapy and compare HAI,TACE,and IHP in terms of overall survival(OS).The three approaches showed no obvious difference in OS results.

Transcriptome analysis reveals tumor antigen and immune subtypes of melanoma

Purpose:To screen potential tumor antigens for melanoma vaccine development and identify different immune subtypes.Methods:Transcriptional data(HTSEQ-FPKM)and clinical information of a 472 Melanoma cohort GDC TCGA Melanoma(SKCM)were downloaded from the UCSC XENA website(http://xena.ucsc.edu/).Subsequently,transcriptome data and clinical information of 210 melanoma cohort GSE65904 were downloaded from Gene Expression Omnibus(GEO),a large global public database.All the transcriptome expression data matrices were log2 transformed for subsequent analysis.GEPIA,TIMER,and IMMPORT databases are also used for analysis.Cell function experiments were performed to validate the role of the IDO1 gene in melanoma cell line A375.Results:Our study provides potential tumor antigens for vaccine development in melanoma patients:GZMB,GBP4,CD79A,APOBEC3F,IDO1,JCHAIN,LAG3,PLA2G2D,XCL2.In addition,we divide melanoma patients into two immune subtypes that have significant differences in tumor immunity and may have different responses to vaccination.In view of the unclear role of IDO1 in melanoma,we selected IDO1 for cell assay validation.Cell function assay showed that IDO1 was significantly overexpressed in the melanoma A375 cell line.After IDO1 knockdown,the activity,invasion,migration and healing ability of A375 cell lines were significantly decreased.Conclusion:Our study could provide a reference for the development of vaccines for melanoma patients.

Arithmetic Optimization with Ensemble Deep Transfer Learning Based Melanoma Classification

Melanoma is a skin disease with high mortality rate while earlydiagnoses of the disease can increase the survival chances of patients. Itis challenging to automatically diagnose melanoma from dermoscopic skinsamples. Computer-Aided Diagnostic (CAD) tool saves time and effort indiagnosing melanoma compared to existing medical approaches. In this background,there is a need exists to design an automated classification modelfor melanoma that can utilize deep and rich feature datasets of an imagefor disease classification. The current study develops an Intelligent ArithmeticOptimization with Ensemble Deep Transfer Learning Based MelanomaClassification (IAOEDTT-MC) model. The proposed IAOEDTT-MC modelfocuses on identification and classification of melanoma from dermoscopicimages. To accomplish this, IAOEDTT-MC model applies image preprocessingat the initial stage in which Gabor Filtering (GF) technique is utilized.In addition, U-Net segmentation approach is employed to segment the lesionregions in dermoscopic images. Besides, an ensemble of DL models includingResNet50 and ElasticNet models is applied in this study. Moreover, AOalgorithm with Gated Recurrent Unit (GRU) method is utilized for identificationand classification of melanoma. The proposed IAOEDTT-MC methodwas experimentally validated with the help of benchmark datasets and theproposed model attained maximum accuracy of 92.09% on ISIC 2017 dataset.