Relief of pain in mice by an antibody with high affinity for cell adhesion molecule 1 on nerves.

AIMS: Cell adhesion molecule 1 (CADM1) is a member of the immunoglobulin superfamily and is abundantly expressed on nerve fibers. Recently, the anti-CADM1 ectodomain antibody 3E1 has proven useful as a drug delivery vector for CADM1-expressing cells in vitro. When injected subcutaneously into mice, whether 3E1 accumulates on nerve fibers and serves as an analgesic was examined. MAIN METHODS: Injected 3E1 was detected by immunohistochemistry and double immunofluorescence. Analgesic effects were verified by a formalin-induced chemical-inflammatory pain test and video-recorded behavior analysis that were performed 6, 12, and 24 h after antibody injection. Primary cultures of mouse dorsal root ganglion (DRG) cells were incubated with 3E1 and expressions of CADM1 and its key downstream molecules were examined by Western blot analyses and live cell imaging. DRG cells were loaded with a Ca2+ fluorescent indicator Fluo-8 and a femtosecond laser pulse was irradiated near the cell body to mechanically stimulate the nerves. KEY FINDINGS: Subcutaneously injected 3E1 was widely localized almost exclusively on peripheral nerve fibers in the dermis. In formalin tests, 3E1-injected mice exhibited less pain-related behavior than control mice. When 3E1 was added to DRG cell cultures, it localized to neurites and resulted in decreased expression of CADM1, increased phosphorylation of Src and Akt, and CADM1-3E1 complex formation. Femtosecond laser-induced stimulation transmission along neurites was clearly visualized by Fluo-8 fluorescence in control cells, whereas it was markedly suppressed in 3E1-treated cells. SIGNIFICANCE: 3E1 was suggested to be a potential long-acting analgesic based on its high affinity for CADM1.

Clinicopathologic and molecular study of superficial CD34-positive fibroblastic tumours mimicking atypical fibrous histiocytoma (dermatofibroma).

AIMS: Superficial CD34-positive fibroblastic tumour (SCD34FT) is an uncommon but distinctive low-grade neoplasm of the skin and subcutis that shows frequent CADM3 expression by immunohistochemistry (IHC). In this study, prompted by an index case resembling 'atypical fibrous histiocytoma (FH)' that was positive for CADM3 IHC, we systematically examined a cohort of tumours previously diagnosed as 'atypical FH' by applying CADM3 and fluorescence in situ hybridization (FISH) for PRDM10 rearrangement, to investigate the overlap between these tumour types. METHODS AND RESULTS: Forty cases of atypical FH were retrieved, including CD34-positive tumours (n = 20) and CD34-negative tumours (n = 20). All tumours were stained for CADM3. All CADM3-positive tumours were evaluated by FISH to assess for PRDM10 rearrangement. Eleven CD34-positive tumours (11/20, 55%) coexpressed CADM3 and were reclassified as SCD34FT. None (0/20) of the CD34-negative atypical FH were CADM3-positive. Reclassified SCD34FT (10/11) arose on the lower extremity, with frequent involvement of the thigh (n = 8). Features suggestive of atypical FH were observed in many reclassified cases including variable cellularity, spindled morphology, infiltrative tumour margins, collagen entrapment, epidermal hyperpigmentation, and acanthosis. Variably prominent multinucleate giant cells, including Touton-like forms, were also present. An informative FISH result was obtained in 10/11 reclassified tumours, with 60% (6/10) demonstrating PRDM10 rearrangement. CONCLUSION: A significant subset of tumours that histologically resemble atypical FH, and are positive for CD34, coexpress CADM3 and harbour PRDM10 rearrangement, supporting their reclassification as SCD34FT. Awareness of this morphologic overlap and the application of CADM3 IHC can aid the distinction between SCD34FT and atypical FH.

Genome-wide association studies of lifetime and frequency cannabis use in 131,895 individuals.

Cannabis is one of the most widely used drugs globally. Decriminalization of cannabis is further increasing cannabis consumption. We performed genome-wide association studies (GWASs) of lifetime (N=131,895) and frequency (N=73,374) of cannabis use. Lifetime cannabis use GWAS identified two loci, one near CADM2 (rs11922956, p=2.40E-11) and another near GRM3 (rs12673181, p=6.90E-09). Frequency of use GWAS identified one locus near CADM2 (rs4856591, p=8.10E-09; r2 =0.76 with rs11922956). Both traits were heritable and genetically correlated with previous GWASs of lifetime use and cannabis use disorder (CUD), as well as other substance use and cognitive traits. Polygenic scores (PGSs) for lifetime and frequency of cannabis use associated cannabis use phenotypes in AllofUs participants. Phenome-wide association study of lifetime cannabis use PGS in a hospital cohort replicated associations with substance use and mood disorders, and uncovered associations with celiac and infectious diseases. This work demonstrates the value of GWASs of CUD transition risk factors.

Bioinformatics gene analysis for potential biomarkers and therapeutic targets of Parkinson's disease based on neutrophil extracellular traps.

Introduction: Neutrophil extracellular traps (NETs) provide key innate immune mechanisms, and studies have shown innate immunity and adaptive immunity are directly linked to Parkinson's disease (PD) pathology. However, limited research has been conducted on NETs in the context of PD. Methods: A differential analysis was implemented to acquire differentially expressed genes (DEGs) between PD and control as well as between high- and low-score groups determined by a gene set variation analysis (GSVA). Then, the genes within the critical module, obtained through a weighted gene co-expression network analysis (WGCNA), were intersected with the DEGs to identify the overlapping genes. Then, five kinds of algorithms in the protein-protein interaction (PPI) were performed to identify potential biomarkers. Subsequently, a nomogram for forecasting PD probability was created. An enrichment analysis and an immune infiltration analysis were performed on the identified biomarkers. qRT-PCR was performed to validate the expression trends of three biomarkers. Results: We revealed 798 DEGs between PD and control groups as well as 168 DEGs between high- and low-score groups obtained by differential analyses. The pink module containing 926 genes was identified as the critical module. According to the intersection of these gene sets, a total of 43 overlapping genes were screened out. Furthermore, GPR78, CADM3, and CACNA1E were confirmed as biomarkers. Moreover, we found that biomarkers mainly participated in pathways, such as the 'hydrogen peroxide catabolic process', and 'cell cycle'; five kinds of differential immune cells between PD and control groups were identified. Finally, the qRT-PCR analysis demonstrated the up-regulation of GPR78, CADM3, and CACNA1E in the PD group. Discussion: Our study authenticated GPR78, CADM3, and CACNA1E as the biomarkers associated with PD. These findings provide an original reference for the diagnosis and treatment of PD.

Molecular landscape of borderline ovarian tumours: A systematic review.

Borderline ovarian tumours (BOTs) show intriguing characteristics distinguishing them from other ovarian tumours. The aim of the systematic review was to analyse the spectrum of molecular changes found in BOTs and discuss their significance in the context of the overall therapeutic approach. The systematic review included articles published between 2000 and 2023 in the databases: PubMed, EMBASE, and Cochrane. After a detailed analysis of the available publications, we qualified for the systematic review: 28 publications on proto-oncogenes: BRAF, KRAS, NRAS, ERBB2, and PIK3CA, 20 publications on tumour suppressor genes: BRCA1/2, ARID1A, CHEK2, PTEN, 4 on adhesion molecules: CADM1, 8 on proteins: B-catenin, claudin-1, and 5 on glycoproteins: E-Cadherin. In addition, in the further part of the systematic review, we included eight publications on microsatellite instability and three describing loss of heterozygosity in BOT. Molecular changes found in BOTs can vary on a case-by-case basis, identifying carcinogenic mutations through molecular analysis and developing targeted therapies represent significant advancements in the diagnosis and treatment of ovarian malignancies. Molecular studies have contributed significantly to our understanding of BOT pathogenesis, but substantial research is still required to elucidate the relationship between ovarian neoplasms and extraneous disease, identify accurate prognostic indicators, and develop targeted therapeutic approaches.

Successful Treatment of Ultrasound-confirmed Synovitis in Anti-MDA5 Antibody-positive Clinically Amyopathic Dermatomyositis with Corticosteroid Therapy.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive clinically amyopathic dermatomyositis (CADM) is a subtype of dermatomyositis without severe myositis but with characteristic cutaneous manifestations and severe interstitial lung disease. Joint symptoms can occur in patients with anti-MDA5 antibody-positive CADM. However, the treatment strategy and utility of ultrasound for treating joint symptoms remain unknown. We herein report an 85-year-old man with anti-MDA5 antibody-positive CADM who presented with ultrasound-confirmed synovitis that improved with medium-dose corticosteroid therapy.

CADM2 participates in endometriosis development by influencing the epithelial-mesenchymal transition.

Endometriosis (EM) is a common gynecologic condition that often leads to infertility in women of reproductive age. Cell adhesion molecule 2 (CADM2) is involved in maintaining cell adhesion and polarity, as well as suppressing tumors. However, the role and mechanism of CADM2 in endometriosis is unclear. Therefore, this study evaluated the expression levels of CADM2 and epithelial-mesenchymal transition (EMT)-related marker proteins (E-cadherin, α-SMA, and N-cadherin). Compared to normal endometrial tissue, CADM2 was expressed at low levels in ectopic endometrial tissue from patients with EM. We performed clone formation assays, wound healing assays, and Transwell cell invasion assays to investigate the effects of CADM2 on the biological behavior of endometriosis epithelial cells (11Z) and ectopic endometrial stromal cells (EESCs). The growth, migration, and invasion abilities of these cells were significantly inhibited by overexpression of CADM2. The results were reversed after the knockdown of CADM2. Finally, western blotting (WB) was utilized to detect the effect of CADM2 on EMT in endometriosis cells. CADM2 inhibited EMT in endometriosis cells. In conclusion, our study suggests that CADM2 is a negative regulator of endometriosis development and may inhibit endometriosis development by suppressing EMT.

Clinical significance of low expression of CADM3 in breast cancer and preliminary exploration of related mechanisms.

BACKGROUND: Cell adhesion molecule 3 (CADM3), a transmembrane glycoprotein on cell membranes, plays a role in the way of ligand and receptor interaction. However, there are few studies on CADM3 in tumors, and how it works in breast cancer (BC) remains unclear. METHODS: The Cancer Genome Atlas (TCGA) database and clinical samples were used to analyze CADM3 expression and its correlation with clinicopathological factors and prognosis. Its correlation with immune infiltration was analyzed by TCGA. The effects of CADM3 on proliferation and migration were investigated by cell clonal formation, CCK-8, cell scratch and transwell assay. Protein interaction network was prepared and the function prediction of related genes was conducted. The correlation between CADM3 and MAPK pathway was further explored by western blot experiment. RESULTS: The expression of CADM3 in BC tissues were significantly lower than that in adjacent normal tissues. High level of CADM3 was related to better prognosis of BC patients. CADM3 was an independent prognostic factor for BC. Expression of CADM3 was significantly associated with the status of ER and PR, age and PAM50 subtypes. CADM3 positively related to many immune infiltrating cells. Overexpression of CADM3 can notably reduce cell proliferation and migration. CADM3 was related to MAPK pathway and the phosphorylation of ERK1/2 and JNK1 was inhibited in BC cells with high CADM3. CONCLUSIONS: Our research reveals the clinical significance of CADM3 in BC and indicates the critical roles of CADM3 in immune infiltration and MAPK pathway.

The intestinal microbial metabolite acetyl l-carnitine improves gut inflammation and immune homeostasis via CADM2.

Intestinal symbiotic bacteria play a key role in the regulation of immune tolerance in inflammatory bowel disease (IBD) hosts. However, the bacterial strains directly involved in this regulation and their related metabolites are largely unknown. We sought to investigate the effects of intestinal microbial metabolites on intestinal epithelium and to elucidate their therapeutic potential in regulating intestinal mucosal inflammation and immune homeostasis. Here, we used metagenomic data from Crohn's disease (CD) patients to analyze the composition of intestinal flora and identify metabolite profiles associated with disease behavior, and used the mouse model of dextran sodium sulfate (DSS)-induced colitis to characterize the therapeutic effects of the flora metabolite acetyl l-carnitine (ALC) on DSS-induced colitis. We found that intraperitoneal injection of ALC treatment could significantly alleviate the symptoms of DSS-induced colitis in mice, including prevention of weight loss, reduction in disease activity index (DAI) scores, increasing of colonic length, reduction in histological scores, and improvement in intestinal barrier function. Further, transcriptome sequencing analysis and gene silencing experiments revealed that the absence of CADM2 abolished the inhibitory effect of ALC on the TLR-MyD88 pathway in colonic epithelial cells, thereby reducing the release of inflammatory factors in colon epithelial cells. And we confirmed a significant downregulation of CADM2 expression in intestinal tissues of CD patients compared to healthy people in a population cohort. In addition, we also found that ALC increased the ratio of Treg cells in colon, and decreased the ratio of Th17 cells and macrophages, thereby improving the immune tolerance of the organism. The proposed study could be a potential approach for the treatment of CD.

Predicting the death of patients with anti-melanoma differentiation-associated protein-5-positive dermatomyositis-associated interstitial lung disease: A systematic review and meta-analysis.

OBJECTIVES: To investigate the risk factors for death in anti-melanoma differentiation-associated protein-5-positive dermatomyositis-associated interstitial lung disease (ILD). METHODS: Studies were identified by searching PubMed, Embase, Web of Science, and Cochrane Library. We calculated pooled risk ratios (RRs) or standardized mean differences (SMDs) and 95% confidence intervals (CIs) using random-effects models. RESULTS: Twenty studies were selected. Factors that may increase death risk included older age (SMD: 0.62, 95% CI: 0.42-0.81), elevated Krebs von den Lungen-6 (SMD: 0.66, 95% CI: 0.47-0.86), lactate dehydrogenase (SMD: 0.87, 95% CI: 0.72-1.02), C-reactive protein (SMD: 0.62, 95% CI: 0.44-0.80), ferritin (SMD: 0.93, 95% CI: 0.71-1.15), creatine kinase (SMD: 0.28, 95% CI: 0.13-0.44), neutrophil (SMD: 0.34, 95% CI: 0.04-0.64), neutrophil-to-lymphocyte ratio (SMD: 0.52, 95% CI: 0.24-0.79), aspartate aminotransferase (SMD: 0.70, 95% CI: 0.45-0.94), shorter disease duration (SMD: -0.44, 95% CI: -0.67 to -0.21), rapidly progressive ILD (RR: 4.08, 95% CI: 3.01-5.54), fever (RR: 1.98, 95% CI: 1.46-2.69), dyspnoea (RR: 1.63, 95% CI: 1.32-2.02), and anti-Ro52 antibody positive (RR: 1.28, 95% CI: 1.11-1.49). Female (RR: 0.86, 95% CI: 0.78-0.94), increased albumin (SMD: -1.20, 95% CI: -1.76 to -0.64), lymphocyte (SMD: -0.49, 95% CI: -0.67 to -0.30), and arthralgia (RR: 0.53, 95% CI: 0.37-0.78) were protective factors. CONCLUSION: Older age, shorter disease duration, rapidly progressive ILD, fever, dyspnoea, anti-Ro52 antibody positive, and some inflammatory markers were risk factors for death in patients with anti-melanoma differentiation-associated protein-5-positive dermatomyositis-associated ILD.

Novel variant in CADM3 causes Charcot-Marie-Tooth disease.

CADM3 has been recently reported causing a rare axonal Charcot-Marie-Tooth disease in three independent Caucasian families carrying a recurrent change. We describe the first alternative causative mutation in CADM3 in a family from black African and also observed de novo in a patient of Caucasian ancestry. The disease inheritance was consistent with autosomal dominant and sporadic patterns, respectively. Eight patients and their relatives were enroled from both families. The mean age at diagnosis was 33.9 years, and walking difficulty was commonly the first symptom. Neurological examination showed distal muscle weakness and atrophy, sensory loss and foot and hand deformities. A high clinical variability was noted, but as seen in CADM3-associated neuropathy, symptoms were more pronounced in the arms in some patients. Nerve conduction studies showed no response in most of the examined nerves, and an axonal type of neuropathy, where recorded. Whole exome sequencing revealed a novel missense variant (c.1102G>T; Gly368Cys) in CADM3, segregating with the disease. Functional analyses showed a significant decrease in CADM3-Gly368Cys protein levels in the membrane and major structural changes in its predicted secondary structure. Therefore, we extend the genotype spectrum of CADM3, underlining the need for genetic studies in underrepresented populations like in Africa.

hsa_circ_0002980 prevents proliferation, migration, invasion, and epithelial-mesenchymal transition of liver cancer cells through microRNA-1303/cell adhesion molecule 2 axis.

BACKGROUND: Liver cancer (LC) is a rare malignancy. Circular RNA (circRNA) dysregulation is associated with LC metastasis. hsa_circ_0002980 was found to be unexpectedly downregulated in LC tissues; however, its specific function remains unclear. METHODS: hsa_circ_0002980 expression was confirmed using RT-qPCR. The effects of circ_0002980 on the proliferation, metastasis, and EMT-related proteins of LC cells were assessed using clone formation, flow cytometry, Transwell assays, and Western blotting. The relationship between circ_0002980 and miR-1303 or miR-1303 and CADM2 was analyzed using a dual-luciferase reporter assay. Thereafter, the influence of these three genes on LC cell progression was determined through rescue experiments. RESULTS: hsa_circ_0002980 expression was lower in LC. circ_0002980 overexpression inhibited the proliferation, migration, invasion, and EMT of LC cells. In addition, circ_0002980 specifically binds to miR-1303, and the accelerated effect of miR-1303 overexpression on LC progression was partially reversed by circ_0002980. Moreover, miR-1303 can also target CADM2, and CADM2-mediated prevention can also be attenuated by miR-1303 overexpression. CONCLUSIONS: In LC cells, circ_0002980 upregulation prevents cell proliferation, metastasis, and EMT by affecting the miR-1303/CADM2 axis. Therefore, this axis may be a novel therapeutic target in LC.

CircDDX17 inhibits invasive progression of pituitary adenomas by sponging miR-1279 and regulating CADM2 expression.

Purpose: Increasing evidence has revealed that circDDX17 plays significant regulatory roles in tumor progression. In the present study, we investigated the role of circDDX17 in pituitary adenomas (PAs). Methods: Reverse transcription-quantitative PCR was performed to detect the expression of Circular RNA DDX17 (circDDX17), microRNA-1279 (miR-1279), and cell adhesion molecule 2 (CADM2) in PA tissues. Cell abilities of migration and invasion were examined by wound healing and transwell assays. Dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays were applied to confirm the associations among circDDX17, miR-1279, and CADM2. Xenograft tumor experiments were performed to investigate the roles of circDDX17 in vivo. Results: In the present study, we found that circDDX17 was downregulated in PA tissues correlated with invasion, tumor size, and progression-free survival of patients with PA. Enforced expression of circDDX17 significantly inhibited migration and invasion through miR-1279. Notably, CADM2 was verified as the direct binding target of miR-1279, and silencing the expression of CADM2 reverses the tumor suppressing effects induced by circDDX17 overexpression. We demonstrated that circDDX17 upregulated the expression of CADM2 by sponging miR-1279, which suppressed the invasive biological behaviors of PA. Conclusion: CircDDX17 may serve as a tumor suppressor and potential promising biomarker and effectively therapeutic target for the management of PA.

CADM1 impairs the effect of miR-1246 on promoting cell cycle progression in chemo-resistant leukemia cells.

The interruption of normal cell cycle execution acts as an important part to the development of leukemia. It was reported that microRNAs (miRNAs) were closely related to tumorigenesis and progression, and their aberrant expression had been demonstrated to play a crucial role in numerous types of cancer. Our previous study showed that miR-1246 was preferentially overexpressed in chemo-resistant leukemia cell lines, and participated in process of cell cycle progression and multidrug resistant regulation. However, the underlying mechanism remains unclear. In present study, bioinformatics prediction and dual luciferase reporter assay indicated that CADM1 was a direct target of miR-1246. Evidently decreased expression of CADM1 was observed in relapsed primary leukemia patients and chemo-resistant cell lines. Our results furtherly proved that inhibition of miR-1246 could significantly enhance drug sensitivity to Adriamycin (ADM), induce cell cycle arrest at G0/G1 phase, promote cell apoptosis, and relieve its suppression on CADM1 in K562/ADM and HL-60/RS cells. Interference with CADM1 could reduce the increased drug sensitivity induced by miR-1246 inhibition, and notably restore drug resistance by promoting cell cycle progression and cell survival via regulating CDKs/Cyclins complexes in chemo-resistant leukemia cells. Above all, our results demonstrated that CADM1 attenuated the role of miR-1246 in promoting cell cycle progression and cell survival, thus influencing multidrug resistance within chemo-resistant leukemia cells via CDKs/Cyclins. Higher expression of miR-1246 and lower expression of CADM1 might be risk factors for leukemia.

IFN-γ: An overlooked cytokine in dermatomyositis with anti-MDA5 antibodies.

Dermatomyositis with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 DM) is a rare autoimmune disease, often complicated by life-threatening, rapidly progressive interstitial lung disease. Additional manifestations of the disease include skin lesions, vascular abnormalities, joints and muscles pain. Despite its clinical significance, the pathogenesis of anti-MDA5 DM remains largely unknown. Currently, the disease is perceived as driven by type I interferon (IFN) whose expression is increased in most of the patients. Importantly, the regulation of IFN-γ is also altered in anti-MDA5 DM as evidenced by the presence of IFN-γ positive histiocytes in the lungs of patients, and the identification of autoantibodies that directly stimulate the production of IFN-γ by mononuclear cells. This review critically examines the pathogenesis of the disease, shedding light on recent findings that emphasize a potential role of IFN-γ. A novel conceptual framework is proposed, which integrates the molecular mechanisms altering IFN-γ regulation in anti-MDA5 DM with the known functional effects of IFN-γ on key tissues affected during the disease, such as the lungs, skin, and vessels. Understanding the precise role and relevance of IFN-γ in the pathogenesis of the disease will not only enhance the selection of available therapies for anti-MDA5 DM patients but also pave the way for the development of new therapeutic approaches targeting the altered molecular pathways.

Pitfalls in the Diagnosis and Management of an Unusual Presentation of Clinically Amyopathic Dermatomyositis: A Case Report Written With the Assistance of ChatGPT.

Clinically amyopathic dermatomyositis (CADM) is a rare form of dermatomyositis. Patients with this condition present with the typical skin findings of dermatomyositis but lack the characteristic muscle weakness associated with dermatomyositis. This case presentation highlights the unusual clinical manifestation of CADM in a 49-year-old Vietnamese female. The patient initially presented with persistent hyperpigmented plaques on her hands, which did not respond to the standard treatment for atopic dermatitis. The patient later developed respiratory failure and lung fibrosis in Vietnam. This case underscores the challenges in diagnosing and managing CADM, particularly in patients with atypical presentations, and emphasizes the difficulties in managing such cases of CADM in the community setting.

Expression of Protein Markers in Spermatogenic and Supporting Sertoli Cells Affected by High Abdominal Temperature in Cryptorchidism Model Mice.

Cryptorchidism is a congenital abnormality resulting in increased rates of infertility and testicular cancer. We used cryptorchidism model mice that presented with the translocation of the left testis from the scrotum to the abdominal cavity. Mice underwent the surgical procedure of the left testis at day 0 and were sacrificed at days 3, 5, 7, 14, 21, and 28 post-operatively. The weight of the left cryptorchid testis decreased significantly at days 21 and 28. The morphological changes were observed after 5 days and showed detached spermatogenic cells and abnormal formation of acrosome at day 5, multinucleated giant cells at day 7, and atrophy of seminiferous tubules at days 21 and 28. The high abdominal temperature disrupted the normal expression of cell adhesion molecule-1, Nectin-2, and Nectin-3 which are essential for spermatogenesis. In addition, the pattern and alignment of acetylated tubulin in cryptorchid testes were also changed at days 5, 7, 14, 21, and 28. Ultrastructure of cryptorchid testes revealed giant cells that had been formed by spermatogonia, spermatocytes, and round and elongating spermatids. The study's findings reveal that cryptorchidism's duration is linked to abnormal changes in the testis, impacting protein marker expression in spermatogenic and Sertoli cells. These changes stem from the induction of high abdominal temperature.

Interaction of the Hemagglutinin Stalk Region with Cell Adhesion Molecule (CADM) 1 and CADM2 Mediates the Spread between Neurons and Neuropathogenicity of Measles Virus with a Hyperfusogenic Fusion Protein.

Measles virus (MeV), the causative agent of measles, is an enveloped RNA virus of the family Paramyxoviridae, which remains an important cause of childhood morbidity and mortality. MeV has two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. During viral entry or virus-mediated fusion between infected cells and neighboring susceptible cells, the head domain of the H protein initially binds to its receptors, signaling lymphocytic activation molecule family member 1 (SLAM) and nectin-4, and then the stalk region of the H protein transmits the fusion-triggering signal to the F protein. MeV may persist in the human brain and cause a fatal neurodegenerative disease, subacute sclerosing panencephalitis (SSPE). Recently, we showed, using in vitro cell culture, that cell adhesion molecule (CADM) 1 and CADM2 are host factors that trigger hyperfusogenic mutant F proteins, causing cell-to-cell fusion and the transfer of the MeV genome between neurons. Unlike conventional receptors, CADM1 and CADM2 interact in cis (on the same membrane) with the H protein and then trigger membrane fusion. Here, we show that alanine substitutions in part of the stalk region (positions 171-175) abolish the ability of the H protein to mediate membrane fusion triggered by CADM1 and CADM2, but not by SLAM. The recombinant hyperfusogenic MeV carrying this mutant H protein loses its ability to spread in primary mouse neurons as well as its neurovirulence in experimentally infected suckling hamsters. These results indicate that CADM1 and CADM2 are key molecules for MeV propagation in the brain and its neurovirulence in vivo. IMPORTANCE Measles is an acute febrile illness with skin rash. Despite the availability of highly effective vaccines, measles is still an important cause of childhood morbidity and mortality in many countries. The World Health Organization estimates that more than 120,000 people died from measles worldwide in 2021. Measles virus (MeV), the causative agent of measles, can also cause a fatal progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. There is currently no effective treatment for this disease. In this study, using recombinant MeVs with altered receptor usage patterns, we show that cell adhesion molecule (CADM) 1 and CADM2 are host factors critical for MeV spread in neurons and its neurovirulence. These findings further our understanding of the molecular mechanism of MeV neuropathogenicity.

Clinicopathological Significance of Cell Adhesion Molecule 4 Expression in Gallbladder Cancer and Its Prognostic Role.

Cell adhesion molecule 4 (CADM4) is involved in intercellular interactions and is a tumor-suppressor candidate. The role of CADM4 in gallbladder cancer (GBC) has not been reported. Therefore, the clinicopathological significance and prognostic value of CADM4 expression in GBC were evaluated in the present study. Immunohistochemistry (IHC) was performed on 100 GBC tissues to assess CADM4 expression at the protein level. The association between CADM4 expression and the clinicopathological characteristics of GBC was analyzed, and the prognostic significance of CADM4 expression was evaluated. Low CADM4 expression was significantly associated with advanced T category (p = 0.010) and high AJCC stage (p = 0.019). In a survival analysis, low CADM4 expression was associated with shorter overall survival (OS; p = 0.001) and recurrence-free survival (RFS; p = 0.018). In univariate analyses, low CADM4 expression was associated with shorter OS (p = 0.002) and RFS (p = 0.023). In multivariate analyses, low CADM4 expression was an independent prognostic factor of OS (p = 0.013). Low CADM4 expression was associated with tumor invasiveness and poor clinical outcomes in patients with GBC. CADM4 may play an important role in cancer progression and patient survival and can be used as a potential prognostic marker of GBC.

Effect of CADM1 on TPF-induced chemotherapy in laryngeal squamous cell carcinoma.

OBJECTIVES: To explore the relationship between CADM1 expression and sensitivity to TPF-induced chemotherapy in laryngeal squamous cell carcinoma (LSCC) patients, then investigate its potential mechanisms. METHODS: Differential CADM1 expression was examined in chemotherapy-sensitive and chemotherapy-insensitive LSCC patient samples after TPF-induced chemotherapy using microarray analysis. Receiver operating characteristic (ROC) curve analysis and bioinformatics approaches were used to investigate the diagnostic value of CADM1. Small interfering RNAs (siRNAs) were used to knock down CADM1 expression in an LSCC cell line. Differential CADM1 expression was compared by qRT-PCR assays in 35 LSCC patients treated with chemotherapy, including 20 chemotherapy-sensitive and 15 chemotherapy-insensitive patients. RESULTS: Public database and primary patient data both suggest that CADM1 mRNA is expressed at lower levels in chemotherapy-insensitive LSCC samples, suggesting its potential usefulness as a biomarker. Knockdown of CADM1 with siRNAs led to decreased sensitivity of LSCC cells to TPF chemotherapy. CONCLUSIONS: Upregulation of CADM1 expression can alter the sensitivity of LSCC tumors to TPF induction chemotherapy. CADM1 is a possible molecular marker and therapeutic target for induction chemotherapy in LSCC patients.