Tumor necrosis factor type 1A receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated autoinflammatory syndrome (CAPS) are rare monogenic autoinflammatory diseases (AIDs) mainly caused by pathogenic variations in the TNFRSF1A and NLRP3 genes, respectively. Here, we describe a unique patient presenting with symptoms overlapping both TRAPS and CAPS, without known pathogenic variants in the respective genes. The patient harbored the p.Val200Met variation in NLRP3 and the p.Ser226Cys variation in TNFRSF1A, prompting us to delve deeper into the functional analysis due to conflicting or inconclusive pathogenicity interpretations of the variants across various databases. Molecular dynamics analysis of the p.Val200Met variation in NLRP3 revealed a rigid conformation in the helical domain 2 subdomain of the NACHT domain. This increased rigidity suggests a potential mechanism by which this variation supports the assembly of the NLRP3 inflammasome. Notably, the patient\'s peripheral mononuclear blood cells demonstrated an elevated IL-1β response upon lipopolysaccharides (LPS) induction. Subsequent initiation of anti-IL-1β therapy resulted in a significant alleviation of the patient\'s symptoms, further supporting our hypothesis. We interpret these findings as suggestive of a potential pathophysiological role for the NLPR3 p.Val200Met variation in shaping the patient\'s clinical phenotype, which was also supported by clinical and genetic analysis of the family. This case underscores the complexity of the genetic landscape in AIDs and highlights the value of combining family genetic and functional data to refine the understanding and management of such challenging cases.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS, OMIM: #142680) is a rare autoinflammatory disease (AID) with recurrent febrile episodes. To our knowledge, we report herein the first case of a patient with TRAPS in South Korea whose symptoms included fever, arthralgia, abdominal pain, rash, myalgia, cough, and lymphadenopathy. A pathogenic de novo mutation, c.175T>C (p.Cys59Arg), in the tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) gene, was confirmed by gene sequencing. The patient has been with tocilizumab (an interleukin-6 inhibitor); tocilizumab administration every other week has completely alleviated the patient\'s symptoms. Our report further expands the clinical spectrum of patients with TRAPS and reaffirms the use of tocilizumab as a viable alternative treatment option for those patients who are unsatisfactorily responsive to other commonly used biologics, such as canakinumab, anakinra, infliximab, and etanercept. Furthermore, our report may aid in increasing awareness about the existence of mutation-confirmed TRAPS in South Korea in addition to emphasizing the importance of actively pursuing genetic testing to correctly diagnose rare AID.

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UNASSIGNED: Osteosarcoma (OS) is a relatively rare malignant bone tumor in teenagers; however, its molecular mechanisms are not yet understood comprehensively.
UNASSIGNED: The study aimed to use necroptosis-related genes (NRGs) and their relationships with immune-related genes to construct a prognostic signature for OS.
UNASSIGNED: TARGET-OS was used as the training dataset, and GSE 16091 and GSE 21257 were used as the validation datasets. Univariate regression, survival analysis, and Kaplan-Meier curves were used to screen for hub genes. The immune-related targets were screened using immune infiltration assays and immune checkpoints. The results were validated using nomogram and decision curve analyses (DCA).
UNASSIGNED: Using univariate Cox regression analysis, TNFRSF1A was screened from 14 NRGs as an OS prognostic signature. Functional enrichment was analyzed based on the median expression of TNFRSF1A. The prognosis of the TNFRSF1A low-expression group in the Kaplan-Meier curve was notably worse. Immunohistochemistry analysis showed that the number of activated T cells and tumor purity increased considerably. Furthermore, the immune checkpoint lymphocyte activation gene 3 (LAG-3) is a possible target for intervention. The nomogram accurately predicted 1-, 3-, and 5-year survival rates. DCA validated the model (C = 0.669).
UNASSIGNED: TNFRSF1A can be used to elucidate the potential relationship between the immune microenvironment and NRGs in OS pathogenesis.

Multiple myeloma (MM) is a hematological tumor with high mortality and recurrence rate. Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM. However, the development of drug resistance is a pervasive obstacle to treating MM. Therefore, elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies. To elucidate the mechanisms of carfilzomib resistance, we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells. Differential gene expression analyses revealed major alterations in the major histocompatibility complex (MHC) and cell adhesion molecules. The upregulation of the tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) gene was accompanied by the downregulation of MHC genes and cell adhesion molecules. Furthermore, to investigate the roles of these genes, we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules. Furthermore, TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice, indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity. Furthermore, our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules. The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity. Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.

This research delves into the intricate landscape of tumor necrosis factor-alpha (TNF-α) signaling, a multi-functional cytokine known for its diverse cellular effects. Specifically, we investigate the roles of two TNF receptors, TNFR1 and TNFR2, in mediating TNF-α-induced transcriptional responses. Using human K562 cell lines with TNFR1 and TNFR2 knockouts, we explore changes in gene expression patterns following TNF-α stimulation. Our findings reveal distinct transcriptional profiles in TNFR1 and TNFR2 knockout cells, shedding light on the unique contributions of these receptors to TNF-α signaling. Notably, several key pathways associated with inflammation, apoptosis, and cell proliferation exhibit altered regulation in the absence of TNFR1 or TNFR2. This study provides valuable insights into the intricate mechanisms governing TNF-α signaling and its diverse cellular effects, with potential implications for targeted therapeutic strategies.

This article reports a case of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) misdiagnosed as Kawasaki disease and summarizes the clinical features and therapeutic progress of TRAPS and the relationship between its clinical manifestations and gene mutations. We retrospectively analyzed a patient with tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) -mutated auto-inflammatory disease who was misdiagnosed with Kawasaki disease in another hospital. The clinical features and therapeutic progress of TRAPS were analyzed by combining clinical features and gene reports of this case and literature review. TRAPS onset occurred in a female pediatric patient at the age of 4 months. The child and in his father at the age of 6 years, both of whom manifested periodic fever, and recurrent rash, as well as elevated leukocytes, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) during episodes but normal between episodes. This child carried a heterozygous mutation in TNFRSF1A located in the region 6442923-6442931 on chromosome 12. The nucleic acid alteration was: c.298 (exon3) _c.306 (exon3) 291 delCTCAGCTGC, resulting in a 3 amino acid deletion p.L100_C 102del 292 (p.Leu100_Cys102del) (NM_001065). After etanercept treatment, the symptoms of fever and rash disappeared, and the levels of ESR, CRP, interleukin (IL)-1, IL-6, and TNF-α levels were normal. Subsequently, no liver, kidney, or cardiac amyloidosis and severe etanercept-related adverse events were observed at 1-year follow-up. TRAPS pathogenesis is associated with TNFRSF1A mutation, which is characterized by periodic episodes of fever, mostly accompanied by recurrent rashes, periorbital edema, abdominal pain, and serious complications of organ amyloidosis. Moreover, etanercept can effectively alleviate the clinical symptoms and high inflammation level of TRAPS.

Alternative splicing is a part of mRNA processing that expands the diversity of proteins encoded by a single gene. Studying the full range of proteins-products of translation of alternatively spliced mRNA is extremely important for understanding the interactions between receptor proteins and ligands since different receptor protein isoforms can provide variation in the activation of signaling pathways. In this study, we investigated the expression of isoforms of TNFR1 and TNFR2 receptors before and after exposure to TNFα in two cell lines that had previously demonstrated diverse effects on cell proliferation under TNFα incubation using RT-qPCR. We found that after incubation with TNFα: (1) expression of isoform 3 of the TNFRSF1A gene was increased in both cell lines; (2) the cell line with increased proliferation, K562, had decreased expression of isoforms 1 and 4 of the TNFRSF1A gene and expression of isoform 2 of TNFRSF1B gene was absent at all; (3) the cell line with decreased proliferation-MCF-7 had significantly increased expression of isoform 2 of TNFRSF1B gene. Thus, we can conclude that TNFα exposure to the K562 and MCF-7 cell lines leads to changes in the expression of TNFα receptor isoforms, which, in turn, can appear via diverse proliferative effects.

BACKGROUND: Genomic studies have identified numerous genetic variants associated with susceptibility to multiple sclerosis (MS); however, each one explains only a small percentage of the risk of developing the disease. These variants are located in genes involved in specific pathways, which supports the hypothesis that the risk of developing MS may be linked to alterations in these pathways, rather than in specific genes. We analyzed the role of the TNFRSF1A gene, which encodes one of the TNF-α receptors involved in a signaling pathway previously linked to autoimmune disease.
METHODS: We included 138 individuals from 23 families including at least 2 members with MS, and analyzed the presence of exonic variants of TNFRSF1A through whole-exome sequencing. We also conducted a functional study to analyze the pathogenic mechanism of variant rs4149584 (-g.6442643C > G, NM_001065.4:c.362 G > A, R92Q) by plasmid transfection into human oligodendroglioma (HOG) cells, which behave like oligodendrocyte lineage cells; protein labeling was used to locate the protein within cells. We also analyzed the ability of transfected HOG cells to proliferate and differentiate into oligodendrocytes.
RESULTS: Variant rs4149584 was found in 2 patients with MS (3.85%), one patient with another autoimmune disease (7.6%), and in 5 unaffected individuals (7.46%). The 2 patients with MS and variant rs4149584 were homozygous carriers and belonged to the same family, whereas the remaining individuals presented the variant in heterozygosis. The study of HOG cells transfected with the mutation showed that the protein does not reach the cell membrane, but rather accumulates in the cytoplasm, particularly in the endoplasmic reticulum and near the nucleus; this suggests that, in the cells presenting the mutation, TNFRSF1 does not act as a transmembrane protein, which may alter its signaling pathway. The study of cell proliferation and differentiation found that transfected cells continue to be able to differentiate into oligodendrocytes and are probably still capable of producing myelin, although they present a lower rate of proliferation than wild-type cells.
CONCLUSIONS: Variant rs4149584 is associated with risk of developing MS. We analyzed its functional role in oligodendrocyte lineage cells and found an association with MS in homozygous carriers. However, the associated molecular alterations do not influence the differentiation into oligodendrocytes; we were therefore unable to confirm whether this variant alone is pathogenic in MS, at least in heterozygosis.

Objective: The purpose of this study was to investigate the associations of genetic variants in double-strand break (DSB) repair pathway genes with prognosis in patients with lung cancer treated with platinum-based chemotherapy. Methods: Three hundred ninety-nine patients with lung cancer who received platinum-based chemotherapy for at least two cycles were included in this study. A total of 35 single nucleotide polymorphisms (SNPs) in DSB repair, base excision repair (BER), and nucleotide excision repair (NER) repair pathway genes were genotyped, and were used to evaluate the overall survival (OS) and the progression-free survival (PFS) of patients who received platinum-based chemotherapy using Cox proportional hazard models. Results: The PFS of patients who carried the MAD2L2 rs746218 GG genotype was shorter than that in patients with the AG or AA genotypes (recessive model: p = 0.039, OR = 5.31, 95% CI = 1.09-25.93). Patients with the TT or GT genotypes of TNFRSF1A rs4149570 had shorter OS times than those with the GG genotype (dominant model: p = 0.030, OR = 0.57, 95% CI = 0.34-0.95). We also investigated the influence of age, gender, histology, smoking, stage, and metastasis in association between SNPs and OS or PFS in patients with lung cancer. DNA repair gene SNPs were significantly associated with PFS and OS in the subgroup analyses. Conclusion: Our study showed that variants in MAD2L2 rs746218 and TNFRSF1A rs4149570 were associated with shorter PFS or OS in patients with lung cancer who received platinum-based chemotherapy. These variants may be novel biomarkers for the prediction of prognosis of patients with lung cancer who receive platinum-based chemotherapy.