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Age-related macular degeneration (AMD) is a major global health problem as it is the leading cause of irreversible loss of central vision in the aging population. Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective but do not respond optimally in all patients. This study investigates the genetic factors associated with susceptibility to AMD and response to treatment, focusing on key polymorphisms in the ARMS2 (rs10490924), IL1B1 (rs1143623), TNFRSF1B (rs1061622), TNFRSF1A (rs4149576), VEGFA (rs3024997), ARMS2, IL1B1, TNFRSF1B, TNFRSF1A, and VEGFA serum levels in AMD development and treatment efficacy. This study examined the associations of specific genetic polymorphisms and serum protein levels with exudative and early AMD and the response to anti-VEGF treatment. The AA genotype of VEGFA (rs3024997) was significantly associated with a 20-fold reduction in the odds of exudative AMD compared to the GG + GA genotypes. Conversely, the TT genotype of ARMS2 (rs10490924) was linked to a 4.2-fold increase in the odds of exudative AMD compared to GG + GT genotypes. In females, each T allele of ARMS2 increased the odds by 2.3-fold, while in males, the TT genotype was associated with a 5-fold increase. Lower serum IL1B levels were observed in the exudative AMD group compared to the controls. Early AMD patients had higher serum TNFRSF1B levels than controls, particularly those with the GG genotype of TNFRSF1B rs1061622. Exudative AMD patients with the CC genotype of TNFRSF1A rs4149576 had lower serum TNFRSF1A levels compared to the controls. Visual acuity (VA) analysis showed that non-responders had better baseline VA than responders but experienced decreased VA after treatment, whereas responders showed improvement. Central retinal thickness (CRT) reduced significantly in responders after treatment and was lower in responders compared to non-responders after treatment. The T allele of TNFRSF1B rs1061622 was associated with a better response to anti-VEGF treatment under both dominant and additive genetic models. These findings highlight significant genetic and biochemical markers associated with AMD and treatment response. This study found that the VEGFA rs3024997 AA genotype reduces the odds of exudative AMD, while the ARMS2 rs10490924 TT genotype increases it. Lower serum IL1B levels and variations in TNFRSF1B and TNFRSF1A levels were linked to AMD. The TNFRSF1B rs1061622 T allele was associated with better anti-VEGF treatment response. These markers could potentially guide risk assessment and personalized treatment for AMD.

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.

The human nervous system exhibits limited regenerative capabilities following damage to the central nervous system (CNS), leading to a scarcity of effective treatments for nerve function recovery. In contrast, zebrafish demonstrate remarkable regenerative abilities, making them an ideal model for studying the modulation of inflammatory processes after injury. Such research holds significant translational potential to enhance our understanding of recovery from damage and disease. Macrophages play a crucial role in tissue repair and regeneration, with their subpopulations indirectly promoting axonal regeneration through developmental signals. The AP-1 signaling pathway, mediated by TNF/Tnfrsf1a, can elevate HDAC1 expression and facilitate regeneration. Furthermore, following spinal cord injury (SCI), pMN progenitors have been observed to switch between oligodendrocyte and motor neuron fates, with macrophage-secreted TNF-α potentially regulating the differentiation of ependymal–radial glia progenitors and oligodendrocytes. Radial glial cells (RGs) are also essential for CNS regeneration in zebrafish, as they perform neurogenesis and gliogenesis, with specific RG subpopulations potentially existing for the generation of neurons and oligodendrocytes. This review article underscores the critical role of macrophages and their subpopulations in tissue repair and regeneration, focusing on their secretion of TNF-α, which promotes axonal regeneration in zebrafish. We also offer insights into the molecular mechanisms underlying TNF-α’s ability to facilitate axonal regeneration and explore the potential of pMN progenitor cells and RGs following SCI in zebrafish. The review concludes with a discussion of various unresolved questions in the field, and ideas are suggested for future research. Studying innate immune cell interactions with neuroglia following injury may lead to the development of novel strategies for treating the inflammatory processes associated with regenerative medicine, which are commonly observed in injury and disease.

TNFα is a common drug target in the treatment of autoimmune diseases, with pro-inflammatory functions that are primarily mediated through its receptor, TNFRSF1A. TNFRSF1A has been genetically associated with many immune-mediated diseases including ankylosing spondylitis, multiple sclerosis, and inflammatory bowel disease. Many of the genetic variants within or near TNFRSF1A that have been associated with disease through genome-wide association studies (GWAS) lie in non-coding regions of the genome. Understanding the functional consequences of these genetic variants is limited by incomplete understanding of TNFRSF1A gene regulation, including for specific cellular contexts relevant to inflammation and immunity such as macrophages. This work used CRISPR/Cas9 in human induced pluripotent stem cells followed by differentiation into macrophages to investigate putative regulatory elements in the TNFRSF1A gene locus. Through gene editing, with functional genomic readouts including the assay for transposase-accessible chromatin using sequencing (ATAC-Seq), chromatin immunoprecipitation with sequencing (ChIP-Seq), and RNA-Seq to assess the consequences of these edits, we present evidence for an enhancer of TNFRSF1A contained within an intron of the gene. Understanding gene regulation and the genomic context in which GWAS variants lie could bring us closer to deconvoluting the genetic basis of common disease aetiology and uncover effective drug targets.

Background Alzheimer’s disease (AD) is a complex, irreversible neurodegenerative disorder. At present there are neither reliable markers to diagnose AD at an early stage nor therapy. To investigate underlying disease mechanisms, induced pluripotent stem cells (iPSCs) allow the generation of patient-derived neuronal cells in a dish. Results In this study, employing iPS technology, we derived and characterized iPSCs from dermal fibroblasts of an 82-year-old female patient affected by sporadic AD. The AD-iPSCs were differentiated into neuronal cells, in order to generate disease-specific protein association networks modeling the molecular pathology on the transcriptome level of AD, to analyse the reflection of the disease phenotype in gene expression in AD-iPS neuronal cells, in particular in the ubiquitin-proteasome system (UPS), and to address expression of typical AD proteins. We detected the expression of p-tau and GSK3B, a physiological kinase of tau, in neuronal cells derived from AD-iPSCs. Treatment of neuronal cells differentiated from AD-iPSCs with an inhibitor of γ-secretase resulted in the down-regulation of p-tau. Transcriptome analysis of AD-iPS derived neuronal cells revealed significant changes in the expression of genes associated with AD and with the constitutive as well as the inducible subunits of the proteasome complex. The neuronal cells expressed numerous genes associated with sub-regions within the brain thus suggesting the usefulness of our in-vitro model. Moreover, an AD-related protein interaction network composed of APP and GSK3B among others could be generated using neuronal cells differentiated from two AD-iPS cell lines. Conclusions Our study demonstrates how an iPSC-based model system could represent (i) a tool to study the underlying molecular basis of sporadic AD, (ii) a platform for drug screening and toxicology studies which might unveil novel therapeutic avenues for this debilitating neuronal disorder.

This study was designed to determine the effect of acute caffeine (CAF) administration, which exerts a broad spectrum of anti-inflammatory activity, on the synthesis of pro-inflammatory cytokines and their receptors in the hypothalamus and choroid plexus (ChP) during acute inflammation caused by the injection of bacterial endotoxin—lipopolysaccharide (LPS). The experiment was performed on 24 female sheep randomly divided into four groups: control; LPS treated (iv.; 400 ng/kg of body mass (bm.)); CAF treated (iv.; 30 mg/kg of bm.); and LPS and CAF treated. The animals were euthanized 3 h after the treatment. It was found that acute administration of CAF suppressed the synthesis of interleukin (IL-1β) and tumor necrosis factor (TNF)α, but did not influence IL-6, in the hypothalamus during LPS-induced inflammation. The injection of CAF reduced the LPS-induced expression of TNF mRNA in the ChP. CAF lowered the gene expression of IL-6 cytokine family signal transducer (IL6ST) and TNF receptor superfamily member 1A (TNFRSF1) in the hypothalamus and IL-1 type II receptor (IL1R2) in the ChP. Our study on the sheep model suggests that CAF may attenuate the inflammatory response at the hypothalamic level and partly influence the inflammatory signal generated by the ChP cells. This suggests the potential of CAF to suppress neuroinflammatory processes induced by peripheral immune/inflammatory challenges.

During the progression of renal cell carcinoma (RCC), tumor growth, metastasis and treatment response heterogeneity are regulated by both the tumor itself and the tumor microenvironment (TME). The aim of the present study was to investigate the role of the TME in RCC and construct a crosstalk network for clear cell RCC (ccRCC). An additional aim was to evaluate whether TNF receptor superfamily member 1A (TNFRSF1A) is a potential therapeutic target for ccRCC. Single-cell data analysis of RCC was performed using the GSE152938 dataset, focusing on key cellular components and their involvement in the ccRCC TME. Additionally, cell-cell communication was analyzed to elucidate the complex network of the ccRCC microenvironment. Analyses of data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases were performed to further mine the key TNF receptor genes, with a particular focus on the prediction and assessment of the cancer-associated features of TNFRSF1A. In addition, following the silencing of TNFRSF1A using small interfering RNA in the 786-O ccRCC cell line, a number of in vitro experiments were conducted to further investigate the cancer-promoting characteristics of TNFRSF1A. These included 5-ethynyl-2′-deoxyuridine incorporation, Cell Counting Kit-8, colony formation, Transwell, cell cycle and apoptosis assays. The TNF signaling pathway was found to have a critical role in the development of ccRCC. Based on the specific crosstalk identified between TNF and TNFRSF1A, the communication of this signaling pathway within the TME was elucidated. The results of the cellular phenotype experiments indicated that TNFRSF1A promotes the proliferation, migration and invasion of ccRCC cells. Consequently, it is proposed that targeting TNFRSF1A may disrupt tumor progression and serve as a therapeutic strategy. In conclusion, by understanding the TME and identifying significant crosstalk within the TNF signaling pathway, the potential of TNFRSF1A as a therapeutic target is highlighted. This may facilitate an advance in precision medicine and improve the prognosis for patients with RCC.

Materials and Methods: A retrospective analysis of clinical data from the Slovak national database of patients with periodic fever syndromes was performed, including 7 TRAPS patients diagnosed between 2019 and 2022 in Slovakia. Treatment with canakinumab resulted in a significant reduction in flare frequency and decreases in inflammatory markers. In TRAPS, approximately 25% of patients carrying TNFRSF1A mutations involving cysteine residues develop amyloidosis, compared to only 2% of patients with lower penetrance variants.8 Tumor necrosis factor receptor- associated periodic syndrome symptoms typically start at a young age (median age of 2.4 years), but late-onset forms have also been documented.9,10 Prior to the introduction of biologic therapy, systemic amyloidosis was the main cause of morbidity and mortality in TRAPS.6 The diagnosis of TRAPS relies on a combination of clinical features and genetic testing and is supported by elevated laboratory markers of inflammation during flares (such as elevated erythrocyte sedimentation rate, C-reactive protein, and/or high levels of serum amyloid A (SAA)), with a positive family history serving as an important, but not essential diagnostic criterion.3,10,11 Furthermore, evidencebased classification criteria developed by the Eurofever Registry and the Pediatric Rheumatology International Trials Organisation (PRINTO) can facilitate the diagnostic process.12 Regarding treatment, biologic therapy targeting interleukin-1ß (IL-1ß) with canakinumab has emerged as the first-line option approved by both the European Medicines Agency and the US Food and Drug Administration.13-15 Anakinra, another IL-1 blocking agent, has also demonstrated efficacy, while other biological agents such as the anti-TNF agent etanercept or the anti-IL-6 agent tocilizumab may be considered in some cases.3,15-21 Interestingly, TNF-α inhibitors like adalimumab and infliximab were reported to cause paradoxical worsening of disease flares in TRAPS patients.17 Tumor necrosis factor receptor-associated periodic syndrome is very rare, with a prevalence of around 1 in 1 000 000, according to the literature;9,16 therefore, a comprehensive understanding of TRAPS is essential for timely diagnosis and effective management. The aim of this study was to describe the clinical and genotypical characteristics of TRAPS patients diagnosed in Slovakia, to estimate disease prevalence within the country, and to compare these findings with data from other geographical regions to find whether the clinical presentation is different based on geographical location.

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.

The Infevers database (http://fmf.igh.cnrs.fr/infevers/) was established in 2002 to provide investigators with access to a central source of information about all sequence variants associated with periodic fevers: Familial Mediterranean fever (FMF), TNF Receptor Associated Periodic Syndrome (TRAPS), Hyper IgD Syndrome (HIDS), Familial Cold Autoinflammatory Syndrome/Muckle‐Wells Syndrome/Chronic Infantile Neurological Cutaneous and Articular Syndrome (FCAS/MWS/CINCA). The prototype of this group of disorders is FMF, a recessive disease characterized by recurrent bouts of unexplained inflammation. FMF is the pivotal member of an expanding family of autoinflammatory disorders, a new term coined to describe illnesses resulting from a defect of the innate immune response. Therefore, we decided to extend the Infevers database to genes connected with autoinflammatory diseases. We present here the biological content of the Infevers database, including the introduction of two new entries: Crohn/Blau and Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA syndrome). Infevers has a range of query capabilities, allowing for simple or complex interrogation of the database. Currently, the database contains 291 sequence variants in related genes (MEFV, TNFRSF1A, MVK, CARD15, PSTPIP1, and CIAS1), consisting of published data and personal communications, which has revealed or refined the preferential mutational sites for each gene. This database will continue to evolve in its content and to improve in its presentation. Hum Mutat 24:194–198, 2004. © 2004 Wiley‐Liss, Inc.