T cell involvement in antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by arterial and venous thrombosis, and obstetric complications in the presence of antiphospholipid antibodies (aPL), including lupus anticoagulant, anticardiolipin and anti-ß2-glycoprotein I antibodies. APS manifests as single, often as recurrent events, and rarely as a catastrophic condition. Most studies of APS pathogenesis to date have focused on the prothrombotic role of aPL, while innate immune responses such as monocyte, complement and neutrophil activation have been also recognized as part of the thrombo-inflammatory cascade in APS. While the presence of autoreactive T cells against ß2-glycoprotein I has been long known, less data are available on their pathogenetic role in APS. In this review, we summarize current knowledge on the involvement of T cells in APS pathophysiology, alterations of T cell subsets in peripheral blood, and clinical associations. We also highlight potential therapeutic opportunities by targeting T helper-B cell interactions in these patients.

Liver endothelial cells in NAFLD and transition to NASH and HCC.

Non-alcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome, which is characterised by obesity, insulin resistance, hypercholesterolemia and hypertension. NAFLD is the most frequent liver disease worldwide and more than 10% of NAFLD patients progress to the inflammatory and fibrotic stage of non-alcoholic steatohepatitis (NASH), which can lead to end-stage liver disease including hepatocellular carcinoma (HCC), the most frequent primary malignant liver tumor. Liver sinusoidal endothelial cells (LSEC) are strategically positioned at the interface between blood and hepatic parenchyma. LSECs are highly specialized cells, characterised by the presence of transcellular pores, called fenestrae, and exhibit anti-inflammatory and anti-fibrotic characteristics under physiological conditions. However, during NAFLD development they undergo capillarisation and acquire a phenotype similar to vascular endothelial cells, actively promoting all pathophysiological aspects of NAFLD, including steatosis, inflammation, and fibrosis. LSEC dysfunction is critical for the progression to NASH and HCC while restoring LSEC homeostasis appears to be a promising approach to prevent NAFLD progression and its complications and even reverse tissue damage. In this review we present current information on the role of LSEC throughout the progressive phases of NAFLD, summarising in vitro and in vivo experimental evidence and data from human studies.

Deregulated DNA damage response network in Behcet's disease.

Behcet's disease (BD) is a chronic, relapsing systemic vasculitis of unknown etiology. Since the DNA repair enzyme NEIL1 has been identified as one of the two genetic risk factors for BD by whole exome study, we examined the potential involvement of the DNA damage response (DDR) network in BD. Peripheral blood mononuclear cells from 26 patients and 26 age-/sex-matched healthy controls were studied. Endogenous DNA damage levels were increased in active BD patients compared to controls or patients in remission. In parallel, BD patients had defective nucleotide excision repair capacity. RNA-sequencing revealed reduced expression of NEIL1 that negatively correlated with DNA damage accumulation. On the other hand, expression of genes involved in senescence and senescence-associated secretory phenotype positively correlated with individual endogenous DNA damage levels. We conclude that deregulated DDR contributes to the proinflammatory environment in BD.

Chronological Age and DNA Damage Accumulation in Blood Mononuclear Cells: A Linear Association in Healthy Humans after 50 Years of Age.

Aging is characterized by the progressive deregulation of homeostatic mechanisms causing the accumulation of macromolecular damage, including DNA damage, progressive decline in organ function and chronic diseases. Since several features of the aging phenotype are closely related to defects in the DNA damage response (DDR) network, we have herein investigated the relationship between chronological age and DDR signals in peripheral blood mononuclear cells (PBMCs) from healthy individuals. DDR-associated parameters, including endogenous DNA damage (single-strand breaks and double-strand breaks (DSBs) measured by the alkaline comet assay (Olive Tail Moment (OTM); DSBs-only by γH2AX immunofluorescence staining), DSBs repair capacity, oxidative stress, and apurinic/apyrimidinic sites were evaluated in PBMCs of 243 individuals aged 18-75 years, free of any major comorbidity. While OTM values showed marginal correlation with age until 50 years (rs = 0.41, p = 0.11), a linear relationship was observed after 50 years (r = 0.95, p < 0.001). Moreover, individuals older than 50 years showed increased endogenous DSBs levels (γH2Ax), higher oxidative stress, augmented apurinic/apyrimidinic sites and decreased DSBs repair capacity than those with age lower than 50 years (all p < 0.001). Results were reproduced when we examined men and women separately. Prospective studies confirming the value of DNA damage accumulation as a biomarker of aging, as well as the presence of a relevant agethreshold, are warranted.

Adenosine-to-inosine Alu RNA editing controls the stability of the pro-inflammatory long noncoding RNA NEAT1 in atherosclerotic cardiovascular disease.

Long non-coding RNAs (lncRNAs) have emerged as critical regulators in human disease including atherosclerosis. However, the mechanisms involved in the post-transcriptional regulation of the expression of disease-associated lncRNAs are not fully understood. Gene expression studies revealed that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) lncRNA expression was increased by >2-fold in peripheral blood mononuclear cells (PBMCs) derived from patients with coronary artery disease (CAD) or in carotid artery atherosclerotic plaques. We observed a linear association between NEAT1 lncRNA expression and prevalence of CAD which was independent of age, sex, cardiovascular traditional risk factors and renal function. NEAT1 expression was induced by TNF-α, while silencing of NEAT1 profoundly attenuated the TNF-α-induced vascular endothelial cell pro-inflammatory response as defined by the expression of CXCL8, CCL2, VCAM1 and ICAM1. Overexpression of the RNA editing enzyme adenosine deaminase acting on RNA-1 (ADAR1), but not of its editing-deficient mutant, upregulated NEAT1 levels. Conversely, silencing of ADAR1 suppressed the basal levels and the TNF-α-induced increase of NEAT1. NEAT1 lncRNA expression was strongly associated with ADAR1 in CAD and peripheral arterial vascular disease. RNA editing mapping studies revealed the presence of several inosines in close proximity to AU-rich elements within the AluSx3+/AluJo- double-stranded RNA complex. Silencing of the stabilizing RNA-binding protein AUF1 reduced NEAT1 levels while silencing of ADAR1 profoundly affected the binding capacity of AUF1 to NEAT1. Together, our findings propose a mechanism by which ADAR1-catalyzed A-to-I RNA editing controls NEAT1 lncRNA stability in ASCVD.

The role of A-to-I RNA editing in infections by RNA viruses: Possible implications for SARS-CoV-2 infection.

RNA editing is a fundamental biological process with 2 major forms, namely adenosine-to-inosine (A-to-I, recognized as A-to-G) and cytosine-to-uracil (C-to-U) deamination, mediated by ADAR and APOBEC enzyme families, respectively. A-to-I RNA editing has been shown to directly affect the genome/transcriptome of RNA viruses with significant repercussions for viral protein synthesis, proliferation and infectivity, while it also affects recognition of double-stranded RNAs by cytosolic receptors controlling the host innate immune response. Recent evidence suggests that RNA editing may be present in SARS-CoV-2 genome/transcriptome. The majority of mapped mutations in SARS-CoV-2 genome are A-to-G/U-to-C(opposite strand) and C-to-U/G-to-A(opposite strand) substitutions comprising potential ADAR-/APOBEC-mediated deamination events. A single nucleotide substitution can have dramatic effects on SARS-CoV-2 infectivity as shown by the D614G(A-to-G) substitution in the spike protein. Future studies utilizing serial sampling from patients with COVID-19 are warranted to delineate whether RNA editing affects viral replication and/or the host immune response to SARS-CoV-2.

Effective DNA damage response after acute but not chronic immune challenge: SARS-CoV-2 vaccine versus Systemic Lupus Erythematosus.

Whether and how an acute immune challenge may affect DNA Damage Response (DDR) is unknown. By studying vaccinations against Influenza and SARS-CoV-2 (mRNA-based) we found acute increases of type-I interferon-inducible gene expression, oxidative stress and DNA damage accumulation in blood mononuclear cells of 9 healthy controls, coupled with effective anti-SARS-CoV-2 neutralizing antibody production in all. Increased DNA damage after SARS-CoV-2 vaccine, partly due to increased oxidative stress, was transient, whereas the inherent DNA repair capacity was found intact. In contrast, in 26 patients with Systemic Lupus Erythematosus, who served as controls in the context of chronic immune activation, we validated increased DNA damage accumulation, increased type-I interferon-inducible gene expression and induction of oxidative stress, however aberrant DDR was associated with deficiencies in nucleotide excision repair pathways. These results indicate that acute immune challenge can indeed activate DDR pathways, whereas, contrary to chronic immune challenge, successful repair of DNA lesions occurs.

Adenosine-to-inosine RNA editing contributes to type I interferon responses in systemic sclerosis.

OBJECTIVE: Adenosine deaminase acting on RNA-1 (ADAR1) enzyme is a type I interferon (IFN)-stimulated gene (ISG) catalyzing the deamination of adenosine-to-inosine, a process called A-to-I RNA editing. A-to-I RNA editing takes place mainly in Alu elements comprising a primate-specific level of post-transcriptional gene regulation. Whether RNA editing is involved in type I IFN responses in systemic sclerosis (SSc) patients remains unknown. METHODS: ISG expression was quantified in skin biopsies and peripheral blood mononuclear cells derived from SSc patients and healthy subjects. A-to-I RNA editing was examined in the ADAR1-target cathepsin S (CTSS) by an RNA editing assay. The effect of ADAR1 on interferon-α/ß-induced CTSS expression was assessed in human endothelial cells in vitro. RESULTS: Increased expression levels of the RNA editor ADAR1, and specifically the long ADAR1p150 isoform, and its target CTSS are strongly associated with type I IFN signature in skin biopsies and peripheral blood derived from SSc patients. Notably, IFN-α/ß-treated human endothelial cells show 8-10-fold increased ADAR1p150 and 23-35-fold increased CTSS expression, while silencing of ADAR1 reduces CTSS expression by 60-70%. In SSc patients, increased RNA editing rate of individual adenosines located in CTSS 3' UTR Alu elements is associated with higher CTSS expression (r = 0.36-0.6, P < 0.05 for all). Similar findings were obtained in subjects with activated type I IFN responses including SLE patients or healthy subjects after influenza vaccination. CONCLUSION: ADAR1p150-mediated A-to-I RNA editing is critically involved in type I IFN responses highlighting the importance of post-transcriptional regulation of proinflammatory gene expression in systemic autoimmunity, including SSc.

Distinct transcriptional profile of blood mononuclear cells in Behçet's disease: insights into the central role of neutrophil chemotaxis.

OBJECTIVES: Both innate and adaptive immune responses are reportedly increased in Behçet's disease (BD), a chronic, relapsing systemic vasculitis lying at the intersection between autoinflammation and autoimmunity. To further study pathophysiologic molecular mechanisms operating in BD, we searched for transcriptome-wide changes in blood mononuclear cells from these patients. METHODS: We performed 3' mRNA next-generation sequencing-based genome-wide transcriptional profiling followed by analysis of differential expression signatures, Kyoto Encyclopedia of Genes and Genomes pathways, GO biological processes and transcription factor signatures. RESULTS: Differential expression analysis clustered the transcriptomes of 13 patients and one healthy subject separately from those of 10 healthy age/gender-matched controls and one patient. Among the total of 17 591 expressed protein-coding genes, 209 and 31 genes were significantly upregulated and downregulated, respectively, in BD vs controls by at least 2-fold. The most upregulated genes comprised an abundance of CC- and CXC-chemokines. Remarkably, the 5 out of top 10 upregulated biological processes involved leucocyte recruitment to peripheral tissues, especially for neutrophils. Moreover, NF-kB, TNF and IL-1 signalling pathways were prominently enhanced in BD, while transcription factor activity analysis suggested that the NF-kB p65/RELA subunit action underlies the observed differences in the BD transcriptome. CONCLUSION: This RNA-sequencing analysis in peripheral blood mononuclear cells derived from patients with BD does not support a major pathogenetic role for adaptive immunity-driven mechanisms, but clearly points to the action of aberrant innate immune responses with a central role played by upregulated neutrophil chemotaxis.

Clinical value of amyloid-beta1-40 as a marker of thrombo-inflammation in antiphospholipid syndrome.

OBJECTIVE: Amyloid-beta1-40 (Aß40) is a pro-inflammatory peptide under investigation as a novel biomarker of vascular inflammation, endothelial dysfunction and atherothrombosis in the general population. Herein we tested the hypothesis that Aß40 is deregulated in APS, a systemic autoimmune disease characterized by a thrombo-inflammatory state. METHODS: Between January 2016 and July 2017, we consecutively recruited 80 regularly followed thrombotic APS patients (44 primary, 36 SLE/APS) and 80 age- and sex-matched controls. Plasma Aß40 levels were measured using ELISA and APS-related clinical and laboratory characteristics were recorded. The adjusted Global Anti-Phospholipid Syndrome Score (aGAPSS), a validated risk score in APS, was calculated as a comparator to Aß40 performance to detect arterial thrombotic APS-related events. RESULTS: Higher Aß40 levels were significantly associated with the presence of APS [odds ratio (OR) 1.024 per 1 pg/ml (95% CI 1.007, 1.041)] after adjustment for cardiovascular risk factors (CVRFs), including smoking, arterial hypertension, dyslipidaemia and BMI, and for estimated glomerular filtration rate (eGFR). Among APS patients, increased high-sensitivity CRP (hs-CRP) serum levels was the only independent determinant of Aß40 levels. Importantly, Aß40 levels above the optimal receiver operating characteristics (ROC)-derived cut-off value were independently associated with recurrent arterial events [OR 4.93 (95% CI 1.31, 18.51)] after adjustment for age, sex, CVRFs, hs-CRP and high anti-ß2 glycoprotein I IgG titres. Finally, by ROC curve analysis, Aß40 provided incremental additive value over the aGAPSS by significantly improving its discrimination ability for recurrent arterial thromboses. CONCLUSION: In APS, Aß40 plasma levels are elevated and associated with an adverse thrombo-inflammatory profile. The pathophysiological and prognostic role of Aß40 in APS merits further investigation.

Increased adenosine-to-inosine RNA editing in rheumatoid arthritis.

OBJECTIVE: Adenosine-to-inosine (A-to-I) RNA editing of Alu retroelements is a primate-specific mechanism mediated by adenosine deaminases acting on RNA (ADARs) that diversifies transcriptome by changing selected nucleotides in RNA molecules. We tested the hypothesis that A-to-I RNA editing is altered in rheumatoid arthritis (RA). METHODS: Synovium expression analysis of ADAR1 was investigated in 152 RA patients and 50 controls. Peripheral blood mononuclear cells derived from 14 healthy subjects and 19 patients with active RA at baseline and after 12-week treatment were examined for ADAR1p150 and ADAR1p110 isoform expression by RT-qPCR. RNA editing activity was analysed by AluSx+ Sanger-sequencing of cathepsin S, an extracellular matrix degradation enzyme involved in antigen presentation. RESULTS: ADAR1 was significantly over-expressed in RA synovium regardless of disease duration. Similarly, ADAR1p150 isoform expression was significantly increased in the blood of active RA patients. Individual nucleotide analysis revealed that A-to-I RNA editing rate was also significantly increased in RA patients. Both baseline ADAR1p150 expression and individual adenosine RNA editing rate of cathepsin S AluSx+ decreased after treatment only in those patients with good clinical response. Upregulation of the expression and/or activity of the RNA editing machinery were associated with a higher expression of edited Alu-enriched genes including cathepsin S and TNF receptor-associated factors 1,2,3 and 5. CONCLUSION: A previously unrecognized regulation and role of ADAR1p150-mediated A-to-I RNA editing in post-transcriptional control in RA underpins therapeutic response and fuels inflammatory gene expression, thus representing an interesting therapeutic target.

DNA damage accumulation, defective chromatin organization and deficient DNA repair capacity in patients with rheumatoid arthritis.

We investigated the DNA damage response and repair network in 18 patients with active rheumatoid arthritis and tested the hypothesis that treatment influences this network. A 3-fold increase of endogenous DNA damage (single- and double-strand breaks) was detected in patient-derived peripheral blood mononuclear cells than controls (alkaline comet assay; mean ±â€¯SD Olive Tail Moment of 11.8 ±â€¯7.3 versus 4.3 ±â€¯2.2, p < .001). Patients exhibited significantly higher formation of DNA damage (oxidative stress and abasic sites), deficient global genome repair and more condensed chromatin structure than controls. Twelve weeks following treatment, chromatin structure loosened, global genome repair capacity was restored, oxidative stress and abasic sites decreased and levels of endogenous DNA damage reached control values in all 8 patients examined. We conclude that deregulated chromatin organization, deficient DNA repair capacity and augmented formation of DNA damage, which are reversible after treatment, contribute to the accumulation of endogenous DNA damage in rheumatoid arthritis.

DNA Damage Response and Oxidative Stress in Systemic Autoimmunity.

The DNA damage response and repair (DDR/R) network, a sum of hierarchically structured signaling pathways that recognize and repair DNA damage, and the immune response to endogenous and/or exogenous threats, act synergistically to enhance cellular defense. On the other hand, a deregulated interplay between these systems underlines inflammatory diseases including malignancies and chronic systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Patients with these diseases are characterized by aberrant immune response to self-antigens with widespread production of autoantibodies and multiple-tissue injury, as well as by the presence of increased oxidative stress. Recent data demonstrate accumulation of endogenous DNA damage in peripheral blood mononuclear cells from these patients, which is related to (a) augmented DNA damage formation, at least partly due to the induction of oxidative stress, and (b) epigenetically regulated functional abnormalities of fundamental DNA repair mechanisms. Because endogenous DNA damage accumulation has serious consequences for cellular health, including genomic instability and enhancement of an aberrant immune response, these results can be exploited for understanding pathogenesis and progression of systemic autoimmune diseases, as well as for the development of new treatments.

Cadherin-11 as a therapeutic target in chronic, inflammatory rheumatic diseases.

Cadherin-11 has been identified as a key regulator of synovial architecture mediating contact between Fibroblast-like Synoviocytes and organization in the lining layer. A central role for cadherin-11 has also been suggested in the formation of the rheumatoid pannus. Therapeutic targeting of cadherin-11 results in amelioration of autoimmune experimental arthritis, as well as of experimental fibrosis. In addition, cadherin-11 expression is upregulated in the synovium of patients with chronic inflammatory arthritis, whereas detection of cadherin-11 mRNA transcripts in the peripheral blood has been associated with more severe disease phenotypes in two prototypic conditions of chronic joint inflammation and fibrosis, namely, rheumatoid arthritis and systemic sclerosis, respectively. Currently, a monoclonal antibody against cadherin-11 is in early phases of clinical trials in patients with rheumatoid arthritis. Herein, we review the current knowledge regarding the potential role of cadherin-11 in pathogenesis, as well as a biomarker and therapeutic target in chronic inflammatory rheumatic diseases.

Increased frequency of the PTPN22W* variant in primary Sjogren's Syndrome: Association with low type I IFN scores.

Recent data suggest the association of the autoimmune gene variant PTPN22W* with dampened type I Interferon (IFN) responses, seen in a subset of primary Sjogren's Syndrome (pSS) patients. We sought to explore the potential contribution of PTPN22W* in this setting. PTPN22W* was identified in DNA samples derived from 352 pSS patients and 482 healthy controls (HC). Type I IFN score was determined in available peripheral blood cDNA of 164 pSS patients by Real-Time PCR. Increased prevalence of the PTPN22W* variant was detected in pSS patients compared to HC [9.7% vs 5.0%, p-value: 0.02]. Of interest, only the low but not the high type I IFN pSS subgroup displayed higher PTPN22W* rates compared to HC (12.2% vs 5.0%, p-value: 0.03). PTPN22W* risk variant increases susceptibility for pSS, particularly the low type I IFN subset implying the presence of distinct genetic backgrounds among low and high type I IFN autoimmune subgroups.

The causative agents in infective endocarditis: a systematic review comprising 33,214 cases.

Infective endocarditis (IE) incidence remains high with considerable fatality rates; guidelines for prophylaxis against IE are currently under review in some settings which highlights the importance of maintaining up-to-date epidemiological estimates about the most common microbial causes. The objective of this systematic review, following PRISMA guidelines, was to identify the most common microbial causes of IE in recent years. Medline was searched from January 1, 2003 to March 31, 2013 for all articles containing the term "infective endocarditis". All relevant studies reporting diagnostic results were included. Special patient subpopulations were assessed separately. A total of 105 studies were included, from 36 countries, with available data on a total of 33,214 cases. Staphylococcus aureus was found to be the most common microorganism, being the most frequent in 54.3 % of studies (N = 57) (and in 55.4 % of studies using Duke's criteria for diagnosis [N = 51]). Viridans group streptococci (VGS), coagulase-negative staphylococci (CoNS), Enterococcus spp and Streptococcus bovis were among the most common causes. S. aureus was the most common pathogen in almost all population subgroups; however, this was not the case in patients with implantable devices, prosthetic valves, or immunocompromised non-HIV, as well as in the sub-group from Asia, emphasizing that a global one-size-fits-all approach to the management of suspected IE is not appropriate. This review provides an evidence-based map of the most common causative agents of IE, highlighting S. aureus as the leading cause in the 21st century. The changing epidemiology of IE in some patient sub-groups in the last decade and the very high number of microbiologically undiagnosed cases (26.6 %) suggest the need to revisit IE prophylaxis and diagnostic strategies.

Diurnal production of cortisol and prediction of treatment response in rheumatoid arthritis: a 6-month, real-life prospective cohort study.

OBJECTIVES: A reduced adrenal reserve-associated cortisol production relative to the enhanced needs of chronic inflammation (disproportion principle) has been observed in rheumatoid arthritis (RA). We examined the possible clinical value of diurnal cortisol measurements in active RA on treatment response prediction. METHODS: Diurnal cortisol production (measured at: 08-12:00/18:00-22:00) was assessed by electrochemiluminescence immunoassay in 28 consecutive patients with moderately/highly active RA, as well as 3 and 6 months after treatment initiation or/escalation. Twenty-eight COVID-19 patients and 28 age-matched healthy individuals (HC) served as controls. RESULTS: Saliva diurnal cortisol production in patients with RA was similar to that of HC, despite 12-fold higher serum C reactive protein (CRP) levels, and lower than COVID-19 patients (area under the curve: RA: 87.0±37.6 vs COVID-19: 146.7±14.3, p<0.001), having similarly high CRP. Moreover, a disturbed circadian cortisol rhythm at baseline was evident in 15 of 28 of patients with RA vs 4 of 28 and 20 of 28 of HC and COVID-19 patients, respectively. Treatment-induced minimal disease activity (MDA) at 6 months was achieved by 16 of 28 patients. Despite comparable demographics and clinical characteristics at baseline, non-MDA patients had lower baseline morning cortisol and higher adrenocorticotropic hormone (ACTH) levels compared with patients on MDA (cortisol: 10.9±4.0 vs 18.4±8.2 nmol/L, respectively, p=0.005 and ACTH: 4.8±3.3 vs 2.4±0.4 pmol/L, respectively, p=0.047). Baseline morning cortisol <13.9 nmol/L predicted non-MDA at 6 months (75% sensitivity, 92% specificity, p=0.006). Prospective measurements revealed that individualised diurnal cortisol production remained largely unchanged from baseline to 3 and 6 months. CONCLUSIONS: An impaired adrenal reserve is present in patients with RA. Further studies to confirm that assessment of diurnal cortisol production may be useful in guiding treatment decisions and/or predicting treatment response in RA are warranted. TRIAL REGISTRATION NUMBER: NCT05671627.

Geriatric Frailty Is Associated With Oxidative Stress, Accumulation, and Defective Repair of DNA Double-Strand Breaks Independently of Age and Comorbidities.

Defects in the DNA damage response and repair (DDR/R) network accumulate during the aging process. Physical frailty, a state of reduced physiological function and decreased resilience to biological stressors, is also exacerbated by aging, but its link with DDR/R aberrations beyond the effect of age and comorbidities is unclear. Fifty-three community-dwelling older adults, aged 65-102 years, who underwent frailty classification according to the Rockwood Clinical Frailty Scale (CFS), and 51 healthy adults younger than 45 years were examined in parallel. The following DDR/R parameters were determined in their peripheral blood mononuclear cells (PBMCs): (a) oxidative stress and abasic (apurinic/apyrimidinic; AP) sites, (b) endogenous DNA damage (alkaline comet assay olive tail moment [OTM] indicative of DNA single-strand breaks [SSBs] and double-strand breaks [DSBs] and γH2AX levels by immunofluorescence [DSBs only]), (c) capacity of the 2 main DNA repair mechanisms (DSB repair and nucleotide excision repair). Older individual-derived PBMCs displayed reduced-to-oxidized glutathione ratios indicative of increased levels of oxidative stress and increased AP sites, as well as increased accumulation of endogenous DNA damage (OTM and γH2AX) and defective DSB-repair capacity, compared with younger controls. These DDR/R aberrations were more pronounced in frail versus nonfrail older adults. Notably, oxidative stress, AP sites, DSBs, and DSB-repair capacity were associated with individual CFS levels after adjusting for chronological age, sex, Charlson Comorbidity Index, and polypharmacy. Geriatric frailty is independently associated with increased DNA damage formation and reduced DSB-R capacity, supporting further research into these measures as potential frailty biomarkers.

Targeting senescence and inflammation in chronic destructive TNF-driven joint pathology.

We had shown that administration of the senolytic Dasatinib abolishes arthritis in the human TNF transgenic mouse model of chronic destructive arthritis when given in combination with a sub-therapeutic dose of the anti-TNF mAb Infliximab (1 mg/kg). Herein, we found that while the number of senescent chondrocytes (GL13+/Ki67-), assessed according to guideline algorithmic approaches, was not affected by either Dasatinib or sub-therapeutic Infliximab monotherapies, their combination reduced senescent chondrocytes by 50 %, which was comparable to levels observed with therapeutic Infliximab monotherapy (10 mg/kg). This combination therapy also reduced the expression of multiple factors of senescence-associated secretory phenotype in arthritic joints. Studies to elucidate the interplay of inflammation and senescence may help in optimizing treatment strategies also for age-related pathologies characterized by chronic low-grade joint inflammation.