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While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either BRCA1 or BRCA2. In silico SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing. We identified five pathogenic variants in our sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, we found a pathogenic FANCM variant (R1931*) which has been recently implicated in familial breast cancer risk. Numerous rare and predicted to be damaging variants of unknown significance were detected in genes on current commercial testing panels, most prominently in ATM (n = 6) and PALB2 (n = 5). The BRCA2 variant p.K3326*, resulting in a 93 amino acid truncation, was overrepresented in our sample (odds ratio = 4.95, p = 0.01) and coexisted in the germline of these women with other deleterious variants, suggesting a possible role as a modifier of genetic penetrance. Furthermore, we detected loss of function variants in non-panel genes involved in OVCA relevant pathways; DNA repair and cell cycle control, including CHEK1, TP53I3, REC8, HMMR, RAD52, RAD1, POLK, POLQ, and MCM4. In summary, our study implicates novel risk loci as well as highlights the clinical utility for retesting BRCA1/2 negative OVCA patients by genomic sequencing and analysis of genes in relevant pathways.

Lately, vitamin D has been linked with metabolic and immunological processes, which established its role as an essential component of human health preservation. Vitamin D has been defined as natural immune modulators, and upon activation of its receptors (VDRs), it regulates calcium metabolism, cellular growth, proliferation and apoptosis, and other immunological functions. Epidemiological data underline a strong correlation between poor vitamin D status and higher risk for chronic inflammatory illnesses of various etiologies, including autoimmune diseases. Epidemiological, genetic, and basic studies indicated a potential role of vitamin D in the pathogenesis of certain systemic and organ-specific autoimmune diseases. These studies demonstrate correlation between low vitamin D and prevalence of diseases. In addition, VDRs’ polymorphisms observed in some of these autoimmune diseases may further support a plausible pathogenic link. Notably, for some autoimmune disease, no correlation with vitamin D levels could be confirmed. Thus, in the current review we present the body of evidence regarding the plausible roles of vitamin D and VDR’s polymorphism in the pathogenesis of autoimmunity. We summarize the data regarding systemic (i.e., systemic lupus erythematosus, rheumatoid arthritis, etc.) and organ-specific (i.e., multiple sclerosis, diabetes mellitus, primary biliary cirrhosis, etc.) autoimmune diseases, in which low level of vitamin D was found comparing to healthy subjects. In addition, we discuss the correlations between vitamin D levels and clinical manifestations and/or activity of diseases. In this context, we address the rational for vitamin D supplementation in patients suffering from autoimmune diseases. Further studies addressing the mechanisms by which vitamin D affects autoimmunity and the proper supplementation required are needed.

Vaccination prevents infectious diseases by inducing/enhancing protective immunity, potentially translating into a lower rate of invasive infections and hospital admissions. Patients with autoimmune inflammatory rheumatic diseases (AIIRD), and particularly systemic lupus erythematosus (SLE) are at increased risk of vaccine-preventable infections, attributed to the underlying autoimmune disease, additional comorbidities and immunosuppressive therapies. Yet, this population of patients is generally sub-optimally immunized due to concerns about efficacy, immunogenicity, and safety of vaccines shared both by patients and their treating physicians. In this regard, vaccination may be less efficacious in subgroups of patients with AIIRD, such as SLE and could potentially be associated with temporal (usually mild) exacerbation of the underlying autoimmune disease. Immunization protocols which take into consideration the AIIRD itself, timing of immunization and the number of vaccines doses may enable safe and efficacious immunization.1–6In recent years updated recommendations for immunization of AIIRD patients were issued. These recommendations comprise several overarching principles as: annual vaccination status assessment, shared decision-making, timing of vaccination (e.g. favoring vaccination during quiescent disease, preferably prior to initiation of immunosuppression), and avoidance of some live-attenuated vaccines both for patients and their household members. Additionally, new data suggest that increasing the doses of vaccine (e.g. anti-COVID vaccines) may overcome lower immunogenicity among SLE and other AIIRD patients.Herein, an up-to-date guidance for immunization of SLE patients in 2023 will be reviewed.Furer V, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2020 Jan;79(1):39–52. doi: 10.1136/annrheumdis-2019-215882.Furer V, et al. Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): a systemic literature review informing the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD. RMD Open. 2019 Sep 19;5(2):e001041. doi: 10.1136/rmdopen-2019-001041.Furer V, et al. Point of view on the vaccination against COVID-19 in patients with autoimmune inflammatory rheumatic diseases. RMD Open. 2021 Feb;7(1):e001594. doi: 10.1136/rmdopen-2021-001594.Scanzi F, et al. Are the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and the undifferentiated connective tissue disease (UCTD) related to each other? A case-control study of environmental exposures. Immunol Res. 2017 Feb;65(1):150–156. doi: 10.1007/s12026-017-8912-4.Tunitsky-Lifshitz Y, et al. The third dose of BNT162b2 COVID-19 vaccine is efficacious and safe for systemic lupus erythematosus patients receiving belimumab. Lupus. 2023 Apr;32(5):675–679. doi: 10.1177/09612033231164262.Kharouf F, et al. A deep look into the storm: Israeli multi-center experience of coronavirus disease 2019 (COVID-19) in patients with autoimmune inflammatory rheumatic diseases before and after vaccinations. Front Immunol. 2023 Mar 13;14:1064839. doi: 10.3389/fimmu.2023.1064839Learning ObjectivesDescribe immunization protocols that may enable safe and efficacious immunizationDiscuss updated recommendations for immunization of AIIRD patients, in particular those with SLEDiscuss plausible options to lower immunogenicity among SLE patients

In this article, the authors review the global burden of autoimmune rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome and ankylosing spondylitis, across regions and ethnic populations, and discuss how evidence from geoepidemiological studies could provide insights into the genetic and environmental determinants of these conditions. The accumulative global burden of autoimmune and inflammatory rheumatic diseases is substantial. Studying the distribution of these conditions across various global regions and ethnic groups by means of geoepidemiology might readily provide epidemiological data and also advance our understanding of their genetic and environmental underpinnings. In order to depict the geoepidemiology of autoimmune and inflammatory rheumatic diseases, namely rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, ankylosing spondylitis and Sjögren's syndrome, we present a comprehensive collection of epidemiological reports from various world regions, including the prevalence of each of these conditions. The accumulated data show that the reviewed rheumatic diseases are global phenomena, and, with some variance, seem to be relatively evenly distributed. This finding is in contrast with the obviously uneven distribution of some major nonrheumatic autoimmune conditions. In addition, geoepidemiology demonstrates that ethnogenetic susceptibility interacts with lifestyle and environmental factors, which include socioeconomic status, infectious agents (triggering or protective agents), environmental pollutants, and vitamin D (dependent on sunlight exposure), in determining the risk of developing rheumatic autoimmunity. Key Points Geoepidemiology provides a comprehensible picture of the burden of autoimmune and inflammatory rheumatic diseases across various regions and ethnicities, and helps to unravel potential causative factors The global distribution of rheumatic autoimmune diseases, with some variance, seems to be ubiquitous, although prominent gradients are present in the distribution of some major nonrheumatic autoimmune conditions Our knowledge of the genetics of rheumatic autoimmunity is supported and advanced by geoepidemiology The risk of developing these illnesses is also affected by environmental factors, such as socioeconomic status and exposure to infectious agents (protective or pathogenic), ultraviolet radiation and pollution

Approximately 25% of all cases of ovarian cancer (OVCA) cases are associated with inherited risk. However, accurate risk assessment is limited by the presence of variants of unknown significance (VUS). Previously, we performed whole-exome sequencing on 48 OVCA patients with familial predisposition, yet negative for pathogenic BRCA1/2 mutations. In our cohort, we uncovered thirteen truncating mutations in genes associated with apoptosis (~35% of our patient cohort). The TP53I3 p.S252X premature stop gain was identified in two unrelated patients. TP53I3 is transcriptionally activated by p53 and believed to play a role in DNA damage response and reactive oxygen species-induced apoptosis. In addition, nonsense variants in apoptosis-related genes TP53AIP1, BCLAF1, and PIK3C2G were identified in our cohort; highlighting the potential relevance of genes involved in apoptotic processes to hereditary cancer. In the current study, we employed functional assays and demonstrated that cells expressing TP53I3 p.S252X displayed decreased homologous recombination repair efficiency and increased sensitivity to chemotherapeutic drugs bleomycin, mitomycin c, and etoposide. In addition, in the presence of oxidative stress from hydrogen peroxide or etoposide we observed a reduction in the formation of reactive oxygen species, an important precursor to apoptosis with this variant. Our findings suggest that the combination of in silico and wet laboratory approaches can better evaluate VUSs, establish novel germline predisposition genetic loci, and improve individual cancer risk estimates.

Bispecific antibodies (BsAbs) are regarded as promising therapeutic agents due to their ability to simultaneously bind two different antigens. Several bispecific modalities have been developed, but their utility is limited due to problems with stability and manufacturing complexity. Here we report a versatile technology, based on a scaffold antibody and pharmacophore peptide heterodimers, that enables rapid generation and chemical optimization of bispecific antibodies, which are termed bispecific CovX-Bodies. Two different peptides are joined together using a branched azetidinone linker and fused to the scaffold antibody under mild conditions in a site-specific manner. Whereas the pharmacophores are responsible for functional activities, the antibody scaffold imparts long half-life and Ig-like distribution. The pharmacophores can be chemically optimized or replaced with other pharmacophores to generate optimized or unique bispecific antibodies. As a prototype, we developed a bispecific antibody that binds both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) simultaneously, inhibits their function, shows efficacy in tumor xenograft studies, and greatly augments the antitumor effects of standard chemotherapy. This unique antiangiogenic bispecific antibody is in phase-1 clinical trials.

Objective In the phase 3 head‐to‐head MANDARA study (NCT04157348), benralizumab demonstrated noninferiority to mepolizumab in inducing remission (defined as Birmingham Vasculitis Activity Score [BVAS] of 0 and oral glucocorticoid [OGC] dosage ≤4 mg/day at weeks 36 and 48) in patients with eosinophilic granulomatosis with polyangiitis (EGPA). This analysis investigated a more stringent definition of remission that included discontinuation of OGCs and being relapse‐free. Methods Patients aged ≥18 years with documented relapsing or refractory EGPA receiving OGCs at ≥7.5 mg/day with or without immunosuppressive therapy for ≥4 weeks before enrollment were randomized (1:1) to benralizumab at 30 mg or mepolizumab at 300 mg subcutaneously every 4 weeks for 52 weeks. The proportion of patients achieving remission off OGCs, defined as BVAS of 0, OGC dose of 0 mg/day (at weeks 36 and 48) and no relapses during the double‐masked period, was assessed. Results Patients (n = 140) were randomized to benralizumab (n = 70) or mepolizumab (n = 70). The adjusted percentage of patients with remission off OGCs was 23.5% (n = 16) with benralizumab versus 11.1% (n = 8) with mepolizumab (difference 12.47 [95% confidence interval 0.46–24.48], P = 0.042). Of those who achieved remission off OGCs, 100% of benralizumab‐treated patients and 98.6% of mepolizumab‐treated patients achieved remission within the first 36 weeks of treatment. Conclusion The administration of anti–interleukin‐5/receptor (IL‐5/R) therapies, benralizumab and mepolizumab, enable discontinuation of OGCs in some patients with EGPA, while avoiding relapses. These findings suggest that adding anti‐IL‐5/R therapy to standard primary treatment for patients with EGPA may improve response.

In the last few months the world has witnessed a global pandemic due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19). Obviously, this pandemic affected individuals differently, with a significant impact on populations considered to be at high-risk. One such population, was assumed to be patients with primary genetic defect involving components or pathways of the immune system. While human immunity against COVID-19 is not fully understood, it is, so far, well documented, that both adaptive and innate cells have a critical role in protection against SARS-CoV-2. Here, we aimed to summarize the clinical and laboratory data on primary immunodeficiency (PID) patients in Israel, who were tested positive for SARS-CoV-2, in order to estimate the impact of COVID-19 on such patients. Data was collected from mid-February to end-September. During this time Israel experienced two “waves” of COVID-19 diseases; the first, from mid-February to mid-May and the second from mid-June and still ongoing at the end of data collection. A total of 20 PID patients, aged 4 months to 60 years, were tested positive for SARS-CoV-2, all but one, were detected during the second wave. Fourteen of the patients were on routine monthly IVIG replacement therapy at the time of virus detection. None of the patients displayed severe illness and none required hospitalization; moreover, 7/20 patients were completely asymptomatic. Possible explanations for the minimal clinical impact of COVID-19 pandemic observed in our PID patients include high level of awareness, extra-precautions, and even self-isolation. It is also possible that only specific immune pathways (e.g. type I interferon signaling), may increase the risk for a more severe course of disease and these are not affected in many of the PID patients. In some cases, lack of an immune response actually may be a protective measure against the development of COVID-19 sequelae.

Background Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). Methods Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). Results Sixty-one individuals were randomised (HVs: placebo, n  = 12; volixibat, n  = 38; T2DM: placebo, n  = 3; volixibat, n  = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6–3.2 times higher in HVs (643.73–1239.3 μmol/24 h) and ~8 times higher in T2DM (1786.0 μmol/24 h) than with placebo (HVs: 386.93 μmol/24 h; T2DM: 220.00 μmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3–5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. Conclusions Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).

Antiphospholipid syndrome (APS) presents with various clinical features and some patients exhibit progressive, refractory disease that does not meet the catastrophic APS (cAPS) criteria. This study describes a new subcategory of APS patients, \"Terrible APS\" (TrAPS), characterized by recurrent thrombosis despite optimal anticoagulation, often requiring immunomodulation or surgery. We analyzed 306 primary APS patients, excluding those with obstetric, non-criteria APS, or cAPS. TrAPS was defined as >2 breakthrough thrombotic events despite anticoagulation (without provocation or cardiovascular risk) or the need for >1 immunomodulatory or surgical intervention. Among 209 patients with thrombotic primary APS, 27 (12.7%) met the TrAPS criteria. These patients had higher rates of venous thrombosis, microvascular involvement, heart valve disease, thrombocytopenia, and triple-positive antiphospholipid antibodies. TrAPS was associated with (18.5% . 5.1%) and anticoagulant resistance (81.4% with breakthrough events). Based on multivariate analysis, we identified four key predictors that formed the basis of the TrAPScore: severe thrombocytopenia (<50,000, 4 points), heart valve involvement (4 points), microvascular manifestations (3 points), and triple-positive serology (2 points). A TrAPScore >6 had a positive predictive value (PPV) of 78%-82.5%, while a score <4 had a negative predictive value (NPV) of 96.9% for TrAPS diagnosis. We herein individualized a particularly refractory APS subcategory, TrAPS. The TrAPScore incorporates severe thrombocytopenia, heart valve disease, microvascular manifestations, and triple-positive serology. A TrAPS score >6 predicted a high likelihood of severe, refractory disease while effectively excluding TrAPS.