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Molecular mimicry is one of the leading mechanisms by which infectious agents can induce autoimmunity. Whether a similar mechanism triggers an antitumor immune response is unexplored, and the role of antiviral T cells infiltrating the tumor has remained anecdotal. To address these questions, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we demonstrated that, in mice, preexisting immunity toward specific viral epitopes enhanced the efficacy of cancer immunotherapy via molecular mimicry in different settings. To understand whether this mechanism could partly explain immunotherapy responsiveness in humans, we analyzed a cohort of patients with melanoma undergoing anti-PD1 treatment who had a high IgG titer for cytomegalovirus (CMV). In this cohort of patients, we showed that high levels of CMV-specific antibodies were associated with prolonged progression-free survival and found that, in some cases, peripheral blood mononuclear cells (PBMC) could cross-react with both melanoma and CMV homologous peptides. Finally, T-cell receptor sequencing revealed expansion of the same CD8þ T-cell clones when PBMCs were expanded with tumor or homologous viral peptides. In conclusion, we have demonstrated that preexisting immunity and molecular mimicry could influence the response to immunotherapies. In addition, we have developed a free online tool that can identify tumor antigens and neoantigens highly similar to pathogen antigens to exploit molecular mimicry and cross-reactive T cells in cancer vaccine development.

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF, For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidak p ≤ 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition. publishedVersion

Source at https://doi.org/10.18632/aging.101900. Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life. We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries. The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect. Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.

BACKGROUND: Social inequalities in the prevalence of childhood overweight and obesity are well-established, but less is known about when the social gradient first emerges and how it evolves across childhood and adolescence.OBJECTIVE: This study examines maternal education differentials in children's body mass trajectories in infancy, childhood and adolescence using data from four contemporary European child cohorts.METHODS: Prospective data on children's body mass index (BMI) were obtained from four cohort studies-Generation XXI (G21-Portugal), Growing Up in Ireland (GUI) infant and child cohorts, and the Millennium Cohort Study (MCS-UK)-involving a total sample of 41,399 children and 120,140 observations. Children's BMI trajectories were modelled by maternal education level using mixed-effect models.RESULTS: Maternal educational inequalities in children's BMI were evident as early as three years of age. Children from lower maternal educational backgrounds were characterised by accelerated BMI growth, and the extent of the disparity was such that boys from primary-educated backgrounds measured 0.42 kg/m2 (95% CI 0.24, 0.60) heavier at 7 years of age in G21, 0.90 kg/m2 (95% CI 0.60, 1.19) heavier at 13 years of age in GUI and 0.75 kg/m2 (95% CI 0.52, 0.97) heavier in MCS at 14 years of age. The corresponding figures for girls were 0.71 kg/m2 (95% CI 0.50, 0.91), 1.31 kg/m2 (95% CI 1.00, 1.62) and 0.76 kg/m2 (95% CI 0.53, 1.00) in G21, GUI and MCS, respectively.CONCLUSIONS: Maternal education is a strong predictor of BMI across European nations. Socio-economic differentials emerge early and widen across childhood, highlighting the need for early intervention.

Background Two different polymorphisms (TPH2 G-703T and 5-HTTLPR) involved in the serotonergic pathway have been reported to play a role, both alone and in interaction with the environment, in early and adult emotion regulation. As most of these studies are cross-sectional, we know little about the impact of these polymorphisms over time, particularly during adolescence. Methods Because we were interested in the effects of these polymorphisms and environment (i.e., family structure) at different time-points on the emotional dysregulation profile, we performed a path analysis model in a general adolescent population sample of a five-year follow-up study. Results We found a high stability of Dysregulation Profile problems independently from the examined allelic variants. We also found that early family structure directly influences the levels of dysregulation problems in early adolescence, both alone and in interaction with TPH2, suggesting the presence of a gene-environment interaction effect. Furthermore, we found that in adolescents homozygous for the TPH2 G allele, the effect of the early family structure remains active during late adolescence, albeit mediated by earlier emotional problems. Limitations The high attrition rate, the use of only one source on behavioral problems of adolescents, and the focus on a single polymorphism in the investigated genes could limit the generalizability of the present results. Conclusions These results suggest that early family structure could play a significant role in the development and maintenance of emotional and behavioral problems not only in early adolescence but also in late-adolescence, although this effect was mediated and moderated by behavioral and genetic variables.

Sleep disturbance is an important contributor to poor quality of life in rheumatic disorders. This study aims to test whether clinical, autoimmune and psychological factors are associated with sleep disturbance in systemic sclerosis (SSc) compared to rheumatoid arthritis (RA) patients and controls.101 female subjects (SSc=33, RA=34, healthy controls=34) participated in this observational, cross-sectional, parallel group study. Sleep disturbance was assessed with the Pittsburgh Sleep Quality Index (PSQI). Other assessments included the visual analogue scale (VAS) for pain, 36-item Short-Form Health Survey (SF-36), Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI). Clinical parameters, therapeutic regimen, and serologic status were recorded.In SSc patients, PSQI scores were higher than in RA patients and controls. Linear regression analysis showed that in SSc patients PSQI scores was associated with BDI, disease duration, modified Rodnan skin score and VAS, while DAS28 and BDI were associated with PSQI scores in RA patients. Anti-Scl70 and ANA positive SSc patients showed higher PSQI scores compared to those ANA positive only, while no differences were observed in RA patients classified according to rheumatoid factor positivity. SSc patients treated with immunosuppressants had lower PSQI scores compared to those not on therapy, whereas only corticosteroid treatment was significantly associated with higher PSQI scores in RA patients. RA patients with disease activity higher than moderate (DAS28≥3.2) had higher PSQI scores than those with lower than moderate (DAS283.2).Longitudinal studies are needed to identify disease-specific patterns associated with sleep disturbances and the influence on sleep function induced by immunosuppressive therapy among rheumatic patients.

From August 2000 through January 2001, a large epidemic of Ebola hemorrhagic fever occurred in Uganda, with 425 cases and 224 deaths. Starting from three laboratory-confirmed cases, we traced the chains of transmission for three generations, until we reached the primary case-patients (i.e., persons with an unidentified source of infection). We then prospectively identified the other contacts in whom the disease had developed. To identify the risk factors associated with transmission, we interviewed both healthy and ill contacts (or their proxies) who had been reported by the case-patients (or their proxies) and who met the criteria set for contact tracing during surveillance. The patterns of exposure of 24 case-patients and 65 healthy contacts were defined, and crude and adjusted prevalence proportion ratios (PPR) were estimated for different types of exposure. Contact with the patient’s body fluids (PPR = 4.61%, 95% confidence interval 1.73 to 12.29) was the strongest risk factor, although transmission through fomites also seems possible.

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95 confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95 CI: 0.95-0.99), rs10719 (OR 0.97; 95 Cl: 0.94-0.99), rs4687554 (OR 0.97; 95 CI: 0.95-0.99, and rs3134615 (OR 1.03; 95 CI: 1.01 -1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects. This is an open-access article free of all copyright.

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign’. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS foetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus., peer-reviewed

Hernia repair is the most common surgical procedure in general surgery in Italy and in the Lombardy region. In the last decade, the use of mesh, the concept of a tension-free technique, and the postoperative rate of recurrences after Bassini or Shouldice operations have completely changed the surgical approach to hernia repair. For this reason, we sent a questionnaire to 148 surgical departments in the Lombardy region to investigate about total hernia operations performed in 2000 in Lombardy, the surgical approach, the surgical techniques used, the type of anesthesia and the hospital stay. One hundred five out of 148 surgical departments returned the questionnaire, and we collected information on a total of 16,935 surgical operations for hernia: 16,494 were performed using tension-free techniques. The inguinal anterior approach is the one of choice for primary and recurrent inguinal hernia, whereas the open preperitoneal and laparoscopic approaches are limited to bilateral and recurrent hernias. The majority of cases were treated under locoregional anesthesia and with a hospital stay of two nights.

In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod. METHODS: Patients randomly assigned to receive 0.5 mg or 1.25 mg daily oral fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 μg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0.5 mg or 1.25 mg fingolimod. The initial randomisation and dose of fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834. FINDINGS: 1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous fingolimod showed persistent benefits in ARR (0.5 mg fingolimod [n=356], 0.12 [95% CI 0.08-0.17] in months 0-12 vs 0.11 [0.08-0.16] in months 13-24; 1.25 mg fingolimod [n=330], 0.15 [0.10-0.21] vs 0.11 [0.08-0.16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to fingolimod compared with the previous 12 months (interferon beta-1a to 0.5 mg fingolimod [n=167], 0.31 [95% CI 0.22-0.43] in months 0-12 vs 0.22 [0.15-0.31], in months 13-24 p=0.049; interferon beta-1a to 1.25 mg fingolimod [n=174], 0.29 [0.20-0.40] vs 0.18 [0.12-0.27], p=0.024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p

During the year 1993 a series of surveys aimed to estimate the immunization coverage against measles and pertussis have been carried out in seven Italian regions and two large towns (Milan and Naples). Mothers of children aged between 12 and 23 months, randomly selected from the list of newborns, by using the EPI cluster sampling, have been interviewed in order to determine the reasons for absent or incomplete vaccinations. The observed coverage for pertussis ranges between 8% in the Molise region and 71% in the town of Milan; coverage for measles ranges between 9% in the town of Naples and 52% in the region Lombardy. The most commonly reported reason for not-vaccinating for pertussis has been the negative advise given by the caring physician. Immunization against measles has often not been administered because of relative contraindications and the negative advise by the physicians. The coverage for the two non-compulsory vaccinations are low compared to compulsory vaccinations and to the immunization level reported for most European countries, pointing out that further health education is needed for improving the up-take of such voluntary vaccinations.

Between 1980 and 1982 in the Campania region of Italy, several cases of encephalopathy in children who had only a week previously been given diphtheria-tetanus immunizations were reported to the Italian Ministry of Health in Rome. A case-control study was therefore set up to test the association between the syndrome and immunization. For this purpose, cases were defined as children between 3 and 48 months who had been admitted to an intensive care unit with symptoms such as convulsions of unknown origin, Reye's syndrome, or death from unknown causes. The fatality rate from encephalopathy among the immunized children in the study was 25 out of 29 (86%). In Campania (population 5.4 million), the annual incidence of encephalopathy associated with diphtheria-tetanus immunization was estimated to be 2.9 per 100 000 doses of the vaccine.

To investigate potential risk factors for surgical wound infections in clean surgery.Multicenter prospective study in eight general surgical wards and one thoracic surgical ward.All patients undergoing clean operations in the nine wards were included in the study. The following data were collected for each study participant: demographic characteristics, underlying disease, predisposing factors, type of surgery, length of operation, preoperative shaving, type and duration of surgical drains, and length of hospital stay. After surgery, patients were visited daily by an intern surgeon in order to detect infections. Infections occurring after discharge were not actively surveyed. A multiple logistic regression was performed to obtain an adjusted estimate of the odds ratios and to identify which factors were independently associated with surgical infection.2,262 patients were included in the study: eighty three patients (3.7%) developed a surgical infection. The highest infection rates were observed following vascular surgery, thoracic surgery and herniorraphy. Seven factors appeared to be significantly and independently associated with an increased risk of SWIs in a logistic regression model; age greater than 85 years, obesity, patients undergoing high risk operations or more than one operation during stay, length of operation greater than 120, preoperative shaving, open surgical drains lasting more than three days.The high incidence of infection observed in our study population indicates potential problems in quality of care. In order to prevent SWIs in patients undergoing clean operations, more efforts should be placed on the prevention of the risk associated with two modifiable risk factors, that is preoperative shaving and use of open surgical drains.

To evaluate the changes in patient care practices following an intervention program in general surgery and their impact on surgical wound infections (SWI) associated with clean operations.A "before-after" study design was used. Active surveillance was implemented in each ward; the intervention consisted of an educational program, whose effectiveness was evaluated comparing SWI rates before and after its implementation.A total of 799 patients undergoing clean operations from three general surgical wards were included in the study: 606 before and 193 after the intervention program. The observed reduction in the SWI incidence was 79.2%; the most striking change in patient care practices observed after the intervention was the substitution of open surgical drains with closed drains. High risk operations (RR 8.4), length of operation greater than 2 hours (RR 11.2), and open surgical drains lasting more than three days (RR 5.1) significantly increased the risk of SWIs in the preintervention phase, according to the logistic regression analysis. Of the observed pre-intervention SWIs, 46.2% was attributable to exposure to open drains.Many postoperative infections can be prevented in environments where patient care practices fall well below the accepted standards. More efforts should be placed on the prevention of the risk associated with modifiable risk factors, such as open surgical drains.

This review describes the HIV prevention strategies adopted since 1990 by the Italian Ministry of Health and Ministry of Education, coordinated by the National Health Institute, for use in Italian schools. It sets out reasons for believing that action in schools is essential in containing the spread of the HIV epidemic and presents teaching materials prepared for school use. An analysis is made of the IV national HIV information campaign, in which the Ministry of Health trained 4,000 middle and senior schools principals. The prospects for continuing the work with these 4,000 principals in the V information campaign, are also reported.

Since 1982, 2911 adult AIDS cases have been officially reported in Italy up to December 31, 1988. The clinical presentation of all cases, reported to the Istituto Superiore di Sanità, Rome, and contained into the National AIDS Register, has been analyzed, with particular attention to opportunistic infections. 168 cases (mainly homosexual men) were found exclusively affected at diagnosis by Kaposi's Sarcoma (KS), while the other 2743 patients were affected by opportunistic infections and/or other pathologies. At diagnosis, 23.5% of patients had Pneumocystis carinii pneumonia (PCP), 32% esophageal or pulmonary candidiasis, and 7% cerebral toxoplasmosis. A decrease in frequency of Cytomegalovirus (CMV) diseases has been observed, as well as an increase of HIV encephalopathy from 1982 to 1988. The clinical picture of full-blown AIDS showed stability during the whole period of observation, with slight geographical variations.

Background Socio-economic inequalities in mortality are well established, yet the contribution of intermediate risk factors that may underlie these relationships remains unclear. We evaluated the role of multiple modifiable intermediate risk factors underlying socio-economic-associated mortality and quantified the potential impact of reducing early all-cause mortality by hypothetically altering socio-economic risk factors. Methods Data were from seven cohort studies participating in the LIFEPATH Consortium (total n = 179 090). Using both socio-economic position (SEP) (based on occupation) and education, we estimated the natural direct effect on all-cause mortality and the natural indirect effect via the joint mediating role of smoking, alcohol intake, dietary patterns, physical activity, body mass index, hypertension, diabetes and coronary artery disease. Hazard ratios (HRs) were estimated, using counterfactual natural effect models under different hypothetical actions of either lower or higher SEP or education. Results Lower SEP and education were associated with an increase in all-cause mortality within an average follow-up time of 17.5 years. Mortality was reduced via modelled hypothetical actions of increasing SEP or education. Through higher education, the HR was 0.85 [95% confidence interval (CI) 0.84, 0.86] for women and 0.71 (95% CI 0.70, 0.74) for men, compared with lower education. In addition, 34% and 38% of the effect was jointly mediated for women and men, respectively. The benefits from altering SEP were slightly more modest. Conclusions These observational findings support policies to reduce mortality both through improving socio-economic circumstances and increasing education, and by altering intermediaries, such as lifestyle behaviours and morbidities.

Tumors undergo dynamic immunoediting as part of a process that balances immunologic sensing of emerging neoantigens and evasion from immune responses. Tumor-infiltrating lymphocytes (TIL) comprise heterogeneous subsets of peripheral T cells characterized by diverse functional differentiation states and dependence on T-cell receptor (TCR) specificity gained through recombination events during their development. We hypothesized that within the tumor microenvironment (TME), an antigenic milieu and immunologic interface, tumor-infiltrating peripheral T cells could reexpress key elements of the TCR recombination machinery, namely, Rag1 and Rag2 recombinases and Tdt polymerase, as a potential mechanism involved in the revision of TCR specificity. Using two syngeneic invasive breast cancer transplantable models, 4T1 and TS/A, we observed that Rag1, Rag2, and Dntt in situ mRNA expression characterized rare tumor-infiltrating T cells. In situ expression of the transcripts was increased in coisogenic Mlh1-deficient tumors, characterized by genomic overinstability, and was also modulated by PD-1 immune-checkpoint blockade. Through immunolocalization and mRNA hybridization analyses, we detected the presence of rare TDT+RAG1/2+ cells populating primary tumors and draining lymph nodes in human invasive breast cancer. Analysis of harmonized single-cell RNA-sequencing data sets of human cancers identified a very small fraction of tumor-associated T cells, characterized by the expression of recombination/revision machinery transcripts, which on pseudotemporal ordering corresponded to differentiated effector T cells. We offer thought-provoking evidence of a TIL microniche marked by rare transcripts involved in TCR shaping.

Summary Human CD4+CD25hiFOXP3+ regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell in vitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.

Background: CCAAT enhancer-binding protein epsilon (C/EBP epsilon) is a transcription factor involved in late myeloid lineage differentiation and cellular function. The only previously known disorder linked to C/EBP epsilon is autosomal recessive neutrophil-specific granule deficiency leading to severely impaired neutrophil function and early mortality. Objective: The aim of this study was to molecularly characterize the effects of C/EBP epsilon transcription factor Arg219His mutation identified in a Finnish family with previously genetically uncharacterized autoinflammatory and immunodeficiency syndrome. Methods: Genetic analysis, proteomics, genome-wide transcriptional profiling by means of RNA-sequencing, chromatin immunoprecipitation (ChIP) sequencing, and assessment of the inflammasome function of primary macrophages were performed. Results: Studies revealed a novel mechanism of genome-wide gain-of-function that dysregulated transcription of 464 genes. Mechanisms involved dysregulated noncanonical inflammasome activation caused by decreased association with transcriptional repressors, leading to increased chromatin occupancy and considerable changes in transcriptional activity, including increased expression of NLR family, pyrin domain-containing 3 protein (NLRP3) and constitutively expressed caspase-5 in macrophages. Conclusion: We describe a novel autoinflammatory disease with defective neutrophil function caused by a homozygous Arg219His mutation in the transcription factor C/EBP epsilon. Mutated C/EBPe acts as a regulator of both the inflammasome and interferome, and the Arg219His mutation causes the first human monogenic neomorphic and noncanonical inflammasomopathy/immunodeficiency. The mechanism, including widely dysregulated transcription, is likely not unique for C/EBP epsilon. Similar multiomics approaches should also be used in studying other transcription factor-associated diseases.

We report the second case, to the best of our knowledge, of a mother with Prader–Willi syndrome (PWS) who gave birth to a daughter with Angelman syndrome (AS). The menarche occurred when she was 16, and the following menstrual cycles were irregular, but she never took sexual hormone replacement therapy. At the age of 26, our patient with PWS became pregnant. The diagnosis was confirmed by molecular genetic testing that revealed a ~5.7 Mb deletion in the 15q11.1–15q13 region on the paternal allele in the mother with PWS and the maternal one in the daughter with AS, respectively. Both the mother with PWS and the daughter with AS showed peculiar clinical and genetic features of the two syndromes. Our case report reaffirms the possible fertility in PWS; therefore, it is very important to develop appropriate socio-sexual education programs and fertility assessments in order to guarantee the expression of a healthy sexuality.

BackgroundIn 2011, WHO member states signed up to the 25 × 25 initiative, a plan to cut mortality due to non-communicable diseases by 25% by 2025. However, socioeconomic factors influencing non-communicable diseases have not been included in the plan. In this study, we aimed to compare the contribution of socioeconomic status to mortality and years-of-life-lost with that of the 25 × 25 conventional risk factors.MethodsWe did a multicohort study and meta-analysis with individual-level data from 48 independent prospective cohort studies with information about socioeconomic status, indexed by occupational position, 25 × 25 risk factors (high alcohol intake, physical inactivity, current smoking, hypertension, diabetes, and obesity), and mortality, for a total population of 1 751 479 (54% women) from seven high-income WHO member countries. We estimated the association of socioeconomic status and the 25 × 25 risk factors with all-cause mortality and cause-specific mortality by calculating minimally adjusted and mutually adjusted hazard ratios [HR] and 95% CIs. We also estimated the population attributable fraction and the years of life lost due to suboptimal risk factors.FindingsDuring 26·6 million person-years at risk (mean follow-up 13·3 years [SD 6·4 years]), 310 277 participants died. HR for the 25 × 25 risk factors and mortality varied between 1·04 (95% CI 0·98–1·11) for obesity in men and 2 ·17 (2·06–2·29) for current smoking in men. Participants with low socioeconomic status had greater mortality compared with those with high socioeconomic status (HR 1·42, 95% CI 1·38–1·45 for men; 1·34, 1·28–1·39 for women); this association remained significant in mutually adjusted models that included the 25 × 25 factors (HR 1·26, 1·21–1·32, men and women combined). The population attributable fraction was highest for smoking, followed by physical inactivity then socioeconomic status. Low socioeconomic status was associated with a 2·1-year reduction in life expectancy between ages 40 and 85 years, the corresponding years-of-life-lost were 0·5 years for high alcohol intake, 0·7 years for obesity, 3·9 years for diabetes, 1·6 years for hypertension, 2·4 years for physical inactivity, and 4·8 years for current smoking.InterpretationSocioeconomic circumstances, in addition to the 25 × 25 factors, should be targeted by local and global health strategies and health risk surveillance to reduce mortality.FundingEuropean Commission, Swiss State Secretariat for Education, Swiss National Science Foundation, the Medical Research Council, NordForsk, Portuguese Foundation for Science and Technology.

Human ciliopathies are hereditary conditions caused by defects of proteins expressed at the primary cilium. Among ciliopathies, Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS) and nephronophthisis (NPH) present clinical and genetic overlap, being allelic at several loci. One of the most interesting gene is TMEM67, encoding the transmembrane protein meckelin. We performed mutation analysis of TMEM67 in 341 probands, including 265 JSRD representative of all clinical subgroups and 76 MKS fetuses. We identified 33 distinct mutations, of which 20 were novel, in 8/10 (80%) JS with liver involvement (COACH phenotype) and 12/76 (16%) MKS fetuses. No mutations were found in other JSRD subtypes, confirming the strong association between TMEM67 mutations and liver involvement. Literature review of all published TMEM67 mutated cases was performed to delineate genotype-phenotype correlates. In particular, comparison of the types of mutations and their distribution along the gene in lethal versus non lethal phenotypes showed in MKS patients a significant enrichment of missense mutations falling in TMEM67 exons 8 to 15, especially when in combination with a truncating mutation. These exons encode for a region of unknown function in the extracellular domain of meckelin.

Angelman Syndrome (AS), characterized by mental retardation, absence of speech, seizures and motor dysfunction, is caused by genetic defects leading to loss of expression of the maternal copy of the chromosome 15q11-13 imprinted region. Most cases are sporadic, being caused by de novo deletion of maternal chromosome 15q11-13 (75%) or by paternal uniparental disomy (3-4%). Familial cases can occur, due to mutations in the UBE3A gene or in the imprinting center. We describe the case of a pregnant woman having two nephews with AS caused by a UBE3A mutation; lack of communication within the family led the woman to be completely unaware of the risk of disease recurrence until 15 weeks of gestation. UBE3A genetic testing revealed she carried the familial mutation 892-893delCT. Prenatal diagnosis was performed on amniotic fluid and demonstrated that the fetus had inherited the mutation. The unexpected diagnosis and the subsequent termination of the pregnancy caused the woman to undergo acute psychological distress showing relevant psychopathological symptoms. Nevertheless, at 2-year follow-up, adverse consequences were minimized, and the couple was planning a new pregnancy. Factors affecting the psychological outcome of abortion and the role of psychological support in reducing the risk of long-term unfavorable consequences are discussed.

The sensing by T cells of metabolic and energetic changes in the microenvironment can determine the differentiation, maturation, and activation of these cells. Although it is known that mammalian target of rapamycin (mTOR) gauges nutritonal and energetic signals in the extracellular milieu, it is not known how mTOR and metabolism influence CD4+CD25−FOXP3− effector T cell (Teff) responses. In this article, we show that leptin-induced activation of mTOR, which, in turn, controls leptin production and signaling, causes a defined cellular, biochemical, and transcriptional signature that determine the outcome of Teff responses, both in vitro and in vivo. The blockade of leptin/leptin receptor signaling, induced by genetic means or by starvation, leads to impaired mTOR activity that inhibits the proliferation of Teffs in vivo. Notably, the transcriptional signature of Teffs in the presence of leptin blockade appears similar to that observed in rapamycin-treated Teffs. These results identify a novel link between nutritional status and Teff responses through the leptin–mTOR axis and define a potential target for Teff modulation in normal and pathologic conditions.

The glial cell line-derived neurotrophic factor (GDNF) exerts trophic actions on a number of cell types, including mesencephalic dopaminergic (mDA) neurons. Using rat mesencephalic primary cultures enriched in mDA neurons, we show that protracted GDNF stimulation increases their survival and neurite outgrowth. It modulates the expression of genes essential for DA function (tyrosine hydroxylase, TH and dopamine transporter, dat) and of DA high affinity uptake. To identify genes involved in GDNF signaling pathways, we have used DNA microarray on mDA cultures stimulated with GDNF for 3 h. Here we show that GDNF signaling sequentially activates the genes encoding for the transcription factors EGR1 and TIEG. In addition, it increases the expression of cav1, which encodes for the major component of caveolae. GDNF also modulates the expression of the genes encoding for the Calcineurin subunits ppp3R1 and ppp3CB, and inhibits calcium-calmodulin-dependent protein kinase II β isoform (CaMKIIβ) gene expression. These proteins are involved in neuronal differentiation and synaptic plasticity. Moreover, GDNF stimulation down regulates the expression of the glycogen synthase kinase 3β (gsk3β) gene, involved in neuronal apoptosis. Using inhibitors of specific intracellular signal transduction pathways we show that changes of egr1, tieg, cav1, CaMkIIβ and gsk3β genes expression are extracellular-signal regulated kinases 1/2 (ERK)-dependent, while the cAMP-dependent protein kinase (PKA) pathway influences the up-regulation of ppp3R1 and ppp3CB gene expression. These results demonstrate that GDNF stimulation results in the transcriptional modulation of genes involved in neuronal plasticity and survival and in mDA function, mediated in part by ERK and PKA signaling. © 2007 Elsevier B.V. All rights reserved.

Within the framework of a FISH screening protocol to detect cryptic subtelomeric rearrangements in autistic disorder (AD), a patient bearing three copies of the subtelomeric portion of the q arm of chromosome 13 has been identified. Beside AD, the patient also has severe mental retardation and displays several dysmorphic features. Further FISH analyses revealed that the trisomy was caused by the translocation of a 13q subtelomeric fragment to the acrocentric tip of one chromosome 21 [46,XY.ish der(21) t(13;21) (q34;p13)(D13S1825+)]. Gene dosage experiments carried out with three multiallelic polymorphisms of the subtelomeric region of chromosome 13q showed that the putative length of the triplicate region does not exceed 300 kb about, that is, the distance from telomere to the first normally inherited marker. In addition, gene dosage analysis performed on the derivative chromosome 21, did not reveal loss of the most telomeric protein-encoding genes on 21p. The potential relationship between a postulated increased expression of genes on 13q34 and the complex phenotype in this trisomic patient is discussed.