Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma.

BACKGROUND: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. METHODS: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. RESULTS: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. CONCLUSIONS: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).

Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity.

Glial cells are key players in the initiation of innate immunity in neurodegeneration. Upon damage, they switch their basal activation state and acquire new functions in a context and time-dependent manner. Since modulation of neuroinflammation is becoming an interesting approach for the treatment of neurodegenerative diseases, it is crucial to understand the specific contribution of these cells to the inflammatory reaction and to select experimental models that recapitulate what occurs in the human disease. Previously, we have characterized a region-specific activation pattern of CD11b+ cells and astrocytes in the α-synuclein overexpression mouse model of Parkinson´s disease (PD). In this study we hypothesized that the time and the intensity of dopaminergic neuronal death would promote different glial activation states. Dopaminergic degeneration was induced with two administration regimens of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), subacute (sMPTP) and chronic (cMPTP). Our results show that in the sMPTP mouse model, the pro-inflammatory phenotype of striatal CD11b+ cells was counteracted by an anti-inflammatory astrocytic profile. In the midbrain the roles were inverted, CD11b+ cells exhibited an anti-inflammatory profile and astrocytes were pro-inflammatory. The overall response generated resulted in decreased CD4 T cell infiltration in both regions. Chronic MPTP exposure resulted in a mild and prolonged neuronal degeneration that generated a pro-inflammatory response and increased CD4 T cell infiltration in both regions. At the onset of the neurodegenerative process, microglia and astrocytes cooperated in the removal of dopaminergic terminals. With time, only microglia maintained the phagocytic activity. In the ventral midbrain, astrocytes were the main phagocytic mediators at early stages of degeneration while microglia were the major phagocytic cells in the chronic state. In this scenario, we questioned which activation pattern recapitulates better the features of glial activation in PD. Glial activation in the cMPTP mouse model reflects many pathways of their corresponding counterparts in the human brain with advanced PD. Altogether, our results point toward a context-dependent cooperativity of microglia/myeloid cells and astrocytes in response to neuronal damage and the relevance of selecting the right experimental models for the study of neuroinflammation.

Microglia and astrocyte activation is region-dependent in the α-synuclein mouse model of Parkinson's disease.

Inflammation is a common feature in neurodegenerative diseases that contributes to neuronal loss. Previously, we demonstrated that the basal inflammatory tone differed between brain regions and, consequently, the reaction generated to a pro-inflammatory stimulus was different. In this study, we assessed the innate immune reaction in the midbrain and in the striatum using an experimental model of Parkinson's disease. An adeno-associated virus serotype 9 expressing the α-synuclein and mCherry genes or the mCherry gene was administered into the substantia nigra. Myeloid cells (CD11b+ ) and astrocytes (ACSA2+ ) were purified from the midbrain and striatum for bulk RNA sequencing. In the parkinsonian midbrain, CD11b+ cells presented a unique anti-inflammatory transcriptomic profile that differed from degenerative microglia signatures described in experimental models for other neurodegenerative conditions. By contrast, striatal CD11b+ cells showed a pro-inflammatory state and were similar to disease-associated microglia. In the midbrain, a prominent increase of infiltrated monocytes/macrophages was observed and, together with microglia, participated actively in the phagocytosis of dopaminergic neuronal bodies. Although striatal microglia presented a phagocytic transcriptomic profile, morphology and cell density was preserved and no active phagocytosis was detected. Interestingly, astrocytes presented a pro-inflammatory fingerprint in the midbrain and a low number of differentially displayed transcripts in the striatum. During α-synuclein-dependent degeneration, microglia and astrocytes experience context-dependent activation states with a different contribution to the inflammatory reaction. Our results point towards the relevance of selecting appropriate cell targets to design neuroprotective strategies aimed to modulate the innate immune system during the active phase of dopaminergic degeneration.

Multiple sclerosis incidence rate in southern Iran: a Bayesian epidemiological study.

BACKGROUND: Multiple Sclerosis (MS) remains to be a public health challenge, due to its unknown biological mechanisms and clinical impacts on young people. The prevalence of this disease in Iran is reported to be 5.30 to 74.28 per 100,000-person. Because of high prevalence of this disease in Fars province, the purpose of this study was to assess the spatial pattern of MS incidence rate by modeling both the associations s of spatial dependence between neighboring regions and risk factors in a Bayesian Poisson model, which can lead to the improvement of health resource allocation decisions. METHOD: Data from 5468 patients diagnosed with MS were collected, according to the McDonald's criteria. New cases of MS were reported by the MS Society of Fars province from 1991 until 2016. The association between the percentage of people with low vitamin D intake, smoking, abnormal BMI and alcohol consumption in addition to spatial structure in a Bayesian spatio-temporal hierarchical model were used to determine the relative risk and trend of MS incidence rate in 29 counties of Fars province. RESULTS: County-level crude incidence rates ranged from 0.22 to 11.31 cases per 100,000-person population. The highest relative risk was estimated at 1.80 in the county of Shiraz, the capital of Fars province, while the lowest relative risk was estimated at 0.11 in Zarindasht county in southern of Fars. The percentages of vitamin D supplementation intake and smoking were significantly associated with the incidence rate of MS. The results showed that 1% increase in vitamin D supplementation intake is associated with 2% decrease in the risk of MS and 1% increase in smoking is associated with 16% increase in the risk of MS. CONCLUSION: Bayesian spatio-temporal analysis of MS incidence rate revealed that the trend in the south and south east of Fars province is less steep than the mean trend of this disease. The lower incidence rate was associated with a higher percentage of vitamin D supplementation intake and a lower percentage of smoking. Previous studies have also shown that smoking and low vitamin D, among all covariates or risk factors, might be associated with high incidence of MS.

Comprehensive study of the exposome and omic data using rexposome Bioconductor Packages.

SUMMARY: Genomics has dramatically improved our understanding of the molecular origins of certain human diseases. Nonetheless, our health is also influenced by the cumulative impact of exposures experienced across the life course (termed 'exposome'). The study of the high-dimensional exposome offers a new paradigm for investigating environmental contributions to disease etiology. However, there is a lack of bioinformatics tools for managing, visualizing and analyzing the exposome. The analysis data should include both association with health outcomes and integration with omic layers. We provide a generic framework called rexposome project, developed in the R/Bioconductor architecture that includes object-oriented classes and methods to leverage high-dimensional exposome data in disease association studies including its integration with a variety of high-throughput data types. The usefulness of the package is illustrated by analyzing a real dataset including exposome data, three health outcomes related to respiratory diseases and its integration with the transcriptome and methylome. AVAILABILITY AND IMPLEMENTATION: rexposome project is available at https://isglobal-brge.github.io/rexposome/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Educational Interventions on Human Papillomavirus for Oral Health Providers.

The aim of this study was to evaluate the effectiveness of an educational intervention on HPV infection, HPV-related cancers and prevention modalities to improve Oral Health Care Providers (OHPs) knowledge and awareness about these topics, considering the rise of HPV-related malignancies in the USA. Educational sessions on HPV were offered to OHPs between 2016 and 2018 in the New England area. Participants were asked to fill out a questionnaire both before and after each session. Responses from the pre-questionnaire were compared to those from the post-questionnaire to evaluate the effectiveness of the lectures in increasing HPV-related knowledge of the OHPs. Among 277 participants, 263 completed both the pre- and post-questionnaire. A significant improvement was observed for the following categories: epidemiology of HPV infections, HPV-related diseases, and HPV vaccination and prevention. After the educational intervention, OHPs also indicated an increased comfort level in regard to educating their patients about the importance of HPV vaccination. Educational lectures can be effective in increasing OHPs knowledge and awareness about HPV, HPV-related cancers, and vaccination. More educational sessions on HPV are needed to reach a larger number of OHPs. OHPs may be the first to identify signs and symptoms of HPV-related oropharyngeal cancers. In addition, they may encourage their patients to take advantage of the HPV vaccine.

Inflammation and immunity in ovarian cancer.

The standard first-line therapy for ovarian cancer is a combination of surgery and carboplatin/paclitaxel-based chemotherapy. Patients with longer survival and improved response to chemotherapy usually present T-cell inflamed tumours. The presence of tumour-infiltrating T cells (TILs) notably varies among the different subtypes of ovarian tumours, being highest in high-grade serous ovarian carcinoma, intermediate in endometrioid tumours, and lowest in low-grade serous, mucinous and clear cell tumours. Interestingly, the presence of TILs is often accompanied by a strong immunosuppressive tumour environment. A better understanding of the immune response against ovarian cancer and the tumour immune evasion mechanisms will enable improved prognostication, response prediction and immunotherapy of this disease. This article provides an overview of some ovarian cancer cell features relevant for antitumour response, such as tumour-associated antigens, including neoantigens, expression of inhibitory molecules, and other mechanisms of immune evasion. Moreover, we describe relevant immune cell types found in epithelial ovarian tumours, including T and B lymphocytes, regulatory T cells, natural killer cells, tumour-associated macrophages, myeloid-derived suppressor cells and neutrophils. We focus on how these components influence the burden of the tumour and the clinical outcome.

Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts.

Several studies have indicated weakly increased risk for kidney cancer among occupational groups exposed to gasoline vapors, engine exhaust, polycyclic aromatic hydrocarbons and other air pollutants, although not consistently. It was the aim to investigate possible associations between outdoor air pollution at the residence and the incidence of kidney parenchyma cancer in the general population. We used data from 14 European cohorts from the ESCAPE study. We geocoded and assessed air pollution concentrations at baseline addresses by land-use regression models for particulate matter (PM10 , PM2.5 , PMcoarse , PM2.5 absorbance (soot)) and nitrogen oxides (NO2 , NOx ), and collected data on traffic. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effects models for meta-analyses to calculate summary hazard ratios (HRs). The 289,002 cohort members contributed 4,111,908 person-years at risk. During follow-up (mean 14.2 years) 697 incident cancers of the kidney parenchyma were diagnosed. The meta-analyses showed higher HRs in association with higher PM concentration, e.g. HR = 1.57 (95%CI: 0.81-3.01) per 5 µg/m3 PM2.5 and HR = 1.36 (95%CI: 0.84-2.19) per 10-5 m-1 PM2.5 absorbance, albeit never statistically significant. The HRs in association with nitrogen oxides and traffic density on the nearest street were slightly above one. Sensitivity analyses among participants who did not change residence during follow-up showed stronger associations, but none were statistically significant. Our study provides suggestive evidence that exposure to outdoor PM at the residence may be associated with higher risk for kidney parenchyma cancer; the results should be interpreted cautiously as associations may be due to chance.

Childhood leukemia and residential proximity to industrial and urban sites.

BACKGROUND: Few risk factors for the childhood leukemia are well established. While a small fraction of cases of childhood leukemia might be partially attributable to some diseases or ionizing radiation exposure, the role of industrial and urban pollution also needs to be assessed. OBJECTIVES: To ascertain the possible effect of residential proximity to both industrial and urban areas on childhood leukemia, taking into account industrial groups and toxic substances released. METHODS: We conducted a population-based case-control study of childhood leukemia in Spain, covering 638 incident cases gathered from the Spanish Registry of Childhood Tumors and for those Autonomous Regions with 100% coverage (period 1990-2011), and 13,188 controls, individually matched by year of birth, sex, and autonomous region of residence. Distances were computed from the respective subject's residences to the 1068 industries and the 157 urban areas with ≥10,000 inhabitants, located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to industrial and urban pollution sources were calculated, with adjustment for matching variables. RESULTS: Excess risk of childhood leukemia was observed for children living near (≤2.5 km) industries (OR=1.31; 95%CI=1.03-1.67) - particularly glass and mineral fibers (OR=2.42; 95%CI=1.49-3.92), surface treatment using organic solvents (OR=1.87; 95%CI=1.24-2.83), galvanization (OR=1.86; 95%CI=1.07-3.21), production and processing of metals (OR=1.69; 95%CI=1.22-2.34), and surface treatment of metals (OR=1.62; 95%CI=1.22-2.15) - , and urban areas (OR=1.36; 95%CI=1.02-1.80). CONCLUSIONS: Our study furnishes some evidence that living in the proximity of industrial and urban sites may be a risk factor for childhood leukemia.

Geographical analysis of the sporadic Creutzfeldt-Jakob disease distribution in the autonomous community of the Basque Country for the period 1995-2008.

BACKGROUND: The Basque Country, in Spain, shows one of the highest sporadic Creutzfeldt-Jakob disease (sCJD) incidence rates in Europe. The purpose is to analyse a possible focus of unidentified external or environmental factors which could trigger the high incidence rates of sCJD in the Basque Country. METHODS: We estimated the relative risk and the posterior relative risk distribution of sCJD cases for each town of the Basque Country and for the period 1995-2008. RESULTS: 58 sCJD cases (44 definite and 14 probable) were selected for the geographic cluster analysis. In a first approach, referring to the relative risk, several municipalities in the Autonomous Community of the Basque Country showed more sCJD cases than expected. However, the posterior relative risk distribution showed no excess risk areas. CONCLUSIONS: RESULTS from this survey indicate that a possible common source of development of the disease does not seem to be the reason of the high sCJD incidence.

Application of Graph Models to the Identification of Transcriptomic Oncometabolic Pathways in Human Hepatocellular Carcinoma.

Whole-tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been defined, yet whether these different metabolic classes are clinically relevant or derive in actionable cancer vulnerabilities is still an unanswered question. Publicly available gene sets or gene signatures have been used to infer functional changes through gene set enrichment methods. However, metabolism-related gene signatures are poorly co-expressed when applied to a biological context. Here, we apply a simple method to infer highly consistent signatures using graph-based statistics. Using the Cancer Genome Atlas Liver Hepatocellular cohort (LIHC), we describe the main metabolic clusters and their relationship with commonly used molecular classes, and with the presence of TP53 or CTNNB1 driver mutations. We find similar results in our validation cohort, the LIRI-JP cohort. We describe how previously described metabolic subtypes could not have therapeutic relevance due to their overall downregulation when compared to non-tumoral liver, and identify N-glycan, mevalonate and sphingolipid biosynthetic pathways as the hallmark of the oncogenic shift of the use of acetyl-coenzyme A in HCC metabolism. Finally, using DepMap data, we demonstrate metabolic vulnerabilities in HCC cell lines.

Efficient and safe therapeutic use of paired Cas9-nickases for primary hyperoxaluria type 1.

The therapeutic use of adeno-associated viral vector (AAV)-mediated gene disruption using CRISPR-Cas9 is limited by potential off-target modifications and the risk of uncontrolled integration of vector genomes into CRISPR-mediated double-strand breaks. To address these concerns, we explored the use of AAV-delivered paired Staphylococcus aureus nickases (D10ASaCas9) to target the Hao1 gene for the treatment of primary hyperoxaluria type 1 (PH1). Our study demonstrated effective Hao1 gene disruption, a significant decrease in glycolate oxidase expression, and a therapeutic effect in PH1 mice. The assessment of undesired genetic modifications through CIRCLE-seq and CAST-Seq analyses revealed neither off-target activity nor chromosomal translocations. Importantly, the use of paired-D10ASaCas9 resulted in a significant reduction in AAV integration at the target site compared to SaCas9 nuclease. In addition, our study highlights the limitations of current analytical tools in characterizing modifications introduced by paired D10ASaCas9, necessitating the development of a custom pipeline for more accurate characterization. These results describe a positive advance towards a safe and effective potential long-term treatment for PH1 patients.

Identification of HLA class I-restricted immunogenic neoantigens in triple negative breast cancer.

Immune checkpoint inhibitor (ICI)-based immunotherapy in triple negative breast cancer (TNBC) is achieving limited therapeutic results, requiring the development of more potent strategies. Combination of ICI with vaccination strategies would enhance antitumor immunity and response rates to ICI in patients having poorly infiltrated tumors. In heavily mutated tumors, neoantigens (neoAgs) resulting from tumor mutations have induced potent responses when used as vaccines. Thus, our aim was the identification of immunogenic neoAgs suitable as vaccines in TNBC patients. By using whole exome sequencing, RNAseq and HLA binding algorithms of tumor samples from a cohort of eight TNBC patients, we identified a median of 60 mutations/patient, which originated a putative median number of 98 HLA class I-restricted neoAgs. Considering a group of 27 predicted neoAgs presented by HLA-A*02:01 allele in two patients, peptide binding to HLA was experimentally confirmed in 63% of them, whereas 55% were immunogenic in vivo in HLA-A*02:01+ transgenic mice, inducing T-cells against the mutated but not the wild-type peptide sequence. Vaccination with peptide pools or DNA plasmids expressing these neoAgs induced polyepitopic T-cell responses, which recognized neoAg-expressing tumor cells. These results suggest that TNBC tumors harbor neoAgs potentially useful in therapeutic vaccines, opening the way for new combined immunotherapies.

DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity.

Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α-mediated CD8+-killing and immune-resistant lung tumors to anti-PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.

Multi-omics signatures of the human early life exposome.

Environmental exposures during early life play a critical role in life-course health, yet the molecular phenotypes underlying environmental effects on health are poorly understood. In the Human Early Life Exposome (HELIX) project, a multi-centre cohort of 1301 mother-child pairs, we associate individual exposomes consisting of >100 chemical, outdoor, social and lifestyle exposures assessed in pregnancy and childhood, with multi-omics profiles (methylome, transcriptome, proteins and metabolites) in childhood. We identify 1170 associations, 249 in pregnancy and 921 in childhood, which reveal potential biological responses and sources of exposure. Pregnancy exposures, including maternal smoking, cadmium and molybdenum, are predominantly associated with child DNA methylation changes. In contrast, childhood exposures are associated with features across all omics layers, most frequently the serum metabolome, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions, among others. Our comprehensive and unique resource of all associations ( https://helixomics.isglobal.org/ ) will serve to guide future investigation into the biological imprints of the early life exposome.

The role of family history of Cancer in Oral Cavity Cancer.

OBJECTIVES: Oral and oropharyngeal squamous cell carcinoma (SCC) is the 10th most common cancer in the United States (8th in males, 13th in females), with an estimated 54,010 new cases expected in 2021, and is primarily associated with smoked tobacco, heavy alcohol consumption, areca nut use and persistent high-risk human papillomavirus (HPV). Family history of cancer (FHC) and family history of head and neck cancer (FHHNC) have been reported to play an important role in the development of OSCC. We aimed to investigate the role of FHC, FHHNC and personal history of cancer in first/second degree-relatives as co-risk factors for oral cancer. METHODS: This was a retrospective study of patients diagnosed with OSCC at the Division of Oral Medicine and Dentistry at Brigham and Women's Hospital and at the Division of Head and Neck Oncology at Dana Farber Cancer Institute. Conditional logistic regressions were performed to examine whether OSCC was associated with FHC and FHHNC of FDRs and SDRs, personal history of cancer and secondary risk factors. RESULTS: Overall, we did not find an association between FHC, FHHNC and OSCC risk, whereas patients with a cancer history in one of their siblings were 1.6-times more likely to present with an OSCC. When secondary risk factors were considered, patients with a history of oral leukoplakia and dysplasia had a 16-times higher risk of having an OSCC. CONCLUSIONS: Our study confirmed that a previous history of oral leukoplakia or dysplasia was an independent risk factor for OSCC. A positive family history of cancer in one or more siblings may be an additional risk factor for OSCC.

Prenatal exposure to a wide range of environmental chemicals and child behaviour between 3 and 7 years of age - An exposome-based approach in 5 European cohorts.

BACKGROUND: Studies looking at associations between environmental chemicals and child behaviour usually consider only one exposure or family of exposures. OBJECTIVE: This study explores associations between prenatal exposure to a wide range of environmental chemicals and child behaviour. METHODS: We studied 708 mother-child pairs from five European cohorts recruited in 2003-2009. We assessed 47 exposure biomarkers from eight chemical exposure families in maternal blood or urine collected during pregnancy. We used the Strengths and Difficulties Questionnaire (SDQ) to evaluate child behaviour between three and seven years of age. We assessed associations of SDQ scores with exposures using an adjusted least absolute shrinkage and selection operator (LASSO) considering all exposures simultaneously and an adjusted exposome-wide association study (ExWAS) considering each exposure independently. RESULTS: LASSO selected only copper (Cu) as associated with externalizing behaviour. In the ExWAS, bisphenol A [BPA, incidence rate ratio (IRR): 1.06, 95% confidence interval (95%CI): 1.01;1.12] and mono-n-butyl phthalate (MnBP, IRR: 1.06, 95%CI: 1.00;1.13) were associated with greater risk of externalizing behaviour problems. Cu (IRR: 0.90, 95%CI: 0.82;0.98), perfluoroundecanoate (PFUnDA, IRR: 0.92, 95%CI: 0.84;0.99) and organochlorine compounds (OCs) were associated with lower risk of externalizing behaviour problems, however the associations with OCs were mainly seen among women with insufficient weight gain during pregnancy. Internalizing score worsen in association with exposure to diethyl thiophosphate (DETP, IRR: 1.11, 95%CI: 1.00;1.24) but the effect was driven by the smallest cohort. Internalizing score improved with increased concentration of perfluorooctane sulfonate (PFOS, IRR: 0.92, 95%CI: 0.85;1.00), however the association was driven by the two smallest cohorts with the lowest PFOS concentrations. DISCUSSION: This study added evidence on deleterious effects of prenatal exposure to BPA and MnBP on child behaviour. Other associations should be interpreted cautiously since they were not consistent with previous studies or they have not been studied extensively.

Somatic and germline analysis of a familial Rothmund-Thomson syndrome in two siblings with osteosarcoma.

Rothmund-Thomson syndrome (RTS) is characterized by a rash that begins in the first few months of life and eventually develops into poikiloderma. Associated symptoms are alterations in the teeth, sparse hair, thin eyebrows, lack of eyelashes, low stature, bone abnormalities, hematological illnesses, gastrointestinal disease, malnutrition, cataracts, and predisposition to cancer, principally to bone tumors and skin cancer. Diagnostic certitude is provided by a genetic study involving detection of pathogenic variants of the RECQL4 gene. We hereby present a familiar case of RTS in two siblings from a Portuguese family, both diagnosed with osteosarcoma. Genomic analysis (203 genes) of both tumors as well as germline analysis of the RECQL4 gene, thus confirming the syndrome in the family, have been performed. The relevance of clinical recognition of the hallmarks of the disease and thus early diagnosis with early intervention is highlighted.

Prenatal air pollution exposure and growth and cardio-metabolic risk in preschoolers.

OBJECTIVES: We investigated the association between outdoor air pollutants exposure in the first trimester of pregnancy, and growth and cardio-metabolic risk at four years of age, and evaluated the mediating role of birth weight. METHODS: We included mother-child pairs (N = 1,724) from the Spanish INMA birth cohort established in 2003-2008. First trimester of pregnancy nitrogen dioxide (NO2) and fine particles (PM2.5) exposure levels were estimated. Height, weight, waist circumference, blood pressure, and lipids were measured at four years of age. Body mass index (BMI) trajectories from birth to four years were identified. RESULTS: Increased PM2.5 exposure in the first trimester of pregnancy was associated with decreased z-scores of weight (zWeight) and BMI (zBMI) (zWeight change per interquartile range increase in PM2.5 exposure = -0.12; 95% CI: -0.23, -0.01; zBMI change = -0.12; 95% CI: -0.23, -0.01). Higher NO2 and PM2.5 exposure was associated to a reduced risk of being in a trajectory with accelerated BMI gain, compared to children with the average trajectory. Birth weight partially mediated the association between PM2.5 and zWeight and zBMI. PM2.5 and NO2 were not associated with the other cardio-metabolic risk factors. CONCLUSIONS: This comprehensive study of many growth and cardio-metabolic risk related outcomes suggests that air pollution exposure during pregnancy may be associated with delays in physical growth in the early years after birth. These findings imply that pregnancy exposure to air pollutants has a lasting effect on growth after birth and require follow-up at later child ages.