Mifepristone treatment during early adolescence fails to restore maternal deprivation-induced deficits in behavioral inhibition of adult male rats

Development Psychopathology in context: famil

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Primary vulvar squamous cell carcinomas with high T cell infiltration and active immune signaling are potential candidates for neoadjuvant PD-1/PD-L1 immunotherapy

Background A profound insight into the immune landscape of vulvar squamous cell carcinoma (VSCC) is lacking. Here, an in-depth interrogation of T cell infiltration, local immune contexture, signaling pathways and checkpoint molecule expression was performed in early-stage and late-stage VSCC.Methods The type, location, and infiltration pattern of T cells were studied in 109 patients with primary VSCC FIGO stage I-III. RNA expression of genes involved in immune oncology and oncogenic signaling pathways was analyzed in 40 VSCC, matched for prognostic clinicopathological variables, analyzed for HPV and p53 status, and selected based on T cell infiltration.Results High intraepithelial infiltration with CD4 or CD8 T cells was associated with longer overall and recurrence-free survival and formed an independent prognostic factor, outperforming molecular subtype and stage of the disease. Strong T cell infiltrated VSCC displayed a coordinated immune response reflected by a positive association between T cells and different lymphocyte and myeloid cell subsets. The expression of genes involved in the migration of T cells and myeloid cells, T cell activation and costimulation, interferon (IFN)-gamma signaling, cytotoxicity and apoptosis was higher than in low infiltrated tumors. An active immune signaling profile was observed in all inflamed, part of the altered-excluded and not in altered-immunosuppressed or deserted VSCC. While several checkpoint molecules were overexpressed, only PD-L1 expression displayed discriminatory ability and clinical usefulness. High PD-L1 expression was detected in all inflamed and similar to 60% of the altered-excluded VSCC.Conclusion An active immune signaling profile is present in 35% of primary FIGO I-III VSCCs, suggesting potential responsiveness to neoadjuvant PD-1/PD-L1 immunotherapy.Experimental cancer immunology and therap

Insignificant Change in Antarctic Snowfall Since the International Geophysical Year

Antarctic snowfall exhibits substantial variability over a range of timescales, with consequent impacts on global sea level and the mass balance of the ice sheets. To assess how snowfall has affected the thickness of the ice sheets in Antarctica and to provide an extended perspective, we derived a 50-year time series of snowfall accumulation over the continent is derived by combining model simulations and observations primilarly from ice cores. There has been no statistically significant change in snowfall since the 1950s indicating that Antarctic precipitation is not mitigating global sea level rise as expected, despite recent winter warming of the overlying atmosphere

Fatigue in Sjögren's Syndrome: A Search for Biomarkers and Treatment Targets

Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, where patients often suffer from fatigue. Biological pathways underlying fatigue are unknown. In this study aptamer-based SOMAscan technology is used to identify potential biomarkers and treatment targets for fatigue in pSS.Methods: SOMAscan® Assay 1.3k was performed on serum samples of healthy controls (HCs) and pSS patients characterized for interferon upregulation and fatigue. Differentially expressed proteins (DEPs) between pSS patients and HC or fatigued and non-fatigued pSS patients were validated and discriminatory capacity of markers was tested using independent technology.Results: Serum concentrations of over 1,300 proteins were compared between 63 pSS patients and 20 HCs resulting in 58 upregulated and 46 downregulated proteins. Additionally, serum concentrations of 30 interferon positive (IFNpos) and 30 interferon negative (IFNneg) pSS patients were compared resulting in 25 upregulated and 13 downregulated proteins. ELISAs were performed for several DEPs between pSS patients and HCs or IFNpos and IFNneg all showing a good correlation between protein levels measured by ELISA and relative fluorescence units (RFU) measured by the SOMAscan. Comparing 22 fatigued and 23 non-fatigued pSS patients, 16 serum proteins were differentially expressed, of which 14 were upregulated and 2 were downregulated. Top upregulated DEPs included neuroactive synaptosomal-associated protein 25 (SNAP-25), alpha-enolase (ENO1) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). Furthermore, the proinflammatory mediator IL36a and several complement factors were upregulated in fatigued compared to non-fatigued pSS patients. ROC analysis indicated that DEPs showed good capacity to discriminate fatigued and non-fatigued pSS patients.Conclusion: In this study we validated the use of aptamer-based proteomics and identified a novel set of proteins which were able to distinguish fatigued from non-fatigued pSS patients and identified a so-called “fatigue signature.

Immune dynamics in SARS-CoV-2 experienced immunosuppressed rheumatoid arthritis or multiple sclerosis patients vaccinated with mRNA-1273

BACKGROUND: Patients affected by different types of autoimmune diseases, including common conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA), are often treated with immunosuppressants to suppress disease activity. It is not fully understood how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific humoral and cellular immunity induced by infection and/or upon vaccination is affected by immunosuppressants. METHODS: The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HCs) before and 7 days after the first and second vaccination. RESULTS: OCR-treated MS patients exhibit a preserved recall response of CD8(+) T central memory cells following first vaccination compared to HCs and a similar CD4(+) circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2-specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4(+) and CD8(+) T cells. CONCLUSIONS: Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may still benefit from vaccination by inducing a broad CD8(+) T cell response which has been associated with milder disease outcome. The delayed vaccine-induced IgG kinetics in RA-MTX patients indicate an increased risk after the first vaccination, which might require additional shielding or alternative strategies such as treatment interruptions in vulnerable patients. FUNDING: This research project was supported by ZonMw (The Netherlands Organization for Health Research and Development, #10430072010007), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#792532 and #860003), the European Commission (SUPPORT-E, #101015756) and by PPOC (#20_21 L2506), the NHMRC Leadership Investigator Grant (#1173871)

Caries experience among children born after a complicated pregnancy

Objectives: Behavioural and lifestyle factors, as oral hygiene and diet, are well-established risk factors in the pathogenesis of dental caries, though displaying large differences in susceptibility across individuals. Since enamel formation already starts in utero, pregnancy course and outcome may eventually play a role in enamel strength and caries susceptibility. Therefore, we studied the association between history of pregnancy complications and the caries experience in their six-year-old children. The pregnancy complications included small for gestational age (SGA), spontaneous preterm birth (sPTB), gestational hypertension (GH), pre-eclampsia (PE), individually, and a combination of those, designated as placental syndrome. Methods: This study was embedded in Generation R, a prospective longitudinal Dutch multiethnic pregnancy cohort study. Information about pregnancy complications was obtained from questionnaires completed by midwives and obstetricians with cross-validation in medical records. These included SGA, sPTB, GH and PE. Caries experience was assessed with the decayed, missing and filled teeth (dmft) index at a mean age of six years. The association between dental caries experience and a history of pregnancy complications was studied by using hurdle negative binomial (HNB) models. Results: We were able to assess the dmft index in 5323 six-year-old children (mean age 6.2 years, SD 0.5). We did not find an association between the different pregnancy complications and dental caries experience in childhood, whether for SGA, sPTB, GH, PE, or for the combined outcome placental syndrome (HNB estimates: OR 1.02, 95%CI 0.87 - 1.19; RR 0.90, 95%CI 0.78 - 1.04). Further adjustment of the models with different confounders did not alter the outcome. Conclusions: Although it is expected that prenatal stress can be a risk factor for caries development later in life, our findings do not support this hypothesis. Therefore, we believe disparities in caries experience between children are probably not explained by early life events during a critical intrauterine period of development