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Women have a reduced cardiovascular disease (CVD) risk compared with men, which could be partially driven by sex hormones influencing lipid levels post puberty. The interrelationship between sex hormones and lipids was explored in pre-pubertal children, young post-pubertal cis-men/women, and transgender individuals on cross-sex-hormone treatment (trans-men/women) using serum metabolomics assessing 149 lipids. High-density lipoproteins (HDL, typically atheroprotective) were significantly increased and very-low- and low-density lipoproteins (typically atherogenic) were significantly decreased in post-pubertal cis-women compared with cis-men. These differences were not observed pre-puberty and were induced appropriately by cross-sex-hormone treatment in transgender individuals, supporting that sex hormones regulate lipid metabolism in vivo . Only atheroprotective apolipoprotein (Apo)A1 expressing lipoproteins (HDL) were differentially expressed between all hormonally unique comparisons. Thus, estradiol drives a typically atheroprotective lipid profile through upregulation of HDL/ApoA1, which could contribute to the sexual dimorphism observed in CVD risk post puberty. Together, this could inform sex-specific therapeutic strategies for CVD management., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Background: Cardiovascular disease is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE). Traditional factors for cardiovascular risk (CVR) prediction are less robust in younger patients. More reliable CVR biomarkers are needed for JSLE patient stratification and to identify therapeutic approaches to reduce cardiovascular morbidity and mortality in JSLE., Methods: Serum metabolomic analysis (including >200 lipoprotein measures) was performed on a discovery (n=31, median age 19) and validation (n=31, median age 19) cohort of JSLE patients. Data was analysed using cluster, receiver operating characteristic analysis and logistic regression. RNA-sequencing assessed gene expression in matched patient samples., Findings: Hierarchical clustering of lipoprotein measures identified and validated two unique JSLE groups. Group-1 had an atherogenic and Group-2 had an atheroprotective lipoprotien profile. Apolipoprotein(Apo)B:ApoA1 distinguished the two groups with high specificity (96.2%) and sensitivity (96.7%). JSLE patients with high ApoB:ApoA1 ratio had increased CD8+ T-cell frequencies and a CD8+ T-cell transcriptomic profile enriched in genes associated with atherogenic processes including interferon signaling. These metabolic and immune signatures overlapped statistically significantly with lipid biomarkers associated with sub-clinical atherosclerosis in adult SLE patients and with genes overexpressed in T-cells from human atherosclerotic plaque respectively. Finally, baseline ApoB:ApoA1 ratio correlated positively with SLE disease activity index (r=0.43, p=0.0009) and negatively with Lupus Low Disease Activity State (r=-0.43, p=0.0009) over 5-year follow-up., Interpretation: Multi-omic analysis identified high ApoB:ApoA1 as a potential biomarker of increased cardiometabolic risk and worse clinical outcomes in JSLE. ApoB:ApoA1 could help identify patients that require increased disease monitoring, lipid modification or lifestyle changes., Funding: Lupus UK, The Rosetrees Trust, British Heart Foundation, UCL & Birkbeck MRC Doctoral Training Programme and Versus Arthritis., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detected preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable using a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the immunoglobulin G (IgG) class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Juvenile-onset systemic lupus erythematosus (SLE) is a rare autoimmune rheumatic disease characterised by more severe disease manifestations, earlier damage accrual, and higher mortality than in adult-onset SLE. We aimed to use machine-learning approaches to characterise the immune cell profile of patients with juvenile-onset SLE and investigate links with the disease trajectory over time., Methods: This study included patients who attended the University College London Hospital (London, UK) adolescent rheumatology service, had juvenile-onset SLE according to the 1997 American College of Rheumatology revised classification criteria for lupus or the 2012 Systemic Lupus International Collaborating Clinics criteria, and were diagnosed before 18 years of age. Blood donated by healthy age-matched and sex-matched volunteers who were taking part in educational events in the Centre for Adolescent Rheumatology Versus Arthritis at University College London (London, UK) was used as a control. Immunophenotyping profiles (28 immune cell subsets) of peripheral blood mononuclear cells from patients with juvenile-onset SLE and healthy controls were determined by flow cytometry. We used balanced random forest (BRF) and sparse partial least squares-discriminant analysis (sPLS-DA) to assess classification and parameter selection, and validation was by ten-fold cross-validation. We used logistic regression to test the association between immune phenotypes and k-means clustering to determine patient stratification. Retrospective longitudinal clinical data, including disease activity and medication, were related to the immunological features identified., Findings: Between Sept 5, 2012, and March 7, 2018, peripheral blood was collected from 67 patients with juvenile-onset SLE and 39 healthy controls. The median age was 19 years (IQR 13-25) for patients with juvenile-onset SLE and 18 years (16-25) for healthy controls. The BRF model discriminated patients with juvenile-onset SLE from healthy controls with 90·9% prediction accuracy. The top-ranked immunological features from the BRF model were confirmed using sPLS-DA and logistic regression, and included total CD4, total CD8, CD8 effector memory, and CD8 naive T cells, Bm1, and unswitched memory B cells, total CD14 monocytes, and invariant natural killer T cells. Using these markers patients were clustered into four distinct groups. Notably, CD8 T-cell subsets were important in driving patient stratification, whereas B-cell markers were similarly expressed across the cohort of patients with juvenile-onset SLE. Patients with juvenile-onset SLE and elevated CD8 effector memory T-cell frequencies had more persistently active disease over time, as assessed by the SLE disease activity index 2000, and this was associated with increased treatment with mycophenolate mofetil and an increased prevalence of lupus nephritis. Finally, network analysis confirmed the strong association between immune phenotype and differential clinical features., Interpretation: Machine-learning models can define potential disease-associated and patient-specific immune characteristics in rare disease patient populations. Immunological association studies are warranted to develop data-driven personalised medicine approaches for treatment of patients with juvenile-onset SLE., Funding: Lupus UK, The Rosetrees Trust, Versus Arthritis, and UK National Institute for Health Research University College London Hospital Biomedical Research Centre., (© 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry. The results identified that immature transitional B cells were significantly expanded in active JDM, actively dividing, and correlated positively with disease activity. Protein and RNAseq analysis revealed high interferon alpha (IFNα) and TLR7-pathway signatures pre-treatment. Stimulation of B cells through TLR7/8 promoted both IL-10 and IL-6 production in controls but failed to induce IL-10 in JDM patient cells. Interrogation of the CD40-CD40L pathway (known to induce B cell IL-10 and IL-6) revealed similar expression of IL-10 and IL-6 in B cells cultured with CD40L from both JDM patients and controls. In conclusion, JDM patients with active disease have a significantly expanded immature transitional B cell population which correlated with the type I IFN signature. Activation through TLR7 and IFNα may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype.

Lung cancer incidence kept increasing dynamically in male population until the late 90s and then there was a sudden drop in the cases and this tendency has been maintained up till now. What seems upsetting, however, is the fact that for female population there is a constant growth in the lung cancer morbidity. Needless to say, Poland still belongs to the countries with high lung cancer incidence and lung cancer mortality. In 2011 the standardized morbidity rate in Poland accounted for 50,0/100 000 in male population and 17,3/100 000 in female population. In Podkarpacie Voivodeship it was 43,6/100 000 for males and 11,8/100 000 for females respectively. Lung cancer incidence and lung cancer mortality seem to increase together with age, and for people 65 and more this type of cancer accounts for approximately 50% of all cancer cases and cancer caused deaths. In spite of various research conducted and great medical progress little can be done to cure lung cancer. The percentage of 5-year survivals increased for males from 10,8% in years 2000-2002 to 11,9% in years 2003-2005, and for females from 15,7% to 16,9%. The main cause of lung cancer is certainly active and passive smoking. It is highly possible that environmental factors are also responsible for lung cancer cases. Among the most devastating are such factors as asbestos, arsenic, aromatic hydrocarbons, individual lifestyle and nutrition, genetic predisposition and finally the pollution, particularly of the air., (© 2015 MEDPRESS.)

Introduction: Prostate cancer is an important epidemiological problem in Podkarpackie province. A significant rise in the number of new cases was reported. The values of crude and standardized rates, percentage share and cumulative risk also increased., Objective: This article aims at analyzing incidence and mortality rates of prostate cancer in 2002-2011., Material and Methods: Analysis was based on data retrieved from the Podkarpackie Cancer Registry in Rzeszów. A total of 4 263 prostate cancer cases and 2 032 fatal cases were analyzed from the list of orderly arranged patients. Crude and standardized rates of incidence and mortality, cumulative risk and percentage share of prostate cancer out of all cancers were calculated., Results: Compared to 2002, the number of cases increased by 150.5% in 2011. Cumulative risk rose from 1.8% in 2002 to 4.7% in 2011. Percentage of prostate cancer cases out of all registered cancers increased more than twofold in the analyzed decade. There was a 22.3% increase in the number of fatal cases due to prostate cancer, accompanied by a slight decrease of standardized mortality rate from 13.2/100 000 in 2002 to 12.6/100 000 in 2011. In the analyzed period, 41.8% of patients were diagnosed with locally adavanced prostate cancer.

In this work, scanning electron microscopy and transmission electron microscopy and also an energy-dispersive X-ray spectroscopy were used to examine the morphology, structure and chemical composition of the beta-Al(3)Mg(2) thin films. The beta-Al-Mg thin films were produced by pulsed laser deposition. For the laser fluence (q) of 1.6 J/cm(2) the amorphous structure was observed while for the higher fluence (13.8 J/cm(2)) nanocrystalline grains were visible. The micrometer-sized droplets were also observed in the films deposited at higher laser fluence. It was found that the thickness of beta-Al-Mg films was equal to 95 nm and 260 nm for laser fluence of 1.6 J/cm(2) and 13.8 J/cm(2), respectively. Energy-dispersive X-ray spectroscopy of thin films revealed that those that were deposited at 1.6 J/cm(2) were characterized by the congruent transfer of the composition of the target to the substrate (Si). However, the contents of aluminium and magnesium varied on the cross-section of films deposited at fluence of 13.8 J/cm(2).

Fas/Fas ligand belongs to the tumor necrosis factor superfamily of receptors/ligands and is best known for its role in apoptosis. However, recent evidence supports its role in other cellular responses, including proliferation and survival. Although Fas has been implicated as an essential mediator of beta-cell death in the pathogenesis of type 1 diabetes, the essential role of Fas specifically in pancreatic beta-cells has been found to be controversial. Moreover, the role of Fas on beta-cell homeostasis and function is not clear. The objective of this study is to determine the role of Fas specifically in beta-cells under both physiological and diabetes models. Mice with Fas deletion specifically in the beta-cells were generated using the Cre-loxP system. Cre-mediated Fas deletion was under the control of the rat insulin promoter. Absence of Fas in beta-cells leads to complete protection against FasL-induced cell death. However, Fas is not essential in determining beta-cell mass or susceptibility to streptozotocin- or HFD-induced diabetes. Importantly, Fas deletion in beta-cells leads to increased p65 expression, enhanced glucose tolerance, and glucose-stimulated insulin secretion, with increased exocytosis as manifested by increased changes in membrane capacitance and increased expression of Syntaxin1A, VAMP2, and munc18a. Together, our study shows that Fas in the beta-cells indeed plays an essential role in the canonical death receptor-mediated apoptosis but is not essential in regulating beta-cell mass or diabetes development. However, beta-cell Fas is critical in the regulation of glucose homeostasis through regulation of the exocytosis machinery.

Phosphatase and tensin homologue (PTEN) deleted on chromosome 10 is a dual-specific phosphatase and a potent antagonist of the phosphoinositide 3-kinase signaling pathway. Although first discovered as a tumor suppressor, emerging evidence supports PTEN as a potential therapeutic target for diabetes. PTEN deletion in beta cells leads to increased beta cell mass and protection from streptozotocin-induced diabetes. Importantly, PTEN deletion does not lead to tumor formation in beta cells. To further assess the potential tumorigenic role of PTEN, we tested the biological role of PTEN in the context of activation of the proto-oncogene c-Myc. We generated and characterized beta cell-specific PTEN knock-out mice expressing an inducible c-Myc transgene in beta cells. Surprisingly, we found that PTEN loss did not confer protection from the overwhelming apoptosis and diabetes development seen with c-Myc activation. Importantly, despite the combined effect of the loss of a tumor suppressor and activation of an oncogene in beta cells, there was no evidence of tumor development with sustained c-Myc activation.