Do circulating neutrophil extracellular traps predict recurrence in early breast cancer?

BackgroundNeutrophil extracellular traps (NETs), three-dimensional structures formed by neutrophil enzymes such as neutrophil elastase (NE) and nuclear components (DNA), have been associated with progression and metastasis in breast cancer (BC). Thus, the aim of this study was to evaluate the association of circulating NETs with clinicopathological characteristics and outcomes in early BC.MethodsA prospective cohort included women with newly diagnosed early BC. NETs were defined as the presence of NE-DNA complexes in plasma, measured by optical density. Levels of NETs were dichotomized according to the median, as low and high levels of circulating NETs. Fisher’s exact test was used to evaluate associations between NETs and clinicopathological characteristics and outcomes. Survival was assessed using the Kaplan Meier method and log-rank test.ResultsForty patients were included, 23 (57.5%) patients with low and 17 (42.5%) with high levels of circulating NETs. No associations were found between clinicopathological characteristics and circulating NETs levels. Recurrence (p = 0.99) and site of recurrence (p = 0.99) were not statistically associated with plasma NETs levels. Overall, recurrence-free survival was not statistically different between circulating levels of NETs.ConclusionsWith a short follow-up and low number of events, our results suggest that circulating levels of NETs at diagnosis of early BC are not associated with more aggressive clinicopathological characteristics, recurrence, or site of recurrence

Familial Papillary Thyroid Carcinoma: A Retrospective Analysis

Background. Whether or not the familial form of papillary thyroid carcinoma is more aggressive than the sporadic form of the disease remains controversial. Methods. To explore this question and whether or not increased aggressiveness is more apparent in families with multiple affected members, we performed a chi square by trend analysis on our patients clinical and pathologic data comparing: first degree families with three or more affected members versus first degree families with two affected members versus sporadic cases of papillary thyroid carcinoma. Results. No statistically significant trends were seen for any presenting surgical pathology parameter, age at presentation, length of follow-up or gender distribution. The familial groups exhibited significant trends for higher rates of reoperation (P = 0.05) and/or requiring additional radioactive iodine therapy (P = 0.03), distant metastases (P = 0.003) and deaths (P = 0.01). These aggressive features were most apparent in certain families with three or more affected members. Conclusions. Using the chi square by trend analysis, a significant trend was seen for the familial form of papillary thyroid cancer to possess more aggressive features than the sporadic disease. Prompt recognition of the familial nature of the disease may provide earlier diagnosis and treatment in similarly affected family members

Genome- and CD4\u3csup\u3e+\u3c/sup\u3e T-Cell Methylome-Wide Association Study of Circulating Trimethylamine-N-Oxide in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)

Background: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels. Methods and results: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, e.g. lipids or inflammatory cytokines. We first estimated TMAO heritability at 27%, indicating a moderate genetic influence. We used 1000 Genomes imputed data (n = 626) to estimate genome-wide associations with TMAO levels, adjusting for age, sex, family relationships, and study site. The genome-wide study yielded one significant hit at the genome-wide level, located in an intergenic region on chromosome 4. We subsequently quantified epigenome-wide DNA methylation using the Illumina Infinium array on CD4þ Tcells. We tested for association of methylation loci with circulating TMAO (n = 847), adjusting for age, sex, family relationships, and study site as the genome-wide study plus principal components capturing CD4þ T-cell purity. Upon adjusting for multiple testing, none of the epigenetic findings were statistically significant. Conclusions: Our findings contribute to the growing body of evidence suggesting that neither genetic nor epigenetic factors play a critical role in establishing circulating TMAO levels in humans

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=−0.09±0.01 mmol l−1, P=3.4 × 10−12), T2D risk (OR[95%CI]=0.86[0.76–0.96], P=0.010), early insulin secretion (β=−0.07±0.035 pmolinsulin mmolglucose−1, P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l−1, P=4.3 × 10−4). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10−6) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l−1, P=1.3 × 10−8). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility. Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1R significantly associated with these traits

Attention-deficit hyperactivity disorder and nonsuicidal self-injury in a clinical sample of adolescents: the role of comorbidities and gender.

BACKGROUND: The aim of the present study was to investigate the possible association between attention-deficit hyperactivity disorder (ADHD) and non-suicidal self-injury (NSSI) with special focus on the role of comorbidities and gender in a clinical sample of adolescents with both a dimensional and a categorical approach to psychopathology. METHODS: Using a structured interview, the Mini International Neuropsychiatric Interview Kid and a self-rated questionnaire, the Deliberate Self-Harm Inventory, the authors examined 202 inpatient adolescents (aged: 13-18 years) in the Vadaskert Child and Adolescent Psychiatric Hospital and Outpatient Clinic, Budapest, Hungary. Descriptive statistics, Mann-Whitney U test, chi-square test and mediator model were used. RESULTS: Fifty-two adolescents met full criteria for ADHD and a further 77 showed symptoms of ADHD at the subthreshold level. From the 52 adolescents diagnosed with ADHD, 35 (67.30%) had NSSI, of whom there were significantly more girls than boys, boys: n = 10 (28.60%), girls: n = 25 (71.40%) ((chi(2)(1) = 10.643 p < .001 varphi = .452). Multiple mediation analyses resulted in a moderated mediation model in which the relationship between symptoms of ADHD and the prevalence of current NSSI was fully mediated by the symptoms of comorbid conditions in both sex. Significant mediators were the symptoms of affective and psychotic disorders and suicidality in both sexes and the symptoms of alcohol abuse/dependence disorders in girls. CONCLUSIONS: ADHD symptoms are associated with an increased risk of NSSI in adolescents, especially in the case of girls. Our findings suggest that clinicians should routinely screen for the symptoms of ADHD and comorbidity, with a special focus on the symptoms of affective disorders and alcohol abuse/dependence psychotic symptoms to prevent NSSI

BRM Immunotherapy of Orthotopically Implanted Murine Bladder Tumours: Treatment Response by Monitoring MRI

The authors evaluated magnetic resonance imaging (MRI) for monitoring orthotopic bladder tumour growth and treatment response to intravesical immunotherapy with the biological response modifiers (BRMs): recombinant tumour necrosis factor alpha (TNF-α), combination of TNF-α plus interferon gamma (IFN-γ) and interleukin-2 (IL-2). MRI demonstrated detection of early superficial murine bladder tumour (MBT-2) and accurate sequential assessment of the topography and depth of intravesical tumour involvement. Response to intravesical instillations with multiple doses ofBRMs was assessed against early stage MBT-2 bladder tumours (confirmed by MRI) 14 days after transurethral tumour implantation. Serial MRI scans of TNF-α treated mice revealed significant retardation of tumour growth which correlated well with corresponding histological examination of the whole mount bladder sections illustrating areas and depth of tumour regression. Intravesical instillation of combination TNF-α plus IFN-γ into tumour-bearing mice caused tumour growth inhibition up to 21 days following treatment; the results, however, were not superior to those noted with TNF-α alone. Sequential MR images of tumour-bearing bladders following intravesical treatment with IL-2 revealed tumour regression with no visible tumour from day 21 to 33 post tumour implant. Histological examination revealed foci of carcinoma in situ only. Control untreated bladders revealed deeply invasive transitional cell carcinoma. These results show that MRI offers a dependable tool for noninvasive monitoring of tumour growth and of the course of experimental bladder tumour during therapy