Toenail selenium status and DNA repair capacity among female <Emphasis Type="Italic">BRCA1</Emphasis> mutation carriers

Selenium is an important cofactor of various antioxidant enzymes and has been shown to enhance DNA repair in normal human fibroblasts. Oral selenium supplementation has also been shown to decrease the number of chromosome breaks in BRCA1 mutation carriers. Because the predisposition to cancer among BRCA1 mutation carriers may be linked to high rates of DNA damage and chromosome breakage, we evaluated the association between toenail selenium concentrations and three measures of DNA repair capacity (the single-cell alkaline gel electrophoresis (comet) assay, the micronucleus test, and the enumeration of γ-H2AX nuclear foci) in female BRCA1 mutation carriers and in non-carriers. Toenail selenium levels were inversely associated with levels of chromosomal damage following exposure to gamma-irradiation, as assessed by the micronucleus test. This association was limited to women with a BRCA1 mutation (p = 0.03). Toenail selenium was not a significant predictor of DNA repair capacity, as quantified by either the comet assay or the number of γ-H2AX foci, in carriers or in non-carriers. These results provide evidence for a possible protective effect of selenium against BRCA1-associated breast cancers.     

Stunting,adiposity, and low-grade inflammation in African adolescents from a township high school

ObjectiveThe objective of this study was to compare the inflammatory status of children with differences in nutritional status.MethodsThis was a cross-sectional study of 184 African children aged 13–18 y from a low socioeconomic background that compared stunted with non-stunted and lean with over-fat (percentage of body fat above normal cutoff points) children. Fasting serum tumor necrosis factor-α, interleukin-6, C-reactive protein, and insulin were measured using high-sensitivity methods. Body composition was assessed using anthropometry and air-displacement plethysmography. T tests for parametric data and the Mann-Whitney test for non-parametric data were used to compare groups. Regression analyses and principal components analyses were done to assess relations between body composition and biochemical variables.ResultsOf all participants 18% were stunted. Serum tumor necrosis factor-α of stunted girls was higher than in non-stunted girls. More of the stunted boys were over-fat compared with their non-stunted counterparts. Regression analyses showed that insulin resistance, diastolic blood pressure, and C-reactive protein contributed significantly to interleukin-6 in boys. Serum C-reactive protein, waist circumference, and body mass index clustered together in factor analysis in boys. Serum interleukin-6, waist–hip ratio, and tumor necrosis factor-α clustered together in factor analysis in girls.ConclusionAn association between adiposity and stunting and between adiposity low-grade inflammation was found in this study. Interventions for stunted children focus mainly on correction of undernutrition by providing feeding schemes. Attention should, however, also be paid to changes in body composition over time to prevent excessive abdominal fat accumulation and risk for cardiovascular diseases later in life.     

Revisiting breast cancer patients who previously tested negative for <Emphasis Type="Italic">BRCA</Emphasis> mutations using a 12-gene panel

Purpose

BRCA mutations contribute to about 20% of all hereditary breast cancers. With full-genome sequencing as the emerging standard for genetic testing, other breast cancer susceptibility genes have been identified and may collectively contribute to up to 30% of all hereditary breast cancers. We re-assessed women who had previously tested negative for a BRCA mutation when outdated techniques were used, and discuss the implications of identifying a mutation several years after initial genetic testing.

Methods

We evaluated the prevalence of mutations in 12 breast cancer susceptibility genes (including BRCA1 and BRCA2) in 190 breast cancer patients with a strong family history of breast cancer. These women had previously tested negative for mutations in the large coding exons of BRCA1 and BRCA2 using the protein truncation test (PTT) between the years of 1996 and 2013.

Results

We identified pathogenic mutations in 17 of 190 (9%) women. Six mutations were detected in BRCA1 (n = 2) and BRCA2 (n = 4). Eleven mutations were found in other breast cancer susceptibility genes including CHEK2 (n = 5), PALB2 (n = 2), BLM (n = 2), ATM (n = 1) and TP53 (n = 1).

Conclusion

Among 190 breast cancer patients with a family history of the disease, and who previously received a negative result for BRCA mutations using the PTT, 17 (9%) women were found to carry a high-risk pathogenic mutation in a breast cancer susceptibility gene. Six of these women were BRCA mutation carriers who were missed previously. These findings support the rationale for updated genetic testing in patients who tested BRCA mutation negative using outdated techniques.

     

Immunohistochemical detection of arginine methylated proteins (MeRP) in archival tissues

Vezzalini M, Aletta J M, Beghelli S, Moratti E, Della Peruta M, Mafficini A, Mojica W D, Mombello A, Scarpa A & Sorio C
(2010) Histopathology 57 , 725–733
Immunohistochemical detection of arginine methylated proteins ( MeRP ) in archival tissues Aims:  To (i) determine whether methylarginine‐specific antibodies can be employed for standard immunohistochemical analysis of paraffin‐embedded tissues, (ii) analyse methylarginine expression in normal and neoplastic tissues and (iii) correlate methylarginine expression with that of protein arginine methyltransferase (PRMT1), the predominant cellular arginine methyltransferase. Methods and results:  Immunohistochemistry of normal and cancer tissues was performed utilizing three commercial polyclonal antibodies: anti‐methylarginine‐specific antibody (anti‐mRG) raised against a methylarginine peptide, Control antibody (anti‐RG), a control antiserum raised against a corresponding arginine peptide without any methylated residues and anti‐PRMT1. Nuclear and/or cytoplasmic methylarginine expression was detected in all keratinized and non‐keratinized epithelia. A preliminary survey of a series of thyroid, pancreatic, colonic and gastric cancers identified a different pattern of methylarginine expression in comparison with normal tissue. A correlation between methylarginine staining and PRMT1 expression was found in all normal and cancer tissues analysed. Conclusion:  Methylarginine‐specific antibodies are capable of recognizing methylarginine proteins (MeRP) in paraffin‐embedded tissues. Methylarginine proteins are expressed widely and show differences in subcellular localization in various organs and neoplastic conditions. The efficient detection of methylproteins by standard immunohistochemistry provides a new tool to investigate the role of methylarginine proteins (MeRP) in biological processes including carcinogenesis.     

Advanced-stage hepatocellular carcinoma with portal vein thrombosis: conventional versus drug-eluting beads transcatheter arterial chemoembolization

Objectives

Our study sought to compare the overall survival in patients with hepatocellular carcinoma (HCC) and portal venous thrombosis (PVT), treated with either conventional trans-arterial chemoembolization (cTACE) or drug-eluting beads (DEB) TACE.

Methods

This retrospective analysis included a total of 133 patients, treated without cross-over and compared head-to-head by means or propensity score weighting. Mortality was compared using survival analysis upon propensity score weighting. Adverse events and liver toxicity grade ≥3 were recorded and reported for each TACE. In order to compare with historical sorafenib studies, a sub-group analysis was performed and included patients who fulfilled the SHARP inclusion criteria.

Results

The median overall survival (MOS) of the entire cohort was 4.53 months (95 % CI, 3.63–6.03). MOS was similar across treatment arms, no significant difference between cTACE (N?=?95) and DEB-TACE (N?=?38) was observed (MOS of 5.0 vs. 3.33 months, respectively; p?=?0.157). The most common adverse events after cTACE and DEB- TACE, respectively, were as follows: post-embolization syndrome [N?=?57 (30.0 %) and N?=?38 (61.3 %)], diarrhea [N?=?3 (1.6 %) and N?=?3 (4.8 %)], and encephalopathy [N?=?11 (5.8 %) and N?=?2 (3.2 %)].

Conclusion

Our retrospective study could not reveal a difference in toxicity and efficiency between cTACE and DEB-TACE for treatment of advanced stage HCC with PVT.

Key Points

? Conventional TACE (cTACE) and drug-eluting-beads TACE (DEB-TACE) demonstrated equal safety profiles. ? Survival rates after TACE are similar to patients treated with sorafenib. ? Child-Pugh class and tumor burden are reliable predictors of survival.

     

Exposure to the Amino Acids Histidine,Lysine, and Threonine Reduces mTOR Activity and Affects Neurodevelopment in a Human Cerebral Organoid Model

Evidence of the impact of nutrition on human brain development is compelling. Previous in vitro and in vivo results show that three specific amino acids, histidine, lysine, and threonine, synergistically inhibit mTOR activity and behavior. Therefore, the prenatal availability of these amino acids could be important for human neurodevelopment. However, methods to study the underlying mechanisms in a human model of neurodevelopment are limited. Here, we pioneer the use of human cerebral organoids to investigate the impact of amino acid supplementation on neurodevelopment. In this study, cerebral organoids were exposed to 10 mM and 50 mM of the amino acids threonine, histidine, and lysine. The impact was determined by measuring mTOR activity using Western blots, general cerebral organoid size, and gene expression by RNA sequencing. Exposure to threonine, histidine, and lysine led to decreased mTOR activity and markedly reduced organoid size, supporting findings in rodent studies. RNA sequencing identified comprehensive changes in gene expression, with enrichment in genes related to specific biological processes (among which are mTOR signaling and immune function) and to specific cell types, including proliferative precursor cells, microglia, and astrocytes. Altogether, cerebral organoids are responsive to nutritional exposure by increasing specific amino acid concentrations and reflect findings from previous rodent studies. Threonine, histidine, and lysine exposure impacts the early development of human cerebral organoids, illustrated by the inhibition of mTOR activity, reduced size, and altered gene expression.     

End-organ damage in urbanized Africans with low plasma renin levels: the SABPA study

The purpose of this study was to evaluate whether active renin concentration is associated with markers of end-organ damage in urbanized Africans. This study forms part of the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. For this study, 81 men and 74 women were divided into low- and high-renin groups. Ambulatory blood pressure measurements were conducted. A resting 12-lead ECG was determined in order to determine the gender-specific Cornell voltage. Cardiovascular variables were continuously recorded with the Finometer. Carotid-dorsalis pedis pulse wave velocity was obtained with the Complior acquisition system. The carotid intima-media thickness (CIMT) was obtained with the SonoSite MicroMaxx. Blood samples were collected; serum and plasma were stored at ?80?°C for analysis. Anthropometric measurements were taken using standard methods. A general health questionnaire was also completed. The urinary creatinine was determined with a calorimetric method and albumin with a turbidimetric method. The serum sodium and potassium were determined by making use of the Konelab TM 20i Sequential Multiple Analyzer Computer (SMAC). The concentration of active renin in the plasma was analyzed by making use of a high-sensitivity radio-immunometric assay. A negative association (r?=??0.29, p?相似文献