Boron Containing Pyrimidines,Nucleosides, and Oligonucleotides for Neutron Capture Therapy

Abstract

The synthesis and encouraging biological findings with boron-containing nucleosides, such as 5-dihydroxyboryl-2′-deoxyuridine, which could be used for boron neutron capture therapy (BNCT) for the treatment of various malignancies, has provided momentum to synthesize several boron containing nucleosides and oligomers. BNCT is based on the property of the non-radioactive boron-10 isotope to capture low energy neutrons, thereby producing a localized cell-destroying nuclear reaction. Thus, irradiation of tumor cells with neutrons, following incorporation of the boronated nucleoside, would result in the destruction of tumor tissue only. Intracellular phosphorylation by nucleoside kinases, and/or incorporation into the cancer cell DNA as a false nucleotide precursor, followed by irradiation by neutrons, would lead primarily to tumor cell death. The synthetic and biological approaches for boronated pyrimidines, nucleosides, and oligonucleotides for BNCT are reviewed.     

A Flexible Approach for the Analysis of Rare Variants Allowing for a Mixture of Effects on Binary or Quantitative Traits

Multiple rare variants either within or across genes have been hypothesised to collectively influence complex human traits. The increasing availability of high throughput sequencing technologies offers the opportunity to study the effect of rare variants on these traits. However, appropriate and computationally efficient analytical methods are required to account for collections of rare variants that display a combination of protective, deleterious and null effects on the trait. We have developed a novel method for the analysis of rare genetic variation in a gene, region or pathway that, by simply aggregating summary statistics at each variant, can: (i) test for the presence of a mixture of effects on a trait; (ii) be applied to both binary and quantitative traits in population-based and family-based data; (iii) adjust for covariates to allow for non-genetic risk factors and; (iv) incorporate imputed genetic variation. In addition, for preliminary identification of promising genes, the method can be applied to association summary statistics, available from meta-analysis of published data, for example, without the need for individual level genotype data. Through simulation, we show that our method is immune to the presence of bi-directional effects, with no apparent loss in power across a range of different mixtures, and can achieve greater power than existing approaches as long as summary statistics at each variant are robust. We apply our method to investigate association of type-1 diabetes with imputed rare variants within genes in the major histocompatibility complex using genotype data from the Wellcome Trust Case Control Consortium.     

Urinary Interleukin-8 Is a Biomarker of Stress in Emergency Physicians,Especially with Advancing Age — The JOBSTRESS* Randomized Trial

Background

Emergency physicians are exposed to greater stress during a 24-hour shift (24 hS) than a 14-hour night shift (14 hS), with an impact lasting several days. Interleukin-8 (IL-8) is postulated to be a chronic stress biomarker. However, no studies have tracked IL-8 over several shifts or used it for monitoring short-term residual stress. The IL-8 response to the shifts may also increase with age. Conveniently, IL-8 can be measured non-intrusively from urine.

Methods

We conducted a shifts-randomized trial comparing 17 emergency physicians’ urinary IL-8 levels during a 24 hS, a 14 hS, and a control day (clerical work on return from leave). Mean levels of IL-8 were compared using a Wilcoxon matched-pairs test. Independent associations of key factors including shifts, stress, and age with IL-8 levels were further assessed in a multivariable generalized estimating equations model.

Results

Mean urinary IL-8 levels almost doubled during and after a 24 hS compared with a 14 hS or a control day. Furthermore, IL-8 levels failed to return to control values at the end of the third day after the shift despite a rest day following the 24 hS. In the multivariable model, engaging in a 24 hS, self-reported stress, and age were independently associated with higher IL-8 levels. A 24 hS significantly increased IL-8 levels by 1.9 ng (p = .007). Similarly, for every unit increase in self-reported stress, there was a 0.11 ng increase in IL-8 levels (p = .003); and for every one year advance in age of physicians, IL-8 levels also increased by 0.11 ng (p = .018).

Conclusion

The 24 hS generated a prolonged response of the immune system. Urinary IL-8 was a strong biomarker of stress under intensive and prolonged demands, both acutely and over time. Because elevated IL-8 levels are associated with cardiovascular disease and negative psychological consequences, we suggest that emergency physicians limit their exposure to 24 hS, especially with advancing age.     

What drives interspecies graft union success? Exploring the role of phylogenetic relatedness and stem anatomy

The underlying mechanisms that determine whether two species can form a successful graft union (graft compatibility) remain obscure. Two prominent hypotheses are (1) the more closely related species are, the higher the graft success and (2) the vascular anatomy at the graft junction influences graft success. In this paper these two hypotheses are examined in a systematic way using graft combinations selected from a range of (a) phylogenetically close and more distant legume species, (b) species displaying different germination patterns and (c) scions and rootstocks possessing contrasting stem tissues and vascular patterns. Relatedness of species was not a good predictor of graft compatibility, as vascular reconnection can occur between distantly related species and can fail to occur in some more closely related species. Similarly, neither the stem tissues present at the graft junction nor the vascular anatomy correlated with the success of vascular reconnection. Relatedness and stem anatomy therefore do not appear to be the determining factors in successful vascular reconnection after grafting in legumes. These results are discussed in conjunction with other hypotheses such as the role of auxin.     

Infrequent Breakfast Consumption Is Associated with Higher Body Adiposity and Abdominal Obesity in Malaysian School-Aged Adolescents

Unhealthy dietary pattern increases the risk of obesity and metabolic disorders in growing children and adolescents. However, the way the habitual pattern of breakfast consumption influences body composition and risk of obesity in adolescents is not well defined. Thus, the aim of the present study was to assess any associations between breakfast consumption practices and body composition profiles in 236 apparently healthy adolescents aged 12 to 19 years. A self-administered questionnaire on dietary behaviour and lifestyle practices and a dietary food frequency questionnaire were used. Body composition and adiposity indices were determined using standard anthropometric measurement protocols and dual energy χ-ray absorptiometry (DXA). Mean age of the participants was 15.3±1.9 years. The majority of participants (71.2%) fell in the normal body mass index (BMI) ranges. Breakfast consumption patterns showed that only half of the participants (50%) were consuming breakfast daily. Gender-specific multivariate analyses (ANCOVA) showed that in both boys and girls, those eating breakfast at least 5 times a week had significantly lower body weight, body mass index (BMI), BMI z-scores, waist circumference, body fat mass and percent body fat (%BF) compared to infrequent breakfast eaters, after adjustment for age, household income, pubertal status, eating-out and snacking practices, daily energy intakes, and daily physical activity levels. The present findings indicate that infrequent breakfast consumption is associated with higher body adiposity and abdominal obesity. Therefore, daily breakfast consumption with healthy food choices should be encouraged in growing children and adolescents to prevent adiposity during these critical years of growth.     

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

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Mutation of a conserved asparagine in the I-like domain promotes constitutively active integrins alphaLbeta2 and alphaIIbbeta3

The leukocyte beta2 integrins are heterodimeric adhesion receptors required for a functional immune system. Many leukocyte adhesion deficiency-1 (LAD-1) mutations disrupt the expression and function of beta2 integrins. Herein, we further characterized the LAD-1 mutation N329S in the beta2 inserted (I)-like domain. This mutation converted alphaLbeta2 from a resting into a high affinity conformer because alphaLbeta2N329S transfectants adhered avidly to ligand intercellular adhesion molecule (ICAM)-3 in the absence of additional activating agent. An extended open conformation is adopted by alphaLbeta2N329S because of its reactivity with the beta2 activation reporter monoclonal antibodies MEM148 and KIM127. A corresponding mutation in beta3 generated constitutively active alphaIIbbeta3 that adhered to fibrinogen. This Asn is conserved in all human beta subunits, and it resides before the last helix of the I-like domain, which is known to be important in activation signal propagation. By mutagenesis studies and review of existing integrin structures, we conjectured that this conserved Asn may have a primary role in shaping the I-like domain by stabilizing the conformation of the alpha7 helix and the beta6-alpha7 loop in the I-like domain.     

Conserved regulation of MAP kinase expression by PUF RNA-binding proteins

Mitogen-activated protein kinase (MAPK) and PUF (for Pumilio and FBF [fem-3 binding factor]) RNA-binding proteins control many cellular processes critical for animal development and tissue homeostasis. In the present work, we report that PUF proteins act directly on MAPK/ERK-encoding mRNAs to downregulate their expression in both the Caenorhabditis elegans germline and human embryonic stem cells. In C. elegans, FBF/PUF binds regulatory elements in the mpk-1 3′ untranslated region (3′ UTR) and coprecipitates with mpk-1 mRNA; moreover, mpk-1 expression increases dramatically in FBF mutants. In human embryonic stem cells, PUM2/PUF binds 3′UTR elements in both Erk2 and p38α mRNAs, and PUM2 represses reporter constructs carrying either Erk2 or p38α 3′ UTRs. Therefore, the PUF control of MAPK expression is conserved. Its biological function was explored in nematodes, where FBF promotes the self-renewal of germline stem cells, and MPK-1 promotes oocyte maturation and germ cell apoptosis. We found that FBF acts redundantly with LIP-1, the C. elegans homolog of MAPK phosphatase (MKP), to restrict MAPK activity and prevent apoptosis. In mammals, activated MAPK can promote apoptosis of cancer cells and restrict stem cell self-renewal, and MKP is upregulated in cancer cells. We propose that the dual negative regulation of MAPK by both PUF repression and MKP inhibition may be a conserved mechanism that influences both stem cell maintenance and tumor progression.