Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation

Can We Really Prevent Suicide?

Every year, suicide is among the top 20 leading causes of death globally for all ages. Unfortunately, suicide is difficult to prevent, in large part because the prevalence of risk factors is high among the general population. In this review, clinical and psychological risk factors are examined and methods for suicide prevention are discussed. Prevention strategies found to be effective in suicide prevention include means restriction, responsible media coverage, and general public education, as well identification methods such as screening, gatekeeper training, and primary care physician education. Although the treatment for preventing suicide is difficult, follow-up that includes pharmacotherapy, psychotherapy, or both may be useful. However, prevention methods cannot be restricted to the individual. Community, social, and policy interventions will also be essentia

Exploring mediating factors in the association between parental psychological distress and psychosocial maladjustment in adolescence

Abstract: Parental psychopathology is associated with increased psychosocial maladjustment in adolescents. We examined, from a psychosocial perspective, the association between parental psychological distress and psychosocial maladjustment in adolescents and assessed the mediating role of psychosocial covariates. This is a cross-sectional survey and the setting include representative sample of Quebec adolescents in 1999. The participants of the study include 13- and 16-year-old children (N = 2,346) in the Social and Health Survey of Quebec Children and Adolescents. The main outcome measures are internalizing disorders, externalizing disorders, substance use, and alcohol consumption. For statistical analysis, we used structural equation modeling to test for mediation. Internalizing and externalizing disorders were significantly associated with parental psychological distress, but not substance use or alcohol consumption. The higher the parental distress, the higher the risk of adolescent mental health disorders. The association between parental psychological distress and internalizing disorders was mediated by adolescent self-esteem, parental emotional support and extrafamilial social support. As for externalizing disorders, these variables only had an independent effect. In conclusion, A family’s well being is a necessary condition for psychosocial adjustment in adolescence. Beyond the psychiatric approach, psychosocial considerations need to be taken into consideration to prevent negative mental health outcomes in children living in homes with distressed parents

Attenuation of Zinc Finger Nuclease Toxicity by Small-Molecule Regulation of Protein Levels

Zinc finger nucleases (ZFNs) have been used successfully to create genome-specific double-strand breaks and thereby stimulate gene targeting by several thousand fold. ZFNs are chimeric proteins composed of a specific DNA-binding domain linked to a non-specific DNA-cleavage domain. By changing key residues in the recognition helix of the specific DNA-binding domain, one can alter the ZFN binding specificity and thereby change the sequence to which a ZFN pair is being targeted. For these and other reasons, ZFNs are being pursued as reagents for genome modification, including use in gene therapy. In order for ZFNs to reach their full potential, it is important to attenuate the cytotoxic effects currently associated with many ZFNs. Here, we evaluate two potential strategies for reducing toxicity by regulating protein levels. Both strategies involve creating ZFNs with shortened half-lives and then regulating protein level with small molecules. First, we destabilize ZFNs by linking a ubiquitin moiety to the N-terminus and regulate ZFN levels using a proteasome inhibitor. Second, we destabilize ZFNs by linking a modified destabilizing FKBP12 domain to the N-terminus and regulate ZFN levels by using a small molecule that blocks the destabilization effect of the N-terminal domain. We show that by regulating protein levels, we can maintain high rates of ZFN-mediated gene targeting while reducing ZFN toxicity

Vendor-based restrictions on pesticide sales to prevent pesticide self-poisoning - a pilot study

Abstract Background In South Asia, up to 20% of people ingesting pesticides for self-poisoning purchase the pesticide from a shop with the sole intention of self-harm. Individuals who are intoxicated with alcohol and/or non-farmers represent 72% of such high-risk individuals. We aimed to test the feasibility and acceptability of vendor-based restrictions on pesticide sales for such high-risk individuals. Methods We conducted a pilot study in 14 (rural = 7, urban = 7) pesticide shops in Anuradhapura District of Sri Lanka. A two-hour training program was delivered to 28 pesticide vendors; the aim of the training was to help vendors recognize and respond to customers at high risk of pesticide self-poisoning. Knowledge and attitudes of vendors towards preventing access to pesticides for self-poisoning at baseline and in a three month follow-up was evaluated by questionnaire. Vendors were interviewed to explore the practice skills taught in the training and their assessment of the program. Results The scores of knowledge and attitudes of the vendors significantly increased by 23% (95% CI 15%–32%, p < 0.001) and by 16% (95% CI 9%–23%, p < 0.001) respectively in the follow-up. Fifteen (60%) vendors reported refusing sell pesticides to a high-risk person (non-farmer or intoxicated person) in the follow-up compared to three (12%) at baseline. Vendors reported that they were aware from community feedback that they had prevented at least seven suicide attempts. On four identified occasions, vendors in urban shops had been unable to recognize the self-harming intention of customers who then ingested the pesticide. Only 2 (8%) vendors were dissatisfied with the training and 23 (92%) said they would recommend it to other vendors. Conclusions Our study suggests that vendor-based sales restriction in regions with high rates of self-poisoning has the potential to reduce access to pesticides for self-poisoning. A large-scale study of the effectiveness and sustainability of this approach is needed

Signatures of Selection in Fusion Transcripts Resulting From Chromosomal Translocations in Human Cancer

BACKGROUND: The recurrence and non-random distribution of translocation breakpoints in human tumors are usually attributed to local sequence features present in the vicinity of the breakpoints. However, it has also been suggested that functional constraints might contribute to delimit the position of translocation breakpoints within the genes involved, but a quantitative analysis of such contribution has been lacking. METHODOLOGY: We have analyzed two well-known signatures of functional selection, such as reading-frame compatibility and non-random combinations of protein domains, on an extensive dataset of fusion proteins resulting from chromosomal translocations in cancer. CONCLUSIONS: Our data provide strong experimental support for the concept that the position of translocation breakpoints in the genome of cancer cells is determined, to a large extent, by the need to combine certain protein domains and to keep an intact reading frame in fusion transcripts. Additionally, the information that we have assembled affords a global view of the oncogenic mechanisms and domain architectures that are used by fusion proteins. This can be used to assess the functional impact of novel chromosomal translocations and to predict the position of breakpoints in the genes involved

ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot

Chromosome translocations induced by DNA damaging agents, such as ionizing radiation and certain chemotherapies, alter genetic information resulting in malignant transformation. Abrogation or loss of the ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, increases the incidence of chromosome translocations. However, how ATM protects cells from chromosome translocations is still unclear. Chromosome translocations involving the MLL gene on 11q23 are the most frequent chromosome abnormalities in secondary leukemias associated with chemotherapy employing etoposide, a topoisomerase II poison. Here we show that ATM deficiency results in the excessive binding of the DNA recombination protein RAD51 at the translocation breakpoint hotspot of 11q23 chromosome translocation after etoposide exposure. Binding of Replication protein A (RPA) and the chromatin remodeler INO80, which facilitate RAD51 loading on damaged DNA, to the hotspot were also increased by ATM deficiency. Thus, in addition to activating DNA damage signaling, ATM may avert chromosome translocations by preventing excessive loading of recombinational repair proteins onto translocation breakpoint hotspots

Long-term protection and mechanism of pacing-induced postconditioning in the heart

Brief periods of ventricular pacing during the early reperfusion phase (pacing-induced postconditioning, PPC) have been shown to reduce infarct size as measured after 2 h of reperfusion. In this study, we investigated (1) whether PPC leads to maintained reduction in infarct size, (2) whether abnormal mechanical load due to asynchronous activation is the trigger for PPC and (3) the signaling pathways that are involved in PPC. Rabbit hearts were subjected to 30 min of coronary occlusion in vivo, followed by 6 weeks of reperfusion. PPC consisted of ten 30-s intervals of left ventricular (LV) pacing, starting at reperfusion. PPC reduced infarct size (TTC staining) normalized to area at risk, from 49.0 ± 3.3% in control to 22.9 ± 5.7% in PPC rabbits. In isolated ejecting rabbit hearts, replacing LV pacing by biventricular pacing abolished the protective effect of PPC, whereas ten 30-s periods of high preload provided a protective effect similar to PPC. The protective effect of PPC was neither affected by the adenosine receptor blocker 8-SPT nor by the angiotensin II receptor blocker candesartan, but was abrogated by the cytoskeletal microtubule-disrupting agent colchicine. Blockers of the mitochondrial KATP channel (5HD), PKC (chelerythrine) and PI3-kinase (wortmannin) all abrogated the protection provided by PPC. In the in situ pig heart, PPC reduced infarct size from 35 ± 4 to 16 ± 12%, a protection which was abolished by the stretch-activated channel blocker gadolinium. No infarct size reduction was achieved if PPC application was delayed by 5 min or if only five pacing cycles were used. The present study indicates that (1) PPC permanently reduces myocardial injury, (2) abnormal mechanical loading is a more likely trigger for PPC than electrical stimulation or G-coupled receptor stimulation and (3) PPC may share downstream pathways with other modes of cardioprotection