The Updated Commentary on the First Geneva Convention – A New Tool for Generating Respect for International Humanitarian Law

Since their publication in the 1950s and the 1980s respectively, the Commentaries on the Geneva Conventions of 1949 and their Additional Protocols of 1977 have become a major reference for the application and interpretation of these treaties. The International Committee of the Red Cross (ICRC), together with a team of renowned experts, is currently updating these Commentaries in order to document developments and provide up-to-date interpretations. The work on the first updated Commentary, the Commentary on the First Geneva Convention relating to the protection of the wounded and sick in the armed forces, has already been finalized. This article provides an overview of the methodology and process of the update and summarizes the main evolutions in the interpretation of the treaty norms reflected in the updated commentary

The Relationship Between Childhood Physical and Sexual Abuse and Adolescent Cannabis Use: A Systematic Review

Background: Among adolescents, cannabis use is a health concern due to associations with drug addiction and mental health disorders across the life course. It has been shown that childhood maltreatment is associated with drug addiction in adulthood. However, a better understanding of the relationship between maltreatment and drug use may improve targeted prevention and interventions. The aim of this systematic review is to describe the association between exposure to childhood maltreatment, specifically physical and sexual abuse, with adolescent cannabis use. Methods: A systematic search strategy was applied to Embase, PsycINFO, and Ovid MEDLINE(R) databases. Methods followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Abstract and title screening was performed to identify papers which reported an estimate of the association between childhood physical or sexual abuse and adolescent cannabis use. Full text screening of each paper was performed, and data were extracted and study quality assessed. Weighted means meta-analysis was performed on studies reporting odds ratios as effect estimates. Results: Of 8,780 screened articles, 13 were identified for inclusion. Eight papers received a quality rating score indicating lower risk of bias. Eleven papers reported the relationship between childhood sexual abuse and adolescent cannabis use; effect estimates ranged from AOR 0.53-AOR 2.18 (weighted mean OR 1.29, 95% CI 1.08-1.49). The relationship between childhood physical abuse and adolescent cannabis use was reported in 7 papers; effect estimates ranged from AOR 1.25-AOR 1.87 (weighted mean OR 1.39, 95% CI 1.12-1.66). Differences in the strength of the evidence were observed by the method of exposure ascertainment, and there was some evidence of differences in association by gender, age of cannabis initiation, and the severity of the abuse. Conclusions: This systematic review indicates childhood physical or sexual abuse may increase risk of adolescent-onset cannabis use. Few studies considered variation in timing of onset, or by gender. Adolescent cannabis use precedes is strongly associated with increased risk of negative mental health outcomes; further exploration of adolescent cannabis use's place on the causal pathway between childhood abuse and adult mental health problems is warranted to improve intervention

Peer Connect for African American breast cancer survivors and caregivers: a train-the-trainer approach for peer support

Racial disparities in breast cancer survivorship are a major concern nationally. How survivors cope with cancer and re-frame their lives is a critical part of survivorship. Community-academic research partnerships may facilitate access to much-needed psychosocial support for African American survivors and caregivers in rural areas, but drivers of successful intervention implementation are not well understood. The purpose of this study was to describe the training and evaluation of Community Coaches and Guides (i.e., peer supporters) using the Peer Connect program for African American breast cancer survivors and caregivers. Community engagement strategies were used to implement the training component of Peer Connect, an evidence-based program grounded in the Diffusion of Innovation Theory utilizing motivational interviewing techniques (MI) and a "train-the-trainer" model. Quantitative and qualitative methods examined implementation outcomes of feasibility, MI fidelity, and acceptability-precursor outcomes that must be achieved before examining intervention impact vis-à-vis changes in support care. Training was feasible to implement and replicable by the trained Community Coaches. Beyond feasibility and replicability, success was modest regarding MI fidelity. Benefits (e.g., serving as role models and having safe sources of support) and lessons learned (e.g., need for additional quality control) were identified as both facilitators and barriers to implementation and as factors that could impact the effectiveness of community-engaged programs to improve survivorship outcomes. Peer Connect, like other programs that employ community-engagement strategies, holds promise to meet the psychosocial support needs of diverse rural cancer survivor populations

Oestrogen shuts the door on SOX9

Oestrogen exerts a robust yet imperfectly understood effect on sexual development in vertebrate embryos. New work by Pask and colleagues in BMC Biology indicates that it may interfere with male development by preventing nuclear localization of SOX9, a master regulator of the testis differentiation pathway

The role of p53 in anti-tumor immunity and response to immunotherapy

p53 is a transcription factor that regulates the expression of genes involved in tumor suppression. p53 mutations mediate tumorigenesis and occur in approximately 50% of human cancers. p53 regulates hundreds of target genes that induce various cell fates including apoptosis, cell cycle arrest, and DNA damage repair. p53 also plays an important role in anti-tumor immunity by regulating TRAIL, DR5, TLRs, Fas, PKR, ULBP1/2, and CCL2; T-cell inhibitory ligand PD-L1; pro-inflammatory cytokines; immune cell activation state; and antigen presentation. Genetic alteration of p53 can contribute to immune evasion by influencing immune cell recruitment to the tumor, cytokine secretion in the TME, and inflammatory signaling pathways. In some contexts, p53 mutations increase neoantigen load which improves response to immune checkpoint inhibition. Therapeutic restoration of mutated p53 can restore anti-cancer immune cell infiltration and ameliorate pro-tumor signaling to induce tumor regression. Indeed, there is clinical evidence to suggest that restoring p53 can induce an anti-cancer immune response in immunologically cold tumors. Clinical trials investigating the combination of p53-restoring compounds or p53-based vaccines with immunotherapy have demonstrated anti-tumor immune activation and tumor regression with heterogeneity across cancer type. In this Review, we discuss the impact of wild-type and mutant p53 on the anti-tumor immune response, outline clinical progress as far as activating p53 to induce an immune response across a variety of cancer types, and highlight open questions limiting effective clinical translation

An essential function for the ATR-Activation-Domain (AAD) of TopBP1 in mouse development and cellular senescence

ATR activation is dependent on temporal and spatial interactions with partner proteins. In the budding yeast model, three proteins – Dpb11TopBP1, Ddc1Rad9 and Dna2 - all interact with and activate Mec1ATR. Each contains an ATR activation domain (ADD) that interacts directly with the Mec1ATR:Ddc2ATRIP complex. Any of the Dpb11TopBP1, Ddc1Rad9 or Dna2 ADDs is sufficient to activate Mec1ATR in vitro. All three can also independently activate Mec1ATR in vivo: the checkpoint is lost only when all three AADs are absent. In metazoans, only TopBP1 has been identified as a direct ATR activator. Depletion-replacement approaches suggest the TopBP1-AAD is both sufficient and necessary for ATR activation. The physiological function of the TopBP1 AAD is, however, unknown. We created a knock-in point mutation (W1147R) that ablates mouse TopBP1-AAD function. TopBP1-W1147R is early embryonic lethal. To analyse TopBP1-W1147R cellular function in vivo, we silenced the wild type TopBP1 allele in heterozygous MEFs. AAD inactivation impaired cell proliferation, promoted premature senescence and compromised Chk1 signalling following UV irradiation. We also show enforced TopBP1 dimerization promotes ATR-dependent Chk1 phosphorylation. Our data suggest that, unlike the yeast models, the TopBP1-AAD is the major activator of ATR, sustaining cell proliferation and embryonic development

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Localization of hRad9 in breast cancer

<p>Abstract</p> <p>Background</p> <p><it>hRad9 </it>is a cell cycle checkpoint gene that is up-regulated in breast cancer. We have previously shown that the mRNA up-regulation correlated with tumor size and local recurrence. Immunohistochemical studies were made to better define the role of <it>hRad9 </it>in breast carcinogenesis.</p> <p>Methods</p> <p>Localisation of hRad9 protein were performed on paired tumor and normal breast tissues. Immunoblotting with and without dephosphorylation was used to define the protein isolated from breast cancer cells.</p> <p>Results</p> <p>Increased hRad9 protein was observed in breast cancer cells nucleus compared to non-tumor epithelium. This nuclear protein existed in hyperphosphorylated forms which may be those of the hRad9-hRad1-hHus1 complex.</p> <p>Conclusion</p> <p>Finding of hyperphosphorylated forms of hRad9 in the nucleus of cancer cells is in keeping with its function in ameliorating DNA instability, whereby it inadvertently assists tumor growth.</p

Multiple ATR-Chk1 Pathway Proteins Preferentially Associate with Checkpoint-Inducing DNA Substrates

The ATR-Chk1 DNA damage checkpoint pathway is a critical regulator of the cellular response to DNA damage and replication stress in human cells. The variety of environmental, chemotherapeutic, and carcinogenic agents that activate this signal transduction pathway do so primarily through the formation of bulky adducts in DNA and subsequent effects on DNA replication fork progression. Because there are many protein-protein and protein-DNA interactions proposed to be involved in activation and/or maintenance of ATR-Chk1 signaling in vivo, we systematically analyzed the association of a number of ATR-Chk1 pathway proteins with relevant checkpoint-inducing DNA structures in vitro. These DNA substrates included single-stranded DNA, branched DNA, and bulky adduct-containing DNA. We found that many checkpoint proteins show a preference for single-stranded, branched, and bulky adduct-containing DNA in comparison to undamaged, double-stranded DNA. We additionally found that the association of checkpoint proteins with bulky DNA damage relative to undamaged DNA was strongly influenced by the ionic strength of the binding reaction. Interestingly, among the checkpoint proteins analyzed the checkpoint mediator proteins Tipin and Claspin showed the greatest differential affinity for checkpoint-inducing DNA structures. We conclude that the association and accumulation of multiple checkpoint proteins with DNA structures indicative of DNA damage and replication stress likely contribute to optimal ATR-Chk1 DNA damage checkpoint responses