Citations

ABSTRACT We examined the pharmacokinetic properties of vancomycin conjugated to a bone-targeting agent (BT) with high affinity for hydroxyapatite after systemic intravenous administration. The results confirm enhanced persistence of BT-vancomycin in plasma and enhanced accumulation in bone relative to vancomycin. This suggests that BT-vancomycin may be a potential carrier for the systemic targeted delivery of vancomycin in the treatment of bone infections, potentially reducing the reliance on surgical debridement to achieve the desired therapeutic outcome.

Abstract Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types. Significance: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer. Cancer Discov; 6(2); 166–75. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109

Staphylococcus aureus, the most common cause of wound infection, produces several exotoxins, including superantigens (SAgs). SAgs are the potent activators of the immune system. Given this unique property, we hypothesized that SAgs produced by S. aureus in wounds would have local, as well as systemic immunologic effects. We tested our hypothesis using a novel staphylococcal skin wound infection model in transgenic mice expressing HLA-DR3. Skin wounds were left uninfected or colonized with S. aureus strains producing SAgs or an isogenic strain not producing any SAg. Animals with wounds challenged with SAg-producing S. aureus had increased morbidity and lower serum IL-17 levels compared to those challenged with the SAg non-producing S. aureus (p = 0.027 and p = 0.032, respectively). At Day 8 following microbial challenge, compared to mice with uninfected wounds, the proportion of Vβ8+CD4+ T cells was increased, while the proportion of Vβ8+CD8+ T cells was decreased only in the spleens of mice challenged with SAg-producing S. aureus (p < 0.001). No such changes were measured in mice challenged with SAg non-producing S. aureus. Lungs, livers and kidneys from mice challenged with SAg-producing, but not SAg non-producing, S. aureus showed inflammatory changes. Overall, SAg-mediated systemic immune activation in wounds harboring S. aureus may have clinical implications.

Abstract Introduction: While effective Brief Tobacco Interventions (BTIs) are available for cigarette smoking and smokeless tobacco, given the changing prevalence of tobacco and nicotine containing products (TNCPs), there is a need for interventions targeting a broader range of TNCPs (eg, cigarettes, smokeless tobacco, electronic cigarettes, and hookah). The purpose of the current investigation was to evaluate the efficacy of a BTI, a 40-minute intervention designed to intervene on four TNCPs in a sample of US military personnel during an 11-week period of involuntary tobacco abstinence, for reducing intentions to use TNCPs and increasing perceptions of harm of TNCPs. Methods: The BTI was administered to 1055 Airmen enrolled in Technical Training in the US Air Force. Assessments of perceived harm and intentions to use nine TNCPs (cigarettes, smokeless tobacco, snus, cigars, cigarillos, pipe, e-cigarettes, roll your own cigarettes, and hookah), were assessed at pretest and posttest (immediately following the BTI). Results: Significant increases in perceived harm were observed across all nine TNCPs (all P &lt; .0001) for both users and nonusers. Intentions to use TNCPs were significantly reduced for most products but mainly among users. Conclusions: Results suggested that a BTI shows promise for impacting TNCP use in a military population. Further research should evaluate the behavioral outcomes (tobacco use) as a result of the intervention. Implications: Given that there are 220 000 new trainees in the military every year, the public health implications of an effective BTI targeting the most commonly used TNCPs for military trainees is considerable.

AbstractSuicide by shotgun is a common method of suicide with high regional variation. We sought to describe their distinct, challenging features and provide demographic and risk characteristics. We reviewed 228 gunshot wounds autopsied at Mayo Clinic from 1994 to 2014; of these, 75 (32.9%) were shotgun wounds. All were suicides and contact range. Ages ranged from 14 to 92 years old; of these, 97% were men. The majority involved the head (70.9%), were intraoral (48.2%), and had upward (73.2%) and backward (73.2%) directionality. Next most common was the chest (21.5%), with backward (94.1%) and downward (64.7%) directionality. Four involved multiple wounds. Wadding was recovered in 16 (21.3%) cases. Six (8.0%) had a survival period. Most (66.7%) took place at home. Seventy‐one percent had a known psychiatric history; 32.4% had positive toxicology. Although contact range shotgun wounds cause severe destruction, entrance wound and other characteristic are identifiable with thorough scene, autopsy, and radiographic documentation.

ABSTRACTEpithelial‐mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single‐nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome‐wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT‐related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive‐cancer patients and 23,447 controls. A P‐value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07–1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69–0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.