On being “actionable”: clinical sequencing and the emerging contours of a regime of genomic medicine in oncology

This article explores commercial, academic, and national initiatives aimed at using sequencing technologies to generate “actionable” genomic results that can be applied to the clinical management of oncology patients. We argue that the term “actionable” is not merely a buzzword, but signals the emergence of a distinctive sociotechnical regime of genomic medicine in oncology. Unlike other regimes of genomic medicine that are organized around assessing and managing inherited risk for developing cancer (e.g. BRCA testing), actionable regimes aim to generate predictive relationships between genetic information and drug therapies, thereby generating new kinds of clinical actions. We explore how these genomic results are made actionable by articulating them with existing clinical routines, clinical trials, regulatory regimes, and health care systems; and in turn, how clinical sequencing programs have begun to reconfigure knowledge and practices in oncology. Actionability regimes confirm the emergence of bio-clinical decision-making in oncology, whereby the articulation of molecular hypotheses and experimental therapeutics become central to patient care.     

The capacity of conophthorin to enhance the attraction of two Xylosandrus species (Coleoptera: Curculionidae: Scolytinae) to ethanol and the efficacy of verbenone as a deterrent

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Caloric restriction augments radiation efficacy in breast cancer

Dietary modification such as caloric restriction (CR) has been shown to decrease tumor initiation and progression. We sought to determine if nutrient restriction could be used as a novel therapeutic intervention to enhance cytotoxic therapies such as radiation (IR) and alter the molecular profile of triple-negative breast cancer (TNBC), which displays a poor prognosis. In two murine models of TNBC, significant tumor regression is noted with IR or diet modification, and a greater regression is observed combining diet modification with IR. Two methods of diet modification were compared, and it was found that a daily 30% reduction in total calories provided more significant tumor regression than alternate day feeding. At the molecular level, tumors treated with CR and IR showed less proliferation and more apoptosis. cDNA array analysis demonstrated the IGF-1R pathway plays a key role in achieving this physiologic response, and multiple members of the IGF-1R pathway including IGF-1R, IRS, PIK3ca and mTOR were found to be downregulated. The innovative use of CR as a novel therapeutic option has the potential to change the biology of tumors and enhance the opportunity for clinical benefit in the treatment of patients with TNBC.     

The Contribution of Non-Conventional T Cells and NK Cells in the Mycobacterial-Specific IFNγ Response in Bacille Calmette-Guérin (BCG)-Immunized Infants

Background

The Mycobacterium bovis Bacille Calmette-Guérin (BCG) vaccine is given to >120 million infants each year worldwide. Most studies investigating the immune response to BCG have focused on adaptive immunity. However the importance of TCR-gamma/delta (γδ) T cells and NK cells in the mycobacterial-specific immune response is of increasing interest.

Methods

Participants in four age-groups were BCG-immunized. Ten weeks later, in vitro BCG-stimulated blood was analyzed for NK and T cell markers, and intracellular IFNgamma (IFNγ) by flow cytometry. Total functional IFNγ response was calculated using integrated median fluorescence intensity (iMFI).

Results

In infants and children, CD4 and CD4-CD8- (double-negative (DN)) T cells were the main IFNγ-expressing cells representing 43-56% and 27-37% of total CD3+ IFNγ+ T cells respectively. The iMFI was higher in DN T cells compared to CD4 T cells in all age groups, with the greatest differences seen in infants immunized at birth (p=0.002) or 2 months of age (p<0.0001). When NK cells were included in the analysis, they accounted for the majority of total IFNγ-expressing cells and, together with DN Vδ2 γδ T cells, had the highest iMFI in infants immunized at birth or 2 months of age.

Conclusion

In addition to CD4 T cells, NK cells and DN T cells, including Vδ2 γδ T cells, are the key populations producing IFNγ in response to BCG immunization in infants and children. This suggests that innate immunity and unconventional T cells play a greater role in the mycobacterial immune response than previously recognized and should be considered in the design and assessment of novel tuberculosis vaccines.     

Electron Microscopic,Genetic and Protein Expression Analyses of Helicobacter acinonychis Strains from a Bengal Tiger

Colonization by Helicobacter species is commonly noted in many mammals. These infections often remain unrecognized, but can cause severe health complications or more subtle host immune perturbations. The aim of this study was to isolate and characterize putative novel Helicobacter spp. from Bengal tigers in Thailand. Morphological investigation (Gram-staining and electron microscopy) and genetic studies (16SrRNA, 23SrRNA, flagellin, urease and prophage gene analyses, RAPD DNA fingerprinting and restriction fragment polymorphisms) as well as Western blotting were used to characterize the isolated Helicobacters. Electron microscopy revealed spiral-shaped bacteria, which varied in length (2.5–6 µm) and contained up to four monopolar sheathed flagella. The 16SrRNA, 23SrRNA, sequencing and protein expression analyses identified novel H. acinonychis isolates closely related to H. pylori. These Asian isolates are genetically very similar to H. acinonychis strains of other big cats (cheetahs, lions, lion-tiger hybrid and other tigers) from North America and Europe, which is remarkable in the context of the great genetic diversity among worldwide H. pylori strains. We also found by immunoblotting that the Bengal tiger isolates express UreaseA/B, flagellin, BabA adhesin, neutrophil-activating protein NapA, HtrA protease, γ-glutamyl-transpeptidase GGT, Slt lytic transglycosylase and two DNA transfer relaxase orthologs that were known from H. pylori, but not the cag pathogenicity island, nor CagA, VacA, SabA, DupA or OipA proteins. These results give fresh insights into H. acinonychis genetics and the expression of potential pathogenicity-associated factors and their possible pathophysiological relevance in related gastric infections.     

A Systematic Review of the Relationships between Intimate Partner Violence and HIV/AIDS

Background

Intimate partner violence (IPV) is a significant health problem that has been associated with HIV infection in numerous studies. We aimed to systematically review the literature on relationships between IPV and HIV in order to describe the prevalence of IPV in people with HIV, the prevalence of HIV in people experiencing IPV, the association between IPV and HIV, and evidence regarding mechanisms of risk and interventions.

Methods

Data sources were 10 electronic databases and reference lists. Studies were included if they reported data on the relationship between IPV and HIV. All records were independently reviewed by two authors at the stages of title and abstract review and full text review. Any abstract considered eligible by either reviewer was reviewed in full, and any disagreement regarding eligibility of full texts or data extracted was resolved by discussion.

Results

101 articles were included. Experiencing IPV and HIV infection were associated in unadjusted analyses in most studies, as well as in adjusted analyses in many studies. The findings of qualitative and quantitative studies assessing potential mechanisms linking IPV and HIV were variable. Few interventions have been assessed, but two identified in this review were promising in terms of preventing IPV, though not HIV infection.

Conclusions

Experiencing IPV and HIV infection tend to be associated in unadjusted analyses, suggesting that IPV screening and linkage with relevant programs and services may be valuable. It is unclear whether there is a causal association between experiencing IPV and HIV infection. Research should focus on defining parameters of IPV which are relevant to HIV infection, including type of IPV and period of exposure and risk, on assessing potential mechanisms, and on developing and assessing interventions which build on the strengths of existing studies.     

Personal and Household Hygiene,Environmental Contamination,and Health in Undergraduate Residence Halls in New York City, 2011

Background

While several studies have documented the importance of hand washing in the university setting, the added role of environmental hygiene remains poorly understood. The purpose of this study was to characterize the personal and environmental hygiene habits of college students, define the determinants of hygiene in this population, and assess the relationship between reported hygiene behaviors, environmental contamination, and health status.

Methods

501 undergraduate students completed a previously validated survey assessing baseline demographics, hygiene habits, determinants of hygiene, and health status. Sixty survey respondents had microbiological samples taken from eight standardized surfaces in their dormitory environment. Bacterial contamination was assessed using standard quantitative bacterial culture techniques. Additional culturing for coagulase-positive Staphylococcus and coliforms was performed using selective agar.

Results

While the vast majority of study participants (n = 461, 92%) believed that hand washing was important for infection prevention, there was a large amount of variation in reported personal hygiene practices. More women than men reported consistent hand washing before preparing food (p = .002) and after using the toilet (p = .001). Environmental hygiene showed similar variability although 73.3% (n = 367) of subjects reported dormitory cleaning at least once per month. Contamination of certain surfaces was common, with at least one third of all bookshelves, desks, refrigerator handles, toilet handles, and bathroom door handles positive for >10 CFU of bacteria per 4 cm² area. Coagulase-positive Staphylococcus was detected in three participants'' rooms (5%) and coliforms were present in six students'' rooms (10%). Surface contamination with any bacteria did not vary by frequency of cleaning or frequency of illness (p>.05).

Conclusions

Our results suggest that surface contamination, while prevalent, is unrelated to reported hygiene or health in the university setting. Further research into environmental reservoirs of infectious diseases may delineate whether surface decontamination is an effective target of hygiene interventions in this population.     

FoxP3+ Regulatory T Cells Attenuate Experimental Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) results from severe intestinal inflammation in premature infants. FoxP3⁺ regulatory T cells (Tregs) are central to gut homeostasis. While Treg proportions are significantly reduced in the ileums of premature infants with NEC, it is unknown whether they play a critical function in preventing NEC. This study investigated Treg development in newborn rat pups and their role in experimental NEC induction. Utilizing an established rat model of experimental NEC, the ontogeny of T cells and Tregs in newborn pups was characterized by flow cytometry. To investigate the functions of Tregs, newborn pups were given Tregs harvested from adult rats prior to NEC induction to assess clinical improvement and mechanisms of immune regulation. The results revealed that there were few Treg numbers in the terminal ileums of newborn rats and 8-fold reduction after NEC. Adoptive transfer of Tregs significantly improved weight loss, survival from 53% to 88%, and NEC incidence from 87% to 35%. The Tregs modulated the immune response as manifested in reduced CD80 expression on antigen presenting cells and decreased T cell activation within the mesenteric lymph nodes. These findings suggest that while Tregs are present in the intestines, their numbers might be insufficient to dampen the excessive inflammatory state in NEC. Adoptive transfer of Tregs attenuates the severity of NEC by limiting the immune response. Strategies to enhance Tregs have a therapeutic potential in controlling the development of NEC.