Advances in screening for radiation-associated cardiotoxicity in cancer patients

PURPOSE OF REVIEW: Radiation is foundational to the treatment of cancer and improves overall survival. Yet, it is important to recognize the potential cardiovascular effects of radiation therapy and how to best minimize or manage them. Screening-both through imaging and with biomarkers-can potentially identify cardiovascular effects early, allowing for prompt initiation of treatment to mitigate late effects. RECENT FINDINGS: Cardiac echocardiography, magnetic resonance imaging (MRI), computed tomography, and measurements of troponin and natriuretic peptides serve as the initial screening tests of choice for RICD. Novel imaging applications, including positron emission tomography and specific MRI parameters, and biomarker testing, including myeloperoxidase, growth differentiation factor 15, galectin 3, micro-RNA, and metabolomics, hold promise for earlier detection and more specific characterization of RICD. Advances in imaging and novel applications of biomarkers have potential to identify subclinical RICD and may reveal opportunities for early intervention. Further research is needed to elucidate optimal imaging screening modalities, biomarkers, and surveillance strategies

The Effects of Olfactory Enrichment on Shelter Dog Behavior

Shelter environments are stressful for dogs due to loud noises and unfamiliar surroundings. Previous research showed that exposure to some scents resulted in reductions in activity and vocalizations in shelter dogs. We investigated the effects of two calming (lavender and vetiver) and two stimulating (lemon and rosemary) essential oils on crate position and active, resting, and stress behaviors. There were 8, 5-min observations conducted each week per dog, split between baseline and scent exposure. Our analysis using the Wilcoxon Signed-Rank test found that dogs exposed to lavender (n = 13), lemon (n = 10), rosemary (n = 13), and vetiver (n = 12) did not show a significant difference in crate position or amount of time they engaged in stress, resting, or active behaviors compared to baseline. The lack of behavioral improvement indicates that scent enrichment alone may not be enough to have a significant effect on shelter dog behavior

Implications of Visual Social Access on the Welfare and Behavior of Shelter Dogs

Animal shelter environments have many stressful factors that impact the welfare of shelter dogs, such as lack of predictability and control, and social isolation. Social isolation has been found to increase abnormal behavior and lead to poorer adoption outcomes. Providing visual access to shelter dogs is a relatively easy environmental modification that increases social opportunities and allows for more predictability and control over the environment, potentially improving welfare. To investigate the impact of visual access on the behavior of dogs, we used a within-subject design, conducting 5-min focal observations four times weekly before, during, and after visual access was provided by partially removing a barrier between crates at a suburban dog shelter. Our preliminary analysis of 17 subjects using non-parametric Friedman’s Tests (alpha = .05) found no significant difference between phases in regard to anxiety behaviors (χ2 (2) = .50, p = .78), frustration behaviors (χ2 (2) = .51, p = .77), time spent in the front of the crate (χ2 (2) = 4.50, p = .11), self-directed behaviors (χ2 (2) = 1.86, p = .40), resting behaviors (χ2 (2) = 4.59, p = .10), or vocalizations (χ2 (2) = 4.59, p = .10). The absence of an increase in vocalizations during visual access may encourage shelters to implement this change. However, the lack of a decrease in anxiety or frustration behaviors may indicate that visual access alone is insufficient for providing welfare benefits and that shelters should prioritize increasing social contact in dogs through playgroups or group housing

#6 - Implications of Visual Social Access on the Welfare and Behavior of Shelter Dogs

Given the large number of dogs housed in animal shelters each year, it is important to consider how the shelter environment impacts dog welfare. The shelter environment is stressful due to factors such as excessive noise, lack of predictability and control, and social isolation. Social isolation in shelter dogs has been found to increase abnormal behavior and aggression and lead to poorer adoption outcomes. While social housing is ideal, it requires resources not available to all shelters. Providing visual access to other dogs is a relatively easy environmental modification that increases social opportunities and allows for more predictability and control over the environment, potentially improving welfare. To investigate the impact of visual access on the behavior of dogs, we used a within-subject design, conducting 5-min focal observations four times weekly before, during, and after visual access was provided by partially removing a barrier between crates at a suburban dog shelter. Our preliminary analysis of 17 subjects using non-parametric Friedman’s Tests (alpha = .05) found no significant difference between phases in regard to anxiety behaviors (χ2 (2) = .50, p = .78), frustration behaviors (χ2 (2) = .51, p = .77), time spent in the front of the crate (χ2 (2) = 4.50, p = .11), self-directed behaviors (χ2 (2) = 1.86, p = .40), resting behaviors (χ2 (2) = 4.59, p = .10), or vocalizations (χ2 (2) = 4.59, p= .10). The absence of an increase in vocalizations during visual access may encourage shelters to implement this change. However, the lack of a decrease in anxiety or frustration behaviors may indicate that visual access alone is insufficient for providing welfare benefits and that shelters should prioritize increasing social contact in dogs through playgroups or group housing. Keywords: shelter dog, animal welfare, barking, social housing, visual access, social contact, anxiety, environmental predictability, choic

Recent advances in serum biomarkers for risk stratification and patient management in cardio-oncology

PURPOSE OF REVIEW: Following significant advancements in cancer therapeutics and survival, the risk of cancer therapy-related cardiotoxicity (CTRC) is increasingly recognized. With ongoing efforts to reduce cardiovascular morbidity and mortality in cancer patients and survivors, cardiac biomarkers have been studied for both risk stratification and monitoring during and after therapy to detect subclinical disease. This article will review the utility for biomarker use throughout the cancer care continuum. RECENT FINDINGS: A recent meta-analysis shows utility for troponin in monitoring patients at risk for CTRC during cancer therapy. The role for natriuretic peptides is less clear but may be useful in patients receiving proteasome inhibitors. Early studies explore use of myeloperoxidase, growth differentiation factor 15, galectin 3, micro-RNA, and others as novel biomarkers in CTRC. Biomarkers have potential to identify subclinical CTRC and may reveal opportunities for early intervention. Further research is needed to elucidate optimal biomarkers and surveillance strategies

Logistical Lessons Learned in Designing and Executing a Photo-Elicitation Study in the Veterans Health Administration

Participatory photography research methods have been used to successfully engage and collect in-depth information from individuals whose voices have been traditionally marginalized in clinical or research arenas. However, participatory photography methods can introduce unique challenges and considerations regarding study design, human subject protections, and other regulatory barriers, particularly with vulnerable patient populations and in highly regulated institutions. Practical guidance on navigating these complex, interrelated methodological, logistical, and ethical issues is limited. Using a case exemplar, we describe our experiences with the planning, refinement, and initiation of a research study that used photo-elicitation interviews to assess the healthcare experiences of homeless and marginally housed United States Veterans. We discuss practical issues and recommendations related to study design, logistical “pitfalls” during study execution, and ensuring human subjects protections in the context of a study with a highly vulnerable patient population taking place in a highly risk-averse research environment

Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor

Background: Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells. Methods: Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1st generation (SCF-CD3ζ, 1st gen) and 2nd generation (SCF-CD28-CD3ζ, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions. Results: We successfully produced the 1st and 2nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1st and 2nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1st and 2nd gen dTc proliferated and produced IFNγ. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1st or 2nd gen human anti-KIT dTc led to significant reductions in tumor growth rates. Conclusions: We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc

Omics-driven identification and elimination of valerolactam catabolism in Pseudomonas putida KT2440 for increased product titer.

Pseudomonas putida is a promising bacterial chassis for metabolic engineering given its ability to metabolize a wide array of carbon sources, especially aromatic compounds derived from lignin. However, this omnivorous metabolism can also be a hindrance when it can naturally metabolize products produced from engineered pathways. Herein we show that P. putida is able to use valerolactam as a sole carbon source, as well as degrade caprolactam. Lactams represent important nylon precursors, and are produced in quantities exceeding one million tons per year (Zhang et al., 2017). To better understand this metabolism we use a combination of Random Barcode Transposon Sequencing (RB-TnSeq) and shotgun proteomics to identify the oplBA locus as the likely responsible amide hydrolase that initiates valerolactam catabolism. Deletion of the oplBA genes prevented P. putida from growing on valerolactam, prevented the degradation of valerolactam in rich media, and dramatically reduced caprolactam degradation under the same conditions. Deletion of oplBA, as well as pathways that compete for precursors L-lysine or 5-aminovalerate, increased the titer of valerolactam from undetectable after 48 h of production to ~90 mg/L. This work may serve as a template to rapidly eliminate undesirable metabolism in non-model hosts in future metabolic engineering efforts

Omics-driven identification and elimination of valerolactam catabolism in Pseudomonas putida KT2440 for increased product titer.

Pseudomonas putida is a promising bacterial chassis for metabolic engineering given its ability to metabolize a wide array of carbon sources, especially aromatic compounds derived from lignin. However, this omnivorous metabolism can also be a hindrance when it can naturally metabolize products produced from engineered pathways. Herein we show that P. putida is able to use valerolactam as a sole carbon source, as well as degrade caprolactam. Lactams represent important nylon precursors, and are produced in quantities exceeding one million tons per year (Zhang et al., 2017). To better understand this metabolism we use a combination of Random Barcode Transposon Sequencing (RB-TnSeq) and shotgun proteomics to identify the oplBA locus as the likely responsible amide hydrolase that initiates valerolactam catabolism. Deletion of the oplBA genes prevented P. putida from growing on valerolactam, prevented the degradation of valerolactam in rich media, and dramatically reduced caprolactam degradation under the same conditions. Deletion of oplBA, as well as pathways that compete for precursors L-lysine or 5-aminovalerate, increased the titer of valerolactam from undetectable after 48 h of production to ~90 mg/L. This work may serve as a template to rapidly eliminate undesirable metabolism in non-model hosts in future metabolic engineering efforts

A dynamic network approach for the study of human phenotypes

The use of networks to integrate different genetic, proteomic, and metabolic datasets has been proposed as a viable path toward elucidating the origins of specific diseases. Here we introduce a new phenotypic database summarizing correlations obtained from the disease history of more than 30 million patients in a Phenotypic Disease Network (PDN). We present evidence that the structure of the PDN is relevant to the understanding of illness progression by showing that (1) patients develop diseases close in the network to those they already have; (2) the progression of disease along the links of the network is different for patients of different genders and ethnicities; (3) patients diagnosed with diseases which are more highly connected in the PDN tend to die sooner than those affected by less connected diseases; and (4) diseases that tend to be preceded by others in the PDN tend to be more connected than diseases that precede other illnesses, and are associated with higher degrees of mortality. Our findings show that disease progression can be represented and studied using network methods, offering the potential to enhance our understanding of the origin and evolution of human diseases. The dataset introduced here, released concurrently with this publication, represents the largest relational phenotypic resource publicly available to the research community.Comment: 28 pages (double space), 6 figure