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Background: TreatER+ight is the 1st prospective observational study in Canadian HR+ HER2- advanced breast cancer patients currently receiving endocrine therapy (ET) alone or in combination with targeted therapy (TT) (NCT02753686). Methods: This exploratory analysis displays real-world evidence on baseline demographics, treatment patterns, sequencing, and method of access to therapy. More specifically this abstract focuses on treatment decisions around CDK4/6-based therapy at various lines of treatment. At data cut-off of April 1st 2019, 305 patients were enrolled from 24 sites since Mar'16 with 113 patients receiving CDK4/6is at baseline. 300 patients were evaluable for treatment analysis. Results: Baseline CharacteristicsOverall (n=305)CDK4/6 + ET (n=113)Median age, years (range)67 (23 - 92)67 (23-87)ECOG 0,1,2*95, 104, 1941,32, 4Post-menopausal*21468Pre/peri-menopausal*6530Therapy by disease severity at baselineVisceral (n = 196)Bone only (n = 101)CDK4/6 + ET7338ET5941mTOR + ET6421PI3K + ET01Current therapy on the study Overall (N = 300)CDK4/6 + ET113ET100mTOR + ET86 PI3K + ET1Current CDK therapy by line of treatmentAll CDK4/6 (N = 113)First line60Second line38Third line13 Fourth line2Overall treatment patterns by lineFirst-Line (n = 154)Second-Line (n = 111)Third-Line (n = 64)CDK 4/6i + ET855317ET582711mTOR + Exemestane82114Chemo31022Median duration on therapy in months1L2LCDK4/6 + ET8.87 (median follow-up of 9.6 mos)8.77 (median follow-up of 11.6 mos)*Data missing for some patients at the time of this analysis Conclusions: The majority of patients enrolled (66.6%) are receiving combination therapy with the most common treatment being a CDK4/6-based therapy (56.5%). Of the patients receiving CDK4/6 at baseline a majority are receiving this therapy in the 1L (53.1%) and 2L (33.6%), with the median duration on therapy of respectively 8.87 and 8.77 months. For patients receiving CDK4/6 therapy in 1L, the most common 2L treatment is either endocrine therapy single agent and in certain parts of the country everolimus + exemestane. Further sequencing information will be analyzed and shared for this abstract. Citation Format: Catherine Doyle, Nadia Califaretti, Cristiano Ferrario, Nayyer Iqbal, John Hilton, Theodore Vandenberg, Mihaela Mates, Vivian Glenns, Swati Kulkarni, Puneet Bains, Sina Haftchenary, Sabrina Perri, Stephen Chia. Exploratory analysis of TreatER+ight; a Canadian prospective real-world observational study in HR+ advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-36.

Cassava mosaic disease (CMD) represents a serious threat to cassava, a major root crop for more than 300 million Africans. CMD is caused by single-stranded DNA begomoviruses that evolve rapidly, making it challenging to develop durable disease resistance. In addition to the evolutionary forces of mutation, recombination, and reassortment, factors such as climate, agriculture practices, and the presence of DNA satellites may impact viral diversity. To gain insight into the factors that alter and shape viral diversity in planta, we used high-throughput sequencing to characterize the accumulation of nucleotide diversity after inoculation of infectious clones corresponding to African cassava mosaic virus (ACMV) and East African cassava mosaic Cameroon virus (EACMCV) in the susceptible cassava landrace Kibandameno. We found that vegetative propagation had a significant effect on viral nucleotide diversity, while temperature and a satellite DNA did not have measurable impacts in our study. EACMCV diversity increased linearly with the number of vegetative propagation passages, while ACMV diversity increased for a time and then decreased in later passages. We observed a substitution bias toward C→T and G→A for mutations in the viral genomes consistent with field isolates. Non-coding regions excluding the promoter regions of genes showed the highest levels of nucleotide diversity for each genome component. Changes in the 5’ intergenic region of DNA-A resembled the sequence of the cognate DNA-B sequence. The majority of nucleotide changes in coding regions were non-synonymous, most with predicted deleterious effects on protein structure, indicative of relaxed selection pressure over 6 vegetative passages. Overall, these results underscore the importance of knowing how cropping practices affect viral evolution and disease progression.

Cassava mosaic disease (CMD), which is caused by single-stranded DNA begomoviruses, severely limits cassava production across Africa. A previous study showed that CMD symptom severity and viral DNA accumulation increase in cassava in the presence of a DNA sequence designated as SEGS-2 (sequence enhancing geminivirus symptoms). We report here that when SEGS-2 is co-inoculated with African cassava mosaic virus (ACMV) onto Arabidopsis thaliana, viral symptoms increase. Transgenic Arabidopsis with an integrated copy of SEGS-2 inoculated with ACMV also display increased symptom severity and viral DNA levels. Moreover, SEGS-2 enables Cabbage leaf curl virus (CaLCuV) to infect a geminivirus resistant Arabidopsis accession. Although SEGS-2 is related to cassava genomic sequences, an earlier study showed that it occurs as episomes and is packaged into virions in CMD-infected cassava and viruliferous whiteflies. We identified SEGS-2 episomes in SEGS-2 transgenic Arabidopsis. The episomes occur as both double-stranded and single-stranded DNA, with the single-stranded form packaged into virions. In addition, SEGS-2 episomes replicate in tobacco protoplasts in the presence, but not the absence, of ACMV DNA-A. SEGS-2 episomes contain a SEGS-2 derived promoter and an open reading frame with the potential to encode a 75-amino acid protein. An ATG mutation at the beginning of the SEGS-2 coding region does not enhance ACMV infection in Arabidopsis. Together, the results established that SEGS-2 is a new type of begomovirus satellite that enhances viral disease through the action of a SEGS-2 encoded protein that may also be encoded in the cassava genome.IMPORTANCECassava is an important root crop in the developing world and a food and income crop for more than 300 million African farmers. Cassava is rising in global importance and trade as the demands for biofuels and commercial starch increase. More than half of the world’s cassava is produced in Africa, where it is primarily grown by smallholder farmers, many of whom are from the poorest villages. Although cassava can grow under high temperature, drought and poor soil conditions, its production is severely limited by viral diseases. Cassava mosaic disease (CMD) is one of the most important viral diseases of cassava and can cause up to 100% yield losses. We provide evidence that SEGS-2, which was originally isolated from cassava crops displaying severe and atypical CMD symptoms in Tanzanian fields, is a novel begomovirus satellite that can compromise the development of durable CMD resistance.

We deeply sequenced two pairs of widely used infectious clones (4 plasmids) of the bipartite begomoviruses African cassava mosaic virus (ACMV) and East African cassava mosaic Cameroon virus (EACMCV). The ACMV clones were quite divergent from published sequences. Raw reads, consensus plasmid sequences, and the infectious clones themselves are all publicly available.

Introduction The need to provide ‘clean, non-COVID’ surgical areas during the current pandemic has mandated many changes within our organisation, such as the redeployment of cardiac surgical services (albeit without the transfer of interventional cardiology) to a different hospital within our health board. This move necessitated the upskilling of general anaesthetists to provide anaesthesia for emergency procedures in the cardiac catheterisation suite (cath-lab). This is an unfamiliar remote environment which may challenge anaesthetic teams, as they face limited access to the patient, radiation hazards and lack of familiarity with these procedures. As a result, an immediate training response was required to ensure patient safety. Methods We conducted a survey to assess baseline staff experiences and opinions. Following this we created a workgroup to develop specific anaesthesia guidelines, which were provided to candidates. A simulation course was developed, including scenarios designed to familiarise anaesthetists with common cath-lab emergencies and challenges and their potential solutions. Anaesthetists completed surveys before and after their simulation training. Notably, these courses were conducted during the COVID outbreak, hence adhering to social distance and infection control procedures. Results Our surveys highlighted that anaesthetists found the cath-lab a stressful environment, and all felt that multiprofessional teamwork could be improved. 25 individuals completed the simulation training. We measured self-assessed anxiety to the prospect of dealing with an unexpected emergency in the cath lab, both pre and post training, on a Likert scale (0 to 10). This decreased from an average of 7.55 to 5.63. All candidates commented that they found the course useful and advocated for further in situ training. Remarkably, the course provided a number of unexpected clinical safety outcomes: It facilitated interdisciplinary conversations and further team training was agreed upon; infection control measures for aerosol generating procedures were revisited in collaboration with anaesthetists, and the need for a consistent anaesthetic link was identified. Discussion Our results demonstrated that anaesthetists felt safer and better prepared to manage emergencies or unstable patients in the cardiac catheterisation laboratory. Post course reflection identified a need to expand scenarios to include cardiac arrest within the cath lab. Further training will be carried out wearing FFP3 masks and visors in order to increase fidelity and help prepare the team to communicate in this manner. We look forward to continuing exploring non-technical skill challenges during forthcoming multiprofessional training sessions.

We present an optimized protocol for enhanced amplification and enrichment of viral DNA for Next Generation Sequencing of begomovirus genomes. The rapid ability of these viruses to evolve threatens many crops and underscores the importance of using next generation sequencing efficiently to detect and understand the diversity of these viruses. We combined enhanced rolling circle amplification (RCA) with EquiPhi29 polymerase and size selection to generate a cost-effective, short-read sequencing method. This optimized protocol produced short-read sequencing with at least 50% of the reads mapping to the viral reference genome. We provide other insights into common misconceptions about RCA and lessons we have learned from sequencing single-stranded DNA viruses. Our protocol can be used to examine viral DNA as it moves through the entire pathosystem from host to vector, providing valuable information for viral DNA population studies, and would likely work well with other CRESS DNA viruses.HighlightsProtocol for short-read, high throughput sequencing of single-stranded DNA viruses using random primersComparison of the sequencing of total DNA versus size-selected DNAComparison of phi29 and Equiphi29 DNA polymerases for rolling circle amplification of viral single-stranded DNA genomes

The conservation community is increasingly taking a landscape-level approach to wildlife conservation. This approach faces obstacles, including how to ensure transboundary wildlife conservation goa...

Treat ER+ight is the 1st prospective observational study in Canadian postmenopausal women with HR+ HER2– advanced breast cancer currently receiving endocrine therapy (ET) alone or in combination with targeted therapy (TT) (NCT02753686). Methods: This pre-planned interim analysis describes baseline characteristics, treatment sequence, monitoring patterns, patient-reported quality-of-life (QoL) and resource utilization of patients enrolled in ET and ET+TT cohorts within the 1st 3 months of therapy. At data cut-off (13Mar'17), 100 patients were enrolled from 24 sites since Mar'16. Results: Baseline Patient and Disease Characteristics ET (n=42)ET + TT (n=58)Median age, years (range)70 (37-88)63 (39-80)ECOG 0-1, (%)6072Median time since primary BC diagnosis, years (range)4.5 (0-37)5 (0-25)Median time with advanced BC diagnosis, years (range)1 (0-16)1 (0-7)Sites of metastases (%) Bone only3829Visceral only3338Bone + visceral2924Last prior line of therapy included but not limited to (%) Letrozole4131Anastrozole1219Tamoxifen1214Exemestane122Palbociclib+Fulvestrant07Line (L) of metastatic therapy (%) 1L19222L38433L4335 Enrollment therapy (%): everolimus+exemestane (35), fulvestrant (15), palbociclib + letrozole (15), tamoxifen (14), exemestane (7), palbociclib+fulvestrant (7), letrozole (4) and palbociclib+exemestane (1). Follow-up visits with physician after therapy initiation ET, ET+TT (%): week 2 (5, 47), month 1 (71, 67), month 3 (43, 31). Numerical differences were observed in EORTC QLQ C30 and BR23 global health status/QoL, functional and symptom scale scores between ET and ET+TT cohorts. Mean changes in transformed scores from baseline to month 3 were generally similar between cohorts however 'therapy side effects' symptom item worsened in ET+TT cohort (P = 0.031, Wilcoxon rank sum). Resource utilization in between scheduled visits during 1st 3 months of therapy was similar between cohorts for physician/radiology, hospitalizations and ER visits however patient calls to supportive care nurse was increased in ET+TT cohort (P = 0.008, Fisher's exact). Treatment discontinuation rate (20%) was similar between cohorts with progression as predominant reason for initiating next therapy. Chemotherapy (CT) was the most frequent subsequent therapy and represented 1st line metastatic CT for majority of patients. Conclusions: ET+TT patients were younger, had better ECOG, more visceral disease and 60% received everolimus+exemestane with Citation Format: Dent S, Califaretti N, Doyle C, Ferrario C, Chouinard E, Kulkarni S, Roy J-A, Perri SR, Chia S. Treat ER+ight Canadian prospective observational study in HR+ advanced breast cancer: 2nd interim analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-15-02.

Small peat-forming ecosystems in arctic landscapes may play a significant role in the regional biogeochemistry of high-latitude systems, yet they are understudied compared to arctic uplands and other major peat-forming regions of the North. We present a new data set of 25 radiocarbon-dated permafrost peat cores sampled around eight low arctic lake sites in northern Manitoba (Canada) to examine the timing of peat initiation and controls on peat accumulation throughout the Holocene. We used macrofossils and charcoal to characterize changes in the plant community and fire, and we explored potential impacts of these local factors, as well as regional climatic change, on rates of C accumulation and C stocks. Peat initiation was variable across and within sites, suggesting the influence of local topography, but 56% of the cores initiated after 3000 B.P. Most cores initiated and remained as drier bog hummock communities, with few vegetation transitions in this landscape. C accumulation was relatively slow and did not appear to be correlated with Holocene-scale climatic variability, but C stocks in this landscape were substantial (mean = 45.4 kg C m−2), potentially accounting for 13.2 Pg C in the Taiga Shield ecozone. To the extent that small peat-forming systems are underrepresented in peatland mapping, soil organic carbon (SOC) stocks may be underestimated in arctic regions. Mean fire severity appeared to be negatively correlated with C accumulation rates. Initiation and accumulation of soil C may respond to both regional and local factors, and substantial lowland soil C stocks have the potential for biogeochemical impacts on adjacent aquatic ecosystems.

Wildlife conservation is losing ground in the U.S. for many reasons. The net effect is declines in species and habitat. To address this trend, the wildlife conservation institution (i.e., all customs, practices, organizations and agencies, policies, and laws with respect to wildlife) must adapt to contemporary social–ecological conditions. Adaptation could be supported by clear guidelines reflecting contemporary expectations for wildlife governance. We combine elements of public trust thinking and good governance to produce a broad set of wildlife governance principles. These principles represent guidance for ecologically and socially responsible wildlife conservation. They address persistent, systemic problems and, if adopted, will bring the institution into line with modern expectations for governance of public natural resources. Implementation will require changes in values, objectives, and processes of the wildlife conservation institution. These changes may be difficult, but promise improved wildlife conservation outcomes and increased support for conservation. We introduce challenges and opportunities associated with the principles, and encourage dialogue about them among scientists, practitioners, and other leaders in U.S. wildlife conservation. The principles alone will not change the course of conservation for the better, but may be necessary for such change to occur.

103 Background: Yttrium 90-labeled ibritumomab tiuxetan (Zevalin) is a radioimmunotherapy agent which combines the action of a beta-emitting isotope, yttrium-90, with the anti-CD20 monoclonal antibody, rituximab. The purpose of this study was to evaluate the efficacy of Zevalin in the treatment of Non-Hodgkin Lymphoma (NHL) in terms of response to therapy, overall survival (OS) and progression free survival (PFS). Methods: A total of 171 patients with NHL referred for treatment with Zevalin between September 2005 and January 2017 were identified for retrospective analysis. Clinical characteristics, treatments, and outcomes were extracted from clinical chart review. Survival rates and survival curves were generated using Kaplan-Meier analysis. Chi-square and independent student t test were used for comparison of categorical variables. Multivariate analysis (MVA) Cox proportional hazards ratios (HR) model was used to assess OS and PFS. Results: Of the 171 patients referred for treatment, median age was 70 years old, 54% were male (n = 93), and each patient had received a median of 2 prior chemotherapy regimens. The majority of patients were treated for follicular lymphoma (n = 107) and diffuse large B-cell lymphoma (n = 34). Seventy-three patients (53%) achieved complete response, and 23 patients achieved partial response (17%). One-year progression free survival was 71%, and median PFS was 31 months. Adverse events included cytopenic events, GI side effects, and mucocutaneous toxicity. Conclusions: Use of Zevalin for treatment of NHL demonstrated a significant improvement in PFS. In addition to improved efficacy, Zevalin was well-tolerated in this study and demonstrated an adequate safety profile. Further considerations will be given as to which treatment factors are associated with a complete response and improved PFS.

Elephants are among the world’s most intelligent land mammals, with a social structure so complex it rivals that of human societies. When brought into captivity, elephants are subjected to conditions that are the opposite of the dynamic ecological and social environments to which they are evolutionarily adapted, causing varying degrees of physical and psychological deterioration, suffering, and premature death. Much of the debate over the welfare of captive elephants rightfully centers on these harms. However, far less attention is given to what it means for elephants when they are unable to fully engage in the seminal activities that define them as individuals. The ethical argument against confining elephants is rooted in the inherent limitations of captivity that make it impossible for these animals to wholly realize their physical, social, and cultural worlds.

BACKGROUND AND OBJECTIVES Pure tubular carcinomas (TC) of the breast are generally considered to have an excellent prognosis. This study aimed to analyze the characteristics and survival of patients with TC. METHODS This was a retrospective study conducted at the CHU de Quebec-Universite Laval. Databases were searched for all cases treated between April 1997 and December 2010. Survival was retrieved from the Province of Quebec Ministry of Health. Follow-up was censored on December 31, 2011. Overall survival (OS) was compared to patients with invasive ductal carcinoma (ICD) matched for age, tumor size, lymph node involvement, year of diagnosis, ER, PgR, and HER2, histological grade, lymphovascular invasion, and chemotherapy. RESULTS The frequency of TC was 2.9% (n = 223/7563). Tumors size was 7.4 ± 8.8 mm, without lymphovascular invasion (95.1%), ER-positive (98.2%), PgR-positive (69.5%), and HER2-negative (100%). Patients were followed up for 7.1 ± 2.7 years. The actuarial 13-year OS was 89.0% for TC, compared to 85.8% for IDC (P = 0.13). For TC, the 13-year OS was 95.8% in NO patients compared to 90.0% for N1-3 (P = 0.01). CONCLUSION Despite the general popular belief that patients with TC fare better than patients with IDC, the 13-year OS of TC was similar to that of grade I IDC.

The public trust doctrine (PTD) is the common law basis for governments to hold wildlife in trust for the benefit of current and future generations of Americans. Wildlife as a public trust resource...

312 Background: Radium-223 dichloride (Xofigo) is an FDA-approved radionuclide used to treat symptomatic bone metastases in patients with castration-resistant prostate cancer (CRPC) with no known visceral metastases. Outside of clinical trial, the benefits of Radium-223 dichloride (Ra-223) in the treatment of CRPC have not yet been fully delineated in real life setting. Therefore, the purpose of this study was to evaluate the outcome of patients with CRPC who were treated with Ra-223, especially studying the variables associated with completion of 6 cycles of therapy. Methods: A total of 114 patients with CRPC and bone metastases referred for treatment with Ra-223 between March 2010 and February 2018 were identified for retrospective analysis. A chart review was conducted to analyze clinical characteristics, treatments, and outcomes including radiologic bone scans. Categorical variables were compared using Chi-square and independent student t test, and survival rates were generated using Kaplan-Meier analysis. Multivariate analysis (MVA) Cox proportional hazard ratios (HR) model was used in the assessment of OS and PFS. Results: Of the 114 patients referred for treatment, the overall median OS was 12.6 months. In MVA, improved OS was most strongly associated with completion of all six doses (p < 0.001). Median OS for the 56 patients who received full treatment was 24 months, while median OS for the 107 patients who did not complete treatment was 5.9 months. In univariate analysis, treatment completion was significantly associated with prior Sipuleucel-T (p = 0.002), concurrent Denosumab (p = 0.027), and baseline PSA < 30 ng/mL (p = 0.004). Conclusions: Completion of treatment with Ra-223 is a significant factor associated with improved OS. Therefore it is clinically important to delineate which patients are to the most appropriate candidates to complete treatment. Factors notable for treatment completion suggest patients might benefit from initiating Ra-223 treatment after receiving Sipuleucel-T and while their PSA remains low. Further consideration should be given to the sequence of Ra-223 in clinical practice, including use of concurrent Abiraterone and Enzalutamide.

Background: Generic formulations are not necessarily identical to the original in terms of efficacy and adverse events. Generic docetaxel has been available in Canada since 2011. Objective: To compare the occurrence of grade III to IV adverse events between original docetaxel and a generic formulation in breast cancer patients. Methods: A consecutive series of 400 patients were assessed retrospectively: 200 who received the original docetaxel and 200 who received a generic formulation. Patients who received both formulations or received their chemotherapy outside our center were excluded. The primary outcome was the occurrence of grade III to IV adverse events related to docetaxel (febrile neutropenia, hand and foot syndrome, intestinal perforation, thrombotic event, and death). Results: Three hundred-sixty-four patients were available for analysis (182/group). The use of a granulocyte colony-stimulating factor (G-CSF) was more frequent in the generic group (44.5% vs 28.8%), as well as treatment discontinuation (26.4% vs 14.8%). The occurrence of grade III to IV febrile neutropenia, hand and foot syndrome, intestinal perforation, thrombotic event, and docetaxel-related deaths were similar between the 2 formulations. However, grade IV febrile neutropenia was more frequent with the generic formulation (78.8% vs 56.3%). Limitations were the retrospective nature of the study and the variety of chemotherapy regimens. Conclusion: Adverse events occurrence was similar between the 2 formulations. However, febrile neutropenia was more serious with generic docetaxel, despite increased G-CSF use. Results suggest that the studied generic formulation may be safe, but more caution during treatments might be warranted, especially concerning febrile neutropenia events.

Viewpoints and debates Tumor size should be taken into consideration when planning treatments, but final decisions should also be made on the basis of the biological characteristics of the tumor in order to achieve a personalized approach to each individual cancer and to offer the best possible treatment to each patient.

Background Clinical trial recruitment can be impeded by eligibility criteria being too numerous or too restrictive. Purpose This study’s principal objective was to determine whether a specific category of eligibility criteria could be identified as a major barrier to patient enrollment. Methods Nine phase II or III clinical trials, opened between June 2004 and July 2008, were selected. A retrospective cohort of women diagnosed with invasive, nonmetastatic breast cancer and potentially eligible for these clinical trials was used. All eligibility criteria were sorted into the following categories: definition of disease, precision, safety, ethical and legal, or administrative. A total of 985 patient-trials were evaluated, defined as the experimental unit since one patient could be eligible to more than one trial. Proportions of cases with ‘not met’ eligibility criteria were assessed for each category in each trial. Results Two clinical trials had a ‘not met’ subcategory criterion of over 20%. ‘Pathology’ and ‘consent’ subcategory criteria were ‘not met’ in 24.2% and 92.7% of cases for the NEOCAN and NCIC CTG MA.27 trials, respectively. NCIC CTG MA.27 had the highest proportion of ‘not met’ subcategory due to an inclusion criterion requiring participation to two companion studies. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-38 had a proportion of 18.8% of cases ‘not meeting’ the receptor status subcategory criterion. All other subcategories of eligibility criteria assessed were ‘not met’ by less than 15% of patients. Overall, few subcategories had over 10% of ineligible patients. Limitations Many eligibility criteria were considered ‘nonevaluable’ because the information evaluated would have required additional procedures not performed as part of the general practice. Conclusion The subjects from the study population are not precluded from entry in a trial because of stringent eligibility criteria. Eligibility criteria should reflect as much as possible the whole population to whom the treatment will be offered, with the exception of drugs targeting a specific receptor or pathway where only a subpopulation is hypothesized to benefit from the therapy. In the breast cancer clinical trials evaluated for the present study, no criterion precluding recruitment was shared by many or all trials and no specific eligibility criterion was consistently the reason for patients’ ineligibility.

Introduction: We investigated frameshift suppressor tRNAs previously reported to use five-base anticodon-codon interactions in order to provide a collection of frameshift suppressor tRNAs to the synthetic biology community and to develop modular frameshift suppressor logic devices for use in synthetic biology applications. Results and Discussion: We adapted eleven previously described frameshift suppressor tRNAs to the BioBrick cloning format, and built three genetic logic circuits to detect frameshift suppression. The three circuits employed three different mechanisms: direct frameshift suppression of reporter gene mutations, frameshift suppression leading to positive feedback via quorum sensing, and enzymatic amplification of frameshift suppression signals. In the course of testing frameshift suppressor logic, we uncovered unexpected behavior in the frameshift suppressor tRNAs. The results led us to posit a four-base binding hypothesis for the frameshift suppressor tRNA interactions with mRNA as an alternative to the published five-base binding model. Conclusion and Prospects: The published five-base anticodon/codon rule explained only 17 of the 58 frameshift suppression experiments we conducted. Our deduced four-base binding rule successfully explained 56 out of our 58 frameshift suppression results. In the process of applying biological knowledge about frameshift suppressor tRNAs to the engineering application of frameshift suppressor logic, we discovered new biological knowledge. This knowledge leads to a redesign of the original engineering application and encourages new ones. Our study reinforces the concept that synthetic biology is often a winding path from science to engineering and back again; scientific investigations spark engineering applications, the implementation of which suggests new scientific investigations.

The impact of a gynecological cancer diagnosis and the subsequent treatment on women is profound, both physically and psychologically, in particular with respect to sexual function and sexuality. We describe our experience creating a specialized clinic to address concerns about sexual health and rehabilitation. We used a case study approach to describe the clinic's inception and first 2 years of operation. Fifty-six survivors of gynecological cancer were seen at the clinic in the first 2 years. These patients had a significant symptom burden, many related to menopause, as well as those aftereffects of radiation therapy, chemotherapy, and surgical operation as well as psychological and emotional responses to cancer. The most common interventions were education and counseling. Patients reported high levels of satisfaction with their experience at the clinic. We hope our experience may be of assistance to others considering a similar endeavor.

Research indicates that sexual health and function frequently are overlooked by healthcare professionals despite being identified as an essential aspect of patient care. This article discusses the topic of sexuality as it pertains to women with gynecologic cancers, highlights barriers to addressing sexuality with patients with cancer, and provides nurses with a framework to guide them in providing information and support to patients who are experiencing sexual difficulties or who need information about sexual function. A case study addresses the challenges a woman with cervical cancer faces and the role of the nurse in supporting the patient and her partner within the PLISSIT model.

Chronic low back pain (CLBP) is associated with a number of costly disability-related outcomes. It has received increasing attention from qualitative researchers studying its consequences for personal, social, and health care experiences. As research questions and methods diversify, there is a growing need to integrate findings emerging from these studies. A meta-ethnography was carried out to synthesise the findings of 38 separate qualitative articles published on the subjective experience of CLBP between 1994 and 2011. Studies were identified following a literature search and quality appraisal. Four themes were proposed after a process of translating the meaning of text extracts from the findings sections across all the articles. The themes referred to the undermining influence of pain, its disempowering impact on all levels, unsatisfying relationships with health care professionals, and learning to live with the pain. The findings are dominated by wide-ranging distress and loss but also acknowledge self-determination and resilience. Implications of the meta-ethnography for clinicians and future qualitative research are outlined, including the need to study relatively unexamined facets of subjective experience such as illness trajectory and social identity.

Current use of microbes for metabolic engineering suffers from loss of metabolic output due to natural selection. Rather than combat the evolution of bacterial populations, we chose to embrace what makes biological engineering unique among engineering fields – evolving materials. We harnessed bacteria to compute solutions to the biological problem of metabolic pathway optimization. Our approach is called Programmed Evolution to capture two concepts. First, a population of cells is programmed with DNA code to enable it to compute solutions to a chosen optimization problem. As analog computers, bacteria process known and unknown inputs and direct the output of their biochemical hardware. Second, the system employs the evolution of bacteria toward an optimal metabolic solution by imposing fitness defined by metabolic output. The current study is a proof-of-concept for Programmed Evolution applied to the optimization of a metabolic pathway for the conversion of caffeine to theophylline in E. coli. Introduced genotype variations included strength of the promoter and ribosome binding site, plasmid copy number, and chaperone proteins. We constructed 24 strains using all combinations of the genetic variables. We used a theophylline riboswitch and a tetracycline resistance gene to link theophylline production to fitness. After subjecting the mixed population to selection, we measured a change in the distribution of genotypes in the population and an increased conversion of caffeine to theophylline among the most fit strains, demonstrating Programmed Evolution. Programmed Evolution inverts the standard paradigm in metabolic engineering by harnessing evolution instead of fighting it. Our modular system enables researchers to program bacteria and use evolution to determine the combination of genetic control elements that optimizes catabolic or anabolic output and to maintain it in a population of cells. Programmed Evolution could be used for applications in energy, pharmaceuticals, chemical commodities, biomining, and bioremediation.

1067Background: Treat ER+ight is the first Canadian real-world study enrolling patients (pts) previously exposed to NSAI therapy and currently receiving endocrine therapy (ET) alone or in combination with targeted therapy (ET+TT). Methods: This first planned IA describes baseline parameters and adverse event (AE) prevention strategies adopted by 16 centers since Feb 2016 upon enrolling pts initiating ET or ET+TT. Results: See Table.Conclusions: This IA suggests that pts initiating ET+TT are younger, have a better ECOG status, mostly visceral disease and receive more prophylactic/proactive AE prevention therapies. Insights into real-world dosing and sequence will be presented. Clinical trial information: NCT02753686.Baseline characteristicsOverall(n=72)ET(n=34)ET+TT(n=38)Age, median yrs (range)69.0 (37.0 – 88.0)71.5 (37.0 – 88.0)65.0 (39.0 – 80.0)Family history of BC, n (%)26 (36.1)11 (32.4)15 (39.5)ECOG 0-1, n (%)46 (63.9)19 (55.9)27 (71.1)Time from diagnosis, median yrs (range)---Primary5.1 (0.1-37.4)5.0...

e13078 Background: Central review of NSABP B-31 showed that some central-review HER2-negative patients benefited from trastuzumab, but survival according to different levels of HER2 expression by immunohistochemistry (IHC) is unknown. The aim of the present study was to examine the survival of trastuzumab-naïve patients with breast cancer according to the level of HER2 expression by IHC. Methods: This was a retrospective study of all women who were treated for an invasive breast cancer at the Centre des maladies du Sein Deschênes-Fabia (Quebec City, Province of Quebec, Canada) between July 1999 and December 2010. Patients were grouped according to the HER2 status by IHC of their primary cancer (0 vs. 1+ vs. 2+ vs. 3+). Survival was obtained from the death registry of the Ministry of Health. Follow-up was censored on December 31st, 2012. Results: During the study period, 2571 patients with invasive breast cancer, with available HER2 status by IHC and survival data, and naïve to anti-HER2 therapy were treated at our center. Both 5- and 9-year overall survival (OS) decreased with increasing HER2 expression by IHC (9-year OS: 0: 86.2% vs. 1+: 71.3% vs. 2+: 73.9% vs. 3+: 69.3%; unadjusted log-rank test: P < 0.0001; adjusted P = 0.04 for 3+). Both 5- and 9-year breast cancer-specific survival (BCSS) decreased with increasing HER2 expression by IHC (9-year BCSS: 0: 90.7% vs. 1+: 81.8% vs. 2+: 77.0% vs. 3+: 75.4%; unadjusted log-rank test: P < 0.0001; adjusted P = 0.04 for 3+). Conclusions: Survival among trastuzumab-naïve breast cancer patients seems to follow a continuum across HER2 expression by IHC.

e14026 Background: Due to eligibility criteria, most, if not all, randomized controlled trials (RCTs) exclude patients at the outset, before randomization. Understanding which patients are excluded is important to evaluate the external validity of the results. The proportion of trials that report the entire flow diagram of patient enrollment, in accordance with the CONSORT 2010 statement, is unknown. Failure to do so makes it more difficult to discuss the generalizability of the trial findings. Methods: We performed the systematic retrieval and analysis of all phases II and III RCTs published in paper form between 2013 and 2015, in four high impact factor journals, in the field of clinical oncology. Our main objective was to determine the proportion of trials that report the number of patients assessed for eligibility before randomization. We further aimed to identify the variables that affect this reporting as well as the reasons for patient exclusion, to calculate the recruitment fraction and the number needed to screen and to determine the proportion of trials that include a discussion on the generalizability of the trial findings. Results: 462 RCTs were reviewed. Among them, 426 (92.2%) included the flow diagram in the article and 224 (48.5%) reported the number of patients assessed for eligibility. This proportion varied significantly between the journals studied, but it did not increase over time. A total of 116 (25.1%) included a discussion of generalizability. Among the trials that reported the entire enrollment process, the reason for patient exclusion could not be found in 50 (22.3%). Conclusions: There is still room for improvement in the reporting of the determinants of external validity in clinical oncology RCTs. Increasing the reporting of the enrollment process could help clinicians and health policy makers establish to whom the results of a trial apply.

Objectives: To determine if there is an association between overall and breast cancer specific-survival and participation in clinical trials (CT’s) in patients with invasive non-metastatic breast cancer. Materials and Methods: All women (6,794) diagnosed between 1982 and 2008 with invasive non-metastatic breast cancer from our database were used. Survival data was compared between women diagnosed with invasive nonmetastatic breast cancer who participated in a CT and with those who did not. Results: A total of 1,137 (16.7%) patients participated in a CT. These patients were younger and exhibited more unfavourable prognostic factors compared to non-participant. The crude hazard ratio for the overall survival rate for those who participated in a CT was 0.84 (95% CI [0.73-0.97]; p=0.02), and was 0.90 (CI 95% [0.78-1.04]; p=0.16) after an adjustment for body mass index (BMI), hormone receptors, treatments and histological grade. Conclusion: Breast cancer patients who participate in a CT exhibit different baseline characteristics. Assuming that difference, trial participation in itself did not improve survival rate in breast cancer patients. However, it can be concluded that the CTs does not have a deleterious effect on the participants.

PURPOSE: The value of palliative chemotherapy in women with refractory and recurrent ovarian cancer is difficult to quantify, and little is known about patient expectations from these treatments. We evaluated in the current prospective study patient expectations, palliative outcomes of chemotherapy, and the inherent resource utilization in patients undergoing second- or third-line chemotherapy for recurrent or refractory advanced ovarian cancer. METHODS: The European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ C30) and Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaires were used to assess palliative benefit and an in-house questionnaire was used to gauge patient expectations. The minimal clinically important difference (MCID) was calculated by asking women to make a global rating of change and correlating this to the EORTC QLQ C30. Resource use was recorded and costs were calculated. RESULTS: Twenty-seven patients were accrued. Objective response was documented on seven of 27. The median survival was 11 months. Sixty-five percent of women expected that chemotherapy would make them live longer and 42% that it would cure them. After two cycles, quality-of-life (QL) improvement was seen particularly in global function (11 of 21) and emotional function (13 of 21) with EORTC QLQ C-30. Improvement was sustained for a median of 2 and 3 months, respectively, in these categories. The MCID was calculated to be 0.39 on a seven-point scale for physical function and 0.13 for global function. The mean total cost per patient for the study period was Can $12,500. CONCLUSION: Patient expectations from these treatments are often unrealistic. Although objective responses are low, active palliation with chemotherapy is associated with substantive improvement in patients’ emotional function and global QL, with overall costs that seem relatively modest.