Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.

Cancer immunoediting1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features-'non-selfness'  based on neoantigen similarity to known antigens4,5, and 'selfness'  based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer.

GRASSY TILLERS1 (GT1) and SIX-ROWED SPIKE1 (VRS1) homologs share conserved roles in growth repression.

Crop engineering and de novo domestication using gene editing are new frontiers in agriculture. However, outside of well-studied crops and model systems, prioritizing engineering targets remains challenging. Evolution can guide us, revealing genes with deeply conserved roles that have repeatedly been selected in the evolution of plant form. Homologs of the transcription factor genes GRASSY TILLERS1 (GT1) and SIX-ROWED SPIKE1 (VRS1) have repeatedly been targets of selection in domestication and evolution, where they repress growth in many developmental contexts. This suggests a conserved role for these genes in regulating growth repression. To test this, we determined the roles of GT1 and VRS1 homologs in maize (Zea mays) and the distantly related grass brachypodium (Brachypodium distachyon) using gene editing and mutant analysis. In maize, gt1; vrs1-like1 (vrl1) mutants have derepressed growth of floral organs. In addition, gt1; vrl1 mutants bore more ears and more branches, indicating broad roles in growth repression. In brachypodium, Bdgt1; Bdvrl1 mutants have more branches, spikelets, and flowers than wild-type plants, indicating conserved roles for GT1 and VRS1 homologs in growth suppression over ca. 59 My of grass evolution. Importantly, many of these traits influence crop productivity. Notably, maize GT1 can suppress growth in arabidopsis (Arabidopsis thaliana) floral organs, despite ca. 160 My of evolution separating the grasses and arabidopsis. Thus, GT1 and VRS1 maintain their potency as growth regulators across vast timescales and in distinct developmental contexts. This work highlights the power of evolution to inform gene editing in crop improvement.

Lagging Adaptation to Climate Supersedes Local Adaptation to Herbivory in an Annual Monkeyflower.

While native populations are often adapted to historical biotic and abiotic conditions at their home site, populations from other locations in the range may be better adapted to current conditions due to changing climates or extreme conditions in a single year. We examine whether local populations of a widespread species maintain a relative advantage over distant populations that have evolved at sites better matching the current climate. Specifically, we grew lines derived from low- and high-elevation annual populations in California and Oregon of the common monkeyflower (Erythranthe guttata) and conducted phenotypic selection analyses in low- and high-elevation common gardens in Oregon to examine relative fitness and the traits mediating relative fitness. Californian low-elevation populations have the highest relative fitness at the low-elevation site, and Californian high-elevation populations have the highest relative fitness at the high-elevation site. Relative fitness differences are mediated by selection for properly timed transitions to flowering, with selection favoring more rapid growth rates at the low-elevation site and greater vegetative biomass prior to flowering at the high-elevation site. Fitness advantages for Californian plants occur despite incurring higher herbivory at both sites than the native Oregonian plants. Our findings suggest that a lag in adaptation causes maladaptation in extreme years that may be more prevalent in future climates, but local populations still have high growth rates and thus are not yet threatened.

The role of unregulated care providers in home care: A scoping review.

AIM AND BACKGROUND: Health care needs of individuals living in the community are increasing. To meet the rising need, unregulated care providers are providing more complex patient care. The aim of this review is to articulate the unregulated care provider role by identifying patient care activities offered by unregulated care providers in home care. METHODS: A scoping review was conducted. One thousand and eleven published manuscripts were identified in CINAHL, Ageline and MEDLINE. Eleven additional manuscripts were identified through hand searching. Manuscripts were screened for relevancy and data were abstracted to address the research question. RESULTS: Twenty-eight studies originating from Canada, Sweden, Belgium, UK, USA and New Zealand were included. Three categories of patient care activities provided by unregulated care providers were found: (1) personal care and core skills; (2) delegated tasks and added skills; and (3) specialty roles. CONCLUSION: Unregulated care providers predominantly provide assistance with personal care and activities of daily living. However, unregulated care providers also provide care outside their training, including care once provided by nurses. IMPLICATIONS FOR NURSING MANAGEMENT: Guidelines clearly articulating responsibilities of nurses transferring care activities to unregulated care providers should be developed. Processes and policies regarding evaluation and supervision of unregulated care providers providing added skills should be developed to ensure appropriate monitoring and support.

Home-based care: barriers and facilitators to expanded personal support worker roles in Ontario, Canada.

To accommodate the increasing demand for home care in Ontario, Canada, some care tasks traditionally performed by regulated health professionals are being transferred to personal support workers (PSW). However, this expansion of PSW roles is not uniform across the province. Between December 2014 and April 2015, barriers and facilitators to expansion of PSW roles in home care were explored in a series of 13 focus groups. Home care staff identified seven categories of factors affecting the expansion of PSW roles in home care including: communication and documentation; organization and structures of care; attitudes and perceptions of the expanding PSW role; adequate staffing; education, training and support; PSW role clarity and variation in practices, policies, and procedures. Addressing barriers and promoting facilitators at the funder and employer levels will enable the provision of safe, effective, and equitable care by PSWs.

Work-related factors influencing home care nurse intent to remain employed.

BACKGROUND: Health care is shifting out of hospitals into community settings. In Ontario, Canada, home care organizations continue to experience challenges recruiting and retaining nurses. However, factors influencing home care nurse retention that can be modified remain largely unexplored. Several groups of factors have been identified as influencing home care nurse intent to remain employed including job characteristics, work structures, relationships and communication, work environment, responses to work, and conditions of employment. PURPOSE: The aim of this study was to test and refine a model that identifies which factors are related to home care nurse intentions to remain employed for the next 5 years with their current home care employer organization. METHODOLOGY/APPROACH: A cross-sectional survey design was implemented to test and refine a hypothesized model of home care nurse intent to remain employed. Logistic regression was used to determine which factors influence home care nurse intent to remain employed. FINDINGS: Home care nurse intent to remain employed for the next 5 years was associated with increasing age, higher nurse-evaluated quality of care, having greater variety of patients, experiencing greater meaningfulness of work, having greater income stability, having greater continuity of client care, experiencing more positive relationships with supervisors, experiencing higher work-life balance, and being more satisfied with salary and benefits. PRACTICE IMPLICATIONS: Home care organizations can promote home care nurse intent to remain employed by (a) ensuring nurses have adequate training and resources to provide quality client care, (b) improving employment conditions to increase income stability and satisfaction with pay and benefits,

Generation-specific incentives and disincentives for nurse faculty to remain employed.

AIMS: The aims of this paper are to: (1) describe work characteristics that nurse faculty report encourage them to remain in or leave their academic positions; and (2) determine if there are generational differences in work characteristics selected. BACKGROUND: Nurse faculty play key roles in preparing new nurses and graduate nurses. However, educational institutions are challenged to maintain full employment in faculty positions. DESIGN: A cross-sectional, descriptive survey design was employed. METHODS: Ontario nurse faculty were asked to select, from a list, work characteristics that entice them to remain in or leave their faculty positions. Respondent data (n = 650) were collected using mailed surveys over four months in 2011. RESULTS: While preferred work characteristics differed across generations, the most frequently selected incentives enticing nurse faculty to stay were having: a supportive director/dean, reasonable workloads, supportive colleagues, adequate resources, manageable class sizes and work/life balance. The most frequently selected disincentives included: unmanageable workloads, unsupportive organizations, poor work environments, exposure to bullying, belittling and other types of incivility in the workplace and having an unsupportive director/dean. CONCLUSION: This research yields new and important knowledge about work characteristics that nurse faculty report shape their decisions to remain in or leave their current employment. Certain work characteristics were rated as important among all generations. Where similarities exist, broad strategies addressing work characteristics may effectively promote nurse faculty retention. However, where generational differences exist, retention-promoting strategies should target generation-specific preferences.

Palmitoylation controls the dynamics of budding-yeast heterochromatin via the telomere-binding protein Rif1.

The posttranslational addition of palmitate to cysteines occurs ubiquitously in eukaryotic cells, where it functions in anchoring target proteins to membranes and in vesicular trafficking. Here we show that the Saccharomyces cerevisiae palmitoyltransferase Pfa4 enhanced heterochromatin formation at the cryptic mating-type loci HMR and HML via Rif1, a telomere regulatory protein. Acylated Rif1 was detected in extracts from wild-type but not pfa4Δ mutant cells. In a pfa4Δ mutant, Rif1-GFP dispersed away from foci positioned at the nuclear periphery into the nucleoplasm. Sir3-GFP distribution was also perturbed, indicating a change in the nuclear dynamics of heterochromatin proteins. Genetic analyses indicated that PFA4 functioned upstream of RIF1. Surprisingly, the pfa4Δ mutation had only mild effects on telomeric regulation, suggesting Rif1's roles at HM loci and telomeres were more complexly related than previously thought. These data supported a model in which Pfa4-dependent palmitoylation of Rif1 anchored it to the inner nuclear membrane, influencing its role in heterochromatin dynamics.

Factors influencing home care nurse intention to remain employed.

AIM: To identify factors affecting Canadian home care nurse intention to remain employed (ITR). BACKGROUND: In developed nations, healthcare continues to shift into community settings. Although considerable research exists on examining nurse ITR in hospitals, similar research related to nurses employed in home care is limited. In the face of a global nursing shortage, it is important to understand the factors influencing nurse ITR across healthcare sectors. METHODS: A qualitative exploratory descriptive design was used. Focus groups were conducted with home care nurses. Data were analysed using qualitative content analysis. RESULTS: Six categories of influencing factors were identified by home care nurses as affecting ITR: job characteristics; work structures; relationships/communication; work environment; nurse responses to work; and employment conditions. CONCLUSION: Findings suggest the following factors influence home care nurse ITR: having autonomy; flexible scheduling; reasonable and varied workloads; supportive work relationships; and receiving adequate pay and benefits. Home care nurses did not identify job satisfaction as a single concept influencing ITR. IMPLICATIONS FOR NURSING MANAGEMENT: Home care nursing management should support nurse autonomy, allow flexible scheduling, promote reasonable workloads and create opportunities for team building that strengthen supportive relationships among home care nurses and other health team members.

Clinical education models in rural practice settings: A scoping review.

AIM: The objective of this review is to identify and synthesize the literature on clinical nursing education models in rural settings, with the goal of developing a better understanding of effective clinical education models suitable for rural nursing education. BACKGROUND: Clinical education is an integral part of nursing education, yet very little clinical education occurs in rural and remote areas. This leaves the rural landscape vulnerable to inadequate health care staffing because many graduates will begin their nursing practice in the geographical areas where they studied. The rural nursing workforce is currently insufficient to meet the health care needs of rural populations. This insufficiency is likely to worsen because statistical trends suggest that rural and remote communities might be among the worst affected by the global nursing shortage. Many new graduate nurses are ill prepared for rural nursing practice, primarily due to limited exposure to rural nursing content and rural clinical experiences in their entry-to-practice education. Increasing opportunities for nursing students to learn in rural clinical settings will likely support the recruitment and retention of nurses in rural practice. Despite the key role of rural nursing education in sustaining the rural health workforce, little is known about rural clinical learning in nursing education. DESIGN: A scoping review. METHODS: This scoping review was conducted using the steps outlined by Arksey and O'Malley with updated methodological guidance from the Joanna Briggs Institute. RESULTS: Of 1880 potential data sources, 82 were included in data analysis. Although no distinct model of rural clinical nursing education could be identified, several features of clinical nursing education were described in the context of rural clinical learning. Preceptorship was the most used mentorship/clinical supervision model (n=41). The most common placement design was a block model design (n=41) lasting between one and 16 weeks, with most learners engaging in episodic care with individual clients (n=42). Interestingly, 24 sources reported learners engaging in rural clinical education across multiple contexts (e.g., acute care, home care, and primary care). CONCLUSION: These findings suggest there exists great variability in rural clinical learning opportunities for nursing students. Academic practice partnerships could continue to be leveraged to provide learners with rural clinical education that meets the needs of both the educational institution as well as the rural communities in which learning takes place. An area of further research would be to focus on formal evaluation of the effectiveness of clinical education models in the rural context.

Nonpharmacological nursing interventions for the management of patient fatigue: a literature review.

AIMS AND OBJECTIVES: To identify and describe nonpharmacological interventions for the management of fatigue that are within the scope of nursing practice. BACKGROUND: Fatigue is a complex multidimensional symptom experienced by patients with varying diagnoses. Limited details are available on the nature of nursing interventions to manage fatigue, which preclude fidelity of implementation in day-to-day practice. DESIGN: Literature review. METHODS: Multiple databases were searched for publications reporting on the evaluation of nurse-delivered interventions for the management of fatigue. Data were extracted on study and intervention characteristics and results pertaining to the effects of the intervention on fatigue. RESULTS: The studies (n = 16) evaluated eight interventions: psycho-education, cognitive behavioural therapy, exercise, acupressure, relaxation, distraction, energy conservation and activity management, and a combination of exercise, education and support. CONCLUSION: Psycho-education was evaluated in several studies and demonstrated effectiveness when delivered in both acute and community settings. RELEVANCE TO CLINICAL PRACTICE: This review focused on interventions that are within the scope of nursing practice for the management of fatigue. The findings provide nurses with an overview of the effectiveness of interventions they may use in their day-to-day practice to help patients manage fatigue. A detailed description of interventions found effective is provided to assist nurses in translating evidence into practice.

Interleukin-13 receptor alpha2 is a novel therapeutic target for human adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a relatively rare but aggressive malignancy with limited therapeutic options. Previous genome-wide expression studies have demonstrated the overexpression of interleukin-13 receptor alpha2 (IL13Rα2) in some human malignancies. METHODS: The authors evaluated IL13Rα2 mRNA and protein expression in 21 normal samples, 78 benign samples, 10 primary malignant samples, and 25 metastatic/recurrent samples and performed functional analyses with IL13 ligand and IL13 Rα2 knockdown in vitro. The sensitivity of 2 ACC cell lines (NCI-H295R [high IL13Rα2 expression] and SW13 [low IL13Rα2 expression]) to a highly specific IL-13 conjugated with Pseudomonas exotoxin (IL-13-PE) also was evaluated in both in vitro and in vivo models. RESULTS: IL13Rα2 was overexpressed in malignant tumors compared with benign and normal samples (15-fold higher; P < .05). Immunohistochemistry also confirmed higher protein expression in malignant and benign tumors than in normal adrenocortical tissues (P < .05). The half-maximal inhibitory concentration for IL-13-PE was 1.3 ng/mL in the NCI-H295R cell line and 1000 ng/mL in the SW13 cell line. Mice that received intratumoral or intraperitoneal IL-13-PE injection had a significant reduction in tumor size and increased tumor necrosis compared with control groups (P < .05) and also had prolonged survival (P < .05). IL13Rα2 protein expression increased in cells that were treated with IL-13 ligand along with cell invasion (P < .05). Direct IL13Rα2 knockdown decreased cellular proliferation and invasion (P < .05). CONCLUSIONS: The current results indicated that IL13Rα2 is overexpressed in ACC and regulates cell invasion and proliferation. IL13Rα2 is a novel therapeutic target for the treatment of human ACC.

Association of type O blood with pancreatic neuroendocrine tumors in Von Hippel-Lindau syndrome.

BACKGROUND: ABO blood type antigens are expressed not only on human red blood cells, but also throughout the gastrointestinal tract and in normal pancreatic tissue. Previous studies have identified an association between ABO blood type and various malignancies. We analyzed the association of ABO blood type with pancreatic neuroendocrine tumors (PNETs) in a high-risk cohort of patients with Von Hippel-Lindau (VHL) syndrome. METHODS: A retrospective review was performed of 798 patients with VHL syndrome. Blood type was confirmed for 181 patients. Fisher's exact test and Mehta's modification to Fisher's exact test were used to test for an association between ABO blood type and manifestations of VHL syndrome. RESULTS: We found a strong trend for association between O blood type and pancreatic disease manifestation in patients with VHL syndrome (P = 0.047). More importantly, there was a significant association of O blood type with solid pancreatic lesions consistent with PNETs (P = 0.0084). Patients with solid pancreatic lesions who met criteria for surgical resection at the National Institutes of Health also had a higher rate of O blood type than those who did not require surgery (P = 0.051). CONCLUSIONS: Our findings suggest an association between O blood type and pancreatic manifestation of disease in patients with VHL syndrome, especially for PNETs. Screening and surveillance approaches for pancreatic lesions in patients with VHL syndrome should also consider patient blood type. The possibility of A, B, H misexpression in PNETs should also be explored to determine whether the serologic association with disease translates into a relationship with tissue pathology.

Boundary domain genes were recruited to suppress bract growth and promote branching in maize.

Grass inflorescence development is diverse and complex and involves sophisticated but poorly understood interactions of genes regulating branch determinacy and leaf growth. Here, we use a combination of transcript profiling and genetic and phylogenetic analyses to investigate tasselsheath1 (tsh1) and tsh4, two maize genes that simultaneously suppress inflorescence leaf growth and promote branching. We identify a regulatory network of inflorescence leaf suppression that involves the phase change gene tsh4 upstream of tsh1 and the ligule identity gene liguleless2 (lg2). We also find that a series of duplications in the tsh1 gene lineage facilitated its shift from boundary domain in nongrasses to suppressed inflorescence leaves of grasses. Collectively, these results suggest that the boundary domain genes tsh1 and lg2 were recruited to inflorescence leaves where they suppress growth and regulate a nonautonomous signaling center that promotes inflorescence branching, an important component of yield in cereal grasses.

Expression profiling of difficult-to-diagnose thyroid histologic subtypes shows distinct expression profiles and identify candidate diagnostic microRNAs.

BACKGROUND: The incidence of thyroid cancer is increasing worldwide. The findings of up to 30% of thyroid fine-needle aspiration biopsies (FNAB) are inconclusive, primarily as a result of several thyroid histologic subtypes with overlapping cytologic features. MicroRNAs (miRNAs) are small noncoding RNAs and have been implicated in carcinogenesis. We hypothesized that there are miRNAs that are differentially expressed between benign and malignant thyroid tumors that are difficult to distinguish by FNAB. METHODS: The expression of 1263 human miRNAs was profiled in 47 tumor samples representing difficult to diagnose histologic subtypes of thyroid neoplasm (21 benign, 26 malignant). Differentially expressed miRNAs were validated by quantitative real-time reverse transcriptase-polymerase chain reaction. The area under the receiver operating characteristic curve (AUC) was used to determine the diagnostic accuracy of differentially expressed miRNAs. RESULTS: Supervised hierarchical cluster analysis demonstrated grouping of 2 histologies (papillary and follicular thyroid carcinoma). A total of 34 miRNAs were differentially expressed in malignant compared to benign thyroid neoplasms (P<0.05). A total of 25 of the 34 nonproprietary miRNAs were selected for validation, and 15 of the 25 miRNAs were differentially expressed between benign and malignant samples with P-value<0.05. Seven miRNAs had AUC values of >0.7. miR-7 and miR-126 had the highest diagnostic accuracy with AUCs values of 0.81 and 0.77, respectively. CONCLUSION: To our knowledge, this is the first study to evaluate the diagnostic accuracy of miRNAs in thyroid histologies that are difficult to distinguish as benign or malignant by FNAB. miR-126 and miR-7 had high diagnostic accuracy and could be helpful adjuncts to thyroid FNAB.

Two MYB Proteins in a Self-Organizing Activator-Inhibitor System Produce Spotted Pigmentation Patterns.

Many organisms exhibit visually striking spotted or striped pigmentation patterns. Developmental models predict that such spatial patterns can form when a local autocatalytic feedback loop and a long-range inhibitory feedback loop interact. At its simplest, this self-organizing network only requires one self-activating activator that also activates a repressor, which inhibits the activator and diffuses to neighboring cells. However, the molecular activators and inhibitors fully fitting this versatile model remain elusive in pigmentation systems. Here, we characterize an R2R3-MYB activator and an R3-MYB repressor in monkeyflowers (Mimulus). Through experimental perturbation and mathematical modeling, we demonstrate that the properties of these two proteins correspond to an activator-inhibitor pair in a two-component, reaction-diffusion system, explaining the formation of dispersed anthocyanin spots in monkeyflower petals. Notably, disrupting this pattern impacts pollinator visitation. Thus, subtle changes in simple activator-inhibitor systems are likely essential contributors to the evolution of the remarkable diversity of pigmentation patterns in flowers.

The Ku complex in silencing the cryptic mating-type loci of Saccharomyces cerevisiae.

Sir1 establishes transcriptional silencing at the cryptic mating-type loci HMR and HML (HM loci) by recruiting the three other Sir proteins, Sir2, -3, and -4, that function directly in silenced chromatin. However, SIR1-independent mechanisms also contribute to recruiting the Sir2-4 proteins to the HM loci. A screen to elucidate SIR1-independent mechanisms that establish HMR silencing identified a mutation in YKU80. The role for Ku in silencing both HMR and HML was masked by SIR1. Ku's role in silencing the HM loci was distinct from its shared role with the nuclear architecture protein Esc1 in tethering the HM loci and telomeres to the nuclear periphery. The ability of high-copy SIR4 to rescue HMR silencing defects in sir1Delta cells required Ku, and chromatin immunoprecipitation (ChIP) experiments provided evidence that Ku contributed to Sir4's physical association with the HM loci in vivo. Additional ChIP experiments provided evidence that Ku functioned directly at the HM loci. Thus Ku and Sir1 had overlapping roles in silencing the HM loci.